AU2013202666B2 - Antiviral compounds - Google Patents

Abstract

5 The invention is related to anti-viral compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds. C:\pof\temp\SPEC-966759.docx

Description

ANTIVIRAL COMPOUNDS PRIORITY OF INVENTION 5 This application is a divisional of Australian application No. 2010249043, which in turn claims priority to United States Provisional Application Numbers 61/177,972, filed 13 May 2009; 61/224,745, filed 10 July 2009; and 61/238,760, filed 01 September 2009. The entire content of each of these applications is hereby incorporated herein by reference. BACKGROUND OF THE INVENTION 10 Hepatitis C is recognized as a chronic viral disease of the liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Inhibitors of hepatitis C virus (HCV) are useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV. 15 There is a need for new HCV therapeutic agents. SUMMARY OF THE INVENTION In one embodiment the invention provides a compound of the invention which is a compound of formula (I): J-Y-J (I) 20 as described herein, or a pharmaceutically acceptable salt, or prodrug thereof. The invention also provides isotopically enriched compounds that are compounds of formula I that comprise an enriched isotope at one or more positions in the compound. The present invention also provides a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier. 25 The present invention also provides a pharmaceutical composition for use in treating disorders associated with HCV. The present invention also provides a pharmaceutical composition further comprising an interferon or pegylated interferon. The present invention also provides a pharmaceutical composition further comprising a 30 nucleoside analog. The present invention also provides for a pharmaceutical composition wherein said nucleoside analogue is selected from ribavirin, viramidine, levovirin, an L-nucleoside, and isatoribine and said interferon is a-interferon or pegylated a-interferon.

The present invention also provides for a method of treating disorders associated with hepatitis C, said method comprising administering to an individual a pharmaceutical composition which comprises a therapeutically effective amount of a compound of the invention. 5 The present invention also provides a method of inhibiting HCV, comprising administering to a mammal afflicted with a condition associated with HCV activity, an amount of a compound of the invention, effective to inhibit HCV. The present invention also provides a compound of the invention for use in medical therapy (preferably for use in inhibiting HCV activity or treating a condition associated with 10 HCV activity), as well as the use of a compound of the invention for the manufacture of a medicament useful for inhibiting HCV or the treatment of a condition associated with HCV activity in a mammal. The present invention also provides synthetic processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. Some of the 15 compounds of the invention are useful to prepare other compounds of the invention. In another aspect the invention provides a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, for use in the prophylactic or therapeutic treatment of hepatitis C or a hepatitis C associated disorder. In another aspect the invention provides a method of inhibiting HCV activity in a sample 20 comprising treating the sample with a compound of the invention. In one embodiment the invention provides a compound having improved inhibitory or pharmacokinetic properties, including enhanced activity against development of viral resistance, improved oral bioavailability, greater potency (for example, in inhibiting HCV activity) or extended effective half-life in vivo. Certain compounds of the invention may have fewer side 25 effects, less complicated dosing schedules, or be orally active. DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they 30 are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the embodiments. 2 Compounds of the Invention The compounds of the invention exclude compounds heretofore known. However, it is within the invention to use compounds that previously were not known to have antiviral 5 properties for antiviral purposes (e.g. to produce an anti-viral effect in an animal). With respect to the United States, the compounds or compositions herein exclude compounds that are anticipated under 35 USC §102 or that are obvious under 35 USC § 103. Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "RI" or "A 3 ", then it will be understood that the groups may be the same 10 or different, i.e., each group is independently selected. "Absent" - Some groups are defined such that they can be absent. When a group is absent it becomes a bond connector. The two groups that would otherwise be connected to that absent group are connected to each other through a bond. For example, when W is absent, M is bonded to M. 15 "Alkyl" is Cl-Cl 8 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), I -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (j-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, CH2CH2CH2CH3), 2-methyl-l -propyl (j-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, 20 CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2 methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-I butyl (-CH2CH2CH(CH3)2), 2-methyl-I -butyl (-CH2CH(CH3)CH2CH3), I -hexyl ( CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl ( CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl 25 (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3 pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2 butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and cyclopropylmethyl CH2 A) "Alkenyl" is C2-C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon 30 atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond. Examples include, but are not limited to, ethylene or vinyl (-CH=CH 2 ), allyl (-CH 2

CH=CH

2 ), cyclopentenyl (-C 5

H

7 ), and 5-hexenyl (-CH 2

CH

2

CH

2

CH

2

CH=CH

2 ). 3 "Alkynyl" is C2-C I 8 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylenic (-C-CH) and propargyl (-CH 2 C=CH). "Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 5 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -) 1,2-ethyl (-CH 2

CH

2 -), 1,3-propyl

(-CH

2

CH

2 C1H 2 -), 1,4-butyl (-CH 2

CH

2

CH

2

CH

2 -), and the like. "Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon 10 radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-). "Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of 15 two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene (-C-C-), propargyl (-C H 2 C=C-), and 4-pentynyl (-CH 2

CH

2

CH

2 C=CH). "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. 20 Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1 -yl, 25 naphthylmethyl, 2-naphthylethan- I -yl, naphthobenzyl, 2-naphthophenylethan- I -yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is I to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms. The term "polycarbocycle" refers to a saturated or unsaturated polycyclic ring system 30 having from about 6 to about 25 carbon atoms and having two or more rings (e.g. 2, 3, 4, or 5 rings). The rings can be fused and/or bridged to form the polycyclic ring system. For example, the term includes bicyclo [4,5], [5,5], [5,6] or [6,6] ring systems, as well as the following bridged ring systems: 35 4 and (i.e., [2.1.1], [2.2.1], [3.3.3], [4.3.1], [2.2.2], [4.2.2], [4.2.1], [4.3.2], [3.1.1], [3.2.1], [4.3.3], [3.3.2], [3.2.2] and [3.3.1] polycyclic rings, respectively) that can be linked to the remainder of 5 the compound of formula (I) through any synthetically feasible position. Like the other polycarbocycles, these representative bicyclo and fused ring systems can optionally comprise one or more double bonds in the ring system. The term "polyheterocycle" refers to a polycarbocycle as defined herein, wherein one or more carbon atoms is replaced with a heteroatom (e.g., 0, S, S(O), S(O) 2 , N'(O~)Rx, or NR,); 10 wherein each Rx is independently H, (C I -l 0)alkyl, (C2-1 O)alkenyl, (C2-1O)alkynyl, (C l I0)alkanoyl, S(O) 2 NRnRp, S(O) 2 Rx, or (CI-1O)alkoxy, wherein each (CI -l0)alkyl, (C2 1O)alkenyl, (C2-1O)alkynyl, (CI -O)alkanoyl, and (CI-O)alkoxy is optionally substituted with one or more halo). "Substituted alkyl", "substituted aryl", and "substituted arylalkyl" mean alkyl, aryl, and 15 arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Typical substituents include, but are not limited to: halo (e.g. F, Cl, Br, I), -R, -OR, -SR, -NR 2 , -CF 3 , -CCl 3 , -OCF 3 , -CN, -NO 2 , -N(R)C(=O)R, -C(=O)R, OC(=O)R, -C(O)OR, -C(=O)NRR, -S(=O)R, -S(=0) 2 0R, -S(=0) 2 R, -OS(=0) 2 0R, -S(=0) 2 NRR, and each R is independently -H, alkyl, aryl, arylalkyl, or heterocycle. Alkylene, alkenylene, and 20 alkynylene groups may also be similarly substituted. The term "optionally substituted" in reference to a particular moiety of the compound of formula I, (e.g., an optionally substituted aryl group) refers to a moiety having 0, 1, 2, or more substituents. 5 The symbol "-----" in a ring structure means that a bond is a single or double bond. In a L E E non-limiting example, D can be D a or D "Haloalkyl" as used herein includes an alkyl group substituted with one or more 5 halogens (e.g. F, Cl, Br, or I). Representative examples of haloalkyl include trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro-l-(trifluoromethyl)ethyl. "Heterocycle" as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; Principles of Modem Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of 10 Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. 0, N, or S). 15 Examples of heterocycles include by way of example and not limitation pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, 20 tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, I H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 25 4H-carbazolyl, carbazolyl, $-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl: 300 6 By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an 5 oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6 10 pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5 thiazolyl. By way of example and not limitation, nitrogen bonded heterocycles are bonded at position I of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, 15 piperidine, piperazine, indole, indoline, I H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or P-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, I pyrazolyl, and I -piperidinyl. "Carbocycle" refers to a saturated, unsaturated or aromatic ring having up to about 25 20 carbon atoms. Typically, a carbocycle has about 3 to 7 carbon atoms as a monocycle, about 7 to 12 carbon atoms as a bicycle, and up to about 25 carbon atoms as a polycycle. Monocyclic carbocycles typically have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. The term 25 carbocycle includes "cycloalkyl" which is a saturated or unsaturated carbocycle. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, I-cyclopent-l-enyl, I cyclopent-2-enyl, I -cyclopent-3-enyl, cyclohexyl, I -cyclohex- I -enyl, I -cyclohex-2-enyl, 1 cyclohex-3-enyl, phenyl, spiryl and naphthyl. The term "chiral" refers to molecules which have the property of non-superimposability 30 of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose 35 molecules are not mirror images of one another. Diastereomers have different physical 7 properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable 5 mirror images of one another. The term "treatment" or "treating," to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. 10 Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active 15 compound, the prefixes (D and L) or (R and S) are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and I or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or I meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of 20 one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of 25 optical activity. The invention includes all stereoisomers of the compounds described herein. Specific Definitions for Groups A 0 , MO, W', LO, P'J,. To, V 0 , Z 0 , E0, and R9 0 For the groups A , M 0 , W 0 , L', P', J', T 0 , VD, Z 0 , E 0 , and R9 0 the following definitions apply. These definitions also apply for all other A, M, W, L, P, J, T, B, V, Z, E, and R9 30 groups unless those groups are otherwise defined herein. Unless stated otherwise, all aryl, cycloalkyl, and heterocyclyl groups of the present disclosure may be substituted as described in each of their respective definitions. For example, the aryl part of an arylalkyl group may be substituted as described in the definition of the term 'aryl'. 8 The term "alkenyl," as used herein, refers to a straight or branched chain group of two to six carbon atoms containing at least one carbon-carbon double bond. The term "alkenyloxy," as used herein, refers to an alkenyl group attached to the parent molecular moiety through an oxygen atom. 5 The term "alkenyloxycarbonyl," as used herein, refers to an alkenyloxy group attached to the parent molecular moiety through a carbonyl group. The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with one, 10 two, or three alkoxy groups. The term "alkoxyalkylcarbonyl," as used herein, refers to an alkoxyalkyl group attached to the parent molecular moiety through a carbonyl group. The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. 15 The term "alkoxycarbonylalkyl," as used herein, refers to an alkyl group substituted with one, two, or three alkoxycarbonyl groups. The term "alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six carbon atoms. The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to the parent 20 molecular moiety through a carbonyl group. The term "alkylcarbonylalkyl," as used herein, refers to an alkyl group substituted with one, two, or three alkylcarbonyl groups. The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group attached to the parent molecular moiety through an oxygen atom. 25 The term "alkylsulfanyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfur atom. The term "alkylsulfonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group. The term "aryl," as used herein, refers to a phenyl group, or a bicyclic fused ring system 30 wherein one or both of the rings is a phenyl group. Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of 35 the present disclosure are optionally substituted with one, two, three, four, or five substituents 9 independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, -(NRXRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen 5 and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro. 10 The term "arylalkenyl," as used herein, refers to an alkenyl group substituted with one, two, or three aryl groups. The term "arylalkoxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an alkoxy group. The term "arylalkoxyalkyl," as used herein, refers to an alkyl group substituted 15 with one, two, or three arylalkoxy groups. The term "arylalkoxyalkylcarbonyl," as used herein, refers to an arylalkoxyalkyl group attached to the parent molecular moiety through a carbonyl group. The term "arylalkoxycarbonyl," as used herein, refers to an arylalkoxy group attached to 20 the parent molecular moiety through a carbonyl group. The term "arylalkyl," as used herein, refers to an alkyl group substituted with one, two, or three aryl groups. The alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and -NRcRd, wherein the heterocyclyl is further optionally 25 substituted with one or two substituents independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and -NRxRY; The term "arylalkylcarbonyl," as used herein, refers to an arylalkyl group attached to the parent molecular moiety through a carbonyl group. 30 The term "arylcarbonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a carbonyl group. The term "aryloxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an oxygen atom. The term "aryloxyalkyl," as used herein, refers to an alkyl group substituted with one, 35 two, or three aryloxy groups. 10 The term "aryloxycarbonyl," as used herein, refers to an aryloxy group attached to the parent molecular moiety through a carbonyl group. The term "arylsulfanyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfur atom. 5 The term "arylsulfonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group. The terms "Cap" and "cap" as used herein, refer to the group which is placed on the nitrogen atom of the terminal nitrogen-containing ring. It should be understood that "Cap" or

"

1 cap" can refer to the reagent used to append the group to the terminal nitrogen-containing ring 10 or to the fragment in the final product. The term "carbonyl," as used herein, refers to -C(=O)-. The term "carboxy," as used herein, refers to -CO 2 H. The term "cyano," as used herein, refers to -CN. The term "cyanoalkyl" as used herein, refers to an alkyl group having at least one -CN 15 substituent. The term "cycloalkyl," as used herein, refers to a saturated monocyclic, hydrocarbon ring system having three to seven carbon atoms and zero heteroatoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups of the present disclosure are optionally substituted with 20 one, two, three, four, or five substituents independently selected from alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, nitro, and -NR'RY wherein the aryl and the heterocyclyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro. 25 The term "(cycloalkyl)alkenyl," as used herein, refers to an alkenyl group substituted with one, two, or three cycloalkyl groups. The term "(cycloalkyl)alkyl," as used herein, refers to an alkyl group substituted with one, two, or three cycloalkyl groups. The alkyl part of the (cycloalkyl)alkyl is further optionally substituted with one or two groups independently selected from cd 30 hydroxy and -NRcR. The term "cycloalkyloxy," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom. The term "cycloalkyloxyalkyl," as used herein, refers to an alkyl group substituted with one, two, or three cycloalkyloxy groups. S1I The term "cycloalkylsulfonyl," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through a sulfonyl group. The term "formyl," as used herein, refers to -CHO. The terms "halo" and "halogen," as used herein, refer to F, Cl, Br, or I. 5 The term "haloalkoxy," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. The term "haloalkoxycarbonyl," as used herein, refers to a haloalkoxy group attached to the parent molecular moiety through a carbonyl group. The term "haloalkyl," as used herein, refers to an alkyl group substituted by one, two, 10 three, or four halogen atoms. The term "haloalkylsulfanyl," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through a sulfur atom. The term "heterocyclyl," as used herein, refers to a four-, five-, six-, or seven-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, 15 oxygen, and sulfur. The four-membered ring has zero double bonds, the five-membered ring has zero to two double bonds, and the six- and seven-membered rings have zero to three double bonds. The term "heterocyclyl" also includes bicyclic groups in which the heterocyclyl ring is fused to another monocyclic heterocyclyl group, or a four- to six-membered aromatic or non aromatic carbocyclic ring; as well as bridged bicyclic groups such as 7-azabicyclo[2.2.l]hept-7 20 yl, 2-azabicyclo[2.2.2]oc-2-tyl, and 2-azabicyclo[2.2.2]oc-3-tyl. The heterocyclyl groups of the present disclosure can be attached to the parent molecular moiety through any carbon atom or nitrogen atom in the group. Examples of heterocyclyl groups include, but are not limited to, benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, 25 thiazolyl, thienyl, thiomorpholinyl, 7-azabicyclo[2.2. I ]hept-7-yl, 2-azabicyclo[2.2.2]oc-2-tyl, and 2- azabicyclo[2.2.2]oc-3-tyl. The heterocyclyl groups of the present disclosure are optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, 30 heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRy, -(NRxRy)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, 35 alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro. 12 The term "heterocyclylalkenyl," as used herein, refers to an alkenyl group substituted with one, two, or three heterocyclyl groups. The term "heterocyclylalkoxy," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an alkoxy group. 5 The term "heterocyclylalkoxycarbonyl," as used herein, refers to a heterocyclylalkoxy group attached to the parent molecular moiety through a carbonyl group. The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with one, two, or three heterocyclyl groups. The alkyl part of the heterocyclylalkyl is further optionally substituted with one or two additional groups independently selected 10 from alkoxy, alkylcarbonyloxy, aryl, halo, haloalkoxy, haloalkyl, hydroxy, and -NRcRd, wherein the aryl is further optionally substituted with one or two substituents independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and -NRxRY. The term "heterocyclylalkylcarbonyl," as used herein, refers to a heterocyclylalkyl 15 group attached to the parent molecular moiety through a carbonyl group. The term "heterocyclylcarbonyl," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through a carbonyl group. The term "heterocyclyloxy," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an oxygen atom. 20 The term "heterocyclyloxyalkyl," as used herein, refers to an alkyl group substituted with one, two, or three heterocyclyloxy groups. The term "heterocyclyloxycarbonyl," as used herein, refers to a heterocyclyloxy group attached to the parent molecular moiety through a carbonyl group. The term "hydroxy," as used herein, refers to -OH. 25 The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with one, two, or three hydroxy groups. The term "hydroxyalkylcarbonyl," as used herein, refers to a hydroxyalkyl group attached to the parent molecular moiety through a carbonyl group. The term "nitro," as used herein, refers to -NO 2 . 30 The term "-NRaR ," as used herein, refers to two groups, Ra and Rb, which are attached to the parent molecular moiety through a nitrogen atom. Ra and Rb are independently selected from hydrogen, alkenyl, and alkyl. The term "(NRaRb)alkyl," as used herein, refers to an alkyl group substituted with one, two, or three -NRaRb groups. 35 The term "(NRaR )carbonyl," as used herein, refers to an -NRa R group attached to the parent molecular moiety through a carbonyl group. 13 The term "-NRcRd," as used herein, refers to two groups, R' and Rd, which are attached to the parent molecular moiety through a nitrogen atom. RC and Rd are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, 5 aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR"R )alkyl, (NR*Rf)alkylcarbonyl, (NR* R)carbonyl, (NR*Rf)sulfonyl, -C(NCN)OR', and - C(NCN)NRxR , wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the 10 arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NR*Rr group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the 15 heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro. The term "(NRcRd)alkenyl," as used herein, refers to an alkenyl group substituted with one, two, or three -NRcRd groups. 20 The term "(NRcRd)alkyl," as used herein, refers to an alkyl group substituted with one, two, or three -NRcRd groups. The alkyl part of the (NRcR d)alkyl is further optionally substituted with one or two additional groups selected from alkoxy, alkoxyalkylcarbonyl, alkoxycarbonyl, alkylsulfanyl, arylalkoxyalkylcarbonyl, carboxy, heterocyclyl, heterocyclylcarbonyl, hydroxy, and (NR*Rr)carbonyl; wherein the 25 heterocyclyl is further optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro. The term "(NRcRd)carbonyl," as used herein, refers to an -NRcRd group attached to the parent molecular moiety through a carbonyl group. 30 The term "-NR*Rr," as used herein, refers to two groups, Re and Rr, which are attached to the parent molecular moiety through a nitrogen atom. Reand Rfare independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, (NRxRY)alkyl, and -(NRXRY)carbonyl. 14 The term "(NReRf)alkyl," as used herein, refers to an alkyl group substituted with one, two, or three -NR*Rf groups. The term "(NRCRf)alkylcarbonyl," as used herein, refers to an (NRCRf)alkyl group attached to the parent molecular moiety through a carbonyl group. 5 The term "(NReRf)carbonyl," as used herein, refers to an -NR*Rf group attached to the parent molecular moiety through a carbonyl group. The term "(NReRr)sulfonyl," as used herein, refers to an -NReRf group attached to the parent molecular moiety through a sulfonyl group. The term "-NRxRY," as used herein, refers to two groups, Rx and R , which are 10 attached to the parent molecular moiety through a nitrogen atom. RX and RY are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NRxRY)carbonyl, wherein Rx and R' are independently selected from hydrogen and alkyl. 15 The term "(NRXRY)alkyl," as used herein, refers to an alkyl group substituted with one, two, or three -NRXRY groups. The term "oxo," as used herein, refers to =0. The term "sulfonyl," as used herein, refers to -SO 2 -. The term "trialkylsilyl," as used herein, refers to -SiR 3 , wherein R is alkyl. The R groups 20 may be the same or different The term "trialkylsilylalkyl," as used herein, refers to an alkyl group substituted with one, two, or three trialkylsilyl groups. The term "trialkylsilylalkoxy," as used herein, refers to a trialkylsilylalkyl group attached to the parent molecular moiety through an oxygen atom. 25 The term "trialkylsilylalkoxyalkyl," as used herein, refers to an alkyl group substituted with one, two, or three trialkylsilylalkoxy groups. Prodrugs The term "prodrug" as used herein refers to any compound that when administered to a 30 biological system generates a compound of the invention that inhibits HCV activity ("the active inhibitory compound"). The compound may be formed from the prodrug as a result of: (i) spontaneous chemical reaction(s), (ii) enzyme catalyzed chemical reaction(s), (iii) photolysis, and/or (iv) metabolic chemical reaction(s). 35 "Prodrug moiety" refers to a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic 15 cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes which are capable of an enzymatic activation mechanism with the prodrug compounds of the invention include, but are 5 not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. A prodrug moiety may include an active metabolite or drug itself. Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl 10 esters -CH 2 0C(=O)R 99 and acyloxymethyl carbonates -CH 2 0C(=O)OR 9 9 where R 99 is Ci-C 6 alkyl, CI-C 6 substituted alkyl, C 6

-C

2 0 aryl or C 6

-C

20 substituted aryl. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used to 15 deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM)

-CH

2 0C(=O)C(CH 3

)

3 . An exemplary acyloxymethyl carbonate prodrug moiety is 20 pivaloyloxymethylcarbonate (POC) -CH 2 0C(=O)OC(CH 3

)

3 . Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (De Lombaert et al. (1994) J Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to a phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate parent phosphonic acids. 25 In some cases, substituents at the ortho- orpara- position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate phosphoric acid and a quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc. 30 Perkin Trans. I12345; Glazier WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a 35 disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate 16 which subsequently breaks down to the phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996)J. Med. Chem. 39: 4958). Protecting Groups In the context of the present invention, protecting groups include prodrug moieties and 5 chemical protecting groups. "Protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. 10 Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common 15 analytical tools. Chemically protected intermediates may themselves be biologically active or inactive. Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects 20 may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of 25 prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous. Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or 30 methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group "PG" will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. PGs do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In 17 general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as 5 determined by the artisan. Various functional groups of the compounds of the invention may be protected. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functions) include "ether- or ester-forming groups". Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set 10 forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below. A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic 15 Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471 62301-6) ("Greene"). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, 20 Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155 184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below. By way of example and not limitation, R', R', R^, RA 3 , and XA are recursive substituents in certain embodiments. Typically, each of these may independently occur 20, 19, 25 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically, each of these may independently occur 12 or fewer times in a given embodiment. Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "R"' or "R 3 ", then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines indicate the site of 30 covalent bond attachments to the adjoining groups, moieties, or atoms. In one embodiment of the invention, the compound is in an isolated and purified form. Generally, the term "isolated and purified" means that the compound is substantially free from biological materials (e.g. blood, tissue, cells, etc.). In one specific embodiment of the invention, the term means that the compound or conjugate of the invention is at least about 50 wt.% free 35 from biological materials; in another specific embodiment, the term means that the compound or 18 conjugate of the invention is at least about 75 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 98 wt.% free from biological 5 materials; and in another embodiment, the term means that the compound or conjugate of the invention is at least about 99 wt.% free from biological materials. In another specific embodiment, the invention provides a compound or conjugate of the invention that has been synthetically prepared (e.g., ex vivo). Stereoisomers 10 The compounds of the invention may have chiral centers, e.g., chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are 15 provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures are separated into their individual, substantially optically pure isomers through well known techniques such as, for example, the separation of diastereomeric salts formed with 20 optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material. The compounds of the invention can also exist as tautomeric isomers in certain cases. 25 Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention. Salts and Hydrates 30 Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C 1

-C

4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, 19 isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a 5 suitable cation such as Na* and NX 4 * (wherein X is independently selected from H or a Ci-C4 alkyl group). For therapeutic use, salts of active ingredients of the compounds of the invention will typically be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically 10 acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention. Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, 15 Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCI, HBr, H 2 SO4, H3PO4 or organic sulfonic acids, to basic centers, typically amines, or to acidic groups. Finally, it is to be understood that the compositions herein comprise 20 compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates. Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the natural or unnatural amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino 25 acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine. Methods of Inhibition of HCV Another aspect of the invention relates to methods of inhibiting the activity of HCV 30 comprising the step of treating a sample suspected of containing HCV with a compound or composition of the invention. Compounds of the invention may act as inhibitors of HCV, as intermediates for such inhibitors or have other utilities as described below. The inhibitors will generally bind to locations on the surface or in a cavity of the liver. Compounds binding in the liver may bind 20 with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compounds are useful as probes for the detection of HCV. Accordingly, the invention relates to methods of detecting NS3 in a sample suspected of containing HCV 5 comprising the steps of: treating a sample suspected of containing HCV with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in conventional fashion using functional groups 10 such as hydroxyl or amino. In one embodiment the invention provides a compound of formula (I) that comprises or that is bound or linked to one or more detectable labels. Within the context of the invention samples suspected of containing HCV include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the 15 like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing HCV. Samples can be contained in any medium including water and organic solvent/water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures. 20 The treating step of the invention comprises adding the compound of the invention to the sample or it comprises adding a precursor of the composition to the sample. The addition step comprises any method of administration as described above. If desired, the activity of HCV after application of the compound can be observed by any method including direct and indirect methods of detecting HCV activity. Quantitative, 25 qualitative, and semiquantitative methods of determining HCV activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable. Many organisms contain HCV. The compounds of this invention are useful in the treatment or prophylaxis of conditions associated with HCV activation in animals or in man. 30 However, in screening compounds capable of inhibiting HCV activity it should be kept in mind that the results of enzyme assays may not always correlate with cell culture assays. Thus, a cell based assay should typically be the primary screening tool. Pharmaceutical Formulations The compounds of this invention are formulated with conventional carriers and 21 excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the 5 Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10. While it is possible for the active ingredients to be administered alone it may be 10 preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof. 15 The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which 20 constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of 25 the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste. A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the 30 active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient 35 therefrom. 22 For administration to the eye or other external tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), 5 preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% 10 w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl 15 sulphoxide and related analogs. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with 20 a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilizers suitable for use in the formulation of the invention 25 include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or 30 branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft 35 paraffin and/or liquid paraffin or other mineral oils are used. 23 Pharmaceutical formulations according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When 5 used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving 10 agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize 15 starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl 20 monostearate or glyceryl distearate alone or with a wax may be employed. Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. 25 Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a 30 condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p 24 hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid 5 paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules of the invention suitable for preparation of an aqueous 10 suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in 15 water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial 20 esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent. The pharmaceutical compositions of the invention may be in the form of a sterile 25 injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized 30 powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. 25 The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately I to 1000 mg of active material compounded with an 5 appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 10 30 mL/hr can occur. Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w. 15 Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. 20 Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is 25 administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of conditions associated with 30 HCV activity. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration include aqueous and non-aqueous 35 sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes 26 which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only 5 the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. 10 It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The invention further provides veterinary compositions comprising at least one active 15 ingredient as above defined together with a veterinary carrier therefor. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route. 20 Compounds of the invention can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provides compositions comprising one or more compounds of the invention formulated for sustained or controlled release. 25 Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. Routes of Administration 30 One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the 27 recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally. HCV Combination Therapy 5 In another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of the present invention with one or more interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase I inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, 10 cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV. More specifically, one or more compounds of the present invention may be combined with one or more compounds selected from the group consisting of I) interferons, e.g., pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a 15 (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-I (Infergen), interferon alpha-nI (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005), 20 PEG-Infergen, PEGylated interferon lambda-I (PEGylated IL-29), and belerofon, 2) ribavirin and its analogs, e.g., ribavirin (Rebetol, Copegus), and taribavirin (Viramidine), 3) HCV NS3 protease inhibitors, e.g., boceprevir (SCH-503034, SCH-7), telaprevir (VX 950), TMC435350, B1-1335, BI-1230, MK-7009, VBY-376, VX-500, GS-9256, GS-9451, 25 BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, and ITMN 191, 4) alpha-glucosidase I inhibitors, e.g., celgosivir (MX-3253), Miglitol, and UT-23I B, 5) hepatoprotectants, e.g., emericasan (IDN-6556), ME-3738, GS-9450 (LB-8445 1), silibilin, and MitoQ, 30 6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase, e.g., R1626, R7128 (R4048), IDX 184, IDX-102, BCX-4678, valopicitabine (NM-283), and MK-0608, 7) non-nucleoside inhibitors of HCV NS5B polymerase, e.g., PF-868554, VCH-759, VCH-916, JTK-652, MK-3281, GS-9190, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN 35 1941, XTL-2125, and GS-9190, 28 8) HCV NS5A inhibitors, e.g., AZD-2836 (A-83 1), BMS-790052, and A-689, 9) TLR-7 agonists, e.g., imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), and SM-360320, 10) cyclophillin inhibitors, e.g., DEBIO-025, SCY-635, and NIM81 1, 5 11) HCV IRES inhibitors, e.g., MCI-067, 12) pharmacokinetic enhancers, e.g., BAS-100, SPI-452, PF-4194477, TMC-41629, GS 9350, GS-9585, and roxythromycin, 13) other drugs for treating HCV, e.g., thymosin alpha I (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), 10 GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-l 11, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1 106 (ONO-4538), Oglufanide, and VX-497 (merimepodib). In yet another embodiment, the present application discloses pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable 15 salt, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or excipient. According to the present invention, the therapeutic agent used in combination with the compound of the present invention can be any agent having a therapeutic effect when used in combination with the compound of the present invention. For example, the therapeutic agent 20 used in combination with the compound of the present invention can be interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase I inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV. In another embodiment, the present application provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, 25 and/or ester thereof, in combination with at least one additional therapeutic agent selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, locteron, AVI-005, PEG infergen, pegylated IFN-beta, oral interferon alpha, feron, reaferon, intermax alpha, r-IFN-beta, infergen + actimmune, IFN-omega with DUROS, albuferon, rebetol, copegus, levovirin, VX 30 497, viramidine (taribavirin), A-831, A-689, NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433, XTL-2125, SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN-191, and BILN 2065, MX-3253 (celgosivir), UT-231B, IDN-6556, ME 3738, MitoQ, and LB-84451, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives, 35 zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 29 4065, bavituximab, oglufanide, PYN-17, KPE02003002, actilon (CPG-1010 1), KRN-7000, civacir, GI-5005, ANA-975 (isatoribine), XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and NIM81 1 and a pharmaceutically acceptable carrier or excipient. In yet another embodiment, the present application provides a combination 5 pharmaceutical agent comprising: a) a first pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or ester thereof; and b) a second pharmaceutical composition comprising at least one additional therapeutic agent selected from the group consisting of HIV protease inhibiting compounds, 10 HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, H IV nucleotide inhibitors of reverse transcriptase, H IV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, alpha-glucosidase I inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV, and combinations thereof. 15 Combinations of the compounds of formula I and additional active therapeutic agents may be selected to treat patients infected with HCV and other conditions such as HIV infections. Accordingly, the compounds of formula I may be combined with one or more compounds useful in treating HIV, for example HIV protease inhibiting compounds, non-nucleoside inhibitors of HIV reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide 20 inhibitors of reverse transcriptase, HIV integrase inhibitors, gp4l inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase I inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV. More specifically, one or more compounds of the present invention may be combined 25 with one or more compounds selected from the group consisting of 1) HIV protease inhibitors, e.g., amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-l 14, mozenavir (DMP 450), JE-2147 (AG1776), AG1859, DG35, L-756423, R00334649, KNI-272, DPC-681, DPC 684, and GW640385X, DGI7, PPL-100, 2) a HIV non-nucleoside inhibitor of reverse 30 transcriptase, e.g., capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355 BS, VRX 840773, UK-453,061, RDEA806, 3) a HIV nucleoside inhibitor of reverse transcriptase, e.g., zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, 35 racivir (±-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, fosalvudine tidoxil, 30 apricitibine (AVX754), amdoxovir, KP-1461, abacavir+ lamivudine, abacavir + lamivudine + zidovudine, zidovudine + lamivudine, 4) a HIV nucleotide inhibitor of reverse transcriptase, e.g., tenofovir, tenofovir disoproxil fumarate + emtricitabine, tenofovir disoproxil fumarate + emtricitabine + efavirenz, and adefovir, 5) a HIV integrase inhibitor, e.g., curcumin, derivatives 5 of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, and L 870810, MK-0518 (raltegravir), BMS-707035, MK-2048, BA-011, BMS-538158, 10 GSK364735C, 6) a gp 4 l inhibitor, e.g., enfuvirtide, sifuvirtide, FBO06M, TRI-I 144, SPC3, DES6, Locus gp41, CovX, and REP 9, 7) a CXCR4 inhibitor, e.g., AMD-070, 8) an entry inhibitor, e.g., SPOIA, TNX-355, 9) a gp120 inhibitor, e.g., BMS-488043 and BlockAide/CR, 10) a G6PD and NADH-oxidase inhibitor, e.g., immunitin, 10) a CCR5 inhibitor, e.g., aplaviroc, vicriviroc, INCB9471, PRO-140, INCB 15050, PF-232798, CCR5mAbOO4, and maraviroc, 11) 15 an interferon, e.g., pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha 2b XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, locteron, AVI-005, PEG-infergen, pegylated IFN-beta, oral interferon alpha, feron, reaferon, intermax alpha, r-IFN-beta, infergen + actimmune, IFN-omega with DUROS, and albuferon, 12) ribavirin analogs, e.g., rebetol, copegus, levovirin, VX-497, and viramidine (taribavirin) 13) NS5a inhibitors, e.g., A-831, A 20 689, and BMS-790052, 14) NS5b polymerase inhibitors, e.g., NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433, and XTL-2125, 15) NS3 protease inhibitors, e.g., SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN-191, and BILN-2065, 16) alpha-glucosidase I inhibitors, e.g., MX-3253 (celgosivir) and UT-231 B, 17) hepatoprotectants, e.g., IDN-6556, ME 3738, MitoQ, and LB 25 84451, 18) non-nucleoside inhibitors of HCV, e.g., benzimidazole derivatives, benzo-1,2,4 thiadiazine derivatives, and phenylalanine derivatives, 19) other drugs for treating Hepatitis C, e.g., zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17, KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975 (isatoribine), XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, 30 and NIM81 1, 19) pharmacokinetic enhancers, e.g., BAS-100 and SP1452, 20) RNAse H inhibitors, e.g., ODN-93 and ODN-1 12, 21) other anti-HIV agents, e.g., VGV-1, PA-457 (bevirimat), ampligen, HRG214, cytolin, polymun, VGX-41 0, KD247, AMZ 0026, CYT 99007, A-221 HIV, BAY 50-4798, MDX010 (iplimumab), PBS1 19, ALG889, and PA-1050040. 35 31 Metabolites of the Compounds of the Invention Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, 5 primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g., C 1 4 or H 3 ) compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, 10 mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or 15 NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HCV -inhibitory activity of their own. Methods for determining stability of compounds in surrogate gastrointestinal secretions 20 are known. Compounds of formula (I) In one embodiment the invention provides a compound of formula (I): J-Y-J (I) 25 wherein: Y is -L-L-, -M-W-M- or YY; J is T-P-, -P-T or -J m ; W is a bond or -W'-; L is -M-A-, -A-M-, or -L"; 30 T is R9-Z-, -Z-R9, or -TP; R9 is E-V-, or -V-E, or -R91; each A is selected from -As; each M is selected from -M t ; each P is selected from -P'; 32 each Z is selected from -Z'; each V is selected from -V"; each E is selected from -E'; each m is 1 5 each n is 0, 1, 2, 3, 4, 5, 6, 7, 9, or 10; each p is 1, 2, 3, 4, 5, 6, 7, or 8; each q is 0, 1, 2, or 3; each r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; each s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 21; 10 each t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; each u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; each v is 0, 1, 2, 3, 4, 5, or 6; each w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24; 15 each x is 0, 1, 2, 3, 4, 5, 6, or 7; each y is 0, 1, or 2; wherein the sum of m, n, p, q, r, s, t, u, v, w, x, and y is not 0; P is connected to M, L, or Y ; A is connected to A or L; M is connected to P or J; Z is connected to P; V is connected to Z; and when W is a bond M is connected to M; 20 each Y' is independently: a fused nine-ring system with up to thirty-five atoms that may be fully aromatic or partially saturated and contains atoms selected from C, N, 0, and S and which ring system is optionally substituted with one or more groups independently selected from H, oxo, R and RA 3 ; 25 each Y 2 is independently: a fused five to eight ring system with up to thirty-two atoms that may be fully aromatic or partially saturated and contains atoms selected from C, N, 0, and S and which ring system is optionally substituted with one or more groups independently selected from H, oxo, R^I and 30 RA 3 ; each J' is independently a fused bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is substituted with one or more -N(R )C(=0)OR L, and that is optionally substituted with one or more groups independently selected from oxo, halo, -RL 7 , -OR 35 L, -SR L7, -CF 3 , -CCla, -OCF 3 ,-CN, -NO 2 , -N(R L)C(=O)R L7, -C(=O)R ', -OC(=O)R L7, 33 -C(O)OR L7, -C(=O)NR L, -S(=O)R L7, -S(=0) 2 0R L7, -S(=0) 2 R L7, -OS(=0) 2 0R L, -S(=0)2NR L7, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NRaR', (NRaRb)alkyl, and (NRaRb)carbonyl; each R U is independently -H, alkyl, aryl, arylalkyl, or heterocycle; 5 Ra and Rb are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each LO is independently: 10

(RL

2 )aa wherein: each RL 2 is independently selected from hydrogen, alkenyl, alkoxy, alkyl, halo, 1 5 and haloalkyl; and each aa is independently 1, 2, 3, or 4; each L' is independently: (RL)aa

(RL

2 )bb 20 wherein: each RL 2 is independently selected from hydrogen, alkenyl, alkoxy, alkyl, halo, and haloalkyl; each RL is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , 25 haloalkoxy, cyanoalkyl, NR 4 S0 2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, 34 (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each bb is 0, 1, 2, 3, or 4; each aa is 1, 2, 3, or 4; and the sum of bb and aa is 1, 2, 5 3,or4; each L 2 is independently: R L4 Hi RL4 10 wherein: the phenyl ring shown in L2 is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, 15 (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each RL4 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; 20 Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each H' is a 5 membered saturated, partially unsaturated, or aromatic ring comprising one or more heteroatoms; 25 each L 3 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, ab a b ab formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NR R )alkyl, (NRaR )carbonyl, 30 cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, 35 (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 5 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L 4 is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently 10 selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR', (NRaR )alkyl, (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; 15 each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 20 each L 5 is independently a -CR=CR-fusedbicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NRa R )alkyl, (NRaR )carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, 25 (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each R is independently selected from H or alkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and b R' and R are independently selected from the group consisting of hydrogen, alkenyl, 30 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L 6 is independently a -CR=CR-fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently 35 selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, 36 formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; 5 each R is independently selected from H or alkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 10 each L 7 is independently:

(R

2 )aa

HI

15 wherein: each H"' is independently a fused-bicyclic saturated, partially unsaturated, or 2 aromatic heterocyclic ring system that is optionally substituted with one or more R each R 2 is independently selected from halo, -RL 7 , -OR L7, -SR L7, -N(R L7) 2 , -CF 3 , UL7L7UL -CC13, -OCF 3 ,-CN, -NO 2 , -N(R )C(=O)R L, -C(=0)R ', -OC(=O)R L, -C(O)OR L, 20 -C(=O)NR L7, -S(=O)R L, -S(=0) 2 0R ", -S(=0) 2 R ", -OS(=0) 2 0R L7, and -S(=0) 2 NR '7; each R U is independently -H, alkyl, aryl, arylalkyl, or heterocycle; and each aa is independently 1, 2, 3, or 4; each L 9 is independently a fused-tetracyclic saturated, partially unsaturated, or aromatic 25 heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -RL 7 , -OR L7, -SR L7, -CF 3 , -CC 3 , -OCF 3 ,-CN, -NO 2 , -N(R L 7 )C(=O)R L7, L77 L7 L7 LU7 -C(=O)R ", -OC(=O)R , -C(O)OR , -C(=O)NR L, -S(=O)R L, -S(=0) 2 0R , -S(=0) 2 R L _ OS(=0) 2 0R L7, -S(=0) 2 NR L7, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NRaR', (NRaRb)alkyl, and (NRaRb)carbonyl; 30 each R U is independently -H, alkyl, aryl, arylalkyl, or heterocycle; 37 Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 5 each L' 0 is independently a fused-pentacyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -R , -OR L7, -SR L7, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R L 7 )C(=O)R L7, LIL L7 L7U L7 -C(=O)R L, -OC(=O)R , -C(O)OR , -C(=O)NR L, -S(=O)R L7, -S(=0) 2 OR , -S(=0) 2 R , OS(=0) 2 0R L7, -S(=0) 2 NR U7, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, 10 -NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl; each R L is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; I5 each L" is independently a six-ring fused saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -R , -OR L, -SR -7, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R L 7 )C(=0)R L7, L7 L7 L7 L7UU -C(=O)R L, -OC(=O)R , -C(O)OR , -C(=O)NR L7, -S(=0)R L, -S(=O) 2 0R , -S(=0) 2 R L _ 20 OS(=O)2OR L, -S(=0) 2 NR L 7 , alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NRa R , (NRa R b)alkyl, and (NRaRb)carbonyl; each R L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, 25 heterocyclyl, and heterocyclylalkyl; each R9 0 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, 30 heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, cd cddd hydroxyalkyl, -NRcR , (NRcR )alkenyl, (NRCRd)alkyl, and (NRCRd)carbonyl; Rc and Rd are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, 35 cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, 38 heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NReRr)alkyl, (NReRr)alkylcarbonyl, (NReRr)carbonyl, (NRCRr)sulfonyl, -C(NCN)OR', and - C(NCN)NRxRY, wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the 5 arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NR*Rf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the 10 heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; RX and RY are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NRXRY)carbonyl, wherein RX and RT 1 5 are independently selected from hydrogen and alkyl; each R9' is independently -N(R 9 a)-NHC(=O)O-R 9 b, wherein each R 9 a is independently arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO 2 alkyl, cycloalkylalkylSO 2 alkyl, cyanoalkyl, 20 haloalkyl, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and wherein arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl 25 part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, 30 arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRXRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the 35 arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the 39 heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, 5 arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRxRY)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further 10 optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R is independently H, alkyl, aryl, haloalkyl, or arylalkyl; each R9 2 is independently -N(R 9 a)-NHC(=O)NR 9 b 2 ; wherein each R 9 a is independently 15 arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO 2 alkyl, cycloalkylalkylSO 2 alkyl, cyanoalkyl, haloalkyl cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is 20 independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; 25 and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRXRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen 30 and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; 40 and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRxRY)alkyl, and oxo, wherein 5 the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R 9 b is independently H, alkyl, aryl, 10 haloalkyl, or arylalkyl; each R9 3 is independently -N(R 9 a)-NHC(=O)R 9 b, wherein each R 9 a is independently arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO 2 alkyl, cycloalkylalkylSO 2 alkyl, cyanoalkyl, 15 haloalkyl, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is 20 further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, 25 heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRXRY, (NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the 30 heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, 35 heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, -(NRxRy)alkyl, and oxo, wherein 41 the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, 5 alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R 9 b is independently H, alkyl, aryl, haloalkyl, or arylalkyl; each A 0 is independently:

(RA

3 )bb 10 wherein: each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, a b alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR R, (NRaRb)alkyl, and (NRaR )carbonyl; Ra and R b are each independently selected from the group 15 consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each bb is independently 0, 1, 2, 3, or 4; or each A 0 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 RA 3 groups; 20 each A' is independently: (RAl) wherein: 25 each RAl is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, 42 (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each cc is independently 1, 2, 3, or 4 5 each A 2 is independently:

(RA

3 )bb (RA1) wherein: 10 each RAl is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, 15 arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR"R , (NRaRb)alkyl, and (NRaRb)carbonyl; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; 20 Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bb and cc is 1, 2, 3, or 4; 25 each A 3 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is substituted with one or more R groups, and which ring is optionally substituted with one or more RA 3 groups; each A 4 is independently: 30 43 XA-H5-XA H5-XA wherein: each H 5 is independently a phenyl ring or a six-membered heteroaromatic ring, which H5 is optionally substituted with one or more groups independently selected from 5 R^' and R A; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A 5 is independently: 10 XA- H-XA wherein: each H 6 is independently a phenyl ring or a six-membered heteroaromatic 15 ring, which H6 is optionally substituted with one or more groups independently selected from RA ' and RA 3 ; and each XA is independently 0, NR, SO, S02, C(O), NRC(=0), C(=O)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; provided that at least one XA is present and each R is independently selected from H or alkyl; 20 each A 6 is independently:

XA-XA-XA

wherein: 25 each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=O), C(=0)NR, CR=CR, allenyl, alkynyl, or absent; provided that at least one XA is present and each R is independently selected from H or alkyl; each A 7 is independently: 30 XA- H 7 -XA 44 wherein: each H 7 is independently a five-membered heteroaromatic ring, which H7 is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and 5 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; and each R is independently selected from H or alkyl; each A 8 is independently: 10 XA-H8-XA 7-XA wherein: each H 7 is independently a five-membered heteroaromatic ring, which H7 is 15 optionally substituted with one or more groups independently selected from RAI and RA 3 ; each H 8 is independently a phenyl ring, which is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 20 or alkyl; each A 9 is independently: XA-H7-XA 7-XA 25 wherein: each H 7 is independently a five-membered heteroaromatic ring, which H7 is optionally substituted with one or more groups independently selected from RA' and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, 30 CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A' 0 is independently: 45 -XA H8XA H9-XA wherein: each H 8 is independently a phenyl ring, which is optionally substituted with 5 one or more groups independently selected from R and RA; each H9 is independently a six-membered heteroaromatic ring, which is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 10 or alkyl; each A" is independently: XA -H10-XA 15 wherein: each XA is independently 0, NR, SO, SO2, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each H' 0 is independently a 5-15 carbon unsaturated, partially unsaturated or 20 saturated bicyclic ring system that is optionally fused to an aryl, which H ' is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRa R, (NRaR )alkyl, and (NRaR b)carbonyl, cyano, nitro, SOR', SO 2 R, -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, 25 (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl each A' 2 is independently: XA ll-XA 30 wherein: 46 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each H " is independently a 5-15 carbon unsaturated, partially unsaturated or 5 saturated bicyclic ring system that contains one or more heteroatoms that is optionally fused to an aryl, which H" is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR SO 2

R

4 , cycloalkyl, 10 (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and each A 3 is independently: 15 -XAH l 2 -XA-. wherein: each H' 2 is independently a fused aromatic bicyclic carbocycle, which is 20 optionally substituted with one or more groups independently selected from RAI and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=O), NRC(=O), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 25 each A' 4 is independently: XA-H -XA wherein: 30 each H' 3 is independently a fused aromatic bicyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from RA' and RA 3 ; and 47 each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 5 each A1 5 is independently: -XAH 14xA wherein: 10 each H' 4 is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from oxo, RAI and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H 15 or alkyl; each A' 6 is independently: XA1H 1 5 -XA-. 20 wherein: each H ' 5 is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected 25 from RAt and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 30 each A 7 is independently: XA 16 -XA 48 wherein: each H1 6 is independently a fused bicyclic carbocyclic ring system wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is 5 optionally substituted with one or more groups independently selected from oxo, RA and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=O), NRC(=0), C(O)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 10 each A' 8 is independently: -XA 17-XA.. wherein: 15 each H' 7 is independently a fused bicyclic ring system comprising at least one heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; and 20 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A 2 ' is independently: 25 XA 4o-XA. wherein: each H 40 is independently an anti-aromatic monocyclic or fused carbocyclic 30 ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from RA' and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 35 49 each W1 is independently -XA: wherein: each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H 5 or alkyl; each W 2 is independently: XA.20-XA 10 wherein: each H 20 is independently a fused aromatic bicyclic carbocycle, which is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, 15 CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 3 is independently: -A21-XA 20 wherein: each H21 is independently a fused bicyclic carbocyclic ring system wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is 25 optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 30 each W 4 is independently: 50 XAH22-XA wherein: each H22 is independently a fused aromatic bicyclic heterocycle that comprises 5 at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from R^' and R^ 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 10 each W 5 is independently:

XA-H

2 3 XA wherein: 15 each H 2 3 is independently a fused bicyclic ring system comprising at least one heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, RA 1 and RA 3 ; and 20 each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=O)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 6 is independently: 25 XA1

H

24 -XA. wherein: each H 24 is independently a fused unsaturated, partially unsaturated or 30 saturated tricyclic carbocycle, which is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; and 51 each XA is independently 0, NR, SO, S02, C(=0), NRC(=O), C(=O)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 5 each W 7 is independently: XA 26-XA wherein: 10 each H 26 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system which ring system is optionally substituted with one or more groups independently selected from oxo, RA 1 and R 3; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 15 or alkyl; each W 8 is independently: XA27..XA 20 wherein: each H 27 is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected 25 from RAI and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 30 each W 9 is independently: XA-H29-XA wherein: 52 each H 29 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that contains one or more heteroatoms; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=O)NR, 5 CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 10 is independently -H 30

=C=H

3

'

wherein each of -H 30 and H 3 ' is independently a saturated 6-membered heterocyclic 10 ring comprising one or more heteroatoms, which ring is optionally substituted with oxo; each W 1 is independently -H 3 2

=C=H-

3 3 wherein each of -H 3 2 and H 33 is independently a saturated 5-membered heterocyclic ring comprising one or more heteroatoms, which ring is optionally substituted with oxo; 15 each W12 is independently an anti-aromatic monocyclic or fused carbocyclic ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from R and RA3; 20 each W 13 is independently a phenyl ring that is optionally substituted with one or more groups independently selected from RAI and RA 3 ; each W 14 is independently a 5 or 6 membered heteroaryl ring that is optionally substituted with one or more groups independently selected from RA and RA 3 ; 25 each W 5 is independently a fused unsaturated, partially unsaturated or saturated tetracyclic carbocyclic ring, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; 30 each W1 6 is independently a fused unsaturated, partially unsaturated or saturated tetracyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, RAI and RA 3 ; each W 7 is independently a fused unsaturated, partially unsaturated or saturated pentacyclic 35 carbocyclic ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, RA and RA 3 ; 53 each W 8 is independently a fused unsaturated, partially unsaturated or saturated pentacyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, RA I and RA 3 ; 5 each W1 9 is independently a fused unsaturated, partially unsaturated or saturated hexacyclic carbocyclic ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, RA and RA 3 ; each W 20 is independently a fused unsaturated, partially unsaturated or saturated hexacyclic 10 heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; each MO is independently a five membered heteroaryl group optionally substituted with one or more alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NRaRb)carbonyl and 15 trial kylsilylalkoxyalkyl; each M 1 is independently selected from -C(=O)NH-, -C(=O)NH-C(R

M

)

2 -, -NHC(=O) -,

-C(RM)

2 NHC(=0)-, -NHC(=0)N Rm -, -NHC(=0)O -; wherein each Rm is independently selected from H and alkyl; 20 each M 2 is independently a six-membered heteroaromatic ring, which is optionally substituted with one or more groups independently selected from RA and RA 3 ; each M 3 is independently: 25 H NO each M 4 is independently: N 30 OH each M 5 is independently: 54 H N wherein the bond designated with --- is fused to a ring defined for P; 5 each M 6 is independently a bicyclic bridged ring system comprising 5-15 atoms wherein at least one of the atoms is a heteroatom; each M 7 is independently a pyrid-di-yl; 10 each M 8 is independently partially saturated or a saturated five-membered ring that comprises one or more heteroatoms and that is optionally substituted with one or two oxo; each M 9 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic 15 heterocyclic ring system that is optionally substituted with one or more R1 each M' 0 is independently a five membered heteroaryl group substituted with at least one alkoxy, cycloalkyl, cyano, alkylsulfonyl, arylsulfonyl, NRh R h, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkoxy, haloalkoxyalkyloxy, 20 cycloalkoxyalkoxy, aryloxyalkoxy, heteroaryloxyalkoxy, heterocyclyloxyalkyloxy, (NRhRh)alkoxy, cyanoalkoxy, cycloalkoxy, heterocyclyl, alkoxyalkyl, cycloalkoxyalkyl, (NRhRh)alkyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyloxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, and sulfonylalkyl; and wherein the five membered ring is also optionally 25 substituted with one or more alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, and (NRaRb)carbonyl; each M" is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more oxo, halo, -RM 7 , -ORM 7 30 -SR M7, -N(R m')2, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R M 7 )C(=O)R M7, -C(=O)R M7, -OC(=O)R m' 7M77M 7M -C(O)OR 7 , -C(=)NR 7, -S(=0)R , -S(=0) 2 0R 7 , -S(=O) 2 R M7, -OS(=O) 2 0R , or

-S(=O)

2 NR M7; each R M 7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; 55 each M 12 is independently a fused-pentacyclic, hexacyclic, or heptacyclic partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more oxo halo,

-RM

7 , -OR M 7 , -SR M 7 , -N(R M7) 2 , -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R M 7 )C(=O)R m 7 , -C(=O)R M7, -OC(=)R 7, -C(O)OR 7 -C(=O)NR 7 -S(=O)R 7 , -S(=0) 2 0R M7, -S(=0) 2

RM

7 5 OS(=0) 2 0R m7 , or -S(=0) 2 NR M7; each R M 7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; each P 0 is independently: ((R)pq k IX I-X N )pn N pm (RP5)p (R P6) p PP P R N 7 R P 8 Ir )" F ( )orV 9 10 wherein: X is selected from 0, S, S(O), S02, CH 2 , CHR 0, and C(R"'P) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP 10 , and C(RE' 0

)

2 ; 15 each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaR , wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, PaPb 20 halo, haloalkyl, hydroxy, and -NReaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; RPa and Reb are each independently H, alkyl, aryl, or arylalkyl; or RPa and RPb taken together with the atom to which they are attached form a heterocycle; 25 pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 56 RP' and R" are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NRPaRPb)alkyl; or R'7 and RP 8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NRN, 0, and S; wherein Ra is selected from hydrogen and alkyl; 5 RP 9 is selected from hydrogen and alkyl; each P' is independently:

(RM

1 )p f-x pn 10 wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHRela, and C(RP' 0

)

2 ; provided that when pn is 0, X is selected from CH 2 , CHRP' 0 , and C(R ' 0

)

2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, PaR Pb haloalkyl, hydroxy, and -NRaR , wherein the alkyl can optionally form a fused three 15 to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; at least one R" is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, 20 heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR R ha)lkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhhRh, (NRhRh)alkyl, (NR hhR h)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two 25 Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhR )sulfonyl, heteroarylsulfonyl, -S(=0) 2 R h, -C(=O)R , -C(=O)NRh R; and the remaining 30 RP1" are independently selected from R , cyano, alkylsulfonyl, arylsulfonyl, (NRh R)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 57 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhR h)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 5 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; 10 each P 2 is independently: (R P12)S I-N Npn 15 wherein: each RP is independently selected from R 5 , R ,C(=O)ORh, cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, 20 heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come 25 together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; each P 3 is independently a ring of the formula: 30 58

(R

1 )S N pn wherein: the ring is substituted with one or more oxo group; 5 each RP' 3 is independently selected from RP 5 , cyano, alkylsulfonyl, arylsulfonyl, (NR R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R is independently -H, 10 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 0, 1, 2, 3, or 4; 15 pn is 0, 1, or 2; each P 4 is independently a ring of the formula: /Rf N N pn 20 wherein: the ring is optionally substituted with one or more groups R '4 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NR PaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an 25 adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups RP14 that are attached to the same carbon 59 when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; pn is 0, 1, or 2; each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, 5 heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NR R, -S(=0)2Rh, C(=O)R h, C(=O)OR h, -C(=O)NRhRh ; each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 10 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 5 is independently a ring of the formula: (C z 15 wherein: the ring is optionally substituted with one or more groups RP is that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and 20 NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups RP1 5 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; 25 pn is 0, 1, or 2; Z is 0, S, S(=0), S(=0) 2 , or NR; each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0)2NRhR , 30 -S(=0) 2 Rh, C(=O)Rh, C(=O)ORh, -C(=0)NRhRh ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 60 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 6 is independently a ring of the formula: 5 ( f z wherein: the ring is substituted with one or more oxo and is optionally substituted with one 10 or more groups RP' 6 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRaR Pb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; Z is 0, S, S(=0), S(=0) 2 , or NRf; 15 pn is 0, 1, or 2; each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NR R , -S(=0)2Rh, C(=0)Rh, C(=0)ORh, -C(=O)NRhRh ; each Rh is independently -H, alkyl, 20 alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 25 each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from RP 6 and R' "; each P 8 is independently a ring of the formula: 30 61 (RP13)P N pn wherein: ps is 2, 3, 4, 5, or 6; 5 pn is 0, 1 or 2; each RP' 3 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRP"R b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least 10 one case two groups R 3 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring; each P 1 0 is independently: 15 (R P),S (RP 6 )pq POP N\ Po N wherein: X is selected from 0, S, S(O), S02, CH 2 , CHR 'O, and C(RP 10

)

2 ; 20 provided that when pn or pm is 0, X is selected from CH 2 , CHRE' 0 , and C(R ")2; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR Pb, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 25 each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, PPb halo, haloalkyl, hydroxy, and -NReaRP , wherein the alkyl can optionally form a fused 62 three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; 5 po and pp are independently 1, 2, or 3; each P' is independently: (RP5)PS (RP 6 )pq Po( PP( IN )pn N 10 wherein: X is selected from 0, S, S(0), SO 2 , CH 2 , CHRP'", and C(R' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP' 0 , and C(R ' 0

)

2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, 15 haloalkyl, hydroxy, and -NReaR b, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NReaR b, wherein the alkyl can optionally form a fused 20 three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 25 each P' 2 is independently: 63 (RP6)pg (RP1 )PS P N pm wherein: 5 each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRea R , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 10 pm is independently 0, 1, or 2; pp is independently 1, 2, or 3; ps is 1, 2, 3, or 4; R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR R )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 15 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR R h, (NR hR )alkyl, (NRhhRh)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 20 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR R h)sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=0)R, 25 -C(=O)NRhRh; and the remaining R'' are independently selected from R , cyano, alkylsulfonyl, arylsulfonyl, (NRh R )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR R h)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R is independently -H, 30 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 64 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P1 3 is independently: 5 (R1 1), (RP6g pn 6PP N pm wherein: X is selected from 0, S, S(O), S02, or NR ; 10 each R 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR aR P, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 15 pq is independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2 but the sum of pn and pm is greater than zero; pp are independently 1, 2, or 3; ps is 1, 2, 3, or 4; 20 each R'' is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRh R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR hhR h, (NRh Rh)alkyl, (NRh R h)carbonyl, wherein each Rh is independently 25 -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, 30 alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 65 dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=O) 2 Rh, -C(=O)R, h h P5h -C(=O)NR R , R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, 5 cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered 10 heterocyclic ring; each P' 4 is independently: (R )ps(R 6 )pq N pm 15 wherein: the ring is substituted with one or more oxo group; X is NRf each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, 20 heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhR , -S(=0) 2 Rh, C(=O)Rh, C(=O)ORh, -C(=O)NRhRh ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 25 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRRPa RP, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is 30 optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 66 pm is independently 0, 1, or 2; ps is 1, 2, 3, or 4; RP" 1is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 5 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or sulfonylalkyl; and when 10 two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 1 5 is: 15 which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl; 20 each P 16 is: 25 which is substituted with methylene; each P 17 is: 30 which is substituted with one or two groups independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkylalkenyl, and cycloalkylalkynyl; 35 each P18 is: 67 T T N,,A N \, C orC 5 which is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl; each P' 9 is: R R orN RP19b RP19a 10 RP19b wherein each R is independently selected from H and halo; and each R 19b is independently selected from halo; 15 each -Z4- is -C(=O)- or -C(=S)-; each -Z'- is independently a bond, or -C(Rzl) 2 -; wherein each RzI is independently H, alkyl, haloalkyl, or halo; 20 each - is independently saturated or partially unsaturated (C 3

-C

8 )cycloalkyl that is optionally substituted with one or more groups independently selected from RA' and RA 3 ; each -Z3- is independently saturated, partially unsaturated, or aromatic 4-8 membered 25 heterocyclic or heteroaryl ring that is optionally substituted with one or more groups independently selected from RAI and RA3; each -Z4- is independently: 68 ,R Z 4 wherein each RZ 4 is independently H, alkyl, cyano, aryl, or heteroaryl; 5 each -Z 5 - is independently: Rz -Rz 5 N N wherein each Rz 5 is independently H, alkyl, cyano, aryl, or heteroaryl; or two Rzss together 10 with the nitrogen to which they are attached form a 4-8 membered heterocyclic ring that is optionally substituted with one or more oxo and with one or more groups independently selected from R and R A3 each -Z 6 - is independently -C(RzI)- and is doublebonded to a carbocyclic P; wherein RzI is 15 independently H, alkyl, haloalkyl, or halo; each EO is independently -NRcREd wherein R Ec and REd are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, 20 arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NRcRr)alkyl, (NRe R)alkylcarbonyl, (NR Rr)carbonyl, (NR*Rr)sulfonyl, -C(NCN)OR', and - C(NCN)NRxR , 25 wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NReRr group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the 30 heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the 69 heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; 5 each E' is independently -OC(=O)NREeREF wherein each REe and REf are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, 10 heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NRCRf)alkyl, (NReR)alkylcarbonyl, (NReRr)carbonyl, (NReRf)sulfonyl, -C(NCN)OR', and - C(NCN)NRR , wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NRe Rf group; and wherein 15 the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, 20 haloalkoxy, haloalkyl, and nitro; or wherein REe and REf. together with the nitrogen atom to which they are attached, form a heterocycle; each E is independently -NR R , wherein Ra is haloalkyl and Rb is H, alkyl, alkoxycarbonyl or haloalkyl; 25 each E 3 is independently -NREc RE 3 a, wherein RE 3 a is (C3-C6)cycloalkyloxycarbonyl; each E 4 is independently -OC(=O)ORE 4 a, wherein RE 4 a is cycloalkyl, aryl, or alkyl; 30 each E 5 is independently -NREc S(=0) 2 0RE 5 a, wherein RE 5 a is is cycloalkyl, aryl or alkyl; each E 6 is independently -NREcS(=0)2RE6a, wherein RE6a is Cycloalkyl, aryl, or alkyl; each E7 is independently -NREcOR)E7a, wherein RE 7 a is cycloalkyl, aryl, oalkyl, 35 cycloalkylalkyl or heteroaryl; 70 each V 0 is independently H, alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, 5 hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, 10 heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, 15 -NRxR , -(NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents 20 independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, 25 (NRXRY)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, 30 haloalkyl, and nitro; each V' is independently cyanoalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRyaRv'C(=O)O-; Rva and R are each independently selected from 35 hydrogen, alkenyl, and alkyl; 71 each V2 is independently haloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaRvbC(=O)O-; Rva and RVb are each independently selected from 5 hydrogen, alkenyl, and alkyl; each V 3 is independently alkyl, which is substituted with one or more oxo, and which is optionally substituted with one or more groups independently selected from cycloalkyl, halo, aryl, alkenyl, and cyano; 10 each V 4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRva R vbC(=O)O-; wherein RVa and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 15 each V 5 is independently alkylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR VbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 20 each V 6 is independently arylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaR C(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 25 each V 7 is independently heterocyclosulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V 8 is independently spirocycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvR vbC(=0)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 35 72 each V9 is independently spirocycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 5 each V1 0 is independently fusedbicycliccycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 10 each V 11 is independently fusedbicycliccycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 15 each V1 2 is independently bridged-bicycliccycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 20 each V1 3 is independently bridged-bicyclic-cycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 25 each V1 4 is independently aryloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRva R vC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V1 5 is independently arylalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaR C(=O)O-; RVa and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 35 73 each V' 6 is independently cycloalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaRvbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 5 each V 7 is independently cycloalkylalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRva RvC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 10 each V1 is independently heterocyclooxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 15 each V' 9 is independently heterocycloalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 20 each V 20 is independently heteroaryloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and R b are each independently selected from hydrogen, alkenyl, and alkyl; 25 each V is independently heteroarylalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V 22 is independently cycloalkenylalkyl; each V 23 is independently arylalkyl, wherein the aryl is substituted with one or more groups independently selected from cycloalkyl, alkenyl, cycloalkylalkyl, cyanoalkyl, cycloalkoxy, 35 hydroxyalkoxy, -C(=O)NRxRY, S(=0) 2 NRxRY, alkylsulfanyl, alkylsulfonyl, haloalkylsulfanyl, 74 haloalkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, arylsulfanyl, arylsulfonyl, alkoxyalkoxy, alkynyl, aryloxy, heteroaryloxy, alkylsulfonylamino; Rx and RY are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, 5 unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NRxRY)carbonyl, wherein Rx and Ry are independently selected from hydrogen and alkyl; each V 2 4 is independently heterocycloalkyl, wherein the heterocycle is substituted with one or more groups independently selected from cycloalkyl, alkenyl, cycloalkylalkyl, cyanoalkyl, 10 cycloalkoxy, hydroxyalkoxy, -C(=O)NRXRY, S(=0) 2 NRxRY, alkylsulfanyl, alkylsulfonyl, haloalkylsulfanyl, haloalkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, arylsulfanyl, arylsulfonyl, alkoxyalkyoxy, alkynyl, aryloxy, heteroaryloxy, alkylfulfonylamino; Rx and RY are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, 15 unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR' R y)carbonyl, wherein Rx and Ry are independently selected from hydrogen and alkyl; each T' is independently a spiro, branched or fused bicycloalkyl; each T 2 is independently aryl; 20 each T 3 is independently heteroaryl; each T 4 is independently arylalkyl; each T 5 is independently haloalkyl; each T 6 is independently heteroarylalkyl; each T 7 is independently heterocycle; and 25 each T 8 is independently heterocycloalkyl. In another specific embodiment the invention provides a compound of formula (1): J-Y-J (I) 30 wherein: Y is -L-L-, -M-W-M- or YY; J is T-P-, -P-T or -J"; W is a bond or -W'-; L is -M-A-, -A-M-, or -L"; 35 T is R9-Z-, -Z-R9, or -TP; 75 R9 is E-V-, or -V-E, or -R9; each A is selected from -As; each M is selected from -M'; each P is selected from -P"; 5 each Z is selected from -Z'; each V is selected from -V"; each E is selected from -E'; each m is 1; each n is 0, 1, 2, 3, 4, 5, 6, 7, 9, or 10; 10 each p is 1, 2, 3, 4, 5, 6, 7, or 8; each q is 0, 1, 2, or 3; eachris 1,2,3,4,5,6,7,8,9, 10, 11, 12,13, 14, 15, 16, 17,18, 19,or20; each s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 21; each tis 0, 1,2, 3, 4,5,6,7, 8, 9, 10, or 11; 15 each u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, or 14; each v is 0, 1, 2, 3, 4, 5, or 6; each w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21; each x is 0 or 1; each y is 0, 1, or 2; 20 wherein the sum of m, n, p, q, r, s, t, u, v, w, x, and y is not 0; P is connected to M, L, or Y; A is connected to A or L; M is connected to P or J; Z is connected to P; V is connected to Z; and when W is a bond M is connected to M; each Y' is independently: 25 a fused nine-ring system with up to thirty-five atoms that may be fully aromatic or partially saturated and contains atoms selected from C, N, 0, and S, and which ring system is optionally substituted with one or more groups independently selected from H, oxo, R and RAl; each Y2 is independently: 30 a fused five to eight ring system with up to thirty-two atoms that may be fully aromatic or partially saturated and contains atoms selected from C, N, 0, and S, and which ring system is optionally substituted with one or more groups independently selected from H, oxo, RAI and

RA

3 ; 76 each J' is independently a fused bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is substituted with one or more -N(R )C(=0)OR 'L, and that is optionally substituted with one or more groups independently selected from oxo, halo, -RL 7 , -OR , -SR L, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R L)C(=0)R L, -C(=0)R L, -OC(=O)R L7 5 -C(O)OR L, -C(=O)NR L7, -S(=O)R L7, -S(=0) 2 0R L, -S(=0) 2 R L7, -OS(=0) 2 0R L7, -S(=0) 2 NR L7, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl; each R U is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 10 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L is independently:

(RL

2 )aa 15 wherein: each RL 2 is independently selected from hydrogen, alkenyl, alkoxy, alkyl, halo, and haloalkyl; and 20 each aa is independently 1, 2, 3, or 4; each L' is independently: (RL)aa _N H

(RL

2 )bb 25 wherein: 77 each R is independently selected from hydrogen, alkenyl, alkoxy, alkyl, halo, and haloalkyl; each RL is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkyISO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, 5 (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each bb is 0, 1, 2, 3, or 4; each aa is 1, 2, 3, or 4; and the sum of bb and aa is 1, 2, 3, or 4; 10 each L 2 is independently: R L4 Hi R L4 15 wherein: the phenyl ring shown in L2 is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, (NRa R b)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , 20 cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each RL' is independently -H, alkyl, aryl, arylalkyl, or heterocycle; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 25 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each H' is a 5 membered saturated, partially unsaturated, or aromatic ring comprising one or more heteroatoms; 78 each L3 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, (NRaR)carbonyl, 5 cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 10 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L 4 is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently 15 selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NRaRb)alkyl, (NRaR)carbonyl, cyano, nitro, SOR 4 , SO 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; 20 each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 25 each L 5 is independently a -CR=CR-fusedbicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NRaRb)alkyl, (NRaR)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, 30 (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each R is independently selected from H or alkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and 79 Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 5 each L 6 is independently a -CR=CR-fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NRa R )alkyl, (NRa R )carbonyl, 10 cyano, nitro, SOR 4 , SO 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each R is independently selected from H or alkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and 15 Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L 7 is independently:

(R

2 )aa 20 wherein: each H" is independently a fused-bicyclic saturated, partially unsaturated, or 25 aromatic heterocyclic ring system that is optionally substituted with one or more R2 each R 2 is independently selected from halo, -RL 7 , -OR L7, -SR L7, -N(R L7) 2 , -CF 3 , -CC13, -OCF 3 ,-CN, -NO 2 , -N(R L)C(=0)R L, -C(=0)R L, -OC(=O)R ", -C(O)OR '7 -C(=0)NR L7, -S(=0)R L7, -S(=O)20R L7, -S(=0) 2 R L7, -OS(=0) 2 OR L7, and -S(=0) 2 NR L7; each R L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; and 30 each aa is independently 1, 2, 3, or 4; 80 each L 9 is independently a fused-tetracyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -RL 7 , -OR L7, -SR -, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R L 7 )C(=0)R L7 -C(=O)R L, -OC(=O)R L7, -C(O)OR L7, -C(=O)NR L7, -S(=O)R L7, -S(=0) 2 0R L7, -S(=0) 2 R L7, 5 OS(=0) 2 0R L 7 , -S(=0) 2 NR U, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NRaRb, (NRaR)alkyl, and (NRaRb)carbonyl; each R L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, 10 heterocyclyl, and heterocyclylalkyl; each L1 0 is independently a fused-pentacyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -R", -OR L, -SR ', -CF 3 , -CCI 3 , -OCF 3 ,-CN, -NO 2 , -N(R L)C(=0)R L, L7 L7 L7 17 U7 U L7 15 -C(=O)R , -OC(=O)R , -C(O)OR , -C(=O)NR , -S(=O)R , -S(=0) 2 0R , -S(=0) 2 R , OS(=0) 2 0R L7, -S(=0) 2 NR U, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NRaR', (NRaRb)alkyl, and (NRaRb)carbonyl; each R L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, 20 alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L 1 is independently a six-ring fused saturated, partially unsaturated, or aromatic 25 heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -R' 7 , -OR L, -SR L, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R ")C(=O)R L, L7L7 L7 L7 U 7L7 -C(=O)R ", -OC(=O)R , -C(O)OR , -C(=O)NR , -S(=O)R L, -S(=0) 2 0R L, -S(=0) 2 R , OS(=0) 2 0R L, -S(=0) 2 NR L7, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NR aR', (NRaRb)alkyl, and (NRaRb)carbonyl; 30 each R L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 35 81 each R9 0 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, 5 hydroxyalkyl, -NRcRd, (NRCRd)alkenyl, (NRcRd)alkyl, and (NRCRd)carbonyl; Rc and Rd are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, I0 heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NRCRf)alkyl, (NR"Rf)alkylcarbonyl, (NR Rf)carbonyl, (NRCRr)sulfonyl, -C(NCN)OR', and - C(NCN)NRXRY, wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally 15 substituted with one -NReRf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents 20 independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; RX and RY are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NRxRY)carbonyl, wherein Rx and R' are independently selected from hydrogen and alkyl; 25 each R9' is independently -N(R 9 a)-NHC(=O)O-R 9 b, wherein each R 9 a is independently arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO 2 alkyl, cycloalkylalkylSO 2 alkyl, cyanoalkyl, haloalkyl, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, 30 alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups 82 independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, 5 arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the 10 arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, 15 arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, -(NRxRY)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further 20 optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R is independently H, alkyl, aryl, haloalkyl, or arylalkyl; each R92 is independently -N(R 9a)-NHC(=O)NR 92; wherein each R9a is independently 25 arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO2alkyl, cycloalkylalkylSO2alkyl, cyanoalkyl, haloalkyl, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is 30 independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; 83 and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, 5 (NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents 10 independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, -(NRxRY)alkyl, and oxo, wherein 15 the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R 9 b is independently H, alkyl, aryl, 20 haloalkyl, or arylalkyl; each R9 3 is independently -N(R 9 a)-NHC(=O)R 9 b, wherein each R 9 a is independently arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSO 2 alkyl, cycloalkylalkylSO 2 alkyl, cyanoalkyl, 25 haloalkyl cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from H or alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl 30 part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, 35 arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, 84 heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRXRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the 5 arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, 10 arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, -(NRxRy)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further 15 optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R 9b is independently H, alkyl, aryl, haloalkyl, or arylalkyl; each A 0 is independently:

(RA

3 )bb 20 wherein: each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, 25 (NRaR )alkyl, and (NRaRb)carbonyl; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each bb is independently 0, 1, 2, 3, or 4; or 85 each A 0 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 RA 3 groups; each A' is independently: 5 (RA1) wherein: each RAI is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, 10 (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each cc is independently 1, 2, 3, or 4; 15 each A 2 is independently:

(RA

3 )bb (RA1)C wherein: each RAl is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , 20 haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , 25 (NRaRb)alkyl, and (NRaRb)carbonyl; Ra and R b are each independently selected from the group 86 consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 5 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bb and cc is 1, 2, 3, or 4; each A 3 is independently a six-membered heteroaromatic ring containing one, two, or three 10 nitrogen atoms, which ring is substituted with one or more RA groups, and which ring is optionally substituted with one or more RA 3 groups; each A 4 is independently: XA-H 5-XA 5-XA 15 wherein: each H 5 is independently a phenyl ring or a six-membered heteroaromatic 20 ring, which H5 is optionally substituted with one or more groups independently selected from R^' and RA; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 25 each A 5 is independently: XA - H 6

_XA.

wherein: 30 each H 6 is independently a phenyl ring or a six-membered heteroaromatic ring, which H6 is optionally substituted with one or more groups independently selected from RA and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=O)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; provided that at least one XA is present and each R is independently selected from H or alkyl; 87 each A 6 is independently: XA-XA-XA._ 5 wherein: each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, allenyl, alkynyl, or absent; provided that at least one X^ is present and each R is independently selected from H or alkyl; 10 each A 7 is independently: XA- H 7

-XA

wherein: 15 each H 7 is independently a five-membered heteroaromatic ring, which H 7 is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H 20 or alkyl; each A 8 is independently: XA- -H8-XA 7-XA 25 wherein: each H 7 is independently a five-membered heteroaromatic ring, which H 7 is optionally substituted with one or more groups independently selected from RA' and RA 3 ; each H 8 is independently a phenyl ring, which is optionally substituted with 30 one or more groups independently selected from RA1 and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 88 each A 9 is independently: XA-H7-XA 7-XA wherein: 5 each H 7 is independently a five-membered heteroaromatic ring, which H 7 is optionally substituted with one or more groups independently selected from RA1 and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 10 or alkyl; each A1 0 is independently: XA-H8-XA---H9-XAA 15 wherein: each H 8 is independently a phenyl ring, which is optionally substituted with one or more groups independently selected from RAI and RA 3 each H 9 is independently a six-membered heteroaromatic ring, which is 20 optionally substituted with one or more groups independently selected from RA and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=O)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 25 each A" is independently: XA-H10-XA_. wherein: each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, 30 CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each H10 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that is optionally fused to an aryl, which H '" is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, 89 alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR aRb, (NRa R b)alkyl, and (NRaRb)carbonyl, cyano, nitro, SOR4, SO 2 R4, -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR SO 2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is 5 optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each A 2 is independently: XAH 11XA 10 wherein: each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each H" is independently a 5-15 carbon unsaturated, partially unsaturated or 15 saturated bicyclic ring system that contains one or more heteroatoms that is optionally fused to an aryl, which H"' is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NRaRb)alkyl, and (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, 20 (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and 25 each A' 3 is independently: XAl12xA. wherein: each H is independently a fused aromatic bicyclic carbocycle, which is 30 optionally substituted with one or more groups independently selected from RA and RA 3 ; and 90 each XA is independently 0, NR, SO, SO 2 , C(=O), NRC(=O), C(=O)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 5 each A 4 is independently: -XA 13.-XA. wherein: 10 each H 3 is independently a fused aromatic bicyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 15 or alkyl; each A1 5 is independently: XI- 14-XA 20 wherein: each H' 4 is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from RA1 and RA 3 ; and 25 each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=O), C(=O)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A' 6 is independently: 30 XA -H 15 -XA wherein: 91 each H 5 is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected 5 from RA and RAl; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 10 each A' 7 is independently: X-H XA g 6

..XA

wherein: 15 each H1 6 is independently a fused bicyclic carbocyclic ring system wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, RA1 and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, 20 CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A 1 8 is independently: XA-H17-XA 25 wherein: each H1 7 is independently a fused bicyclic ring system comprising at least one heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, 30 which ring system is optionally substituted with one or more groups independently selected from oxo, RA1 and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=O), NRC(=0), C(=O)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 35 92 each A 2 1 is independently: LXA_40-XA wherein: 5 each H 40 is independently an anti-aromatic monocyclic or fused carbocyclic ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from R and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, 10 CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W1 is independently -XA-: 15 wherein: each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=O)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 20 each W 2 is independently: XA-20-XA wherein: 25 each H 20 is independently is independently a fused aromatic bicyclic carbocycle, which is optionally substituted with one or more groups independently selected from RA and RAl; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, 30 CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 3 is independently: 93

XA-H

2 1-XA wherein: each H 2 1 is independently a fused bicyclic carbocyclic ring system wherein 5 one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, RAI and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 10 or alkyl; each W 4 is independently: FXA- 22-XA 15 wherein: each H 22 is independently a fused aromatic bicyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and 20 each XA is independently 0, NR, SO, SO2, C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 5 is independently: 25 XA-H XA wherein: each H 2 3 is independently a fused bicyclic ring system comprising at least one 30 heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; and 94 each XA is independently 0, NR, SO, S02, C(=0), NRC(=O), C(=O)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 5 each W 6 is independently: XA 24-XA wherein: 10 each H 24 is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle, which is optionally substituted with one or more groups independently selected from RA' and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 15 or alkyl; each W 7 is independently: XAH26XA6-A 20 wherein: each H 26 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system which ring system is optionally substituted with one or more groups independently selected from oxo, R and R 3; and 25 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 30 each W is independently: XA 27-XAA 95 wherein: each H is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, 5 which ring system is optionally substituted with one or more groups independently selected from RA' and RAl; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 10 each W 9 is independently: XA-H 29-XA.

wherein: 15 each H 2 9 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that contains one or more heteroatoms; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H 20 or alkyl; each W 10 is independently -H 30

=C=H

3

'

wherein each of -H 30 and H 3 ' is independently a saturated 6-membered heterocyclic ring comprising one or more heteroatoms, which ring is optionally substituted with oxo; 25 each W"' is independently -H 32

=C=H-

33 _ wherein each of-H32 and H 33 is independently a saturated 5-membered heterocyclic ring comprising one or more heteroatoms, which ring is optionally substituted with oxo; 30 each W' 2 is independently an anti-aromatic monocyclic or fused carbocyclic ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from RA' and RA 3 ; each W' 3 is independently a phenyl ring that is optionally substituted with one or more groups 35 independently selected from R and RA3; 96 each W 14 is independently a 5 or 6 membered heteroaryl ring that is optionally substituted with one or more groups independently selected from RA' and RA 3 ; each W' 5 is independently a fused unsaturated, partially unsaturated or saturated tetracyclic 5 carbocyclic ring, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA3 each W' 6 is independently a fused unsaturated, partially unsaturated or saturated tetracyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is 10 optionally substituted with one or more groups independently selected from oxo, RA and RA 3 ; each W 17 is independently a fused unsaturated, partially unsaturated or saturated pentacyclic carbocyclic ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R^ 'and RA 3 ; 15 each W 18 is independently a fused unsaturated, partially unsaturated or saturated pentacyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; 20 each W' 9 is independently a fused unsaturated, partially unsaturated or saturated hexacyclic carbocyclic ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; 25 each W 2 0 is independently a fused unsaturated, partially unsaturated or saturated hexacyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, RAI and RA 3 ; each MO is independently a five membered heteroaryl group optionally substituted with one or 30 more alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NRaRb)carbonyl and trialkylsilylalkoxyalkyl; each M 1 is independently selected from -C(=0)NH-, -C(=0)NH-C(R) 2 -, -NHC(=O) -,

-C(RM)

2 NHC(=O)-, -NHC(=O)N RM -, -NHC(=O)O -; wherein each RM is independently 35 selected from H and alkyl; 97 each M 2 is independently a six-membered heteroaromatic ring, which is optionally substituted with one or more groups independently selected from RA and RA 3 ; each M 3 is independently: 5 H kN O each M 4 is independently: "N 10 OH each M 5 is independently: H N 15 N wherein the bond designated with --- is fused to a ring defined for P; each M 6 is independently a bicyclic bridged ring system comprising 5-15 atoms wherein at least 20 one of the atoms is a heteroatom; each M 7 is independently a pyrid-di-yl; each M 8 is independently partially saturated or a saturated five-membered ring that comprises 25 one or more heteroatoms and that is optionally substituted with one or two oxo; each M 9 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more RP' 1 98 each M'0 is independently a five membered heteroaryl group; each M 1 is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more oxo, halo, -RM 7 , -ORM 7 , 5 -SR M7, -N(R M7)2, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R M 7 )C(=O)R M 7 , -C(=O)R M 7 , -OC(=O)R M7 M7 M7 M7 M7M77 , -C(O)OR M7, -C(=O)NR , -S(=O)R , -S(=0) 2 0R , -S(=0) 2 R M7, -OS(=0)2OR or -S(=0)2NR M7; each R M7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; 10 each P 0 is independently: (R P)ps (R P6) I-X -_X N pn N pm (RPs (R 6 )pq F))po f PP or N R 8 wherein: 15 X is selected from 0, S, S(O), S02, CH 2 , CHR ' 0 , and C(RP' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR 10 , and C(R '4) 2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, aRPb haloalkyl, hydroxy, and -NRPaR , wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered 20 ring is optionally substituted with one or two alkyl groups; each RE 5 and R~ 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; RPa and R are each independently 25 H, alkyl, aryl, or arylalkyl; or RPa and RPb taken together with the atom to which they are attached form a heterocycle; pq and ps are independently 0, 1, 2, 3, or 4; 99 pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; R7 and RP 8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NRPaR b)alkyl; or R' and RE 8 , together with the carbon atom to which they 5 are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NRE', 0, and S; wherein RP is selected from hydrogen and alkyl; R"9 is selected from hydrogen and alkyl; each P' is independently: (R' 1)PS I-x N pn 10 wherein: X is selected from 0, S, S(0), SO 2 , CH 2 , CHRP' 0 , and C(Rp 0

)

2 ; provided that when pn is 0, X is selected from CH 2 , CHRP"l, and C(R E)2; 15 each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaRb, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; at least one RP1 1 is independently selected from cyano, alkylsulfonyl, 20 arylsulfonyl, (NRh Rh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRh R , (NRh R h)alkyl, (NR hhR )carbonyl, wherein each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, 25 heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 30 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=O)R , -C(=0)NRh R; and the remaining R P11 are independently selected from R 5 , cyano, alkylsulfonyl, arylsulfonyl, 100 (NR R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, 5 heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; 10 pn is 0, 1, or 2; each P2 is independently: (R P12) N N pn 15 wherein: each R ' is independently selected from R 5 , R ,-C(=O)ORh, cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclyisulfonyl, heteroarylsulfonyl, 20 haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRR h)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 25 dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; 30 each P 3 is independently a ring of the formula: 101 (RP13)P ') N pn wherein: the ring is substituted with one or more oxo group; 5 each RP' 3 is independently selected from R P, cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclyisulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, 10 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 0, 1, 2, 3, or 4; 15 pn is 0, 1, or 2; each P 4 is independently a ring of the formula: Rf N N pn 20 wherein: the ring is optionally substituted with one or more groups RP ' 4 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NRPa R , wherein the alkyl can optionally form a fused three-to six-membered ring with an 25 adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups RP' 4 that are attached to the same carbon 102 when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; pn is 0, 1, or 2; each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, 5 heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NR R, -S(=0)2Rh, C(=O)R h, C(=O)ORh, -C(=O)NRhR' ; each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 10 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 5 is independently a ring of the formula: (CZ 15 wherein: the ring is optionally substituted with one or more groups R 15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and 20 NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R' that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; 25 pn is 0, 1, or 2; Z is 0, S, S(=0), S(=0) 2 , or NR; each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhRh, 30 -S(=0) 2 Rh, C(=0)Rh, C(=0)ORh, -C(=O)NRhRh ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 103 dialkylaminoalkyl, sulfonylalkyl; or when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 6 is independently a ring of the formula: 5 pn z wherein: the ring is substituted with one or more oxo and is optionally substituted with one 10 or more groups RP' 6 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPR Pb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; Z is 0, S, S(=0), S(=0) 2 , or NR ; 15 pn is 0, 1, or 2; each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhRh, -S(=0) 2 Rh, C(=0)Rh, C(=O)ORh, -C(=0)NRhRh ; each Rh is independently -H, alkyl, 20 alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 25 each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from RP 6 and RP "; each P 8 is independently a ring of the formula: 30 104 %Pfl N pn wherein: ps is 2, 3, 4, 5, or 6; 5 pn is 0, l, or 2; each R 13 is independently selected from alkoxy, alkyl, aryl, halo, Pa Pb haloalkyl, hydroxy, and -NR R , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least 10 one case two groups RP' 3 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring; each P' 0 is independently: 15 (RP5)PS (RP6)pq N_"I PO 0 wherein: X is selected from 0, S, S(0), SO 2 , CH 2 , CHR' 0 , and C(R" 0) 2 ; 20 provided that when pn or pm is 0, X is selected from CH 2 , CHRP' 0 , and C(RE' 0

)

2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 25 each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaR , wherein the alkyl can optionally form a fused 105 three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; 5 po and pp are independently 1, 2, or 3; each P" is independently: (RPs),S (RP 6 )pq po( PP( N>N N 10 wherein: X is selected from O, S, S(O), SO 2 , CH 2 , CHR ", and C(RE 10

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP 1 ", and C(R P'0)2; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, 15 haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, PaPb halo, haloalkyl, hydroxy, and -NR "R , wherein the alkyl can optionally form a fused 20 three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 25 each P 12 is independently: 106

(RP

6 )pq (RPi 1)ps Pp N pm wherein: 5 each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 10 pm is independently 0, 1, or 2; pp is independently 1, 2, or 3; ps is 1, 2, 3, or 4; RP' Iis independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR Rh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 15 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhR h, (NR R h)alkyl, (NR R h)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 20 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, NRhRhsulfonyl, heteroarylsulfonyl, -S(=0) 2 R, -C(=0)Rh hh P5P 25 -C(=O)NR Rh; and the remaining RP' are independently selected from R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR R )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, 30 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 107 ,h dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P' 3 is independently: 5 (RPI ), (RP6 pn 6 PP N pm wherein: X is selected from 0, S, S(O), SO 2 , or NRh 10 each R 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR Pa R Pb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 15 pq is independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2 but the sum of pn and pm is greater than zero; pp are independently 1, 2, or 3; ps is 1, 2, 3, or 4; 20 each Re"1 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhRh, (NRhhRh)alkyl, (NRRh)carbonyl, wherein each Rh is independently 25 -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, 30 alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 108 dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=0)Rh, -C(=O)NRh R h, R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, 5 cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered 10 heterocyclic ring; each P1 4 is independently: (RP6)Pq (R) ) N pm 15 wherein: the ring is substituted with one or more oxo group; X is NR ; each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, 20 heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRRh, -S(=0) 2 Rh, C(=O)Rh, C(=O)ORh, -C(=0)NRhR ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 25 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRea R , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is 30 optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 109 pm is independently 0, 1, or 2; ps is 1, 2, 3, or 4; R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 5 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or sulfonylalkyl; and when 10 two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each -Z 0 - is -C(=O)- or -C(=S)-; 15 each -Z'- is independently a bond, or -C(Rzl) 2 -; wherein each RzI is independently H, alkyl, haloalkyl, or halo; each -Z 2 - is independently saturated or partially unsaturated (C 3

-C

8 )cycloalkyl that is optionally substituted with one or more groups independently selected from RA I and RA 3 ; 20 each -Z 3 - is independently saturated, partially unsaturated, or aromatic 4-8 membered heterocyclic or heteroaryl ring that is optionally substituted with one or more groups independently selected from R^1 and RA3; 25 each -Z 4 - is independently: 1 "RZ 4 wherein each RZ 4 is independently H, alkyl, cyano, aryl, or heteroaryl; 30 110 each -Z 5 - is independently: R& Z5-RZ 5 N N 5 wherein each RZs is independently H, alkyl, cyano, aryl, or heteroaryl; or two Rzss together with the nitrogen to which they are attached form a 4-8 membered heterocyclic ring that is optionally substituted with one or more oxo and with one or more groups independently selected from RA' and RA 3 ; 10 each -Z 6 - is independently -C(RzI)- and is doublebonded to a carbocyclic P; wherein RzI is independently H, alkyl, haloalkyl, or halo; each Ea is independently -NR EcR Ed wherein R and R are each independently selected from hydrogen, alkenyloxycarbonyl, 15 alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NRCRr)alkyl, 20 (NR"Rf)alkylcarbonyl, (NR"Rf)carbonyl, (NR"Rf)sulfonyl, -C(NCN)OR', and - C(NCN)NRxRY, wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NR"Rf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, 25 and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; 30 each El is independently -OC(=0)NR EREf wherein each REc and REf are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl,

III

alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, 5 hydroxyalkylcarbonyl, (NR *Rf)alkyl, (NR*Rf)alkylcarbonyl, (NReRr)carbonyl, (NRRf)sulfonyl, -C(NCN)OR', and - C(NCN)NRxRY, wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NReRf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the 10 arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; or wherein REe and REf, together with the nitrogen atom to which 15 they are attached, form a heterocycle; each V 0 is independently H, alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, 20 hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, 25 heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxR', 30 (NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents 35 independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; 112 and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRXRY, 5 (NRxRY)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, 10 haloalkyl, and nitro; each V' is independently cyanoalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaR VC(=O)O-; RVa and R Vb are each independently selected from 15 hydrogen, alkenyl, and alkyl; each V 2 is independently haloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR VbC(=O)O-; Rva and RVb are each independently selected from 20 hydrogen, alkenyl, and alkyl; each V 3 is independently alkyl, which is substituted with one or more oxo, and which is optionally substituted with one or more groups independently selected from cycloalkyl, halo, aryl, alkenyl, and cyano; 25 each V4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V 5 is independently alkylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaRvC(=O)O-; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl; 35 113 each V6 is independently arylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 5 each V 7 is independently heterocyclosulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O; Rva and R Vb are each independently selected from hydrogen, alkenyl, and alkyl; 10 each V8 is independently spirocycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaR C(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 15 each V 9 is independently spirocycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaRvbC(=O)O-; RVa and R are each independently selected from hydrogen, alkenyl, and alkyl; 20 each V10 is independently fusedbicycliccycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR C(=O)O-; RVa and R b are each independently selected from hydrogen, alkenyl, and alkyl; 25 each V 1 is independently fusedbicycliccycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR bC(=O)O-; Rva and R b are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V' is independently bridged-bicycliccycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl; 35 114 each V 13 is independently bridged-bicyclic-cycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 5 each V 4 is independently aryloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VC(=0)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 10 each V 15 is independently arylalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR VbC(=O)O- ; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 15 each V 16 is independently cycloalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VC(=O)O-; RVa and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 20 each V " is independently cycloalkylalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 25 each V' 8 is independently heterocyclooxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and R b are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V19 is independently heterocycloalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 35 115 each V is independently heteroaryloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRva R vC(=O)O-; Rva and R b are each independently selected from hydrogen, alkenyl, and alkyl; 5 each V 2 1 is independently heteroarylalkylalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaRVbC(=O)O-; RVa and R Vb are each independently selected from hydrogen, alkenyl, and alkyl; 10 each T' is independently a spiro, branched or fused bicycloalkyl; each T2 is independently aryl; each T3 is independently heteroaryl; each T4 is independently arylalkyl; 15 each T 5 is independently haloalkyl; each T 6 is independently heteroarylalkyl; each T 7 is independently heterocycle; and each T 8 is independently heterocyclealkyl. In another specific embodiment the invention provides a compound of formula (1) which 20 comprises M 0

-W-M

0 , Mc-W-M 9 , M 9 -W-M', or M 9

-W-M

9 , M' 0 -W-M, M 0

-W-M'

0 , M'w-W-M 9 ,

M

9 -W-M'", or M' 0 -W-M'". In another specific embodiment the invention provides a compound of formula (I) wherein W is W 2 . In another specific embodiment the invention provides a compound of formula (I) 25 wherein W is W 8 . In another specific embodiment the invention provides a compound of formula (I) wherein W is Wis. In another specific embodiment the invention provides a compound of formula (I) wherein W is W 16 . 30 In another specific embodiment the invention provides a compound of formula (I) wherein W is W' 8 . In another specific embodiment the invention provides a compound of formula (I) which comprises M 0

-A-A-M

0 , M 0

-A-A-M

9 , M 9

-A-A-M

0 , or M 9

-A-A-M

9 , M' 0

-A-A-M

0 , M 0 -A-A-M'U,

M'

0

-A-A-M

9 , M 9

-A-A-M'

0 , or M' 0

-A-A-M'

0 . 116 In another specific embodiment the invention provides a compound of formula (I) wherein -A-A- is -A -A4-. In another specific embodiment the invention provides a compound of formula (I) 05_ wherein -A-A- is -A -A -. 5 In another specific embodiment the invention provides a compound of formula (1) 0- 13_ wherein -A-A- is -A A In another specific embodiment the invention provides a compound of formula (I) wherein -A-A- is -A "-A"-. In another specific embodiment the invention provides a compound of formula (I) 10 wherein -A-A- is -A -A"-. In another specific embodiment the invention provides a compound of formula (I) 13 6_ wherein -A-A- is -A -A In another specific embodiment the invention provides a compound of formula (I) wherein W is W 6 . 15 In another specific embodiment the invention provides a compound of formula (I) wherein each XA is absent where it is allowed to be absent. In another specific embodiment the invention provides a compound of formula (I) AA wherein one or two X are present and X^ is alkynyl. In another specific embodiment the invention provides a compound of formula (I) 20 wherein one or two X^ are present and XA is alkenyl. In another specific embodiment the invention provides a compound of formula (I) wherein W 6 is selected from: and 25 In another specific embodiment the invention provides a compound of formula (I) wherein W 6 is selected from: 0 and 30 117 In another specific embodiment the invention provides a compound of formula (1) wherein Wis W 8 . In another specific embodiment the invention provides a compound of formula (1) wherein W8 is selected from: 5 0 N 000 H - 0- -

-

-

/M0 0 0 0 -0 F3C -~ 00 0 0"0 0 0 \/ N N NM N \/ and N \ S S 16S 10 In another specific embodiment the invention provides a compound of formula (1) wherein W 8is selected from: 118 Oslt Hf 0~ N S H N N 0 00 0 and a 5 In another specific embodiment the invention provides a compound of formula (1) W 8 is selected from: and I0 In another specific embodiment the invention provides a compound of formula (1) W 8 is selected from: S S N N SH CN " and S N S N 0 15 In another specific embodiment the invention provides a compound of formula (1) wherein W 8 isselected from: 119 NH NH NH H H H N N H H NH and N N NN In another specific embodiment the invention provides a compound of formula (I) wherein W is W 8 that is unsubstituted. 5 In another specific embodiment the invention provides a compound of formula (I) wherein W 12 is: - /. 10 In another specific embodiment the invention provides a compound of formula (I) 15 16 wherein W is W or W In another specific embodiment the invention provides a compound of formula (I) wherein W is a ring system of formula: x =U u=U u-u u-u U U 15 x wherein: U is CH or N; and X is -CH 2 -, -C(=0)-, -CH 2

CH

2 -, -CH 2

CH

2

CH

2 -, or -CH=CH-; Al A3 wherein the ring system is optionally substituted with one or more R or R 20 In another specific embodiment the invention provides a compound of formula (1) wherein W is a ring system of formula: 120 _k=x - U>- U -Uu,> -- u or U-U U-U U x wherein: U is CH or N; and X is -OCH 2 -, -CH 2 0-, -CH 2 0CH 2 -, or CF 2 ; 5 wherein the ring system is optionally substituted with one or more R^! or RA 3 . In another specific embodiment the invention provides a compound of formula (I) wherein W is W 1 5 . In another specific embodiment the invention provides a compound of formula (I) wherein W is selected from: -10- and - 5nand 10 ~ " ~ In another specific embodiment the invention provides a compound of formula (I) wherein W is selected from: S -S dand 15 S In another specific embodiment the invention provides a compound of formula (I) wherein W is selected from: - - / and - / 20 In another specific embodiment the invention provides a compound of formula (I) wherein W is W1 8 . 121 In another specific embodiment the invention provides a compound of formula (I) wherein W is selected from: - 0 ---- 0 and 0 5 In another specific embodiment of the invention W is or 10 In another specific embodiment of the invention W is or 15 In another specific embodiment of the invention W is S - S 20 In another specific embodiment the invention provides a compound of formula (I) wherein one A is AO and one A is A 5 , wherein one XA in the A 5 is absent and the other XA in the A5 is alkynyl. 122 In another specific embodiment the invention provides a compound of formula (1) wherein -A 0

-A

5 - has the following structure: In another specific embodiment the invention provides a compound of formula (I) 5 wherein one A is A 0 and one A is A13, wherein both XA in the A 13 are absent. In another specific embodiment the invention provides a compound of formula (1) wherein -AA 1 3 - has the following structure: In another specific embodiment the invention provides a compound of formula (I) that 10 comprises A - A', wherein all X^ in both A'" are absent. In another specific embodiment the invention provides a compound of formula (I) wherein -A' 3 -A 3 - has the following structure: 15 In another specific embodiment the invention provides a compound of formula (I) that comprises A 0 - A' wherein all XA in both the A 0 and the A", are absent or alkynyl. In another specific embodiment the invention provides a compound of formula (I) wherein -A -A"- has the following structure: 20 In another specific embodiment the invention provides a compound of formula (I) that comprises one A' 3 and one A 6 wherein all XA in the A 3 are bonds. In another specific embodiment the invention provides a compound of formula (I) wherein -A -A 6- has the following structure: 25 123 In another specific embodiment the invention provides a compound of formula (I) wherein W is W2 and within the W2 one X^ is absent and one XA is RC=CR and each R is independently selected from H or alkyl. In another specific embodiment the invention provides a compound of formula (I) 5 wherein W 2 has the following structure: In another specific embodiment the invention provides a compound of formula (I) wherein W is W 2 and within the W2 one X^ is absent and one XA is selected from absent, alkynyl, or RC=CR and each R is independently selected from H or alkyl; and M is selected 10 from MO or M 9 . In another specific embodiment the invention provides a compound of formula (I) wherein MO is imidazolyl and M 9 is benzimidazolyl. In another specific embodiment the invention provides a compound of formula (I) that 9- 2_ 9 comprises a group M -W -M . In another specific embodiment the invention provides a 15 compound of formula (I) wherein the group M 9 - W 2

-M

9 has the following structure: H N N VH In another specific embodiment the invention provides a compound of formula (I) wherein A is A 0 and L is L 2 . 20 In another specific embodiment the invention provides a compound of formula (I) wherein A 0

-L

2 has the following structure: H In another specific embodiment the invention provides a compound of formula (I) that comprises two A 0 and one M is M 9 . 25 In another specific embodiment the invention provides a compound of formula (I) that comprises two A 0 and one M is M4 and another M is M 9 . In another specific embodiment the invention provides a compound of formula (1) wherein A 0

-A

0

-M

9 has the following structure: 124 H N - ~ N In another specific embodiment the invention provides a compound of formula (I) that comprises M 0

-A-A

0

-M

9 . In another specific embodiment the invention provides a compound of formula (I) wherein M 0

-A

0

-A

0

-M

9 has the following structure: H N 5 In another specific embodiment the invention provides a compound of formula (I) that comprises A-A 7

-M

9 . In another specific embodiment the invention provides a compound of formula (I) wherein A 0

-A

7

-M

9 has the following structure: N 10 In another specific embodiment the invention provides a compound of formula (I) that comprises one or two M and each M is Mo. In another specific embodiment the invention provides a compound of formula (I) that comprises one or two M and each M is imidazolyl. In another specific embodiment the invention provides a compound of formula (I) that 15 comprises one or two M and each M is M 9 . In another specific embodiment the invention provides a compound of formula (I) that comprises one or two M and each M is benzimidazolyl. In another specific embodiment the invention provides a compound of formula (I) that comprises two M wherein one M is Mo and one M is M 9 . 20 In another specific embodiment the invention provides a compound of formula (I) that comprises two M wherein one M is imidazolyl and one M is benzimidazolyl. In another specific embodiment of the invention Mo is: N 25 H 125 In another specific embodiment of the invention M9 is: H N 5 In another specific embodiment of the invention M is M" and is: H H H N N N N N O N N NN o r N. In another specific embodiment the invention provides a compound of formula (I) that 10 comprises one or two L wherein each L is L 3 . In another specific embodiment the invention provides a compound of formula (I) that comprises one or two L wherein each L is benzimidazolyl. In another specific embodiment the invention provides a compound of formula (I) wherein W is a ring system of formula: u-u "U 15 U-U U-U wherein: U is CH or N; and X is -CH 2 -, -C(=0)-, -CH 2

CH

2 -, -CH 2

CH

2

CH

2 -, or -CH=CH-; wherein the ring system is optionally substituted with one or more RA I or RA 3 . 20 In another specific embodiment the invention provides a compound of formula (I) wherein W is selected from: 126 0 In another specific embodiment the invention provides a compound of formula (I) wherein A-A is selected from: 5 and In another specific embodiment the invention provides a compound of formula (1) wherein M-W-M is: H - N

N

10 H In another specific embodiment the invention provides a compound of formula (I) wherein -A-L- is selected from: H - ~ N and H 15 1N 127 In another specific embodiment the invention provides a compound of formula (I) that has the formula E-V-Z-P-M-A-L-P-Z-V-E. In another specific embodiment the invention provides a compound of formula (I) that has the formula E-V-Z-P-M-A-L"-P-Z-V-E. 5 In another specific embodiment the invention provides a compound of formula (I) wherein W is selected from: F F 0 -F F 0 010 00 0 0 ; 0

-

0 0 00 0 N / 100 In another specific embodiment the invention provides a compound of formula (I) wherein W is W17. 128 In another specific embodiment the invention provides a compound of formula (I) wherein W is selected from: 0s - - and - / 5 In another specific embodiment the invention provides a compound of formula (I) that has the formula J-M-W-M-J. In another specific embodiment the invention provides a compound of formula (I) that has the formula E-V-Z-P-M-W-M- P-Z-V-E. 10 In another specific embodiment the invention provides a compound of formula (I) that has the formula E-V-Z-P-M-A-A-M-P-Z-V-E. In another specific embodiment the invention provides a compound of formula (I) that has the formula E-V-Z-P-M-A-L-P-Z-V-E. In another specific embodiment the invention provides a compound of formula (I) that 15 has the formula E-V-Z-P-M-A-L"-P-Z-V-E. In another specific embodiment the invention provides a compound of formula (I) wherein -M-W-M- is selected from M 0

-W-M

0 , M 0

-W-M

9 , M 9 -W-M4, and M 9 -W-M'. In another specific embodiment the invention provides a compound of formula (I) wherein -M-W-M- is selected from M 10

-W-M

0 , M4-W-M' 0 , M' 0

-W-M

9 , M 9

-W-M"

0 , and 20 M' 0

-W-M'

0 . In another specific embodiment the invention provides a compound of formula (I) wherein -M-A-A-M- is selected from M 0

-A-A-M

0 , M 0

-A-A-M

9 , M 9

-A-A-M

0 , and M 9

-A-A-M

9 . In another specific embodiment the invention provides a compound of formula (I) wherein -M-W-M- is selected from M1 0

-A-A-M

0 , M4-A-A-M' 0 , M' 0

-A-A-M

9 , M 9

-A-A-M'

0 , 25 and M' 0

-A-A-M'

0 . In another specific embodiment the invention provides a compound of formula (I) wherein each E is E 0 . In another specific embodiment the invention provides a compound of formula (1) wherein each E is -NHC(=0)Oalkyl. 129 In another specific embodiment the invention provides a compound of formula (I) wherein each E is methoxycarbonylamino. In another specific embodiment the invention provides a compound of formula (I) wherein each V is V 0 . 5 In another specific embodiment the invention provides a compound of formula (I) wherein each V is alkyl. In another specific embodiment the invention provides a compound of formula (I) wherein each V is isopropyl. In another specific embodiment the invention provides a compound of formula (I) 10 wherein each V is V 2 . In another specific embodiment the invention provides a compound of formula (I) wherein each V is haloalkyl. In another specific embodiment the invention provides a compound of formula (I) wherein each Z is Z 0 . 15 In another specific embodiment the invention provides a compound of formula (I) wherein each Z is -C(=0)-. In another specific embodiment the invention provides a compound of formula (I) wherein each M is independently a 5-membered heteroaryl ring. In another specific embodiment the invention provides a compound of formula (I) 20 wherein each M is 2,4-imidazoldiyl. In another specific embodiment the invention provides a compound of formula (I) wherein -M-A-L- is selected from: N H H - /)\ N S// NS N~ H H H and S 25 In another specific embodiment the invention provides a compound of formula (I) wherein M is M 6 . 130 In another specific embodiment the invention provides a compound of formula (I) wherein M is selected from: and 5 In another specific embodiment the invention provides a compound of formula (I) wherein M is M 7 . In another specific embodiment the invention provides a compound of formula (I) wherein M is: 10 In another specific embodiment the invention provides a compound of formula (I) wherein M is M 8 . In another specific embodiment the invention provides a compound of formula (I) wherein M is: N and N N >NH -NH 6' 0 0 15 In another specific embodiment the invention provides a compound of formula (I) wherein P is P 0 . In another specific embodiment the invention provides a compound of formula (1) wherein P is N 20 In another specific embodiment the invention provides a compound of formula (1) wherein P is: N 25 131 In another specific embodiment the invention provides a compound of formula (I) wherein P is FF N In another specific embodiment the invention provides a compound of formula (I) 5 wherein P is P'. In another specific embodiment the invention provides a compound of formula (I) wherein P is P 2 . In another specific embodiment the invention provides a compound of formula (I) wherein P is P 2 ; and pn is 1. 10 In another specific embodiment the invention provides a compound of formula (I) wherein P is P 2 ; pn is 1; and Rm1 2 is independently selected from alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, -C(=O)Rh, -C(=O)NRhRh; -C(=O)ORh, and haloalkyl. In another specific embodiment the invention provides a compound of formula (I) 15 wherein P is P 3 ; pn is l and ps is zero. In another specific embodiment the invention provides a compound of formula (1) wherein P is P 5 . In another specific embodiment the invention provides a compound of formula (I) wherein P is P 5 ; pn is 1; and Z is 0, S, S(=0), S(=0)2, or NRf. 20 In another specific embodiment the invention provides a compound of formula (I) wherein P is P 5 ; pn is 1; and Z is 0, or S. In another specific embodiment the invention provides a compound of formula (I) wherein P is P 6 . In another specific embodiment the invention provides a compound of formula (I) 25 wherein P is P 6 ; pn is 1; and Z is 0, S, S(=0), S(=0)2, or NRf. In another specific embodiment the invention provides a compound of formula (I) wherein P is P 7 wherein P7 is a [2.2.1] or a [2.2.2] ring system. In another specific embodiment the invention provides a compound of formula (1) wherein P is P 7 wherein P 7 is a [2.2.1] ring system. 30 132 In another specific embodiment the invention provides a compound of formula (I) wherein P is N 5 optionally substituted with one or more groups independently selected from R" and Re"'. In another specific embodiment the invention provides a compound of formula (1) wherein P is /N 10 " optionally substituted with one or more groups independently selected from R' 6 and Re". In another specific embodiment the invention provides a compound of formula (I) wherein P is 15 or optionally substituted with one or more groups independently selected from RP 6 and Re". In another specific embodiment the invention provides a compound of formula (1) 20 wherein P is P 8 . In another specific embodiment the invention provides a compound of formula (I) wherein P is P ; and pn is I. In another specific embodiment the invention provides a compound of formula (1) wherein P is P ; pn is 1; and ps is 2. 25 In another specific embodiment the invention provides a compound of formula (I) wherein P is P' 0 . In another specific embodiment the invention provides a compound of formula (I) wherein P is P' 0 ; pn is 1; and X is 0, S, S(=0), S(=0) 2 , CHR' 0 , or CH(R' 0

)

2 . 133 In another specific embodiment the invention provides a compound of formula (I) wherein P is P' 0 ; pn is 1; po is 1; and X is 0, S, S(=0), S(=O) 2 , CHRP'", or CH(RPio In another specific embodiment the invention provides a compound of formula (I) wherein P is P 10 ; pn is 1; po is 1; ps is 0; and X is 0, S, S(=0), S(=0) 2 , CHRP' , or CH(R'0) 2 . 5 In another specific embodiment the invention provides a compound of formula (I) wherein P is P". In another specific embodiment the invention provides a compound of formula (I) wherein P is P"; pn is 1; po is 1; ps is 0; and X is 0, S, S(=0), S(=0) 2 , CHRP' 0 , or CH(RP' 0

)

2 . In another specific embodiment the invention provides a compound of formula (I) 10 wherein P is P' 2 . In another specific embodiment the invention provides a compound of formula (1) wherein P is P2; pm is l; and pp is 1. In another specific embodiment the invention provides a compound of formula (I) wherein P is P' 3 . 15 In another specific embodiment the invention provides a compound of formula (I) wherein P is P 1 3 ; pm is 1; pn is 0; ps is 0; pp is 1; pq is 0; and X is 0, S, or S(=0)2. In another specific embodiment the invention provides a compound of formula (1) wherein P is P' 4 . In another specific embodiment the invention provides a compound of formula (1) 20 wherein P is P' 4 ; pm is 0; and pq is 0. In another specific embodiment the invention provides a compound of formula (I) wherein P is selected from: K1 N C3 134 .y>~HN/ and In another specific embodiment the invention provides a compound of formula (I) having a formula selected from: 5 T-P-Y-P-T; T-P-Y-J; J-Y-J; T-P-Y- P-Z- R9; R9-Z-P-Y- P-Z- R9; J-Y- P-Z- R9; T-P-Y-P-Z-V E; E-V-Z-P-Y-P-Z-V-E; J-Y-P-Z-V-E; T-P-L-L-P-T; T-P-L-L-J; J-L-L-J; T-P-L-L- P-Z- R9; R9-Z-P-L-L- P-Z- R9; J-L-L- P-Z- R9; T-P-L-L-P-Z-V-E; E-V-Z-P-L-L-P-Z-V-E; J-L-L-P-Z V-E; T-P-M-A-L-P-T; T-P-M-A -L-J; J-M-A -L-J; T-P-M-A-L- P-Z- R9; R9-Z-P-M-A-L- P-Z R9; J-M-A-L-P-Z-R9; L-P-M-A-L-P-Z-V-E; E-V-Z-P-M-A-L-P-Z-V-E; J-M-A-L-P-Z-V-E; T 10 B-A-L-P-T; T-B-A-L-J; T-B-A-L-P-Z- R9; R9-Z-B-A-L- P-Z- R9; T-B-A-L-P-Z-V-E; E-V-Z B-A-L-P-Z-V-E; T-P-M-A-A-M-P-T; T-P-M-A-A-M -J; J-M-A-A-M -J; T-P-M-A-A-M -P-Z R9; R9-Z-P-M-A-A-M-P-Z-R9 ; J-M-A-A-M -P-Z-R9; T-P-M-A-A-M-P-Z-V-E; E-V-Z-P-M A-A-M-P-Z-V-E; J-M-A-A-M-P-Z-V-E; T-B-A-A-M-P-T; T-B-A-A-M-J; T-B-A-A-M-P-Z R9; R9-Z-B-A-A-M-P-Z- R9; T-B-A-A-M-P-Z-V-E; E-V-Z-B-A-A-M-P-Z-V-E; T-P-M-A-A 15 B-T; T-P-M-A-A-B-Z- R9; R9-Z-P-M-A- A-B-Z-R9 J-M-A- A-B-Z-R9; T-P-M-A-A-B-Z-V-E; E-V-Z-P-M-A- A-B-Z-V-E; J-M-A-A-B-Z-V-E; T-B-A-A-B-T; T-B-A-A-B-Z-R9; R9-Z-B-A A-B-Z- R9; T-B-A-A-B-Z-V-E; E-V-Z-B-A-A-B-Z-V-E; T-P-M-W-M-P-T; T-P-M-W-M -J; J M-W-M -J; T-P-M-W-M -P-Z- R9; R9-Z-P-M-W-M-P-Z-R9; J-M-W-M -P-Z-R9; T-P-M-W M-P-Z-V-E; E-V-Z-P-M-W-M-P-Z-V-E; J-M-W-M-P-Z-V-E; T-B-W-M-P-T; T-B-W-M -J; T 20 B-W-M-P-Z- R9; R9-Z-B-W-M-P-Z- R9; T-B-W-M-P-Z-V-E; E-V-Z-B-W-M-P-Z-V-E; T-P M-W-B-T; T-P-M-W-B-Z- R9; R9-Z-P-M-W-B-Z-R9; J-M-W-B-Z-R9; T-P-M-W-B-Z-V-E; E V-Z-P-M-W-B-Z-V-E J-M-W-B-Z-V-E; T-B-W-B-T; T-B-W-B-Z-R9; R9-Z-B-W-B-Z-R9; T B-W-B-Z-V-E; E-V-Z-B-W-B-Z-V-E; T-P-M-M-P-T; T-P-M-M -J; J-M-M -J; T-P-M-M -P-Z R9; R9-Z-P-M-M-P-Z-R9; J-M-M -P-Z-R9; T-P-M-M-P-Z-V-E; E-V-Z-P-M-M-P-Z-V-E; J 25 M-M-P-Z-V-E; T-B-M-P-T; T-B-M -J; T-B-M-P-Z- R9; R9-Z-B-M-P-Z- R9; T-B-M-P-Z-V-E; E-V-Z-B-M-P-Z-V-E; T-P-M-B-T; T-P-M-B-Z-R9; R9-Z-P-M-B-Z-R9; J-M-B-Z-R9; T-P-M 135 B-Z-V-E; E-V-Z-P-M-B-Z-V-E; J-M-B-Z-V-E; T-B-B-T; T-B-B-Z-R9; R9-Z-B-B-Z-R9; and T B-B-Z-V-E; E-V-Z-B-B-Z-V-E; or a pharmaceutically acceptable salt thereof. In another specific embodiment the invention provides a compound of formula (I) having a formula selected from: 5 T-P-Y-P-T; T-P-Y-J; J-Y-J; T-P-Y-P-Z-R9; R9-Z-P-Y-P-Z-R9; J-Y-P-Z-R9; T-P-Y-P-Z-V-E; E-V-Z-P-Y-P-Z-V-E; J-Y-P-Z-V-E; R9-Z-P-Y-P-Z-V-E; T-P-L-L-P-T; T-P-L-L-J; J-L-L-J; T P-L-L- P-Z-R9; R9-Z-P-L-L-P-Z-R9; J-L-L-P-Z-R9; T-P-L-L-P-Z-V-E; E-V-Z-P-L-L-P-Z-V-E; J-L-L-P-Z-V-E; R9-Z-P-L-L-P-Z-V-E; T-P-M-A-L-P-T; T-P-M-A-L-J; J-M-A-L-J; T-P-M-A L-P-Z-R9; R9-Z-P-M-A-L-P-Z-R9; J-M-A-L-P-Z-R9; T-P-M-A-L-P-Z-V-E; E-V-Z-P-M-A-L 10 P-Z-V-E; J-M-A-L-P-Z-V-E; J-M-A-L-P-T; R9-Z-P-M-A-L-J; R9-Z-P-M-A-L-P-T; R9-Z-P-M A-L-P-Z-V-E; E-V-Z-P-M-A-L-J; E-V-Z-P-M-A-L-P-T; E-V-Z-P-M-A-L-P-Z-R9; T-P-M-A A-M-P-T; T-P-M-A-A-M-J; J-M-A-A-M-J; T-P-M-A-A-M-P-Z-R9; R9-Z-P-M-A-A-M-P-Z-R9 ; J-M-A-A-M-P-Z-R9; T-P-M-A-A-M-P-Z-V-E; E-V-Z-P-M-A-A-M-P-Z-V-E; J-M-A-A-M-P Z-V-E; R9-Z-P-M-A-A-M-P-Z-V-E; T-P-M-W-M-P-T; T-P-M-W-M-J; J-M-W-M-J; T-P-M-W 15 M-P-Z-R9; R9-Z-P-M-W-M-P-Z-R9; J-M-W-M-P-Z-R9; T-P-M-W-M-P-Z-V-E; E-V-Z-P-M W-M-P-Z-V-E; J-M-W-M-P-Z-V-E; R9-Z-P-M-W-M-P-Z-V-E; T-P-M-M-P-T; T-P-M-M-J; J M-M-J; T-P-M-M-P-Z-R9; R9-Z-P-M-M-P-Z-R9; J-M-M-P-Z-R9; T-P-M-M-P-Z-V-E; E-V-Z P-M-M-P-Z-V-E; J-M-M-P-Z-V-E; R9-Z-P-M-M-P-Z-V-E; or a pharmaceutically acceptable salt thereof. 20 In another specific embodiment the invention provides a compound of formula (I) having a formula selected from: TP-Pu-YY-Pu-TP; TP-Pu-Y -J'; J"'-YY-J'; TP-P"-YY-P"-Z'-R94; R9j-Z'-P"-YY-P"-Z"-R9q; J'"Y-pu Zv-R9q; TP-Pu-YY -P"-Z'-VW-E; E-V-Zv-P"-YY-P"-Z"-V"-Ex; J"'-Y -Pu-Zv-V"-Ex; R9V-Z"-P"-Y.

P"-Zv-V"-E'; TP-P"-L"n-L"-_P"-TP; TP-P"-L"n-L"-j"'; J"'-L"n-L"-~J'"; TP-P"- L"-L"-_P"-Z"-R9q; R9q-Z' 25 Pu-L"-L"-P"-Zv-R9q; j"-L" n-L"-P"-Zl-R9; TP-Pu-L -L n -Pu-Z'-V-EX; Ex-Vw-Zv-Pu-L"-L-nPuZ Vw-Ex; J"-L"-L"-P"-Z'-V"-Ex; R94-Z"-P"-L"-L"-P"-Zv-V"-Ex; TP-P"-Mt-As-L- P"-TP; TP-Pu-Mt As-L"-J'"; J'-Mt-As-L"-j"'; TP-P"-Mt-As-L"-P"-Z"-R94; R94-Zv-P"-ML-AS-L"-P"-Z'-R9q; J"'-M-A' L"-_P"-Z"-R9q ; TP-P"-Mt-As-L"-_P"-Z"-V"-Ex; Ex-V' -Z"-P"-M'-As-L"-_P"-Zv-V"-Ex; J"'-Mt-As-L"n P"-Zv-Vw-Ex; J"'-Mt-As-L"-nP"-TP; R9q-Zv-P"-Mt-As-L"-~j'"; R9q -Zv-P"-Mt-As-L"-_P"-TP; R9q-Z'-P" 30 Mt-As-L"n-P"-Z"-Vw-Ex; Ex-Vw-Zv-Pu-M'-As-L"-~j'"; Ex-Vw-Z"-P"-Mt-As-L"-_P"-TP; Ex-Vw-Zv-P" M-As-L"-P"-Z"-R9q; TP-P"-M'-As-As-Mt-P"-TP; TP-Pu-M-As-As-Mi-J"'; J'-M-AS-As-M-J'; T P"-Mt-As-As-Mt-P"-Z'-R9q ; R94-Zv-P"-M'-As-As-M'-P"-Z"-R94; J"'-Mt-A'-As-M'-P"-Z"-R9q ; TP Pu-Mt-As-As-Mt-Pu-Z"-V"-Ex; Ex-V"-Z"-P"-M-A'-As-M -P"-Zv-V"-Ex; J"-Mt-As-As-M-Pu-Zv V"-E'; R9-Z-P"-Mt-As-As-Mt-P"-Zv-Vw-Ex; TP-P"-Mt-Wr-Mt-P"-TP; TP-P"-Mt-Wr-Mt-J"'; J'-Mt 35 W r-Mt-j"'; TP-P"-Mt-Wr-Mt-P"-Z"-R94 ; R94-Zv-P"-M,-Wr-M,-P"-Z'-R9q; J'"-Mt-Wr-M'-P"-Zv-R9q; 136 TP-P"-M'-Wr-M'-P"-Z'-V"-E'; E'-V"-Zv-P"-M'-Wr-M'-P"-Z"-V"-Ex; J"'-Mt-Wr-Mt-P"-Z"-V"-Ex; R94-Z'-P"-M,-Wr-M'-P" Zv-V' -Ex; T'-P"-Mi-M'-P"-TPTPP-Pu-Mt-M-JM; J'-M-Mt-J"M; TP-Pu-M M'-P"-Z"-R9'; R9q-Z'-P"-Mt-M'-P"-Z'-R9'; J"'-M-Mi-P"-Z'-R9'; TP-P"-Mt-M1-P"-Z"-V"-E'; E' V"-Z"-P"-M'-M'-P"-Zv-V"-Ex; J"-Mt-Mt-P"-Z"-V"-Ex; R9 4-Z"-P"-Mt-Mt-P"-Z"-V"-E or a 5 pharmaceutically acceptable salt thereof. In another specific embodiment of the invention s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, 18, 19, 20, or 21. In another specific embodiment of the invention r is 1, 2, 3, 4, 5, 6, 8, 13, 14, 15, 16, 17, 18, 19, or 20. 10 In another specific embodiment the invention provides a compound which is a prodrug or a pharmaceutically acceptable salt of a compound of formula (I). In one specific embodiment the invention provides a compound of formula (I) wherein W is not a group of the following formula:

RA

4

RA

4 ' 15 (RA 3 )bb (RA 3 )bb wherein: each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, a b ab) 20 (NR R )alkyl, and (NRaR )carbonyl; Ra and R are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each bb is independently 0, 1, 2, or 3; and 25 R and R A4, together with the atoms to which they are attached, form a five- to eight membered unsaturated ring optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the five- to eight-membered unsaturated ring is optionally substituted with one, two or three substituents independently selected from R 3, oxo and a spirocycle. 30 In one specific embodiment the invention, the sum of m, n, p, q, s, t, u, v, w, x, and y is not 0 when W is a group of the following formula: 137

RA

4

RA

4 '

(RA

3 )bb

(RA

3 )bb wherein: each R is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, 5 arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRa R b)alkyl, and (NRaRb)carbonyl; Ra and Rb are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 10 each bb is independently 0, 1, 2, or 3; and RA4 and RA 4 , together with the atoms to which they are attached, form a five- to eight membered unsaturated ring optionally containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the five- to eight-membered unsaturated ring is optionally substituted with one, two or three substituents independently selected from RA 3 , oxo 1 5 and a spirocycle. In one embodiment when M comprises an imidazole ring it is connected to P through the 2-position. In one embodiment when M or L comprises a benzimidazole it is connected to P through the 2-position. 20 138 Compounds of formula (la) In one embodiment of the invention, the compound of formula (I) is a compound of formula (1a): E-V-Z-P-M-W-M-P-Z-V-E (la) 5 wherein: W is a bond or -Wr_ each M is selected from -M; each P is selected from -Pu; 10 each Z is selected from -Z"; each V is selected from -V'; each E is selected from -E'; each r is 1,2,3,4,5,6,7,8,9, 10,11,12, 13, 14, 15, 16,17,18, 19, or20; each t is0, 1,2,3,4,5,6,7,8,9, 10, or 11; 15 each u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, or 14; each v is 0, 1, 2, 3, 4, 5, or 6; each w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21; each x is 0 or I ; wherein the sum of r, t, u, v, w, and x is not 0; 20 each WI is independently -XA_: wherein: 25 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 2 is independently: 30 XA 20-XA wherein: 139 each H20 is independently is independently a fused aromatic bicyclic carbocycle, which is optionally substituted with one or more groups independently selected from RAl and RAl; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, 5 CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 3 is independently: XA--H21-XA 10 wherein: each H 2 ' is independently a fused bicyclic carbocyclic ring system wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is 15 optionally substituted with one or more groups independently selected from oxo, RAl and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 20 each W 4 is independently: XAH22-XA wherein: 25 each H 2 2 is independently a fused aromatic bicyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from RA' and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, 30 CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 140 each W 5 is independently:

XAH

23 -XA. wherein: 5 each H 23 is independently a fused bicyclic ring system comprising at least one heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, RAI and RA 3 ; and 10 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 6 is independently: 15 -XA H 2 4 .. XA. wherein: each H 24 is independently a fused unsaturated, partially unsaturated or 20 saturated tricyclic carbocycle, which is optionally substituted with one or more groups independently selected from RA and RA 3 ; and each X^ is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 25 each W 7 is independently: XA H 26-XA.. wherein: 30 each H 26 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system which ring system is optionally substituted with one or more groups independently selected from oxo, RAI and RA 3 ; and 141 each X^ is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 5 each W 8 is independently: - XA 27-XAA wherein: 10 each H 27 is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from RA' and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, 15 CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W 9 is independently: XA--H29-XAA 20 wherein: each H29 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that contains one or more heteroatoms; and 25 each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W' 0 is independently -H 3 0

=C=H-

3 1 30 wherein each of -H 3 0 and H 31 is independently a saturated 6-membered heterocyclic ring comprising one or more heteroatoms, which ring is optionally substituted with oxo; each W" is independently -H 32

=C=H-

33 wherein each of -H 32 and H 33 is independently a saturated 5-membered heterocyclic 35 ring comprising one or more heteroatoms, which ring is optionally substituted with oxo; 142 each W1 2 is independently an anti-aromatic monocyclic or fused carbocyclic ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from R and RA 3 ; 5 each W' 3 is independently an phenyl ring that is optionally substituted with one or more groups independently selected from RA1 and RA 3 ; each W 14 is independently a 5 or 6 membered heteroaryl ring that is optionally substituted 10 with one or more groups independently selected from RA and RA 3 ; each W 15 is independently a fused unsaturated, partially unsaturated or saturated tetracyclic carbocyclic ring, which ring system is optionally substituted with one or more groups independently selected from oxo, RA1 and RA 3 ; 15 each W 1 6 is independently a fused unsaturated, partially unsaturated or saturated tetracyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, RAI and RA 3 ; 20 each W 17 is independently a fused unsaturated, partially unsaturated or saturated pentacyclic carbocyclic ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, RA I and RA 3 ; each W1 8 is independently a fused unsaturated, partially unsaturated or saturated pentacyclic 25 heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; each W 1 9 is independently a fused unsaturated, partially unsaturated or saturated hexacyclic carbocyclic ring system, which ring system is optionally substituted with one or more groups 30 independently selected from oxo, RA' and RA3; each W 20 is independently a fused unsaturated, partially unsaturated or saturated hexacyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R^t and R^ 3 ; 35 143 each MO is independently a five membered heteroaryl group optionally substituted with one or more alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NRaR)carbonyl and trialkylsilylalkoxyalkyl; 5 each M' is independently selected from -C(=O)NH-, -C(=O)NH-C(R

M

)

2 -, -NHC(=O) -,

-C(RM)

2 NHC(=O)-, -NHC(=O)N Rm -, -NHC(=0)O -; wherein each Rm is independently selected from H and alkyl; each M 2 is independently a six-membered heteroaromatic ring, which is optionally substituted 10 with one or more groups independently selected from RA and RA 3 ; each M 3 is independently: H N O 15 each M 4 is independently: N OH 20 each M 5 is independently: H N N 25 wherein the bond designated with --- is fused to a ring defined for P; each M 6 is independently a bicyclic bridged ring system comprising 5-15 atoms wherein at least one of the atoms is a heteroatom; 30 each M 7 is independently a pyrid-di-yl; 144 each M 8 is independently partially saturated or a saturated five-membered ring that comprises one or more heteroatoms and that is optionally substituted with one or two oxo; 5 each M 9 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more RP,1 each M' 0 is independently a five membered heteroaryl group; 10 each M" is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more oxo halo, -RM 7 , -OR7 -SR M 7 , -N(Rm 7 )2, -CF 3 , -CC 3 , -OCF 3 ,-CN, -NO 2 , -N(R M 7 )C(=O)R M 7 , -C(=O)R M 7 , -OC(=O)R M7M7 7 M77 M7 , -C(O)OR m', -C(=0)NR m', -S(=0)R M7, -S(=0) 2 0R M7, -S(=0) 2 R M7, -OS(=0) 2 0R , or -S(=0) 2 NR M7' 15 each R M7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; each P 0 is independently: (RP)ps (R6)pq F -X IX N pn Np Pm (R P5 (RP 6 )pq P o PP or R

P

8 20 wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHR ' 0 , and C(RPl) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR 0 , and C(R '') 2 ; each R'P" is independently selected from alkoxy, alkyl, aryl, halo, 25 haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 145 each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, PaPb halo, haloalkyl, hydroxy, and -NRP'R , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; RPa and R Pb are each independently 5 H, alkyl, aryl, or arylalkyl; or RPa and RPb taken together with the atom to which they are attached form a heterocycle; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 10 R'7 and RP 8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NRPaR )alkyl; or R7 and R 8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NRe ', 0, and S; wherein RPz is selected from hydrogen and alkyl;

R"

9 is selected from hydrogen and alkyl; 15 each P' is independently:

(R

1 1)pS /-x N pn wherein: 20 X is selected from 0, S, S(O), SO 2 , CH 2 , CHRP' 0 , and C(R 10

)

2 ; provided that when pn is 0, X is selected from CH 2 , CHRP'", and C(R ') 2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, Pa RPb haloalkyl, hydroxy, and -NRR' , wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered 25 ring is optionally substituted with one or two alkyl groups; at least one RP" is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (N RhRh)alkyloxy, cyanoalkoxy, hh h h 30 cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR R , (NR'R )akyl, (NRR h)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 146 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 5 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=O)R, -C(=O)NRhRh; and the remaining Rp'" are independently selected from R 5 , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, 10 heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to 15 form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; each P 2 is independently: 20 (RP 2)P I-N N pn wherein: 25 each RE" is independently selected from R 5 , R ",-C(=O)ORh, cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, 30 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 147 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; 5 each P 3 is independently a ring of the formula: (RP1 3 )PS ') N pn 10 wherein: the ring is substituted with one or more oxo group; each R P13 is independently selected from R"P, cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, 15 heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come 20 together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 0, 1, 2, 3, or 4; pn is 0, 1, or 2; each P 4 is independently a ring of the formula: 25 Rf N N pn 148 wherein: the ring is optionally substituted with one or more groups R 14 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an 5 adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups RP' 4 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; pn is 0, 1, or 2; 10 each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NR R, -S(=0) 2 Rh, C(=O)Rh, C(=0)ORh, -C(=O)NRhRh ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, 15 alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 5 is independently a ring of the formula: 20 ( z wherein: the ring is optionally substituted with one or more groups R 15 that are 25 independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups Rei 5 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 30 membered carbocyclic or heterocyclic ring; pn is 0, l, or 2; Z is 0, S, S(=0), S(=0) 2 , or NRr, 149 each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NR R, -S(=0) 2 R h, C(=0)R , C(=O)ORh, -C(=O)NRhRh ; each Rh is independently -H, alkyl, 5 alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 10 each P 6 is independently a ring of the formula: ( z wherein: 15 the ring is substituted with one or more oxo and is optionally substituted with one or more groups RP' 6 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPa R , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 20 Z is 0, S, S(=O), S(=0) 2 , or NRf; pn is 0, 1, or 2; each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NR R', 25 -S(=0) 2 R h, C(=0)R h, C(=0)OR , -C(=O)NRhRh ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 30 each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R P6and R" I; 150 each P 8 is independently a ring of the formula: (R 1 3 )PS N)pn 5 wherein: ps is 2, 3, 4, 5, or 6; each RP 3 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR , wherein the alkyl can optionally form a fused 10 three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups RP 13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring; 15 each P1 0 is independently: (RP5

(RP

6 )pq NPo N' N)I 20 wherein: X is selected from 0, S, S(0), SO 2 , CH 2 , CHRP' 0 , and C(RP' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR"' 0 , and C(RP' 0

)

2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three 25 to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 151 each RPS and RP6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 5 pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; each P" is independently: 10 (R P5)P (RP6)pq P o( pP( x IN ))pn N )P wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHRP' 0 , and C(RP' 0

)

2 ; 15 provided that when pn or pm is 0, X is selected from CH 2 , CHRE' 0 , and C(R ' 0

)

2 ; each RP 10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 20 each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRP"R b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; 25 pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; each P' 2 is independently: 152

(RP

6 )pq (RP1 )PS PP N pm wherein: 5 each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR P, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 10 pm is independently 0, 1, or 2; pp is independently 1, 2, or 3; ps is 1, 2, 3, or 4; RP1 1is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRh R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 15 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhhRh, (NRhRh)alkyl, (NRhhRh)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 20 dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=O)Rh, 25 -C(=0)NRh R; and the remaining RP'' are independently selected from R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cyc loalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, 30 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 153 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P' 3 is independently: 5 (RP1 1) (R P6)pg pn 6PP N pm wherein: X is selected from 0, S, S(O), S02, or NRh 10 each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 15 pq is independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2 but the sum of pn and pm is greater than zero; pp are independently 1, 2, or 3; ps is 1, 2, 3, or 4; 20 each Re'' is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhR', (NRhhRh)alkyl, (NRhh Rh)carbonyl, wherein each Rh is independently 25 -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, 30 alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 154 dialkylaminoalkyl, sulfonylalkyl, (NRhRh)Sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=O)Rh -C(=O)NR R h, R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclyisulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, 5 cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered 10 heterocyclic ring; each P' 4 is independently: R (R 6 )pq N Pm 15 wherein: the ring is substituted with one or more oxo group; X is NR ; each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, 20 heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhR , -S(=0) 2 Rh, C(=O)Rh, C(=O)ORh, -C(=O)NRh Rh ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 25 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRpb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is 30 optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 155 pm is independently 0, 1, or 2; ps is 1, 2, 3, or 4; R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRh Rh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 5 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or sulfonylalkyl; and when 10 two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each -Z 0 - is -C(=O)- or -C(=S)-; 15 each -Z'- is independently a bond, or -C(Rzl) 2 -; wherein each Rzi is independently H, alkyl, haloalkyl, or halo; each -Z 2 - is independently saturated or partially unsaturated (C 3

-C

8 )cycloalkyl that is optionally substituted with one or more groups independently selected from RA1 and RA 3 ; 20 each -Z 3 - is independently saturated, partially unsaturated, or aromatic 4-8 membered heterocyclic or heteroaryl ring that is optionally substituted with one or more groups independently selected from RA' and RA 3 ; 25 each -Z 4 - is independently:

RZ

4 wherein each RZ4 is independently H, alkyl, cyano, aryl, or heteroaryl; 30 each -Z 5 - is independently: 156 RzN -RZ 5 N wherein each RZ 5 is independently H, alkyl, cyano, aryl, or heteroaryl; or two RZss together with the nitrogen to which they are attached form a 4-8 membered heterocyclic ring that is 5 optionally substituted with one or more oxo and with one or more groups independently selected from RA and RA 3 ; each -Z 6 - is independently -C(RzI)- and is doublebonded to P; wherein Rzi is independently H, alkyl, haloalkyl, or halo; 10 each E is independently -NREcREd wherein R Ecand REd are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, 15 cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NReRr)alkyl, (NReRr)alkylcarbonyl, (NReRf)carbonyl, (NReRf)sulfonyl, -C(NCN)OR', and - C(NCN)NRxRY, wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the 20 arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NRcRf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the 25 heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; each E' is independently -OC(=0)NREeREf wherein each RFe and R Efare each 30 independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, 157 formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR'R )alkyl, (NRCRf)alkylcarbonyl, (NReRr)carbonyl, (NR*Rr)sulfonyl, -C(NCN)OR', and - C(NCN)NRR , wherein R' is selected from alkyl and unsubstituted phenyl, 5 and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NReRf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the 10 heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; or wherein REe and REf, together with the nitrogen atom to which they are attached, form a heterocycle; 15 each V 0 is independently H, alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl 20 part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, 25 arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the 30 arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, 35 arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, 158 heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR RY, (NRxRY)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the 5 heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; each V 1 is independently cyanoalkyl, which is optionally substituted with one or more groups 10 independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and R b are each independently selected from hydrogen, alkenyl, and alkyl; each V 2 is independently haloalkyl, which is optionally substituted with one or more groups 15 independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR VbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 3 is independently alkyl, which is substituted with one or more oxo, and which is 20 optionally substituted with one or more groups independently selected from cycloalkyl, halo, aryl, alkenyl, and cyano; each V 4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 25 heteroaryl, hydroxy, and NRvaR C(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 5 is independently alkylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 30 heteroaryl, hydroxy, and NRvaR vbC(=O)O; R Va and R b are each independently selected from hydrogen, alkenyl, and alkyl; each V 6 is independently arylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 159 heteroaryl, hydroxy, and NR vaR C(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 7 is independently heterocyclosulfonylalkyl, which is optionally substituted with one or 5 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 8 is independently spirocycloalkyl, which is optionally substituted with one or more 10 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and R b are each independently selected from hydrogen, alkenyl, and alkyl; each V 9 is independently spirocycloalkylalkyl, which is optionally substituted with one or 15 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and R b are each independently selected from hydrogen, alkenyl, and alkyl; each V 1 0 is independently fusedbicycliccycloalkyl, which is optionally substituted with one or 20 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and R are each independently selected from hydrogen, alkenyl, and alkyl; each V 1 is independently fusedbicycliccycloalkylalkyl, which is optionally substituted with 25 one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRva R vC(=O)O-; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl; each V2 is independently bridged-bicycliccycloalkyl, which is optionally substituted with one 30 or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V 13 is independently bridged-bicyclic-cycloalkylalkyl,] which is optionally substituted 35 with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, 160 Va Vb V cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvR C(=0)O-; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl; each V1 4 is independently aryloxyalkyl, which is optionally substituted with one or more 5 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; Rva and R b are each independently selected from hydrogen, alkenyl, and alkyl; each V' 5 is independently arylalkoxyalkyl, which is optionally substituted with one or more 10 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V' 6 is independently cycloalkyloxyalkyl, which is optionally substituted with one or more 15 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 7 is independently cycloalkylalkyloxyalkyl, which is optionally substituted with one or 20 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V1 8 is independently heterocyclooxyalkyl, which is optionally substituted with one or 25 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRVbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V' 9 is independently heterocycloalkyloxyalkyl, which is optionally substituted with one 30 or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR VbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V 20 is independently heteroaryloxyalkyl, which is optionally substituted with one or more 35 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 161 heteroaryl, hydroxy, and NRaR vbC(=0)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; and 5 each V 2 1 is independently heteroarylalkylalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR VbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; or a pharmaceutically acceptable salt, or prodrug thereof. 10 In another specific embodiment of the invention r is 1, 2, 3, 4, 5, 6, 8, 13, 14, 15, 16, 17, 18, 19, or 20. In another specific embodiment of the invention W is W 2 . In another specific embodiment the invention W is W 4 . In another specific embodiment of the invention W is W 8 . 15 In another specific embodiment of the invention W is W 6 . In another specific embodiment of the invention W is W' 5 . In another specific embodiment of the invention W is W 16 In another specific embodiment of the invention W' 6 is selected from: S -S and \/ S 20 S In another specific embodiment of the invention W is W 17 . In another specific embodiment of the invention W is W' 8 . In another specific embodiment of the invention W 6 is selected from: and 25 In another specific embodiment of the invention W 6 is selected from: 0 and 162 In another specific embodiment of the invention W 8 is selected from: CF3 - N 0 06 0 H - - / N 0 0 o0 0 0 \/ N~ NN N H

F

3 C 00 00 S \\ S,(/ 0 S 0 0o" 0 0 \0 0 N H \ N) 5 C Cr 3 H NM\ N \/ and N S S S In another specific embodiment of the invention W 8 is selected from: 0 H\ 0~ N S H KNM N 100 163 N and 0 S8 In another specific embodiment of the invention W is selected from: N=N and / \/ \ In another specific embodiment of the invention W 8 is selected from: S S ' N 0 N I ,\N I and \ N0 SS N 0 In another specific embodiment of the invention W 8 is selected from: 10 NH NH N "N N "' H H N HHN NH and N NH In another specific embodiment of the invention W is W 8 that is unsubstituted. In another specific embodiment of the invention W1 is: 15 In another specific embodiment of the invention W is W1 5 or W 16 . In another specific embodiment of the invention W is a ring system of formula: 164 X U=U U=U -U or - -. U U-U U-U U ( U wherein U is CH or N; and X is -CH 2 -, -C(=0)-, -CH 2

CH

2 -, -CH 2

CH

2

CH

2 -, or -CH=CH-; 5 wherein the ring system is optionally substituted with one or more R or RA 3 In another specific embodiment of the invention W is selected from: and _ In another specific embodiment of the invention W is selected from: 10 and In another specific embodiment of the invention W is selected from: 0 ---- 0 and 0 15 In another specific embodiment of the invention W is W 2 and within the W 2 one XA is absent and one XA is RC=CR and each R is independently selected from H or alkyl. In another specific embodiment of the invention W 2 has the following structure: 165 In another specific embodiment of the invention W is W2 and within the W2 one XA is absent and one XA is selected from absent, alkynyl, or RC=CR and each R is independently selected from H or alkyl; and M is selected from MO or M 9 . In another specific embodiment of the invention W is a ring system of formula: 5 U-U \,U Uu U-U U-U wherein: U is CH or N; and X is -CH 2 -, -C(=0)-, -CH 2

CH

2 -, -CH 2

CH

2

CH

2 -, or -CH=CH-; 10 wherein the ring system is optionally substituted with one or more R or RA. In another specific embodiment of the invention W is selected from: 0 and In another specific embodiment of the invention W is selected from: F F 0 0 15 / 166 00 /0 i\ \ / 0 0 0 0 0 and N 0 In another specific embodiment of the invention W is selected from: 5 and In another specific embodiment of the invention W is 10 or 167 In another specific embodiment of the invention W is or 5 In another specific embodiment of the invention W is I \/ or J\ 10 In another specific embodiment of the invention W is or A 15 In another specific embodiment of the invention W is S - S 20 In another specific embodiment of the invention each XA within W is absent. In another specific embodiment of the invention t is 0, 9, 10, or 11. 168 In another specific embodiment of the invention Mo is imidazolyl and M 9 is benzimidazolyl. In another specific embodiment of the invention the compound of formula (Ia) comprises a group M 9

-W

2

-M

9 . 5 In another specific embodiment of the invention M is Mo. In another specific embodiment of the invention M is imidazolyl. In another specific embodiment of the invention M is M 9 . In another specific embodiment of the invention each M is benzimidazolyl. In another specific embodiment of the invention one M is Mo and one M is M 9 . 10 In another specific embodiment of the invention one M is imidazolyl and one M is benzimidazolyl. In another specific embodiment of the invention each M is independently a 5-membered heteroaryl ring. In another specific embodiment of the invention each M is 2,4-imidazoldiyl. 15 In another specific embodiment of the invention M is M 6 . In another specific embodiment of the invention M is selected from: and N In another specific embodiment of the invention M is M 7 . 20 In another specific embodiment of the invention M is: 8 In another specific embodiment of the invention M is M In another specific embodiment of the invention M is: N" and N N ,NH --NH 25 o0 00 In another specific embodiment of the invention M is: N H 169 In another specific embodiment of the invention M9 is: H N 5 In another specific embodiment of the invention M is M" and is: H H H N N N N * N . N N Nor wherein * designates the site of connection to P. 10 In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula (Ia I): E-V-Z-P-M 0

-W

6

-M

9 -P-Z-V-E (lal). In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula (la2): E -VO-Z -P-M -W6-M -P-Z 0

-V

0

-E

0 (la2) In another specific embodiment of the invention the compound of formula (1a) is a 15 compound of formula (1a3): E-V-Z-P 0

-M

0

-W

6

-M

9

-P

7 -Z-V-E (la3). In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula (la4): E 0

-V

0

-Z

0

-P

0

-MO-W

6

-M

9

-P

7

-Z

0

-V-E

0 (a4). In another specific embodiment of the invention the compound of formula (1a) is a compound of formula (la5): 20 H O O NVoj P-M-W-M-P VOs O I(Ia5) In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula (Ia6): 25 170 0 ON N M-W-M N H00. In another specific embodiment of the invention the compound of formula (1a) is a compound of formula (la7): 5 0 O N, H N W. O (la7) H H O In another specific embodiment the invention provides a compound of formula (la5), 10 (a6) or (1a7), wherein W is W 2 . In another specific embodiment the invention provides a compound of formula (a5), (a6) or (1a7), wherein W is W 6 . In another specific embodiment the invention provides a compound of formula (a5), (a6) or (1a7), wherein W is W 8 . I 5 In another specific embodiment the invention provides a compound of formula (la5), (a6) or (Ia7), wherein W is W 16 . In another specific embodiment the invention provides a compound of formula (la5), (a6) or (1a7), wherein W'6 is selected from: S -S ~ 20 and \/ S 20 S In another specific embodiment of the invention the compound of formula (1a) is a compound of formula (la9): 171 0 N--- o H P-M-W-M _ I (1a9) 0 v-N o 0 0 In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula (lal 0): P-M-W-M- H o v-- os(la10) 0 5 In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula (Ial 1): ov P -- M-W-M (1all) O v--N O 0 0 10 In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula (Ial2): O 1 --- O Hpo-M--W--M-- 7 0 V-Na12) 0 In another specific embodiment of the invention the compound of formula (Ia) is a 15 compound of formula (la1 3): 172 H ___N H, H w o v- No (1a13) H 0 In another specific embodiment of the invention the compound of formula (1a) is a compound of formula (la1 4): 5 H o H V w / V- o (1a14) H 0 In another specific embodiment of the invention the compound of formula (1a) is a compound of formula (lal5): H ___N 7 0 - 0 H H N w \ N v (1a15) 10 H 0 In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula (Ia16): H 0 -: 0

N>P

7 H W / N 0 (1a16) N P H 0 15 In one embodiment of the invention, the compound of formula (la) is a compound of formula (la8): Ex-V"-Z'-P"-M'-Wr-Mt-P" -Z' -Vwl -Ex (la8) wherein: 20 r is 2, 4, 6, 8, or 16; t is 0 or 10; u is 0, 1, 3, 5, 7, 8, 10, or l; v is 0; w is 0, 1, 2, 3, 4, or 5; x is 0; tl is 9; ul is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; wl is 0, l, 2, 3, 4, or 5; and xl is 0. 173 In one embodiment of the invention, the compound of formula (1a) is a compound of formula (a8) wherein: r is 6; t is 0 or 10; u is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; w is 0, 1, 2, 3, 4, or 5; x is 0; tI is 9; ul is 0, 1, 3, 5, 7, 8, 10, or I1; v is 0; wl is 0, 1, 2, 3, 4, or 5; and xl is 0. In one embodiment of the invention, the compound of formula (Ia) is a compound of 5 formula (a8) wherein E 0 is: H N O N - or 0 In one embodiment of the invention, the compound of formula (Ia) is a compound of formula (a8) wherein M is: N 10 H In one embodiment of the invention, the compound of formula (Ia) is a compound of formula (a8) wherein M9 is: H N In one embodiment of the invention, the compound of formula (1a) is a compound of 15 formula (1a8) wherein r is 6 and W6 is: F F 0 10 or -o In one embodiment of the invention, the compound of formula (1a) which is selected 20 from: 174 o H o ---- V~> N ~ H 0 H NN O -V>0O\V---O_ O H H 0 HN pN H H HI o -O V- - O H N H N O n H H N N H P I N0 V N O n d formula (1a8) wherein r is 2 and W is: 5 In one embodiment of the invention, the compound of formula (Ia) is a compound of formula (la8) which is: 0 ~H0 NO . H p-- N~ I H -- - 0" 10 In one embodiment of the invention, the compound of formula (Ia) is a compound of formula (la8) wherein r is 4 and W2 is: 175 In one embodiment of the invention, the compound of formula (Ia) is a compound of formula (a8) which is: v 0 V-N O H 0 5 In one embodiment of the invention, the compound of formula ([a) is a compound of formula (a8) wherein r is 8 and W 8 is: 0 S or In one embodiment of the invention, the compound of formula (la) is a compound of 10 formula (a8) which is selected from: H 0 0--vO V--- H O H ~ N / / 0N 0" H H 0 H O H 0 and o!i% H~JJ\ 0 H 0 0 - --- P V - O In one embodiment of the invention, the compound of formula (Ia) is a compound of formula (Ia8) wherein r is 16 and W'0 is: 15 176 0 i\/ \ / -or 0 In one embodiment of the invention, the compound of formula (1a) is a compound of formula (la8) which is selected from: 0r N H 0 --- v 0 V N O0 0 -N RH --- I- 0 V-N 0" O -- - v O 0 H0 N, H and 0 N-V-- O N- P H~~ N \/ / \_ H H \ V-N 0 5 H O In one embodiment of the invention, the compound of formula (1a) is a compound of formula (la8) wherein: r is 6, or 8; t is 0 or 10; u is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; w is 0, 1, 2, 3, 4, or 5; x is 0; tI is 9; ul is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; wl is 0, 1, 2, 3, 4, or 5; and xl is 10 0. In- one embodiment of the invention, the compound of formula (1a) is a compound of formula (la8) wherein: r is 6, or 8; t is 0 or 10; u is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; w is 1, 2, 3, 4, or 5; x is 0; tl is 9; ul is 0, 1, 3, 5, 7, 8, 10, or l1; v] is 0; wl is 0, 1, 2, 3, 4, or 5; and xl is 0. In one embodiment of the invention, the compound of formula (Ia) is a compound of 15 formula (la8) wherein: r is 6, or 8; t is 0 or 10; u is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; w is 0, 1, 2, 3, 4, or 5; x is 0; tl is 9; ul is 1, 3, 5, 7, 8, 10, or l1; v Iis 0; w is 0, 1, 2, 3, 4, or 5; and x is 0. In one embodiment of the invention, the compound of formula (Ia) is a compound of formula (Ia8) wherein: r is 6, or 8; t is 0 or 10; u is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; w is 1, 2, 3, 4, or 5; x is 0; tI is 9; ul is 1, 3, 5, 7, 8, 10, or 11; vI is 0; wl is 0, 1, 2, 3, 4, or 5; and xl is 0. 20 In one embodiment of the invention, the compound of formula (1a) is a compound of formula (la8) which is selected from: 177 F F 0~~~~- O s-. 0 H I IN > H Oo _ Nt 0 V-N 0 . __H Ft 0 N-V ON R H \/ \/ P~~~ NN V-N O" H . O V-N 0 " HO ad 0 H r H O V N I N 0 V-N 0 0 H 0 H NO . H 07 P N o V N 0II H 0 ~N - 0R -N 0 H 5 0 N -V 178 In one embodiment of the invention, the compound of formula (1a) is a compound of formula (Ia8) wherein: r is 6, or 8; t is 0 or 10; u is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; w is 0, 1, 2, 3, 4, or 5; x is 0; tl is 0 or 10; ul is 1, 3, 5, 7, 8, 10, or 11; v] is 0; w is 0, 1, 2, 3, 4, or 5; and x1 is 0. 5 In one embodiment of the invention, the compound of formula (1a) is a compound of formula (la8) which has the formula: 0 .W HN P N 0 V- - O" H 0 In one embodiment of the invention, the compound of formula (1a) is a compound of 10 formula (1a8) which is selected from: O -- v 0NS S N H 0O -- N Os H H N~~ / H : r % ---- N V- Oand 0 N- 0 ~ / 0 H H . PN 0 N N 0 V N y0" V~~~\ /~j N\0 and NN N 0 pI~ H 0 In one embodiment of the invention, the compound of formula (1a) is a compound of formula (Ia8) wherein: r is 16 or 18; t is 0 or 10; u is 0, 1, 3, 5, 7, 8, 10, or 11; v is 0; w is 0, 1, 2, 15 3 , 4 , or 5; x is 0; tl is 0 or 10; ul is 0, 1, 3, 5, 7, 8, 10, or 11; v I is 0; wl is 0, 1, 2, 3, 4, or 5; and xl is 0. In one embodiment of the invention, the compound of formula (1a) is a compound of formula (Ia8) wherein r is 16 and W 1 6 is: 179 -0or 00 In one embodiment of the invention, the compound of formula (Ia) is a compound of formula (la8) which is selected from: 5 O -V- - 0 H H N N R >~p H 0 V-N O O N- ---- V o O y 0N o V'-OO Va H H I 08 H 0 H H V~.\N- N H P NH - r I NN I 0 H N Np, PN H I H 0 VN 0" 0 0 180 H o

-

V--N 1 H V-Y0 p \ 0and H H NA N % H - H 0 V--N O 0 In one embodiment of the invention, the compound of formula (1a) is a compound of formula (la8) wherein r is 18 and W 18 is: 5 or- \ In one embodiment of the invention, the compound of formula (1a) is a compound of formula (la17): 10 E'-V"-ZO-P"-Mt-W -M-2_Pu-ZO-V"-Eo (1al7) wherein: each u is independently 0, 1, 3, 5, 7, 8, 10, or I 1; each w is independently 0, 1, 2, 3, 4, or 5; 15 t is 0, 9, 10, or 11; W is a bond; M12 is a fused unsaturated, partially unsaturated or saturated hexacyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; 20 each R^t is independently selected from cyano, nitro, SOR 4 , SOR 4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, 25 arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaR )alkyl, and (NRaRb)carbonyl; Ra and R b are each independently selected from the group 181 consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 5 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl. In one embodiment the invention provides a compound of formula (Ial7) wherein M'" is: - x-x XXX \ / \ / \ / N N orN XX X-X H wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CI-1 2 -0, 0-CH 2 , CH 2

-CH

2

-CH

2 , and 10 CH 2 -0-CH 2 . In one embodiment the invention provides a compound of formula (la17) wherein MO is: H N In one embodiment the invention provides a compound of formula (la17) which is 15 selected from: N x-x X-X 0 / 0p)IIN V- O HN-V N P-N H 0 HN-H N X-X H O 0 182 N\

-

-NO HN-V H- \ x--x 0 0 and HN- H - '\ / 0 HN- NN HN-x- x-x 0\ wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, 0-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 5 In one embodiment the invention provides a compound of formula (la17) wherein M 9 is: H In one embodiment the invention provides a compound of formula (la17) which is selected from: - x-x X-X0 O O -P N / ,tNP HN-V H 0 0 /O HN-V H X-X H 0 HN8 0 183 HN-VH -X H OIand N -N O H x-x 0 HN-V 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, O-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 5 In one embodiment the invention provides a compound of formula (Ial7) wherein M" is: H0 wherein X-X is selected from 0, CH 2 , CIH=CH, CH 2

-CH

2 , CH 2 -O, 0-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; and wherein * designates the site of connection to P. In one embodiment of the invention, the compound of formula (Ia) is selected from: 0 H N P O N -- V O H NH H p / 1 N 0 V-NOO H V\ - 0H and H

-----

V O_ V0, O 10 0 . In one embodiment the invention provides a compound of formula (al8):

E

0 -V 0 v-EH (1a18) 15 wherein: each P is independently selected from: 184 NA NC/ N N N and each M is independently M, M 9 , or M' 0 ; and W 6 is selected from: 5 and or a pharmaceutically acceptable salts or prodrug thereof. In one embodiment the invention provides a compound of formula (la1 9): 0 HN-V O $P-M-V\-M-P O V-NH 0-0 10 0 (Ia]9) wherein: each P is independently selected from: N NC O NsA and 15 each M is independently M 0 , M 9 , or M 1 0 ; and

W

8 is selected from: 185 Y yand or a pharmaceutically acceptable salts or prodrug thereof. In one embodiment the invention provides a compound of formula (1al8) or (lal 9) wherein each E 0 is methoxycarbonylamino. 5 In another specific embodiment of the invention the compound of formula (Ia) is: A -HF FH N N H H -N ION N N - - -_ 0-) H~~ H,"O HON 0 ON' F FH H N or N\ o/ u /\eeof N el - H H'NY0 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ia) is: ~O N (S)o 0 F HH (S) H N HH N- /() R N /\/_/\ 'PN H 0 10 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula: R9-Z-P-M-W-M-P-Z-R9. In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula: R9-Z-P-Mv-W,-wdn-P-Z-R9. 15 In another specific embodiment of the invention the compound of formula (Ia) is a compound of formula: R9-Z-P,-Mt-W -M-P-Z-R9. In another specific embodiment the invention provides a compound of formula (Ia) wherein the sum of t, u, v, w, and x is not 0. In another specific embodiment the invention provides a compound of formula (1a) 20 wherein at least two of r, t, u, v, w, and x are other than 0. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least three of r, t. u, v, w, and x are other than 0. 186 In another specific embodiment the invention provides a compound of formula (1a) wherein at least four of r, t, u, v, w, and x are other than 0. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least five of r, t, u, v, w, and x are other than 0. 5 In another specific embodiment the invention provides a compound of formula (1a) wherein at least two of r, t, u, v, w or x are not zero and at least one t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, and 11. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two of r, t, u, v, w and x are not zero and at least two of the non-zero groups are 10 not the same letter (for example, one w and two u's can be non zero, but just having two u's being non-zero and the remaining r, t, v, w, and x values all zero is not acceptable). In another specific embodiment the invention provides a compound of formula (1a) wherein at least three of r, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. 15 In another specific embodiment the invention provides a compound of formula (la) wherein at least three of r, t, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least four of r, t, u, v, w or x are not zero and at least two of the non-zero groups are 20 not the same letter. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least four of r, t, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ia) 25 wherein at least four of r, t, u, v, w or x are not zero and at least four of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ia) wherein the sum of t, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (Ia) 30 wherein the sum of r, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein r is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and at least one t is not zero. In another specific embodiment the invention provides a compound of formula ([a) wherein at least one u is not zero. 187 In another specific embodiment the invention provides a compound of formula (la) wherein r, and at least one t and at least one u are all not zero. In another specific embodiment the invention provides a compound of formula (la) wherein at least two of u, w and t are not zero. 5 In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two of r, u, and w are not zero. In another specific embodiment the invention provides a compound of formula (la) wherein at least two of r, u, and w are not zero and at least two of the non-zero groups are not the same letter. 10 In another specific embodiment the invention provides a compound of formula (Ia) wherein at least r and both u are not zero. In another specific embodiment the invention provides a compound of formula (la) wherein at least two of u, v, w and x are not zero and at least two of the non-zero groups are not the same letter. 15 In another specific embodiment the invention provides a compound of formula (la) wherein at least one of u and or w is not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two of u and or w are not zero. In another specific embodiment the invention provides a compound of formula (Ia) 20 wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two u are not zero. In another specific embodiment the invention provides a compound of formula (la) wherein at least one w is not zero. 25 In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two w are not zero. In another specific embodiment the invention provides a compound of formula (la) wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (la) 30 wherein both t are 9 and r is 2, 3, 4, 5, 6, 7, 8, 9, 10, I1, 12, 15, 16, 17, 18, 19, or 20. In another specific embodiment the invention provides a compound of formula (la) wherein r is 1, 13, or 14; one t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; and the other t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, or 11. 188 In another specific embodiment the invention provides a compound of formula (Ia) wherein one t is 0; the other t is I1; and r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, or 20. In another specific embodiment the invention provides a compound of formula (1a) 5 wherein r is 13; one t is 0; and the other t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In another specific embodiment the invention provides a compound of formula (Ia) wherein r is 13; one t is I I; and the other t is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11. In another specific embodiment the invention provides a compound of formula (la) wherein both t are l1; and W is not a bond, or r is 2, 3, 4, 5, 6, 7, 8, 9, 10, l1, 12, 13, 14, 15, 16, 10 17, 18, 19, or 20. In another specific embodiment the invention provides a compound of formula (1a) wherein, when W is a bond or W 1 is absent, then one t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or I I and the other t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In another specific embodiment the invention provides a compound of formula (la) 15 wherein when W is Wr and r is 6 or 8 then at least one t is not 0. In another specific embodiment the invention provides a compound of formula (Ia) wherein when both t are 0, then r is 1, 2, 3, 4, 5, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least one of t, u, v, w or x are not zero. 20 In another specific embodiment the invention provides a compound of formula (Ia) wherein at least one of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two of r, t, u, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ia) 25 wherein at least three of r, t, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least four of r, t, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two of r, t, u, w or x are not zero and at least one t is selected from 0, 1, 2, 3, 4, 30 5, 6, 7, 8, 10, 11. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two of r, t, u, w or x are not zero and at least two of the non-zero groups are not in the same letter. 189 In another specific embodiment the invention provides a compound of formula (1a) wherein at least three of r, t, u, v, w or x are not zero and at least two of the non-zero groups are not in the same letter. In another specific embodiment the invention provides a compound of formula (Ia) 5 wherein at least three of r, t, u, v, w or x are not zero and at least three of the non-zero groups are not in the same letter. In another specific embodiment the invention provides a compound of formula (la) wherein at least four of r, t, u, v, w or x are not zero and at least two of the non-zero groups are not in the same letter. 10 In another specific embodiment the invention provides a compound of formula (Ia) wherein the sum of t, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein the sum of r, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (la) 15 wherein r is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and at least one t is not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein r, and at least one t, and at least one u are all not zero. 20 In another specific embodiment the invention provides a compound of formula (Ia) wherein at least two of u, w and t are not zero. In another specific embodiment the invention provides a compound of formula ([a) wherein at least two of r, u, and w are not zero. In another specific embodiment the invention provides a compound of formula (Ia) 25 wherein at least two of r, u, and w are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula ([a) wherein at least r and both u are not zero. In another specific embodiment the invention provides a compound of formula ([a) 30 wherein at least two of u, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula ([a) wherein the sum of u, v, w and x is not zero. In another specific embodiment the invention provides a compound of formula ([a) 35 wherein at least one of u, or w are not zero. 190 In another specific embodiment the invention provides a compound of formula (1a) wherein at least two of u, or w are not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least one u is not zero, and at least one w is not zero. 5 In another specific embodiment the invention provides a compound of formula ([a) wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of formula (Ia) 10 wherein both of u are not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein at least one of w is not zero. In another specific embodiment the invention provides a compound of formula (Ia) wherein both w are not zero. 15 In another specific embodiment the invention provides a compound of the following formula (la35): Ex-V"-Zv-Pu- M 9 -Wr-M 9 -P-Z-Vw-Ex (1a35) wherein r is 1, 13, or 14. In another specific embodiment the invention provides a compound of formula (la) wherein for a compound of formula (1a35) at least one of u, w or x are not zero. In another specific embodiment of the invention for a compound of formula (1a35) at 20 least two of u, v, w or x are not zero. In another specific embodiment of the invention for a compound of formula (1a35) at least three of u, v, w or x are not zero. In another specific embodiment of the invention for a compound of formula (1a35) at least four of u, v, w or x are not zero. 25 In another specific embodiment of the invention for a compound of formula (Ia35) at least two u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment of the invention for a compound of formula (1a35) at least three of u, v, w or x are not zero and at least two of the non-zero groups are not in the same letter. 30 In another specific embodiment of the invention for a compound of formula (1a35) at least three of u, v, w or x are not zero and at least three of the non-zero groups are not in the same letter. In another specific embodiment of the invention for a compound of formula (la35) at least four of u, v, w or x are not zero and at least two of the non-zero groups are not in the same 35 letter. 191 In another specific embodiment of the invention for a compound of formula (la35) the sum of u, v, w and x is not zero. In another specific embodiment of the invention for a compound of formula (la35) at least one of u, or w are not zero. 5 In another specific embodiment of the invention for a compound of formula (la35) at least two of u, or w are not zero. In another specific embodiment of the invention for a compound of formula (Ia35) at least one u is not zero, and at least one w is not zero. In another specific embodiment of the invention for a compound of formula (Ia35) both 10 u are not zero, and at least one w is not zero. In another specific embodiment of the invention for a compound of formula (la35) at least one u is not zero. In another specific embodiment of the invention for a compound of formula (1a35) both of u are not zero. 15 In another specific embodiment of the invention for a compound of formula (1a35) at least one of w is not zero. I In another specific embodiment of the invention for a compound of formula (la35) both w are not zero. In another specific embodiment the invention provides a compound of the following 20 formula (Ia36): Ex-Vw-Zv-P"- M -W3-m"-P"-Zv-V"-Ex (Ia36). In another specific embodiment of the invention for a compound of formula (la36) at least one of u, w or x are not zero. In another specific embodiment of the invention for a compound of formula (Ia36) at least two of u, v, w or x are not zero. 25 In another specific embodiment of the invention for a compound of formula (la36) at least three of u, v, w or x are not zero. In another specific embodiment of the invention for a compound of formula (la36) at least four of u, v, w or x are not zero. In another specific embodiment of the invention for a compound of formula (la36)at 30 least two u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment of the invention for a compound of formula (Ia36) at least three of u, v, w or x are not zero and at least two of the non-zero groups are not in the same letter. 192 In another specific embodiment of the invention for a compound of formula (la36) at least three of u, v, w or x are not zero and at least three of the non-zero groups are not in the same letter. In another specific embodiment of the invention for a compound of formula (1a36) at 5 least four of u, v, w or x are not zero and at least two of the non-zero groups are not in the same letter. In another specific embodiment of the invention for a compound of formula (Ia36) the sum of u, v, w and x is not zero. In another specific embodiment of the invention for a compound of formula (la36) at 10 least one of u or w are not zero. In another specific embodiment of the invention for a compound of formula (la36) at least two of u or w are not zero. In another specific embodiment of the invention for a compound of formula (1a36) at least one u is not zero, and at least one w is not zero. 15 In another specific embodiment of the invention for a compound of formula (la36) both u are not zero, and at least one w is not zero. In another specific embodiment of the invention for a compound of formula (1a36) at least one u is not zero. In another specific embodiment of the invention for a compound of formula (Ia36) both 20 ofu are not zero. In another specific embodiment of the invention for a compound of formula (la36) at least one of w is not zero. I In another specific embodiment of the invention for a compound of formula (la36) both w are not zero. 25 In another specific embodiment the invention provides a compound of the following formula (la37): Ex-V"-Z -Pu- M"-M -P" Z"-V'-E' (la37). In another specific embodiment of the invention for a compound of formula (Ia37) at least one of u, w or x are not zero. In another specific embodiment of the invention for a compound of formula (la37) at 30 least two of u, v, w or x are not zero. In another specific embodiment of the invention for a compound of formula (Ia37) at least three of u, v, w or x are not zero. In another specific embodiment of the invention for a compound of formula (la37) at least four of u, v, w or x are not zero. 193 In another specific embodiment of the invention for a compound of formula (1a37) at least two u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment of the invention for a compound of formula (la37) at least three of u, v, w or x are not zero and at least two of the non-zero groups are not in the same 5 letter. In another specific embodiment of the invention for a compound of formula (la37) at least three of u, v, w or x are not zero and at least three of the non-zero groups are not in the same letter. In another specific embodiment of the invention for a compound of formula (Ia37) at 10 least four of u, v, w or x are not zero and at least two of the non-zero groups are not in the same letter. In another specific embodiment of the invention for a compound of formula (Ia37) the sum of u, v, w and x is not zero. In another specific embodiment of the invention for a compound of formula (Ia37) at 15 least one of u, or w are not zero. In another specific embodiment of the invention for a compound of formula (la37) at least two of u, or w are not zero. In another specific embodiment of the invention for a compound of formula (1a37) at least one u is not zero, and at least one w is not zero. 20 In another specific embodiment of the invention for a compound of formula (la37) both u are not zero, and at least one w is not zero. In another specific embodiment of the invention for a compound of formula (la37) at least one u is not zero. In another specific embodiment of the invention for a compound of formula (1a37) both 25 of u are not zero. In another specific embodiment of the invention for a compound of formula (la37) at least one of w is not zero. I In another specific embodiment of the invention for a compound of formula (1a37) both w are not zero. 30 In another specific embodiment the invention provides a compound of the following formula (la38): Ex-V'-Z-P"- M -W'-M0-P"-ZY-Vw-E (la38) wherein r is 6 or 8. In another specific embodiment of the invention for a compound of formula (1a38) at least one of u, w or x are not zero. In another specific embodiment of the invention for a compound of formula (Ia38) at 35 least two of u, v, w or x are not zero. 194 In another specific embodiment of the invention for a compound of formula (1a38) at least three of u, v, w or x are not zero. In another specific embodiment of the invention for a compound of formula (1a38) at least four of u, v, w or x are not zero. 5 In another specific embodiment of the invention for a compound of formula (la38) at least two u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment of the invention for a compound of formula (la38) at least three of u, v, w or x are not zero and at least two of the non-zero groups are not in the same letter. 10 In another specific embodiment of the invention for a compound of formula (la38) at least three of u, v, w or x are not zero and at least three of the non-zero groups are not in the same letter. In another specific embodiment of the invention for a compound of formula (la38) at least four of u, v, w or x are not zero and at least two of the non-zero groups are not in the same 15 letter. In another specific embodiment of the invention for a compound of formula (la38) the sum of u, v, w and x is not zero. In another specific embodiment of the invention for a compound of formula (la38) at least one of u, or w are not zero. 20 In another specific embodiment of the invention for a compound of formula (la38) at least two of u or w are not zero. In another specific embodiment of the invention for a compound of formula (1a38) at least one u is not zero, and at least one w is not zero. In another specific embodiment of the invention for a compound of formula (Ia38) both 25 u are not zero, and at least one w is not zero. In another specific embodiment of the invention for a compound of formula (la38) at least one u is not zero. In another specific embodiment of the invention for a compound of formula (Ia38) both of u are not zero. 30 In another specific embodiment of the invention for a compound of formula (1a38) at least one of w is not zero. In another specific embodiment of the invention for a compound of formula (1a38) both w are not zero. 35 195 Compounds of formula (Ib) In one embodiment of the invention, the compound of formula (I) is a compound of formula (Ib): E-V-Z-P-M-A-L-P-Z-V-E (Ib) 5 wherein: L is-L"; each A is selected from -As; each M is selected from -Mt; each P is selected from -P'; 10 each Z is selected from -Z'; each V is selected from -V"; each E is selected from -E'; each n is 0, 1, 2, 3, 4, 5, 6, 7, 9, or 10; each s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 21; 15 each tis0, 1, 2, 3,4, 5,6, 7, 8, 9, 10, or 11; each u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, or 14; each v is 0, 1, 2, 3, 4, 5, or 6; each w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21; each x is 0 or I ; 20 wherein the sum of n, s, t, u, v, w, and x is not 0; each LO is independently:

(RL

2 )aa 25 wherein: each R'1 2 is independently selected from hydrogen, alkenyl, alkoxy, alkyl, halo, and haloalkyl; and each aa is independently 1, 2, 3, or 4; 30 196 each L' is independently: (RL)aa

(RL

2 )b wherein: 5 each RL 2 is independently selected from hydrogen, alkenyl, alkoxy, alkyl, halo, and haloalkyl; each RL is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is 10 optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each bb is 0, 1, 2, 3, or 4; each aa is 1, 2, 3, or 4; and the sum of bb and aa is 1, 2, 3, or 4; 15 each L 2 is independently: R L4 /H RL4 wherein: 20 the phenyl ring shown in L2 is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each 25 alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; 197 each RL4 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, 5 and heterocyclylalkyl; and each H' is a 5 membered saturated, partially unsaturated, or aromatic ring comprising one or more heteroatoms; each L 3 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic 10 heterocyclic ring system that is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR b, (NRaR b)alkyl, (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, 15 heterocycle and cycloalkyl is optionally substituted with one or more halo; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 20 each L 4 is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NRaR )alkyl, (NR aR carbonyll, 25 cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR SO 2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 30 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L 5 is independently a -CR=CR-fusedbicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently 35 selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, 198 formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR b, (NRa R b)alkyl, (NRaR )carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkyISO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; 5 each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 10 each L 6 is independently a -CR=CR-fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NRaR)alkyl, (NRaR)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, 15 (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, 20 and heterocyclylalkyl; each L 7 is independently: H" 25 wherein: each H' is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more R2 each R 2 is independently selected from halo, -RL 7 , -OR L7, -SR L7, -N(R L7) 2 , -CF 3 , 30 -CC1 3 , -OCF 3 ,-CN, -NO 2 , -N(R L)C(=O)R L, -C(=O)R L7, -OC(=O)R ", -C(O)OR L, -C(=0)NR L7, -S(=0)R L7, -S(=0) 2 0R 7, -S(=0) 2 R L7, -OS(=0) 2 0R L7, and -S(=0) 2 NR U; 199 each R L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; and each aa is independently 1, 2, 3, or 4; each L 9 is independently a fused-tetracyclic saturated, partially unsaturated, or aromatic 5 heterocyclic ring system that is optionally substituted with one or more groups independently L7 L7 LL7L selected from oxo, halo, -R , -OR L, -SR L7, -CF 3 , -CC1 3 , -OCF 3 ,-CN, -NO 2 , -N(R L)C(=0)R L7 L7L7, L7 L7LIL -C(=O)R ", -OC(=O)R , -C(O)OR , -C(=O)NR ", -S(=O)R L, -S(=0) 2 0R , -S(=0) 2 R L, OS(=0) 2 0R L7, -S(=0)2NR L7, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NRa R b, (NR aRb)alkyl, and (NRaRb)carbonyl; 10 each R L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 15 each L1 0 is independently a fused-pentacyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -R , -OR L, -SR L, -CF 3 , -CC1 3 , -OCF 3 ,-CN, -NO 2 , -N(R L)C(=O)R L7, U7 UL77 L7 L7 L7 -C(=O)R , -OC(=O)R , -C(O)OR , -C(=O)NR ", -S(=0)R L, -S(=0) 2 0R , -S(=0) 2 R , OS(=0) 2 0R L7, -S(=0) 2 NR ", alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, a b a 20 -NR R , (NRaRb)alkyl, and (NRaRb)carbonyl; each R L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 25 each L" is independently a six-ring fused saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -RL 7 , -OR L7, -SR L7, -CF 3 , -CC1 3 , -OCF 3 ,-CN, -N02, -N(R L 7 )C(=0)R L7 LL7L7 L7 L77 L7 -C(=O)R '7, -OC(=O)R L7, -C(O)OR , -C(=O)NR , -S(=O)R L, -S(=0) 2 0R , -S(=0) 2 R , 30 OS(=0) 2 0R -, -S(=0) 2 NR L7, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl; each R L is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, 35 heterocyclyl, and heterocyclylalkyl; 200 each A 0 is independently:

(RA

3 )bb 5 wherein: each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl; Ra and R b are each independently selected from the group 10 consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each bb is independently 0, 1, 2, 3, or 4; or each AO is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 RA 3 groups; 15 each A' is independently: (RA1)9 wherein: 20 each RA is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; 25 each cc is independently 1, 2, 3, or 4 201 each A 2 is independently:

(RA

3 )bb A1) wherein: 5 each RA is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, 10 arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRa R b)alkyl, and (NRaR b)carbonyl; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; 15 Ra and Rb are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bb and cc is 1, 2, 3, or 4; 20 each A 3 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is substituted with one or more RAI groups, and which ring is optionally substituted with one or more R A3 groups; each A 4 is independently: XA-H5-XAH5-XA 25 wherein: 202 each H 5 is independently a phenyl ring or a six-membered heteroaromatic ring, which H5 is optionally substituted with one or more groups independently selected from R A'and RAl; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, 5 CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A 5 is independently: -XA

H

6 -XA. 10 wherein: each H is independently a phenyl ring or a six-membered heteroaromatic ring, which H6 is optionally substituted with one or more groups independently selected from 15 R^' and RAl; and each X^ is independently 0, NR, SO, SO 2 , C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; provided that at least one XA is present and each R is independently selected from H or alkyl; each A 6 is independently: 20

XA-XA.XA

wherein: each X^ is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, 25 CR=CR, allenyl, alkynyl, or absent; provided that at least one XA is present and each R is independently selected from H or alkyl; each A 7 is independently: XA H 7 -XA 30 wherein: 203 each H 7 is independently a five-membered heteroaromatic ring, which H is optionally substituted with one or more groups independently selected from RA and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=O), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H 5 or alkyl; each A 8 is independently: XA-H8-XA -H7XA 10 wherein: each H 7 is independently a five-membered heteroaromatic ring, which H7 is optionally substituted with one or more groups independently selected from RAI and RA 3 ; each H 8 is independently a phenyl ring, which is optionally substituted with 15 one or more groups independently selected from R and R 3; and each X^ is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 20 each A 9 is independently: XA -H7-XA 17-XA wherein: 25 each H7 is independently a five-membered heteroaromatic ring, which H7 is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 30 each A' 0 is independently: [XA-HB-XAA--H9-XA wherein: 204 each H 8 is independently a phenyl ring, which is optionally substituted with one or more groups independently selected from RA' and RA 3 ; each H 9 is independently a six-membered heteroaromatic ring, which is 5 optionally substituted with one or more groups independently selected from RA1 and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=O), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 10 each A'' is independently: -XAH 10-XA wherein: each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, 15 CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each H 0 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that is optionally fused to an aryl, which H 0 is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, 20 alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , (NRaR )alkyl, and (NRaRb)carbonyl, cyano, nitro, SOR 4, SO 2 R4, -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and 25 each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl each A1 2 is independently: XA-H ll-XA 30 wherein: each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=O)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 205 each H" is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that contains one or more heteroatoms that is optionally fused to an aryl, which H " is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, 5 formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and 10 each A 3 is independently: -XAH 12xA 15 wherein: each H' 2 is independently a fused aromatic bicyclic carbocycle, which is optionally substituted with one or more groups independently selected from R' and R 3 ; and 20 each XA is independently 0, NR, SO, SO 2 , C(=O), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A 1 4 is independently: 25 HXA 13xA_ wherein: each H 1 3 is independently a fused aromatic bicyclic heterocycle that comprises 30 at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from RA and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 206 each A 5 is independently: -XA 14..XA 5 wherein: each H 4 is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from R and RA 3 ; and 10 each XA is independently 0, NR, SO, S02, C(=O), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A' 6 is independently: 15 XAH 15-XA wherein: each H 15 is independently a fused unsaturated, partially unsaturated or 20 saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from R and RAl; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 25 or alkyl; each A' 7 is independently: XA -l 6

-XA-

30 wherein: 207 each H1 6 is independently a fused bicyclic carbocyclic ring system wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; and 5 each X^ is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A' 8 is independently: 10 XA1H 17

-XA

wherein: each H 7 is independently a fused bicyclic ring system comprising at least one 15 heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R^1 and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=O)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H 20 or alkyl; each A21 is independently: XA-H4-XA 25 wherein: each H 40 is independently an anti-aromatic monocyclic or fused carbocyclic ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from R and R 3; and 30 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=O)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; 208 each MO is independently a five membered heteroaryl group optionally substituted with one or more alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NRaRb)carbonyl and trialkylsilylalkoxyalkyl; 5 each M' is independently selected from -C(=O)NH-, -C(=0)NH-C(R) 2 -, -NHC(=0) -, -C(Rm) 2 NHC(=O)-, -NHC(=0)N R" -, -NHC(=O)O -; wherein each RM is independently selected from H and alkyl; 10 each M 2 is independently a six-membered heteroaromatic ring, which is optionally substituted with one or more groups independently selected from RA and RA 3 ; each M 3 is independently: H N O 15 each M 4 is independently: N OH 20 each M 5 is independently: H N. N 25 wherein the bond designated with --- is fused to a ring defined for P; each M6 is independently a bicyclic bridged ring system comprising 5-15 atoms wherein at least one of the atoms is a heteroatom; 209 each M 7 is independently a pyrid-di-yl; each M 8 is independently partially saturated or a saturated five-membered ring that comprises 5 one or more heteroatoms and that is optionally substituted with one or two oxo; each M 9 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more R 1 1; 10 each M 1 0 is independently a five membered heteroaryl group; each M' is independently a fused-tricyclic saturated, partially unsaturated, or aromatic M7 M7 heterocyclic ring system that is optionally substituted with one or more oxo halo, -RM 7 , -OR -SR M7, -N(R M7)2, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R M7)C(=O)R M7, -C(=O)R M7, -OC(=O)R M7 M7M 7 M7 M7 M7 M 15 , -C(O)OR , -C(=)NR 7, -S(=0)R 7, -S(=0)2R , -S(=0)2R 7, -OS(=0)20R 7 or -S(=0) 2 NR M7; each R M 7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; each P 0 is independently: 20 (RP5ps (R'Pq ( P P(R 6 )pq Po N P or NR RP9 wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHR ' 0 , and C(Rp")2; 25 provided that when pn or pm is 0, X is selected from CH 2 , CHR ' 0 , and C(R P'0) 2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three 210 to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused 5 three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; RPa and RPb are each independently H, alkyl, aryl, or arylalkyl; or Rea and R Ptaken together with the atom to which they are attached form a heterocycle; pq and ps are independently 0, 1, 2, 3, or 4; 10 pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; R7 and RP 8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, Pa b alkyl, haloalkyl, and (NR R )alkyl; or R7 and R , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two 1 5 heteroatoms selected from NR P, 0, and S; wherein Ra' is selected from hydrogen and alkyl; R"9 is selected from hydrogen and alkyl; each P' is independently:

(RP

1 1)ps /-x Npn 20 wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHRE 1 0 , and C(R ') 2 ; provided that when pn is 0, X is selected from CH 2 , CHRP'", and C(R P'0)2; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, 25 haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; at least one RP1 1 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, 30 alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (N RhRh)alkyloxy, cyanoalkoxy, hh h h cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR R , (NRhR )alkyl, 211 (NRhhR carbonyll, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to 5 form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 R h, -C(=O)R h, -C(=O)NRR h; and the remaining RP' 1are independently selected from RP 5 , cyano, alkylsulfonyl, arylsulfonyl, 10 (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 15 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; 20 each P 2 is independently: (R P12) H IN IN pn 25 wherein: each RP' is independently selected from R 5 , R ,C(=O)ORh, cyano, alkylsulfonyl, arylsulfonyl, (NRh R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, 30 heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, 212 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 5 ps is l, 2, 3, or 4; pn is 0, 1, or 2; each P 3 is independently a ring of the formula: (R P 3 )ps N pn 10 wherein: the ring is substituted with one or more oxo group; each RP is independently selected from R 5 , cyano, alkylsulfonyl, 15 arylsulfonyl, (NRhR)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, 20 alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 0, 1, 2, 3, or 4; pn is 0, 1, or 2; 25 each P 4 is independently a ring of the formula: 213 Rf N N pn wherein: the ring is optionally substituted with one or more groups R 14 that are 5 independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R P14 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 10 membered carbocyclic or heterocyclic ring; pn is 0, l, or 2; each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhRh, 15 -S(=0) 2 Rh, C(=O)Rh, C(=O)ORh, -C(=O)NRhRh ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 20 each P 5 is independently a ring of the formula: (z 25 wherein: the ring is optionally substituted with one or more groups RP 1 5 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NRPaR P, wherein the alkyl can optionally form a fused three-to six-membered ring with an 214 adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R 15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; 5 pn is 0, 1, or 2; Z is 0, S, S(=0), S(=0) 2 , or NRr; each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NR R , 10 -S(=O) 2 R', C(=O)R , C(=O)OR , -C(=0)NRR h ; each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 15 each P 6 is independently a ring of the formula: pn( Z 20 wherein: the ring is substituted with one or more oxo and is optionally substituted with one or more groups RP1 6 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is 25 optionally substituted with one or two alkyl groups; Z is 0, S, S(=0), S(=0) 2 , or NRr; pn is 0, l, or 2; each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 30 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRRh, -S(=0)2R', C(=0)R h, C(=O)OR h, -C(=0)NRh R ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 215 dialkylaminoalkyl, sulfonylalkyl; or when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder 5 of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from RP 6 and R' ; each P 8 is independently a ring of the formula: (RP 1 3 ) P N pn 10 wherein: ps is 2, 3, 4, 5, or 6; each RP' 3 is independently selected from alkoxy, alkyl, aryl, halo, 15 haloalkyl, hydroxy, and -NReaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups RP" that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 20 membered heterocyclic ring; each P1 0 is independently: (R P),S (RP 6 )pq I ) )pp 25 wherein: 216 X is selected from 0, S, S(O), SO 2 , CH 2 , CHR ', and C(R 'P) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP', and C(R ' 0

)

2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three 5 to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR ', wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered 10 ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 15 each P" is independently: (R P5)P

(RP

6 )pq Po( X IN )pn N wherein: 20 X is selected from 0, S, S(O), S02, CH 2 , CHR 'O, and C(RPl') 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR'"", and C(R ' 0

)

2 ; each RP 10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered 25 ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaReb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 30 pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; 217 po and pp are independently 1, 2, or 3; each P 2 is independently:

(RP

6 )pq (RP 1),S P N pm 5 wherein: each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, 10 haloalkyl, hydroxy, and -NReaR P, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; pm is independently 0, 1, or 2; 15 pp is independently 1, 2, or 3; ps is 1, 2, 3, or 4; RP" 1is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, 20 heterocyclooxyalkyloxy, (NRh R h)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhhR, (NRhhRh)alkyl, (NRhhRh)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come 25 together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=O)Rh -C(=O)NRhRh; and the remaining RP1 1 are independently selected from RP 5 , cyano, 30 alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, 218 heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (N RhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 5 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 13 is independently: (RP1 ) (RP6g p n 6 PP N pm 10 wherein: X is selected from 0, S, S(O), SO 2 , or NR ; 15 each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NReaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 20 pm and pn are independently 0, 1, or 2 but the sum of pn and pm is greater than zero; pp are independently 1, 2, or 3; ps is 1, 2, 3, or 4; each RP 11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, 25 (NR R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (N Rh R h)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, h h hh h hh h h oxo, heterocyclyl, -NR hR , (NR'R )alkyl, (NR R )carbonyl, wherein each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, 30 alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 219 dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 5 dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 R, -C(=O)Rh -C(=O)NRhRh, R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)Sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR R h)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is 10 independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 15 each P' 4 is independently: (R1)S(R P6)p N pm 20 wherein: the ring is substituted with one or more oxo group; X is NR ; each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, h h 25 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NR R, -S(=0) 2 Rh, C(=O)Rh, C(=O)ORh, -C(=O)NRhRh ; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come 30 together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 220 each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 5 pq is independently 0, 1, 2, 3, or 4; pm is independently 0, 1, or 2; ps is 1, 2, 3, or 4; R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRh R )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 10 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (N RhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or sulfonylalkyl; and when 15 two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each -Z 0 - is -C(=O)- or -C(=S)-; 20 each -Z'- is independently a bond, or -C(Rz) 2 -; wherein each Rz' is independently H, alkyl, haloalkyl, or halo; each -Z 2 - is independently saturated or partially unsaturated (C 3

-C

8 )cycloalkyl that is optionally substituted with one or more groups independently selected from R and RA3; 25 each -Z 3 - is independently saturated, partially unsaturated, or aromatic 4-8 membered heterocyclic or heteroaryl ring that is optionally substituted with one or more groups independently selected from R and RA 3 ; 30 each -Z 4 - is independently: 1RZ 4 221 wherein each RZ4 is independently H, alkyl, cyano, aryl, or heteroaryl; each -Z 5 - is independently: 5 RZ5 -RZ 5 N N wherein each RZ 5 is independently H, alkyl, cyano, aryl, or heteroaryl; or two Rzss together with the nitrogen to which they are attached form a 4-8 membered heterocyclic ring that is 10 optionally substituted with one or more oxo and with one or more groups independently selected from R and R 3; each -Z 6 - is independently -C(Rzi)- and is doublebonded to P; wherein RzI is independently H, alkyl, haloalkyl, or halo; 15 each E 0 is independently -NR EcREd wherein R Ec and REd are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, 20 cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR"Rf)alkyl, (NReRf)alkylcarbonyl, (NReRf)carbonyl, (NReR)sulfonyl, -C(NCN)OR', and - C(NCN)NRxRY, wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the 25 arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NRcRf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the 30 heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; 222 each E' is independently -OC(=O)NREeREf wherein each RFe and REf are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, 5 arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR*Rf)alkyl, (NR*Rf)alkylcarbonyl, (NReR )carbonyl, (NR*Rf)sulfonyl, -C(NCN)OR', and - C(NCN)NRxRY, wherein R' is selected from alkyl and unsubstituted phenyl, 10 and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NRcRf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the 15 heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; or wherein REe and R Ef, together with the nitrogen atom to which they are attached, form a heterocycle; 20 each V 0 is independently H, alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl 25 part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, 30 arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the 35 arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the 223 heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, 5 arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRXRY)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the 10 heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; each V 1 is independently cyanoalkyl, which is optionally substituted with one or more groups 15 independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V2 is independently haloalkyl, which is optionally substituted with one or more groups 20 independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 3 is independently alkyl, which is substituted with one or more oxo, and which is 25 optionally substituted with one or more groups independently selected from cycloalkyl, halo, aryl, alkenyl, and cyano; each V 4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 30 heteroaryl, hydroxy, and NRaRbC(=O)O-; Ra and Rb are each independently selected from hydrogen, alkenyl, and alkyl; each V 5 is independently alkylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 224 heteroaryl, hydroxy, and NR vaR C(=O)O-; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl; each V 6 is independently arylsulfonylalkyl, which is optionally substituted with one or more 5 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 7 is independently heterocyclosulfonylalkyl, which is optionally substituted with one or 10 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V 8 is independently spirocycloalkyl, which is optionally substituted with one or more 15 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V 9 is independently spirocycloalkylalkyl, which is optionally substituted with one or 20 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V' 0 is independently fusedbicycliccycloalkyl, which is optionally substituted with one or 25 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR bC(=O)O-; R Va and R Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V 1 1 is independently fusedbicycliccycloalkylalkyl, which is optionally substituted with 30 one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V1 2 is independently bridged-bicycliccycloalkyl, which is optionally substituted with one 35 or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, 225 heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and R Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V1 3 is independently bridged-bicyclic-cycloalkylalkyl, which is optionally substituted 5 with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=0)O-; Rva and Rb are each independently selected from hydrogen, alkenyl, and alkyl; each V 4 is independently aryloxyalkyl, which is optionally substituted with one or more 10 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR C(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V' 5 is independently arylalkoxyalkyl, which is optionally substituted with one or more 15 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=0)O-; Rva and Rb are each independently selected from hydrogen, alkenyl, and alkyl; each V1 6 is independently cycloalkyloxyalkyl, which is optionally substituted with one or more 20 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaRvbC(=O)O-; Rv and R are each independently selected from hydrogen, alkenyl, and alkyl; each V 7 is independently cycloalkylalkyloxyalkyl, which is optionally substituted with one or 25 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; each V1 is independently heterocyclooxyalkyl, which is optionally substituted with one or 30 more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRVbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V' 9 is independently heterocycloalkyloxyalkyl, which is optionally substituted with one 35 or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, 226 heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V20 is independently heteroaryloxyalkyl, which is optionally substituted with one or more 5 groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; and each V 2 1 is independently heteroarylalkylalkoxyalkyl, which is optionally substituted with one 10 or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; or a pharmaceutically acceptable salt, or prodrug thereof. 15 In another specific embodiment of the invention L is L 3 . In another specific embodiment of the invention L is benzimidazolyl. In another specific embodiment of the invention -A-L- is selected from: H - ~ N and H N 20 In another specific embodiment of the invention -M-A-L- is selected from: '\ - N HH H N' HH HH H q and 227S 22 optionally substituted with one or more groups independently selected from RP 6 and R". In another specific embodiment of the invention the compound of formula (Ib) is a 5 compound of formula (lb 1): E 0

-V

0

-Z

0

-P-M-A'

5

-L-P-Z

0

-V

0

-E

0 (lb 1). In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (Ib2): E 0

-V

0

-Z

0

-P-M-A'

5

-L

3

-P-Z

0

-V

0 -Ea (Ib2). In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (Ib3): E 0

-V

0

-Z

0

-P-M

0

-A

1 i-L 3

-P-Z

0

-V

0

-E

0 (Ib3). 10 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (Ib4): E 0

-V

0

-Z

0 -P-M-A' 6

-L-P-Z

0

-V

0

-E

0 (Ib4). In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (Ib5): E 0

-V

0

-Z

0 -P-M-A 16-L-P-Z-V 0

-E

0 (Ib5). In another specific embodiment of the invention the compound of formula (Ib) is a 15 compound of formula (Ib6): EU-V0-Z"-P-M -A 16L -P-Z -V -E (b6). In another specific embodiment of the invention the compound of formula (Ib) is a o 0 9 16 3_p 0 0 0_E compound of formula (Ib7): E -V -Z -P-M -A -LP3_,-v -E (1b7). In another specific embodiment of the invention the compound of formula (Ib) is: 0 H + NH N N 0\ N N ON N N - H N O H H 0 O H H N 2N N N , -N- H N H 0 - -NH N N N~ N 0 HH H N 200 228 o 0 N N N - - 0- -0 H N N

N

£ H HN-.f 0- _0 H NH N N N N N NA0 N HN. H 0- }-NH S N N 0 *-~ N A\ N N - -- H N H f 0--~ _~~0 H NH N N N N N H 0- 0F F H / NH N, N 0 N N N H 0--~ 229 0F F HPH 4YNH N oo N N N - - -H N H 0--~ _00 H }-NH N ~>-{ N N N - -- H N H 0--~ 0F F HPH ~NH N o 0 N\ N N -H N H 0--~ N F0F H H }-NH N NN N N N 0 - 0N 0- FF H H / NH N N N N - -- H N H F0F H /NH N N N N - -- H N H /4 0- N 230 O H NHN N O N O- N a H H O O H0 N0-0 O H HH N NH S \ 2 N3 0 0 N N - HNyf H 0 H f-7 NH N N 0 0 N N N 0 - N N H 0- 231 _~~0 N H NHH ON H N 0or 0 H : NH d-' - 0 N NN H0 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ib) is a 5 compound of formula (Ib60): E 0

-V-Z

0 -P-M-A '-L-P-Z 0

-V-E

0 (Ib60). In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (Ib6I): E 0

-V-Z

0 -P-M-A6 -L-P-Z -V-E 0 (Ib61). In another specific embodiment the invention provides a compound of formula (Ib35): H ' P-M-A15-L--- V-NH (Ib35) N-V 0 o=K 10 / wherein: V is alkyl; L is benzimidazolyl; M is a 5-membered heteroaryl ring; 15 A' 5 is: -XAH 14-XA 232 each H 1 4 is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from RAI and R^ 3 ; and each X^ is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, 5 NRC(=O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each R^' is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; 10 each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 1 5 each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and each P is independently selected from: HN - NN N" N and 20 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (1b36): 233 O0 H V'N H P-M-A15 P 0 H (Ib36) N-V N /P or a pharmaceutically acceptable salt, or prodrug thereof. 5 In another specific embodiment the invention provides a compound of formula (1b37): 0)= 0 H V'NH

N

1 Nr A 15 (Ib37) H O H N -V or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib35), 10 (Ib36), or (Ib37) wherein P is selected from: (~~nd In another specific embodiment the invention provides a compound of formula (1b35), 15 (Ib36), or (Ib37): wherein P is: 234 N In another specific embodiment the invention provides a compound of formula (1b35), (Ib36), or (Ib37): wherein P is: 5 N optionally substituted with one or more groups independently selected from RP 6 and RI'; each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, 10 hydroxy, and -NR PaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; RPa and RPb are each independently H, alkyl, aryl, or arylalkyl; or RPa and RPb taken together with the atom to which they are attached form a heterocycle; 15 each R 11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRh R h)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhh h, (NRh Rh)alkyl, (NR R h)carbonyl, wherein each Rh is independently 20 -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, 25 alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, and -S(=0) 2 Rh, -C(=O)Rh, -C(=0)NRR . In another specific embodiment the invention provides a compound of formula (Ib38): 235 0 H H I-NH N N 0 0IIM H, P-M-A15 N (b38) 0= /P or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (1b39): 0 - , H H V-N% % H N 1 0 A15 N (lb39) H H N -V 5 / or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib4O): 0 oo O = o N H H H I % H V O N N (1b40) M-A15/ N 10 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib41): 236 O/ H H V'N O N 0N N VN N O (Ib41) N A 1 5 N H or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib42): 0 >O H H I H N N 0 / l (1b42) Ft P-M-A15 N 0--V 0= /P 5 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib43): O 0 >= H HV -N,H N O )§~ ~A 15 /\ N (1b43) H , H 'N-V I00 10 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib44): 237 0 0 >=O 0 N H H V O N N O( 4 N M-A 15- N or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib45): O 'H H V-t O A1 N 1 0 (11b45) N9T 1 ) -A 15 N 5 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib4I), (Ib42), (1b43), (Ib44), or (Ib45) wherein each XA that is allowed to be absent is absent. 10 In another specific embodiment the invention provides a compound of formula (1b35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib4I), (Ib42), (lb43), (1b44), or (Ib45) wherein A' 5 is selected from: FF or In another specific embodiment the invention provides a compound of formula (1b35), 15 (1b36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib4 1), (Ib42), (Ib43), (1b44), or (Ib45) wherein A's is selected from: F F In another specific embodiment the invention provides a compound of formula (Ib35), (Ib36), (Ib37), (1b38), (Ib39), (Ib40), (Ib41), (Ib42), (1b43), (Ib44), or (Ib45) wherein each V is: 20 238

H

3 C CH 3 In another specific embodiment the invention provides a compound which is: 0 H H, O 5O or 0 NF F H N AN 1 0 -0"N O H HN O 5 0 or a pharmaceutically acceptable salt, or prodrug thereof. 10 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (Ib8) 04 HO N--V 0 0 wherein: V is alkyl; 15 L is benzimidazolyl; M is a 5-membered heteroaryl ring;

A'

5 is 239 XAH 14-XA each H' 4 is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from RA1 and RA 3 ; and 5 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each RAl is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with 10 one or more halo; each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, and (NRaRb)carbonyl; Ra and Rb are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, 15 cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and P is selected from: N40 240 N - N >NN )N0 y N and or a pharmaceutically acceptable salt, or prodrug thereof. 5 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (lb9): 0 H V'N H P-M-A15 N PH (b9) N-V N 0= /P or a pharmaceutically acceptable salt, or prodrug thereof. 10 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (lb 10): 0 = H V-N N P H

A'

5 ONIb0 0 ~~'N (lb 10) H O N -V or a pharmaceutically acceptable salt, or prodrug thereof. 241 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (IbI 1): 0 H H V-N, NH (Ib11) H o P-M-A15 / \ N 0=-V O /U 5 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (lb 12): 0~= A15 N VNH (Ib12) H O

V

N -V II 10 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (lb 13): N MN Nb 15 or a pharmaceutically acceptable salt, or prodrug thereof. 242 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (Ib1 4): 0 H N= ,H H H V-NH o N N H V 0 N O (Nbl4) N A15 N N or a pharmaceutically acceptable salt, or prodrug thereof. 5 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (IbI 5): 0 H H N N V 0 ll (1b15) H P-M-A15 / 0 N -V /U or a pharmaceutically acceptable salt, or prodrug thereof. 10 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (lb 16): 0 >= H H V-N,H H H N N A \ N (Ib16) H H N -V or a pharmaceutically acceptable salt, or prodrug thereof. 15 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula (lb17): 243 0 0 = "kN N H HH V 0 N N O (1b17) M- A15 N or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ib) is a 5 compound of formula (Ib18): 0 1H -H o HH H N%-N N (1b18) VII 15 N or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment the invention provides a compound of formula (Ib) wherein P is 10 N 244 In another specific embodiment the invention provides a compound of formula (Ib) wherein P is N 5 optionally substituted with one or more groups independently selected from RP 6 and Re"; each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaR Pb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally 10 substituted with one or two alkyl groups; RPa and RPb are each independently H, alkyl, aryl, or arylalkyl; or RP" and RPb taken together with the atom to which they are attached form a heterocycle; each RP' is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 15 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhRh, (NRRh)alkyl, (NRhhRh)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 20 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, and -S(=0) 2 Rh, 25 -C(=O)Rh, -C(=0)NRR. In another specific embodiment the invention provides a compound of formula (Ib) wherein each XA that is allowed to be absent is absent. In another specific embodiment the invention provides a compound of formula (Ib) 30 wherein A 1 is selected from: 245 F F or In another specific embodiment the invention provides a compound of formula (Ib) wherein each V is: 5

H

3 C CH 3 H. In one embodiment of the invention, the compound of formula (1) is a compound of formula (Ib1 9): 10 EU-V"-Z'-P"-M'-As-L'-P"-Z'-V"-E' (Ibl9) wherein: each u is independently 0, 1, 3, 5, 7, 8, 10, or 11; each w is independently 0, 1, 2, 3, 4, or 5; and each s is 0, 6, 13, or 14. 15 In one embodiment the invention provides a compound of formula (lb19) wherein L 9 is: x-x /\x -x H wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, O-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; wherein * designates the site of connection to P. In one embodiment the invention provides a compound of formula (Ib19) wherein MO is: 20 H 246 In one embodiment the invention provides a compound of formula (lb19) which is: 0 o N~-~~ x-x O v N O 0 H-- 0 -o HH o N H, _ I 0 V-N 0" O , ---- f 0Nro x-- o H -N O o- v-"o 0 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (bl 9) wherein A is: 5is: In one embodiment the invention provides a compound of formula ( Ib 9) which is: H24 H \ H /\ - 0. H - / - N or P !11 N R/ H 0 or a pharmnaceutically acceptable salt, or prodrug thereof. 10 In one embodiment the invention provides a compound of formula (lb 19) wherein A is: 15 In one embodiment the invention provides a compound of formula (IbI19) which is: 247 0 o N-V-0 - XX H _ H NN x-x H-N \N\----v-oNor 0 Nv-N O 0 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ibl 9) wherein A' is: In one embodiment the invention provides a compound of formula (Ibl9) which is: H No-r H --- v N H N o- X o v N O o - -- vN H or o v-N O 0 or a pharmaceutically acceptable salt, or prodrug thereof. 10 In one embodiment the invention provides a compound of formula (lb1 9) wherein Al" is: ~- - ~ or. In one embodiment the invention provides a compound of formula (lb 19) which is: 248 0 ON N- - x-x N R H H H O N--- o O x O V-N O H H H O V-N O 0 0 0 p - 0 , N H H H O H N H O V- 0 S N -X-X H \ N HH O N--- -X O - H H O V-N ON 0 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment of the invention, the compound of formula (I) is a compound of 5 formula (1b20): EUV'- P"M-A--"Zo-V"'-Eo (Ib20) wherein: 249 each u is independently 0, 1, 3, 5, 7, 8, 10, or 11; and each w is independently 0, 1, 2, 3, 4,or5. In one embodiment of the invention, the compound of formula (I) is a compound of formula (Ib21): 5 E -Vw-ZO-P"'-MI-A-L4-Pu2-Z4-V"-E (Ib2 1) wherein: each ul is l,3,5, 7, 8, 10,or II;u2is0, 1,3,5,7,8, 10,or Il;andeachwis independently 0, 1, 2, 3, 4, or 5. 10 In one embodiment of the invention, the compound of formula (I) is a compound of formula (Ib22): E -V"I-ZO-P"-MO-AO-L4-Pu2-Zo-Vw2-E 0 (Ib22) wherein: 15 each u is independently 0, 1, 3, 5, 7, 8, 10, or 11; each u2 is independently 0, 1, 3, 5, 7, 8, 10, or 11; w I is independently 0, 1, 2, 3, 4, or 5; and each w2 is independently 1, 2, 3, 4, or 5. In one embodiment of the invention, the compound of formula (I) is a compound of formula (Ib23): 20 EO-Vw'-ZO-P"-MO-AO-L4-Pu2-Z-Vw2 -EO (Ib23) wherein: each u is independently 0, 1, 3, 5, 7, 8, 10, or 11; each u2 is independently 0, 1, 3, 5, 7, 8, 10, or 1I; w I is independently 1, 2, 3, 4, or 5; and each w2 is independently 0, 1, 2, 3, 4, or 5. In one embodiment the invention provides a compound of formula (lb20)-(Ib23) wherein 25 MO is: H In one embodiment the invention provides a compound of formula (Ib20)-(1b23) wherein

A

0 is: 30 250 In one embodiment the invention provides a compound of formula (Ib20)-(Ib23) wherein

L

4 is: X-X H wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, 0-CH 2 , CH 2

-CH

2

-CH

2 , and 5 CH 2 -0-CH 2 ; and wherein * designates the site of connection to P. In one embodiment of the invention, the compound of formula (1) is a compound of formula (Ib24): 10 Ea-Vw-Z0-P"-MO-As-L4-Pu2-ZO-V*-E0 (Ib24) wherein: each u is independently 0, 1, 3, 5, 7, 8, 10, or 1I; each u2 is independently 0, 1, 3, 5, 7, 8, 10, or 11; each w is independently 0, 1, 2, 3, 4, or 5; and s is 5, 6, 13, 14, 15, or 16. In one embodiment the invention provides a compound of formula (Ib24) wherein s is 16 15 and A' 6 is: In one embodiment the invention provides a compound of formula: x-x O N - - V OA / N HH H HH O V--N O 0 20 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, O-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; and A is A 0 ; or a pharmaceutically acceptable salt, or prodrug thereof. 251 In one embodiment the invention provides a compound of formula: 0 x-x o N-V.f H H N N H H O V-N O 0 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, O-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 5 In one embodiment the invention provides a compound of formula (Ib24) wherein s is 6 and A6 is: 10 In one embodiment the invention provides a compound of formula (Ib25): 0 X-X H - \ / N (1b25) P N N H H O V-N O 0 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, 0-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 15 In one embodiment the invention provides a compound of formula (Ib24) wherein s is 5 and As is: 20 252 In one embodiment the invention provides a compound of formula (1b26): O xx HN V N ___ (1b26) H RH H H 0 V-N O 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, 0-CH 2 , CH 2

-CH

2 5 CH 2 , and CH 2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ib24) wherein s is 13 and A' 3 is: 10 In one embodiment the invention provides a compound of formula (Ib27): 0 o N-V QO X-X H P -- / \ -N/ N (1b27) P H O V-N O s1 NO 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, O-CH 2 , CH 2

-CH

2

-CH

2 , and 15 CH 2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ib24) wherein s is 14 and A 4 is: S or 20 In one embodiment the invention provides a compound of formula: 253 H - O- / N (1b29) HH HX-X RH /N O V-N O..0 O N-V O , N o H \ /N O N-V O H -Y H S X-X O (1Ib3 0) N or H N P H (Ib31) 0 V-N 0 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, O-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2

-O-CH

2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 5 In one embodiment the invention provides a compound of formula (Ib24) wherein s is 15 and A 15 is: F F or In one embodiment the invention provides a compound of formula: FF X-X ON V O/ (1b32) H ~ N _ j O O N 0 O-*-N O H (b33) O V---N ON 100 254 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, O-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ib34): 0 0 x-x 0 V O-

-

(1b34) o N N H H 5 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, O-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula: R9-Z-P-M-A 5 -L-P-Z-R9. 10 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula: R9-Z-P-M-A 15

-L

3 -P-Z-R9. In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula: R9-Z-P-M 0 -A-L-P-Z-R9. In another specific embodiment of the invention the compound of formula (Ib) is a 15 compound of formula: R9-Z-P-M-A 16 -L-P-Z-R9. In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula: R9-Z-P-M-A 6

-L

3 -P-Z-R9. In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula: R9-Z-P-M 0 -A ' 6

-L

3 -P-Z-R9. 20 In another specific embodiment of the invention the compound of formula (Ib) is a compound of formula: R9-Z-P-M 9-A 16-L-P-Z-R9. In another specific embodiment the invention provides a compound of the following formula (Ib50): E'-V"-Zv-P"-M'-As-L" -Pu-Zv-Vw-Ex (Ib50) wherein the sum of t, s, n, u, v, w and x is not zero. 25 In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least two of n, s, t, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least three of n, s, t, u, v, w or x are not zero. 255 In another specific embodiment the invention provides a compound of formula (Ib50) wherein at least two of n, s, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ib50) 5 wherein at least three of n, s, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ib50) wherein at least three of n, s, t, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. 10 In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least four of n, s, t, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ib50) wherein at least four of n, s, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. 15 In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least four of n, s, t, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least four of n, s, t, u, v, w or x are not zero and at least four of the non-zero groups 20 are not the same letter. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein the sum of n, t, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein the sum of s, u, v, w or x is not zero. 25 In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of formula (Ib50) wherein s, and at least one t, and at least one u are all not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) 30 wherein at least two of u, w and t are not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least two of s, u, and w are not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least two of s, u, and w are not zero and at least two of the non-zero groups are not 35 the same letter. 256 In another specific embodiment the invention provides a compound of formula (Ib50) wherein at least s and both u are not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least two of u, v, w or x are not zero and at least two of the non-zero groups are not 5 the same letter In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least one of u, or w is not zero. In another specific embodiment the invention provides a compound of formula (Ib50) wherein at least two of u, or w are not zero. 10 In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least two of u are not zero. In another specific embodiment the invention provides a compound of formula (lb50) 15 wherein at least one of w is not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein at least two of w are not zero. In another specific embodiment the invention provides a compound of formula (Ib5O) wherein both u are not zero, and at least one w is not zero. 20 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein t is 0 or l0; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and s is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13,14, 15, 16,17,18, or21. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein t is 0 or 10; n is 0, 1, 2, 4, 5, 6, 7, 8, 9, or 10; and s is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 25 13,14,15, 16, 17, 18,21. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein t is 9; n is 3; and s is 3, 4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 21. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein t is 0, 1, 2, 4, 5, 6, 7, 8, 9, 10, or Il; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and s is 1, 2, 3, 30 4,5,6,7,8,9, 10, l1, 12, 13, 14, 15, 16, 17,18,21. In another specific embodiment the invention provides a compound of the formula (Ib50) wherein t is 0; n is 0, 1, 2, 3, 5, 6, 7, 8, 9, or 10; and s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 20. 257 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein t is 1, 2, 4, 5, 6, 7, 8, 9, 1,or l1; n is 4; and s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, I1, 12, 13, 14, 15, 16, 17, 18, or21. In another specific embodiment the invention provides a compound of the formula (Ib5O) 5 wherein at least one of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of n, s, t, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least three of n, s, t, u, v, w or x are not zero. 10 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of n, s, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least three of n, s, t, u, v, w or x are not zero and at least two of the non-zero groups 15 are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least three of n, s, t, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5O) 20 wherein at least four of n, s, t, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least four of n, s, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5O) 25 wherein at least four of n, s, t, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least four of n, s, t, u, v, w or x are not zero and at least four of the non-zero groups are not the same letter. 30 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein the sum of n, t, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein the sum of s, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) 35 wherein at least one u is not zero. 258 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein s, and at least one t, and at least one u are all not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of u, w and t are not zero. 5 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of s, u, and w are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of s, u, and w are not zero and at least two of the non-zero groups are not the same letter. 10 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least s and both u are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. 15 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least one of u, or w is not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of u, or w are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) 20 wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of u are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least one of w is not zero. 25 In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein at least two of w are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5O) wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of the following 30 formula (Ib5 1): Ex-Vw-Zv-Pu-M 9 -As-L 3 -P-Z-V"-Ex (Ib5 I) wherein s is 0, 1, 2, 5, 6, or 7. In another specific embodiment the invention provides a compound of the formula (Ib5 I) wherein at least one of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5 I) wherein at least two of u, v, w or x are not zero. 259 In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein at least three of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of the formula (1b51) wherein at least four of u, v, w or x are not zero. 5 In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein at least two u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein at least three of u, v, w or x are not zero and at least two of the non-zero groups are not 10 the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein at least three of u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5 1) 15 wherein at least four of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein the sum of u, v, w and x is not zero. In another specific embodiment the invention provides a compound of the formula (lb5 1) 20 wherein at least one of u, or w are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein at least two of u, or w are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5 I) wherein at least one u is not zero, and at least one w is not zero. 25 In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of the formula (Ib5 I) 30 wherein both of u are not zero. In another specific embodiment the invention provides a compound of the formula (Ib5 I) wherein at least one of w is not zero. In another specific embodiment the invention provides a compound of the formula (Ib5 1) wherein both w are not zero. 260 In another specific embodiment the invention provides a compound of the following formula (Ib52): E'-V--Z'-Pu-Mo-A 0

-L

4 -Pu-Zv-Vw-Ex (Ib52). In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least one of u, v, w or x are not zero. 5 In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least two of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least three of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of the formula (Ib52) 10 wherein at least four of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least two u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib52) 15 wherein at least three of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least three of u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. 20 In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least four of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of the formula (Ib52) wherein the sum of u, v, w and x is not zero. 25 In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least one of u, or w are not zero. In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least two of u, or w are not zero. In another specific embodiment the invention provides a compound of the formula (Ib52) 30 wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Ib52) wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least one u is not zero. 261 In another specific embodiment the invention provides a compound of the formula (Ib52) wherein both of u are not zero. In another specific embodiment the invention provides a compound of the formula (Ib52) wherein at least one of w is not zero. 5 In another specific embodiment the invention provides a compound of the formula (1b52) wherein both w are not zero. 262 Compounds of formula (c) In one embodiment of the invention, the compound of formula (I) is a compound of formula (Ic): E-V-Z-P-M-A-A-M-P-Z-V-E (Ic) 5 wherein: each A is selected from -As; each M is selected from -M'; each P is selected from -P'; each Z is selected from -Z'; 10 each V is selected from -V"; each E is selected from -E'; each s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21; each t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; each u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, l3, or 14; 15 each v is 0, 1, 2, 3, 4, 5, or 6; each w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, l1, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21; each x is 0 or 1; wherein the sum of s, t, u, v, w, and x is not 0; each A 0 is independently:

(RA

3 )bb 20 wherein: each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, ab alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRa R, 25 (NRaRb)alkyl, and (NRaR )carbonyl; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each bb is independently 0, 1, 2, 3, or 4; or 263 each A 0 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 RA 3 groups; each A' is independently: 5 (RA1)9 wherein: each RAI is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, 10 (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each cc is independently 1, 2, 3, or 4; 1 5 each A 2 is independently:

(RA

3 )bb (RA1)cc wherein: each R^! is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , 20 haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, abb arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR , 25 (NRa R b)alkyl, and (NRaRb)carbonyl; Ra and R b are each independently selected from the group 264 consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 5 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bb and cc is 1, 2, 3, or 4; each A 3 is independently a six-membered heteroaromatic ring containing one, two, or three 10 nitrogen atoms, which ring is substituted with one or more RAI groups, and which ring is optionally substituted with one or more RA 3 groups; each A 4 is independently: [-HXAH5-XA 5-XA 15 wherein: each H5 is independently a phenyl ring or a six-membered heteroaromatic 20 ring, which H5 is optionally substituted with one or more groups independently selected from R A and R 3; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent 25 each A 5 is independently: XA H 6

-XA

wherein: 30 each H6 is independently a phenyl ring or a six-membered heteroaromatic ring, which H 6 is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; provided that at least one XA is present; 265 each A 6 is independently:

XA-XA-XA

5 wherein: each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, allenyl, alkynyl, or absent; provided that at least one X^ is present; 10 each A 7 is independently: XA- H 7

-XA

15 wherein: each H 7 is independently a five-membered heteroaromatic ring, which H7 is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and 20 each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; each A 8 is independently: 25 XA-H8-XA7-XA wherein: 30 each H7 is independently a five-membered heteroaromatic ring, which H 7 is optionally substituted with one or more groups independently selected from RAI and RA 3 ; each H 8 is independently a phenyl ring, which is optionally substituted with one or more groups independently selected from RA 1 and RA 3 ; and 266 each X is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; each A 9 is independently: 5 [XA-H7-XA 7-XA wherein: 10 each H 7 is independently a five-membered heteroaromatic ring, which H 7 is optionally substituted with one or more groups independently selected from RA' and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=O), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; 15 each A' 0 is independently: XA-H8-XA -H9XA wherein: 20 each H8 is independently a phenyl ring, which is optionally substituted with one or more groups independently selected from RAI and RA 3 ; each H 9 is independently a six-membered heteroaromatic ring, which is optionally substituted with one or more groups independently selected from RAI and RA 3 ; and 25 each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent each A 1 ' is independently: 30 XA 10 -XA_ wherein: 267 each XA is independently 0, NR, SO, S02, C(=O), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; each H10 is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that is optionally fused to an aryl, which H ' 0 is optionally 5 substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR"Rb, (NRaRb)alkyl, and (NRaRb)carbonyl, cyano, nitro, SOR 4, SO 2 R4, -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is 10 optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl each A 1 is independently: XA 11-XA 15 wherein: each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; 20 each H" is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that contains one or more heteroatoms that is optionally fused to an aryl, which H ' is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR, (NRaR)alkyl, and (NRaR )carbonyl, 25 cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR SO 2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and 30 each A' 3 is independently: 268 - 12-XA_ wherein: 5 each H1 2 is independently a fused aromatic bicyclic carbocycle, which is Al A3 optionally substituted with one or more groups independently selected from R and RA3; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; 10 each A' 4 is independently: XA 13-XA 15 wherein: each H 3 is independently a fused aromatic bicyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from RA1 and RA 3 ; and 20 each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; each A1 5 is independently: XAH14-XA 25 wherein: each H' 4 is independently a fused unsaturated, partially unsaturated or 30 saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from RA' and RA 3 ; and each XA is independently 0, NR, SO, SO2, C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; 269 each A' 6 is independently: X-XAH 15 -XA. 5 wherein: each H' 5 is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, 10 which ring system is optionally substituted with one or more groups independently selected from R and R A3; and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; 15 each A' 7 is independently: XA-H16

-

XA. 20 wherein: each H' 6 is independently a fused bicyclic carbocyclic ring system wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; 25 and each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; 30 each A' 8 is independently:

FXA-H

7

-XA

270 wherein: each H' 7 is independently a fused bicyclic ring system comprising at least one heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, 5 which ring system is optionally substituted with one or more groups independently selected from oxo, R and RA 3 ; and each XA is independently 0, NR, SO, S02, C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; 10 each A 2 ' is independently: XA H40-XA 15 wherein: each H 40 is independently an anti-aromatic monocyclic or fused carbocyclic ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from R and RA 3 ; and 20 each XA is independently 0, NR, SO, SO 2 , C(=0), NRC(=O), C(=0)NR, CR=CR, NRC(=O)NR, allenyl, alkynyl, or absent; each Mo is independently a five membered heteroaryl group optionally substituted with one or more alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NRaRl)carbonyl and 25 trialkylsilylalkoxyalkyl; each M' is independently selected from -C(=O)NH-, -C(=O)NH-C(R

M

)

2 -, -NHC(=O) -,

-C(RM)

2 NHC(=O)-, -NHC(=0)NRm-, -NHC(=0)O -; wherein each RM is independently selected from H and alkyl; 30 each M 2 is independently a six-membered heteroaromatic ring, which is optionally substituted with one or more groups independently selected from RAI and RA 3 ; 271 each M 3 is independently: H 5 each M4 is independently: N OH 10 each M 5 is independently: H N . N wherein the bond designated with --- is fused to a ring defined for P; 15 each M 6 is independently a bicyclic bridged ring system comprising 5-15 atoms wherein at least one of the atoms is a heteroatom; each M 7 is independently a pyrid-di-yl; 20 each M 8 is independently partially saturated or a saturated five-membered ring that comprises one or more heteroatoms and that is optionally substituted with one or two oxo; each M 9 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic 25 heterocyclic ring system that is optionally substituted with one or more Rp''L each M' 0 is independently a five membered heteroaryl group; 272 each M" is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more oxo halo, -RM 7 , OR7 -SR M7, -N(R M7)2, -CF 3 , -CCl 3 , -OCF 3 ,-CN, -NO 2 , -N(R m 7 )C(=O)R M 7 , -C(=O)R M 7 , -OC(=O)R M7, -C(O)OR 7 , -C(=0)NR 7, -S(=0)R 7, -S(=0) 2 0R 7 , -S(=0) 2 R 7 , -OS(=0) 2 0R M 7 or 5 -S(=0) 2 NR M7; each R M7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; each P 0 is independently: (RP)ps (RP6)pq F IX IX N pn N pm (R P5)P (R 6 )pq Po pp or RP 7 R P 8 10 Npm wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHR ", and C(RE 10 )2; provided that when pn or pm is 0, X is selected from CH 2 , CHRF 0 , and C(R ' 0

)

2 ; 15 each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NReaR P, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, 20 halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; RPa and Reb are each independently H, alkyl, aryl, or arylalkyl; or RPa and RPb taken together with the atom to which they are attached form a heterocycle; 25 pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 273 R' and R8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NRaRPb)alkyl; or R"' and R , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NRE, 0, and S; wherein RPZ is selected from hydrogen and alkyl; 5 RP 9 is selected from hydrogen and alkyl; each P 1 is independently: (R1 )ps IX Npn 10 wherein: X is selected from 0, S, S(0), SO 2 , CH 2 , CHRP' 0 , and C(RE' 0

)

2 ; provided that when pn is 0, X is selected from CH 2 , CHRP'U, and C(R P'O) 2 ; each RF' 0 is independently selected from alkoxy, alkyl, aryl, halo, 15 haloalkyl, hydroxy, and -NR R P, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; at least one RP1 1 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, 20 alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRh R )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR hhR h, (NRhhRh)alkyl, (NR hhR )carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 25 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, 30 (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=O)Rh, -C(=0)NRhR; and the remaining R1 are independently selected from R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 274 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 5 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; 10 each P 2 is independently: (R P12) IN IN pn 15 wherein: each Rm is independently selected from RE 5 , R ,-C(=O)OR , cyano, alkylsulfonyl, arylsulfonyl, (NR R h)Sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, 20 heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR Rh )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come 25 together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; each P 3 is independently a ring of the formula: 30 275 '3) N pn wherein: the ring is substituted with one or more oxo groups; 5 each RP" is independently selected from R", cyano, alkylsulfonyl, arylsulfonyl, (NRh R h)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, 10 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 0, 1, 2, 3, or 4; 15 pn is 0, 1, or 2; each P 4 is independently a ring of the formula: /Rf N pn 20 wherein: the ring is optionally substituted with one or more groups R 14 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NR PaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an 25 adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups RP' 4 that are attached to the same carbon 276 when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; pn is 0, 1, or 2; each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, 5 heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhRh, -S(=0) 2 Rh, C(=0)R , C(=0)OR , -C(=O)NRh R h; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 10 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 5 is independently a ring of the formula: pn Z 15 wherein: the ring is optionally substituted with one or more groups RP'' that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and 20 NRPaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R P15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; 25 pn is 0, 1, or 2; Z is 0, S, S(=0), S(=0) 2 , or NR; each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhRh, 30 -S(=0) 2 Rh, C(=0)Rh, C(=O)ORh, -C(=O)NRh Rh; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 277 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P 6 is independently a ring of the formula: 5 (f z wherein: the ring is substituted with one or more oxo and is optionally substituted with one 10 or more groups Rei that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; Z is 0, S, S(=0), S(=0) 2 , or NRC; 15 pn is 0, l, or 2; each Rf is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhR , -S(=0) 2 Rh, C(=0)Rh, C(=0)ORh, -C(=0)NRhRh; each Rh is independently -H, alkyl, 20 alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 25 each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from RP 6 and R' I; each P is independently a ring of the formula: 30 278 (RP1 3 )PS N pn wherein: ps is 2, 3, 4, 5, or 6; 5 pn is 0, 1 or 2; each R 13 is independently selected from alkoxy, alkyl, aryl, halo, PaPb haloalkyl, hydroxy, and -NRPaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least 10 one case two groups RP' 3 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring; each P' 0 is independently: 15 (R 5),S

(RP

6 )pq N PO X wherein: X is selected from 0, S, S(0), SO 2 , CH 2 , CHRP' 0 , and C(R"' 0

)

2 ; 20 provided that when pn or pm is 0, X is selected from CH 2 , CHRP' 0 , and C(R " 1

)

2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 25 each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, Pa Pb halo, haloalkyl, hydroxy, and -NR R , wherein the alkyl can optionally form a fused 279 three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; 5 po and pp are independently 1, 2, or 3; each P" is independently:

(RP

5 )ps (RP 6 )pq P0 ( IPP( po( N pn N M 10 wherein: X is selected from 0, S, S(O), S02, CH 2 , CHRP' 0 , and C(RP' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP' 0 , and C(R 10

)

2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, 15 haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, PPb halo, haloalkyl, hydroxy, and -NReaRP , wherein the alkyl can optionally form a fused 20 three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 25 each P' 2 is independently: 280

(RP

6 )pq pp N pm wherein: 5 each RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 10 pm is independently 0, 1, or 2; pp is independently 1, 2, or 3; ps is 1, 2, 3, or 4; RP' 1is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR R )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 15 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhhRh, (NRhhRh)alkyl, (NRhh Rh)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 20 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 R', -C(=O)Rh, 25 -C(=O)NRhRh; and the remaining R 1 '' are independently selected from RP 5 , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, 30 alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 281 h dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P' 3 is independently: 5 (R1 1), (RMP6 pn pp N pm wherein: X is selected from 0, S, S(O), SO 2 , or NRh 10 each RP6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR P, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 1 5 pq is independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2 but the sum of pn and pm is greater than zero; pp are independently 1, 2, or 3; ps is 1, 2, 3, or 4; 20 each R''1 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR R )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NRhhRh, (NRhhRh)alkyl, (NRhhRh)carbonyl, wherein each Rh is independently 25 -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; hh wherein each R is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, 30 alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 282 dialkylaminoalkyl, sulfonylalkyl, (NRh Rh)Sulfonyl, heteroarylsulfonyl, -S(=0) 2 Rh, -C(=O)Rh, -C(=O)NRh R , R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR R h)alkyloxy, 5 cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered 10 heterocyclic ring; each P 4 is independently:

(RP

6 )pq (R) ) N pm 15 wherein: the ring is substituted with one or more oxo group; X is NRf each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, 20 heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhh, -S(=0)2Rh, C(=0)R , C(=0)OR h, -C(=O)NRhRh; each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 25 dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each R is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRR Pb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is 30 optionally substituted with one or two alkyl groups; pq is independently 0, 1, 2, 3, or 4; 283 pm is independently 0, 1, or 2; ps is 1, 2, 3, or 4; RP 1 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 5 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, NRhRhalkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or sulfonylalkyl; and when 10 two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each -Z 0 - is -C(=O)- or -C(=S)-; 15 each -Z'- is independently a bond, or -C(Rzl)2-; wherein each RzI is independently H, alkyl, haloalkyl, or halo; each -Z 2 - is independently saturated or partially unsaturated (C 3

-C

8 )cycloalkyl that is optionally substituted with one or more groups independently selected from RA1 and RA3; 20 each -Z 3 - is independently saturated, partially unsaturated, or aromatic 4-8 membered heterocyclic or heteroaryl ring that is optionally substituted with one or more groups independently selected from R and R^3; 25 each -Z 4 - is independently: N

RZ

4 wherein each RZ 4 is independently H, alkyl, cyano, aryl, or heteroaryl; 30 each -Z 5 - is independently: 284 R4 -RZ 5 N wherein each RZ 5 is independently H, alkyl, cyano, aryl, or heteroaryl; or two RZ 5 s together with the nitrogen to which they are attached form a 4-8 membered heterocyclic ring that is 5 optionally substituted with one or more oxo and with one or more groups independently selected from RA and RA 3 ; each -Z 6 - is independently -C(RzI)- and is doublebonded to P; wherein RZI is independently H, alkyl, haloalkyl, or halo; 10 each E 0 is independently -NREcREd wherein REC and REd are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, 15 arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NRcRf)alkyl, (NR Rf)alkylcarbonyl, (NR*Rf)carbonyl, (NReRf)sulfonyl, -C(NCN)OR', and - C(NCN)NRxR , 20 wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NReRf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the 25 heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; 30 each El is independently -OC(=O)NREeREf wherein each REe and REf are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, 285 arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NReRf)alkyl, (NReRr)alkylcarbonyl, (NR*Rf)carbonyl, (NR*Rf)sulfonyl, 5 -C(NCN)OR', and - C(NCN)NRxRY, wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NReRf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl 10 part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; or wherein REc and REr, together with the nitrogen atom to which they are attached, form a heterocycle; 15 each V 0 is independently H, alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and 20 alkyl; and wherein arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; 25 and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen 30 and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; 286 and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRXRY, 5 (NRxRY)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, 10 haloalkoxy, haloalkyl, and nitro; each V' is independently cyanoalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from 15 hydrogen, alkenyl, and alkyl; each V 2 is independently haloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR VbC(=O)O-; Rva and RVb are each independently selected from 20 hydrogen, alkenyl, and alkyl; each V 3 is independently alkyl, which is substituted with one or more oxo, and which is optionally substituted with one or more groups independently selected from cycloalkyl, halo, aryl, alkenyl, and cyano; 25 each V 4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRaRbC(=0)O-; Ra and Rb are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V 5 is independently alkylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 35 287 each V 6 is independently arylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR bC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 5 each V 7 is independently heterocyclosulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 10 each V 8 is independently spirocycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 15 each V 9 is independently spirocycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRaR vbC(=O)O-; RVa and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 20 each V1 0 is independently fusedbicycliccycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl; 25 each V 1 is independently fusedbicycliccycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; RVa and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V 12 is independently bridged-bicycliccycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaR C(=O)O; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl; 35 288 each V 1 3 is independently bridged-bicyclic-cycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaR VbC(=O)O; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 5 each V 14 is independently aryloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRva R vbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 10 each V 15 is independently arylalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR VaRVbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 15 each V 16 is independently cycloalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR vaR C(=0)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 20 each V 17 is independently cycloalkylalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 25 each V1 8 is independently heterocyclooxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 30 each V 1 9 is independently heterocycloalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRVaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl; 35 289 each V20 is independently heteroaryloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaR VbC(=O)O-; Rva and RVb are each independently selected from hydrogen, alkenyl, and alkyl; and 5 each V 2 1 is independently heteroarylalkylalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; RVa and RVb are each independently selected from hydrogen, alkenyl, and alkyl. 10 In another specific embodiment of the invention the compound of formula (Ic) comprises: M 0

-A-A-M

0 , M 0

-A-A-M

9 , M 9 -A-A-M', or M 9

-A-A-M

9 , M' 0

-A-A-M

0 , M 0

-A-A-M'

0 ,

M'

0

-A-A-M

9 , M 9

-A-A-M'

0 , or M' 0

-A-A-M'

0 . 0 5 In another specific embodiment of the invention -A-A- is -AG-A -. In another specific embodiment of the invention -A-A- is -A -A -. 13n 13s 15 In another specific embodiment of the invention -A-A- is -A -A In another specific embodiment of the invention -A-A- is -A -A -. In another specific embodiment of the invention -A-A- is -A -A In another specific embodiment of the invention one A is A and one A is A 5 , wherein one XA in the A" 5 is absent and the other XA in the A 5 is alkynyl. 20 In another specific embodiment of the invention -A 0

-A

5 - has the following structure: / \3 In another specific embodiment of the invention one A is A and one A is A3, wherein both XA in the A'1 3 are absent. In another specific embodiment of the invention -A 0 -A1 3 - has the following structure: - \ / \ 25 In another specific embodiment of the invention A-A is A13 A 13 , wherein all XA in both A 13 are absent. In another specific embodiment of the invention -A "-A "- has the following structure: 290 In another specific embodiment of the invention A-A- is A 0 - A' wherein all XA in both the A 0 and the A'", are absent or alkynyl. In another specific embodiment of the invention -AG-A"- has the following structure: 5 In another specific embodiment of the invention the compound of formula (Ic) comprises one A 4 and one A 6 wherein all XA in the A' 3 are absent. In another specific embodiment of the invention-A 13A6- has the following structure: - / \ / In another specific embodiment of the invention M 0 is imidazolyl and M 9 is 10 benzimidazolyl. In another specific embodiment of the invention the compound of formula (Ic) comprises two A 0 and one M is M 9 . In another specific embodiment of the invention the compound of formula (Ic) comprises two A 0 and one M is MO and another M is M9. 15 In another specific embodiment of the invention the compound of formula (Ic) comprises

A

0 0

-M

9 which has the following structure: H N - ~ N In another specific embodiment of the invention the compound of formula (Ic) comprises 20 M 0

-A-A-M

9 . In another specific embodiment of the invention M 0

-A

0

-A

0

-M

9 has the following structure: H NN 25 In another specific embodiment of the invention the compound of formula (Ic) comprises

A

0

-A

7

-M

9 . In another specific embodiment of the invention A-A 7

-M

9 has the following structure: 291 Hl \/ ~ N In another specific embodiment of the invention the compound of formula (Ic) comprises one or two M and each M is Mo. In another specific embodiment of the invention the compound of formula (Ic) comprises 5 one or two M and each M is imidazolyl. In another specific embodiment of the invention the compound of formula (Ic) comprises one or two M and each M is M 9 . In another specific embodiment of the invention the compound of formula (Ic) comprises one or two M and each M is benzimidazolyl. 10 In another specific embodiment of the invention the compound of formula (Ic) comprises two M wherein one M is M 0 and one M is M 9 . In another specific embodiment of the invention the compound of formula (Ic) comprises two M wherein one M is imidazolyl and one M is benzimidazolyl. In another specific embodiment of the invention A-A is selected from: 15 - \ / \ and In another specific embodiment of the invention -M-A-A-M- is selected from

M

0

-A-A-M

0 , M-A-A-M 9 , M 9

-A-A-M

0 , and M 9

-A-A-M

9 . 20 In another specific embodiment of the invention the compound of formula (1c) M-A A-M is selected from M' 0

-A-A-M

0 , M 0

-A-A-M'

0 , M' 0

-A-A-M

9 , M 9

-A-A-M'

0 , and

M'

0

-A-A-M'

0 . In another specific embodiment of the invention each M is independently a 5-membered heteroaryl ring. 25 In another specific embodiment of the invention each M is 2,4-imidazoldiyl. In another specific embodiment of the invention M is M6. In another specific embodiment of the invention M is selected from: 292 and In another specific embodiment of the invention M is M 7 . In another specific embodiment of the invention M is: 5 HO-I In another specific embodiment of the invention M is M 8 . In another specific embodiment of the invention M is selected from the group consisting of: N N and N N NH A NH 10 o 0 0 In another specific embodiment of the invention Ma is: N N H. In another specific embodiment of the invention M is M 9 which is: 15 H N In another specific embodiment of the invention the sum of s, t, u, v, w, and x is not 0; In another specific embodiment of the invention at least two of s, t, u, v, w, and x are 20 other than 0. In another specific embodiment of the invention at least three of s, t, u, v, w, and x are other than 0. In another specific embodiment of the invention at least four of s, t, u, v, w, and x are other than 0. 25 In another specific embodiment of the invention at least five of s, t, u, v, w, and x are other than 0. 293 In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (Ic I): EU-VG-Z 0

-P-M

0 -A -A 6

-M-P-Z

0

-V

0

-E

0 (Ic I) or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ic) is a 5 compound of formula (Ic2): E 0

-V

0

-Z

0

-P-M

9 -A -A -M-P-Z -V -E' (Ic2) or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (1c3): E 0

-V

0

-Z

0

-P-M'

0

-A

3

-A

6 -M-P-Z-V-EU (Ic3) or a pharmaceutically acceptable salt, or prodrug thereof. 10 In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (1c4): E 0

-V

0

-Z

0 -P-M -A-A6-M-P-Z-V-E 0 (Ic4) or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (Ic5): E 0

-V

0

-Z

0

-P-M

0

-A

3

-A

0

-M-P-Z

0

-V

0

-E

0 (Ic5) or a pharmaceutically 15 acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (1c6): EU-V 0

-Z

0

-P-M

9 -A -A -M-P-Z -V -E (1c6) or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ic) is a 20 compound of formula (1c7): E 0 -V-Z"-P-Mia-A -A 0

-M-P-Z

0

-V

0

-E

0 (Ic7) or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (1c8): E 0

-V

0

-Z-P-M'"-A

3 -A 0

-M-P-Z

0

-V

0

-E

0 (Ic8) or a pharmaceutically acceptable salt, or prodrug thereof. 25 In another specific embodiment of the invention A 13-A is: - or In another specific embodiment of the invention the compound of formula (Ic) is: 294 _~~0 0 0 ~NH HH H NN A H - H N 0-~ _~~0 N N -- NN H -N- 0 0- _~0 // NH N\/H N~N N - N - H N 0 _FF >/ NH 0 NH N N N H N~ 0 HN 0 N0 N />NH 0 N N 0 - HN 50 or aphamaceticlly ccetabl sat, o prdrugtheeor 295 z In another specific embodiment of the invention the compound of formula (Ic) is: _~~0 H oN H N N £H - \ N 0 0

HN-

~~~00 0NH N- N N N -c N \ O N O O

HN-

_~~0 +NH N N H - N H ON O

HN-

0 4 NH O o0 N\ /\ H ON N N - - N N £H - \ N HN 4N H o0 . N\ /\ H N~N NN < H N0\/ 4Y-NH 0 0' ..

0 \ \ H 1 N H~ H H2 296 N _-0 I NH N HN N\ /\ H _0 0 N H N N -- N 0 0 0HN-e I/i 0-* NN 4 YNH N NN - HHNN I/I 00 N NN } NH HN N 0 N N I H ~~~ -N~ N40 NN _29 _00 4Y-NH H o >~~ - N N o D

N

0 _~~0 }-NH N \H N / 0 H HP/ N 0 NNH ~ N N H N 0 ~NH N / ' - HN 0 _~0 >NH 0 X--/ N/H H - N 0 - HN- 0 -29 _~~0 / NH 00 0N H N-0 H>N N H 0 0 }NH 0H N N II N N IH N \0\N _0 0 4 NH H 0 N NH } N AN\ N\ H N H N 0 />-NH 0 0 N\/ H NZ'N I £H - /~N 0 0 0 4 0-N NN 299 ~NH 'a- 0 N N I £H N \ N 0 -N/ 0 N H N N -- N N H -N/ ' 0 0 0 _~0 /Q-NH H 0 h0 N\/ - NN N N ~ N 0 4~ 0 H HN 0 0 N0 +NHI o *w ,, N\ /\I- N N H HN 0 0 0

HN

Ii; 0 N 300 O YNH HNN 0 or O0 0 NH N N 0 HN- O 0 or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (1c9): 5 0 EO-VA P-M-A-A-M---P V -E (Ic9) or a pharmaceutically acceptable salt, or prodrug thereof. In another specific embodiment of the invention the compound of formula (Ic) is a 10 compound of formula (Ic 10): O N, M-A-A-M N O''j' (Ic 10) H-'N YON, 0 or a pharmaceutically acceptable salt, or prodrug thereof. 15 In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (Ic 1): 301 ON NH HH A A N' O compound of formula (Ic9), (Ic10), or (Icd ) wherein -A-A- is -A4-A 6 5 In another specific embodiment of the invention the compound of formula (Ic) is a compound of formula (1c9), (Ic10), or (Ic 1) wherein -A-A- is -A "-A'-. In one embodiment of the invention, the compound of formula (I) is a compound of formula (Ic 12): 10 EO-V"-ZO-P"-Mt-As1-As2 -Pu-ZO-V"-Eo (Ic 12) or a pharmaceutically acceptable salt, or prodrug thereof, wherein: each u is independently 0, 1, 3, 5, 7, 8, 10, or 11; each w is independently 0, 1, 2, 3, 4, or 5; each tI is 0 or 10; each t2 is 0 or 10; each sl is 4, 5, 6, 13, 14, 15, or 16; and each s2 is 0, 4, or 13. 15 In one embodiment the invention provides a compound of formula (Ic 12) wherein MO is: H In one embodiment the invention provides a compound of formula (Ic 13) 0 o N-V--- O H A H O V--N O ic3 N 0-,(1c13) 0 20 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic 13) wherein A-A is

A

0

-A

13 and is selected from: and 302 In one embodiment the invention provides a compound of formula (Ic 14) 0 ON- 0 H N\N o v- N Oa N (Ic14) 0 or a pharmaceutically acceptable salt, or prodrug thereof. 5 In one embodiment the invention provides a compound of formula (Ic 12) which is: 0 H -- R V H 0 H V VO\ \ /\ /N 0 V--NOo N N- 0 H or H H A N N p v N O H 0 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic 12) which is: H 0 N v - , o R V - - -N O 0% 0~i& - H 0 10 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic 13) wherein A-A is A -A4 and is: 15 In one embodiment the invention provides a compound of formula (Ic12) which is: j H 01- 1 ~ { H 0 N v - , o R V - - ~ N O H0 or a pharmaceutically acceptable salt, or prodrug thereof. 303 In one embodiment the invention provides a compound of formula (Ic13) wherein A-A is

A

0

-A'

4 and is: S 5 In one embodiment the invention provides a compound of formula (Ic 12) which is: H H ! / \ NN, , H 0 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic13) wherein A-A is 10 A "-A 4 and is: In one embodiment the invention provides a compound of formula (Ic 12) which is: H N P H o N-V -,fo S N H I'-N \/- I N0 V N, - \/ 0 H 15 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic 13) wherein A-A is A"-A'" and is: 20 In one embodiment the invention provides a compound of formula (Ic 12) which is: H 0 _v__ -o N p H

-

0 V - , _ H3O 304 or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic 13) wherein A-A is A 1s-A6 and is: F \ / \ / - 5 In one embodiment the invention provides a compound of formula (Ic 12) which is: FH 0P N, NO- V H !'N N - -V N H O or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic 13) wherein A-A is A 4

-A

6 and is: 10 S In one embodiment the invention provides a compound of formula (Ic12) which is: H O -- v 0 S y ---- OH H 0 or a pharmaceutically acceptable salt, or prodrug thereof. 15 In one embodiment the invention provides a compound of formula (Ic13) wherein A-A is A 1-A6 and is: In one embodiment the invention provides a compound of formula (Ic 12) which is: H -- N P H H N_ O V-N 20 0 or a pharmaceutically acceptable salt, or prodrug thereof. 305 In one embodiment the invention provides a compound of formula (Ic 13) wherein A-A is A '-A 6 and is: 5 In one embodiment the invention provides a compound of formula (Ic 12) which is: 0 - N OH H V H N or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic13) wherein A-A is

A

0

-A

5 and is: 10 In one embodiment the invention provides a compound of formula (Ic 12) which is: 0 V 0 --- N O 0Hj \/ P N

N

0 H 0 or a pharmaceutically acceptable salt, or prodrug thereof. 15 In one embodiment the invention provides a compound of formula (Ic 13) wherein A-A is

A

0

-A

5 and is: In one embodiment the invention provides a compound of formula (Ic 12) which is: H 0 y o vN---N O H 'P N R -H\ 20 H0 or a pharmaceutically acceptable salt, or prodrug thereof. 306 In one embodiment of the invention, the compound of formula (I) is a compound of formula (Ic 15): EO-Vw-ZO-Pu-Mt-A'-A -Mt-P"-ZO-V"-Eo (Ic 15) 5 or a pharmaceutically acceptable salt, or prodrug thereof, wherein: each u is independently 0, 1, 3, 5, 7, 8, 10, or 11; each w is independently 0, 1, 2, 3, 4, or 5; each tl is 0, 10, or 13; t2 is 9; sl is 4, 5, 6, 13, 14, 15, or 16; and s2 is 0, 4, or 13. In one embodiment of the invention, the compound of formula (I) is a compound of formula (Ic 16): 10 EO-VWZO-Pu-Mt-AsI-A s 2 -MaPu-Z0o-Vw-Eo (Ic 16) or a pharmaceutically acceptable salt, or prodrug thereof, wherein: each u is independently 0, 1, 3, 5, 7, 8, 10, or 11; each w is independently 0, 1, 2, 3, 4, or 5; each tI is 9; t2 is 0, 10, or 13; s I is 4, 5, 6, 13, 14, 15, or 16; and s2 is 0, 4, or 13. 15 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein MO is: N_ H. In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein M 9 is: H 20N In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein A-A is A-A' 3 and is: 25 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) which is selected from: 307 H and N O H and pharmaceutically acceptable salts and prodrugs thereof. In one embodiment the invention provides a compound of formula (Ic15) or (Ic 16) wherein A-A is A0-A3 and is: 5 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) which is selected from: 0/ -f N < 0 -vv-N 0" H 1 - /X\ -- .. H H 0 ___~ an-Npan 0 H 0 N----v N H ' 0 V-N Y 0" H 0 10 and pharmaceutically acceptable salts and prodrugs thereof. In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein A-A is A-A4 and is: I5 In one embodiment the invention provides a compound of formula (Ic15) or (Ic16): H N p 00 ITH- \$ \/ \/ \/N H 0 or a pharmaceutically acceptable salt or prodrug thereof. 308 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein A-A is A-A4 and is: 5 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) which is selected from: H 0 NNp o v__ vS H S H H 0 -o N o- V -H and S 0NN 0 HN P I, ]-Y0 H 0 and pharmaceutically acceptable salts and prodrugs thereof. 10 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein A-A is A3A 14 and is: - S 15 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) which is selected from: H 0 N H 0 N- 0~N S N 0 -N 0" H o Np and 0 N V>,,o.\ \/ \N 0 V-N 0" H N1 -] 0 and pharmaceutically acceptable salts and prodrugs thereof. 309 In one embodiment the invention provides a compound of formula (Ic15) or (Ic16) wherein A-A is A13-A and is: 5 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16): H 0 N V 0 N - H H P V-N O H 0 or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment the invention provides a compound of formula (Icl5) or (Ic16) 10 wherein A-A is A 1-A6 and is: FF In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) which 15 is selected from: 0 F H OJL N-

-

V -pO O V N VOH H FN 0 and N_ p/\ H V- afV-N 1 0" H 0 and pharmaceutically acceptable salts and prodrugs thereof. In one embodiment the invention provides a compound of formula (Ic15) or (Ic16) wherein A-A is AO-A5 and is: 20 310 In one embodiment the invention provides a compound of formula (Ic15) or (Ic16): H 0 -v O H O 5 or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein A-A is A-A5 and is: 10 In one embodiment the invention provides a compound of formula (Ic15) or (Ic 16) which is selected from: H H, \ \/ - / N p~ H N P H H and O O -- - v 0 0 V - N O11 H O and pharmaceutically acceptable salts and prodrugs thereof. 15 In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein A-A is A 4

-A

6 and is: S 20 In one embodiment the invention provides a compound of formula (Ic I5) or (Ic 16) which is selected from: 311 H S H o -v o \I-o V o H H and O o -- -o o~- H- o 0~~r HHO \ I V ~ O 0 ~ ~ ~ N-- , O 0 HO and pharmaceutically acceptable salts and prodrugs thereof. In one embodiment the invention provides a compound of formula (Ic15) or (Ic16) wherein A-A is A -A6 and is: 5 In one embodiment the invention provides a compound of formula (Ic15) or (Ic16) which is selected from: H 0 --- v o O% H -- V O V-N O 0 0 and _ -IT- H P N N I H0 V-N YO0 10 0 and pharmaceutically acceptable salts and prodrugs thereof. In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) wherein A-A is A' -_A 6and is: 0 15\/ / In one embodiment the invention provides a compound of formula (Ic 15) or (Ic 16) which is selected from: 312 H ON-vo, HH 0 and 0 v 0 NO 'HH Po v--- O 0 and pharmaceutically acceptable salts and prodrugs thereof. In one embodiment the invention provides a compound of formula (Ic 17) or (Ic 18)

EO-V

5 E- P-M M-P -E or (Ic17) EO-V S 0-P -v P-M M-P-E o S V-EO (Ic 18) wherein: 10 each P is independently selected from: N NN NC O NN N N andN SH ; and each M is independently MO, M 9 , or M' ; 15 or a pharmaceutically acceptable salts or prodrug thereof. In one embodiment the invention provides a compound of formula (Ic 17) or (Ic 18) wherein each E 0 is methoxycarbonylamino. 313 In one embodiment the invention provides a compound of formula (Ic 17) or (Ic 18) wherein at least one E 0 is -NREcREd wherein REC is H, alkyl or cycloalkyl and REd is heterocycle. In another specific embodiment the invention provides a compound of the following formula (1c30): E.-V"-Z.-P"-M'-A.-A'-Mt -Pu-Z-Vw-E (Ic30) wherein at least two of s, t, u, v, 5 w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ic30) wherein at least one of u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (Ic30) wherein at least one t is 0 or 10. 10 In another specific embodiment the invention provides a compound of formula (Ic30) wherein both t are 9; one s is 0; and one s is 0,1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21. In another specific embodiment the invention provides a compound of formula (Ic30) wherein both t are 9; one s is 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, or 21; 15 and one s is 0,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, or 21. In another specific embodiment the invention provides a compound of formula (Ic30) wherein at least two of s, t, u, v, w or x are not zero and at least one t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11 In another specific embodiment the invention provides a compound of formula (1c30) 20 wherein at least three of s, t, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ic30) wherein at least two of s, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (1c30) 25 wherein at least three of s, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ic30) wherein at least three of s, t, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. 30 In another specific embodiment the invention provides a compound of formula (Ic30) wherein at least four of s, t, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ic30) wherein at least four of s, t, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. 314 In another specific embodiment the invention provides a compound of formula (1c30) wherein at least four of s, t, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ic30) 5 wherein at least four of s, t, u, v, w or x are not zero and at least four of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ic30) wherein the sum of t, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (1c30) 10 wherein the sum of s, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (Ic3O) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of formula (1c30) wherein s, and at least one t, and at least one u are all not zero. 15 In another specific embodiment the invention provides a compound of formula (Ic3O) wherein at least two of u, w and t are not zero. In another specific embodiment the invention provides a compound of formula (Ic3O) wherein at least two of s, u, and w are not zero. In another specific embodiment the invention provides a compound of formula (Ic3O) 20 wherein at least two of s, u, and w are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ic30) wherein at least s and both u are not zero. In another specific embodiment the invention provides a compound of formula (Ic30) 25 wherein at least two of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ic3O) wherein at least one of u, or w is not zero. In another specific embodiment the invention provides a compound of formula (1c30) 30 wherein at least two of u or w are not zero. In another specific embodiment the invention provides a compound of formula (1c30) wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (1c30) wherein at least two of u are not zero. 315 In another specific embodiment the invention provides a compound of formula (1c30) wherein at least one of w is not zero. In another specific embodiment the invention provides a compound of formula (1c30) wherein at least two of w are not zero. 5 In another specific embodiment the invention provides a compound of formula (Ic3O) wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Ic3O) wherein both t are 9; one s is 0; and one s is 0, 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, or 21. 10 In another specific embodiment the invention provides a compound of formula (1c30) wherein both t are 9; one s is 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, or 21; and one s is 0,l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, or 21. In another specific embodiment the invention provides a compound of the following formula (Ic3 1): Ex-V"-Zv-P"-M 9

-AS-AS-M

9 -P"-Zv-V"-E' (Ic3 1) wherein one s is 0 or 6 and one s 15 is6. In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein at least one of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein at least two of u, v, w or x are not zero. 20 In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein at least three of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein at least four of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (1c3 1) 25 wherein at least two u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein at least three of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. 30 In another specific embodiment the invention provides a compound of formula (1c3 1) wherein at least three of u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Ic31) wherein at least four of u, v, w or x are not zero and at least two of the non-zero groups are not 35 the same letter. 316 In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein the sum of u, v, w and x is not zero. In another specific embodiment the invention provides a compound of formula (1c3 1) wherein at least one of u or w are not zero. 5 In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein at least two of u or w are not zero. In another specific embodiment the invention provides a compound of formula (1c3 1) wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Ic3 1) 10 wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein both of u are not zero. 15 In another specific embodiment the invention provides a compound of formula (Ic3 1) wherein at least one of w is not zero. In another specific embodiment the invention provides a compound of formula (Ic31) wherein both w are not zero. 20 Compounds of formula (Id) In one embodiment of the invention, the compound of formula (I) is a compound of formula (Id): EU-Vw-Z'-P"-L" -Ln2-P"-ZO-V"-Eo (Id) 25 wherein: n] is 3, 4, or 9; n2 is 9; each u is 0, 1, 3, 5, 7, 8, 10, or 11; each w is 0, 1, 2, 3, 4, or 5; 30 each L 3 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, (NRaR b)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, 317 (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and R b are independently selected from the group consisting of hydrogen, alkenyl, 5 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L 4 is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently 10 selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaR', (NRaRb)alkyl, (NRaRb)carbonyl, cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; 15 each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and Ra and Rb are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 20 each L 9 is independently a fused-tetracyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -RL 7 , -OR L7, -SR L7, -CF 3 , -CC1 3 , -OCF 3 ,-CN, -NO 2 , -N(R L)C(=O)R L7, -C(=)R L7, -OC(=0)R 7, -C(O)OR L7, -C(=0)NR L7, -S(=0)R L7, S(=) 2 OR L7, -S(=0) 2 R L7

OS(=O)

2 OR L7 -S(=0) 2 NR U, alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, 25 -NRaR', (NRaRb)alkyl, and (NRaRb)carbonyl; each R L is independently -H, alkyl, aryl, arylalkyl, or heterocycle; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 30 each P0 is independently: 318 (RPs)ps (RP6eP I-x I-x N pn N pm (R, (Rpq po PP R

N

7 R P 8 wherein: X is selected from O, S, S(O), SO 2 , CH 2 , CHR ", and C(R" 0 ) 2 ; 5 provided that when pn or pm is 0, X is selected from CH 2 , CHR" 0 , and C(R 10

)

2 ; each RP1 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 10 each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, PaPb halo, haloalkyl, hydroxy, and -NRPaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; RPa and R are each independently H, alkyl, aryl, or arylalkyl; or RPa and RPb taken together with the atom to which they are 15 attached form a heterocycle; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; R' and RP 8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, 20 alkyl, haloalkyl, and (NRPaReb)alkyl; or Rp and R 8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NRN', 0, and S; wherein R "' is selected from hydrogen and alkyl;

RP

9 is selected from hydrogen and alkyl; each P1 is independently: 25 319

(RP

1 1) I-x IN pn wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHR'", and C(RP' 0

)

2 ; 5 provided that when pn is 0, X is selected from CH 2 , CHR ', and C(R E )2; each RP 10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 10 at least one R 1'' is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR hhR h, (NR hR h)alkyl, 15 (NRhhR h)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, 20 heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 R h, -C(=O)R , -C(=O)NRh R; and the remaining RP' I are independently selected from R , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, 25 haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two 30 Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; 320 pn is 0, 1, or 2; each P 3 is independently a ring of the formula: (R P13)S Npn 5 wherein: the ring is substituted with one or more oxo groups; each RP" is independently selected from R 5 , cyano, alkylsulfonyl, 10 arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, 15 alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 0, 1, 2, 3, or 4; pn is 0, 1, or 2; 20 each P 5 is independently a ring of the formula: (f z 25 wherein: the ring is optionally substituted with one or more groups R 1' 5 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one 321 or two alkyl groups; and where two groups R P" that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; pn is 0, 1, or 2; 5 Z is 0, S, S(=0), S(=0) 2 , or NRr each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRhR , -S(=0) 2 Rh, C(=O)Rh, C(=O)ORh, -C(=O)NRhRh; each Rh is independently -H, alkyl, 10 alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 15 each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from RP 6 and R '"; each P 8 is independently a ring of the formula: 20

(RP

1 3 ) , ') N pn wherein: ps is 2, 3, 4, 5, or 6; 25 each R 1 3 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NReaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups RP' 3 that are attached to the same carbon are taken 30 together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring; 322 each P' 0 is independently:

(RP

5 )P, (R P6) I P )Pp po N> 7P 5 wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHR '", and C(RP' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP'", and C(R ' 0

)

2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR PaR Pb, wherein the alkyl can optionally form a fused three 10 to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each Re 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered 15 ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 20 each P" is independently: (RP5)PS (RP 6 )pq po( X wherein: 25 X is selected from 0, S, S(0), SO 2 , CH 2 , CHR 'O, and C(R ' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP' 0 , and C(R ' 0

)

2 ; 323 each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 5 each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; pq and ps are independently 0, 1, 2, 3, or 4; 10 pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; each -Z 0 - is -C(=0)- or -C(=S)-; 15 each EO is independently -NREcREd wherein R Ec and REd are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, 20 heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR*Rr)alkyl, (NR*Rf)alkylcarbonyl, (NR*Rr)carbonyl, (NR*Rr)sulfonyl, -C(NCN)OR', and - C(NCN)NRxRY, wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are 25 further optionally substituted with one -NR*Rr group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with 30 one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; each V 0 is independently H, alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, 324 aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups 5 independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, 10 heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRxRy)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the 15 heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, 20 heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, (NRxRy)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, 25 two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; each V 1 is independently cyanoalkyl, which is optionally substituted with one or more groups 30 independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 2 is independently haloalkyl, which is optionally substituted with one or more groups 35 independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 325 heteroaryl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 3 is independently alkyl, which is substituted with one or more oxo, and which is 5 optionally substituted with one or more groups independently selected from cycloalkyl, halo, aryl, alkenyl, and cyano; and each V4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 10 heteroaryl, hydroxy, and NRaRbC(=O)O-; Ra and Rb are each independently selected from hydrogen, alkenyl, and alkyl; and each V 5 is independently alkylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 15 heteroaryl, hydroxy, and NRvR vbC(=O)O-; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl. In one embodiment the invention provides a compound of formula (Id) wherein each L is benzimidazolyl. 20 In one embodiment the invention provides a compound of formula (Id 1) or (Id2) which is selected from: H L_ X-X V-N O (Id1) 0 Y V ~0 / -and H L N I H H H o -v-N o ,'(W (1d2) 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, 0-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 25 In one embodiment the invention provides a compound of formula (Id) wherein L 9 is: 326 x-x H In one embodiment the invention provides a compound of formula (Id) wherein L 9 is: x-x H . In one embodiment the invention provides a compound of formula (1d3) or (Id4) which 5 is selected from: x-x 0 N -O N H

N

x-x x-x N V P/ P V N O (1d3) 0 \~ N - \ Nk 0 ----O ~ - -- H N O (I 4 Hee - H H and -0 H 0 -V-NY 0--(1d4) 0 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-C-

2 , CH- 2 -O, O-CH 2 , CH 2

-CH-

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. In one embodiment the invention provides a compound of formula (Id) wherein L 3 is: H - N 10 In one embodiment the invention provides a compound of formula (Id5) or (d6) which is selected from: 327 H, x-x N V O N O V a O ( 1d5) NH V-N O (d6) N 0 wherein X-X is selected from 0, CH 2 , CH=CH-, CH 2

-CH

2 , CH- 2 -0, 0-CH 2 , CH 2

-CH

2

-CH-

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 5 In one embodiment the invention provides a compound of formula (Id) wherein L 4 is: H In one embodiment the invention provides a compound of formula (Id5) or (Id6) which is selected from: -X/ N \ / N N H N H -0 H N(18) 0 10 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, 0-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 15 328 5 In another specific embodiment the invention provides a compound of the following formula (1d30): EP-V'-Z'-P"-L"n-L" -Pu-Zv-V'-E' (1d30); wherein at least one of u, v, w or x are 10 not zero. In another specific embodiment the invention provides a compound of formula (Id30) wherein one n is 0, 1, 2, 4, 5, 6, 7, 8, 9, or 10; and one n is 1, 2, 3, 5, 6, 7, 8, 9, or 10. In another specific embodiment the invention provides a compound of formula (1d30) wherein at least two of n, u, v, w or x are not zero. 15 In another specific embodiment the invention provides a compound of formula (1d30) wherein at least two of n, u, v, w or x are not zero and at least one n is selected from 0, 1, 2, 4, 5, 6, 7, 8, and 10 In another specific embodiment the invention provides a compound of formula (Id3O) wherein at least two of n, u, v, w or x are not zero and at least one n is selected from 0, 1, 2, 3, 5, 20 6, 7, 8, and 10 Wherein at least three of n, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (1d30) wherein at least two of n, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. 25 In another specific embodiment the invention provides a compound of formula (1d30) wherein at least three of n, u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Id3O) wherein at least three of n, u, v, w or x are not zero and at least three of the non-zero groups are 30 not the same letter. In another specific embodiment the invention provides a compound of formula (Id30) wherein at least four of n, u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (1d30) wherein at least four of n, u, v, w or x are not zero and at least two of the non-zero groups are 35 not the same letter. 329 In another specific embodiment the invention provides a compound of formula (1d30) wherein at least four of n, u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (1d30) 5 wherein at least four of n, u, v, w or x are not zero and at least four of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (1d30) wherein the sum of n, u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (1d30) 10 wherein the sum of u, v, w or x is not zero. In another specific embodiment the invention provides a compound of formula (1d30) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of formula (1d30) wherein at least one n, and at least one u are all not zero. 15 In another specific embodiment the invention provides a compound of formula (1d30) wherein at least two of u, w and n are not zero. In another specific embodiment the invention provides a compound of formula (Id30) wherein at least two of u, and w are not zero. In another specific embodiment the invention provides a compound of formula (1d30) 20 wherein at least two of u, and w are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Id30) wherein at least w and both u are not zero. In another specific embodiment the invention provides a compound of formula (1d30) 25 wherein at least two of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (1d30) wherein at least one of u, or w is not zero. In another specific embodiment the invention provides a compound of formula (Id30) 30 wherein at least two of u, or w are not zero. In another specific embodiment the invention provides a compound of formula (Id30) wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Id30) wherein at least two of u are not zero. 330 In another specific embodiment the invention provides a compound of formula (Id30) wherein at least one of w is not zero. In another specific embodiment the invention provides a compound of formula (Id30) wherein at least two of w are not zero. 5 In another specific embodiment the invention provides a compound of formula (Id3O) wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of the following formula (1d3 1): E'-V"-Zv-P"-L3-L' -PU-Z'-V"-Ex (Id31). In another specific embodiment the invention provides a compound of formula (Id3 I) 10 wherein at least one of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Id3 1) wherein at least two of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Id3 1) wherein at least three of u, v, w or x are not zero. 15 In another specific embodiment the invention provides a compound of formula (Id31) wherein at least four of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (Id3 I) wherein at least two u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. 20 In another specific embodiment the invention provides a compound of formula (Id3 I) wherein at least three of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Id3 I) wherein at least three of u, v, w or x are not zero and at least three of the non-zero groups are not 25 the same letter. In another specific embodiment the invention provides a compound of formula (Id3 1) wherein at least four of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (Id3 I) 30 wherein the sum of u, v, w and x is not zero. In another specific embodiment the invention provides a compound of formula (Id31) wherein at least one of u, or w are not zero. In another specific embodiment the invention provides a compound of formula (Id3 1) wherein at least two of u, or w are not zero. 331 In another specific embodiment the invention provides a compound of formula (ld3 1) wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Id3 1) wherein both u are not zero, and at least one w is not zero. 5 In another specific embodiment the invention provides a compound of formula (1d3 1) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of formula (Id3 1) wherein both of u are not zero. In another specific embodiment the invention provides a compound of formula (Id3 1) 10 wherein at least one of w is not zero. In another specific embodiment the invention provides a compound of formula (Id3 1) wherein both w are not zero. In another specific embodiment the invention provides a compound of the following formula (1d32): Ex-V"'-Zv-Pu-L-L 4 -Pu-Z-Vw-Ex (Id32). 15 In another specific embodiment the invention provides a compound of formula (1d32) wherein at least one of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (1d32) wherein at least two of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (1d32) 20 wherein at least three of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (1d32) wherein at least four of u, v, w or x are not zero. In another specific embodiment the invention provides a compound of formula (1d32) wherein at least two u, v, w or x are not zero and at least two of the non-zero groups are not the 25 same letter. In another specific embodiment the invention provides a compound of formula (1d32) wherein at least three of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (1d32) 30 wherein at least three of u, v, w or x are not zero and at least three of the non-zero groups are not the same letter. In another specific embodiment the invention provides a compound of formula (1d32) wherein at least four of u, v, w or x are not zero and at least two of the non-zero groups are not the same letter. 332 In another specific embodiment the invention provides a compound of formula (1d32) wherein the sum of u, v, w and x is not zero. In another specific embodiment the invention provides a compound of formula (1d32) wherein at least one of u, or w are not zero. 5 In another specific embodiment the invention provides a compound of formula (1d32) wherein at least two of u, or w are not zero. In another specific embodiment the invention provides a compound of formula (1d32) wherein at least one u is not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (1d32) 10 wherein both u are not zero, and at least one w is not zero. In another specific embodiment the invention provides a compound of formula (Id32) wherein at least one u is not zero. In another specific embodiment the invention provides a compound of formula (1d32) wherein both of u are not zero. 15 In another specific embodiment the invention provides a compound of formula (Id32) wherein at least one of w is not zero. In another specific embodiment the invention provides a compound of formula (1d32) wherein both w are not zero. 20 Compounds of formula (le) In one embodiment of the invention, the compound of formula (I) is a compound of formula (le): E -V"-Z'-P"-Y2_Pu-Z0-V"-E0 (le) wherein: 25 each u is 0, 1, 3, 5, 7, 8, 10, or 11; each w is 0, 1, 2, 3, 4, or 5; each Y2 is independently: a fused five to eight ring system with up to thirty-two atoms that may be fully aromatic or partially saturated and contains atoms selected from C, N, 0, S, S02, SO and which ring system 30 is optionally substituted with one or more groups independently selected from H, oxo, RA' and

RA

3 ; each R is independently selected from cyano, nitro, SOR 4 , S0 2

R

4 , -alkylSO 2

R

4 , haloalkoxy, cyanoalkyl, NR 4

SO

2

R

4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, 333 (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; each RA 3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NRaRb 5 (NRaRb)alkyl, and (NRaRb)carbonyl; Ra and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; Ra and R are independently selected from the group consisting of hydrogen, alkenyl, 10 alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each P 0 is independently:

(RP

5 )ps (RP6) -X -X N pn N Pm

(RP

5 ),S (R P6 ) o pp or R PV RP _N pn F N PM N __R9 15 wherein: X is selected from 0, S, S(0), SO 2 , CH 2 , CHReic, and C(RP' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR 10 , and C(RP' 0

)

2 ; 20 each R"1 0 is independently selected from alkoxy, alkyl, aryl, halo, Pa RPb haloalkyl, hydroxy, and -NRaR , wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, 25 halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; RPa and R Pb are each independently 334 H, alkyl, aryl, or arylalkyl; or RPa and RPb taken together with the atom to which they are attached form a heterocycle; pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; 5 po and pp are independently 1, 2, or 3; R'7 and RP 8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, Pa Pb P alkyl, haloalkyl, and (NR R )alkyl; or R7 and R 8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NRPz, 0, and S; wherein RPz is selected from hydrogen and alkyl; 10 R9 is selected from hydrogen and alkyl; each P 1 is independently:

(R

1 1)ps I-x ypn 15 wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHR ", and C(RP' 0

)

2 ; provided that when pn is 0, X is selected from CH 2 , CHRP' 0 , and C(RP P) 2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three 20 to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; at least one R " is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NRh R )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, 25 heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR R h)alkyloxy, cyanoalkoxy, hh h hh h cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR R , (NR R )alkyl, (NR R h)carbonyl, wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two 30 Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each Rhh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, 335 haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NRhRh)sulfonyl, heteroarylsulfonyl, -S(=0) 2 R h, -C(=0)Rh, -C(=0)NRh R; and the remaining R" 1are independently selected from R , cyano, alkylsulfonyl, arylsulfonyl,(NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, 5 alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NRhRh)alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, 10 dialkylaminoalkyl, sulfonylalkyl; and when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; ps is 1, 2, 3, or 4; pn is 0, 1, or 2; 15 each P 3 is independently a ring of the formula: (RP1 3 )PS N pn wherein: 20 the ring is substituted with one or more oxo group; each RP is independently selected from R 5 , cyano, alkylsulfonyl, arylsulfonyl, (NRhRh)sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR R h)alkyloxy, cyanoalkoxy, 25 cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each Rh is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 30 ps is 0, 1, 2, 3, or 4; pn is 0, 1, or 2; 336 each P 5 is independently a ring of the formula: pn Cz 5 wherein: the ring is optionally substituted with one or more groups R 15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an 10 adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups Ri that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring; pn is 0, 1, or 2; 15 Z is 0, S, S(=0), S(=0) 2 , or NRf; each Rr is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, -S(=0) 2 NRR ,

-S(=O)

2 Rh, C(=O)Rh, C(=O)ORh, -C(=0)NRhRh; each Rh is independently -H, alkyl, 20 alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two Rh groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; 25 each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R 'and R "; each P 8 is independently a ring of the formula: 30 337

(RP

1 )p '3) N pn )1,Pfl wherein: ps is 2, 3, 4, 5, or 6; 5 each RP' 3 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaRPb, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups R 13 that are attached to the same carbon are taken 10 together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring; each P' 0 is independently: (RPs) (RP 6 )pq I X N po N" 15 wherein: X is selected from 0, S, S(O), SO 2 , CH 2 , CHRP' 0 , and C(RP' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP'", and C(RE 10

)

2 ; 20 each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, Pa RPb haloalkyl, hydroxy, and -NRaR , wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, 25 halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 338 pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; 5 each P" is independently: (RP5),, (RP6)pq po( X P N pn N wherein: 10 X is selected from 0, S, S(O), SO 2 , CH 2 , CHR'", and C(RP' 0

)

2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHRP' 0 , and C(RPlO) 2 ; each RP' 0 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPaR b, wherein the alkyl can optionally form a fused three to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered 1 5 ring is optionally substituted with one or two alkyl groups; each RP 5 and RP 6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NRPa R b, wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; 20 pq and ps are independently 0, 1, 2, 3, or 4; pm and pn are independently 0, 1, or 2; po and pp are independently 1, 2, or 3; each -Z 0 - is -C(=O)- or -C(=S)-; 25 each E 0 is independently -NREcREd wherein REc and REd are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, 30 cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, 339 heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NRCRf)alkyl, (NR*Rf)alkylcarbonyl, (NR*R )carbonyl, (NRCRf)sulfonyl, -C(NCN)OR', and - C(NCN)NRxR , wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are 5 further optionally substituted with one -NR"Rf group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with 10 one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; each V 0 is independently H, alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, 15 aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, 20 heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, 25 (NRXRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents 30 independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, 35 (NRxRY)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are 340 unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, 5 haloalkyl, and nitro; each V 1 is independently cyanoalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 10 heteroaryl, hydroxy, and NR vaR C(=O)O-; Rva and R are each independently selected from hydrogen, alkenyl, and alkyl; each V2 is independently haloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, 15 heteroaryl, hydroxy, and NR aR C(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; each V 3 is independently alkyl, which is substituted with one or more oxo, and which is optionally substituted with one or more groups independently selected from cycloalkyl, halo, 20 aryl, alkenyl, and cyano; each V 4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRaR C(=0)O-; Ra and Rb are each independently selected from 25 hydrogen, alkenyl, and alkyl; and each V 5 is independently alkylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NRva R vbC(=O)O-; RVa and Rb are each independently selected from 30 hydrogen, alkenyl, and alkyl; In one embodiment the invention provides a compound of formula (le) wherein Y2 is: 341 X-X - N X-X X-X H XXX -x -X -xH -H x-x X-X /y~N-x H~~N X-X N/ \' N N_ \ X-X X-XH wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH

2 , CH 2 -0, 0-CH 2 , CH- 2

-CH

2

-CH

2 , and

CH

2

-O-CH

2 . 5 In one embodiment the invention provides a compound of formula (le) which is selected from: H H O H OH O P- P V' OsX x x X-X H 0 342 oN- P P A A HO 0 N O p V O O x-x Ox- x-x H r 0 \x-\

-

0x H -\ 5 H 0 N- N P ,N O 0 V H N 0- XX X-X H 111H H_" \/ N NpXN V P N \ H H0 00 0 )fN -N -- Hp~ 0 N'\/- -- ( x-x - \N 0 5 wherein X-X is selected from 0, CH 2 , CH=CH, CH 2

-CH-

2 , CH 2 -0, 0-CH 2 , CH 2

-CH

2

-CH

2 , and

CH

2 -0-CH 2 ; or a pharmaceutically acceptable salt, or prodrug thereof. 343 Specific values for E, P, V, and Z In another specific embodiment of the invention each E is E 0 . In another specific embodiment of the invention each E is -NHC(=0)Oalkyl. In another specific embodiment of the invention E 0 is methoxycarbonylamino. 5 In one embodiment the invention E 0 is -NH2, alkylamino or dialkylamino. In one embodiment the invention E 0 is cycloalkylamino or cycloalkyl(alkyl)amino, or dicycloalkylamino. In one embodiment the invention E 0 is heterocyclyl. In one embodiment the invention E 0 is heterocyclylamino where the amino is optionally 10 substituted with alkyl. In one embodiment the invention provides a compound of formula (I) wherein at least one EO is -NREcREd wherein REc is H and Rd is methoxycarbonyl. In one embodiment the invention provides a compound of formula (I) wherein at least one EU is -NREcREd wherein REc is H or alkyl and REd is H or alkyl. 1 5 In one embodiment the invention provides a compound of formula (I) wherein at least one E 0 is -NREcREd wherein REc is H, alkyl or cycloalkyl and REd is cycloalkyl. In one embodiment the invention provides a compound of formula (I) wherein at least one E 0 is an N-linked heterocyclyl. In one embodiment the invention provides a compound of formula (I) wherein at least 20 one E 0 is -NREcREd wherein REc is H, alkyl, or cycloalkyl; and REd is heterocycle. In another specific embodiment of the invention P is selected from: 344 HN NN N' _d wherein R"' is hydrogen or methyl. In another specific embodiment of the invention P is selected from 5 RNN yNN/,, Y r

N

nd and another P is P 0 . 10 In another specific embodiment of the invention P is selected from 345 NN N RN and NN wherein R"' is hydrogen or methyl; and another P is P 0 . 5 In another specific embodiment of the invention P is selected from: HN and Y N In another specific embodiment of the invention at least one P is P 7 and is: 10 In another specific embodiment of the invention at least one P is P 8 and is: 346 0 In another specific embodiment of the invention P is P' 0 and is: 5 In another specific embodiment of the invention P is P 11 and is: N 10 In another specific embodiment of the invention each P is independently selected from: N NN NA N N N,,,,Aand 15 In another specific embodiment of the invention P 0 is N 347 In another specific embodiment of the invention P 7 is a [2.2.1] or a [2.2.2] ring system. In another specific embodiment of the invention P 7 is N 5 optionally substituted with one or more groups independently selected from RP 6 and R'". In another specific embodiment of the invention P is selected from: N N F F and 0 S 10 In another specific embodiment of the invention P is selected from: N N and F F In another specific embodiment of the invention P is selected from: TN and : 15 NC O In another specific embodiment of the invention P is: N NC In another specific embodiment of the invention P is: 348 NA Q In another specific embodiment of the invention P is: H In another specific embodiment of the invention P is: N 5 In another specific embodiment of the invention P is selected from: F O F NN F /-1 \ - ,>2 N\ N, N,,N and In another specific embodiment of the invention P is selected from: A N,.~,A N N,.\ N NA F (,,,A N~ ~ N= Nand F 10 In another specific embodiment of the invention P is selected from: 349 (A (AA N

F

3 O MeO 2 8 F F F3C0 0 MeA (N, A N~ C ,A R R3e a n d

F

3 C N N wherein R is hydrogen or methyl and np is 0 or 1. In another specific embodiment of the invention P is selected from: (,A. ~ N,1\ NA NN N N N0 and Het( NN ,N NO wherein X is 0 or S; and Het is a heterocycle. In another specific embodiment of the invention P is selected from: and 0 In another specific embodiment of the invention P is: N 10 0. In another specific embodiment of the invention P is selected from: N N \ and Ra Rb 350 wherein Ra is hydrogen or methyl and Rb is methyl, or ethyl. In another specific embodiment of the invention P is selected from: N N and In another specific embodiment of the invention P is selected from: N N,, 5 0 In another specific embodiment of the invention P is selected from: T AT and 0 In another specific embodiment of the invention P is selected from: NA N and 10 In another specific embodiment of the invention P is selected from: N N and In another specific embodiment of the invention P is selected from: N N 0 NA N and N 15 N In another specific embodiment of the invention P is selected from: 351 and c N N N N In another specific embodiment of the invention P is selected from: Rp o FyO F N C C1 "S N N N N Rap N,,N N and 5 R 4 , wherein X is 0 or S; Rip and R 2 p are carbon linked and when taken together form a 4-6 membered heterocycle; R 3 p is alkyl or cycloalkyl; and Rap is hydrogen, methyl, or cyclopropyl. In another specific embodiment of the invention P is P 0 and is selected from: N A N N R F F N \ N~A and NJ 10 352 wherein R is alkyl. In another specific embodiment of the invention when P is a divalent group that is linked through a nitrogen of P and through a carbon of P, it is the nitrogen of P that is connected to Z. In another specific embodiment of the invention each V is V 0 . 5 In another specific embodiment of the invention each V is alkyl. In another specific embodiment of the invention each V is isopropyl. In another specific embodiment of the invention each V is isobutyl. In another specific embodiment of the invention each V is V 2 . In another specific embodiment of the invention each V is haloalkyl. 10 In another specific embodiment of the invention each V is independently selected from

V

0 , V', V 2 , V', V 4 , and V 5 . In another specific embodiment of the invention at least one V is selected from: 00 / N F and 15 In another specific embodiment of the invention at least one V is selected from: \ N \ N N N N & and 0 In another specific embodiment of the invention at least one V is selected from: 2 0 and 353 In another specific embodiment of the invention at least one V is selected from: o ,,oo S and 5 In another specific embodiment of the invention at least one V is selected from: N XCN jN 10 In another specific embodiment of the invention at least one V is selected from: N CN a and In another specific embodiment of the invention at least one V is selected from: FF F F F 15

,

F F3C and F In another specific embodiment of the invention at least one V is selected from: F F F F 354 .. and FF In another specific embodiment of the invention at least one V is selected from: and 5 In another specific embodiment of the invention at least one V is: 0 In another specific embodiment of the invention at least one V is selected from: 10 F F F F

F

3 OX OF o and O In another specific embodiment of the invention at least one V is selected from: F yF F yF 15 and > In another specific embodiment of the invention at least one V is selected from:

M

eO2S

M

eO2S 2Me 355 In another specific embodiment of the invention at least one V is: 0 2 Me 5 In another specific embodiment of the invention each V is:

H

3 C

CH

3

C

H. 10 In another specific embodiment of the invention each V 2 is independently haloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, hydroxy, and NRvaRvbC(=O)O-; Rva and Rvb are each independently selected from hydrogen, alkenyl, and alkyl; and each V 4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently 15 selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, hydroxy, and NRvaRvb C(=0)O-; Rva and R Vb are each independently selected from hydrogen, alkenyl, and alkyl. In another specific embodiment of the invention each V 0 is independently arylalkyl or heterocyclylalkyl, wherein arylalkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups 20 independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxRY, 25 (NRxRY)alkyl, oxo, and -P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the heterocyclylalkyl is further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, 30 alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second 356 heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, NR R , -(NRxRy)alkyl, and oxo. In another specific embodiment the invention each V is isobutyl. In another specific embodiment the invention at least one V is isobutyl. 5 In another specific embodiment the invention at least one V is phenylmethyl where the Z and E groups are each connected to the methyl group (i.e. -CH(Ph)- ). In another specific embodiment the invention at least one V is V 0 and at least one V 0 is phenylmethyl where the Z and E groups are each connected to the methyl group and the phenyl can be substitituted as described in the description for the V 0 aryl group. 10 In another specific embodiment the invention at least one V 0 is arylmethyl where the Z and E groups are each connected to the methyl group and the aryl can be substitituted as described in the description for the VO aryl group. In another specific embodiment the invention at least one V is V 0 and at least one V 0 is heterocyclylmethyl where the Z and E groups are each connected to the methyl group. 15 In another specific embodiment the invention at least one V is V and at least one V 0 is heterocyclylmethyl where the Z and E groups are each connected to the methyl group and the heterocyclyl group can be substitituted as described in the description for the V 0 heterocyclyl group. In another specific embodiment the invention each V 2 is independently haloalkyl, which 20 is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, hydroxy, and NRvaRvbC(=O)O-; Rva and R b are each independently selected from hydrogen, alkenyl, and alkyl. In another specific embodiment the invention each V 4 is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently 25 selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, hydroxy, and NR vaR C(=O)O-; wherein Rv and Rvb are each independently selected from hydrogen, alkenyl, and alkyl. In another specific embodiment of the invention each Z is Z 0 . In another specific embodiment of the invention each Z is -C(=O)-. For the compounds of formula (I) described herein, including the compounds of 30 formulae (Ia), (Ib), (Ic), (Id), and (le), any of the above specific values or embodiments for the variables E, P, V, and Z, can be applied. Thus, the invention also includes specific embodiments wherein one or more of the specific values or embodiments for J, T, P, W, L, M, A, R9, E, P, V, and Z described herein are combined with one of formulae (Ia), (Ib), (Ic), (Id), and (le), to provide a sub-set of compounds that represents a specific embodiment of the invention. 357 For example, by selecting a compound of formula (la9) above, along with specific values for P, M, W, and V identified herein, one can identify a specific embodiment the invention which is a compound of formula (la9): H P-M-W-M- H 0 Vo (1 9) 0 5 wherein: Wis or one M is imidazolyl and one M is benzimidazolyl; 10 one P is P 7 and is: N one P is P8 and is: N 15 one V is selected from: 3N 358 0- O h 'and ;and one V is:

H

3 C CH 3 H 5 The invention provides all such combinations as specific embodiments of the invention. Synthetic Intermediates The invention also provides synthetic processes and novel synthetic intermediates disclosed herein. For example, the invention provides the following specific intermediate 10 compounds that are useful for preparing compounds of formula (I):

H

2 H H2N O O0OH H2N O 0 OH O _CF 3 O CF 3

CF

3 2-Amino-5 ,5,5-trif luoro 2-A ino-4-(2,2,2-trifluoro-ethoxy)- 2-Methoxycarbonylamino- pentanoic acid methyl ester butyrc acid methyl ester 4-(2,2,2-trfluoro-ethoxy) butyric acid HH 0 0 00 0

CF

3 F F F F 5,5,5-Trifluoro-2-methoxy 2-tert-Butoxycarbonylamino-3- 3-Difluoromethoxy-2- carbonylamino-pentanoic acid difluoromethoxy-butyric methoxycarbonylamino acid methyl ester butyric acid methyl ester 359 H n ( N \ I H s~ S N N N S n S z S 2-[5-(6-{2-[pyrrolidin-2-yI]-3H-imidazol-4-y} benzo[1 ,2-b:4,5-b Idithiophe ne-2-y)-l H-imidazol-2-yI 2,6-bis(tri-n-butylstannyl)- pyrmolidine tetrahydrochbndde benzo[1 ,2-b:4,5-b Idithiophene O N OH (s)-3Mhxy-2- meth oxycarbo ya mino- F 3-metiy-butyric acid (R)-{4-Fluoro-phenyl). meftxycarbon ylam inc-acetic acid uW OH HO0 OHO F N (S)-{4-Fluoro-phenyl metoybnylamino-actic add (S)Cyar-2-ethoxycarbny aminobutynic acid F F F F H H - N - N-T N BrBoc Br H 2-[5-(4-Bromo-phenyl)- 1H-im idazol- 5-(4-Bromo-phenyl)-2-(4-difluoromethoxy 2-yIJ-4-difluoromethoxy-pyrrolidine- pyrrolidin-2-y)-1 H-imidazole 5 1 -carboxylic acid tert-butyl ester F H - N N 0 Br I/ ~ N N NHO \/ \ OH 0- 0 (1-{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-ylJ- 5, 1 0-Dihydro-chromeno 4-d ifluoromethoxy-pyrrolidine-1 -carbonyl}-2- [5,4, 3-cde]ch ro men e-2 ,7-d io1 methyl-propyl)-carbamic acid methyl ester 360 F F H Bo ] N N N NHN H N 0 2-{5-[6-(4-{2-[4-Difluoromethoxy- 1-(2-metho xycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imid azol-4-yI}- phe nyl)-nap hthalen 2-yl]-1H-imidazol-2-yl}-pyrrolidine-1 -carboxylic acid tert-butyl ester F H F N N O H H N /~ 0 0 HN 0 {1 -[4-Difluoromethoxy-2-(5-{4-[6-(2-pyrrolidin-2-yl-3H imidazol-4-yl)-naphthalen-2-yl]-p hen yl}-1 H-imidazol-2-yl) pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester --O HO O O-kO O N-

N

Dimethylcarbamoyloxy-phenyl- Dimethylcarbamoyloxy acetic acid methyl ester phenyl-acetic acid HO O o 0-o Tf \ \/ O/\/ Trifluoro-methanesulfonic acid 7-trifluoro Dimethylcarbamoyloxy-phenyl- Dimethylcarbamoyloxy- methanesulfonyloxy-5,10-dihydro 5 acetic acid methyl ester phenyl-acetic acid chromeno[5,4,3-cde]chromen-2-yl ester O H N 0 HH-/ \ j N \N 0 {1-[6-(4-{6-[4-(2-tert-Butoxycarbonylamino-acety)-phenyl]-naphthalen-2-y}I) 1H-imidazol-2-yI)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl} carbamic acid methyl ester 361 / H H 0 0 .. _4 N\ N 0 / N~ N {1-[2-(4-{6-[4-(2-tert-Butoxycarbonylamino-acetyl)-phenyl-naphthalen-2-yl}-1

H

imidazol-2-yl)-pyrrolidine- 1-carbonyl]-2-methyl-propyl)-carbamic acid methyl ester H O , H , N IN 2-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-1H-imidazol-4-yl}-naphthalen-2-yI)-phenyl}-1H imidazol-2-yl}-thiazolidine-3-carboxylic acid tert-butyl ester H / I ,\ N N SN 0 - H 1 -{2-[5-(6-{2-[1-carbamic acid tert. buty ester-pyrrolidin-2-yl]-3H imidazol-4-yl}-4,8-dimethyl-1,5-dithia-s-indacen-2-yl)-1H imidazol-2-yl]-pyrrolidine-1-carbamic acid tert.butyl ester OH H /S N N 01 N N, S 0 H "O 1-{2-[5-(6-{2-[1-carbamic acid tert. buty ester-pyrrolidin-2-yl]-3H-imidazol 4 -y}-4,8-dimethoxy-1,5-dithia-s-indacen-2-yl)-1 H-imidazol-2-yl] pyrroidine-1-carbamic acid tert.butyl ester H2 Br S HNSBN 4,8-Dimethyl-1,5 dithia-s-indacene (1-(2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl] 4-oxo-pyrrolidine-1 -carbonyl}-2-methyk 5 propyl)-carbamic acid methyl ester 362 ,CN Br BocN Br NC 2-[5-(4-Bromo-phenyl)-1 H-imidazol 2-[5-(6-Bromo-naphthalen-2-y)- H 2-yl]-4-cyano-pyrrolidine-1 imidazol-2-yl]-4-cyano-pyrrolidine- carboxylic acid tert-butyl ester 1-carboxylic acid tert-butyl ester Boct.\ /o O NJ-N- - \/- Br H NC MeO 4-Cyano-2-{5-[4-(4,4,5,5-tetramethyl- 4-Methoxymethyl-pyrrolidine-1,2 [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2- dicarboxylic acid 2-[2-(4-bromo yl}-pyrrolidine-1-carboxylic acid tert-butyl ester phenyl)-2-oxo-ethyl] ester 1-tert-butyl ester 0 Br N HN N N B MeO' 2-[5-(4-Bromo-phenyl)-1 H- MeO-' imidazol-2-yl]-4-methoxymethyl- (1 -{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2 pyrrolidine-1-carboxylic acid tert- yq]-4-methoxymethyl-pyrrol id ine-1 butyl ester carbonyl)-2-methyl-propyl)-carbamic acid methyl ester BocO BocO F OMe F N OH 0 0 4-Difluoromethoxymethyl- 4-Difluoromethoxymethyl pyrrolidine-1,2-dicarboxylic pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl acid 1-tert-butyl ester ester 363 0 N Br F- H Pyrrolidine-1,2-dicarboxylic acid 1-tert O-' butyl ester 2-[2-(3a,6a-dihydro (1-{2-[5-(4-Bromo-phenyl)-1 H- thieno[3,2-b]thiophen-2-yl)-2-oxo-ethyl] imidazol-2-y]-4- ester difluoromethoxymethyl-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester RocO0 0 S Boc N Br Br 0S N-AN S C: H Pyrrolidine-1,2-dicarboxylic acid 2-[2-(5- 2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2 bromo-3a,6a-dihydro-thieno[3,2-bthlophen- b]thiophen-2-yl)-1 H-imidazol-2-yl] 2-yI)-2-oxo-ethy] ester 1-tert-butyl ester pyrrolidine-1-carboxylic acid tert-butyl ester H MeO 2 CHN O N N Br NO NHCO 2 Me N -N S (1 -{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2- {1-[2-(5-Ethynyl-1 H-imidazol-2-yi) b]thiophen-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 - pyrrolidine-1 -carbonyl]-2-methyl carbonyl}-2-methyl-propyl)-carbamic acid methyl propyl}-carbamic acid methyl ester ester 0/ 0 )=o O HN HN -N 0P Y N N N N <, H H -F F (1-{2-[5-(6-Ethynyl-naphthalen-2-yl)-1H- (1 -{2-[5-(4-Ethynyl-phenyl)-1 H-imidazol-2 imidazol-2-yl]-pyrrolidine-1-carbonyl}-2- y]-4,4-difluoro-pyrrolidine-1-carbonyl}-2 5 methyl-propyl)-carbamic acid methyl ester methyl-propyl)-carbamic acid methyl ester 364 HH N N I0 Br N - B O 0 O= O/ (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol- [2-Methyl-1-(6-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborotan 2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2- 2-yl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-5-aza methyl-propyl)-carbamic acid methyl ester spiro[2.4]heptane-5-carbonyl)-pmpyl]-carbamic acid methyl ester HN F NO/BrF f N-.A N MeO 2 S H Br Nd 2-Bromo-9,9-difluoro-7-iodo-9H-fluorene (1 -{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-y]-4 cyano-pyrrolidine-1-carbonyl}-3 methanesulfonyl-propyl)-carbamic acid methyl ester 0 ON SEM 0 Boc N N

NNB

L H MeO etho methy)-12 rimehiylan2y- [1 -(4-Methoxymethyl-2-{5-[4-(4,4,5,5-tetramethyl pyrrolidine-1-carboxylic acid tert-butyl [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2-y} ester pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester BocO 0 - F N o O Br Br O Boc :0 N F 0 F 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic 4-Difluoromethoxymethyl-pyrrolidine- acid 2-[2-(6-bromo- naphthalen-2-yl)-2 1,2-dicarboxylic acid 2-[2-(4-bromo- oxo-ethyl] ester 1 -tert-butyl ester phenyl)-2-oxo-ethy] ester 1 -tert-butyl 5 ester 365 0Br Fi NJ Br S C H 1-(3a,6a-Dihydro- 2-Bromo-1-(3a,6a thieno[3,2- dihydro-thieno[3,2- 2-[5-(4-Bromo-phenyl)-1 H-imidazol-2 bthiophen-2-yl)- b]thiophen-2-yl)-ethanone yl]-4-difluoromethoxymethyl-pyrrolidine ethanone 1-carboxylic acid tert-butyl ester N H O Boc s I N\ B / " NH NJ0 00 BocH 2-[2-(4-Bromo-pheny)-2-oxo- 2-{5-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) ethylcarbamoyl]-4-cyano- 3a,6a-dihydro-thieno[3,2-bthiophen-2-y]-1 H-imidazol pyrrolidine-1-carboxylic acid tert- 2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester butyl ester ol F FH N Br Br obz 6-[5-(6-Bromo-naphthalen-2-yl)-1

H

1-(7-Bromo-9,9-difluoro-9H- imidazol-2-yl]-5-aza-spiro[2.4]heptane fluoren-2-yl)-2-ch loro-ethanone 5-carboxylic acid benzyl ester BocN HO O O FF O Br 5 Br 0 F H H F YF O

H~~

1 jyH H HO Br N N OH H BrO N O0 O 0 366 BocN HOB Boc~ Nj~~~~ ~NH FF N N N F H H ~ / ~Br H - N-H BrBoc Br NSEM B 2-[4-(4-Bromo-phenyl)-l -(2-trimethylsilanyl- 5-(4-Bromo-phenyl)-2-(4-(2-methoxy ethoxymethyl)-1 H-imidazol-2-yI)-4-(2-mrethoxy- ethoxy)-pyrrolid in-2-yIJ-1H-imidazole ethoxy)-pyrrolidine-I -carboxylic acid tert-butyl ester oI N HfO F- NN 0 / N~ N N NB r \/ ~ . Boc 0- SEM [1 -(4-{2 -Me th oxy-etho xy)-2-{5- [4-(4,4,5,5-te tram ethyl- 2J[4-(4 -Bromo- ph enyl) 1- -(2-trimeth ylsilanyl (1 ,3,2]dioxa borolan-2-yl)-phenyl]-1 H-midazol-2-yl}-pyrrolidine- ethoxymethy)-1 H-imidazal-2-yq-4-(pyrazin-2-yloxy) 1 -carbonylY-2-me thylI-propyl]-carba mic acid methyl ester pyrrolidine-1-carboxylic acid tert-butyl ester 5 0 - J N N HH - N N N o - N N H0 HN-- 0 0- 0 (1-f2-(5-(4-Bramo-phenyl)-1H-imidazol.2-yl]-4- (2-Methyl-i -(4-(pyrazin-2-yloxy)-2-{5-[4-(4,4,5,5-tetramethyl (pyrazin-2-yloxy)-pyrralidine-1-carbonyl]-2- [1 ,3,2]dbxaborolan-2-yf)-phenyl]-1 H-imidazal-2-yl}-pyrrolidine methyl-propyl}-carbamic acid methyl ester 1 -carbonyl)-prapyl]-carbamic acid methyl ester N-r N F HI' \/'Sr'~ Br F\ F Br- H N 0 0N~-m ' 0- Boc 2-(5-5-(4-Bromo-phenyl)-IH-imidazol 4-Difkioromethoxy-pyrrolidine-1 .2- 2-yll-pyrinlicin-3-ylaxy)-pyrazne (1 -2-f5-(4-Bromo-phenyl)-1 H-imidazol-2-yJ- dicarboxylc acid 2-[2-(4-bromo-phenyl) 40-(2-methoxy-ethoxy-pyrrolidine-1 -carbonyl]- 2-oxo-ethyl] ester 1 -ter-butyl ester 2-methyl-propyI)-carbamic acid methyl ester 367

-

Br HO

-

r Tf-t 0 o1 -d b a TfO/ OTf BB 0 O O<N N OMe 0 H N OMe 0 H N OMe H, I \- _ O N O 0 0 < N7N H I O H N N O 0 0 . 0 5 0Br 0 0~N H H3 N NN- ~ < HH'N 0 0+ (CF 3 (F 3 N N O\H N ArOMe 0 H N \ N N~ N 0 Br 10 368 H \H H H N _ N N . N O1A N and O NN Br Br Exemplary Methods of Making the Compounds of the Invention. The invention also relates to methods of making the compositions of the invention. The 5 compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy 10 G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing). Other methods suitable for preparing compounds of the invention are described in International Patent 15 Application Publication Number WO 2006/020276. A number of exemplary methods for the preparation of the compositions of the invention are provided in the schemes and examples below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods. Generally, the reaction conditions such as temperature, reaction time, solvents, work-up 20 procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be -100 C to 200*C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic 25 layer system (extraction) and separating the layer containing the product. Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20'C), although for metal hydride reductions frequently the temperature is reduced to 0 0 C to -I 00*C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions. 369 Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0*C to -100*C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions). 5 Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g., inert gas environments) are common in the art and will be applied when applicable. The terms "treated", "treating", "treatment", and the like, when used in connection with a chemical synthetic operation, mean contacting, mixing, reacting, allowing to react, bringing into 10 contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities. This means that "treating compound one with compound two" is synonymous with "allowing compound one to react with compound two", "contacting compound one with compound two", "reacting compound one with compound two", and other expressions common in the art of organic 15 synthesis for reasonably indicating that compound one was "treated", "reacted", "allowed to react", etc., with compound two. For example, treating indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01 M to IOM, typically 0.1 M to I M), temperatures (-100 C to 250'C, typically -78*C to 150*C, more typically -78'C to 100 C, still more typically 0*C to 100*C), reaction vessels (typically glass, 20 plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis is used in selecting the conditions and apparatus for "treating" in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably 25 expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art. Modifications of each of the exemplary schemes and in the Examples (hereafter "exemplary schemes") leads to various analogs of the specific exemplary materials produce. The above-cited citations describing suitable methods of organic synthesis are applicable to such 30 modifications. In each of the exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, 35 crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. 370 Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin 5 layer and flash chromatography. Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents 10 can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like. Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, 15 presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation. A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of 20 diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113, 3) 283 302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of 25 diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, c-methyl-p-phenylethylamine 30 (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. 371 Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral 5 derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched substrate. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the 10 NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography 15 (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. 20 372 Schemes and Examples General aspects of these exemplary methods are described below and in the Examples. Each of the products of the following processes is optionally separated, isolated, and/or purified prior to its use in subsequent processes. 5 A number of exemplary methods for the preparation of compounds of the invention are provided herein, for example, in the Examples hereinbelow. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods. Certain compounds of the invention can be used as intermediates for the preparation of other compounds of the invention. In the exemplary methods described herein, the fragment 10 E-V- can also be written as R9-. Subsequently, the fragment E-V-Z- or R9-Z- can be written as T-. The fragments E-V-Z-P, R9-Z-P-, or T-P- can all be written as J-. Scheme 1: Representative synthesis of T-P-M-A-A-M-P-T

T-P-M-A-B(OR)

2 Br-A-M-P-T T-P-M-A-A-M-P-T 1 2 3

T-P-M-A-A-B(OR)

2 + Br-M-P-T T-P-M-A-A-M-P-T 15 4 5 3 Scheme I shows a general synthesis of the T-P-M-A-A-M-P-T molecule of the invention, wherein transition metal-mediated cross-coupling reaction is utilized to construct the A-A bond and/or A-M bond. For illustrative purposes, the Suzuki reaction is employed to couple a Br-M 20 P-T and an (RO) 2 B-A-A-M-P-T intermediate or a Br-A-M-P-T and a (RO) 2 B-A-M-P-T intermediate. Boronic ester 1 (or 4) is coupled with an appropriate coupling partner (e.g. arylbromide 2 or 5) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 3. Palladium mediated cross-coupling reactions that enable the A-A bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and 25 Stille reactions. 373 Scheme la: Representative synthesis of T-P-M-W-M-P-T

T-P-M-W-B(OR)

2 + Br-M-P-T T-P-M-W-M-P-T 6 5 7

P-M-W-B(OR)

2 + Br-M-P P-M-W-M-P 6.1 5.1 8 5 Scheme I a shows a general synthesis of the T-P-M-W-M-P-T molecule and the P-M-W-M-P molecule of the invention, wherein transition metal-mediated cross-coupling reaction is utilized to construct the W-M bond. For illustrative purposes, the Suzuki reaction is employed to couple a Br-M-P-T and a (RO) 2 B-W-M-P-T intermediate or a Br-M-P-PG to a (RO) 2 B-W-M-P-PG intermediate. Boronic ester 6 (or 6.1) is coupled with an appropriate coupling partner (e.g. 10 arylbromide 5 or 5.1) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 7 and 8. Palladium mediated cross-coupling reactions that enable the A-A bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. 15 374 Scheme 2: Representative synthesis of A-M-P-T OH HN-P-T Br-A-$ + H 2 N-P-T , Br-A 9 10 11 H HO 0 0 Br\ N P -T Br--A Br H P-T Br--A P-T Ars - Br N _ 12.1 13 14.1 15 H O HO O0O Br\ NyP Br-A + HO P-T Br-A 00 P-T -r A

NH

2 6' NH N 12.2 13 14.2 15 NH CIN P-T Br-A4 + P-T Br-A Y

NH

2 0 N 16 17 18 0 H 2 N H Br-A B + H2-P-T Br\A N P-T -Br HN \I 12 19 15 5 Scheme 2 shows a general synthesis of an A-M-P-T molecule of the invention wherein, for illustrative purposes, M is an amide or an imidazole. Coupling of amine 10 with acid 9 is accomplished using a peptide coupling reagent (e.g. HATU) to afford amide containing 11. The acid 13 is coupled with an a-haloketone, such as a-bromoketone 12.1, under basic 10 conditions (e.g. Et 3 N) to afford 14.1. Alternatively, the acid 13 is coupled with an a aminoketone 12.2, under amide formation conditions (e.g. EDC, Et 3 N) to afford 14.2. Reaction of 14.1 or 14.2 with an amine or amine salt (e.g. ammonium acetate) affords the imidazole containing molecule Br-A-M-P-T. The benzamidine 16 is coupled with an a-haloketone such as a -chloroketone 17 under basic 15 conditions such as K 2

CO

3 to afford the imidazole containing molecule Br-A-M-P-T 18. A-M P-T 15 can be prepared analogously. 375 Scheme 3: Representative synthesis of A-M-P-T Br-A-M-P-T . (OR) 2 B-A-M-P-T 2.1 1.1 5 Scheme 3 shows a general synthesis of an A-M-P-T molecule of the invention wherein borate or boronic acid 1.1 can be synthesized from bromide 2.1. Scheme 4: Representative synthesis of A-M-P-Z-R9 HO

A-

A-M N + R9 .N H O R9 0 10 20 21 22 Scheme 4 shows a general synthesis of an A-M-P-Z-R9 fragment of the invention wherein, for illustrative purposes, P = pyrrolidine and Z = carbonyl. Coupling of amine 20 with acid 21 is accomplished using a peptide coupling reagent (e.g. HATU) to afford 22. 15 Scheme 5: Representative synthesis of L-P

NH

2

NH

2 O H HO N /\ N H 2 + H O X 23 24 25 26 H

NH

2 N P

XO/NH

2 X 23 27 26 Scheme 5 shows a general synthesis of an L-P molecule of the invention wherein, for illustrative 20 purposes, L = benzimidazole. The acid 24 is coupled with 23 using a peptide coupling reagent such as HATU to afford 25. Heating in solvent (such as refluxing ethanol) affords L-P fragment 26. 376 Alternatively, the L-P fragment 26 is obtained by reaction of diamine (such as 23) and carbonyl compound (such as aldehyde 27) in a solvent under heating conditions (e.g. ethanol under microwave irradiation). Scheme 6: Representative synthesis of P-M-A-A-M-P fragment 5 Br-A-A-Br -A-A 0 0 27.1 27 HO OH Br Br

H

3

C-A-A-CH

3 A-A-- A-A 0 0 0 0 28 29 30 30 + H P P A-A P 0 0 0 O 24 31 H A- A H 32 Scheme 6 shows a general synthesis of P-M-A-A-M-P molecule of the invention wherein, for illustrative purposes, M = imidazole. For example, the diketone 27 is converted to 30 using 10 bromine. Compound 27 can be commercially available or can be prepared from dibromide 27.1 through coupling with a vinyltin reagent such as tributyl(ethoxyvinyl)stannane with palladium. Coupling of 30 with acid 24 under basic conditions such as diisopropylethylamine affords diester 31. Imidazole formation is accomplished by treatment of 31 with ammonium acetate to provide the imidazole containing molecule P-M-A-A-M-P. 15 Alternatively, bromide 30 can be synthesized from 28. The methyl compound 28 can be converted to the corresponding diacid 29 using potassium permanganate as oxidant. Conversion of 29 to 30 can be accomplished by a multi-step reaction, first treatment of 29 with oxalyl chloride, then by trimethylsilyl diazomethane, then with hydrobromic acid to afford compound 30. 20 377 Scheme 7: Representative synthesis of E-V-P-M-A-A-M-P-V-E H E-V O N M-A-A-M-- 1 + HO V-E M-A-A-M 4 7 H 33 34 35 0 5 Scheme 7 shows a general synthesis of an E-V-P-M-A-A-M-P-V-E molecule of the invention wherein, for illustrative purposes, P = pyrrolidine and Z = carbonyl. Coupling of amine 33 with acid 34 is accomplished using a peptide coupling reagent, such as HATU, to afford 35. Scheme 8: Representative synthesis of P-M-W-M-P 10 Br-M-P Br-W-Br - (RO) 2

B-W-B(OR)

2 PG-P-M-W-M-P 36 37 37.1 38 Scheme 8 shows a general synthesis of P-M-W-M-P molecule of the invention wherein, for illustrative purposes, W = polycyclic. Conversion of 36 to 37 was accomplished using transition 15 metal-mediated reactions. Diboronic ester or acid 37 is coupled with a suitable reaction partner, such as bromide 37.1 using Suzuki coupling conditions to afford 38. Scheme 9: Representative synthesis of E-V-P-M-W-M-P-V-E H OE-V O N+N

M-W-M+

7 HO V-E M-W-M H 38.1 34 39 O V-E 20 Scheme 9 shows a general synthesis of an E-V-P-M-W-M-P-V-E molecule of the invention wherein, for illustrative purposes, P = pyrrolidine and Z = carbonyl. Coupling of amine 38.1 with acid 34 is accomplished using a peptide coupling reagent, such as HATU, to afford 39. 25 378 Scheme 9a: Representative synthesis of P-M-W-M-P 0 Br-W-Br ' Br-W Br HO P Br-W O Br 36.5 36 36.1 36.2 0 H0 00 0 J Br W O P 0- O 36.3 36.5 36.4 H H W 38.1 5 Scheme 9a shows a general synthesis of a P-M-W-M-P molecule of the invention wherein, for illustrative purposes, M = imidazole, W = polycyclic. The compound 36 was coupled with a vinyltin reagent such as tributyl(ethoxyvinyl)stannane with palladium, followed by bromination and hydrolysis with NBS and water, to give bromoketone 36.1. The reaction between bromide 36.1 and a carboxylic acid (36.5) under basic condition generated ester 36.2. Following the 10 same reaction sequence, compound 36.2 was converted to diester 36.4. Conversion of 36.4 to 38.1 was accomplished with ammonia reagents such as ammonium acetate at elevated temperature. Scheme 10: Representative synthesis of M-P N P PG Br N 15 40 40.1 40.2 Scheme 10 shows a general synthesis of an M-P molecule of the invention wherein, for illustrative purposes, PG is a protecting group. Imidazole 40 can be halogenated, for example, under the action of N-bromosuccinimide to provide bromoimidazole 40.1. Bromoimidazole 40.1 can be protected using standard conditions to give 40.2, such as SEM-Cl and sodium 20 hydride when PG = SEM. 379 Scheme 11: Representative synthesis of P-M-A-A-M-P P-M-A-Br - P-M-A-B(OR) 2 + Br-A(PG) - P-M-A-A 41 42 42.1 43 40.2 10 P-M-A-A-M-P 45 5 Scheme I I shows a general synthesis of a P-M-A-A-M-P molecule of the invention wherein, for illustrative purposes, M = imidazole. Boronic ester 42, which can be prepared from bromide 41, is coupled with a suitably protected appropriate coupling partner (e.g. arylbromide 42.1, optionally protected with PG) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 43. 10 Palladium mediated cross-coupling reactions that enable the A-A bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada and Stille reactions. If optionally protected, removal of the protecting group (PG) (for example, catalytic hydrogenation of a benzyl ether) provides the deprotected compound 43. Coupling of 43 with suitably protected imidazole 40.2 (for example, PG = SEM ether) using a metal catalyst (e.g. 15 Cul) gives protected P-M-A-A-M-P (45). Deprotection (for example deprotection of a SEM ether using an acid such as TFA) provides the imidazole containing fragment P-M-A-A-M-P 45. Scheme 12: Representative synthesis of P-M-W-M-P PG PG H 2

N-W-NH

2 X Ti 10 HOOC 46\ \_ NN 46 40.3 40.4 NPG H HN-W-NH N P P HN-W-NH N P N H PG 0 N 20 47 48 Scheme 12 shows a general synthesis of a P-M-W-M-P molecule of the invention wherein, for illustrative purposes, X = halogen or triflate, M = imidazole, and W is 46, PG = protecting group. Haloimdiazole 40.3, such as a bromoimidazole, is subjected to a metal-halogen exchange 25 reaction, such as BuLi in THF, and then treated with a CO 2 source, such as solid CO 2 , to give 380 40.4. Coupling of 40.4 and 46 using peptide coupling conditions, such as HATU, gives 47. PG deprotection, such as TFA deprotection of a SEM group, gives the compound P-M-W-M-P 48. Scheme 13: Representative synthesis of P-M-A-A-M-P 5 0 P-COOH H

PG

1 -A-COOH PG1-A PO PG 1 A N 49 12.3 50

PG

2 PG 2 PG2 X-A-M-P PN PG1 ' NP-M-A-A \ N 51 52 H NI P -. P-M-A-A 53 Scheme 13 shows a general synthesis of a P-M-A-A-M-P molecule of the invention wherein, for illustrative purposes, X = halogen, amine or triflate, M = imidazole, PG and PG 2 = 10 protecting groups. The protected acid 49 (PGI is a suitable protecting group, such as Cbz) is converted to a-halomethyl ketone 12.3., which is then transformed to PGi-A-M-P 50 using the analogous conditions for converting 12.1 and 12.2 to 15. The imidazole is subjected to protection, with SEM for instance, to afford 51, which is deprotected, with H 2 and Pd to remove a Cbz for example, followed by coupling with fragment X-A-M-P, using standard Pd coupling 15 conditions for example, to afford 52. PG deprotection, such as TFA deprotection of a SEM group, gives the compound P-M-A-A-M-P 53. 381 Scheme 14: Representative synthesis of A-M-P OH HN-P Br-A-i + H 2 N-P , Br-A-i 0 9 54 55 H O HO 0 0 Br\ N P Br-A r+ p ,B Br-A O p - A - Br--\\ 12.1 56 57.1 58 H Br-A 0 2 HO Br-A 0 0 Br\ N - NH 2 0 NHN 12.2 56 57.2 58 NH CN P Br-A + P ' Br-A-

NH

2 O N 18 59 60 0H 2 N H Br- 0A + H , Br\A N - Br HN 12.1 61 58 5 Scheme 14 shows a general synthesis of an A-M-P molecule of the invention wherein, for illustrative purposes, M is an amide bond, or an imidazole. Coupling of amine 54 with acid 9 is accomplished using a peptide coupling reagent (e.g. HATU) to afford amide containing 55. The acid 56 is coupled with an a-haloketone, such as a-bromoketone 12.1, under basic conditions (e.g. Et 3 N) to afford 57.1. Alternatively, the acid 56 is coupled with an a 10 aminoketone 12.2, under amide formation conditions (e.g. EDC, Et 3 N) to afford 57.2. Reaction of 57.1 and 57.2 with an amine or amine salt (e.g. ammonium acetate) affords the imidazole containing molecule A-M-P. The benzamidine 18 is coupled with an a-haloketone such as a -chloroketone 59 under basic conditions such as K 2

CO

3 to afford the imidazole containing molecule A-M-P 60. A-M-P 58 15 can be prepared analogously. 382 Scheme 15: Representative synthesis of P-M-A-A-M-P Br-A-M-P - P-M-A-B(OR) 2 + Br-A-Br : P-M-A-A-Br ' 62 63 64 65 Br-M-P

P-M-A-A-B(OR)

2 P-M-A-A-M-P 65.1 67 Br-A-M-P P-M-A-B(OR) 2 + Br-A-M-P P-M-A-A-M-P 62 63 66 67 5 Scheme 15 shows a general synthesis of a P-M-A-A-M-P molecule of the invention. Boronic acid or its ester 63, can be prepared from bromide 62 using a palladium catalyst (e.g. Pd(PPh 3

)

4 ) and a boron reagent (bis(pinacolato)diboron, for example), is coupled with an excess of appropriate coupling partner (e.g. a di-halo-aromatic or di-halo-heteroaromatic moiety 64) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford bromide 65, which then is converted to 10 boronic acid or ester 65.1. Palladium mediated cross-coupling reactions that enable the A-A bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada and Stille reactions. Suzuki coupling of 65.1 with halo-imidazole such as bromo-imidazole using a palladium catalyst (such as Pd(PPh 3

)

4 ) gives P-M-A-A-M-P fragment 67. 15 Alternatively, Suzuki coupling of 63 with halo-A-M-P fragment using a palladium catalyst (such as Pd(PPh 3

)

4 ) gives P-M-A-A-M-P fragment 67. Scheme 16: Representative synthesis of R9-P-L-A-M-P-R9 and R9-P-L-L-P-R9 20 R9-P-L-B(OR) 2 + Br-A-M-P-R9 R9-P-L-A-M-P-R9 68 69 70 R9-P-L-B(OR) 2 + Br-L-P-R9 R9-P-L-L-P-R9 68 71 72 Scheme 16 shows a general synthesis of an R9-P-L-A-M-P-R9 molecule and a R9-P-L-L-P-R9 molecule of the invention wherein a transition metal-mediated cross-coupling reaction is utilized 25 to construct the A-A bond. For illustrative purposes, the Suzuki reaction is employed to couple 383

(RO)

2 B-L-P-R9 and Br-A-M-P-R9. Boronic ester 68 is coupled with an appropriate coupling partner (e.g. arylbromide 69) using a palladium catalyst (such as Pd(PPh 3

)

4 ) to afford 70. Similarly, R9-P-L-L-P-R9 72 is prepared by coupling compounds 68 and 71. 5 Scheme 17: Representative synthesis of P-T PG PG PG 0n ~ n( 0Qn( HO EtO N' EtO m N HO H H O V'E E 13 73 74 75 Scheme 17 shows a general synthesis of a P-T molecule of the invention wherein, for illustrative 10 purposes, P = either an acyclic or cyclic amino ester (such as ethyl ester), optionally protected with PG if necessary, Z = carbonyl, X = carbon or heteroatom, and m and n = 0 - 5, independently. Coupling of amine 73 with acid 34 is accomplished using a peptide coupling reagent, such as HATU, to afford 75, which after removal of ethyl group provides the P-T compound. 15 Scheme 18: Representative synthesis of P PG X

X

On( 0 <n( ,) n( EtO m NH 2 EtO m N EtO N H H 76 73.1 73 Scheme 18 shows a general synthesis of a P molecule of the invention wherein X = carbon or 20 heteroatom and m and n = 0 - 5, independently. For illustrative purposes, P is substituted with an ethoxylcarbonyl group. Commercially available amino ester such an ethyl ester is converted to substituted or cyclized amino ester 73.1, through for example, reductive amination or Mitsunobu reaction. Compound 73.1 can be protected to provide compound 73 if necessary. 25 384 Scheme 19: Representative Synthesis of E-V 0 0

H

2 N 0 'H '0 N H 00 77 78 5 Scheme 19 shows a general synthesis of an E-V molecule of the invention wherein, for illustrative purposes, V is isobutyl and E is methoxycarbonylamino. Amino acid 77 can be converted to the corresponding carbamate 78, such as a methyl carbamate by reaction with methyl chloroformate under basic conditions (sodium bicarbonate). 10 Scheme 20: Synthesis of the E-V-Z-P-M-A N OH NH P6 0 0 79 V-E N N 80 O HN A 82 0N NH2 8 NH O NH V-E 81 Scheme 20 shows the synthesis of a E-V-Z-P-M-A molecule of the invention wherein, for 15 illustrative purposes, M is imidazole, P is pyrrolidine, and Z is carbonyl. An amino acid derivative can be reacted with an N-protected proline derivative via reaction conditions employing a coupling reagent, such as HATU, deprotection of the resulting coupling product, for example in the case of tert-butoxy carbonyl, the treatment with a proton source such as HCI yielded compound 80. The conversion of 80 to E-V-Z-P-M-A (82) can be obtained under 20 reaction conditions of nucleophilic aromatic substitution, for example the displacement of methyl sulfonate under basic conditions and elevated temperatures. Alternatively, for illustrative purposes, the amino acid derivative 80 can be converted to a guanidinium containing compound 81, via a reaction with a guanidylation reagent. The E-V-Z P-M-A compound 82 can be obtained via reaction with a 1,2 di-electrophile such as an a 25 halogenated carbonyl group under basic conditions. 385 Scheme 21: Representative synthesis of P-M-W-M-P p p -RO 2 Cn(H 2 C) M \/ Br + M \/ B(OR) 2

-

P\M M

(CH

2 )nCO 2 R

(CH

2 )mCO 2 R

(CH

2 )mCO 2 R 83 84 85 HO'm(H 2 C)

OHC,(H

2 C) ~P- p M M M MI

(CH

2 )n'OH

(CH

2 )mCHO 86 87 m, n, m', n'= 0, 1,2, etc MIM M M -, NI 'm(H 2 C)- N(CH2)n' 89 R 88 5 Scheme 21 shows a general synthesis of a P-M-W-M-P molecule of the invention wherein. Boronic ester 84 is coupled with an appropriate coupling partner (e.g. arylbromide 83) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 85. Carboxylate 85 is reduced with reagents such as DIBAL-H to afford diol 86. The treatment of diol 86 with acids such as H 3

PO

4 at 10 elevated temperature generates P-M-W-M-P compound 89. Alternatively, diol 86 can be oxidized with reagents such as pyridine-sulfur trioxide to form dialdehyde 87, which react with amines in the presence of reducing reagents such as NaBH(OAc) 3 to provide P-M-W-M-P compound 88. 15 386 Scheme 21a: Representative synthesis of P-M-W-M-P

FG

1

(CH

2 )mCO 2 R (CH 2 )mCHO P-M-A-A-M-P P-M-A-A-M-P P-M-A-A-M-P

FG

2

(CH

2 )nCO 2 R 87.1 (CH 2 )nCHO 85.1 85.2

(CH

2 )mOH H P-M-A-A-M-P N

(CH

2 )n'OH m(H 2 C) (CH 2 )n 86.1 P-M-A-A-M-P = P-M-W-M-P 0 89.4 m(H 2 C) / (CH 2 )n' P-M-A-A-M-P = P-M-W-M-P 89.3 0

(CH

2 )mCO 2 R (CH 2 )mCO 2 R O P-M-A-A-M-P P-M-A-A-M-P (CH2)m(CH 2 )n'

(CH

2 )nCO 2 R (CH 2 )n-OH P-M-A-A-M-P 85.2 86.2 = P-M-W-M-P 89.1 O

(CH

2 )mCO 2 R NH P-M-A-A-M-P ' (CH2)m(CH 2 )n'

(CH

2 )n'NH 2 P-M-A-A-M-P 86.3 = P-M-W-M-P 89.2 5 Scheme 21a shows a general synthesis of a P-M-W-M-P molecule of the invention. For illustrative purposes, FG, and FG 2 can be converted to esters attached to an A group. Carboxylate 85.2 is reduced with reagents, such as DIBAL-H, to afford diol 86.1. The treatment of diol 86.1 with acids, such as H 3

PO

4 , at elevated temperature generates P-M-W-M-P compound 89.3. Alternatively, diol 86.1 can be oxidized with reagents such as pyridine-sulfur 10 trioxide to form dialdehyde 87.1, which reacts with amines in the presence of reducing reagents such as NaBH(OAc) 3 to provide P-M-W-M-P compound 89.4. The carboxylate 85.2 is selectively reduced to provide hydroxyl ester 86.2, which can be cyclized to form P-M-W-M-P compound 89.1. Compound 86.1 is converted to amine ester 86.3, for example through azide 387 formation and reduction with hydrogenation. Compound 86.3 can be cyclized to form P-M-W M-P compound 89.2. 5 Scheme 22: Construction of a R9-Z-P-M-A N OtBu R9 NH R9 H IR9-Z R9-Z HN A 90 91 92 Scheme 22 shows the general synthesis of a R9-Z-P-M-A molecule, for illustrative purposes 10 starting with tert-butoxy carbonyl derivative 90 (J. Am. Chem. Soc. 2003, 1221). Compound 90 can be acylated with substituent T wherein Z is carbonyl, via reaction conditions employing a coupling reagent such as HATU. Removal of the protecting group, for example in the case of tert-butoxycarbonyl by the treatment with a proton source such as HCI, yields compound 91. A compound like 91 can be obtained under reaction conditions of nucleophilic aromatic 15 substitution, for example the displacement of methyl sulfonate under basic conditions and elevated temperatures to provide the R9-Z-P-M-A compound 92. Alternatively, 91 can be converted into a guanidinium derivative. When suitably substituted, cyclization provides the R9-Z-P-M-A compound 92. 20 388 Scheme 23: Representative synthesis of T-P-M-A-A-M-P-T Br OHC- N N N P H 93 94 T-P-M-A P-T + Br-A-M-P-T 'I P-T N N H 95.1 H 95 96 5 Scheme 23 shows a general synthesis of a T-P-M-A-A-M-P-T molecule of the invention wherein, for illustrative purposes, M = imidazole and A = alkyne. Bromoimidazole 93 is alkynylated by lithiation and trapping with a formate equivalent (e.g. DMF). The aldehyde 94 is converted to alkyne 95 using a phosphorus-based reagent (e.g. Ohira-Bestmann reagent). Compound 95 is coupled with a Br-A-M-P-T under Sonagashira conditions to afford the alkyne 10 containing compound 96. Scheme 24: Representative Synthesis of R9 Fragment 0 0 H 0

H

2 N N AO' R 1 R2 N N AO'R1 R 2 RN 1 R3

R

3 97 98 99 15 Scheme 24 shows a general synthesis of an R9 molecule of the invention. Reaction of hydrazine carboxylate 97 with a ketone or aldehyde, such as acetone, under acidic conditions (e.g. AcOH) affords the imine 98. Reaction of 98 under reducing conditions, such as PtO 2 and hydrogen gas, affords the substituted hydrazinecarboxylate 99. 20 389 Scheme 25: Representative synthesis of E-V-Z-P-M-A-A-M-P-Z-V-E

E-V-Z-P-M-A-B(OR)

2 + Br-A-M-P-Z-V-E E-V-Z-P-M-A-A-M-P-Z-V-E 25a 25b 25c

E-V-Z-P-M-A-A-B(OR)

2 + Br-M-P-Z-V-E E-V-Z-P-M-A-A-M-P-Z-V-E 25d 25e 25c

(RO)

2

B-A-A-B(OR)

2 + 2 Br-M-P-Z-V-E E-V-Z-P-M-A-A-M-P-Z-V-E 25f 25e 25c 5 Scheme 25 shows a general synthesis of the E-V-Z-P-M-A-A-M-P-Z-V-E molecule of the invention, wherein a transition metal-mediated cross-coupling reaction is utilized to construct the A-A bond and/or A-M bond. For illustrative purposes, the Suzuki reaction is employed to couple Br-M-P-Z-V-E and (RO) 2 B-A-A-M-P-Z-V-E or (RO) 2 B-A-M-P-Z-V-E and Br-A-M P-Z-V-E. Boronic ester 25a (or 25d) is coupled with an appropriate coupling partner (e.g. 10 arylbromide 25b or 25e) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 25c. Formation of multiple A-M bonds can be conducted in a similar manner. For example, the Suzuki reaction can also be employed to couple (RO) 2

B-A-A-B(OR)

2 (25f) and two equivalents of Br-M-P-Z V-E. For each transition metal-mediated cross-coupling reaction the roles of the nucleophile and electrophile can be reversed to provide the same coupling product. Palladium mediated 1 5 cross-coupling reactions that enable the A-A and/or A-M bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. 390 Scheme 26: Representative synthesis of E-V-Z-P-M-A-A-M-P-Z-V-E OH HN-P-Z-V-E E-V-Z-P-M-A-A-- + H 2 N-P-Z-V-E . E-V-Z-P-M-A-A- 26a 26b 26c O HO 00 E-V-Z-P-M-A-A + >-P-Z-V-E - E-V-Z-P-M-A-A P-Z-V-E 26d Br 0 26e 26f E-V-Z-P-M-A-A NLrP-Z-V-E 26g O HO 00 E-V-Z-P-M-A-A + H-P-Z-V-E E-V-Z-P-M-A-A P-Z-V-E -- NH 2 NH 26h 26e 26i H P-Z-V-E E-V-Z-P-M-A-A 26g 0 0 HO 0 0 0 0 A-A + 2 H>-P-Z-V-E E-V-Z-P-K A-A >P-Z-V-E BBr r 0 0 0 26j 26e 26k H N N P-Z-V-E I ' A-A--\ I E-V-Z-P N N H 261 5 Scheme 26 shows a general synthesis of an E-V-Z-P-M-A-A-M-P-Z-V-E molecule of the invention wherein, for illustrative purposes, M is an amide, or an imidazole. Coupling of acid 26a with amine 26b is accomplished using a peptide coupling reagent (e.g. HATU) to afford the amide product 26c. The formation of an imidazole is accomplished by coupling the acid 26d with an a-haloketone, 10 such as a-bromoketone 26e, under basic conditions (e.g. Et 3 N) to afford 26f. Alternatively, the acid 26d is coupled with an a-aminoketone 26h, under amide formation conditions (e.g. EDC, Et 3 N) to afford 26i. Reaction of 26f or 26i with an amine or amine salt (e.g. ammonium acetate) affords the imidazole containing molecule 26g. The formation of multiple imidazoles is performed in the same manner, starting with a bis- a-haloketone such as a-bromoketone 26j, to 15 provide molecule 261. 391 Scheme 27: Representative synthesis of E-V-Z-P-M-A-A-M-P-Z-V-E E-V-Z-P-M-A-A-M N + HO E-V-Z-P-M-A-A-M 7 N H O 27a 27b OV-E 27c H E-V O HHO K/-M A-AM- + 2 - N MAAM- 7 27d 27b 27e O V-E 5 Scheme 27 shows a general synthesis of an E-V-Z-P-M-A-A-M-P-Z-V-E molecule of the invention wherein, for illustrative purposes, P is pyrrolidine and Z is a carbonyl. Coupling of amine 27a with acid 27b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 27c. Alternatively, amine 27d is coupled with two equivalents of 27b under similar conditions to provide 27e. 10 Scheme 28: Representative synthesis of E-V-Z-P-M-A-A-M-P-Z-V-E CI

E-V-Z-P-M-A-A-M-P-Z-V-NH

2 + O E-V-Z-P-M-A-A-M-P-Z-V-NH 28a 28b 28c CI

H

2

N-V-Z-P-M-A-A-M-P-Z-V-NH

2 + 2 O HN-V-Z-P-M-A-A-M-P-Z-V-NH O 0 /0 28d 28b 0 28e 0 15 Scheme 28 shows a general synthesis of an E-V-Z-P-M-A-A-M-P-Z-V-E molecule of the invention wherein, for illustrative purposes, E is methoxycarbonylamino. The treatment of either 28a or 28d with one or two equivalents respectively of 28b under basic conditions (e.g. sodium bicarbonate) provides the molecule 28c or 28e. 20 392 Scheme 29: Representative synthesis of E-V-Z-P-M-W-M-P-Z-V-E

E-V-Z-P-M-W-B(OR)

2 + Br-M-P-Z-V-E E-V-Z-P-M-W-M-P-Z-V-E 29a 29b 29c

(RO)

2

B-W-B(OR)

2 + 2 Br-M-P-Z-V-E E-V-Z-P-M-W-M-P-Z-V-E 29d 29b 29c 5 Scheme 29 shows a general synthesis of the E-V-Z-P-M-W-M-P-Z-V-E molecule of the invention, wherein transition metal-mediated cross-coupling reaction is utilized to construct the W-M bond. For illustrative purposes, the Suzuki reaction is employed to couple Br-M-P-Z-V E to a (RO) 2 B-W-M-P-Z-V-E or (RO) 2

B-W-B(OR)

2 molecule. Boronic ester 29a (or 29d) is coupled with an appropriate coupling partner (e.g. arylbromide 29b) using a palladium catalyst, 10 such as Pd(PPh 3

)

4 , to afford 29c. For each transition metal-mediated cross-coupling reaction the roles of the nucleophile and electrophile can be reversed to provide the same coupling product. Palladium mediated cross-coupling reactions that enable the M-W bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. 15 Scheme 30: Representative synthesis of E-V-Z-P-M-W-M-P-Z-V-E E-V-Z-P-M-W-M + HO V E-V-Z-P-M-W-M H 0 30a 30b 0 V-E 30c H E-V O \ M-W-M + 2 HO V-E ' M-W-M N N J H 30d 30b 30e 0 V-E 20 Scheme 30 shows a general synthesis of an E-V-Z-P-M-W-M-P-Z-V-E molecule of the invention wherein, for illustrative purposes, P is pyrrolidine and Z is a carbonyl. Coupling of amine 30a with acid 30b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 30c. Alternatively, amine 30d is coupled with two equivalents of 30b under similar conditions to provide 30e. 25 393 Scheme 31: Representative synthesis of E-V-Z-P-M-W-M-P-Z-V-E Cl

E-V-Z-P-M-W-M-P-Z-V-NH

2 + O ' E-V-Z-P-M-W-M-P-Z-V-NH / O O 31a 31b 31c Cl

H

2

N-V-Z-P-M-W-M-P-Z-V-NH

2 + 2 \ HN-V-Z-P-M-W-M-P-Z-V-NH 31d 31b 0 31e 0 5 Scheme 31 shows a general synthesis of an E-V-Z-P-M-W-M-P-Z-V-E molecule of the invention wherein, for illustrative purposes, E is methoxycarbonylamino. The treatment of either 31a or 31d with one or two equivalents respectively of 31b under basic conditions (e.g. sodium bicarbonate) provides the molecule 31c or 31e. 10 Scheme 32: Representative synthesis of E-V-Z-P-M-A-L-P-Z-V-E

E-V-Z-P-M-A-B(OR)

2 + Br-L-P-Z-V-E E-V-Z-P-M-A-L-P-Z-V-E 32a 32b 32c

E-V-Z-P-L-A-B(OR)

2 + Br-M-P-Z-V-E E-V-Z-P-M-A-L-P-Z-V-E 32d 32e 32c Scheme 32 shows a general synthesis of the E-V-Z-P-M-A-L-P-Z-V-E molecule of the 15 invention, wherein transition metal-mediated cross-coupling reaction is utilized to construct the M-A or A-L bond. For illustrative purposes, the Suzuki reaction is employed to couple a boronic ester to an arylbromide. Boronic ester 32a (or 32d) is coupled with an appropriate coupling partner (e.g. arylbromide 32b or 32e) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 32c. For each transition metal-mediated cross-coupling reaction the roles of the 20 nucleophile and electrophile can be reversed to provide the same coupling product. Palladium mediated cross-coupling reactions that enable either the M-A or A-L bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. 25 Scheme 33: Representative synthesis of E-V-Z-P-M-A-L-P-Z-V-E 394 E-V-Z-P-M-A-L + H VE E-V-Z-P-M-A-L0 H O 33a 33b 33c E-V-Z-P-L-A-M HO VE-V-Z-P-L-A-M N H0 WE NV 33d 33b O' V-E 33e M-A-L + 2 HO V-E M-A-L N 0 N H 33f 33b 33g 0 V-E Scheme 33 shows a general synthesis of an E-V-Z-P-M-A-L-P-Z-V-E molecule of the invention wherein, for illustrative purposes, P is pyrrolidine and Z is a carbonyl. Coupling of 5 amine 33a or 33d with acid 33b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 33c or 33e, respectively. Alternatively, amine 33f is coupled with two equivalents of 33b under similar conditions to provide 33g. Scheme 34: Representative synthesis of E-V-Z-P-M-A-L-P-Z-V-E 10 CI

E-V-Z-P-M-A-L-P-Z-V-NH

2 + O ' E-V-Z-P-M-A-L-P-Z-V-NH 34a 34b 34c CI

E-V-Z-P-L-A-M-P-Z-V-NH

2 + o ' E-V-Z-P-L-A-M-P-Z-V-NH 34d 34b 34e CI

H

2

N-V-Z-P-M-A-L-P-Z-V-NH

2 + 2 $0 \ HN-V-Z-P-M-A-L-P-Z-V-NH 34f 34b 0 34g O Scheme 34 shows a general synthesis of an E-V-Z-P-M-A-L-P-Z-V-E molecule of the invention wherein, for illustrative purposes, E is methoxycarbonylamino. The treatment of 15 either 34a or 34d with 34b under basic conditions (e.g. sodium bicarbonate) provides the molecule 34c or 34e. Correspondingly, the treatment of 34f with two equivalents of 34b provides 34g under similar conditions. 395 Scheme 35: Representative synthesis of E-V-Z-P-L-L-P-Z-V-E

E-V-Z-P-L-B(OR)

2 + Br-L-P-Z-V-E E-V-Z-P-L-L-P-Z-V-E 35a 35b 35c 5 Scheme 35 shows a general synthesis of the E-V-Z-P-L-L-P-Z-V-E molecule of the invention, wherein transition metal-mediated cross-coupling reaction is utilized to construct the L-L bond. For illustrative purposes, the Suzuki reaction is employed to couple a boronic ester to an arylbromide. Boronic ester 35a is coupled with an appropriate coupling partner (e.g. arylbromide 35b) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 35c. For each 10 transition metal-mediated cross-coupling reaction the roles of the nucleophile and electrophile can be reversed to provide the same coupling product. Palladium mediated cross-coupling reactions that enable either the L-L bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. 15 Scheme 36: Representative synthesis of E-V-Z-P-L-L-P-Z-V-E E-V-Z-P-L- + HOV-E E-V-Z-P-L-L N 0- N H O 36a 36b O' VE 36c H E-V O'(0 6 N HO L-L + 2 H V-E L-L H 36d 36b 36e O V-E Scheme 36 shows a general synthesis of an E-V-Z-P-L-L-P-Z-V-E molecule of the invention 20 wherein, for illustrative purposes, P is pyrrolidine and Z is a carbonyl. Coupling of amine 36a with acid 36b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 36c. Alternatively, amine 36d is coupled with two equivalents of 36b under similar conditions to provide 36e. 25 Scheme 37: Representative synthesis of E-V-Z-P-L-L-P-Z-V-E 396 CI

E-V-Z-P-L-L-P-Z-V-NH

2 + O0' E-V-Z-P-L-L-P-Z-V-NH 37a 37b 37c CI

H

2

N-V-Z-P-L-L-P-Z-V-NH

2 + 2 0 HN-V-Z-P-L-L-P-Z-V-NH O 0- 0/ 37d 37b 0 37e 0 Scheme 37 shows a general synthesis of an E-V-Z-P-L-L-P-Z-V-E molecule of the invention wherein, for illustrative purposes, E is methoxycarbonylamino. The treatment of either 37a or 5 37d with 37b under basic conditions (e.g. sodium bicarbonate) provides the molecule 37c or 37e. Scheme 38: Representative synthesis of R-A-M-P-R OH HN-P-Z-V-E Br-A- + H 2 N-P-Z-V-E Br-A-i 0 O 38a 38b 38c O HO 0 0 Br-A + P-Z-V-E Br-A - -P-Z-V-E Br O 0 38d 38e 38f H Br N P-Z-V-E A 38g O HO O Br-A 0P-Z-V-E ' Br-A P-Z-V-E

NH

2 0 NH 38h 38e H Br\ N P-Z-V-E A N N 38g NH CI N P-Z-V-E Br-A-KNH + CI P-Z-V-E - Br-A--i

NH

2 0N 38j 38k 38g Br-A + H 2 P-2-V-EN Br\A N P-Z-V-E Br HN A\ N 10 38d 381 38g 397 Scheme 38 shows a general synthesis of an R-A-M-P-R 1 intermediate of the invention wherein, for illustrative purposes, M is an amide or an imidazole, R is a generic group that is depicted as Br, and RI is a generic group that is depicted as -Z-V-E. Coupling of amine 38b with acid 38a 5 is accomplished using a peptide coupling reagent (e.g. HATU) to afford amide containing 38c. The acid 38e is coupled with an a-haloketone, such as a-bromoketone 38d, under basic conditions (e.g. Et 3 N) to afford 38f. Alternatively, the acid 38e is coupled with an a aminoketone 38h, under amide formation conditions (e.g. EDC, Et 3 N) to afford 38i. Reaction of 38f or 38i with an amine or amine salt (e.g. ammonium acetate) affords the imidazole 10 containing intermediate Br-A-M-P-Z-V-E (38g). The benzamidine 38j is coupled with an a-haloketone such as a -chloroketone 38k under basic conditions such as K 2

CO

3 to afford 38g. The Br-A-M-P-Z-V-E intermediate can be prepared analogously from the coupling of 38d and 381. 15 Scheme 39: Representative synthesis of R-W-M-P-R O HO O O Br-W + P-Z-V-E ' Br-W- -P-Z-V-E Br O O 39a 39b 39c N P-Z-V-E ___Br,__ Br W 39d Br -W + HO P Br-W -P-Z-V-E

NH

2 O 39b NH 39e 39f Br N P-Z-V-E W 39d NH CN:N P-Z-V-E Br-W+ P-Z-V-E - Br-W-<\ P

NH

2 O N 39g 39h 39d Br-W 0 B HN-P-Z-V-E Br, H P-Z-V-E Br HN N 39i 39j 39d 398 Scheme 39 shows a general synthesis of an R-W-M-P-R' intermediate of the invention wherein, for illustrative purposes, M is an amide or an imidazole, R is a generic group that is depicted as Br, and R' is a generic group that is depicted as -Z-V-E. The acid 39b is coupled with an a haloketone, such as a-bromoketone 39a, under basic conditions (e.g. Et 3 N) to afford 39c. 5 Alternatively, the acid 39b is coupled with an a-aminoketone 39e, under amide formation conditions (e.g. EDC, Et 3 N) to afford 39f. Reaction of 39c or 39f with an amine or amine salt (e.g. ammonium acetate) affords the imidazole containing intermediate Br-A-M-P-Z-V-E (39d). The benzamidine 39g is coupled with an a-haloketone such as a -chloroketone 39h under basic 10 conditions such as K 2

CO

3 to afford 39d. The Br-A-M-P-Z-V-E intermediate can be prepared analogously from the coupling of 39i and 39j. Scheme 40: Representative synthesis of R-A-R' Br-A-M-P-Z-V-E . (RO) 2 B-A-M-P-Z-V-E 40a 40b Br-A-M-P-PG - (RO) 2 B-A-M-P-PG 40c 40d Br-A-L-P-Z-V-E - (RO) 2 B-A-L-P-Z-V-E 40e 40f Br-A-L-P-PG (RO) 2 B-A-L-P-PG 40g 40h Br-A-PG ' (RO) 2 B-A-PG 15 40i 40j Scheme 40 shows a general synthesis of an R-A-R' intermediate of the invention wherein, for illustrative purposes, R is a generic group that is depicted as a boronic ester and R1 is a generic group that is depicted as -M-P-Z-V-E, -M-P-PG, -L-P-Z-V-E, -L-P-PG, or a protecting group. 20 A transition metal-mediated cross-coupling reaction is utilized to install the boronic ester on an A group. Treatment of the corresponding arylbromide with a palladium catalyst, such as PdCl 2 (dppf), and a boron source such as bis(pinacolato)diborane provides the boronic ester 40b, 40d, 40f, 40h, or 40j. 25 Scheme 41: Representative synthesis of R-W-R' 399 Br-W-M-P-Z-V-E - (RO) 2 B-W-M-P-Z-V-E 41a 41b Br-W-M-P-PG ' (RO) 2 B-W-M-P-PG 41c 41d Br-W-PG

(RO)

2 B-W-PG 41e 41f Scheme 41 shows a general synthesis of an R-W-R' intermediate of the invention wherein, for illustrative purposes, R is a generic group that is depicted as a boronic ester and R' is a generic 5 group that is depicted as -M-P-Z-V-E, -M-P-PG, or a protecting group. A transition metal mediated cross-coupling reaction is utilized to install the boronic ester on a W group. Treatment of the corresponding arylbromide with a palladium catalyst, such as PdCl 2 (dppf), and a boron source such as bis(pinacolato)diborane provides the boronic ester 41b, 41d, or 41f. 10 Scheme 42: Representative synthesis of R-M-R' Br-M-P-Z-V-E ' (RO) 2 B-M-P-Z-V-E 42a 42b Br-M-P-PG

(RO)

2 B-M-P-PG 42c 42d Scheme 42 shows a general synthesis of an R-M-R' intermediate of the invention wherein, for 15 illustrative purposes, R is a generic group that is depicted as a boronic ester and R' is a generic group that is depicted as -P-Z-V-E or -P-PG. A transition metal-mediated cross-coupling reaction is utilized to install the boronic ester on an M group. Treatment of the corresponding arylbromide with a palladium catalyst, such as PdCI 2 (dppf), and a boron source such as bis(pinacolato)diborane provides the boronic ester 42b or 42d. 20 Scheme 43: Representative synthesis of R-L-R Br-L-P-Z-V-E - (RO) 2 B-L-P-Z-V-E 43a 43b Br-L-P-PG I (RO) 2 B-L-P-PG 43c 43d 400 Scheme 43 shows a general synthesis of an R-L-R' intermediate of the invention wherein, for illustrative purposes, R is a generic group that is depicted as a boronic ester and R' is a generic group that is depicted as -P-Z-V-E or -P-PG. A transition metal-mediated cross-coupling reaction is utilized to install the boronic ester on an L group. Treatment of the corresponding 5 arylbromide with a palladium catalyst, such as PdCI 2 (dppf), and a boron source such as bis(pinacolato)diborane provides the boronic ester 43b or 43d. Scheme 44: Representative synthesis of R-A-M-P-Z-V-E + HO PG-A-M H V-E 0 44a 44b 44c PGA-A-M +HO PG-A-A-M _0 PGA--M+ V-E ,N N H 0 AV-E 0 44d 44b 44e PG-P-M-A-A-M + HO PG-P-M-A-A-M H O V-E 44f 44b 44g + HO PG-P-L-A-M N PGP--AM 3 + V-E ,N H O OV-E 0/V 10 44h 44b 44i Scheme 44 shows a general synthesis of an R-A-M-P-Z-V-E intermediate of the invention wherein, for illustrative purposes, P is pyrrolidine, Z is carbonyl, and R is a generic group that is depicted as either -A-PG, -A-M-P-PG, -L-P-PG, or a protecting group. Coupling of amine 44a, 15 44d, 44f, or 44h with acid 44b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 44c, 44e, 44g, or 44i, respectively. 401 Scheme 45: Representative synthesis of R-W-M-P-Z-V-E PG-W-Ml- + +HO PG-W-M-$ PGW- + V-E N HN H O O V-E 45a 45b 45c PG-P-M-W-M + HO PG-P-M-W-M PGP---M+V-E .N N H O- / -E 0 V 45d 45b 45e 5 Scheme 45 shows a general synthesis of an R-W-M-P-Z-V-E intermediate of the invention wherein, for illustrative purposes, P is pyrrolidine, Z is carbonyl, and R is a generic group that is depicted as either -M-P-PG or a protecting group. Coupling of amine 45a or 45d with acid 45b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 45c or 45e, respectively. 10 Scheme 46: Representative synthesis of R-A-L-P-Z-V-E PG-A-L + HO PG-A-L H O V-E 46a 46b 46c HO PG-P-M-A-L PG-P-M-A-L + V-E N N ' H O O V-E 46d 46b 46e 15 Scheme 46 shows a general synthesis of an R-A-L-P-Z-V-E intermediate of the invention wherein, for illustrative purposes, P is pyrrolidine, Z is carbonyl, and R is a generic group that is depicted as either -M-P-PG or a protecting group. Coupling of amine 46a or 46d with acid 46b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 46c or 46e, respectively. 20 402 Scheme 47: Representative synthesis of R-L-P-Z-V-E and R-M-P-Z-V-E Br-L- + HO Br-L N H 0 0 -ENV-E 47a 47b 47c Br-M NHO Br-M-2 BrM0 + V-E ,N H O 0V-E 47d 47b 47e 5 Scheme 47 shows a general synthesis of an R-L-P-Z-V-E or R-M-P-Z-V-E intermediate of the invention wherein, for illustrative purposes, P is pyrrolidine, Z is carbonyl, and R is a generic group that is depicted as Br. Coupling of amine 47a or 47d with acid 47b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 47c or 47e, respectively. 10 Scheme 48: Representative synthesis of R-A-M-P-Z-V-E CI

PG-A-M-P-Z-V-NH

2 + O ' PG-A-M-P-Z-V-NH 0 0 48a 48b 48c O CI

PG-A-A-M-P-Z-V-NH

2 + O ' PG-A-A-M-P-Z-V-NH O 48d 48b 48e O CI

PG-P-M-A-A-M-P-Z-V-NH

2 + O ' PG-P-M-A-A-M-P-Z-V-NH O f 8b 489 CI

PG-P-L-A-M-P-Z-V-NH

2 + 0 PG-P-L-A-M-P-Z-V-NH 48h 48b 48i 0 Scheme 48 shows a general synthesis of an R-A-M-P-Z-V-E intermediate of the invention 15 wherein, for illustrative purposes, E is methoxycarbonylamino and R is a generic group that is depicted as a either -A-PG, -A-M-P-PG, -L-P-PG, or a protecting group. Treatment of 48a, 48d, 48f, or 48h with 48b under basic conditions (e.g. sodium bicarbonate) provides the intermediate 48c, 48e, 48g, or 48i, respectively. 403 Scheme 49: Representative synthesis of R-W-M-P-Z-V-E C1

PG-W-M-P-Z-V-NH

2 + 0 ' PG-W-M-P-Z-V-NH / 49a 49b 49c O C1

PG-P-M-W-M-P-Z-V-NH

2 + O PG-P-M-W-M-P-Z-V-NH / 49d 49b 49e 5 Scheme 49 shows a general synthesis of an R-W-M-P-Z-V-E intermediate of the invention wherein, for illustrative purposes, E is methoxycarbonylamino and R is a generic group that is depicted as either -M-P-PG or a protecting group. Treatment of 49a or 49d with 49b under basic conditions (e.g. sodium bicarbonate) provides the intermediate 49c or 49e, respectively. 10 Scheme 50: Representative synthesis of R-A-L-P-Z-V-E C1

PG-A-L-P-Z-V-NH

2 + 0 ' PG-A-L-P-Z-V-NH / 50a 50b 50c O CI

PG-P-M-A-L-P-Z-V-NH

2 + O ' PG-P-M-A-L-P-Z-V-NH / o \ O 50d 50b 50e Scheme 50 shows a general synthesis of an R-A-L-P-Z-V-E intermediate of the invention 15 wherein, for illustrative purposes, E is methoxycarbonylamino and R is a generic group that is depicted as a either -M-P-PG or a protecting group. Treatment of 50a or 50d with 50b under basic conditions (e.g. sodium bicarbonate) provides the intermediate 50c or 50e, respectively. Scheme 51: Representative synthesis of R-A-L-P-Z-V-E 20 C1 Br-M-P-Z-V-NH 2 + / ' Br-M-P-Z-V-NH 51a 51b 51c O C1 Br-L-P-Z-V-NH 2 + O70 ', Br-L-P-Z-V-NH 51d 51b 51e O 404 Scheme 51 shows a general synthesis of an R-L-P-Z-V-E or R-M-P-Z-V-E intermediate of the invention wherein, for illustrative purposes, E is methoxycarbonylamino and R is a generic group that is depicted as a Br. Treatment of 51a or 51d with 51b under basic conditions (e.g. sodium bicarbonate) provides the intermediate 51c or 5ie, respectively. 5 Scheme Sia: Representative synthesis of R-P-Z-V-E

-

HO-O -O + H V-E , N H O 0 V-E 51a 51b 51c 10 Scheme 51 a shows a general synthesis of an R-P-Z-V-E intermediate of the invention wherein, for illustrative purposes, P is pyrrolidine, Z is carbonyl, and R is a generic group that is depicted as a methoxycarbonyl. Coupling of amine 51a with acid 51b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 51c. 15 Scheme 52: Representative synthesis of R-Z-V-E CI

HO-Z-V-NH

2 + O HO-Z-V-NH / 52a 52b 52c o Scheme 52 shows a general synthesis of an R-Z-V-E intermediate of the invention wherein, for 20 illustrative purposes, E is methoxycarbonylamino and R is a generic group that is depicted as a hydroxyl. Treatment of 52a under basic conditions (e.g. sodium bicarbonate) with 52b provides the intermediate 52c. 405 Scheme 53: Representative synthesis of R-L-P-R' NH2 HO O N P-PG Br \ NH 2 P-PG Br N P-PG B Br-0 H+ 0 Br /\NY 53a 53b 53c 53d

NH

2 N P-PG Br -< /NH 2 + PG Br _d :N 53a 53e 53d 5 Scheme 53 shows a general synthesis of an R-L-P-R' intermediate of the invention wherein, for illustrative purposes, L is benzimidazole, R is a generic group that is depicted as a bromide, and R' is a protecting group. The acid 53b is coupled with 53a using a peptide coupling reagent such as HATU to afford 53c. Heating in solvent (such as refluxing ethanol) affords the R-L-P R' intermediate 53d. 10 Alternatively, the R-L-P-R' intermediate 53d is obtained by reaction of a diamine (such as 53a) and carbonyl compound (such as aldehyde 53e) in a solvent under heating conditions (e.g. ethanol under microwave irradiation). Scheme 54: Representative synthesis of R-M-P-R' 15 H H -GP P-PG N P-PG PG NP-PG Br \N Br 54a 54b 54c PG N P-PG PG PG r PPN P-PG NGP-PG N OHC Mc Md Me Scheme 54 shows a general synthesis of an R-M-P-R' intermediate of the invention wherein, for 20 illustrative purposes, M is imidazole, R is a generic group that is depicted as a bromide, aldehyde, or alkyne and R' is a protecting group. Imidazole 54a can be halogenated, for example, under the action of N-bromosuccinimide to provide bromoimidazole 54b. 406 Bromoimidazole 54b can be protected using standard conditions to give 54c, such as SEM-CI and sodium hydride when PG = SEM. The bromoimidazole 54b can be further elaborated, for example, to the corresponding aldehyde or alkyne. Lithiation of 54c and condensation with a formate equivalent (e.g. DMF) provides the aldehyde 54d. The aldehyde 54d is converted to 5 alkyne 54e using a phosphorus-based reagent (e.g. Ohira-Bestmann reagent). Scheme 55: Representative synthesis of R-P-M-A-A-M-P-R Br-A-A-Br -A-A4 O O 55a 55b HO OH Br Br

H

3

C-A-A-CH

3 -- {-A-A- A-A 55c 55d 55e HO 0 0 55e + HO P-PG - PG-P- A-A P-PG 0 00 0 55f 55g H A-A N P-PG PG-P H 55h 10 Scheme 55 shows a general synthesis of an R-P-M-A-A-M-P-R intermediate of the invention wherein, for illustrative purposes, M is imidazole and R is a generic group that is depicted as a protecting group. For example, the diketone 55b is converted to 55e using bromine. Compound 55b can be commercially available or can be prepared from the corresponding dibromide 55a 15 through coupling with a vinyltin reagent such as tributyl(ethoxyvinyl)stannane in the presence of a palladium catalyst. Coupling of 55e with acid 55f under basic conditions such as diisopropylethylamine affords diester 55g. Imidazole formation is accomplished by treatment of 55g with ammonium acetate to provide the imidazole containing intermediate R-P-M-A-A-M P-R (55h). 20 Alternatively, bromide 55e can be synthesized from 55c. The dimethyl compound 55c can be converted to the corresponding diacid 55d using potassium permanganate as oxidant. 407 Conversion of 55d to 55e can be accomplished by a multi-step homologation. For example, the treatment of 55d with oxalyl chloride, followed by trimethylsilyl diazomethane and then hydrobromic acid can afford compound 55e. 5 Scheme 56: Representative synthesis of R-P-M-W-M-P-R 0 0 0 0 Br-W-Br - Br-W Br + HOi. P-PG Br-W O P-PG Br H P-G0 56a 56b 56c 56d 0 0 0 0 00 0 0 W P-PG + HOi.P-PG PG-P--K W >-P-PG 06H PP 0 0 Br 56e 56c 56f H H PG-p N N P-PG W N 56g Scheme 56 shows a general synthesis of an R-P-M-W-M-P-R intermediate of the invention 10 wherein, for illustrative purposes, M is imidazole and R is a generic group that is depicted as a protecting group. The compound 56a is coupled with vinyltin reagent such as tributyl(ethoxyvinyl)stannane in the presence of a palladium catalyst, followed by bromination and hydrolysis with NBS and water, to give the bromoketone 56b. The reaction between bromide 56b and a carboxylic acid under basic condition generates the ester 56d. Following the 15 same reaction sequence, compound 56d can be elaborated to the diester 56f. Conversion of 56f to 56g is accomplished with ammonia reagents such as ammonium acetate at elevated temperature. 408 Scheme 57: Representative synthesis of R-A-A-M-P-R' OH HN-P-Z-V-E Br-A-A + H 2 N-P-Z-V-E ' Br-A-A 57a 57b 57c O HO 00 Br-A-A + H P-Z-V-E - Br-A-A - P-Z-V-E Br + 0 57d 57e 57f H N P-Z-V-E Br-A-A 57g O HO 0 0 Br-A-A + P-Z-V-E Br-A-A - - P-Z-V-E

NH

2 O NH 57h 57e 57i H _N 'P-Z-V-E 'I Br-A-A 57g H NH N P-Z-V-E Br-A-A-K + P-Z-V-E - Br-A-A-<\ Y1

NH

2 0 N 57j 57k 57g Br-A-A o + H 2 P_ r-A-A N P-Z-V-E Br HNN 57d 571 57g 5 Scheme 57 shows a general synthesis of an R-A-A-M-P-R' intermediate of the invention wherein, for illustrative purposes, M is an amide or an imidazole, R is a generic group that is depicted as Br, and R' is a generic group that is depicted as -Z-V-E. Coupling of amine 57b with acid 57a is accomplished using a peptide coupling reagent (e.g. HATU) to afford amide containing 57c. 10 The acid 57e is coupled with an a-haloketone, such as a-bromoketone 57d, under basic conditions (e.g. Et 3 N) to afford 57f. Alternatively, the acid 57e is coupled with an a aminoketone 57h, under amide formation conditions (e.g. EDC, Et 3 N) to afford 57i. Reaction of 57f or 57i with an amine or amine salt (e.g. ammonium acetate) affords the imidazole containing intermediate Br-A-M-P-Z-V-E (57g). Coupling of 57j and 57k and, in the 409 alternative, coupling of 57d and 571 under appropriate conditions can also be used in preparation of intermediate Br-A-M-P-Z-V-E (57g). Scheme 58: Representative synthesis of R-A-A-M-P-R' 5

E-V-Z-P-M-A-A-B(OR)

2 + Br-M-P-PG - ' E-V-Z-P-M-A-A-M-P-PG 58a 58b 58c

PG-P-M-A-A-B(OR)

2 + Br-M-P-PG ' PG-P-M-A-A-M-P-PG 58d 58b 58.

PG-A-A-B(OR)

2 + Br-M-P-PG PG-A-A-M-P-PG 58f 58b 58g

(RO)

2

B-A-A-B(OR)

2 + 2 Br-M-P-PG - PG-P-M-A-A-M-P-PG 58h 58b 58e

PG-P-M-A-B(OR)

2 + Br-A-M-P-PG ' PG-P-M-A-A-M-P-PG 581 58j 58e Scheme 58 shows a general synthesis of the R-A-A-M-P-R molecule of the invention, wherein a transition metal-mediated cross-coupling reaction is utilized to construct the A-A bond or A-M 10 bond. For illustrative purposes, the Suzuki reaction is employed to couple two corresponding intermediates, R is a generic group that is depicted as -M-P-Z-V-E, -M-P-PG, or a protecting group, and R' is a generic group that is depicted as a protecting group. Boronic ester 58a, 58d, 58f or 58i is coupled with an appropriate coupling partner (e.g. arylbromide 58b or 58j) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 58c, 58e, or 58g. Formation of multiple A-M 15 bonds can be conducted in a similar manner. For example, the Suzuki reaction can also be employed to couple (RO) 2

B-A-A-B(OR)

2 (58h) and two equivalents of Br-M-P-PG. For each transition metal-mediated cross-coupling reaction the roles of the nucleophile and electrophile can be reversed to provide the same coupling product. Palladium mediated cross-coupling reactions that enable the A-A and/or A-M bond formation, but employ alternative coupling 20 partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. 410 Scheme 59: Representative synthesis of R-W-M-P-R'

E-V-Z-P-M-W-B(OR)

2 + Br-M-P-PG E-V-Z-P-M-W-M-P-PG 59a 59b 59c

PG-P-M-W-B(OR)

2 + Br-M-P-PG ' PG-P-M-W-M-P-PG 59d 59b 59e

PG-W-B(OR)

2 + Br-M-P-PG PG-W-M-P-PG 59f 59b 59g

(RO)

2

B-W-B(OR)

2 + 2 Br-M-P-PG PG-P-M-W-M-P-PG 59h 59b 59i 5 Scheme 59 shows a general synthesis of the R-W-M-P-R' molecule of the invention, wherein a transition metal-mediated cross-coupling reaction is utilized to construct the W-M bond. For illustrative purposes, the Suzuki reaction is employed to couple two corresponding intermediates, R is a generic group that is depicted as -M-P-Z-V-E, -M-P-PG, or a protecting group, and R' is a generic group that is depicted as a protecting group. Boronic ester 59a, 59d, 10 or 59f is coupled with an appropriate coupling partner (e.g. arylbromide 59b) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 59c, 59e, or 59g. Formation of multiple W-M bonds can be conducted in a similar manner. For example, the Suzuki reaction can also be employed to couple (RO) 2

B-W-B(OR)

2 (59h) and two equivalents of Br-M-P-PG. For each transition metal mediated cross-coupling reaction the roles of the nucleophile and electrophile can be reversed to 15 provide the same coupling product. Palladium mediated cross-coupling reactions that enable the W-M bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. Scheme 60: Representative synthesis of R-A-L-P-R 20

E-V-Z-P-M-A-B(OR)

2 + Br-L-P-PG -- E-V-Z-P-M-A-L-P-PG 60a 60b 60c

PG-P-M-A-B(OR)

2 + Br-L-P-PG PG-P-M-A-L-P-PG 60d 60b 60e

PG-A-B(OR)

2 + Br-L-P-PG PG-A-L-P-PG 60f 60b 60g 411 Scheme 60 shows a general synthesis of the R-A-L-P-R' molecule of the invention, wherein a transition metal-mediated cross-coupling reaction is utilized to construct the A-L bond. For illustrative purposes, the Suzuki reaction is employed to couple two corresponding intermediates, R is a generic group that is depicted as -M-P-Z-V-E, -M-P-PG, or a protecting 5 group, and R' is a generic group that is depicted as a protecting group. Boronic ester 60a, 60d, or 60f is coupled with an appropriate coupling partner (e.g. arylbromide 60b) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 60c, 60e, or 60g. For each transition metal-mediated cross coupling reaction the roles of the nucleophile and electrophile can be reversed to provide the same coupling product. Palladium mediated cross-coupling reactions that enable the A-L bond 10 formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. Scheme 61: Representative synthesis of R-A-M-P-R'

E-V-Z-P-L-A-B(OR)

2 + Br-M-P-PG - - E-V-Z-P-L-A-M-P-PG 61a 61b 61c

PG-P-L-A-B(OR)

2 + Br-M-P-PG PG-P-L-A-M-P-PG 61d 61b 61e

PG-A-B(OR)

2 + Br-M-P-PG PG-A-M-P-PG 15 61f 61b 61g Scheme 61 shows a general synthesis of the R-A-M-P-R' molecule of the invention, wherein a transition metal-mediated cross-coupling reaction is utilized to construct the A-M bond. For illustrative purposes, the Suzuki reaction is employed to couple two corresponding 20 intermediates, R is a generic group that is depicted as -L-P-Z-V-E, -L-P-PG, or a protecting group, and R' is a generic group that is depicted as a protecting group. Boronic ester 61a, 61d, or 61f is coupled with an appropriate coupling partner (e.g. arylbromide 61b) using a palladium catalyst, such as Pd(PPh 3

)

4 , to afford 61c, 61e, or 61g. For each transition metal-mediated cross coupling reaction the roles of the nucleophile and electrophile can be reversed to provide the 25 same coupling product. Palladium mediated cross-coupling reactions that enable the A-M bond formation, but employ alternative coupling partners and reagents, include for example the Negishi, Kumada, Sonagashira and Stille reactions. 412 Scheme 62: Representative synthesis of R-P-H PG 0 x 0 xx EtO H 2 EtO H EtO H 62a 62b 62c Scheme 62 shows a general synthesis of a R-P-H molecule of the invention wherein, for 5 illustrative purposes, R is a generic group that is depicted as ethoxycarbonyl and P is a carbocyclic or heterocyclic ring (e.g. X is carbon or heteroatom) and m, n, and o are 0 - 3, independently. The amino ester 62a is converted to the substituted or cyclized amino ester 62b through for example a reductive amination or Mitsunobu reaction. Compound 62b can be protected to provide compound 62c if necessary. 10 Scheme 63: Representative synthesis of R-P-M-W-M-P-R FG, (CH 2 )mOH PG-P-M-A-A-M-P-PG = PG-P-M-A-A-M-P-PG - PG-P-M-W-M-P-PG

FG

2

(CH

2 )nOH 63a 63a 63b

(CH

2 )mCHO = PG-P-M-A-A-M-P-PG - ' PG-P-M-W-M-P-PG

(CH

2 )nCHO 63c 63b

(CH

2 )mCO 2 PG = PG-P-M-A-A-M-P-PG - PG-P-M-W-M-P-PG

(CH

2 )nNH 2 63d 63b 15 Scheme 63 shows a general synthesis of a R-P-M-W-M-P-R intermediate of the invention wherein, for illustrative purposes, R is a generic group that is depicted as a protecting group and A is functionalized with a group depicted as either hydroxyalkyl, aminoalkyl, carbonylalkyl, or alkoxycarbonylalkyl. The cyclization of 63a, 63c, and 63d can be performed through several functional group transformations which include, but are not limited to, Mitsunobu reaction, 20 reductive amination, and lactamization. 413 Scheme 64: Representative Synthesis of H-V-E 0 0 H 0 NN AO O H 'Y H H 64a 64b 64c 5 Scheme 64 shows a general synthesis of a H-V-E intermediate of the invention wherein, for illustrative purposes E is methoxycarbonylamino and V is isopropylamino. The reaction of hydrazine carboxylate 64a with a ketone or aldehyde, such as acetone, under acidic conditions (e.g. AcOH) affords the imine 64b. Reaction of 64b under reducing conditions, such as PtO 2 and hydrogen gas, affords the substituted hydrazinecarboxylate 64c. 10 The invention will now be illustrated by the following non-limiting Examples. EXAMPLES Example AA O 0 H B-B H N N -N N Boc Bo 2-[5-(4-Bromo-phenyl)-1H- Pd(PPh 3

)

4 , Dioxane, 80 *C N / O imidazol-2-y]-pyrrolidine-1- KOAc 2-(5-[4-(4,4,5,5-Tetramethyl carboxylic acid tert-butyl ester (1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol 2-yl}-pyrrolidine-1-carboxylic acid tert-butyl 15 ester

(S)-

2 -{5-14-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yi)-phenyl]-1 H-imidazol-2-yl) pyrrolidine-l-carboxylic acid tert-butyl ester: 1,4-Dioxane (300 mL) was added to a mixture of (S)-2-[5-(4-bromo-phenyl)-I H-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (21.1 g, 53.7 mmol), bis(pinacolato)diboron (27.3g, 107.5 mmol), 20 tetrakis(triphenylphosphine)palladium (0) (3.10 g, 2.68 mmol), and potassium acetate (15.02 g, 153.0 mmol), and heated at 80'C for 16 hours. The mixture was cooled and the resulting solid was filtered. The majority of the 1,4-dioxane was removed from the filtrate under reduced pressure and resulting residue was taken up in ethyl acetate (300 mL). The organic phase was washed with saturated sodium bicarbonate (2x 150 mL), brine (100 mL) and dried over sodium 25 sulfate. After filtration the solvent was removed from the filtrate under reduced pressure. The resulting oil was subjected to silica gel chromatography using a 330 g ISCO column and effluent of 20-100 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide (S)-2-{5-[4-(4,4,5,5-tetramethyl 414 [I ,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine- 1 -carboxylic acid tert-butyl ester (18 g, 76 %) and light yellow solid. Example AB HCI / Dioxane H Boc I DCMH 2-{5-[4-(4,4,5,5-Tetramethyl- 2-Pyrrolidin-2-yl-5-[4-(4,4,5,5 [1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol- tetramethyl-[1,3,2]dioxaborolan-2 2-yi}-pyrrolidine-1-carboxylic acid tert-butyl yl)-phenyl]-1H-imidazole 5 ester (S)-2-Pyrrolidin-2-yl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H imidazole hydrochloride: A solution of hydrogen chloride in 1,4-dioxane (4 N, 75 mL) was added to a solution of (S)-2-{5-[4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-l

H

10 imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (7.0 g, 15.9 mmol) in dichloromethane (50 mL). Gas evolution was observed. After 30 minutes, a solid formed. After 1.5 hours, the resulting solid was isolated by filtration with diethyl ether washing. Any residual solvent was removed under reduced pressure to provide (S)-2-pyrrolidin-2-yl-5-[4 (4,4,5,5-tetramethyl-[ l,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazole hydrochloride (5.6 g, 95 15 %) as an off-white solid. Example AC H 0H N N - 0 0j2 N N - 0 H I B 0UX OO N E HCI N B O COOH 2-Pyrrolidin-2-yl-5-[4-(4,4,5,5- HATU, DIPEA, DMF 0 tetramethyl- 1,3,2]dioxabarolan-2- [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl yI).phenyl]-1 H-imidazole [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2-yl} pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester 20 (S,S)-[2-Methyl-I -(2-{5-14-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-I

H

imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyll-carbamic acid methyl ester: Diisopropylethylamine (7.63 mL, 43.8 mmol) was added to a suspension of (S)-2-pyrrolidin-2 yl-5-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazole hydrochloride (7.33 g, 19.5 mmol), 0-(7-azabenzotriazol- I -yl)-N,N,N',N'-tetramethyluronium 25 hexafluorophosphate (7.6 g, 19.9 mmol) and (S) 2-methoxycarbonylamino-3-methyl-butyric acid (3.59 g, 20.5 mmol) in dimethylformamide (75 mL). All solids dissolved. After 30 min the 415 reaction mixture was diluted with ethyl acetate (300 mL) and was washed with 2 saturated sodium chloride (I x 300 mL), half saturated sodium bicarbonate (2 x 150 mL) and brine (1 x 100 mL). The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting tan foam was subjected to silica gel 5 chromatography with eluate of 20 -100 % ethyl acetate and hexanes, to provide (S,S)-[2-methyl 1-(2-{5-[4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I H-imidazol-2-yl} pyrrolidine-l-carbonyl)-propyl]-carbamic acid methyl ester (6.6 g, 68 %) as a white foam: lH (DMSO-d6): 8 = 1 1.81 (br s, I H), 7.72 (m, 2H), 7.61 (m, 2H), 7.51 (br s, I H), 7.27 (d, J = 8.4 Hz, I H), 5.05 (m, I H), 4.04 (m, 2 H), 3.78 (m, 2H), 3.52 (s, 3H), 2.11 (m, 2 H), 1.93 (m, 2H), 10 1.28 (s, 12H), 0.85 (dd, Ji = 6.6 Hz, J 2 = 11.4 Hz, 6H). Example AD Br

H

2 N O N-\ P H2N B H -Bc Br / o~ HN - N Br0 HATU Bos N o NH40Ac BrN-o 2-Amino-1-(4-bromo- A 150 Br phenyl)-ethanone 3-[2-(4-Bromo-phenyl)-2-oxo- 150 c 3-[5-(4-Bromo-phenyl)-1H ethylcarbamoyl]-pyrrolidine-1- imidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester carboxylic acid tert-butyl ester N- N 0 H HCN-Boc K-HN Pd(PPh 3

)

4 H NaHC03 DME 2-(5{4'-[2-(1- Boc-pyrrolidin-3-yl)-3H-imidazol 4-yl]-biphenyl4-y}-1H-imidazoi-2.yI) pyrrolidine-1-carboxylic acid tert-butyl ester O OH 2 H oNO HCI HATU H (1 -{3-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 3

-[

2

-(

4 -Bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl 15 ester: NN-diisopropylethylamine (5.3 mL, 30.6 mmol) was added dropwise to a mixture of pyrrolidine-l,3-dicarboxylic acid I-tert-butyl ester (2.2 g, 10.1 mmol), HATU (4.0 g, 10.5 mmol), the HCI salt of 2 -amino-l -(4-bromophenyl)ethanone (2.4 g, 9.6 mmol), and DMF (40 mL), and stirred at ambient condition for 1 hour. Most of the volatile component was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (150 mL), washed with water 20 and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was 416 purified by flash chromatography to provide the desired product as a white foam-like solid (3.5 g, 90%). m/z 432.9, 434.9 (M + Na)*. 3-15-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: A 5 mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine- I -carboxylic acid tert butyl ester (1.5 g, 3.6 mmol) and ammonium acetate (1.4 g, 18.2 mmol) in xylene (15 mL) was heated in a sealed tube at 140'C for 2 hours. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL), washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was 10 purified by flash chromatography to provide the desired product as a white solid (795 mg, 56%). m/z 391.8, 393.8 (M + H)+. 2-(5-{4'-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yI)-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester: Pd(Ph 3

)

4 (54 mg, 0.046 mmol) was added to a 15 mixture 3-[5-(4-bromo-phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (378 mg, 0.97 mmol), 2-{5-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-I H imidazol-2-yl}-pyrrolidine-l -carboxylic acid tert-butyl ester (408 mg, 0.93 mmol), NaHCO 3 (273 mg, 3.26 mmol) in 1,2-dimethoxyethane (8 mL) and water (2 mL). The reaction mixture was flushed with nitrogen, heated at 80*C for 6 hours, and then the volatile component was 20 removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHC0 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (370 mg, 64%). m/z 625.1 (M + H)*. 25 (1-{3-15-(4'-12-[I1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yI}-biphenyl-4-yl)-IH-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester: To a solution of 2-(5-{4'-[2-(] -Boc-pyrrolidin-3-yl)-3H-imidazol 4-yl]-biphenyl-4-yl}-1 H-imidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl ester (200 mg, 0.232 mmol) in methanol (5 mL) was added 4.0 M solution of HCI in dioxane (I mL, excess). 30 The mixture was stirred for 3 hours at 50*C and concentrated under reduced pressure. The residue was treated with ether to remove excess HCL. The obtained white solid was dissolved in DMF (5 mL). To the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (123 mg, 0.71 mmol), HATU (285 mg, 0.75 mmol) and NN-diisopropylethylamine (0.14 mL, 0.77 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was 35 removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with I N 417 NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (100 mg, 42%). 'H-NMR (300 MHz, CD 3 0D) 6 8.00-7.80 (m, IOH), 5.26 (t, I H), 4.40 3.42 (m, 15H), 2.65-2.00 (m, 8H), 1.50-0.93 (m, 12H); m/z 739.3 (M + H)+. 5 Example AE N 0 0 Boc,

H

2 N 01 N-- hBoc H OHH N- N Br OOH N Br- / 2-mn-.4br0o AUB NH 4 0Ac 2-Amino-l-(4-bromo- HATU B 150 *C 3-[5-(4-Bromo-phenyl)-1H-imidazol-2 phenyl)ethanone 3-[2-(4-Bromo-phenyl)-2-oxo- yl]-2-aza-bicyclo[2.2.lheptane-2 ethylcarbamoyf}-2-aza-bicyclo[2.2.lheptane- carboxylic acid terf-buty ester 2-carboxylic acid tert-butyt ester HH ON HK N --------- HIP - H HCI Br - / ' ,B / (1-{3-{5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2- [2-Methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl aza-bicyclo[22.1]Jheptane-2-carbonyl}-2- (1,3,2]dicxaborolan-2-yl)-phenyl-1H-imidazol-2 yl)-2-aza-bicycio[2.2. llheptane-2-carbonyl) HO methyl-propyl)-carbamic acid methyl ester propyy- - carb ao and methyl ester Br 7_O H0 H - - N Pd(PPh 3

)

4 H NaHC03 DME (1 -{2-[5-(4'-2-[2-(2-Methoxyca rbonylamino- 3-methy-buty rA)-2-aza bicyclo[2.2. 1 ) hept-3-y-3H- i midazoI4-y}-bi pheny-4-y)y-1 H- imidazol-2-y] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 3-12-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza- bicyclo[2.2.1]heptane-2-carboxylic 10 acid tert-butyl ester: Following the procedure used to prepare compound 3-[2-(4-bromo phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine- I -carboxylic acid tert-butyl ester, except that 2-aza bicyclo[2.2.l ]heptane-2,3-dicarboxylic acid 2-tert-butyl ester was used instead of pyrrolidine 1,3-dicarboxylic acid 1-tert-butyl ester. 15 3-15-(4-Bromo-phenyl)-1H-imidazol-2-yll-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: Following the procedure used to prepare compound 3-[5-(4-bromo-phenyl) I H-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester, except that 3-[2-(4-bromo phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester was used instead of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine- I -carboxylic 20 acid tert-butyl ester. 418 (1-{3-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: To a solution of 3-[5-(4-bromo-phenyl)-l H imidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (1.0 g, 2.4 mmol) 5 in methanol (20 mL) was added 4.0 M solution of HCI in dioxane (4.0 mL, excess). The mixture was stirred for 3 hours at 50*C and concentrated under reduced pressure. The residue was treated with ether to remove excess HCL. The obtained white solid was dissoved in DMF (20 mL). To the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (0.46 g, 2.6 mmol), HATU (1.0 g, 2.6 mmol) and NN-diisopropylethylamine (2.5 mL, 14.4 mmol). The 10 mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with I N NaOH solution, water and brine, dried over MgSO 4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (1.0 g, 89%). m/z 475.1, 477.1 (M + H)*. 15 [2-Methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-iH-imidazol-2 yl}- 2 -aza-bicyclo[ 2 .2.llheptane-2-carbonyl)-propyl]-carbamic acid methyl ester: Pd(PPh 3

)

4 (73 mg, 0.06 mmol) was added to a sealed tube containing a mixture of (I -{3-[5-(4-bromo phenyl)-I H-imidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carbonyl}-2-methyl-propyl)-carbamic 20 acid methyl ester (600 mg, 1.27 mmol), bis(pinacolato)diboron (675 mg, 2.66 mmol), potassium acetate (324 mg, 3.3 mmol) and 1,4-dioxane (15 mL). The reaction mixture was flushed with nitrogen, heated at 80*C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHC0 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified 25 by flash chromatography to provide the desired product as a white solid (440 mg, 66%). m/z 523.2 (M + H)*. (1-{2-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryh)-2-aza-bicyclo[2.2.1]hept-3 yl]-3H-imidazol-4-yl)-biphenyl-4-y)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl 30 propyl)-carbamic acid methyl ester: Following the procedure used to prepare compound 2-(5 {4'-[2-(I- Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl} -I H-imidazol-2-yl) pyrrolidine-l-carboxylic acid tert-butyl ester, except that [2-methyl-l-(3-{5-[4-(4,4,5,5 tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]- IH-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane 2-carbonyl)-propyl]-carbamic acid methyl ester and (I -{2-[5-(4-bromo-phenyl)- 1 H-imidazol-2 35 yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester were used instead of 419 2-{5-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yI)-phenyl]- I H-imidazol-2-yl)-pyrrolidine I-carboxylic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)- I H-imidazol-2-yl]-pyrrolidine- 1 carboxylic acid tert-butyl ester. 'H-NMR (300 MHz, CD 3 0D) 6 7.90-7.70 (m, IOH), 7.20-7.10 (m, I H), 5.24 (t, I H), 4.63 (s, I H), 4.40-3.80 (m, 4H), 3.68 (s, 3H), 3.66 (s, 3H), 2.60-1.60 (m, 5 13H), 1.05-0.90 (m, 12H); m/z 765.2 (M + H)*. (1-{3-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3 yl]-3H-imidazol-4-yl}-biphenyl-4-yI)-1 H-imidazol-2-yl]-2-aza-bicyclo[2.2.1 Iheptane-2 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Following the procedure used to 10 prepare compound 2-(5-{4'-[2-(] -Boc-pyrrolidin-3-yl)-3H-imidazol-4-yI]-biphenyl-4-yl}-I

H

imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester, except that [2-methyl-1-(3-{5-[4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-2-aza bicyclo[2.2.1 ]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester and (I -{3-[5-(4-bromo phenyl)-l-H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}- 2 -methyl-propyl)-carbamic 15 acid methyl ester were used instead of 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) phenyl]- IH-imidazol-2-yI}-pyrrolidine-l -carboxylic acid tert-butyl ester and 3-[5-(4-bromo phenyl)- IH-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester. 'H-NMR (300 MHz,

CD

3 0D) 8 7.90-7.20 (m, I OH), 4.83-4.25 (m, 5H), 3.90-3.40 (m, 6H), 2.90-2.70 (m, 2H), 2.40 2.10 (m, 3H), 2.10-1.40 (m, I I H), 1.10-0.90 (m, 12H); m/z 791.3 (M + H)*. 20 420 Example AF 0 ~Kii~~- 0 0 0 OO Br OBr 1-[4-(4-Acetyl-phenoxy)- 2-Bromo-1-{4-[4-(2-bromo-acetyl) phenyl]-ethanone phenoxy]-phenyl}-ethanone 00 HOc NBoc O O Boc 0 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2 [2-(4-{4-[2-(1- Boc -pyrrolidine-2-carbonyloxy) acetyl]-phenoxy}-phenyl)-2-oxo-ethyl] ester H Boc B H N \ N \ 0/ \ OC

NH

4 0Ac H 150 *C 2-[5-(4-{4-[2-(1- Boc -pyrrolidin-2-yl)-3H-imidazol 4-yl]-phenoxy}-phenyl)-1 H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester

H

H~ NH HI 0 N- N H 0 N HCI H O H [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenoxy)-pheny]-1 H-imidazol-2-y} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 2 -Bromo-1-{ 4

-[

4 -(2-bromo-acetyl)-phenoxyl-phenyl}-ethanone: Bromine (2.02 mL, 39.3 5 mmol) in dichloromethane (25 mL) was added slowly to a stirred solution of 4-acetylphenyl ether (5.0 g, 19.7 mmol) in dichloromethane (65 mL) at 30*C. The mixture was stirred at ambient for 16 hours, and then the volatile component was removed in vacuo. The residue was recrystallized from ethanol (40 mL) to get a yellow crystal like product (2.3 g, 29%). 10 Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-[2-(4-{4-12-(1-Boc-pyrrolidine-2 carbonyloxy)-acetyl]-phenoxy}-phenyl)-2-oxo-ethylI ester: To a stirred mixture of 2-bromo 1-{4-[4-(2-bromo-acetyl)-phenoxy]-phenyl}-ethanone (2.0 g, 4.9 mmol) and pyrrolidine-1,2 dicarboxylic acid I-teri-butyl ester (2.2 g, 10.2 mmol) in acetonitrile (20 mL) was added DIPEA (1.76 mL, 10.1 mmol). The slurry was stirred for 3 hours at ambient temperature. The mixture I5 was diluted with ethyl acetate (150 mL), washed with water and brine, dried over MgSO 4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (2.2 g, 65%). m/z 703.1 (M + Na)*. 421 2-15-(4-{4-12-(1-Boc-pyrrolidin-2-yI)-3H-imidazol-4-yI]-phenoxy}-phenyl)-1H-imidazol-2 yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of pyrrolidine-1,2-dicarboxylic acid I -tert-butyl ester 2-[2-(4-{4-[2-(l -Boc-pyrrolidine-2-carbonyloxy)-acetyl]-phenoxy} phenyl)-2-oxo-ethyl] ester (250 mg, 0.37 mmol) and ammonium acetate (570 mg, 7.3 mmol) in 5 xylene (8 mL) was heated in microwave machine at 140*C for 80 minutes. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, water and brine, dried over MgSO 4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (62 mg, 26%). m/z 641.1 (M + H)*. 10 [1-(2-{5-[4-(4-{2- [1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-ylj-3H imidazol-4-yl}-phenoxy)-phenyl]-1H-imidazol-2-yI}-pyrrolidine-1-carbonyl)-2-methyl propyll-carbamic acid methyl ester: Following the procedure used to prepare compound (1 { 3-[5-(4'-{2-[l-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4 15 yl}-biphenyl-4-yl)-lH-imidazol-2-yl]-pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, except that 2-[5-(4-{4-[2-(1- Boc -pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenoxy} phenyl)- 1 H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester was used instead of 2 (5-{4'-[2-(I- Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}- I H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester. 'H-NMR (300 MHz, CD 3 0D) 6 7.80-7.60 (m, 20 4H), 7.30-7.20 (m, 2H), 7.10-0.95 (m, 4H), 5.16 (t, lH), 4.30-3.50 (m, 12H), 2.40-1.90 (m, IOH), 1.10-0.90 (m, 12H); m/z 755.2 (M + H)*. 422 Example AG HOO 00 KMnO 4 O OH Br -r 0-0 -O b 4 Br 3,4'-dimethylbiphenyl ether 3,4'-Oxybis(benzoic acid) 2-Bromo-1 -{4-[3-(2-bromo-acetyl) phenoxy]-phenyl}-ethanone 0a 0 OBoc O- / HO N 0 Boc Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-[2-(4-{3-[2-(1-Boc pyrrolidine-2-carbonyloxy)-acetyl]-phenoxy-phenyl)-2-oxo-ethyl] ester Boc H N N \/P

NH

4 0Ac H N N 150 "C/ Boc 2-[5-(4-{3-[2-(1 -Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenoxy} phenyl)-1 H-imidazol-2-yl]-pyrrolidine-1 -carboxylic acid tert-butyl ester HKN HN O 0 - H HCI HATUH NH /0 [1-(2-{5-[4-(3-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-y}-phenoxy)-phenyl]-1 H-imidazol-2-yl pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 3,4'-Oxybis(benzoic acid): A mixture of 3,4'-dimethylbiphenyl ether (1.7 g, 8.6 mmol) and 5 potassium permanganate (6.0 g, 38 mmol) in water (200 mL) was refluxed for 6 hours. The hot solution was filtered, cooled, and extracted with chloroform. The aqueous layer was acidified by 2 N HCl. The precipitate was filtered off and washed with water to give a white solid (0.55 g, 25%). m/z 257.1 (M - H)-. 10 2-Bromo-1-{4-[3-(2-bromo-acetyl)-phenoxy]-phenyl}-ethanone: A mixture of 3,4' oxybis(benzoic acid) (0.55 g, 2.1 mmol)) and oxalyl chloride (10.6 mL, 21.3 mmol) in dichloromethane (40 mL) containing DMF (4 drops) was stirred at ambient temperature for 4 hours, then concentrated and co-evaporated with toluene (3x) and dried under high vacuum. The resulting residue was suspended in dichloromethane (15 mL) at 0*C and treated with 2.0 M 15 trimethylsilyldiazomethane in ether (3.2 mL, 6.4 mmol) over 15 minutes to give a brown mixture. Reaction mixture was warmed to ambient temperature overnight and then 423 concentrated. The resulting brown solid was suspended in ethyl acetate (15 mL) and cooled to 0*C. HBr in acetic acid (1.2 mL, 33%W, 6.4 mmol) was added over 5 minutes and reaction mixture was warmed to ambient temperature over I hour. Solid sodium bicarbonate (0.3 g) was added and stirred for 30 minutes. Water was added giving a biphasic mixture with a brown 5 precipitate. The solid was removed by filtration and filtrate was extracted with dichloromethane, dried over MgSO 4 and concentrated. The residue was purified by flash column chromatography to give a brown solid (0.47 g). Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-12-(4-(3-12-(I-Boc-pyrrolidine-2 10 carbonyloxy)-acetyll-phenoxy)-phenyl)-2-oxo-ethyl] ester: Following the procedure used to prepare compound (1 -{3-[5-(4'-{2-[1-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester, except that 2-bromo-I-{4-[3-(2-bromo-acetyl)-phenoxy] phenyl}-ethanone was used instead of 2-bromo-I -{4-[4-(2-bromo-acetyl)-phenoxy]-phenyl} 15 ethanone. m/z 703.1 (M + Na)*. 2 -15-(4-{3-2-(l-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenoxy}-phenyl)-1 H-imidazol-2 yl]-pyrrolidine-l-carboxylic acid tert-butyl ester: Following the procedure used to prepare compound 2-[5-(4-{4-[2-(l -Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenoxy}-phenyl)- I H 20 imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, except that pyrrolidine-1,2 dicarboxylic acid I -tert-butyl ester 2-[2-(4-{3-[2-(I-Boc-pyrrolidine-2-carbonyloxy)-acetyl] phenoxy}-phenyl)-2-oxo-ethyl] ester was used instead of pyrrolidine-1,2-dicarboxylic acid I tert-butyl ester 2-[2-(4-{4-[2-(I-Boc-pyrrolidine-2-carbonyloxy)-acetyl]-phenoxy}-phenyl)-2 oxo-ethyl] ester. m/z 641.0 (M + H)*. 25 i-(2-{5-[4-(3-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenoxy)-phenyl]-I H-imidazol-2-yi}-pyrrolidine-1-carbonyl)-2-methyl propyll-carbamic acid methyl ester: Following the procedure used to prepare compound (1 {3-[5-(4'-{2-[I-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4 30 yl}-biphenyl-4-yl)-lH-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, except that 2-[5-(4-{3-[2-(I-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenoxy} phenyl)-IH-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester was used instead of 2 (5-{4'-[2-(I-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-IH-imidazol-2-yl) pyrrolidine-l-carboxylic acid tert-butyl ester. 'H-NMR (300 MHz, CD 3 0D) 8 7.80-7.10 (m, 424 10H), 5.30-5.15 (m, 2H), 4.30-4.20 (m, 2H), 4.18-4.05 (m, 2H), 3.95-3.80 (m, 2H), 3.70-3.60 (m, 6H), 2.65-2.45 (m, 2H), 2.40-2.00 (m, 8H), 1.05-0.85 (m, 12H); m/z 755.3 (M + H)+. Example AH H r + O Pd(Ph 3

)

4 H NaHCO 3 {1-{2-(6-Brm l 1H-benzaimidaol- [132-Methyl -(3{ )[ ny .5termhl a 2DMElwater 1{-6(-2[-2Mtoyabntmn--eb methyl-propyl} rbmic acid yl}-2-az-tcldo[2.21 ]hetane--a nyl)- but ry)--az-b do[ 2.1 (ept3y3- imdal -) 5 2-methyl-propyl)-carblamic acdd methyl ester (1 -{2- [6-(4-{(2-[1 2 -(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[j2.2. 1]hept-3 yl]-3H-imidazol-4-yl}-phenyl)-1 H-benzoimidazol-2-yI]-pyrrolidine-1 -carbonyl}-2-methyl propyl)-carbamic acid methyl ester: Following the procedure used to prepare compound 2-(5 10 {4'-[2-(1I-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl } -1 H-imidazol-2-yI)-pyrrol idine 1-carboxylic acid tert-butyl ester, except that [2-methyl-I-(3-{5-[4-(4,4,5,5-tetramethyl [ I,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl }-2-aza-bicyclo[2.2. I]heptane-2-carbonyl) propyl]-carbamic acid methyl ester and { I -[2-(6-bromo- I H-benzoimnidazol-2-yl)-pyrrolidine-lI carbonyl]-propyl}-carbamic acid methyl ester were used instead of 2-{5-[4-(4,4,5,5-tetramnethyl 15 [1 ,3,2]dioxaborolan-2-y1)-phenyl]- Il-H-imidazol-2-y } -pyrrolidine- 1-carboxyl ic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)- 1 H-imidazol-2-yl]-pyrrolidine- I-carboxylic acid tert-butyl ester. 'H-NMR (300 M Hz, CD 3 0D) 6 8.10-7.80 (mn, 7H), 5.42-5.30 (in, 1 H), 4.65 (s, I H), 4.40 4.25 (in, 2H-), 4.20-3.90 (mn, 2H, 3.80-3.60 (mn, 6H), 3.00-2.80 (in, I H), 2.70-2.55 (mn, 11H), 2.50 1.60 (in, 12H]), 1.10-0.80 (mn, 12H]); m/z 739.3 (M + H-)*. 20 425 Example Al H 0 N HO 0 Br Br O Na/HNHBr NH 2 6 ~ ' KCN - ; NH NaOH 1-(4-Brmo- (NH 4

)

2

CO

3 5-(4-Bromo-phenyl)-5- water 2-Amino-2-(4-brmo phenyl)-ethanone H/wat methyl-imidazolidine- phenyl)-propionic acid phny)-th nneEtOH/water 2,4-diane N-Boc rN-Boc I0 0 - HN 0 H HCI N 2 Proline B ~ / 0

NH

3 Br ethanol Br Hro n Br Ntn3 B H 2-Amino-2-(4-bromo- 0 ethanolNH phenyl)-propionic acid 2-[1-(4-Bromo-phenyl)-1-carbamoyl p henyl r 2-[1-(4-Bromo-phenyl)-1-ethoxycarbonyl- ethylcarbamoyl]-pyrrolidine-1 ethylcarbamoyl]-pyrrolidine-1-carboxylic carboxylic acid tert-butyl ester acid tert-butyl ester N 'BocO HN N, Boc Boc N Br HN N B4 0 f\ N + N N 1N NaOH Br Pd(PPh 3 )4 B H ethanol 002-[5-(4-Bromo-phenyl)-1

H

2-[5-(4-Bromo-phenyl)-5- 2-{5-Methyl-4-oxo-5-[4-(4,4,5,5- imidazol-2-yl]-pyrrolidine-1 methyl-4-oxo-4,5-dihydro-1H- tetramethyl-[1,3,2]dioxaborolan-2-yl)- carboxylic acid tert-butyl ester imidazol-2-yll-pyrrolidine-1- phenyl]-4,5-dihydro-1 H-imidazol-2-yl) carboxylic acid tert-butyl ester pyrrolidine-1-carboxylic acid tert-butyl ) ester - N. 'Boc N N -N Pd(PPh 3

)

4 H 2-(5-{4'-[4-Boc-2-(1-methyl-pyrrolidin-2-yl)-5-oxo-4,5 dihydro-3H-imidazol-4-yl]-biphenyl-4-yl-1H-imidazol 2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester HO "NH HN O HO HN o"o N\ /\ 00 HCI HATU (1 -{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methy-butyryl)-pyrrolidin-2-yl]-4 methyl-5-oxo-4,5-dihydro-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5-(4-Bromo-phenyl)-5-methyl-imidazolidine-2,4-dione: A mixture of 4-bromo acetophenone 5 (8.0 g, 40.2 mmol), ammonium carbonate (40 g, 402 mmol) and potassium cyanide (3.4 g, 52.3 mmol) in a mixed solvent of ethanol (90 mL) and water (90 mL) was stirred at 55*C for 5 hours, then 12 hours at ambient. The solution was adjusted to pH = 6 with 6 N HCI carefully and subsequently stirred at room temerature for 2 hours. The precipitate was filtered off, washed with water. The collected white solid was dried under vacuum to give the product (9.2 g, 85%). 10 m/z 267.1, 269.1 (M - H)~. 426 2-Amino-2-(4-bromo-phenyl)-propionic acid: A mixture of 5-(4-bromo-phenyl)-5-methyl imidazolidine-2,4-dione (4.0 g, 14.9 mmol) and 3 N NaOH (50 mL) was heated in a sealed tube at 145*C for two days, then diluted with water (100 mL). The solution was adjusted to pH = 4 with 6 N HCI carefully and subsequently stirred at room temerature for 2 hours. The precipitate 5 was filtered off, washed with water. The collected white solid was dried under vacuum to give the product (2.5 g, 65%). m/z 243.7, 245.7 (M + H)*. 2-Amino-2-(4-bromo-phenyl)-propionic acid ethyl ester: To a solution of 2-amino-2-(4 bromo-phenyl)-propionic acid (1.0 g, 4.1 mmol) in ethanol (20 mL) was bubbled through HCl 10 gas for five minutes. The mixture was stirred at ambient for 24 hours, then refluxed for 18 hours. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL), washed with NaHCO 3 solution, water and brine, dried over MgSO 4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (800 mg, 72%). m/z 271.7, 273.7 (M + H)+. 15 2-11-(4-Bromo-phenyl)-1-ethoxycarbonyl-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester: NN-diisopropylethylamine (4.1 mL, 23.6 mmol) was added dropwise to a mixture of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.7 g, 3.2 mmol), HATU (1.2 g, 3.2 mmol) and 2-amino-2-(4-bromo-phenyl)-propionic acid ethyl ester (0.8 g, 2.9 mmol) in 20 DMF (20 mL), and stirred at ambient condition for 3 hours. Most of the volatile componet was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (150 mL), washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a colorless oil (0.8 g, 58%). m/z 490.9, 492.9 (M + Na)*. 25 2-[1-(4-Bromo-phenyl)-1-carbamoyl-ethylcarbamoyll-pyrrolidine-1-carboxylic acid tert butyl ester: To a stirred solution of 2-[1-(4-bromo-phenyl)-l -ethoxycarbonyl-ethylcarbamoyl] pyrrolidine-l-carboxylic acid tert-butyl ester (280 mg, 0.6 mmol) in ethanol (8 mL) was bubbled through NH 3 gas for 5 minutes at -78'C. The solution was stirred at ambient for 3 days in a 30 sealed tube. Most of the volatile component was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (150 mL), washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a colorless oil (169 mg, 64%). m/z 439.8, 441.8 (M + H)+. 427 2 -[5-(4-Bromo-phenyl)-5-methyl-4-oxo-4,5-dihydro-1 H-imidazol-2-yi]-pyrrolidine-1 carboxylic acid tert-butyl ester: To a stirred solution of 2-[I-(4-bromo-phenyl)- I-carbamoyl ethylcarbamoyl]-pyrrolidine-l-carboxylic acid tert-butyl ester (160 mg, 0.36 mmol) in ethanol (10 mL) was added I N NaOH (5 mL), and stirred at ambient condition for 3 hours. Most of 5 the volatile componet was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (100 mL), washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (120 mg, 79%). m/z 421.8, 423.8 (M + H)+. 10 2-{5-Methyl-4-oxo-5-14-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yI)-phenyl]-4,5-dihydro IH-imidazol-2-yI}-pyrrolidine-1-carboxylic acid tert-butyl ester: Pd(PPh 3

)

4 (31 mg, 0.03 mmol) was added to a sealed tube containing a mixture of 2-[5-(4-bromo-phenyl)-5-methyl-4 oxo-4,5-dihydro- I H-imidazol-2-yi]-pyrrolidine- I -carboxylic acid tert-butyl ester (113 mg, 0.27 mmol), bis(pinacolato)diboron (144 mg, 0.57 mmol), potassium acetate (66 mg, 0.68 mmol) and 15 1,4-dioxane (3 mL). The reaction mixture was flushed with nitrogen, heated at 80'C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a colorless oil (100 mg, 79%). m/z 470.0 (M + H)*. 20 2-(5-{4'- [4-Boc-2-(I -methyl-pyrrolid in-2-yl)-5-oxo-4,5-dihyd ro-3H-imidazol-4-yi]-biphenyl 4 -yI}-IH-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: Following the procedure used to prepare compound 2-(5-{4'-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl] biphenyl-4-yl}-lH-imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester, except that 2 25 {5-methyl-4-oxo-5-[4-(4,4,5,5-tetramethyl-[l

,

3 ,2]dioxaborolan-2-yl)-phenyl]-4,5-dihydro- 1 H imidazol-2-yl}-pyrrolidine-l-carboxylic acid tert-butyl ester was used instead of 2-{5-[4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-l carboxylic acid tert-butyl ester. m/z 655.1 (M + H)+. 30 (1-{2-[5-(4'-{2- [1-( 2 -Methoxycarbonylamino-3-methy-butyryl)-pyrrolidin-2-yll-4-methyl 5-oxo-4,5-dihydro-3H-imidazol-4-yI}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester.: Following the procedure used to prepare compound (I -{ 3-[5-(4'- (2-[ I-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrol idin 2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-I H-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl 35 propyl)-carbamic acid methyl ester, except that 2 -(5-{4'-[4-Boc-2-(1 -methyl-pyrrolidin-2-yl)-5 428 oxo-4,5-dihydro-3H-imidazol-4-yI]-biphenyl-4-y}- 1 H-imidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl ester was used instead of 2-(5-{4'-[2-(I-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl] biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester. 'H-NMR (300 MHz, CD 3 0D) 8 7.90-7.50 (m, 9H), 5.25 (t, I H), 4.23 (d, 2H), 4.18-3.75 (m, 4H), 3.75-3.30 (m, 5 6H), 2.65-2.40 (m, 2H), 2.40-1.70 (m, 12H), 1.10-0.80 (m, 12H); m/z 769.2 (M + H)*. Example AJ q /0 6 bromine 10Br r B- a B B 9,I0-Dihydro- trimethyl phosphate 2,7-Dibronmo-9,10- Pd(PPh 3

)

4 phemanthrene dihydro-phenanthrene 4.4,5.5-Tetramethy2-[7-(4,4,5,5-tetramethyl [11,3,2]dioxaborolan-2-yl)-9.10dihydro phenanthren-2-y-1 ,3,2jdioxaborolane Br Boc Pd(PPh 3

)

4 2-(5-(7 2-(-Boc-pyroa in2-yi1)-3H-imidazot4.yIj. 9, 10-dihydro-phenanthren2-y)-1H-imidazo-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester ' OH HN 0H N N N HCI HATU H O NH (1 -2-5-(7-{2-[-(2-Methoxycarbonylamino-3methylbutyryl)pyrrolidin-2 yt]-3H-imidazo-4-yI)-9, 10-dihydro-phenantiren-2-yI)-l H-imidazo-2-ylj pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 10 2

,

7 -Dibromo-9,10-dihydro-phenanthrene: To a stirred solution of 9,10-dihydrophenanthrend (10 g, 55.5 mmol) in trimethylphosphate (60 mL) was added a solution of bromine (6.13 mL, 119.3 mmol) in trimethylphosphate (40 mL) slowly. After addition, the mixture was stirred at ambient for 18 hours, the volatile component was removed in vacuo. The residue was recrystallized from chloroform to give a white crystal (9.45 g, 5 1%). 15 4

,

4

,

5 ,5-Tetramethyl-2-17-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro phenanthren-2-yl]-[1,3,21dioxaborolane: Pd(PPh 3

)

4 (24 mg, 0.03 mmol) was added to a sealed tube containing a mixture of 2 ,7-dibromo-9,I0-dihydro-phenanthrene (1.0 g, 3.0 mmol), bis(pinacolato)diboron (3.8 g, 14.9 mmol), potassium acetate (1.5 g, 14.9 mmol) and 1,4 20 dioxane (30 mL). The reaction mixture was flushed with nitrogen, heated at 80'C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL), washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in 429 vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (1.2 g, 93%). m/z 432.8 (M + H)+. 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-y}-1H 5 imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: Pd(PPh 3

)

4 (31 mg, 0.03 mmol) was added to a mixture 4

,

4 ,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) 9,1 0-dihydro-phenanthren-2-yl]-[ 1,3,2]dioxaborolane (115 mg, 0.27 mmol), 2-(4-bromo- I H imidazol-2-yl)-pyrrolidine-l -carboxylic acid terl-butyl ester (173 mg, 0.55 mmol), NaHCO 3 (159 mg, 1.9 mmol) in 1,2-dimethoxyethane (5 mL) and water (I mL). The reaction mixture 10 was flushed with nitrogen, heated at 80'C for 6 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white solid (42 mg, 24%). m/z 651.0 (M + H)*. 15 (1-{2-[5-(7-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester: Followed the procedure used to prepare compound (1-{3-[5-(4'-{2-[l-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 20 imidazol-4-yl}-biphenyl-4-yl)-l H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl) carbamic acid methyl ester, except that 2-(5-{7-[2-(I-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl] 9,1 0-dihydro-phenanthren-2-yl} - I H-imidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl ester was used instead of 2-(5-{4'-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-

IH

imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester. 'H-NMR (300 MHz, CD 3 0D) 6 25 7.99 (d, 2H), 7.88 (s, 2H), 7.80-7.65 (m, 4H), 5.30-5.20 (m, 2H), 4.24 (d, 2H), 4.20-4.05 (m, 2H), 3.95-3.80 (m, 2H), 3.75-3.60 (m, 6H), 3.00 (s, H), 2.65-2.50 (m, 2H), 2.40-2.00 (m, 8H), 1.05-0.80 (m, 12H); m/z 765.3 (M + H)+. 430 Example AK B-Blo Br /Br B- 0 B B 2,7-Dibromo-9H- Pd(PPh 3

)

4 4,4,5,5-Tetramethyl-2-[7-(4,4,5,5 fluorene tetramethyl-[1,3,2]dioxaborolan-2-y)-9H fluoren-2-yl]-[1,3,2]dioxaborolane N~ N Br NH Boc H B _ _ _ _ _ _ _ Boc Pd(PPh 3

)

4 2-(5-{7-[2-(1 -Boc-pyrrolidin-2-yl)-3H-imidazol-4 yl]-9H-fluoren-2-y}-1 H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester OH HN 0 NHN NI O O NH HCI HATU H (1 -{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-I H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 4,4,5,5-Tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-fluoren-2-yl] 5 [1,3,2]dioxaborolane: Followed the procedure used to prepare 4,4,5,5-tetramethyl-2-[7 (4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-9, I 0-dihydro-phenanthren-2-yl] [1,3,2]dioxaborolane, except that 2,7-dibromofluorene was used instead of 2,7-dibromo-9,10 dihydro-phenanthrene. 'H-NMR (300 MHz, CDC 3 ) 8 8.01 (s, 2H), 7.84 (s, 4H), 3.90 (s, 2H), 1.38 (s, 24H). 10 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9H-fluoren-2-yl}-IH-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester: Followed the procedure used to prepare compound 2-(5-{7-[2-(I-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2 yl}-1H-imidazol-2-yi)-pyrrolidine-l-carboxylic acid tert-butyl ester, except that 4,4,5,5 15 tetramethyl-2-[7-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-9H-fluoren-2-yl] [1,3,2]dioxaborolane was used instead of 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yI]-[I,3,2]dioxaborolane. m/z 637.1 (M + H)+. 431 (1 -(2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolid in-2-yl]-3H imidazol-4-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: Followed the procedure used to prepare compound (I {3-[5-(4'- {2-[I-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-im idazol-4 5 yl}-biphenyl-4-yl)-l H-imidazol-2-yi]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, except that 2-(5-{7-[2-(I-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9H-fluoren-2 yl}-IH-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of 2-(5 {4'-[2-(I-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}- IH-imidazol-2-yl)-pyrrolidine I-carboxylic acid tert-butyl ester. 'H-NMR (300 MHz, CD 3 OD) 6 8.03 (d, 2H), 7.96 (s, 2H), 10 7.88 (s, 2H), 7.77 (d, 2H), 5.26 (t, 2H), 4.24 (d, 2H), 4.20-4.05 (m, 4H), 3.95-3.80 (m, 2H), 3.75 3.60 (m, 6H), 2.65-2.50 (m, 2H), 2.40-2.00 (m, 8H), 1.05-0.90 (m, 12H); m/z 751.3 (M + H)*. Example AL 0 ~B-B 0 0' 0 0 a Br Br B-_O _B B 2,7-Dibromo- Pd(PPh 3

)

4 2,7-Bis-(4,4,5,5-tetramethyl fluoren-9-one [1,3,2]dioxaborolan-2-yl)-fluoren-9-one Br oc Boc o N N N Pd(PPh 3

)

4 H 2-(5-{7-[2-(1 -Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl] 9-oxo-9H-fluoren-2-y}-1 H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester 10- 00 HN.. OH HON HHN N N N 0 NH HCI HATU H

O

(1 -{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-9-oxo-9H-fluoren-2-yl)-1 H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 15 2

,

7 -Bis-( 4

,

4 ,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y)-fluoren-9-one: Followed the procedure used to prepare 4

,

4 ,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2 yl)-9, 10-dihydro-phenanthren-2-yl]-[ 1,3,2]dioxaborolane, except that 2,7-dibromo-9-fluorenone was used instead of 2,7-dibromo-9, I 0-dihydro-phenanthrene. 432 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9-oxo-9H-fluoren-2-yl}-1H-imidazol 2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: Followed the procedure used to prepare compound 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2 yl}- IH-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that 2,7-bis-(4,4,5,5 5 tetramethyl-[I,3,2]dioxaborolan-2-yl)-fluoren-9-one was used instead of 4,4,5,5-tetramethyl-2 [7-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-9, I 0-dihydro-phenanthren-2-yl] [l,3,2]dioxaborolane. m/z 650.9 (M + H)*. (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 10 imidazol-4-yl}-9-oxo-9H-fluoren-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: Followed the procedure used to prepare compound (I-{3-[5-(4'-{2-[l-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yl}-biphenyl-4-yl)-IH-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl) carbamic acid methyl ester, except that 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9 15 oxo-9H-fluoren-2-yl}- IH-imidazol-2-yl)-pyrrolidine-I-carboxylic acid tert-butyl ester was used instead of 2-(5-{4'-[2-(I-Boc-pyrrolidin-3-yl)-3 H-imidazol-4-yl]-biphenyl-4-yl}-I H-imidazol-2 yl)-pyrrolidine-l-carboxylic acid tert-butyl ester. 'lH-NMR (300 MHz, CD 3 OD) 8 8.05-7.85 (m, 8H), 5.22 (t, 2H), 4.23 (d, 2H), 4.20-4.05 (m, 2H), 3.95-3.80 (m, 2H), 3.67 (s, 6H), 2.65-2.50 (m, 2H), 2.40-2.00 (m, 8H), 1.05-0.90 (m, 12H); m/z 765.3 (M + H)*. 20 Example AM I / \ Br MeOH/SOCl2 I /\ Br a CH 2 =C(OEt)SnBu 3 /PdC 2 (PPh 3

)

2 /80 C; Br Br

HO

2 C MeO 2 C MeO 2 C 2-Bromo-5-iodo-benzoic 2-Bromo-5-iodo-benzoic acid methyl ester 2-Bromo-5-(2-bromo-acetyl)-benzoic acid methyl ester acdd 0 0 N BocPrOHtN Bo\ BrC Boc -J I"Br BocrOH/tN Or NH 4 OAc/140 C N Nr RO) 2 BB(OR)2/Pd(PPh 3

)

4 MeO 2 C H MeO 2 C Pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-3- 2-[5-(4-Bromo-3-methoxycarbony-phenyl)-1 H-imidazot-2-yl methoxycarbonyl-phenyi)-2-oxo-ethyl] ester 1-tert-butyl ester ]-pyrrolidine-1-carboxylic acid tert-butyl ester H H \ / N N OB Boc bromide/Pd(PPh 3

)

4 /PdCl 2 (PPh 3

)

2 Boc Boc P\/ 3)/dI2Ph) N! N? - \ "N Bc

CO

2 Me H MeO 2 C CO 2 Me 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl- 4,4'-Bis-[2-(1 -tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl] {1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2- -biphenyl-2,2-dicarboxyic acid dimethyl ester yl)-pyrrolidine-1-carboxylic acid tert-butyl ester H DIBAL-H Boc N NN HO OH 4,4'-Bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H imidazol-4-yl}-biphenyl-2,2'-dimethylhydroxy 2-Bromo-5-iodo-benzoic acid methyl ester: To the solution of 2-bromo-5-iodo-benzoic acid (10 g, 31 mmol) in methanol (100 ml) was added thionyl chloride (5 ml, 68 mmol). The mixture 433 was heated at 55*C for 12 hours. The solvent and reagent were removed under reduced pressure and the mixture was diluted with EtOAc. The organic solution was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration gave 2 bromo-5-iodo-benzoic acid methyl ester (10.5 g). 5 2-Bromo-5-(2-bromo-acetyl)-benzoic acid methyl ester: To the solution of 2-bromo-5-iodo benzoic acid methyl ester (4.33 g, 12.7 mmol) and tributyl(ethoxyvinyl)stannane (4.79 g, 13.3 mmol) in dioxane (56 ml) was added PdCl 2 (PPh 3

)

2 (322 mg). The mixture was heated at 80*C for 17 hours and was cooled to 0*C. Water (19 ml) was added, followed by slow addition of 10 NBS (2.33 g, 12.9 mmol) over 10 minutes period. The mixture was stirred at 0 0 C for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc = 2/1) gave 2-bromo-5-(2-bromo acetyl)-benzoic acid methyl ester (3.48 g). 15 Pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-3-methoxycarbonyl-phenyl)-2-oxo-ethyl] ester 1-tert-butyl ester: To the solution of (s)Boc-PrOH (2.5 g, 11.6 mmol) and triethylamine (1.55 ml, 1.1 mmol) in acetonitrile (34 ml) was added a solution of 2-bromo-5-(2-bromo acetyl)-benzoic acid methyl ester (3.48 g, 10.4 mmol) in acetonitrile (17 ml). The mixture was 20 stirred for 10 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with water and brine, and was dried with sodium sulfate. Purification by flash column chromatography (hexane/EtOAc = 1/1.5) gave pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo 3-methoxycarbonyl-phenyl)-2-oxo-ethyl] ester 1-tert-butyl ester (3.9 g): m/z: 491.9 (M + Na)*. 25 2-[5-(4-Bromo-3-methoxycarbonyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: The mixture of pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-3 methoxycarbonyl-phenyl)-2-oxo-ethyl] ester I -tert-butyl ester (460 mg, I mmol) and ammonium acetate (860 mg, I I mmol) in xylenes (5 ml) was heated at 140*C for 80 minutes under microwave. The mixture was quenched with water, and extracted with EtOAc. The 30 organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 2-[5-(4-bromo-3 methoxycarbonyl-phenyl)-l H-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (320 mg). m/z: 449.8 (M + H)+, 448.1 (M - H)-. 434 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yI)-phenyll-1

H

imidazol-2-yI)-pyrrolidine-l-carboxylic acid tert-butyl ester: To the solution of 2-[5-(4 bromo-3-methoxycarbonyl-phenyl)-I H-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (200 mg, 0.44 mmol) and bis(pinacolato)diboron (225 mg, 0.89 mmol) in 1,4-dioxane (3.4 5 ml) and DMF (2 ml) was added potassium acetate (1 10 g, 1.1 mmol), followed by Pd(PPh 3

)

4 (20 mg) and PdCI 2 (dppf)CH 2

CI

2 (20 mg). The mixture was heated at 80*C for 12 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-phenyl]-1 H 10 imidazol-2-yl}-pyrrolidine-l-carboxylic acid terl-butyl ester (168 mg). m/z: 498.0 (M + H)*. 4,4'-Bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-y)-3H-imidazol-4-y]-biphenyl-2,2' dicarboxylic acid dimethyl ester: To the solution of 2-[5-(4-bromo-3-methoxycarbonyl phenyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (158 mg, 0.35 mmol) 1 5 and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I

H

imidazol-2-yl}-pyrrolidine-l -carboxylic acid tert-butyl ester (166 mg, 0.33 mmol) in 1,2 dimethoxyether (3 ml) and water (I ml) was added sodium bicarbonate (91 mg, 1.1 mmol), followed by Pd(PPh 3

)

4 (15 mg) and PdCl 2 (dppf)CH 2

CI

2 (15 mg). The mixture was heated at 80'C for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, 20 and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 4,4'-Bis-[2-(1 -tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol 4-yl]-biphenyl-2,2'-dicarboxylic acid dimethyl ester (85 mg). m/z: 741.0 (M + H)*, 370.9 (M + 2H)-/2. 25 4

,

4 '-Bis-[2-(l-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2,2' dimethylhydroxy: To the solution of 4,4'-Bis-[2-(I-tert-butoxycarbonyl-pyrrolidin-2-y)-3H imidazol-4-yl]-biphenyl-2,2'-dicarboxylic acid dimethyl ester (85 mg, 0.11 mmol) in TIHF (2 ml) at -78*C was added DIBAL-H THF solution (1.4 ml, 1.4 mmol). The mixture was warmed to 25'C and stirred for 5 hours. The mixture was cooled to 0*C and quenched with 2.0 N NaOH 30 solution until PH=I 1. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/MeOH) gave 4,4'-bis-[2-(l -tert-butoxycarbonyl pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2,2'-dimethylhydroxy (54 mg). m/z: 685.1 (M + H)+, 343.0 (M + 2H)+/2. 35 435 Example AN HH oc SO 3 /pyridine Boc oc N N N N N - / "N HO OH CHO CHO 4,4'-Bis-[2-(1-tert-butoxycarbonyl-pyrroidin-2-yl) 4,4'-Bis-[2-(1-tert-butoxycarbony-pyrrolidin-2-y) -3H-imidazol-4-yl}-biphenyl-2,2'-dimethylhydroxy -3H-imidazol-4-yl}-biphenyl-2,2'-dicarboaldehyde H N I oc HCIMeOH H NN

NH

2 Me/NaBH(OAc) 3 N H (~ H N N 5HCI 6-Methyl-3.9-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-y)-6,7 3,9- bis-[2-(1-tert-butoxycarbonyl-pyralidin-2-y)-3H- dihydro-5H-dibenzo[c,e]azepine imidazol-4-yj -6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine 0 O NH H RCOOHIHATUiBu 2 NEt O \ - N L N N -- N O N HN O O' 0 (1 -{2-[5-(9-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl}-3H-imidazol-4-yl}-6-methy -6,7-dihydrc-5H-dibenzo[c,elazepin-3-yl)-1H-imidazol-2-yI}-pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 4,4'-Bis-12-(1-tert-butoxycarbonyl-pyrrolidin-2-yI)-3H-imidazol-4-yI]-biphenyl-2,2' dicarboaldehyde: To the solution of 4,4'-Bis-[2-(I-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H 5 imidazol-4-yI]-biphenyl-2,2'-dimethylhydroxy (54 mg, 0.08 mmol) in DMSO (1.2 ml) was added triethylamine (0.14 ml). The mixture was stirred for 5 minutes, and pyridine-sulfur trioxide (170 mg) was added. The mixture was stirred for 90 minutes and was quenched with ice-water. The stirring was continued for additional 30 minutes and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium 10 sulfate. Concentration gave 4,4'-bis-[2-( I-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4 yl]-biphenyl-2,2'-dicarboaldehyde (40 mg). m/z: 681.0 (M + H)*. 3,9-Bis-[2-(1-tert-butoxycarbonyl-pyrrolid in-2-yI)-3H-imidazol-4-yl] -6-methyl-6,7 dihydro-5H-dibenzo[c,ejazepine: To the solution of 4,4'-bis-[2-(l -tert-butoxycarbonyl 15 pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2,2'-dicarboaldehyde (40 mg, 0.06 mmol) in MeOH/THF (2.5 ml/0.5 ml) was added methylamine methanol solution (29 pl, 0.06 mmol), followed by acetic acid (14 pl, 0.23 mmol) and NaBH(OAc) 3 (50 mg, 0.23 mmol). The mixture was stirred for 12 hours and was quenched with water. The mixture was extracted with EtOAc. The organic phase was washed with 1.0 N sodium hydroxide solution, water, and brine, and was 20 dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/MeOH) gave compound 3,9- bis-[2-(l -tert-butoxycarbonyl-pyrrolidin-2-yl)-3 H imidazol-4-yi] -6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine (24 mg). m/z: 680.3 (M + H)+. 436 3,9-Bis-[2-(pyrrolidin-2-yl)-3H-imidazol-4-yl]-6-methyl-6,7-dihydro-5H dibenzolc,elazepine: To the solution of 3,9- bis-[2-(I -lert-butoxycarbonyl-pyrrolidin-2-yl)-3H imidazol-4-yl]-6-methyl-6,7-dihydro-5H-dibenzo(c,e]azepine (24 mg) in DCM/MeOH (1.6 ml/0.75 ml) was added hydrochloric acid in dioxane (0.44 ml, 1.7 mmol). The mixture was 5 heated at 50'C for 3 hours and the solvents were evaporated under reduced pressure. The mixture was diluted with water and acetonitrile, and was freezer-dried to give 3,9- bis-[2 (pyrrolidin-2-yl)-3H-imidazol-4-ylI -6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine as brown powder (25 mg). m/z: 480.1 (M + H)+. 10 1-{2-[5-(9-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-6-methyl-6,7-dihydro-5H-dibenzo[c,eazepin-3-yI)-I H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 3,9- bis-[2-(pyrrolidin-2-yl)-3 H-imidazol-4-yl] -6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine (25 mg, 0.035 mmol) and MeOCO-Val-OH (13 mg, 0.074 mmol) in DMF (1.2 ml) was added 15 HATU (28 mg, 0.074 mmol), followed by diisopropylethylamine (61 pl, 0.35 mmol). The mixture was stirred for 90 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. 1 %TFA/H 2 0) gave (1-{2-[5-(9-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-6-methyl-6,7 20 dihydro-5 H-dibenzo[c,e]azepin-3-yl)-I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester (24 mg). m/z: 794.3 (M + H)*, 397.8 (M + 2H)+/2. 'H NMR (CD 3 0D, 300 MHz) 8 8.0-7.9 (8 H, m), 5.27 (2 H, m), 4.3-4.2 (2 H, m), 4.2-3.8 (8 H, m), 3.66 (6 H, s), 3.08 (3 H, s), 2.7-2.5 (2 H, m), 2.4-1.9 (8 H, m), 0.94-0.90 (12 H, m). 25 Example AO H H N N - N N N_ N\ / I BOCN / H NC - /a. H 2 So4/H 2 0. b. NaOHH N N ___________N N H HO OH H0 4,4'-Bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-y 3,9- bis-[2-( pyrrolidin-2-yl)-3H-imidazol )-3H-imidazol-4-yl]-biphenyl-2,2'-dimethylhydroxy -4-yl]--5,7-dihydro-dibenzo[ce]oxepine 0 O 1 NH H RCOOH/HATU/iBu 2 NEt N \ - N N H O HNyON 0 (1-{2-[5-(9-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yI-3H-imidazol-4-yl} -5,7-dihydro-dibenzo[c,e]oxepin-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 437 3,9-Bis-[2-(pyrrolidin-2-yI)-3H-imidazol-4-yl]--5,7-dihyd rodibenzo [c,e]oxepine: To the suspension of 4,4'-bis-[2-( I-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl 2,2'-dimethylhydroxy (8 mg, 0.011 mmol) in water (1.5 ml) was added sulfuric acid (1.5 ml). The mixture was heated at 60*C for 14 hours. The mixture was cooled to 0*C, and 2 N sodium 5 hydroxide solution was added until pH = 7. The mixture was freezer-dried to give 3,9- bis-[2-( pyrrolidin-2-yl)-3H-imidazol-4-yl]--5,7-dihydro-dibenzo[c,e]oxepine. m/z: 467.1 (M + H)*. (1-{2-[5-(9-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-5,7-dihydro-dibenzolc,eloxepin-3-yl)-1H-imidazol-2-yl]-pyrrolidine-l 10 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 3,9- bis-[2-( pyrrolidin-2-yl)-3H-imidazol-4-yl]--5,7-dihydro-dibenzo[c,e]oxepine (0.0 11 mmol) and MeOCO-Val-OH (4 mg, 0.023 mmol) in DMF (5 ml) was added HATU (9 mg, 0.023 mmol), followed by diisopropylethylamine (38 pl, 0.22 mmol). The mixture was stirred for 60 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, 15 and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. I %TFA/H 2 0) gave (1 -{2-[5-(9-{2-[I-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} -5,7-dihydro-dibenzo[c,e]oxepin-3-yl)- 1 H imidazol-2-yl]-pyrrolidine-l -carbonyl } -2-methyl-propyl)-carbamic acid methyl ester (1.5 mg). m/z: 781.2 (M+l), 391.2 (M+2)/2; 'H NMR (CD 3 0D, 300 MHz) 8 7.9-7.8 (8 H, m), 5.27 (2 H, 20 m), 4.44 (4 H, s), 4.22 (2 H, m), 4.17-4.05 (2 H, m), 3.95-3.83 (2 H, m), 5.67 (6 H, s), 2.65-2.50 (2 H, m), 2.35-1.95 (8 H, m), 0.99-0.89 (12 H, m). 438 Example AP BrBocl Br8c B 2MiDIBAL-H cN BSO3pyridine N Br NIBNL-N N H C0 2 1Me HO H CHO 2-[5-(4-Bromo-3-methoxycarbonyl-phenyl) 2-[5-(4-Bromo-3-hydroxymethyl-phenyl) 2-{5-(4-Bromo-3-formyl-phenyl) - H-imidazol-2-yl}-pyrroidine-1 -carboxylic acid tert- -1 H-imidazol-2-yl]-pyrrolidine -1 H-imidazol-2-yl)-pyrolidine butyl ester -1-carboxylic add tert-butyl ester -1-carboxylic acid tert-butyl ester N H Bo N Br 8oi'cnatefPd(PPh 3

)

4 N NB a 2 Me/NaBH(OAc) 3 ; NaPdCI 2 (PPh3) 2 B b.BoO H N -N - / "N NH CO0 2 Me 2-(5-(4-Bromo-3-[(tert-butoxycarbony-methyl amino) 4,4'-Bis-[2-(1-tert-butoxycartnoy-pyrrlidin-2-yl) -methyl}-phenyl}-1H-imidazol-2-yl)-pyrrolidine -3H-imidazol-4-yl}-biphenyt-2-[(tert-butoxycarbony-methy-amino) -1-carboxylic acid tert-butyl ester H -2'-carboxylic acid dimethyl ester H H O N N RFCO/AU/M2~ N N N N H H N N H HH H H N HN a0 (1 -{2-[5-(9-{2-[I-(2-M ethyarb in m - y-pyrrolidin-2-y l}- H- -4-yI-metyl-5-oo- ,hy do--ienz o az in 3-yl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-ropyl)-cartamic acid methyl ester 5 2-[5-(4-Bromo-3-hyd roxymethyl-phenyl)-1IH-imidazol-2-yll1-pyrrolidine- 1-carboxylic acid tert-butyl ester: To the solution of 2-[5-(4-B~romo-3-methoxycarbonyl-phenyl)- I H-im idazol-2 yl]-pyrrolidine-l-carboxylic acid tert-butyl terer (200 mg, 0.44 mmol) in TH F (4 ml) at -78*C was added DIBA L-H THF solution (3.33 ml, 3.33 mmol). The mixture was warmed to 25 0 C and stirred for 5 hours. The mixture was cooled to 0*C and quenched with 2.0 N NaOH] solution 10 until PH=l I. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-[5-(4-bromo-3 hydroxymethyl-phenyl)-lI H-imidazol-2-yl]-pyrrolidine- I -carboxyl ic acid tert-butyl ester (196 mg). m/z: 421.9 (M + H)*, 420.2 (M -- H)-. 15 2-[5-(4-Bromo-3-formyl-phenyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: To the solution of 2-[5-(4-bromo-3-hydroxymethyl-phenyl)-1IH-imidazol-2-yl] pyrrolidine-l -carboxylic acid tert-butyl ester (1 96 mg, 0.46 mmol) in DMSO (3.5 ml) was added triethylamine (0.40 ml). The mixture was stirred for 30 minutes, and pyridine-sulfur trioxide (500 mg) was added. The mixture was stirred for 2 hours and was quenched with ice-water. 20 The stirring was continued for additional 30 minutes and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-[5-(4-Bromo-3-formyl-phenyl)- I H-imidazol-2-yl]-pyrrolidine- I carboxylic acid tert-butyl ester (180 mg). 439 2-(5-{4-Bromo-3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenyl}-1 H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester: To the solution of 2-[5-(4-bromo-3-formyl phenyl)-l H-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (180 mg, 0.46 mmol) in 5 MeOH/THF (2.5 ml/2.5 ml) was added methylamine methanol solution (0.69 ml, 1.38 mmol), followed by acetic acid (1 10 pl, 1.84 mmol) and NaBH(OAc) 3 (975 mg, 4.6 mmol). The mixture was stirred for 12 hours and was quenched with I N sodium hydroxide solution. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration gave the intermediate (171mg). To the solution 10 of the above intermediate (171 mg, 0.39 mmol) in DCM (4 ml) was added di-tert-butyl dicarbonate (86 mg, 0.39 mmol), followed by diisopropylethylamine (135 61, 0.78 mmol). The mixture was stirred for 12 hours, and the solvent and reagent was evaporated. Purification by flash column chromatography (hexanes/EtOAc) gave 2-(5-{4-bromo-3-[(tert-butoxycarbonyl methyl-amino)-methyl]-phenyl}- I H-imidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl 15 ester (142 mg). m/z: 535 (M + H)*. 4,4'-Bis-[2-(1-tert-butoxycarbony-pyrrolidin-2-y)-3H-imidazol-4-yi]-bipheny-2-[(tert butoxycarbonyl-methyl-amino)-2'-carboxylic acid dimethyl ester: To the solution of 2-(5 {4-bromo-3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenyl}-1 H-imidazol-2-yl) 20 pyrrolidine-1-carboxylic acid tert-butyl ester (142 mg, 0.27 mmol) and 2-{5-[3 Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I H-imidazol-2-yl} pyrrolidine-I -carboxylic acid tert-butyl ester (125 mg, 0.25 mmol) in 1,2-dimethoxyether (2.3 ml) and water (0.7 ml) was added sodium bicarbonate (63 mg, 0.75 mmol), followed by Pd(PPh 3

)

4 (12 mg) and PdCl 2 (dppf)CH 2

CI

2 (12 mg). The mixture was heated at 80*C for 20 25 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4'-bis-[2-(l -tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl] biphenyl-2-[(tert-butoxycarbonyl-methyl-amino)-2'-carboxylic acid dimethyl ester (82 mg). m/z: 826 (M + H)*, 413.6 (M + 2H)*/2. 30 2'-Methylaminomethyl-4,4'-bis-(2-pyrrolidin-2-yI-3H-imidazol-4-yl)-biphenyl-2-carboxylic acid methyl ester: To the solution of 4,4'-bis-[2-(l-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H imidazol-4-yl]-biphenyl-2-[(tert-butoxycarbonyl-methyl-amino)-2'-carboxylic acid dimethyl ester (77 mg, 0.09 mmol) in DCM (3 ml) was added trifluoroacetic acid (3 ml). The mixture 35 was stirred for 2 hours, and the solvent and reagent were removed under reduced pressure. The 440 mixture was diluted with acetonitrile and water, was freezer-dried to give 2' methylaminomethyl-4,4'-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-2-carboxylic acid methyl ester as white powder (90 mg). m/z: 526.1 (M + H)*. 5 6-Methyl-3,9-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-6,7-dihydro-dibenzolc,ejazepin-5 one: To the solution of 2'-methylaminomethyl-4,4'-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl) biphenyl-2-carboxylic acid methyl ester (90 mg) in pyridine (5 ml) was added diisopropylethylamine (1 ml). The mixture was heated at 100*C for 2 hours. The solvents were evaporated. The mixture was diluted with acetonitrile and water, was freezer-dried to give 6 10 Methyl-3,9-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-6,7-dihydro-dibenzo[c,e]azepin-5-one as brown powder. m/z: 494.1 (M + H)+. (1-{2-[5-(9-12-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-6-methyl-5-oxo-6,7-dihydro-5H-dibenzoc,ejazepin-3-yl)-1H-imidazol-2-yl] 15 pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 6 methyl-3,9-bis-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-6,7-dihydro-dibenzo[c,e]azepin-5 -one (0.09 mmol) and MeOCO-Val-OH (33 mg, 0.19 mmol) in DMF (3 ml) was added HATU (71 mg, 0.19 mmol), followed by diisopropylethylamine (323 pl, 1.86 mmol). The mixture was stirred for 60 minutes and was diluted with EtOAc. The organic phase was washed with I N 20 NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. I %TFA/H 2 0) gave (I -{2-[5-(9-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-6-methyl-5-oxo 6,7-dihydro-5H-dibenzo[c,e]azepin-3-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester (16 mg). m/z: 808.2 (M+1), 404.8 (M+2)/2, 806.3 (M-1). 25 'H NMR (CD 3 0D, 300 MHz) 8 8.1-7.8 (8 H, m), 5.4-5.2 (2 H, m), 4.6-4.2 (4 H, m), 4.2-4.0 (2 H, m), 3.95-3.80 (2 H, m), 3.64 (6 H, m), 3.25 (3 H, s), 2.65-2.45 (2 H, m), 2.35-2.0 (8 H, m), 1.05-0.9 (12 H, m). 441 Example AQ Br b N H/AcO C Br /&Br . 03: b.Me 2 S; c. BaBH 4 Br Br HO OH 2,7-Dibromo-9,10-dihydro-phenanthrene 2,7-Dibromo-phenanthrene (4,4'-Dibromo-2'-ydroxymehyl-bipheny-2-yl) methanol

H

3

PO

4 /160 C Br Br ad CH 2 =C(OEt)SnBu 3 Br B BocPrOH/Et3N; ________ - /BrPdCV 2 PPh 3

)

2 180 C - "/ BrBorOItN 00 3,9-Dibromo-5,7-dihydro-dibenzo(c,e]oxepine 2-Bromo-1 2-rm -- [9-(2-bromo-acetyl)-5,7-dihydro dibenzo[c,e]oxepin-3-yl)-ethanone 0- ~ 0 0 N \ / -N -O\ /

NH

4 0Ac/140 C: Diketoester 3.9- Bis-{2-(I-tert-butoxycarbonyl-pyrrolidin-2-y) 0 -3H-imidazol-4-yI]-5,7-dihydro-dibenzo[c,e]oxepine a. TFAIDCM: -O NH H b. RCOOHIHATUliBu 2 NEt - N N N N N'N H0 HN 0 (1-{2-[5- (9-{2-{1 -(2-Methoxyc-arbonylam ino-3- methy 1-butyryl)-pyrrol id in- 2-yl)-3Hl-im idazok4-yl)-5,7-dihyd ro-d ibenzo[c, eloxepin-3-yl)-11H imidazol-2-yl}pyrrolidine-1-carbonyl}-2-methylpropyl)-cartamic acid methyl ester 2,7-Dibromo-phenanthrene: The mixture of 2,7-dibromo-9,1 0-dihydro-phenanthrene (2.4 g, 5 7.1 mmol), NBS (1.4 g, 7.8 mmol), and benzoyl peroxide (0.2 g) in carbon tetrachloride (300 ml) was refluxed for 2 hours. Potassium acetate (3.6 g) and acetic acid (3.2 ml) were added, and the refluxing was continued for additional 2 hours. The mixture was cooled and diluted with EtOAc. The organic phase was washed with water, saturated sodium bicarbonate, and brine, and was dried with sodium sulfate. Concentration gave 2,7-dibromo-phenanthrene (2.3 g). 10 (4,4'-Dibromo-2'-hydroxymethyl-biphenyl-2-yl)-methanol: The solution of 2,7-dibromo phenanthrene (3.8 g) in DCM/MeOH (120 ml/I ml) was cooled to -78*C, and it became a suspension. Ozone was bubbled thorough for 20 minutes, and the mixture became blue. Oxygen was bubbled for 5 minutes and dimethyl sulfide (3 ml) was added. The mixture was 15 warmed to 25*C and stirred for 12 hours. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4'-dibromo-biphenyl-2,2'-dicarbaldehyde (600 mg). To the solution of 4,4'-dibromo-biphenyl-2,2'-dicarbaldehyde (600 mg, 1.7 mmol) in THF/MeOH (10 ml/10 ml) at 0 0 C was added sodium borohydride (320 mg, 8.2 mmol). The mixture was warmed to 25*C and stirred for 12 hours. The mixture was quenched with water, 20 and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration gave (4,4'-dibromo-2'-hydroxymethyl-biphenyl-2-y) methanol (550 mg). 442 3,9-Dibromo-5,7-dihydro-dibenzo[c,ejoxepine: The suspension of (4,4'-dibromo-2' hydroxymethyl-biphenyl-2-yl)-methanol (460 mg) in phosphoric acid (25 ml) was heated at 160'C for 4 hours. The mixture was cooled and diluted with water (100 ml), and was extracted with EtOAC. The organic phase was washed with water, saturated sodium bicarbonate, and 5 brine, and was dried with sodium sulfate. Concentration yielded 3,9-dibromo-5,7-dihydro dibenzo[c,e]oxepine (416 mg). 2-Bromo-1-[9-(2-bromo-acetyl)-5,7-dihydro-dibenzo[c,ejoxepin-3-ylI-ethanone: To the solution of 3,9-dibromo-5,7-dihydro-dibenzo[c,e]oxepine (416 mg, 1.2mmol) and 10 tributyl(ethoxyvinyl)stannane (878 pil, 2.6 mmol) in dioxane (6 ml) was added PdC 2 (PPh 3

)

2 (30 mg). The mixture was heated at 80'C for 16 hours and was cooled to 0 0 C. Water (2 ml) was added, followed by slow addition of NBS (464 mg, 2.6 mmol) over 5 minutes period. The mixture was stirred at 0 0 C for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine 15 and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave 2-bromo-l -[9-(2-bromo-acetyl)-5,7-dihydro-dibenzo[c,e]oxepin-3-yl] ethanone (160 mg). Diketoester: To the solution of (S)-Boc-Pro-OH (275 mg, 1.28 mmol) and triethylamine (154 20 pl, 1. 11 mmol) in acetonitrile (3.4 ml) was added a solution of 2-bromo-I-[9-(2-bromo-acetyl) 5,7-dihydro-dibenzo[c,e]oxepin-3-yl]-ethanone (160 mg, 0.37 mmol) in DMF (6 ml). The mixture was stirred for 10 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with water and brine, and was dried with sodium sulfate. Concentration gave the intermediate diketoester. m/z: 729.1 (M + Na)*. 25 3,9-Bis-12-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-5,7-dihydro dibenzo[c,e]oxepine: The mixture of above diketoester (0.37 mmol) and ammonium acetate (860 mg, I 1 mmol) in xylene (5 ml) was heated at 140'C for 80 minutes under microwave. The mixture was quenched with water, and extracted with EtOAc. The organic phase was washed 30 with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/EtOAc) gave 3,9- bis-[2-(] -tert-butoxycarbonyl pyrrolidin-2-yl)-3H-imidazol-4-yl]-5,7-dihydro-dibenzo[c,e]oxepine (195 mg). m/z: 667.1 (M + H)*. 443 (1-{2-[5-(9-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-5,7-dihydro-dibenzo[c,ejoxepin-3-yl)-1 H-imidazol-2-ylI-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 3,9-bis-[2-(1 tert-butoxycarbonyl-pyrrolidin-2-y)-3 H-imidazol-4-yl]-5,7-dihydro-dibenzo[c,e]oxepine (190 5 mg) in DCM (3 ml) was added TFA (1.5 ml). The mixture was stirred for 60 minutes, and the solvent and reagent were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give dipyrrolidine. To the solution of dipyrrolidine (0.29 mmol) and (S-)-Moc-Val-OH (100 mg, 0.57 mmol) in DMF (8 ml) was added HATU (227 mg, 0.60 mmol), followed by diisopropylethylamine (0.5 ml, 2.9 mmol). 10 The mixture was stirred for 90 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by H PLC (0.1%TFA/CH 3 CN/0.I%TFA/H 2 0) gave (1-{2-[5-(9 {2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-5,7 dihydro-dibenzo[c,eloxepin-3-yl)-I H-imidazol-2-yl]-pyrrolidine- I -carbonyl} -2-methyl-propyl) 15 carbamic acid methyl ester (142 mg). m/z: 781.3 (M+1), 779.3 (M-1), 391.3 (M+2)/2. 'H NMR (CD 3 0D, 300 MHz) 8 7.9-7.8 (8 H, m), 5.27 (2 H, m), 4.44 (4 H, s), 4.22 (2 H, m), 4.17 4.05 (2 H, m), 3.95-3.83 (2 H, m), 5.67 (6 H, s), 2.65-2.50 (2 H, m), 2.35-1.95 (8 H, m), 0.99 0.89 (12 H, m). 20 Example AR a. CH 2 =C(OEt)SnBu 3 00 Br r - Br BaCPrOHIEt 3 NN Br / ^ PdC 2 (PPh 3

)

2 /80 C; BrBr Br - 0 - B B r / b . N B S /H ,O O B 0 0 2-Bromo-1-(9-bromo-5,7-dihydro 0 3.9-Dibromo-5,7-dihydro- -dibenzo~c,eloxepin-3-yl)-ethanone Pyrrolidine-1,2-dicarboxylic acid 2-[2-(9 dibenzo[c,e]oxepine brmo-5,7-dihydro-dibenzo[c,eoxepin-3-yl) 2-oxo-ethyl] ester 1-tert-butyl ester a. CH 2 =C(OEt)SnBU 3 0 0 00' PdCI 2 (PPh 3

)

2 /80 C;u s - / Br RCOOHIEt 3 N b. NBSIH 2 0 0 0! 00 c Pyrrolidire-1 2-dicarboxylic acid 2-(2-[9-(2-brcmo-acetyl) 2-Aza-bicycb[212. lheptane-2,3-dicarboxylic acid 3-(2-{9 -S.7-dihydro-dibenzo[c,eoxepin-3-yI]-2-oxo-ethylI ester l-tert-butyl ester [2-(l-tent-butxycarbony-pyridine-2-carbonyloxy) acetyI}-5,7-dihydro-dibenzo[c,eoxepin-3-y)-2-oxo-ethyl) H ester 2-tert-butyl ester

NH

4 0Ac/140 C c \ -c a. TFA/DCM: b. RCOOH/HATU/iBu 2 NEt N N 3-(5-{9-(2-(l -tert-Butoxycarbnyl-pyn-olidin-2-yi)-3H-imidazol-4-yl]-5,7-dihydro-dibenzo[c e]xepin-3-yl}-1 H 0 imidazol-2-yI)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester -O NH H N N N (1-{3-[5-(9-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-ylj N N N 0 -KY -3H-imidazol-4-yl)-5,7-dihydro-dibenzo[c,eoxepin-3-y) H H -1H-imidazol-2-yI)-2-aza-bicyclo[2.2.1]heptane 0 HN4 0 " -2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 0 444 2-Bromo-1-(9-bromo-5,7-dihydro-dibenzo[c,eJoxepin-3-yI)-ethanone: To the solution of 3,9 dibromo-5,7-dihydro-dibenzo[c,e]oxepine (416 mg, 1.2mmol) and tributyl(ethoxyvinyl)stannane (878 pl, 2.6 mmol) in dioxane (6 ml) was added PdCl 2 (PPh 3

)

2 (30 mg). The mixture was heated at 80'C for 16 hours and was cooled to 0 0 C. Water (2 ml) was added, followed by slow addition 5 of NBS (464 mg, 2.6 mmol) over 5 minutes period. The mixture was stirred at 0*C for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave 2-bromo 1-(9-bromo-5,7-dihydro-dibenzo[c,e]oxepin-3-yl)-ethanone (120 mg). 10 Pyrrolidine-1,2-dicarboxylic acid 2-[2-(9-bromo-5,7-dihydro-dibenzo c,eloxepin-3-yl)-2 oxo-ethyll ester 1-tert-butyl ester: To the solution of (S)-Boc-Pro-OH (118 mg, 0.55 mmol) and triethylamine (65 il, 0.46 mmol) in acetonitrile (2 ml) was added a solution of 2-bromo-l (9-bromo-5,7-dihydro-dibenzo[c,e]oxepin-3-yl)-ethanone (120 mg, 0.31 mmol) in DMF (4 ml). 15 The mixture was stirred for 10 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with water and brine, and was dried with sodium sulfate. Concentration gave pyrrolidine-1,2-dicarboxylic acid 2-[2-(9-bromo-5,7-dihydro dibenzo[c,e]oxepin-3-yl)-2-oxo-ethyl] ester 1-tert-butyl ester (160 mg). m/z: 553.8 (M + Na)*. 20 Pyrrolidine-1,2-dicarboxylic acid 2-{2-[9-(2-bromo-acetyl)-5,7-dihydro-dibenzo[c,eoxepin 3-yll-2-oxo-ethyl} ester 1-tert-butyl ester: To the solution of pyrrolidine-1,2-dicarboxylic acid 2-[2-(9-bromo-5,7-dihydro-dibenzo[c,eJoxepin-3-yl)-2-oxo-ethyl] ester I -tert-butyl ester (160 mg, 0.30) and tributyl(ethoxyvinyl)stannane (112 pl, 0.33 mmol) in dioxane (2 ml) was added PdCl 2 (PPh 3

)

2 (8 mg). The mixture was heated at 80*C for 16 hours and was cooled to 0 0 C. 25 Water (0.7 ml) was added, followed by slow addition of NBS (59, 0.33 mmol) over 5 minutes period. The mixture was stirred at 0*C for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave pyrrolidine-1,2-dicarboxylic acid 2-{2-[9-(2-bromo 30 acetyl)-5,7-dihydro-dibenzo[c,e]oxepin-3-yl]-2-oxo-ethyl} ester I-tert-butyl ester (156 mg). m/z: 593.9 (M + Na)*. 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{9-12-(1-tert-butoxycarbonyl pyrrolidine-2-carbonyloxy)-acetyl]-5,7-dihyd ro-d ibenzolc,eloxepin-3-yl}-2-oxo-ethyl) ester 35 2-tert-butyl ester: To the solution of 2-Aza-bicyclo[2.2.l]heptane-2,3-dicarboxylic acid 2-tert 445 butyl ester (100 mg, 0.42 mmol) and triethylamine (50 pl, 0.36 mmol) in acetonitrile (2 ml) was added a solution of pyrrolidine-1,2-dicarboxylic acid 2-{2-[9-(2-bromo-acetyl)-5,7-dihydro dibenzo[c,e]oxepin-3-yl]-2-oxo-ethyl} ester I-tert-butyl ester (136 mg, 0.24 mmol) in DMF (4 ml). The mixture was stirred for 10 hours, and the solvent was evaporated. The mixture was 5 diluted with EtOAc, and washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-aza-bicyclo[2.2. I]heptane-2,3-dicarboxylic acid 3-(2- {9-[2-(] -tert butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-5,7-dihydro-dibenzo[c,e]oxepin-3-yl}-2 oxo-ethyl) ester 2-tert-butyl ester (142 mg). m/z: 731.3 (M - H)-, 755.2 (M + Na)*. 10 3-(5-{9-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-y)-3H-imidazol-4-yll-5,7-dihydro dibenzolc,e]oxepin-3-yl}-I H-imidazol-2-yl)-2-aza-bicyclo[2.2.1] heptane-2-carboxylic acid tert-butyl ester: The mixture of 2-aza-bicyclo[2.2.lheptane-2,3-dicarboxylic acid 3-(2-{9-[2 (1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-5,7-dihydro-dibenzo[c,e]oxepin-3 yl}-2-oxo-ethyl) ester 2-tert-butyl ester (142 mg, 0.19 mmol) and ammonium acetate (860 mg, 15 11 mmol) in xylene (5 ml) was heated at 140'C for 80 minutes under microwave. The mixture was quenched with water, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/EtOAc) gave 3-(5- {9-[2-(1 -tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H imidazol-4-yl]-5,7-dihydro-dibenzo[c,e]oxepin-3-yl}-1 H-imidazol-2-yl)-2-aza 20 bicyclo[2.2.l]heptane-2-carboxylic acid tert-butyl ester (86 mg). m/z: 693.1 (M + H)+. (1-{3-15-(9-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yI}-5,7-dihydro-dibenzolc,eoxepin-3-yl)-1 H-imidazol-2-ylj-2-aza bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To the 25 solution of 3-(5-{9-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-y)-3 H-imidazol-4-yl]-5,7-dihydro dibenzo(c,e]oxepin-3-yl} -I H-imidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert butyl ester (86 mg) in DCM (3 ml) was added TFA (1.5 ml). The mixture was stirred for 60 minutes, and the solvent and reagent were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give brown powder. To the solution 30 of above powder (0.12 mmol) and (S)-Moc-Val-OH (44 mg, 0.25 mmol) in DMF (4 ml) was added HATU (99 mg, 0.26 mmol), followed by diisopropylethylamine (0.22 ml, 1.2 mmol). The mixture was stirred for 90 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1%TFA/CH 3 CN/0.l%TFA/H 2 0) gave (1-{3-[5-(9 35 {2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-5,7 446 dihydro-dibenzo[c,eloxepin-3-yl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carbonyl) 2-methyl-propyl)-carbamic acid methyl ester (84 mg). m/z: 807.4 (M+1), 805.3 (M-1), 404.4 (M+2)/2. H NMR (CD 3 0D, 300 MHz) 8 8.0-7.8 (8 H, m), 5.26 (2 H, m), 4.66 (1 H, m), 4.44 (4 H, m), 4.35 (1 H, m), 4.25 (1 H, m), 4.15 (1 H, m), 3.89 (1 H, m), 3.67 (6 H, in), 2.85 (2 H, m), 5 2.60 (2 H, m), 2.3-1.4 (9 H, m), 1.05-0.85 (12 H, m). Example AS 11RCOOHIHATU 00 Br NH-HCI R T Br NH40Ac/140 C Br N Br~/ NH BrN 2-amino-1-(4-bromo-phenyl)-ethanone 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoy 3 ]-2-aza-bicydlo[2.2. 1 jheptane-2-carboxylic 3-[5-(4-Bmomo-phenyt.IHf-imidazol-2-y1-2-aza acid tert-butyl ester bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester H

(RO)

2

BB(OR)

2 1 -O\H N/ N\ /\ - N 3)0N _ __:S21 Pd(PPh )/KOAC/80 C B bomide/Pd(PPh3)4/80 C -oc I /oc BN Boo _ 3-{S-{4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) -phenyl}-1 H-imidazol-2-yl-2-aza-bicydo[2.2.1] 4,4'-Bis-{2-(2-ter-butoxycarbonyl-2-aza- bicydo[2.2.1] heptane-2-carboxylic acid tet-butyl ester hept-3-yl)-3H-imidazol-4-y)-bipheny O - NH 0H a. HCLIMeOH/5O C; N-A-N Ny N b. RCOOH/HATU/ Bu 2 NEt I H HN (I -{3-5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1lhept-3-yl)-3H-imid aol-4-yl}-biphenyl-4-y)-1 H-imidazol-2-yl 2-aza-bicyclo[2.2. i heplane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 3-12-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.11 heptane-2-carboxylic 10 acid tert-butyl ester: To the solution of 2-amino-I-(4-bromo-phenyl)-ethanone (HCl salt, 1.0 g, 4 mmol) and 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (0.98 g, 4 mmol) in DMF (13 ml) was added HATU (1.64 g, 4.3 mmol), followed by slow addition of diisopropylethylamine (2.2 ml, 12.7 mmol). The mixture was stirred for 4 hours and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was 15 dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave 3 -[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g). m/z: 460.9 (M +Na)*. 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid 20 tert-butyl ester: The mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g, 4 mmol), acetic acid (24 pl), and ammonium acetate (1.54 g, 20 mmol) in xylene (20 ml) was heated at 140'C for 20 hours. The mixture was quenched with saturated sodium carbonate solution, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. 25 Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-[5-(4 447 bromo-phenyl)- Il H-imidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (1.21 g). m/z: 417.9 (M + H)+. 3-{5-14-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl)-2-aza 5 bicyclo[2.2.lheptane-2-carboxylic acid tert-butyl ester: To the solution of 3-[5-(4-Bromo phenyl)-1 H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (667 mg, 1.6 mmol) and bis(pinacolato)diboron (813 mg, 3.2 mmol) in 1,4-dioxane (12.5 ml) was added potassium acetate (401 mg, 4.1 mmol), followed by Pd(PPh 3

)

4 (78 mg). The mixture was heated at 80'C for 12 hours. The mixture was diluted with EtOAc, and was washed with water 10 and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-{ 5-[4-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl) phenyll-I H-imidazol-2-yl}-2-aza-bicyclo[2.2.l]heptane-2-carboxylic acid tert-butyl ester (560 mg). m/z: 466.1 (M + H)*. 15 4,4'-Bis-[2-(2-tert-butoxycarbonyl-2-aza-bicyclo[2.2.11hept-3-yl)-3H-imidazol-4-yl] biphenyl: To the solution of 3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] I H-imidazol-2-yl}-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (560 mg, 1.22 mmol) and 3-[5-(4-bromo-phenyl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (535 mg, 1.28 mmol) in 1,2-dimethoxyether (II ml) and water (3.5 ml) was 20 added sodium bicarbonate (343 mg, 4 mmol), followed by Pd(PPh 3

)

4 (55 mg). The mixture was heated at 80*C for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/MeOH) gave 4

,

4 '-bis-[2-(2-tert-butoxycarbonyl-2-aza bicyclo[2.2.1]hept-3-yl)-3H-imidazol-4-yli]-bipheny (50 mg). m/z: 677.2 (M + H)*. 25 (1-{3-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1Ihept-3 yl]-3H-imidazol-4-yl}-biphenyl-4-yI)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 4,4'-Bis-[2-(2 tert-butoxycarbonyl-2-aza-bicyclo[2.2.1 ]hept-3-yl)-3 H-imidazol-4-yl]-biphenyl (50 mg, 0.07 30 mmol) in MeOH (2 ml) was added hydrochloric acid (0.24 ml, 1.48 mmol) The mixture was heated at 50'C for 5 hours, and the solvent and reagent were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give brown powder. m/z: 477.2 (M+]), 239.1 (M+2)/2. To the solution of above powder (29 mg, 0.047 mmol) and MeOCO-Val-OH (20 mg, 0.0.113 mmol) in DMF (1.5 ml) was added HATU (40 35 mg, 0.10 mmol), followed by diisopropylethylamine (50 ml, 0.28 mmol). The mixture was 448 stirred for 90 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. I %TFA/H 2 0) gave (I -{3-[5-(4'- {2-[2-(2 Methoxycarbonylam ino-3-methyl-butyryl)-2-aza-bicyclo[2.2.l ]hept-3-yl]-3H-imidazol-4-yl}I 5 biphenyl-4-yl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carbonyl} -2-methyl-propyl) carbamic acid methyl ester (15 mg). m/z: 791.2 (M+1), 396.5 (M+2)/2. 'H NMR (CD 3 0D, 300 MHz) 8 7.92-7.82 (10 H, in), 4.82 (2 H, m), 4.32 (2 H, m), 4.05 (2 H, m), 3.65 (6 H, m), 2.85 (2 H, m), 2.3-1.6 (14 H, m), 1.05-0.85 (12 H, m). 10 Example AT 00 N ST,"' N (RO),BB(OR),/Pd(PPh 3

)

4 KOAC/8O Br Y Boc Lawesson's reagent/80 C Br N Bo(O2BO)/dPh)/Oc8 Br ~ NHN 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoy]- 2-[5-(4-Bromo-phenyl)-thiazo-2-y] pyrrolidine-1-carboxylic acid tert-butyl ester -pyrrolidine-1-carboxylic acid tert-butyl ester N\ / - S N 0 s Boc I I 8C N bromide/Pd(PPh 3 )4/80 C N s ,'/ " N B / IT Boc __ _ __ _ 4,4'- Bis-[5-(1-tert-butoxycarbonyl 2-(5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenyl]- pyrrolidin-2-yI)-thiazol-2-y)-bipheny thiazol-2-yI}-pyrrolidine-1-carboxylic acid tert-butyl ester 0 V. a. TFAODCM; b. NaOH; - 0 -NH 0 c. RCOOH/HATUliBu2NEt N_ 'S N HNY O 0 (1-{2-[5-(4'-(2-[1-(2-Methoxycarbonylamino-3-methykbutyryl)-pyrrolidin-2-yl}thiazo-5-y} -biphenyl-4-yl)-thiazol-2-yl]-pyrrolidine-1-carbony-2-methyl-propyl)-carbamic acid methyl ester 2-[5-(4-Bromo-phenyl)-thiazol-2-ylI]-pyrrolidine-1-carboxylic acid tert-butyl ester: The mixture of 2

-[

2

-(

4 -Bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine- I -carboxylic acid tert 15 butyl ester (1.0 g, 2.44 mmol) and Lawesson's reagent (1.23 g, 3.0 mmol) in THF (16 ml) was heated at 80*C for 4 hours. The solvent was removed under reduced pressure and the mixture was diluted with EtOAc. The organic phase was washed with saturated sodium bicarbonate, water, and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 2-[5-(4-Bromo-phenyl)-thiazol-2-yl] 20 pyrrolidine-l -carboxylic acid tert-butyl ester (655 mg). m/z: 410.7 (M + H)*. 2-{5-[4-(4,4,5,5-Tetramethyl-[ 1,3,2] dioxaborolan-2-yi)-phenyl] -thiazol-2-yl}-pyrrolidine-1 carboxylic acid tert-butyl ester: To the solution of 2-[5-(4-Bromo-phenyl)-thiazol-2-yl] pyrrolidine- I -carboxylic acid tert-butyl ester (380 mg, 0.93 mmol) and bis(pinacolato)diboron 25 (500 mg, 2.0 mmol) in 1,4-dioxane (7 ml) was added potassium acetate (240 mg, 2.1 mmol), 449 followed by Pd(PPh 3

)

4 (46 mg). The mixture was heated at 80'C for 20 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 2-{5-[4 (4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiazol-2-yl}-pyrrolidine-l-carboxylic 5 acid tert-butyl ester (400 mg). m/z: 479.0 (M + Na)*. 4,4'- Bis-[5-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-thiazol-2-yll-biphenyl: To the solution of 2-{5-[4-(4,4,5,5-Tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-thiazol-2-yl}-pyrrolidine-l carboxylic acid tert-butyl ester (242 mg, 0.53 mmol) and 2-[5-(4-Bromo-phenyl)-thiazol-2-yl] 10 pyrrolidine-l-carboxylic acid tert-butyl ester (224 mg, 0.55 mmol) in 1,2-dimethoxyether (4.7 ml) and water (1.5 ml) was added sodium bicarbonate (150 mg, 1.8 mmol), followed by Pd(PPh 3

)

4 (24 mg). The mixture was heated at 80'C for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/MeOH) gave 4,4'- bis 15 [5-(I-tert-butoxycarbonyl-pyrrolidin-2-yl)-thiazol-2-yl]-biphenyl (270 mg). (1-{2-15-(4'-{2-I1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-thiazol-5 yl}-biphenyl-4-yl)-thiazol-2-ylI]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 4,4'- Bis-[5-(1 -tert-butoxycarbonyl-pyrrolidin-2-yl)-thiazol-2 20 yl]-biphenyl (270 mg) in DCM (4 ml) was added TFA (2 ml) The mixture was stirred for 4 hours, and the solvent and reagent were removed under reduced pressure. The mixture was diluted DCM, and 1.0 N sodium hydroxide solution was added until pH 11. The organic phase was separated and dried with sodium sulfate. Concentration gave a white solid (182 mg). To the solution of above powder (46 mg, 0.1 mmol) and MeOCO-Val-OH (42 mg, 0.24 mmol) in 25 DMF (3 ml) was added HATU (84 mg, 0.22 mmol), followed by diisopropylethylamine (100 pl, 0.6 mmol). The mixture was stirred for 90 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/EtOAc) gave (1-{2-[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-thiazol-5-yl} 30 biphenyl-4-yl)-thiazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (57 mg). m/z: 773.3 (M+l). 'H NMR (DMSO-d6, 300 MHz) 5 8.14 (2 H, s), 7.8-7.6 (8 H, m), 7.37 (2 H, d, J = 8.6 Hz), 5.32 (2 H, m), 4.11 (2 H, m), 3.80 (4 H, m), 3.51 (6 H, s), 2.3 1.9 (10 H, m), 0.90 (12 H, m). 35 450 Example AU -o H -N 0 Pd(PPh 3

)

4 0 N K 2 C0 3

B

0 jI + Br- - Br DME, 85 *C H [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan- 1,4-dibromo-benzene 2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl) propyll-carbamic acid methyl ester H0 H> 0 N\ / - - N- N N -,N N 0 / ~ ~ H H -/ (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-[1,1';4',1"]terphenyl-4"-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbony}-2 methyl-propyl)-carbamic acid methyl ester (I -{2-[5-(4-{2- [1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 5 imidazol-4-yI)-[1,1';4',1"]terphenyl-4"-yl)-1H-imidazol-2-yI]-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: A solution of [2-methyl-l-(2-{5-[4-(4,4,5,5 tetramethyl-[ ,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-pyrrolidine-I -carbonyl) propyl]-carbamic acid methyl ester (300 mg, 0.60 mmol), I,4-dibromo-benzene (95 mg, 0.40 mmol) and aqueous K 2

CO

3 (800 pl of a 2M solution) in dimethoxyethane (4 mL) was degassed 10 with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 and the reaction was heated to 85 0 C overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The crude product was purified by reverse phase preparative HPLC (10-85% MeCN-H 2 0; 0.1% formic acid modifier) to afford both the monosubstituted product (1-{2-[5-(4'-bromo-biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine- I 15 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (I I I mg, 0.21 mmol, 53% yield) and the desired bis substituted product (1-{2-[5-(4-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-[ 1, l';4', 1 "Iterphenyl-4"-yi)-I H-imidazol-2-yl]-pyrrolidine-I carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (24 mg, 0.074 mmol, 19% yield): ' H NMR: 400 MHz, (DMSO-d 6 ) 8: 11.79 (s, 2H), 7.85-7.62 (m, 12H), 7.53 (s, 2H), 7.29 (d, 2H), 20 5.02 (m, 2H), 4.07 (t, 2H), 3.82 (m, 4H), 3.54 (s, 6H), 2.15-1.90 (m, I OH), 0.91 (d, 6H), 0.86 (d, 6H). LCMS-ESI*: calc'd for C 4 6

H

5 5

N

8 0 6 : 815.4 (M+H*); Found: 815.7 (M + H)*. 451 Example AV N NH HN O -NH O N N O HN - N {1 -[2-(5-{4-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-phenyl)-thiazol-2-yl]-phenyl}-1 H-imidazol-2-yl) pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester {1 -[2-(5-{4-15-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 5 imidazol-4-yl}-phenyl)-thiazol-2-ylI]-phenyl}-1 H-imidazol-2-yl)-pyrrolidine-1 -carbonyl]-2 methyl-propyl}-carbamic acid methyl ester: Title compound was prepared following the method detailed for (1-{2-[5-(4-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-[ 1,1';4',l "]terphenyl-4"-yl)-l H-imidazol-2-yl]-pyrrolidine-I -carbonyl} 2-methyl-propyl)-carbamic acid methyl ester, substituting 2,5-dibromo-thiazole for 2,6 10 dibromobenzene: 1 H (DMSO-d6): 8 = 8.09 (s, 2H), 7.85 (m, 8 H), 7.71 (s, 2H), 7.33 (d, J= 11.2 Hz, 2H), 5.13 (t, J= 8.8 Hz, 2H), 4.11 (t, J= 10.4 Hz, 2H), 3.84 (m, 2H), 3.53 (s, 6H), 2.38 (m, 2H), 2.15 (m, 3H), 2.03 (m, 6H), 0.82 (m 12H). C 4 3

H

5

IN

9 0 6 S calculated 821.4 observed [M + H]*822.6; rt = 1.61 min 15 Example AW N *N O NH HN\ O NH O N N O HN0 0- {1 -[2-(5-{4-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl)-phenyl)-thiophen-2-yl]-phenyl}-1

H

imidazol-2-yl)-pyrrolidine-1 -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester {1-[ 2 -(5-{4-[5-(4-12-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yI}-phenyl)-thiophen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl] 20 2-methyl-propyl}-carbamic acid methyl ester: Title compound was prepared following the method detailed for (1-{2-[5-(4-{2-[I-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-[1,l';4', 1 "]terphenyl-4"-yl)- I H-imidazol-2-yl]-pyrrolidine-I -carbonyl} 2-methyl-propyl)-carbamic acid methyl ester, substituting 2,5-dibromo-thiophene for 2,6 dibromobenzene: I H (DMSO-d6): 8 = 8.47 (s, 2H), 8.09 (m, 4H), 7.89 (m, 6H), 7.33 (d J= 452 10.4 Hz, 2H), 5.12 (t, J= 10.0 ZH, 2H), 4.10 (t, J= 11.2 Hz, 2H), 3.82 (m, 2H), 3.61 (m, 4H), 2.37 (m, 2H), 2.10 (m, 9H), 0.822 (m, 12H). C 4 4

H

52

N

8 0 6 S calculated 820.4 observed [M + I]' 821.8; rt= 1.66 min 5 Example AX HO .<N_ Br2, HOAc 0 BoCO o 0___ 0 / 0 Et 3 N, CH 3 CN NA/ Br - Br C O Boc 1,4-Diacetylbenzene 2-Bromo-1-[4-(2-bromo- Pyrrolidine-1,2-dicarboxylic acd 2-(2-[4 acetyl)-phenyl}-ethanone (1 -tert-butoxycarbonyt-pyrrolidine-2 carbonyloxycarbonyl)-phenyO.2-oxo ethyl} ester 1-tert-butyl ester 1) HCI, Dioxanes NH40Ac N \ - NH N 2) HATU, NMM Xylenes N NH N Boc 2-Methoxycarbonylamino-3 140 C N NH Nmethyl-butyric ad 1-{2-(5-{4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol 4-yt}-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yt}-ethanone -0 H H d-N N N S NN O N ,-N - N Y H H O (1 .{2-[5.(4-{2{1 -2-Methoxycarbonylamino-3-methyl-butyryl)pyrrlidin-2 yI]-3H imidazol-4-y -phenyl) 1H-imidazol-2yIpyrrolidine- .carbony 2 methyl-propyl)-carbamic acid methyl ester 2-Bromo-1-[4-(2-bromo-acetyl)-phenyl]-ethanone: To a solution of Br 2 (1.27 mL, 24.66 mmol) in HOAc (12 mL) was added 1,4-diacetylbenzene (2.00 g, 12.33 mmol). After stirring for 2 h, the reaction was diluted with water and the precipitate collected by filtration. The crude 10 product was then recrystallized from toluene to afford 2-bromo-1 -[4-(2-bromo-acetyl)-phenyl] ethanone (2.87 g, 8.97 mmol, 73% yield). 'H-NMR: 400 MHz, (DMSO-d 6 ) 8: 8.13 (s, 4H), 5.01 (s, 4H). Pyrrolidine-1,2-dicarboxylic acid 2-{2-14-(-tert-butoxycarbonyl-pyrrolidine-2 15 carbonyloxycarbonyl)-phenyl]-2-oxo-ethyl} ester 1-tert-butyl ester: A suspension of 2 bromo-1-[4-(2-bromo-acetyl)-phenyl]-ethanone (2.87 g, 8.97 mmol) in CH 3 CN (15 mL) was added dropwise to a solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.85 g, 17.9 mmol) and triethylamine (2.49 mL, 17.9 mmol) in CH 3 CN (30 mL). The reaction was stirred for 4 hours then concentrated and purified by silica gel chromatography (20-60% EtOAc 20 hexanes gradient) to afford pyrrolidine-1,2-dicarboxylic acid 2-{2-[4-(1-tert-butoxycarbonyl pyrrolidine-2-carbonyloxycarbonyl)-phenyl]-2-oxo-ethyl} ester I -tert-butyl ester (4.91 g, 8.34 453 mmol, 93% yield). 'H-NMR: 400 MHz, (DMSO-d 6 ) 8: 8.11 (s, 4H), 5.69-5.50 (m, 4H), 4.37 4.32 (m, 2H), 3.42-3.29 (m, 6H), 2.34-2.24 (m, 2H), 2.14-2.10 (m, 2H), 1.92-1.82 (m, 4H), 1.40 (s, 9H), 1.37 (s, 9H). 5 1-[2-(5-{4-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-y)-3H-imidazol-4-y]-phenyl}-1H imidazol-2-yI)-pyrrolidin-1-yl]-ethanone: A solution of pyrrolidine-1,2-dicarboxylic acid 2 {2-[4-(I-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxycarbonyl)-phenyl}-2-oxo-ethyl} ester 1 tert-butyl ester (4.91 g, 8.35 mmol) and ammonium acetate (6.44 g, 8.36 mmol) in xylenes (42 mL) was heated to 140*C overnight in a sealed pressure flask. After cooling to room 10 temperature, the reaction was diluted with EtOAc and washed with saturated NaHCO 3 and brine. The organic layer was dried over Na 2

SO

4 then concentrated. The crude material was purified by silica gel chromatography (3-10% MeOH- CH 2 Cl 2 gradient) to afford 1-[2-(5-{4-[2-(l-tert butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl} -l H-imidazol-2-yl)-pyrrolidin-I -yl] ethanone (1.58 g, 2.87 mmol, 34% yield). LCMS-ESI*: calc'd for C 30

H

4 1

N

6 0 4 : 549.3 (M+H*); 15 Found: 549.3 (M+H*). (1 -{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester: To 1-[2-(5-{4-[2-(l -tert-butoxycarbonyl-pyrrolidin-2-yl)-3H 20 imidazol-4-yl]-phenyl}-l H-imidazol-2-yl)-pyrrolidin-1 -yl]-ethanone (500 mg, 0.91 mmol) in dioxanes (5 mL) was added 4N HCI in dioxanes (3 mL). The suspension was stirred for 2 hours then concentrated to afford the HCI salt of the crude amine (530 mg). To a portion of the crude amine (200 mg, 0.41 mmol) in DMF (2 mL) was added N-methylmorpholine (270 pl, 2.44 mmol). After all material dissolved, 2-methoxycarbonylamino-3-methyl-butyric acid (144 mg, 25 0.82 mmol) and HATU (312 mg, 0.82 mmol) were added. After stirring for I hour the reaction was quenched with AcOH then purified by reverse phase preparative HPLC (10-85% MeCN

H

2 0; 0.1% formic acid modifier) to afford (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-I H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (56 mg, 0.085 mmol, 21% yield). IH 30 NMR: 400 MHz, (DMSO-d 6 ) 5: 11.68 (s, 2H), 7.62 (m, 4H), 7.41 (s, 2H), 7.27 (d, 2H), 5.07 5.05 (m, 2H), 4.06 (t, 2H), 3.80 (m, 4H), 3.54 (s, 6H), 2.13 (m, 4H), 1.95 (m, 6H), 0.90 (d, 6H), 0.85 (d, 6H). LCMS-ESI: calc'd for C 34

H

4 7

N

8 0 6 : 663.4 (M+H*); Found: 663.1 (M+H*). 454 Example AY Pd(PPh 3

)

4 -0 H Cul, Et 3 N ~~ H K DMF H 2 C0 3 N 0 s 8 *C O MeOH N ~ Br + - TMS - 0 N ' -TMS H H (1-{2-[5-(4-BrmoD-phenyl)-1H-imidazol-2-yll- (2-Methyl-1-{2-{5-(4-trimethytsilanyiethynyl-phenyl) pyrrolidine-1 -carbonyf}-2-methyI-propy)- IH-lmidazo-2-y]-pyrroidine-1 -carbonyl}-propyl) carbamic acid methyl ester carbamic acid methyl ester Pd(PPh 3

)

4 , Cut, Et 3 N, O H (1 42-{5-(4-Bromo-pheny)-1 H-imidazol-2-y] N O pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic o N-- H acid methyl ester \N~"~ DMF. 80 *C (H (142-5-(4-Ethynyl-phenyl)- l- -r h in H-imidazol-2-y]-yrroidine cazronyl-2-mtyl-ropyl)-carbamic acid methyl ester -0o H 0H d- NN N [1-(2544-2e a(2Met8oy ertn ight.nA3-me ftyrcouty oliing r eeta3Htmidazor4ayl ti phen rethy ey)-phenyll H-imidazolt-2-y-pyrrolidine-l ca an di)-2- waeth erropyl]-car amic acd methyl ester (2-Methyl- I t- 2-a5-(4-trimethylsilanylethyny-phenyl)-1 H-imidazol-2-yl -pyrrol idine-I 5 yrro l-carbonyl})-carbamic acid methyl ester: A solution of(6 -2-[5-(4-bromo-phenyl)- H imidazol-2-yl]-pyrrolidine- I -carbonyl} -2-methyl-propyl)-carbamic acid methyl ester (5.00 g, 11.1 mmol), TMS-acetylene (7.90 mL, 55.5 mmol) and triethylamine (4.64 mL, 33.3 mmol) in DMF (56 mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (1.28 g, 1.11 mmol) and Cul (106 mg, 0.56 mmol). The pressure flask was sealed 10 then heated at 80 C overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back extracted two times then the organic phases were combined and dried over Na 2

SO

4 . After concentration, the crude material was purified by silica gel chromatography (10-80% EtOAc hexanes gradient) to afford (2-methyl- I- {2-[5-(4-trimethylsi lanylethynyl-phenyl)- I H-imidazol 15 2 -yl]-pyrrolidine- I-carbonyl}-propyl)-carbamic acid methyl ester (3.08 g, 6.60 mmol, 59% yield). LCMS-ESI+: calc'd for C 25

H

35

N

4

O

3 Si: 467.3 (M+H+); Found: 467.1 (M-$H +). (1 -(2-[5-(4-EthynyI-phenyI)-I H-imidazol-2-ylJ-pyrrolidine-I -carbonyl}-2-methyl-propyl) carbamic acid methyl ester: To (2-methyl-I -{2-[5-(4-trimethylsilanylethynyl-phenyl)-

IH

20 imidazol-2-yl]-pyrrolidine-l-carbonyl}-propyl)-carbamic acid methyl ester (3.08 g, 6.60 mmol) in MeOH was added K 2 C0 3 (1 .82 g, 13.2 mmol). After stirring for 5 h, the reaction was filtered 455 then concentrated. The residue was diluted with EtOAc then washed with H 2 0. The aqueous phase was back-extracted with EtOAc two times then the organic phases were combined, washed with brine, dried over Na 2

SO

4 , and concentrated. The crude material was purified by silica gel chromatography (5-10% MeOH- CH 2

CI

2 gradient) to afford (I-{2-[5-(4-ethynyl 5 phenyl)- I H-imidazol-2-yi]-pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.62 g, 6.6 mmol, quantitative yield). LCMS-ESI+: calc'd for C 2 2

H

2 7

N

4 0 3 : 395.2 (M+H"); Found: 395.2 (M+H*). [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 10 imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyl]-carbamic acid methyl ester: A solution of(l-{2-[5-(4-bromo-phenyl)-IH imidazol-2-yl]-pyrrolidine- 1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (947 mg, 2.11 mmol), (I- {2-[5-(4-ethynyl-phenyl)- I H-imidazol-2-yl]-pyrrolidine- 1 -carbonyl }-2-methyl propyl)-carbamic acid methyl ester (1.00 g, 2.53 mmol), and triethylamine (882 p1, 6.33 mmol) 1 5 in DMF (13 mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (244 mg, 0.21 mmol) and Cul (40 mg, 0.21 mmol). The pressure flask was sealed then heated at 80*C overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back extracted two times then the organic phases were combined and dried over Na 2

SO

4 . After 20 concentration, the crude material was purified by silica gel chromatography (0-20% MeOH EtOAc gradient) then reverse phase preparative HPLC (10-85% MeCN-H 2 0; 0.1% formic acid modifier) to afford [1 -(2- {5-[4-(4-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3 H-imidazol-4-yl}-phenylethynyl)-phenyl]-I H-imidazol-2-yl} -pyrrolidine- I carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (600 mg, 1.00 mmol, 47% yield). 'H 25 NMR: 400 MIHz, (DMSO-d 6 ) 8: 1I .84 (s, 2H), 7.75 (d, 4H), (7.56 (s, 2H), 7.47 (d, 4H), 7.28 (d, 2H), 5.06 (m, 2H), 4.06-4.04 (m, 2H), 3.80 (m, 4H), 3.54 (s, 6H), 2.14 (m, 4H) 2.00-1.90 (m, 6H), 0.89 (d, 6H), 0.84 (d, 6H). LCMS-ESl*: calc'd for C 4 2

H

51

N

8 0 6 : 763.4 (M+H*); Found: 763.4 (M+H*). 456 Example AZ Pd(PPh 3

)

4 -~ PdCl 2 dppf 2 SH

K

2

C

3 -N N N' DMF O' Br + B N N -- \--H H O (1-(2-{5-(4-Bramo-phenyl)-1H-imidazol-2-yJ- [2-Methyl-i -(2-{5-16-(4,4,5,5-tetramethyl pyrrolidine- -carbny 12-methyl-propyl- [1,3,2}dioxabrolan-2-)-naphthalen-2-y)1H-imidazol-2-yl carbamic acid methyl ester pyrrolidine-1-carbonyl)-propyl)-carbamic acid methyl ester H -O H 0 \ N N "K 'H H a [1 -(2-{5'-[6-(4-2-[1 -(2-Methoxycarboiiylaminomeylbutry)-pyrmlidin-2-y]-3H midazol-4-yl}pheny)-naphthalen-2-yl1 H-imidazol-2-yI)-pyrmlidine-i-carbonyl)-2 methyl-propyl}-carbamic acid methyl ester 1 -(2-{5-16-(4-{2-[ 1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 5 imidazol-4-yl)-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yI}-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester: A solution of (I-{2-[5-(4-bromo-phenyl)-I H imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (244 mg, 0.54 mmol), [2-methyl-l -(2- {5-[6-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-naphthalen-2 yl]-l H-imidazol-2-yl) -pyrrolidine- I -carbonyl)-propyl]-carbamic acid methyl ester (270 mg, 10 0.49 mmol) and aqueous K 2

CO

3 (490 pl of a 2M solution, 0.98 mmol) in toluene (3 mL) and DMF (I mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (31 mg, 0.027 mmol) and PdCI 2 (dppf) (20 mg, 0.027 mmol) then the reaction was heated to 80'C overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The crude product was purified by reverse phase 15 preparative HPLC (10-85% MeCN-H 2 0; 0.1% formic acid modifier) to afford [I-(2-{5-[6-(4 {2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl) naphthalen-2-yl]-l H-imidazol-2-yl}-pyrrolidine-l -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (149 mg, 0.19 mmol, 35% yield). 'H-NMR: 400 MHz, (DMSO-d 6 ) 6: 11.82 (s, I H), 11.79 (s, I H), 8.21-8.16 (m, 2H), 7.92-7.79 (m, 8H), 7.62 (s, I H), 7.54 (s, I H), 7.31-7.29 20 (m, 2H), 5.10 (m, 2H), 4.09-4.07 (m, 2H), 3.82 (m, 4H), 3.54 (s, 6H), 2.20-1.85 (m, IOH), 0.95 0.86 (m, 12H). LCMS-ESI: calc'd for C 4 4

H

53

N

8 0 6 : 789.4 (M+H*); Found: 789.2 (M+H*). 457 Example AA1 Br Bis(pinacolato)diboron, ,0s _ Pd(PPha)4 PdCl 2 dppf 2 , K 2

CO

3 Br PdCdpp 2 KOAc 4 DMF 80'C Br ~DMSO--OO

-

O 2.6-Anthrcere-bis-4A45,5- Br-N BO tetramethyl-1 .32-dioxaborolane Br Boc 2- 5-8romo-1 H-imidazol-2 yf)-prrolidine-1 -carboxylic acid tert-buty ester H OH /N- N 1) HCILDioxanes -N -I,/'- N 8i \ HN- 0 N~ 0 Boc 3 , NY O Y O 0 -1 <' - k 1 62-5-{2-1 -14ert-Butoxycarbony -yrroldin- 2-Methoxycarborylamno-3- (1-{256-{ 21 -2-Metroxycarbonylamino 2-yI)-3N4-imidazol-4-yI].anlhracan-2yI)-1 H- methyl-bulyric acid 3-inethyl-butyryl)-pyrrolidir-2-yJ imidazol-2-yl)-pyrrolidin-1-yl-ethanone 3H-aidazol-4-yi)-anthracen-2-y)- H mridazol-2-yfl-pyrrofidine-l -carbonyI}-2. methyl-propyl)-carbamic acid methyl ester 2,6-Anthracene-bis-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: A mixture of 2,6 5 dibromoanthracene (500 mg, 1.49 mmol), bis(pinacolato)diboron (756 mg, 2.98 mmol)and KOAc (585 mg, 5.96 mmol) in DMSO (10 mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added PdCl 2 (dppf) (55 mg, 0.075 mmol) then the reaction was heated to 80*C overnight. After cooling to room temperature, the reaction was poured into H20 and extracted with CH 2

CI

2 . The organic phase was collected then washed with H20 and brine. 10 After drying over Na 2

SO

4 , the organic phase was concentrated then purified by silica gel chromatography (30-100% CH 2 Cl 2 -hexanes gradient) to afford 2,6-anthracene-bis-4,4,5,5 tetramethyl-l,3,2-dioxaborolane (241 mg, 0.56 mmol, 38% yield). IH-NMR: 400 MHz, (DMSO-d 6 ) 6: 8.57 (s, 2H), 8.46 (s, 2H), 8.00 (d, 2H), 7.79 (d, 2H). 15 1-[2-(5-{6-12-(1-1-tert-Butoxycarbonyl-pyrrolidin-2-yI)-3H-imidazol-4-yll-anthracen-2-yl} 1 H-imidazol-2-yl)-pyrrolidin-1 -yl]-ethanone: A solution of 2,6-anthracene-bis-4,4,5,5 tetramethyl- 1,3,2-dioxaborolane (241 mg, 0.56 mmol), 2-(5-bromo- I H-imidazol-2-yl) pyrrolidine- I -carboxylic acid tert-butyl ester (531 mg, 1.68 mmol) and aq K 2

CO

3 (1.12 mL of a 2M solution, 2.24 mmol) in toluene (6 mL) and DMF (I mL) was degassed with N 2 gas for 20 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (32 mg, 0.028 mmol) and PdCl 2 (dppf) (21 mg, 0.028 mmol) then the reaction was heated to 80'C overnight. After cooling to room temperature, the reaction was concentrated. The crude material was diluted with EtOAc then washed with saturated NaHCO 3 . The aqueous phase was back-extracted two times then the organic layers were combined, dried over Na 2

SO

4 , and concentrated. The crude product was 25 purified by reverse phase preparative HPLC (20-80% MeCN-H 2 0; 0.1% formic acid modifier) 458 to afford 1-[2-(5-{6-[2-(1-I-tert-butoxycarbonyl-pyrrolidin-2-yI)-3H-imidazol-4-yI]-anthracen 2-yl}-I H-imidazol-2-yl)-pyrrolidin-1-yI]-ethanone (117 mg, 0.18 mmol, 32% yield). LCMS ES1*: calc'd for C 38

H

45

N

6 0 4 : 649.4 (M+H+); Found: 648.9 (M+H*). 5 (1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-anth racen-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2-methyl propyl)-carbamic acid methyl ester: To 1-[2-(5-{6-[2-(1-1 -tert-butoxycarbonyl-pyrrolidin-2 yI)-3 H-imidazol-4-yl]-anthracen-2-yl}-1 H-imidazol-2-y)-pyrrolidin-1-yl]-ethanone (117 mg, 0.18 mmol) in dioxanes (5 mL) was added 4N HC in dioxanes (180 pLl, 0.72 mmol). The 10 suspension overnight then concentrated to afford the HCI salt of the crude amine. To the amine in DMF (3 mL) was added N-methylmorpholine (119 l, 1.08 mmol). After all the material dissolved, 2-methoxycarbonylamino-3-methyl-butyric acid (76 mg, 0.43 mmol) and HATU (151 mg, 0.40 mmol) were added. After stirring overnight the reaction was quenched with AcOH then purified by reverse phase preparative HPLC (15-70% MeCN-H 2 0; 0.1% formic acid 1 5 modifier) to afford (1-{2-[5-(6-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3 H-imidazol-4-yl)-anthracen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester (46 mg, 0.098 mmol, 54% yield). 'H-NMR: 400 MHz, (DMSO-d 6 ) 8: 11 .84 (s, 21H), 8.38 (s, 2H), 8.3 1 (s, 2H), 8.00 (d, 2H), 7.86 (d, 2H), 7.62 (s, 2H), 7.30 (d, 2H), 5.12 (m, 2H), 4.10 (m, 2H), 3.84 (m, 4H), 3.55 (s, 6H), 2.18-1.95 (m, 10 H), 0.96 20 (d, 6H), 0.88 (d, 6H). LCMS-ESI*: calc'd for C 4 2

H

51

N

8 0 6 : 763.4 (M+H); Found: 763.1 (M+H*). 459 Example ABI Pd(PPh 3

)

4 Du Et 3 N 1) HCI, Dioxanes BOC B + 2) HATU, NMM TMSSN N Y 0 M F F O N OH F F O 2-[5-(4-Bromo-phenyl)-1 H-imidazo- 4,4-Difluoro-2-[5-(4- 2-Methoxycarbonylamino 2-yl}-4,4-difluoro-pyrroidie-1 - trimethysilanylethynyl-pheny)- 1H- 3-methyt-butyric acid carboxylic acid tert-buty ester imidazol-2-yj-pynolidine-1-carboxyic acid tert-buty ester Pd(PPh 3

)

4 , Cul, Et3N, (1 -{2-[5-(4-Bromo-phenyl)-1 H imidazol-2-y)-pyrrolidine-1 -carbonyl) 2-methyl-propyl)-carbamic acid -0o H Kz3 0NH0 methyl ester ___ Me OH 0/,N DMF. a0 C TMS/ H DMFN80_*C HH FF (1 -{4,4- Difluoro2-{5-(4-trimethysilanylethyny-phenyl)-1 H- (1-{2-[5-(4-Ethynyt-phenyl)-1 H-imidazol-2-y]-4.4-difluoro imidazol-2-yl}-pyrrolidine-1 -carbonyt}-2-methyt-propyl)- pyrrolidine-1-carbony)-2-methy-propy)-carbamic acid carbamic acid methyl ester methyl ester -0 H H N_ 0 .<N \ N O HV H O_ FF [1-(2-{5-4-(4-{2-[44-Difluoro-1-(2-methoxycarbonylamino-3-methyi-butyry)-pyrrolidin-2-y] -3H-imidazol-4-yl)-phenylethynyl)-pheny]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methpropyl-carbamic add methyl ester 4,4-Difluoro-2-[5-(4-trimethylsilanylethyny-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1 5 carboxylic acid tert-butyl ester: A solution of 2-[5-(4-bromo-phenyl)-l H-imidazol-2-yl]-4,4 difluoro-pyrrolidine- I -carboxylic acid tert-butyl ester (700 mg, 1.56 mmol), TMS-acetylene (1.11 mL, 7.79 mmol) and triethylamine (1.1 mL, 7.8 mmol) in DMF (8 mL) was degassed with

N

2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (180 mg, 0.16 mmol) and Cui (14.8 mg, 0.078 mmol). The pressure flask was sealed then heated at 80'C overnight. After 10 cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na 2

SO

4 . After concentration, the crude material was purified by silica gel chromatography (10-50% EtOAc-hexanes gradient) to afford 4,4-difluoro-2-[5-(4 trimethylsilanylethynyl-phenyl)- I H-imidazol-2-yl]-pyrrolidine-I -carboxylic acid tert-butyl ester 15 (547 g, 1.23 mmol, 79% yield). LCMS-ESI*: calc'd for C 2 3

H

3 0

F

2

N

3 0 2 Si: 446.2 (M+H*); Found: 445.8 (M+H*). (1-{4,4-Difluoro-2-15-(4-trimethylsilanylethynyl-phenyl)-IH-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To 4,4-difluoro-2-[5-(4 20 trimethylsilanylethynyl-phenyl)-1 H-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester 460 (547 mg, 1.23 mmol) in dioxanes (6 mL) was added 4N HCI in dioxanes (1.65 mL, 6.6 mmol). The suspension was stirred overnight then concentrated to afford the HCI salt of the crude amine. To the amine in DMF (5 mL) was added N-methylmorpholine (406 p1, 3.69 mmol). After all the material dissolved, 2-methoxycarbonylamino-3-methyl-butyric acid (236 mg, 1.35 5 mmol) and HATU (513 mg, 1.35 mmol) were added. After stirring for 2 hours the reaction was concentrated then diluted with EtOAc and washed with H 2 0. The aqueous phase was back extracted two times then the organic layers were combined, dried over Na 2

SO

4 , and concentrated. The crude product was purified by silica gel chromatography (20-60% EtOAc hexanes gradient) to afford (I -{4,4-difluoro-2-[5-(4-trimethylsilanylethynyl-phenyl)- I H 10 imidazol-2-yl]-pyrrolidine- I -carbonyl }-2-methyl-propyl)-carbamic acid methyl ester (412 mg, 0.82 mmol, 67% yield). LCMS-ESI*: calc'd for C 2 5

H

33

F

2

N

4 0 3 Si: 503.2 (M+H*); Found: 503.2 (M+H*). (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yI]-4,4-difluoro-pyrrolidine-1-carbonyl}-2 15 methyl-propyl)-carbamic acid methyl ester: To (I-{4,4-difluoro-2-[5-(4 trimethylsilanylethynyl-phenyl)-I H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl) carbamic acid methyl ester (412 mg, 0.82 mmol) in MeOH (8 mL) was added K 2

CO

3 (227 mg, 1.64 mmol). After stirring for 5 h, the reaction was filtered then concentrated. The residue was diluted with EtOAc then washed with H 2 0. The aqueous phase was back-extracted with EtOAc 20 two times then the organic phases were combined, washed with brine, dried over Na 2

SO

4 , and concentrated. The crude material was purified by silica gel chromatography (20-80% EtOAc hexanes gradient) to afford (I -{2-[5-(4-ethynyl-phenyl)-l H-imidazol-2-yl]-pyrrolidine- 1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (371 mg, 0.82 mmol, quantitative yield). LCMS-ESI*: calc'd for C 22

H

2 5

F

2

N

4 0 3 : 431.2 (M+H*); Found: 431.1 (M+H*). 25 [l-( 2 -{5-[4-(4-{2-[4,4-Difluoro--(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-ylI-3H-imidazol-4-yl}-phenylethynyl)-phenylI-1 H-imidazol-2-yl}-pyrrolidine-1 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: A solution of (1-{2-[5-(4-bromo phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl 30 ester (400 mg, 0.89 mmol), (1-{2-[5-(4-ethynyl-phenyl)- IH-imidazol-2-yl]-pyrrolidine-l carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (371 mg, 0.89 mmol), and triethylamine (372 pl, 2.67 mmol) in DMF (8 mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (103 mg, 0.089 mmol) and Cul (17 mg, 0.089 mmol). The pressure flask was sealed then heated at 80*C overnight. After cooling to room 35 temperature, the reaction was quenched with AcOH then purified by reverse phase preparative 461 HPLC (10-70% MeCN-H 2 0; 0.1% formic acid modifier) then silica gel chromatography (0-10% MeOH-EtOAc gradient) to afford [1 -(2-{5-[4-(4-{2-[4,4-difluoro-l -(2-methoxycarbonylamino 3-methyl-butyryl)-pyrrolidin-2-yI]-3H-imidazol-4-y}-phenylethynyl)-phenyl]- I H-imidazol-2 yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (231 mg, 0.29 mmol, 5 33% yield). 'H-NMR: 400 MHz, (DMSO-d 6 ) 5: 12.04 (s, 1 H), 1 1.84 (s, I H), 7.78-7.76 (m, 4H), 7.61 (s, I H), 7.56 (s, I H), 7.50-7.48 (m, 6H), 7.28 (d, 2H), 5.29 (t, I H), 5.07 (m, I H), 4.52 (m, I H), 4.24-4.14 (m, I H), 4.06 (t, I H), 3.93 (t, I H), 3.80 (m, 2H), 3.55 (s, 3 H), 3.54 (s, 3H), 2.93 (m, I H), 2.77 (m, I H), 2.14-1.88 (m, 6H), 0.90-0.84 (m, 12H). LCMS-ESI*: calc'd for

C

4 2

H

4 9

N

8 0 6 : 799.4 (M+H*); Found: 799.0 (M+H*). 10 Example ACI HATU. NMM B) HC Dioxanes Boc Boc H 0 4-Bromo-benzoic acid 2-Aminomethyl-pyrroidine- 2-[(4-Bromo-benzoylamino)mthyl]- /O N OH 1-carboxylic acd tert-butyl pyrrolidine- -carboxylic acid tert- 0 ester butyl ester 2-Me oxycarbonyiamino y p) ] i3cmatyl-butyc acid N Na\B pyrrolidine-1-carbony)-pro}-2-methyl-pardopet) carbamic acid methyl ester Pd(PPh 3

)

4 . K 3

PO

4 . DME. 80 *C 0 ~ 0 Br-\/= /14 N V N HN H 0 [1 -(2-iJ4{[ 4 1-(2 hxycarbonyamino 3 -methyl buyy)priin0-2-ytl-3H-abroln-midazoly-4-Hmyazol2)l biphenyi-4-carbonyl)-amino-methy-pyrrolidinre-1 carbony)-2-ehy-ppyl-carbamic acid methyl ester 2-[(4-Bromo-benzoylamino)-methyl]-pyrroidine-1-carboxylic acid tert-butyl ester: To 2 I5 aminomethyl-pyrrolidine--carboxylic acid tert-butyl ester (1.00 g, 4.97 mmol) and 4-bromo benzoic acid (996 mng, 4.97 mnmol) in DMIF (25 mL) was added N-methylmorpholine (655 pl, 5.96 mnmol) and HATU (1.89 g, 4.97 mnmol). After stirring for 3 hours the reaction was concentrated then diluted with EtOAc and washed with IN HCI, saturated NaHCO 3 , and brine. The organic phase was then dried over Na 2

SO

4 and concentrated. The crude material was 20 purified by silica gel chromatography (20-50% EtOAc-hexanes gradient) to afford 2-[(4-bromo benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.91g, 4.97 mmol, 462 quantitative yield). LCMS-ESl*: calc'd for C 17

H

24 BrN 2

O

3 : 383.1 (M+H*); Found: 383.6 (M+H*). (1 -{2-{(4-Bromo-benzoylamino)-methyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl) 5 carbamic acid methyl ester: To 2-[(4-bromo-benzoylamino)-methyl]-pyrrolidine-l -carboxylic acid tert-butyl ester (1.00 g, 2.61 mmol) in dioxanes (15 mL) was added 4N HCI in dioxanes (5 mL, 20 mmol). The solution was stirred overnight then concentrated to afford the HCI salt of the crude amine. To the amine in DMF (13 mL) was added N-methylmorpholine (574 p1l, 5.22 mmol), 2-methoxycarbonylamino-3-methyl-butyric acid (457 mg, 2.61) and HIATU (992 mg, 10 2.61 mmol). After stirring for 2 hours the reaction was concentrated then diluted with EtOAc and washed with IN HCI, saturated NaHCO 3 , and brine. The crude product was purified by silica gel chromatography (100% EtOAc) to afford (I -{2-[(4-bromo-benzoylamino)-methyl] pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (950 mg, 2.18 mmol, 84% yield). LCMS-ESI*: calc'd for C 19 gH 2 7 BrN 3 0 4 : 440.1 (M+H*); Found: 440.2 (M+H). 15 [1-(2-{[(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yIl-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine--carbonyl)-2-methyl propyll-carbamic acid methyl ester: A solution of (1 -{2-[(4-bromo-benzoylamino)-methyl] pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (104 mg, 0.24 mmol), [2 20 methyl- I-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl} pyrrolidine-I -carbonyl)-propyl]-carbamic acid methyl ester (117 mg, 0.24 mmol) and aq K 3 PO4 (480 pd of a 2M solution, 0.96 mmol) in DME (3 mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (13.9 mg, 0.0 12 mmol) then the reaction was heated to 80'C overnight. After cooling to room temperature, the reaction was concentrated and 25 purified by reverse phase preparative HPLC (15-60% MeCN-H 2 0; 0.1% formic acid modifier) to afford [1-(2-{[(4'-{2-[ -(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-I -carbonyl)-2-methyl propyl]-carbamic acid methyl ester (26 mg, 0.036 mmol, 15% yield). 'H-NMR: 400 MHz, (DMSO-d 6 ) 8: 11.8 (s, I H), 8.61 (m, I H), 7.94-7.73 (m, 9H), 7.34 (d, I H), 7.29 (d, I H), 5.08 30 (m, I H), 4.23 (t, I H), 4.30 (m, I H), 4.07 (t, I H), 4.01 (t, I H), 4.07-4.01 (m, I H), 3.18 (m, 2H), 3.73-3.70 (m, I H), 3.61 (m, I H), 3.63 (s, 3H), 3.61 (s, 3H), 2.16-1.81 (m, IOH), 0.90-0.84 (m, 12H). LCMS-ESI: calc'd for C 3 9

H

52

N

7 0 7 : 730.4 (M+H*); Found: 730.1 (M+H*). 35 463 Example AD1 O 0 0 I + H 0 nBu 4 NOH NaOH EO0- Cul, DMF EtO -OH 4-lodo-benzoic acid 2-Oxo-1,2-dihydro- 1-(4-Ethoxycarbonyl ethyl ester pyridine-4-carboxylic phenyl)-2-oxo-1,2-dihydro acid methyl ester pyrdine-4-carboxylic acid Boc O OOH 0 0 z 0 1. SOC12 0 -Pyrrolidine-1,2-dicarboxylic N acid 1-tert-butyl ester HO / -' O 2. TMVSCHN 2 B / N OH 3. HBr A Br 1. DIPEA, ACN 1-(4-Carboxy-phenyl)-2- 4-(2-Bromo-acetyl)-1-[4- 2. NH 4 OAc oxo-1,2-dihydro-pyridine- (2-bromo-acetyl)-phenyl]- Toluene, 100 C 4-carboxylic acid 1H-pyridin-2-one H 1. HCI N\ N Boc Boc NH '/ 2. HATU, NMMIV HO .0 2-[5-(1-{4-[2-(1-Boc-pyrrolidin-2-yl)-3H- HON imidazol-4-yl]-phenyl}-2-oxo-1,2-dihydro- 0 H 0 pyrdin-4-yl)-1 H-imidazol-2-yl]-pyrrolidine- 2-Methoxycarbonylamino-3 1-carboxylic acid tert-butyl ester methyl-butyric acid 0 O0 H O N 0 N- N N NH HN 0s 0 [1-(2-{5-[1-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-phenyl)-2-oxo-1,2-dihydro-pyrdin-4-yl]-1H-imidazol 2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyll-carbamic acid methyl ester 1-(4-Ethoxycarbonyl-phenyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid: A mixture of 5 2-oxo-1,2-dihydro-pyridine-4-carboxylic acid methyl ester (2.00 g), L.0M tetrabutylammonium hydroxide in H 2 0 (13 ml) and toluene (50 mL) was stirred for 2 hours at ambient temperature. Mixture was concentrated and co-evaporated with toluene (3 x 100 mL) and dried under high vacuum. To the residue was added 4-lodo-benzoic acid ethyl ester (2.40 g) and co-evaporated with toluene (2 x 20 mL). Copper iodide (0.829 g) and DMF (10 mL) were added and reaction 10 mixture heated at 95*C for 18 hours, protected from light. To the cooled reaction mixture was added 3N ammonium hydroxide and extracted with dichloromethane (4x). Organic layer was dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 0 to 5% methanol/dichloromethane + 1% triethylamine) to give 1-(4-Ethoxycarbonyl-phenyl)-2-oxo- 1,2 dihydro-pyridine-4-carboxylic acid (1.155 g) as the triethylammonium salt: LCMS-ESI~: calc'd 15 for CI 5

H

1 2 NOs: 286.27 (M-H+); Found: 286.1 (M-H+). 464 1-(4-Carboxy-phenyl)-2-oxo- 1,2-dihyd ro-pyrid ine-4-carboxylic acid: To a solution of 1-(4 Ethoxycarbonyl-phenyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (1.155 g) in THF (20 mL) at 0*C was added 5 M sodium hydroxide (1.19 mL) and mixture stirred overnight at ambient temperature. Reaction mixture was acidified to pH 1 with concentrated HCI, producing 5 a precipitate. The solid was collected by filtration, washed with H 2 0 and dried under high vacuum to give I-(4-Carboxy-phenyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (0.7196 g). LCMS-ESI-: calc'd for C 13

H

8

NO

5 : 258.2 (M-H*); Found: 258.1 (M-H*). 4-(2-Bromo-acetyl)-1 - [4-(2-bromo-acetyl)-phenyl]-1 H-pyrid in-2-one: A mixture of 1-(4 10 Carboxy-phenyl)-2-oxo-l,2-dihydro-pyridine-4-carboxylic acid (0.696 g) and oxalyl chloride (2.34 mL) in dichloromethane (20 mL) containing DMF (4 drops) was stirred at ambient temperature for 4 hours, then concentrated and co-evaporated with toluene (3x) and dried under high vacuum. The resulting residue was suspended in dichloromethane (10 mL) at 0*C and treated with 2.0 M trimethylsilyldiazomethane in ether (4.0 mL) over 15 minutes to give a 15 brown mixture. Reaction mixture was warmed to ambient temperature overnight and then concentrated. The resulting brown solid was suspended in ethyl acetate (10 mL) and cooled to 0 0 C. 5.7 M HBr in acetic acid was added over 5 minutes and reaction mixture was warmed to ambient temperature over I hour. Solid sodium bicarbonate (0.3 g) was added and stirred for 30 minutes. H 2 0 was added giving a biphasic mixture with a brown precipitate. The solid was 20 removed by filtration and filtrate was extracted with dichloromethane (2x), dried (MgSO 4 ) and concentrated. The residue was purified by flash column chromatography (silica gel, 30 to 80% ethyl acetate/hexanes) to give 4-(2-Bromo-acetyl)- I -[4-(2-bromo-acetyl)-phenyl]- I H-pyridin-2 one (0.555 g). LCMS-ESI*: calc'd for C 1 5

H

2 Br 2

NO

3 : 414.06 (M+H*); Found: 411.9, 413.9, 415.8 (M+H*). 25 2-[5-(1-{4-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yll-phenyll-2-oxo-1,2-dihydro-pyridin 4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 4-(2 Bromo-acetyl)-I -[4-(2-bromo-acetyl)-phenyl]- I H-pyridin-2-one (0.555 g) Pyrrolidine- 1,2 dicarboxylic acid I -tert-butyl ester (0.6 g) and diisopropylethylamine (0.48 mL) in acetonitrile 30 (10.8 mL) was stirred for 2 hours at ambient temperature. Reaction mixture was diluted with ethyl acetate, washed with brine and back-extracted with ethyl acetate. The combined organic layer was washed with diluted brine (2x), dried (MgSO 4 ) and concentrated to give a brown oil (1.034 g). LCMS-ESI-: calc'd for C 35

H

42

N

3 0 11 : 680.73 (M-H*); Found: 680.3 (M-H+). Residue was dissolved in toluene (5.5 mL) and ammonium acetate (2.066 g) was added. The 35 reaction mixture was stirred at I 00*C for 2 hours and then concentrated. The residue was 465 partitioned between dichloromethane and dilute sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane containing methanol (3x) and the combined organic layer was dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 0 to 15% methanol/dichloromethane) to give 2-[5-(I-{4-[2-(I-Boc-pyrrolidin-2-yl)-3H-imidazol-4 5 yl]-phenyl}-2-oxo-1,2-dihydro-pyridin-4-yl)-I H-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (0.098 g). LCMS-ESI*: calc'd for C 35

H

4 4

N

7 0 5 : 642.76 (M+H*); Found: 642.1 (M+H*). [1-(2-{5-[1-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 10 imidazol-4-yI}-phenyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-1H-imidazol-2-yl)-pyrrolidine-1 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: 2-[5-(1-{4-[2-(I-Boc-pyrrolidin-2 yl)-3 H-imidazol-4-ylI]-phenyl}-2-oxo- 1,2-dihydro-pyridin-4-yl)-l H-imidazol-2-yl]-pyrrolidine I -carboxylic acid tert-butyl ester (0.098 g) in dichloromethane (6.0 mL) was treated with 4N HCI in dioxane (2.0 mL) for 90 minutes at ambient temperature. Reaction mixture was 15 concentrated and dried overnight under vacuum. Residue was dissolved in DMF (2.0 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.055 g), 4 methylmorpholine (0.099 mL), followed by HATU (0.116 g). Reaction mixture was stirred for 90 minutes at ambient temperature and then concentrated. Residue was dissolved in dichloromethane and washed with dilute sodium bicarbonate solution. Aqueous layer back 20 extracted with dichloromethane and combined organic layer dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product was lyophilized to give [1 -(2-{5-[ 1-(4- {2-[l-(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-phenyl)-2-oxo- 1,2-dihydro-pyridin-4-yl]- I H imidazol-2-yl}-pyrrolidine-l -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester as the bis 25 TFA salt (0.037 g): I H-NMR: 300 MHz, (DMSO-d 6 ) 6: 8.14 (s, 2H), 7.88 (d, J=8.4, 2H), 7.79 (d, J=7.2, I H), 7.63 (d, J=8.4, 2H), 7.35-7.30 (m, 2H), 6.88 (s, H), 6.74 (d, J=8.4, I H), 5.13-5.10 (m, 2H), 3.90-3.80 (m, 8H), 3.53 (s, 6H), 2.40-2.01 (m, 10H), 0.83-0.75 (in, 12 H); LCMS-ESIF: calc'd for C 3 9

H

50

N

9 0 7 : 756.86 (M+H*); Found: 756.3 (M+H*). 30 466 Example AEl B BnBr, AgCO 3 OBn B B PdPPh) Br / NH DF Br-- / 1N '0 K2C' ~ 'P 3

)

4 NM '0N N"C 4-Bromo-1H- 2-Benzyloxy-4- 2-{544-(4,4,5,5-Tetramethyl pyridin-2-one bromo-pyridine [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2 yl}-pyrrolidine-1-carboxylic acid tert-butyl ester 0 1. SEM-CI, NaH, DMF Boc N Boc \ / \ /j \ N NNH + BacNN N ~N - - 2. H 2 , Pd/C, EtOH SEM 2-[5-[4-(2-Oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1 2-{5-[4-(2-Benzyloxy-pyrdin-4-yl)-pheny]-1 H- (2-trmethylsilanyl-ethoxymethyl)-1 H-imidazol-2 imidazol-2-yl)-pyrrolidine-1-carboxylic acd tert- yl]-pyrrolidine-1-carboxylic acid tert-butyl ester butyl ester

N

7 0 Br N nBu 4 NOH 1. TFA N Boc TBAI, Cul BOC N N N SEM N N Boc 2.HATU, NMM 2-[4-Bromo-1-(2-trimethylsilanyl-DMF \ SEM 'SEM ethoxymethyl)-1H-imidazol-2-yl]- 0 pyrrolidine-1-carboxylic acid tert- 2-[4-(4-{4-[2-(1-tert-butylcarbamyl-pyrrolidin-2- HO N butyl ester yl)-3-(2-trmethylsilanyl-ethoxymethyl)-3H- 0 N' imidazol-4-yl]-phenyl}-2-oxo-2H-pyridin-1 -yl)-1- 0 H 0 (2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol- 2-Methoxycarbonylamino 2-yl]-pyrrolidine-1 -carboxylic acid tert-butyl 3-methyl-butyric acid ester 0 O0 '0/l. 0H 0 N NO N NHN 0 [1 -(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yl}-phenyl)-2-oxo-2H-pyrdin-1 -yl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2 methyl-propyl]-carbamic acid methyl ester 2-Benzyloxy-4-bromo-pyridine: A mixture of 4-Bromo-I H-pyridin-2-one (0.613 g), silver 5 carbonate (0.63 g) and benzyl bromide (0.50 mL) in benzene (10 mL) was heated at 50*C for 24 hours, protected from light. Reaction mixture stirred ambient temperature for 16 hours. Reaction mixture was filtered through a pad of CELITE, which was washed ethyl acetate. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 2-Benzyloxy-4-bromo-pyridine (0.6043 g): LCMS-ESI*: calc'd 10 for C1 2 H 11 BrNO: 265.12 (M+H*); Found: 263.8, 265.8 (M+H*). 2-{5-[4-(2-Benzyloxy-pyrid in-4-yl)-phenyl ]-1 H-imidazol-2-yl}-pyrrolidine-l-carboxylic acid tert-butyl ester: A mixture of 2-Benzyloxy-4-bromo-pyridine (0.292 g), 2-{5-[4-(4,4,5,5 Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-I H-imidazol-2-yl}-pyrrolidine-l -carboxylic acid 15 tert-butyl ester (0.533 g, prepared according to W02008021927 A2) and Pd(PPh 3

)

4 (0.064 g) in aq. K 2

CO

3 solution/dimethoxyethane (1.82 mL/5.0 mL) was heated at 80-90'C for 8 hours. 467 Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 2-{5-{4-(2-Benzyloxy-pyridin-4-yl)-phenyl]- I H-imidazol-2-yl) pyrrolidine-l-carboxylic acid tert-butyl ester (0.530 g): LCMS-ESIl: calc'd for C 30

H

33

N

4 0 3 : 5 497.6 (M+H*); Found: 497.0 (M+H*). 2-[5-14-(2-Oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: To a solution of 2-{5-[4-(2 Benzyloxy-pyridin-4-yl)-phenyl]-I H-imidazol-2-yl}-pyrrolidine-I -carboxylic acid tert-butyl 10 ester (0.530 g) in DMF (5.0 mL) at 0 0 C was added 60% sodium hydride (0.047 g). After stirring for 5 minutes, 2-(trimethylsilyl)ethoxylmethyl chloride was added and reaction mixture stirred for 2 hours. Saturated ammonium chloride was added and mixture was extracted with ethyl acetate (2x). Organic layer was washed with 5% lithium chloride solution (2x), brine and dried (MgSO 4 ). Concentrated and purified by flash column chromatography (silica gel, 20 to 80% 15 ethyl acetate/hexanes) to give 2-[5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-l -(2-trimethylsilanyl ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine-I -carboxylic acid tert-butyl ester (0.495 g). LCMS-ESl*: calc'd for C 36

H

4 7

N

4 0 4 Si: 627.87 (M+H*); Found: 627.1 (M+H*). A mixture of 2-[5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]- 1 -(2-trimethylsilanyl-ethoxymethyl)- I H-imidazol 2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g) and 10% Pd/C (0.023 g) in ethanol 20 (5.5 mL) was stirred under hydrogen atmosphere for I hour. Reaction mixture was filtered through a pad of Celite, which was washed with methanol. The filtrate was concentrated and purifed by flash column chromatography (silica gel, 0 to 10% methanol/ethyl acetate) to give 2 [5-[4-(2-Oxo-1,2-dihydro-pyridin-4-yl)-phenyl]- I -(2-trimethylsilanyl-ethoxymethyl)-I H imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (0.3027 g): LCMS-ESI*: calc'd for 25 C 2 9

H

4 1

N

4 0 4 Si: 537.47 (M+H); Found: 537.0 (M+H). 2-14-(4-{4-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yI)-3-(2-trimethylsilanyl-ethoxymethyl) 3H-imidazol-4-yI]-phenyl}-2-oxo-2H-pyridin-1-y1)-1 -(2-trimethylsilanyl-ethoxymethyl)-1 H imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: To a solution of 2-[5-[4-(2 30 Oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-I-(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yl] pyrrolidine-I -carboxylic acid tert-butyl ester (0.3027 g) in ethanol (5.0 mL) was added tetrabutylammonium hydroxide (0.375 mL of 1.5 M solution) and reaction mixture stirred for I hour., then concentrated to give a colorless oil. Residue was lyophilized from acetonitrile to give a yellow residue. To this residue was added 2-[4-Bromo-l-(2-trimethylsilanyl 35 ethoxymethyl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (0.301 g, 468 prepared by reacting 2-(4-Bromo-I H-imidazol-2-yl)-pyrrolidine-I-carboxylic acid lert-butyl ester (prepared according to W02008021927 A2) with 2-(trimethylsilyl)ethoxylmethyl chloride using sodium hydride in DMF) and mixture co-evaporated with toluene (15 mL). DMF (1.0 mL) and copper(l) iodide (0.035 g) were added and the reaction mixture was stirred at 95*C for 5 24 hour, protected from light. To the reaction mixture was added tetrabutylammonium iodide (50 mg) and reaction continued for 2 days. Added more 2-[4-Bromo- -(2-trimethylsilanyl ethoxymethyl)-l H-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (0.35 g) and copper(l) iodide (0.050 g) and reaction continued for 24 hours. Reaction mixture was cooled and diluted with ethyl acetate and washed with 3N ammonium hydroxide. The aqueous layer 10 was back-extracted with ethyl acetate (2x). The combined organic layer was washed with 3N ammonium hydroxide, H 2 0, brine and dried (MgSO 4 ) then concentrated and purified by flash column chromatography (silica gel, 0 to 10% isopropanol/hexane) to give impure product that was repurified by preparative reverse phase HPLC (Gemini, 25 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give 2-[4-(4-{4-[2-(l-tert-butylcarbamyl-pyrrolidin-2-yl)-3 15 (2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl}-2-oxo-2H-pyridin-l-yl)-I-(2 trimethylsilanyl-ethoxymethyl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (0.042g): LCMS-ESl*: calc'd for C 4 7

H

72

N

7 0 7 Si 2 : 903.28 (M+H*); Found: 902.2, 903.2 (M+H*). 20 [1-(2-{5-[4-(4-{2-j1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yl)-phenyl)-2-oxo-2H-pyridin-1-yll-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl) 2-methyl-propyl]-carbamic acid methyl ester: 2-[4-(4-{4-[2-(I -tert-butylcarbamyl pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl }-2-oxo-2H pyridin- I -yl)- I -(2-trimethylsilanyl-ethoxymethyl)- 1 H-imidazol-2-yl]-pyrrolidine- I -carboxylic 25 acid tert-butyl ester (0.042g) in dichloromethane (1.0 mL) was treated with trifluoroacetic acid (0.3 mL) for 7 hours at ambient temperature. Reaction mixture was concentrated and dried for I hour under vacuum. Residue was dissolved in DMF (0.7 mL) and to this solution was added 2 Methoxycarbonylamino-3-methyl-butyric acid (0.013 g), 4-methylmorpholine (0.024 mL), followed by HATU (0.028 g). Reaction mixture was stirred for 45 minutes at ambient 30 temperature and then more 4-methylmorpholine (0.024 mL) was added. Reaction continued for 30 minutes, diluted with ethyl acetate and washed with dilute sodium bicarbonate solution, brine and dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give [1-(2-{5-[4-(4-{2-[l-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl} -phenyl)-2-oxo 35 2H-pyridin-1 -yl]- 1H-imidazol-2-yl}-pyrrolidine-l -carbonyl)-2-methyl-propyl]-carbamic acid 469 methyl ester as the bis-TFA salt (0.077 mg): H-NMR: 300 MHz, (CD 3 0D) 8: 8.48 (d, J=7.2, I H), 7.96-7.80 (m, 6H), 7.64 (s, I H), 6.92-6.85 (m, 2H), 5.29-5.17 (m, 2H), 4.26-3.88 (m, 8H), 3.66 (s, 6H), 2.60-2.01 (m, 12H), 0.83-0.75 (m, 12 H); LCMS-ESI+: calc'd for C 39

H

5 oN 9 0 7 : 756.86 (M+H*); Found: 756.3 (M+H*). 5 Example AF1 B NH 2 Boc-Proline Bo B P )4 Br / Br NirANo+ N N\ Pd(PPh 3 ) HATU, DIPEA o H NaHCO 3 4-Bromo- DMF 2-(4-Bromo-benzylcarbamoyl)- 2-{5-[4-(4,4,5,5-Tetramethy- DME/H20 benzylamine pyrrolidine-i-carboxylic acid [1,3,2]dioxaborolan-2-yl)-pheny] tert-butyl ester 1H-imidazol-2-yl}-pyrrolidine-1 carboxylic acid tert-butyl ester H 1. HCI N N /N Boc Boc 2. HATU, NMM N N 0 <\-HO HO 2-({4'-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3H- O O imidazol-4-yl]-biphenyl-4-ylmethyl}-carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester 2-Methoxycarbonylamino-3 methyl-butyric acid -O O NH H N N N o H HN-_ [1-(2-5-[4'-({[1-(2-Methoxycarbonylamino-3-methy-butyryl)-pyrrolidine 2-carbony]-amino-methyl)-biphenyl-4-yl]-1 H-imidazol-2-yl}-pyrrolidine 1-carbonyl)-2-methyl-propyU-carbamic acid methyl ester 2 -(4-Bromo-benzylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: To a mixture 10 of 4-Bromo-benzylamine (2.00 g), Boc-L-proline (2.01 g), and 4-methylmorpholine (3.26 mL) in DMF (40 mL) was added H ATU (3.48 g). Reaction mixture was stirred for 45 minutes, then concentrated, diluted with dichloromethane and washed with 10:1 H 2 0/saturated sodium bicarbonate solution. The aqueous layer was back-extracted with dichloromethane and the combined organic layers were dried (MgSO 4 ), concentrated and purified by flash column 15 chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give 2-(4-Bromo benzylcarbamoyl)-pyrrolidine-l-carboxylic acid tert-butyl ester (3.38 g): LCMS-ESI*: calc'd for C 17

H

24 BrN 2 NaO 3 : 405.29 (M+Na'); Found: 405.0 (M+Na*). 2-({4'-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3H-imidazol-4-y]-biphenyl4-yI methyl} 20 carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-(4-Bromo benzylcarbamoyl)-pyrrolidine-I -carboxylic acid tert-butyl ester (0.257 g), 2-(5-[4-(4,4,5,5 470 Tetramethyl-[1,3,2]dioxaborolan-2-yI)-phenyl]- 1 H-imidazol-2-yl}-pyrrolidine- I -carboxylic acid tert-butyl ester (0.309 g, prepared according to W02008021927 A2), NaHCO 3 (0.186 g) and Pd(PPh 3

)

4 (0.064 g) in H 2 0 (2.0 mL)/dimethoxyethane (6.0 mL) was heated at 80'C for 16 hours. Reaction mixture was cooled and concentrated. Residue was dissolved in 5 dichloromethane, washed with H 2 0. Aqueous layer was back-extracted with dichloromethane and combined organic layer was dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give 2-({4'-[2-(l-tert butylcarbamyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-4-yl methyl}-carbamoyl) pyrrolidine-l-carboxylic acid tert-butyl ester (0.280 g): LCMS-ESI*: calc'd for C 3 5

H

46

N

5 0 5 : 10 616.76 (M+H*); Found: 616.1 (M+H*). [1-(2-{5-[4'-({[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl] amino}-methyl)-biphenyl-4-yl]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl propyl]-carbamic acid methyl ester: 2-({4'-[2-(l -tert-butylcarbamyl-pyrrolidin-2-yl)-3H 15 imidazol-4-yl]-biphenyl-4-ylmethyl } -carbamoyl)-pyrrolidine- I -carboxylic acid tert-butyi ester (0.280 g) in dichloromethane (5.0 mL) was treated with 4N HCI in dioxane (3.0 mL) for 2 hours at ambient temperature. Reaction mixture was concentrated and dried overnight under vacuum to give a yellow powder (0.2548 g). Yellow powder (0.129 g) was dissolved in DMF (2.0 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.090 g), 4 20 methylmorpholine (0.136 mL), followed by HATU (0.192 g). Reaction mixture was stirred for 90 minutes at ambient temperature and then concentrated. Residue was dissolved in dichloromethane and washed with dilute sodium bicarbonate solution. The aqueous layer was back-extracted with dichloromethane and the combined organic layers were dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 25 0.1% TFA). Product was lyophilized to give [l-(2-{5-[4'-({[-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidine-2-carbonyl]-amino}-methyl)-biphenyl-4-yl]- IH-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester as the bis-TFA salt (0.089 mg). H-NMR: 300 MHz, (DMSO-d 6 ) 8: 8.40-8.37 (m, I H), 8.02 (s, I H), 7.83 (d, J=8.4, 2H), 7.72 30 (d, J=8.1, 2H), 7.63 (d, J=8.4, 2H), 7.37-7.29 (m, 3H), 4.90-4.87 (m, I H), 4.35-4.28 (m, 3H), 4.03-3.95 (m, 4H), 3.90-3.80 (m, 3H), 3.53 (s, 6H), 2.30-1.80 (m, IOH), 0.90 (d, J=6.9, 3H), 0.86 (d, J=6.3, 3H), 0.78 (d, J=6.6, 3H), 0.68 (d, J=6.9, 3H). LCMS-ESI~: calc'd for C 39

H

50

N

7 0 7 : 728.86 (M-H+); Found: 728.2 (M-H*). 35 471 Example AGI -- NH 2 Boc-Proline H N O Br N HATU, NMM BN NBoc + Boc BO NBr 0N-- N - N'0O 6-Bromo-isoquinolin-1 ylamine 2-(6-Bromo-isoquinolin-1- 2-{5-[4-(4,4,5,5-Tetramethyl ylcarbamoyl)-pyrrolidine-1- [1,3,2]dioxaborolan-2-yl)-phenyl] carboxylic acid tert-butyl ester 1H-imidazol-2-yl}-pyrrolidine-1 carboxylic acid tert-butyl ester 1. HCI Pd(PPh 3

)

4 N \ fN aHPBhs)4 Boc N Boc 2. HATU, NMM NaHCO 3 N NN

DME/H

2 0 H O 2-(6-{4-(2-(1-tert-butycarbamyl-pyrrolidin- H 2-yl)-3H-imidazol-4-yl]-phenyl)- H isoquinolin-1-ylcarbamoyl)-pyrrolidine-1- O carboxylic acid tert-butyl ester 2-Methoxycarbonylamino-3 O methyl-butyric acid H H ,L- N N N O [1 -(2-{5-[4-(1-{[1-(2-Methoxycarbonylamino-3- methyl butyryl)-pyrrolidine-2-carbonyl]-amino}-isoquinolin-6 yl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2 methyl-propyl]-carbamic acid methyl ester 2-(6-Bromo-isoquinolin-1-yl carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: To 5 a mixture of6-Bromo-isoquinolin-1-ylamine (0.80 g), Boc-L-proline (0.803 g), and 4 methylmorpholine (0.83 mL) in DMF (10 mL) was added HATU (1.39 g). Reaction mixture was stirred for 6 hours. Additional Boc-L-proline (0.803 g), 4-methylmorpholine (0.83 mL) and HATU (1.39 g) were added and reaction stirred overnight at ambient temperature and then concentrated. The residue was dissolved in ethyl acetate and washed with 10:1 H 2 0/saturated 10 sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 20 to 70% ethyl acetate/hexanes) to give 2-(6-Bromo-isoquinolin- I -yl carbamoyl)-pyrrolidine- I -carboxylic acid tert-butyl ester (1.74 g): LCMS-ESI*: calc'd for Cl 9

H

23 BrN 3 0 3 : 421.31 (M+H*); Found: 419.8, 421.8 (M+H*). 15 2-(6-{4-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3H-imidazol-4-y]-phenyl}-isoquinolin-1 yI carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture 2-(6-Bromo isoquinolin-I -yl carbamoyl)-pyrrolidine-I -carboxylic acid tert-butyl ester (0.426 g), 2-{5-[4 (4,4,5,5-Tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I H-imidazol-2-y }-pyrrolidine-1 472 carboxylic acid tert-butyl ester (0.405 g, prepared according to W02008021927 A2), and Pd(PPh 3

)

4 (0.053 g) in 2M aq. K 2

CO

3 (1.4 mL)/dimethoxyethane (3.0 mL) was heated at 90'C for 16 hours. Reaction mixture was cooled and diluted with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 50 to 5 100% ethyl acetate/hexanes) to give 2-(6-{4-[2-(l-tert-butylcarbamyl-pyrrolidin-2-yl)-3H imidazol-4-yl]-phenyl}-isoquinolin-I-ylcarbamoyl)-pyrrolidine-l-carboxylic acid tert-butyl ester (0.272 g): LCMS-ESI*: calc'd for C 3 7

H

4 5

N

6 0 5 : 653.78 (M+H*); Found: 653.1 (M+H*). i-(2-{5-[4-(1-{[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl] 10 amino}-isoquinolin-6-yI)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl propyl]-carbamic acid methyl ester: 2-(6-{4-[2-(] -tert-butylcarbamyl-pyrrolidin-2-yl)-3H imidazol-4-yl]-phenyl}-isoquinolin-l-yl carbamoyl)-pyrrolidine-l -carboxylic acid tert-butyl ester (0.272 g) in dichloromethane (5.0 mL) was treated with 4N HCI in dioxane (5.0 mL) for 2 hours at ambient temperature. Reaction mixture was concentrated and suspended in ethyl ether. 15 The solid was collected by filtration, washed with ethyl ether and dried overnight under vacuum to give a yellow powder (0.2279 g). Yellow powder (0.1005 g) was dissolved in DMF (1.5 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.061 g), 4 methylmorpholine (0.092 mL), followed by HATU (0.130 g). Reaction mixture was stirred for I hour at ambient temperature and then diluted with ethyl acetate and washed with dilute sodium 20 bicarbonate solution, brine and dried (MgSO 4 ). Organic layer was concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give [1 -(2-{5-[4-(1-{[l-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine 2-carbonyl]-amino}-isoquinolin-6-yl)-phenyl]-I H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-2 methyl-propyl}-carbamic acid methyl ester as the bis-TFA salt (0.093 mg). 25 'H-NMR: 300 MHz, (DMSO-d 6 ) 8: 8.36 (s, I H), 8.30-8.15 (m, 2H), 8.13 (s, I H), 8.05-7.95 (m, 3 H), 7.88 (d, J=8.7, 2H), 7.70 (d, J=8.4, I H), 7.32 (d, J=8.7, 1 H), 7.29 (d, J=8.7, I H), 5.10-5.05 (m, I H), 4.70-4.65 (m, I H), 4.10-3.908 (m, 3H), 4.03-3.95 (m, 4H), 3.90-3.80 (m, 3H), 3.49 (s, 6H), 2.39-1.80 (m, 10H), 0.90-0.70 (m, 12H): LCMS-ESI~: calc'd for C 4 1

H

5 1

N

8 0 7 : 767.89 (M+H*); Found: 767.2 (M+H*). 30 473 Example AHI 0 ,0 0 0 1. Boc-proline HO 1. SOC1 2 Br O DIPEA, ACN OH 2. TMSCH 2

N

2 Br 2. NH 4 0Ac 3. HBr Toluene, 100 C 5,5-Dioxo-5H-5X 6 - 2-Bromo-1 -[7-(2-bromo-acetyl) dibenzothiophene-3,7- 5,5-dioxo-5H-5X 6 dicarboxylic acid dibenzothiophen-3-yl]-ethanone H 1. HCI N BoN \ / - \INI B NH - N Boc 2. HATU, NMM

O

HO 4\ 2-(5-{7-[2-(1 -tertbutyl-carbamyl-pyrrolidin-2-yl)- HO0 3H-imidazol-4-yl]-5,5-dioxo-5H-5X 6 - 2-Methoxycarbonylamino-3 dibenzothiophen-3-yl}- 1 H-imidazol-2-yl)- methyl-butyric acid pyrrolidine-1-carboxylic acid tert-butyl ester 0- Ox,~ O 0_ 0 o HN N 0 NH ,0 (1 -{2-[5-(7-{2-[1 -(2-Methoxy carbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-y}-5,5-dioxo-5H-5x 6 dibenzothiophen-3-yl)-1 H-imidazol-2-y1]-pyrroIidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-Bromo-1 -[7-(2-bromo-acetyl)-5,5-dioxo-5H-5k6-d ibenzoth iophen-3-yl]-ethanone: A 5 mixture of 5,5-Dioxo-5H-5X 6 -dibenzothiophene-3,7-dicarboxylic acid (10.85 g, prepared according to OL' Khouk et. Al. Russian J. Org. Chem. 2006, 42(8) 1164-1168) and oxalyl chloride (31.11 mL) in dichloromethane (250 mL) containing DMF (0.2 mL) was stirred at ambient temperature for 6 hours. A small amount of solid material was removed by filtration and the filtrate was concentrated to give a brown solid. 10 This brown solid was suspended in dichloromethane and cooled to 0*C. To this mixture was added 2.OM (trimethylsilyl)diazomethane in hexane (52.5 mL) and warmed to ambient temperature over 16 hours. Reaction mixture was concentrated providing a brown residue. The resulting brown residue was suspended in ethyl acetate (200 mL) and cooled to 0 0 C. 5.7M Hydrobromic acid in acetic acid (15.3 mL) was added slowly and stirred for 1 hour at 0 0 C, then 15 1 hour at ambient temperature. The reaction mixture was quenched with solid sodium 474 bicarbonate and stirred for 30 minutes Saturated sodium bicarbonate solution was added, giving a brown precipitate. The solid was collected, washed with H 2 0, ethyl acetate and dried under vacuum to give 2-Bromo-l -[7-(2-bromo-acetyl)-5,5-dioxo-5H-5X-dibenzothiophen-3-yl] ethanone as a brown solid (25 g): LCMS-ES~: calc'd for C 16 H 11 Br 2 0 4 S: 459.12 (M+H*); 5 Found: no product mass observed. 2-(5-{7-[2-(1-tertbutyl-carbamyl-pyrrolidin-2-y)-3H-imidazol-4-yl]-5,5-dioxo-5H-5.

6 dibenzothiophen-3-yI)-1H-imidazol-2-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-Bromo-l-[7-(2-bromo-acetyl)-5,5-dioxo-5 H-5X 6 -dibenzothiophen-3-yl]-ethanone 10 (25 g), Boc-L-proline (15.82 g) and diisopropylethylamine (12.6 mL) in acetonitrile (300 mL) was stirred for 3 hours at ambient temperature. Reaction mixture was concentrated and residue dissolved in ethyl acetate, washed with brine and back-extracted with ethyl acetate (3x). The combined organic layer was washed with brine, dried (MgSO 4 ) and purified by flash column chromatography (silica gel, 20 to 800% ethyl acetate/hexanes) to give yellow foam (10 g). 15 LCMS-ESI~: calc'd for C 36

H

4

IN

2 0 1 2 S: 725.79 (M-H*); Found: 725.1 (M-H). A mixture of the yellow foam (7 g) and ammonium acetate (3.72 g) in xylenes (20 mL) was stirred at 120 0 C for 3.5 hours and then cooled. Diluted with ethyl acetate and washed with dilute sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3x), then dichloromethane containing methanol (3x). The combined organic layer was dried (MgSO 4 ), 20 concentrated and purified by flash column chromatography (silica gel, 0 to 5% methanol/ethyl acetate) to give 2-(5-{7-[2-(I-tert-butyl-carbamyl-pyrrolidin-2-yl)-3 H-imidazol-4-yl]-5,5-dioxo 5H-5W-dibenzothiophen-3-yl}-I H-imidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (4.56 g): LCMS-ESI: calc'd for C 3 6

H

43

N

6 0 6 S: 687.82 (M+H*); Found: 687.0 (M+H*). 25 (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yI)-5,5-dioxo-5H-5) 6 -dibenzothiophen-3-yI)-I H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: 2-(5-{7-[2-(l -tertbutyl-carbamyl pyrrolidin-2-yl)-3 H-imidazol-4-yl]-5,5-dioxo-5H-5 6 -dibenzothiophen-3-y}- I H-imidazol-2-yl) pyrrolidine-I-carboxylic acid tert-butyl ester (4.56 g) in dichloromethane (50 mL) was treated 30 with 4N HCI in dioxane (50 mL) for 3 hours at ambient temperature. Reaction mixture was concentrated, triturated with ethyl ether and the orange solid dried overnight under vacuum. A portion of this orange solid (0.15g) was dissolved in DMF (2.5 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.187 g), 4-methylmorpholine (0.13 mL), followed by HATU (0.184 g). Reaction mixture was stirred for I hour at ambient 35 temperature and then diluted with ethyl acetate, washed with dilute sodium bicarbonate solution, 475 5% lithium chloride solution, brine dried (MgSO 4 ). Concentration and purification by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA) and lyophilization gave (I -{2-[5-(7-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2 -yl]-3 H-imidazol-4-yl} -5,5-dioxo-5 H-5X-dibenzothiophen-3-yI)- I H-imidazol-2-yl] 5 pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt (0.150 mg): 1 H-NMR: 300 MHz, (DMSO-d 6 ) 8: 8.40-8.14 (m, 8H), 7.33 (d, J=8.1, 2H), 5.13-5.10 (m, 2H), 4.13-4.07 (m, 2H), 3.90-3.80 (m, 4H), 3.53 (s, 6H), 2.34-1.98 (m, 10H), 0.85 (d, J=6.6, 6H), 0.81 (d, J=6.6, 6H). LCMS-ESI: calc'd for C 40

H

4 9

N

8 0 8 S: 801.92 (M+H*); Found: 801.2 (M+H*). 10 Example AIl B r~S+r Br Pd(PPh 3

)

4 Bo Br Boc B\ Boc \/ N H0 N NH 2,5-Dibromo- K 2 C0 3 Uthiophene

DMVE/H

2 0 2-{5-[4-(4,4,5,5-Tetramethyl- 2-{5-[4-(5-Bromo-thiophen-2-y) [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H- phenyl]-1 H-imidazol-2-yl}-pyrrolidine imidazol-2-yl}-pyrrolidine-1-carboxylic 1-carboxylic acid tert-butyl ester acid tert-butyl ester Bis(pinacolato) S U-0 N diboron N Bo+ Br N Pd(PPh 3

)

4 IN Boc1 \ B 0 N, NH /NH BocC0 Pd(PPh 3

)

4 2-(4-Bromo-1 H-imidazol-2- Na HCO 3 DMF 2-(5-{4-[5-(4,4,5,5-Tetramethyl- yl)-pyrrolidine-1 -carboxylic DME/H 2 0 [1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]- acid tert-butyl ester phenyl}-1 H-imidazol-2-yl)-pyrrolidine-1 carboxylic acid tert-butyl ester H f N\s N ) 1.HCI Boc NH N Boc 2. HATU, NMM N/ NH 2-[5-(5-{4-[2-(1 -tert- HO 0 butylcarbamyl-pyrrolidin-2-y)-3H- N imidazol-4-yl]-phenyl}-thiophen-2- H 0 yl)-1 H-imidazol-2-yl]-pyrrolidine 1-carboxylic acid tert-butyl ester 2-Methoxycarbonylamino-3 methyl-butyric acid 0 0 N' H H , ON H ~~ K ~ N \ - S N T 'j( N N N HH N Os0 0 [1 -(2-{5-[4-(5-{2-(1-(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yIl-3H-imidazol-4-yl)-thiophen-2 yl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2 methyl-propyl]-carbamic acid methyl ester 476 2-{5-[4-(5-Bromo-thiophen-2-yi)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carboxylic acid tert-butyl ester: A mixture of 2,5-Dibromo-thiophene (4.93 g), 2-{5-[4-(4,4,5,5-Tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]- IH-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.896 g, prepared according to W02008021927 A2), and Pd(PPh 3

)

4 (0.118 g) in 2M 5 K 2

CO

3 (3.06 mL)/dimethoxyethane (6.12 mL) was heated at 90*C for 8 hours. Reaction mixture was cooled, diluted with ethyl acetate and washed with brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give 2 {5-[4-(5-Bromo-thiophen-2-yl)-phenyl]- IH-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert butyl ester (0.955 g): LCMS-ESI+: calc'd for C 2 2

H

2 5 BrN 3 0 2 S: 475.42 (M+H*); Found: 473.8, 10 475.9 (M+H'). 2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2 ]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-1 H imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-{5-[4-(5 Bromo-thiophen-2-yl)-phenyl]-I H-imidazol-2-yl}-pyrrolidine-I -carboxylic acid tert-butyl ester 15 (0.4807 g), bis(pinacolato)diboron (0.54 g), Pd(PPh 3

)

4 (0.058) and potassium acetate (0.257 g) in 1,4-dioxane was heated at 90*C for 16 hours. Reaction mixture was cooled to ambient temperatures and diluted with ethyl acetate. Organic layer was washed with brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) 20 thiophen-2-yl]-phenyl}-i H-imidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (0.3752 g) as a brown foam: LCMS-ESI*: calc'd for C 2 8

H

3 7

BN

3 0 4 S: 522.48 (M+H+); Found: 521.9 (M+H-). 2-[5-(5-{4-12-(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2 25 yl)-1H-imidazol-2-yI]-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-(5-{4 [5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-I H-imidazol-2-yl) pyrrolidine-I-carboxylic acid tert-butyl ester (0.1050 g), 2-(4-Bromo-I H-imidazol-2-yl) pyrrolidine- I -carboxylic acid tert-butyl ester (0.070 g, prepared according to W02008021927 A2) and Pd(PPh 3

)

4 (0.012 g) in 2.OM sodium bicarbonate solution (0.33 mL) and 30 dimethoxyethane (0.66 mL) was stirred under microwave irradiation at 120'C for 20 minutes. Reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give 2-[5-(5-{4-[2-(I-tert-butylcarbamyl-pyrrolidin-2-yl)-3H-imidazol-4-yl] phenyl}-thiophen-2-yl)- IH-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (0.069 477 g) as a brown foam: LCMS-ESI*: calc'd for C 3 4

H

4 3

N

6 0 4 S: 631.80 (M+H+); Found: 631.0 (M+H*). [1-(2-{5-[4-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yI]-3H 5 imidazol-4-yl}-thiophen-2-yI)-phenyll-1H-imidazol-2-yl}-pyrrolidine-l-carbonyl)-2-methyl propyll-carbamic acid methyl ester: 2-[5-(5-{4-[2-(1 -tert-butylcarbamyl-pyrrolidin-2-yl)-3H imidazol-4-yl]-phenyl}-thiophen-2-yl)-1 H-imidazol-2-yi]-pyrrolidine-I -carboxylic acid tert butyl ester (0.069 g) in dichloromethane (3.0 mL) was treated with 4N HCI in dioxane (3.0 mL) for 30 minutes at ambient temperature. Reaction mixture was concentrated and dried overnight 10 under vacuum to give a reddish-brown solid (0.084 g). Residue was dissolved in DMF (1.0 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.053 g), 4 methylmorpholine (0.083 mL), followed by HATU (0.113 g). Reaction mixture was stirred for 1 hour at ambient temperature then diluted with ethyl acetate, washed with dilute sodium bicarbonate solution, 5% lithium chloride solution, brine, then dried (MgSO 4 ). Concentration 15 and purification by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA) and lyophilization gave [1-(2-{5-[4-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-thiophen-2-yl)-phenyl]-I H-imidazol-2-yl} pyrrolidine-l-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester as the bis-TFA salt (0.040 mg). 20 1 H-NMR: 300 MHz, (DMSO-d 6 ) 8: 8.09 (s, 1 H), 7.81 (br s, 4H), 7.65-7.60 (m, I H), 7.45-7.40 (m, I H), 7.402-7.30 (m, 21H), 5.20-5.00 (m, 2H), 4.10 (q, J=6.9, 3H), 3.90-3.80 (m, 3H), 3.53 (s, 6H), 2.40-1.90 (m, 10 H), 0.90-0.76 (m, 12H): LCMS-ESI~: calc'd for C 38

H

49

N

8 0 6 S: 745.90 (M+H*); Found: 745.2 (M+H*). 478 Example AJ1 SEM -N N N Br SEM-CI, NaH Br + Br SEM 5-(4-Broo-phenyl)-MF 5-(4-Bromo-phenyl)-1 -(2- 4-(4-Bromo-phenyl)-1 -(2 1H-imidazole trimethylsilanyl- trimethylsilanyl-ethoxymethyl) ethoxymethyl)-1 H-imidazole 1 H-imidazole + H N N / O Pd(PPh 3

)

4 Boc I / -- a N 0 NaHCO 3 2-(5-[4-(4,4,5,5-Tetramethyl-

DME/H

2 0 [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2 yl}-pyrrolidine-1-carboxylic acid tert-butyl ester H SEM H <N N - N N N / \N Bo N BoN-/ \SEM 2-(5-{4'-[3-(2-Trimethylsilanyl-ethoxymethyl)- 2-(5-{4'-[1 -(2-Trimethylsilanyl-ethoxymethyl) 3H-imidazol-4-yl]-biphenyl-4-y)-1 H-imidazol-2- 1 H-imidazol-4-yl]-biphenyl-4-yl}-1 H-imidazol-2 yi)-pyrrolidine-1-carboxylic acid tert-butyl ester yi)-pyrrolidine-1-carboxylic acid tert-butyl ester 0 1. HCI 0 N' H 2. HATU, NMM N ~ HO H O H 0 [1-(2-{5-[4'-(3H-Imidazol-4-yl) 2-Methoxycarbonylamino-3- biphenyl-4-yl]-1H-imidazol-2-yl} methyl-butyric acid pyrrolidine-1-carbonyl)-2-methyl propyl]-carbamic acid methyl ester 5 5-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole and 4-(4-Bromo phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-I H-imidazole: To a solution of 5-(4-Bromo phenyl)-I H-imidazole (0.997 g) in DMF (15.0 mL) at 0C was added 60% sodium hydride (0.197 g). After stirring for 5 minutes, 2-(trimethylsilyl)ethoxylmethyl chloride (1.18 mL) was added and reaction mixture stirred for 2 hours. Reaction mixture was concentrated, dissolved in 10 ethyl acetate. Organic layer was washed with 5% lithium chloride solution (2x), brine and dried (MgSO 4 ). Concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a 1:1 mixture of 5-(4-Bromo-phenyl)-1-(2-trimethylsilanyl ethoxymethyl)-l H-imidazole and 4-(4-Bromo-phenyl)-I-(2-trimethylsilanyl-ethoxymethyl)-1

H

imidazole (0.89 g): LCMS-ESI*: calc'd for CisH 22 BrN 2 OSi: 354.33 (M+H); Found: no 15 product mass observed. 479 2-(5-{4'-[3-(2-Trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yI]-biphenyl-4-yi-1

H

imidazol-2-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-(5-{4'-[1-(2 Trimethylsilanyl-ethoxymethyl)- 1 H-imidazol-4-yi]-biphenyl-4-y}-1 H-imidazol-2-yi) pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 1:1 mixture of 5-(4-Bromo 5 phenyl)-I-(2-trimethylsilanyl-ethoxymethyl)-l H-imidazole and 4-(4-Bromo-phenyl)- 1-(2 trimethylsilanyl-ethoxymethyl)-l H-imidazole (0.145 g), 2-{5-[4-(4,4,5,5-Tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]- IH-imidazol-2-yl}-pyrrolidine-I-carboxylic acid tert-butyl ester (0.150 g, prepared according to W02008021927 A2) and Pd(PPh 3

)

4 (0.020 g) in aq.

K

2

CO

3 solution (0.51 mL)/ dimethoxyethane (1.5 mL) was heated at 80*C for 18 hours. 10 Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO 4 ) and concentrated. The residue was purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give a 1:1 mixture 2-(5-{4'-[3-(2-Trimethylsilanyl-ethoxymethyl)-3H imidazol-4-yl]-biphenyl-4-yl}-1 H-imidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester and 2-(5-{4'-[ 1 -(2-Trimethylsilanyl-ethoxymethyl)-I H-imidazol-4-yl]-biphenyl-4-yl } -1H 15 imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (0.0998 g): LCMS-ESI+: calc'd for

C

3 3

H

4 4

N

5

O

3 Si: 586.82 (M+H+); Found: 586.0 (M+H*). I1-(2-{5-[4'-(3H-Imidazol-4-yI)-biphenyl-4-yl]-1H-imidazol-2-yI}-pyrrolidine-1-carbonyl) 2-methyl-propyll-carbamic acid methyl ester: A 1:1 mixture 2-(5-{4'-[3-(2-Trimethylsilanyl 20 ethoxymethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-I H-imidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester and 2-(5-{4'-[1-(2-Trimethylsilanyl-ethoxymethyl)-1 H-imidazol-4-yl] biphenyl-4-yl}-1 H-imidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (0.0998 g) in dichloromethane (3.0 mL) was treated with trifluoroacetic acid (3.OmL) for 18 hours at ambient temperature. Reaction mixture was concentrated, co-evaporated with acetonitrile and purified 25 by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA) and concentrated to give a yellow film (0.087 g). Residue was dissolved in DMF (1.0 mL) and to this solution was added 2 -Methoxycarbonylamino-3-methyl-butyric acid (0.023 g), 4 methylmorpholine (0.055 mL), followed by HATU (0.049 g). Reaction mixture was stirred for I hour at ambient temperature, diluted with ethyl acetate and washed with dilute sodium 30 bicarbonate solution, brine and dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give [I (2-{5-[4'-(3 H-Imidazol-4-yl)-biphenyl-4-yl]- IH-imidazol-2-yl}-pyrrolidine-l -carbonyl)-2 methyl-propyl]-carbamic acid methyl ester as the bis-TFA salt (0.016 mg): 'H-NMR: 300 MHz, (DMSO-d 6 ) 6: 9.10 (s, I H), 8.20 (s, I H), 8.05 (br s, I H), 7.93-7.80 (in, 8H), 7.32 (d, 35 J=7.8, I H), 5.20-5.12 (m, I H), 4.15-4.05 (m, I H), 3.85-3.80 (m, 3 H), 3.54 (s, 3 H), 2.40-1.85 (m, 480 6H), 0.83 (d, J=7.2, 3H), 0.80 (d, J=6.9, 31-): LCN4S-ESI+: calc'd for C 29

H

33

N

6 0 3 : 513.61 (M+H+); Found: 513.1 (M+H 4 ). 5 Examples AMi and AUl 1. Boc- proline N2 HATU, NMM BH 0 Br / NH 2 .tH N Boc 4-roo-bezee- 110-130 C B ,-dom iezne- 2-(6-Bromo-1 H--benzoimidazol- 1 ,4-benzenediboronic 12daie2-y)-pyoidne- 1arboxylc acid, pinacol ester acid tert-butyl ester N NBoc N -- B dPh) Pcl(PPh ) 4 o-Boc i r P1Pn)

K

2 0 3 OM B N + N N K2O/d -0 - Q : kH NaHCO 3 2-{6-[4-(4,4,5,5-Tetramethy- 2-(5-Bromo-1H-imidazol-2 [1 ,3,2]dioxaborolan-2-y)-phenyl]-lH- yI)-pyrrolidine-1-carboxylic benzoimidazol-2-y)-pyrrolidine-1 - acid tert-butyl ester carboxylic acid tert-butyl ester H N N0cN N + ' o N ~~~ N NBc 1 B!!a N N A IH H 2-(6-(4-[2-(l -tert-butyca ramyI-pyrroIidin-2-y)-3H- 2-(64{4'-[2-(l -tert-butylca rba myl-pyrrolid in-2-y)-3H i miclazol-4-yl]-phenyl)-1I H-benzoimidazo-2-yI). benzoimidazl-5-yi]-bi phenyl-4-y}- 1 H-benzoimidazol pyrrolidine- 1-carboxylic acid tert-butyl ester 2-yI)-pyrrolidine-l-carboxylic acid tert-butyl ester 1. HOI 1. HCI 2. HATU, NMM 2. HATU, NMM HO 0 0 2-Methoxyr-arbonylamino-3- -2-Methoxycarbonylamino-3 0methyl-butyric acdd H , methyl-butyric acid N N \N / \ \NAN H (1 -{2-[5-(4-{2-[1 -(2- Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-benzoimidazol-5-y} phenyl)-l H-imidazol-2-yl]-pyrrolidine-l -carbony) mettiyl-propyl)-carbamic acid methyl esterH o~~N N )..<N \N /0 /\ .\ N (1 -{2-[6-(4-{2-[1 -(2-Methoxycarbonylamino-3-methyl-butyry)-pyrrolidin 2-yI]-3H-benzoimidazol-5y}-biphenyl-4-y)-1 H--benzoimidazol-2-ylJ. pyrralidine-1-carbonyl)-2-methyl-propyf)-carbamic acid methyl ester 481 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: To a mixture of 4-Bromo-benzene-1,2-diamine (5.0 g), Boc-L-proline (6.0 g), and 4 methylmorpholine (5.88 mL) in DMF (100 mL) was added HATU (10.7 g). Reaction mixture was stirred for 16 hours and then concentrated. Residue was dissolved in ethyl acetate and 5 washed with 5% lithium chloride solution (2x), brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 30 to 60% ethyl acetate/hexanes) to a dark brown foam. Brown foam was dissolved in ethanol (100 mL) and heated in a sealed tube at I 10 130'C for 2 days. Reaction mixture was cooled and concentrated. Residue was dissolved in ethyl acetate and extracted with IN HCI (3x). Aqueous layer was basified with 50% NaOH 10 solution to pH 10 and extracted with ethyl acetate (2x). The organic layer was dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 0 to 10% isopropanol/hexanes) to give 2-(6-Bromo- I H-benzoimidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl ester (6.5 g) as an off-white foam: LCMS-ESI*: calc'd for C, 6

H

21 BrN 3 0 2 : 367.26 (M+H*); Found: 365.8, 367.8 (M+H*). 15 2-{6-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-benzoimidazol-2-yl} pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture 2-(6-Bromo- H-benzoimidazol-2 yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (0.257 g), 1,4-benzenediboronic acid, pinacol ester (1.158 g), Pd(PPh 3

)

4 (0.041 g) and potassium carbonate (0.485 g) in H 2 0 (2.0 20 mL)/dimethoxyethane (5.0 mL) was heated in microvave at 120'C for 30 minutes. Reaction mixture was cooled and diluted with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 20 to 70% ethyl acetate/hexanes) to give 2-{6-[4-(4,4,5,5-Tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I

H

benzoimidazol-2-yl}-pyrrolidine-l-carboxylic acid tert-butyl ester (0.187 g): LCMS-ESI: 25 calc'd for C 2 8

H

3 7

BN

3 0 4 : 490.42 (M+H*); Found: 490.0 (M+H*). 2-(6-{4-12-(1-tert-butylcarbamyl-pyrrolidin-2-y)-3H-imidazol-4-yl]-phenyl}-1

H

benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-{6-[4 (4,4,5,5-Tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I H-benzoimidazol-2-yl}-pyrrolidine-l 30 carboxylic acid tert-butyl ester (0.116 g), 2-(5-Bromo- IH-imidazol-2-yl)-pyrrolidine- 1 carboxylic acid tert-butyl ester (0.112 g, prepared according to W02008021927 A2) and Pd(PPh 3

)

4 (0.014 g) in 2.OM potassium carbonate solution (0.35 mL) and dimethoxyethane (1.0 mL) was heated at 90*C for 6 hours. Additional Pd(PPh 3

)

4 (0.014 g) was added and reaction continued for 12 hours. Reaction mixture was cooled, diluted with ethyl acetate, washed with 35 H 2 0, brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica 482 gel, I to 30% isopropanol/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100%

ACN/H

2 0 + 0.1% TFA) to give 2 -(6-{4-[2-(I-tert-butylcarbamyl-pyrrolidin-2-y)-3H-imidazol 4-yl]-phenyl } -I H-benzoimidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl ester (0.035 g) as a bis-TFA salt: LCMS-ESI*: calc'd for C 3 4

H

4 3

N

6 0 4 : 599.74 (M+H*); Found: 599.1 (M+H*). 5 A reaction side-product was also isolated and determined to be 2-(6-{4'-[2-(1-ter butylcarbamyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-ylI]-biphenyl-4-yl}- I H-benzoimidazol-2 yi)-pyrrolidine-l-carboxylic acid tert-butyl ester (0.013 g) as the bis-TFA salt: LCMS-ESI*: calc'd for C 44

H

49

N

6 0 4 : 725.89. (M+H*); Found: 725.1 (M+H*). 10 (1-{ 2

-[

5

-(

4

-{

2 -[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yl)-phenyl)-1 H-imidazol-2-ylJ-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester: 2-(6-{4-[2-(I-tert-butylcarbamyl-pyrrolidin-2-yI)-3H-imidazol-4 yl]-phenyl} -l H-benzoimidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl ester (0.035 g) in dichloromethane (1.0 mL) was treated with 4N HCI in dioxane (1.0 mL) for I hour at ambient 15 temperature. Reaction mixture was concentrated and dried under vacuum. The residue was dissolved in DMF (1.0 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl butyric acid (0.0 155 g), 4-methylmorpholine (0.023 mL), followed by HATU (0.033 g). Reaction mixture was stirred for 1 hour at ambient temperature and then diluted with ethyl acetate and washed with dilute sodium bicarbonate solution, 5% lithium chloride solution, brine 20 and dried (MgSO 4 ). Organic layer was concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (1-{2-[5 (4-{ 2-[I-( 2 -Methoxycarbonylamino-3-methyl-butyry1)-pyrrolidin-2-yl]-3H-benzoimidazo1-5 yl}-phenyl)-I H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt (0.0226 g). 25 1 H-NM R: 300 MHz, (CD 3 0D) 8: 7.98 (s, i H), 7.90-7.70 (m, 8H), 5.32 (t, J=6.9, I H), 5.21 (t, J=6.9, IH), 4.22 (dd, J=10.8, 6.9, 2H), 4.10-3.80 (m, 4H), 3.61 (s, 6H), 2.65-1.80 (m, 10H), 0.950-0.80 (m, 12H): LCMS-ESI~: calc'd for C 3 8

H

4 9

N

8 0 6 : 713.84 (M+H*); Found: 713.3 (M+H'). Example AL1 30 (1-{2-[6-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H benzoimidazol-5-yl}-biphenyl-4-yl)-1H-benzoimidazol-2-ylI]-pyrrolidine-I-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: 2-(6-{4'-[2-(1 -tert-butylcarbamyl-pyrrolidin-2 yl)-3H-benzoimidazol-5-yl]-biphenyl-4-yl}-1 H-benzoimidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (0.013 g) in dichloromethane (1.0 mL) was treated with 4N HCI in dioxane 35 (1.0 mL) for 1 hour at ambient temperature. Reaction mixture was concentrated and dried under 483 vacuum. The residue was dissolved in DMF (1.0 mL) and to this solution was added 2 Methoxycarbonylamino-3-methyl-butyric acid (0.0155 g), 4-methylmorpholine (0.023 mL), followed by HATU (0.033 g). After stirring for 1 hour at ambient temperature, additional 2 Methoxycarbonylamino-3-methyl-butyric acid (0.0 155 g), HATU (0.033 g) were added 5 followed by 4-methylmorpholine (0.023 mL). After stirring for 30 minutes, reaction mixture was diluted with ethyl acetate and washed with dilute sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO 4 ). Organic layer was concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (I -{2-[6-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 10 2-yl]-3 H-benzoimidazol-5-yl}-biphenyl-4-yl)-I H-benzoimidazol-2-yl]-pyrrolidine-I -carbonyl} 2-methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt (0.0106 g). 'H-NMR: 300 MHz, (CD 3 0D) 8: 8.00 (s, 2H), 7.90-7.70 (m, 14H), 5.40-5.35 (m, 2H), 4.28 (d, J=7.2, 2H), 4.15-3.85 (m, 5 H), 3.67 (s, 6H), 2.65-2.06 (m, I OH), 0.95 (d, J=6.6, 6H), 0.88 (d, J=6.6, 6H): LCMS-ESI-: calc'd for C 4 8

H

55

N

8 0 6 : 839.99 (M+H*); Found: 839.4 (M+H*). 15 484 Example AMI H N / \ Br N Pd(PPh 3

)

4 NBoc 1 - \ - NO N 1B N Boc aq. K 2

CO

3 /DME 2-(6-Bromo-1 H-benzoimidazol- 2-{6-[4-(4,4,5,5-Tetramethyl 2-yl)-pyrrolidine-1 -carboxylic [1 ,3,2]dioxaborolan-2-yl)-pheny]-1

H

acid tert-butyl ester benzoimidazol-2-yl}-pyrrolidine-1 carboxylic acid tert-butyl ester HHO N 1. HCI N Boc N "h \ - N 2. HATU, NMM Boc 1 N AN HO 0 C HO )r 2-(6-{4-[2-(1-tert-butylcarbamyl-pyrrolidin- 0 H 0 2-yI)-3H-benzoimidazol-5-yl]-phenyl}-1H- 2-Methoxycarbonylamino-3 benzoimidazol-2-yl)-pyrrolidine-1- methyl-butyric acid carboxylic acid tert-butyl ester

H

HN N /_\_ N N 0 N_\ -0 N N H H (1 -{2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-benzoimidazol-5-yl}-phenyl) 1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester 2

-(

6

-{

4

-[

2 -(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl -phenyl}- 1 H 5 benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-{6-[4 (4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-I H-benzoimidazol-2-yl}-pyrrolidine- carboxylic acid tert-butyl ester (0.058 g), 2-(6-Bromo- H-benzoimidazol-2-yI)-pyrrolidine-I carboxylic acid tert-butyl ester (0.052 g) and Pd(PPh3)4 (0.0069 g) in 2.OM potassium carbonate solution (0.18 mL) and dimethoxyethane (0.36 mL) was heated in microwave at I 10 C for 30 10 minutes, then at 120*C for 60 minutes. Additional Pd(PPh 3

)

4 (0.069 g) was added and reaction was heated conventially at 90*C for 12 hours. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, I to 20% isopropanol/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA) to give 2-(6-{4-[2-(1-tert-butylcarbamyl 15 pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-phenyl}-1 H-benzoimidazol-2-yl)-pyrrolidine-1 485 carboxylic acid tert-butyl ester (0.0315 g) as a bis-TFA salt: LCMS-ESI*: calc'd for

C

3 8

H

4 5

N

6 0 4 : 649.79 (M+H*); Found: 649.1 (M+H*). (1-{2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 5 benzoimidazol-5-yl}-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl propyl)-carbamic acid methyl ester: A solution of 2-(6-{4-[2-(l-tert-butylcarbamyl pyrrolidin-2-yl)-3 H-benzoimidazol-5-yl]-phenyl}-I H-benzoimidazol-2-yl)-pyrrolidine-I carboxylic acid tert-butyl ester (0.0315 g) in dichloromethane (2.0 mL) was treated with 4N HCI in dioxane (1.0 mL) for 1 hour at ambient temperature. Reaction mixture was concentrated 10 and dried under vacuum. The residue was dissolved in DMF (1.0 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.0128 g), 4-methylmorpholine (0.023 mL), followed by HATU (0.027 g). Reaction mixture was stirred for 1 hour at ambient temperature and additional 4-methylmorpholine (0.023 mL) was added. After stirring for 30 minutes, reaction mixture was diluted with ethyl acetate and washed with dilute sodium 15 bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO 4 ). Organic layer was concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (1-{2-[6-(4-{2-[l-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3 H-benzoimidazol-5-yl}-phenyl)-l-H-benzoimidazol-2-yl] pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt 20 (0.0263 g). 'H-NMR: 300 MHz, (CD 3 0D) 5: 8.00 (s, 2H), 7.90-7.70 (m, 8H), 5.40-5.35 (m, 2H), 4.28 (d, J=7.2, 2H), 4.15-3.85 (m, 4H), 3.67 (s, 6H), 2.65-2.06 (m, I OH), 0.95 (d, J=6.6, 6H), 0.88 (d, J=6.6, 6H): LCMS-ESI-: calc'd for C 4 2

H

5

N

8 0 6 : 763.90 (M+H*); Found: 763.3 (M+H-). 486 Example ANI 0 Bo B + Boc NH B'O Pd(PPh 3

)

4 aq. K 2 C0 3 /DME 2-(6-Bromo-1 H-benzoimidazol- 2-(5-{4-[5-(4,4,5,5-Tetramethyl 2-yl)-pyrrolidine-1 -carboxylic [1,3,2]dioxaborolan-2-yl)-thiophen-2-yl] acid tert-butyl ester phenyl}-1 H-imidazol-2-yl)-pyrrolidine-1 carboxylic acid tert-butyl ester H 1. HCI N IN Bo Boc 2. HATU, NMM Boc) -- N 0 HO O 2-[6-(5-{4-[2-(1 -Boc-pyrrolidin-2-yI)-3H- H imidazol-4-yI]-phenyl}-thiophen-2-yl)- 2-Methoxycarbonylamino-3 1 H-benzoimidazol-2-yl]-pyrrolidine-1 - methyl-butyric acid carboxylic acid tert-butyl ester H H N 0 1 0 - S N -N 0 DNH O [1 -(2-{6-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yI]-3H-imidazol-4-yl}-phenyl) thiophen-2-y]-1 H-benzoimidazol-2-yl}-pyrrolidine-1 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 2

-[

6 -(5-{ 4

-[

2 -(l-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yli]-phenyl}-thiophen-2-yl)-1

H

benzoimidazol-2-ylI]-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-(5-{4-[5 (4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-1 H-imidazol-2-yl) pyrrolidine-I -carboxylic acid tert-butyl ester (0.110 g), 2-(6-Bromo-I H-benzoimidazol-2-yl) pyrrolidine-l-carboxylic acid tert-butyl ester (0.115 g) and Pd(PPh 3

)

4 (0.012 g) in 2.0M 10 potassium carbonate solution (0.32 mL) and dimethoxyethane (0.64 mL) was heated in microwave at I I0*C for 30 minutes. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA) to give 2-[6-(5-{4-[2-(] -Formyl-pyrrolidin-2-yl)-3H-imidazol-4 15 y]-phenyl}-thiophen-2-yi)-l H-benzoimidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl 487 ester (0.085 g) as a bis-TFA salt: LCMS-ESlI: calc'd for C 3 8

H

4 5

N

6 0 4 S: 681.86 (M+H*); Found: 681.0 (M+H*). [1-(2-{6-5-(4-{2-[-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 5 imidazol-4-yl)-phenyl)-thiophen-2-yl]-1H-benzoimidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester: A solution of 2-[6-(5-{4-[2-(I-Formyl pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2-yl)-I H-benzoimidazol-2-yl]-pyrrolidine I -carboxylic acid tert-butyl ester (0.085 g) in dichloromethane (2.0 mL) was treated with 4N HCI in dioxane (2.0 mL) for 1.5 hour at ambient temperature. Reaction mixture was 10 concentrated and dried under vacuum. The residue was dissolved in DMF (1.0 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.033 g), 4 methylmorpholine (0.060 mL), followed by HATU (0.070 g). Reaction mixture was stirred for 45 minutes at ambient temperature and reaction mixture was diluted with ethyl acetate and washed with dilute sodium bicarbonate solution, 5% lithium chloride solution, brine and dried 15 (MgSO 4 ). Organic layer was concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give [1-(2-{6-[5-(4 {2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-y} phenyl)-thiophen-2-yl]- I H-benzoimidazol-2-yl}-pyrrolidine- 1 -carbonyl)-2-methyl-propyl] carbamic acid methyl ester as the bis-TFA salt (0.048 mg): 'H-NMR: 300 MHz, (DMSO-d 6 )6: 20 8.09 (br s, I H), 7.90-7.75 (m, 8H), 7.70-7.55 (m, 4H), 7.34 (d, J=8.1, 2H), 5.25-5. 10 (m, 2H), 4.20-4.15 (m, 4H), 4.15-3.85 (m, 4H), 3.54 (s, 6H), 2.50-1.85 (m, 10H), 0.87-0.75 (m, 12H): LCMS-ESI : calc'd for C 4 2

H

5

IN

8 0 6 S: 795.96 (M+H*); Found: 795.2 (M+H+). 488 Example AO1 Bo~ "ix Br is(pinacolato) Boc +/Br Br N-IN N A - C 7 H PdCl 2 (dppf) 2 C H i KOAc, dioxane '2,5-Dibromo 2-(6-Bromo-1 H-benzoimidazol- 2-[6-(4,4,5,5-Tetramethyl- thiophene 2-yl)-pyrrolidine-1-carboxylic [1,3,2]dioxaborolan-2-y)-1 H acid tert-butyl ester benzoimidazol-2-y]-pyrrolidine-1 carboxylic acid tert-butyl ester H / \ S Boc 1. HCI P d C 2 ( d p p f ) 2 AN N M N -2. HATU, NMM aq.K 2

CO

3 /DME N H O' 2-(6-{5-[2-(1-tert-butylcarbamyll-pyrrolidin-2- HO N yl)-3H-benzoimidazol-5-yl]-thiophen-2-yl}- 0 H 0 1 H-benzoimidazol-2-y)-pyrrolidine-1 - 2-Methoxycarbonylamino-3 carboxylic acid tert-butyl ester Methycaboylamin methyl-butyric acid

H

H N 4 O N N H (1 -{2-[6-(5-{2-[1 -(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-benzoimidazol-5-yl} thiophen-2-y)-1 H-benzoimidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-[6-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yi)-1 H-benzoimidazol-2-yI]-pyrrolidine-I 5 carboxylic acid tert-butyl ester: A mixture of 2-(6-Bromo-I H-benzoimidazol-2-yl) pyrrolidine-l -carboxylic acid tert-butyl ester (0.450 g), bis(pinacolato)diboron (0.655 g), PdCl 2 (dppf) (0.050 g) and potassium acetate (0.314 g) in 1,4-dioxane was heated at 90*C for 16 hours. Reaction mixture was cooled to ambient temperatures and diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO 4 ), concentrated and purified by flash 10 column chromatography (silica gel, 30 to 70% ethyl acetate/hexanes) to give 2-[6-(4,4,5,5 Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)- I H-benzoimidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (0.452 g) as an off-white foam: LCMS-ESI: calc'd for C 22

H

33

BN

3 0 4 : 414.32 (M+H*); Found: 414.0 (M+H*). 15 2 -(6-{5-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-y]-thiophen-2-yl} IH-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-[6 (4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-IH-benzoimidazol-2-yI]-pyrrolidine-l 489 carboxylic acid tert-butyl ester (0.149 g), 2,5-Dibromo-thiophene (0.035 g) and PdCl 2 (dppf) 2 (0.006 g) in 2.0M potassium carbonate solution (0.36 mL) and dimethoxyethane (1.0 mL) was heated at 90'C for 18 hours. Additional 2M potassium carbonate solution (0.36 mL) and PdCI 2 (dppf) (0.006 g) was added and reaction was continued for 48 hours. Reaction mixture 5 was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified using preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA) to give 2-(6-{5-[2-(I-tert-butylcarbamyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-thiophen-2-yl} I H-benzoimidazol-2-yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester (0.0475 g) as a bis-TFA salt: LCMS-ESI*: calc'd for C 3 6

H

4 3

N

6 0 4 S: 655.82 (M+H*); Found: 655.0 (M+H*). 10 (1-{2-[6-(5-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yl}-thiophen-2-yl)-1 H-benzoimidazol-2-yli]-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: A solution of 2-(6-{5-[2-(] -tert-butylcarbamyl pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-thiophen-2-yl}- I H-benzoimidazol-2-yl)-pyrrolidine- 15 carboxylic acid tert-butyl ester (0.0475 g)in dichloromethane (1.0 mL) was treated with 4N HCI in dioxane (1.0 mL) for 1.5 hour at ambient temperature. Reaction mixture was concentrated and dried under vacuum. The residue was dissolved in DMF (1.0 mL) and to this solution was added 2 -Methoxycarbonylamino-3-methyl-butyric acid (0.0196 g), 4-methylmorpholine (0.035 mL), followed by HATU (0.042 g). Reaction mixture was stirred for 1 hour at ambient 20 temperature and additional 4-methylmorpholine (0.023 mL) was added. After stirring for 30 minutes, reaction mixture was diluted with ethyl acetate and washed with dilute sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO 4 ). Organic layer was concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (1-{ 2

-[

6 -(5-{2-[1-(2-Methoxycarbonylamino-3 25 methyl-butyryl)-pyrrolidin-2-yl]-3 H-benzoimidazol-5-yl}-thiophen-2-yl)- IH-benzoimidazol-2 yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt (0.0296 g): ' H-NMR: 300 MHz, (DMSO-d 6 ) 6: 7.91(s, 2H), 7.71 (s, 4H), 7.61 (s, 2H), 7.35 (d, J=9.0, 2H), 5.25-5.15 (m, 2H), 4.15-4.00 (m, 4H), 3.95-3.75 (m, 4H), 3.54 (s, 6H), 2.25-1.85 (m, I OH), 0.83 (d, J=6.6, 6H), 0.79 (d, J=6.9, 6H); LCMS-ESr~: calc'd for C 4 oH 4 9

N

8 0 6 S: 30 769.92 (M+H*); Found: 769.2 (M+H*). 490 Example API Boc N Bo + Br Br Pd(PPh 3

)

4 N Br H aq.K 2

CO

3 /DME 2-[6-(4,4,5,5-Tetramethyl- 2,6-Dibromo [1,3,2]dioxaborolan-2-yl)-1 H- naphthalene benzoimidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester H 1 ~1. HCI BoN N IT'-' N N N Boc 2. HATU, NMM N

O

H HO 2-(6-{6-[2-(1 -tert-butylcarbamyl-pyrrolidin-2-yl)-3H- O H 0 benzoimidazol-5-yl]-naphthalen-2-yl}- 1 H-benzoimidazol-2- 0 yl)-pyrrolidine-1-carboxylic acid tert-butyl ester 2-Methoxycarbonylam ino-3 methyl-butyric acid H .- - N 0 -- N SHHO (1 -{2-[6-(6-{2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-benzoimidazo-5-yI}-naphthalen-2-yl)-1 H-benzoimidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-(6-{6-[2-(1 -tert-butylcarbamyl-pyrroidin-2-y)-3H-benzoimidazo-5-y-naphthalen2-yl} 5 1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-[6 (4,4,5,5-Tetramethyl-[ I,3,2]dioxaborolan-2-yl)- I H-benzoimidazol-2-yl]-pyrrolidine- I carboxylic acid tert-butyl ester (0.170 g), 2,6-Dibromo-naphthalene (0.047 g) and Pd(PPh 3

)

4 (0.0095 g) in 2.0M potassium carbonate solution (0.41 mL) and dimethoxyethane (0.8 mL) was heated in microwave at 10 0 C for 40 minutes. Reaction mixture was cooled, diluted with ethyl 10 acetate, washed with brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give 2-(6-{6-[2-(l-tert butylcarbamyl-pyrrol idin-2-yl)-3H-benzoimidazol-5-yl]-naphthalen-2-yl } - H-benzoimidazol-2 yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (0.0961 g) as a yellow film: LCM4S-ESl*: calc'd for C 42

H

47

N

6 0 4 : 699.85 (M+H*l); Found: 699.1 (M+H*). 15 491 (1-{2-16-(6-12-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yl}-naphthalen-2-yl)-1 H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl)-2 methyl-propyl)-carbamic acid methyl ester: A solution of 2-(6-{6-[2-(]-tert-butylcarbamyl pyrrolidin-2-yI)-3 H-benzoimidazol-5-yl]-naphthalen-2-yl}-I H-benzoimidazol-2-yl)-pyrrolidine 5 1-carboxylic acid tert-butyl ester (0.0961 g) in dichloromethane (2.0 mL) was treated with 4N HCI in dioxane (1.0 mL) for I hour at ambient temperature. Reaction mixture was concentrated and dried under vacuum. The residue was dissolved in DMF (1.1 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.050 1 g), 4-methylmorpholine (0.091 mL), followed by HATU (0.107 g). Reaction mixture was stirred for I hour at ambient 10 temperature, diluted with ethyl acetate and washed with dilute sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO 4 ). Organic layer was concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (1 -{2-[6-(6-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-benzoimidazol-5-yl}-naphthalen-2-yl)-1 H-benzoimidazol-2-yl]-pyrrolidine 15 1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt (0.035 mg): 'H NMR: 300 MHz, (DMSO-d 6 ) 6: 8.33 (s, 2H), 8.18-8.01 (m, 4H), 7.95-7.80 (m, 5H), 7.35 (d, J=8.70, 2H), 5.25-5.15 (m, 2H), 4.20-4.00 (m, 4H), 3.95-3.75 (m, 4H), 3.55 (s, 6H), 2.55-1.90 (m, 10 H), 0.84 (d, J=6.6, 6H), 0.79 (d, J=6.9, 6H); LCMS-ESI-: calc'd for C 4 6

H

53

N

8 0 6 : 813.96 (M+H*); Found: 813.3 (M+H*). 20 492 Example AQ1 H2N K 2

CO

3 H

H

2 ~ Br- IN Br Bo HN H 2 O/THF Boc Br 4-Bromo- N 2-(2-Chloro-acetyl)- benzamidine 2-[2-(4-Bromo-pheny)-3H pyrrolidine-1- imidazol-4-yl]-pyrrolidine-1 carboxylic acid terf- carboxylic acid tert-butyl ester butyl ester bis(pinacolato) H H diboron N N ,0H +N N / g Pd(PPh4 Pd(PPh 3

)

4 Boc B, Boc / Br N OH N - aq. K 2 CO3 KOAc dioxane 4-[2-(3H-Imidazol-4-yl)- 2-[2-(4-Bromo-phenyl)-3H- DME pyrrolidine-1-carboxylic acid tert- imidazol-4-yl]-pyrrolidine-1 butyl ester]-phenylboronic acid carboxylic acid tert-butyl ester H 1. HCI Boc N ' N NC N Boc 2. HATU, NMM H - 0 2-(2-{4'-[5-(1 -tert-butyl-carbamyl-pyrrolidin-2-yl)- H 0 1 H-imidazol-2-yl]-biphenyl-4-yl}-3H-imidazol-4- O yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester 2-Methoxycarbonylamino-3 methyl-butyric acid 4 N H H ON N N N

-

NN O HH' (1 -{2-[2-(4'-{5-[1-(2-Methoxycarbonylamino-3-methyl- s butyryl)-pyrrolidin-2-yl]-1 H-imidazol-2-yl}-biphenyl-4 yl)-3H-imidazol-4-yl]-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester 2

-[

2

-(

4 -Bromo-phenyl)-3H-imidazol-4-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: A 5 mixture of 4-Bromo-benzamidine (0.202 g) and potassium carbonate (0.237 g) in H 2 0 (0.286 mL) and THF (1.1 mL) was heated to 65*C. 2-(2-Chloro-acetyl)-pyrrolidine-l-carboxylic acid tert-butyl ester (0.106 g) in THF (0.7 mL) was added over 1 hour and reaction mixture heated at 65*C for 18 hours. Reaction mixture was concentrated to ~ 0.5 mL and extracted with ethyl acetate. Organic layer was washed with H 2 0, brine and dried (MgSO 4 ), concentrated and 10 purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexanes) to give 2-[2-(4-Bromo-phenyl)-3H-imidazol-4-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (0.075 g) as an orange film: LCMS-ESI~: calc'd for C 18

H

2 3 BrN 3 0 2 : 393.30 (M+H*); Found: 391.8, 393.83 (M+H*). 493 4-[2-(3H-Imidazol-4-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester]-phenylboronic acid: A mixture of 2-[2-(4-Bromo-phenyl)-3H-imidazol-4-yI]-pyrrolidine- 1 -carboxylic acid tert-butyl ester (0.075 g), bis(pinacolato)diboron (0.102 g), Pd(PPh 3

)

4 (0.011 g) and potassium acetate 5 (0.049 g) in 1,4-dioxane (1.5 mL) was heated at 100*C for 16 hours. More Pd(PPh 3

)

4 (0.011 g) was added and the reaction was continued for 24 hours. Reaction mixture was cooled to ambient temperatures and diluted with ethyl acetate. Organic layer was washed with brine, dried (MgSO 4 ), concentrated and purified by purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give 4-[2-(3H-Imidazol-4-yl) 10 pyrrolidine- 1 -carboxylic acid tert-butyl ester]-phenylboronic acid (0.027 g) as a white powder: LCMS-ESl*: calc'd for C 18

H

2 5

BN

3 0 4 : 357.21 (M+H+); Found: 357.9 (M+H*). 2-(2-{4'-15-(1-tert-butyl-carbamyl-pyrrolidin-2-yl)-1H-imidazol-2-yl]-biphenyl-4-yl}-3H imidazol-4-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 4-[2-(3H 15 Imidazol-4-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester]-phenylboronic acid (0.0098 g), 2 [2-(4-Bromo-phenyl)-3H-imidazol-4-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (0.0118 g) and Pd(PPh 3

)

4 (0.0012 g) in 2.OM potassium carbonate solution (0.031 mL) and dimethoxyethane (0.8 mL) was heated at 90'C for 18 hours. PdCI 2 (dppf) (0.003 g) was added and reaction mixture was heated at 100 C for 18 hours. Reaction mixture was cooled, diluted 20 with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified using preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give 2-(2-{4'-[5-(I-tert-butyl-carbamyl-pyrrolidin-2-yl)-I H-imidazol-2-yl] biphenyl-4-yl}-3H-imidazol-4-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (0.0018 g) as a white powder: LCMS-ES*: calc'd for C 36

H

4 5

N

6 0 4 : 624.77 (M+H*); Found: 625.0 (M+H*). 25 (1-{2-12-(4'-{5-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H imidazol- 2 -yli-biphenyl-4-yl)-3H-imidazol-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester: A solution of 2-(2-{4'-[5-(l-tert-butyl-carbamyl-pyrrolidin-2-yl) I H-imidazol-2-yli]-biphenyl-4-yl}-3H-imidazol-4-yl)-pyrrolidine- I -carboxylic acid tert-butyl 30 ester (0.0018 g) in dichloromethane (0.5 mL) was treated with 4N HCI in dioxane (0.5 mL) for I hour at ambient temperature. Reaction mixture was concentrated and dried under vacuum. The residue was dissolved in DMF (0.4 mL) and to this solution was added 2 methoxycarbonylamino-3-methyl-butyric acid (0.0008 g), 4-methylmorpholine (0.0024 mL), followed by HATU (0.0016 g). Reaction mixture was stirred for 1.5 hour at ambient 35 temperature, then purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 494 0.1% TFA). Product was lyophilized to give (1-{2-[2-(4'-{5-[LI-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-I H-imidazol-2-yl}-biphenyl-4-yl)-3 H-imidazol-4-yl) pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as a mixture of diastereomers of the bis-TFA salt (0.0017 g): 1 H-NMR: 300 MHz, (CD 3 0D) : 8.10-7.95 (m, 5 8H), 7.55-7.40 (m, 2H), 5.25-5.15 (m, 2H), 4.20-3.65 (m, 6H), 3.62 (s, 6H), 2.40-1.90 (m, I OH), 1.05-0.85 (m, 12H); LCMS-ESI-: calc'd for C 40

H

5

N

8 0 6 : 739.88 (M+H*); Found: 739.3 (M+H*). Example ARI H ,OH + Bo Br Pd(PPh 3

)

4 N N B/OH + N? A \ Boc BOH H aq. K 2 CO3 N H DME 4-[2-(3H-Imidazol-4-yl)- 2-[5-(4-Bromo-pheny)-1 H pyrrolidine-1-carboxylic acid tert- imidazol-2-yl]-pyrrolidine-1 butyl ester]-phenylboronic acid carboxylic acid tert-butyl ester H 1. HCI Bo Boc 2. HATU NMM N N N H ~ 2-(2-(4'-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yl)- H O 3H-imidazol-4-yl]-biphenyl-4-yl}-3H-imidazol-4- O yl)-pyrrolidine-1-carboxylic acid tert-butyl ester 2-Methoxycarbonylamino-3 methyl-butyric acid -O H H' N N 0 (1 -{2-[5-(4'-{5-[1 -(2-Methoxycarbonylamino-3-methyl- O" butyryl)-pyrrolidin-2-yl]-1 H-imidazol-2-yi}-biphenyl-4 yl)-1 H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2-methyl 10 propyl)-carbamic acid methyl ester 2

-(

2

-{

4

'-[

2 -(l-tert-butylcarbamyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-3H imidazol-4-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 4-[2-(3H Imidazol-4-yl)-pyrrolidine-I-carboxylic acid tert-butyl ester]-phenylboronic acid (0.0 177 g), 2 15 [5-(4-Bromo-phenyl)-I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (0.0148 g) and Pd(PPh 3

)

4 (0.0022 g), PdCl 2 (dppf) (0.00 16 g) in 2.OM potassium carbonate solution (0.056 mL) and dimethoxyethane (0.8 mL) was heated at 90'C for 18 hours. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified 495 using preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product was lyophilized to give 2-(2-{4'-[2-(I-ter-butylcarbamyl-pyrrolidin-2-yl)-3H-imidazol-4-ylI] biphenyl-4-yl)-3H-imidazol-4-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (0.0066 g) as a white powder: LCMS-ESI+: calc'd for C 36

H

4 5

N

6 0 4 : 624.77 (M+H*); Found: 625.0 (M+H*). 5 (1-{2-[5-(4'-{5-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-1

H

imidazol-2-yl)-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester: A solution of 2-(2-{4'-[2-(] -tert-butylcarbamyl-pyrrolidin-2-yl) 3H-imidazol-4-yl]-biphenyl-4-yl}-3H-imidazol-4-yl)-pyrrolidine- I -carboxylic acid tert-butyl 10 ester (0.0066 g) in dichloromethane (0.5 mL) was treated with 4N HCI in dioxane (0.5 mL) for I hour at ambient temperature. Reaction mixture was concentrated and dried under vacuum. The residue was dissolved in DMF (0.4 mL) and to this solution was added 2 Methoxycarbonylamino-3-methyl-butyric acid (0.0028 g), 4-methylmorpholine (0.0 12 mL), followed by HATU (0.006 g). Reaction mixture was stirred for 2 hours at ambient temperature, 15 then purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (I -{2-[5-(4'-{5-[l-(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]- I H-imidazol-2-yl)-biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as a mixture of diastereomers of the bis TFA salt (0.0081 g): 'H-NMR: 300 MHz, (CD 3 0D) 8: 8.05-7.80 (m, 9H), 7.55-7.40 (m, I H), 20 5.25-5.15 (m, 2H), 4.20-3.65 (m, 6H), 3.62 (s, 6H), 2.55-1.95 (m, 10 H), 1.05-0.85 (m, 12H); LCMS-ESr: calc'd for C 40

H

5 1

N

8 0 6 : 739.88 (M+H+); Found: 739.3 (M+H 4 ). 496 Example ASI H NoH\ / N ) Pd(PPh 3

)

4 Br + -/ Naq. K 2 C /DME 3-[5-(4-Bromo-pheny)-1 H- 2-{6-[4-(4,4,5,5-Tetramethyl imidazol-2-yl]-2-aza- [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H bicyclo[2.2.1 ]heptane-2- benzoimidazol-2-yl}-pyrrolidine-1 carboxylic acid tert-butyl ester carboxylic acid tert-butyl ester H 1. HCI N NBoc 2. HATU, NMM N N ~-O' BOc HI U N N "0 ' H O O 2-(6-{4'-[2-(2-tert-butylcarbamyl-2-aza- bicyclo[2.2.1]hept-3-yl)-3H-imidazol-4-yl]- 2-Methoxycarbonylamino-3 biphenyl-4-yl}-1H-benzoimidazol-2-yl)- methyl-butyric acid pyrrolidine-1-carboxylic acid tert-butyl ester O O N H NN I N N Ng N N 14 HH (1 -{2-[6-(4'-{2-[2-(2-Methoxycarbonylamino-3 methyl-butyryl)-2-aza-bicyclo[2.2. 1 ]hept-3-yl]-3H imidazol-4-yI}-bipheny-4-y)-1 H-benzoimidazol-2 yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl) carbamic acid methyl ester 2-(6-(4'-[2-(2-tert-butylcarbamyl-2-aza-bicyclo[2.2.11 hept-3-yl)-3H-imidazol-4-ylj 5 biphenyl-4-yl}-1 H-benzoimidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester: A mixture of 2-{6-[4-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]- I H-benzoimidazol 2-yl} -pyrrol idine- I -carboxylic acid tert-butyl ester (0.142 g), 3-[5-(4-Bromo-phenyl)- I H imidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carboxyl ic acid tert-butyl ester (0.1013 g) and Pd(PPh 3

)

4 (0.014 g) in 2.OM potassium carbonate solution (0.036 mL) and dimethoxyethane (0.8 10 mL) was heated in microwave at II 0*C for 30 minutes. Reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO 4 ), concentrated and purified using preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give 2

(

6 -{4'-[2-(2-tert-butylcarbamyl-2-aza-bicyclo[2.2. I ]hept-3-yi)-3H-imidazol-4-yl]-biphenyl-4 yl}-l H-benzoimidazol-2-yI)-pyrrolidine-I-carboxylic acid tert-butyl ester (0.128 g) as a white 15 powder: LCMS-ESI*: calc'd for C 42

H

49

N

6 0 4 : 701.87 (M+H*); Found: 701.1 (M+H*). 497 (1 -{2-16-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclol2.2.1 ]hept-3 yli-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-benzoimidazol-2-ylI-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: A solution of 2-(6-{4'-[2-(2-tert-butylcarbamyl 5 2-aza-bicyclo[2.2.1 ]hept-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl} - I H-benzoimidazol-2-yi) pyrrolidine-I -carboxylic acid tert-butyl ester (0.128 g) in dichloromethane (2.0 mL) was treated with 4N HCI in dioxane (1.0 mL) for I hour at ambient temperature. Reaction mixture was concentrated and dried under vacuum. The residue was dissolved in DMF (2.OmL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (0.050 g), 4 10 methylmorpholine (0.090 mL), followed by HATU (0.106 g). Reaction mixture was stirred for I hour at ambient temperature. Additional 4-methylmorpholine (0.090 mL) was added and reaction mixture stirred for 1 hour. Reaction mixture was diluted with ethyl acetate, washed with dilute sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO 4 ), then concentrated and purified by preparative reverse phase H PLC (Gemini, 5 to 100% 15 ACN/H 2 0 + 0.1% TFA). Product was lyophilized to (1-{2-[6-(4'-{2-[2-(2 Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl} biphenyl-4-yl)- IH-benzoimidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt (0.080 g): 'H-NMR: 300 MHz, (CD 3 0D) 8: 8.05-7.70 (m, 13H), 7.35-7.25 (m, 2H), 5.25-5.15 (m, I H), 4.67 (s, I H), 4.43 (s, I H), 4.20-4.00 (m, 2H), 20 3.85-3.75 (m, 4H), 3.51 (s, 3H), 3.49 (s, 3H), 2.50-1.45 (m, 14H), 0.95-0.75 (m, 12H); LCMS ESI~: calc'd for C 4 6 1-1 5 5

N

8 0 6 : 815.97 (M+H*); Found: 815.3 (M+H*). 498 Example AT1 N COOEt COOt COOEt H-Gly-OtBu MeOOCCI COe O COtNH Boc MNCC Boc O Boc NaBH(OAc) 3 , DCM NMM, DCM 5-Formyl-pyrrolidine-1,2- 0 dicarboxylic acid 1-tert- 5-[(tert-Butoxycarbonylmethyl butyl ester 2-ethyl ester amino)-methyl]-pyrrolidine-1,2 dicarboxylic acid 1 -tert-butyl 5-[(tert-Butoxycarbonylmethyl ester 2-ethyl ester methoxycarbonyl-amino)-methyl] pyrrolidine-1,2-dicarboxylic acid 1 -tert butyl ester 2-ethyl ester COOEt C OOEt LiOH, H 2 0 HCI, Dioxane N O e HATU, NMM N e(~ COOMe -10N _Ix&Q MeOH,THF DCM 0 OH DMF O 5-[(Carboxymethyl-methoxycarbony- 4-Oxo-hexahydro-pyrrolo[1,2 amino)-methyl]-pyrrolidine-2-carboxylic a]pyrazine-2,6-dicarboxyic acid 6 acid ethyl ester ethyl ester 2-methyl ester HATU, NMM, DMF 0 NH 4 0Ac OA O HCH C Br /OHN \/ Br xylenes, 130 *C Y 11H 2 N0 0 2-Amino-1-(4-bromo- 6-[2-(4-Bromo-phenyl)-2-oxo 4-Oxo-hexahydro- phenyl)-ethanone ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[1,2 py2rolbo1y2-ai yraine- a]pyrazine-2-carboxylic acid methyl ester methyl ester H N IN - 0 -O N/ O, -0 0 NNH O_ NH 0 N /Br - Pd(PPh 3

)

4 , K 2

CO

3 , DME, H 2 0, MW 120 "C 6-[5-(4-Bromo-phenyl)-1 H-imidazol-2- [2-Methyl-1 -(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 yl]-4-oxo-hexahydro-pyrrolo[1,2- yl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-propyl] a]pyrazine-2-carboxylic acid methyl carbamic acid methyl ester ester N - - N N

-

HN O 0 6-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester 5-Formyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester: 5-Formyl 5 pyrrolidine-1,2-dicarboxylic acid I -ert-butyl ester 2-ethyl ester was prepared according to: J. Org. Chem. 1995, 60, 5011 - 5015. 5-[(tert-Butoxycarbonylmethyl-amino)-methyll-pyrrolidine-1,2-dicarboxylic acid 1-tert butyl ester 2-ethyl ester: Sodium triacetoxyborohydride (2.08 g, 9.86 mmol) was added to a 499 solution of 5-formyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (891 mg, 3.29 mmol) and glycine t-butyl ester (1.65 g, 9.86 mmol) in dichloromethane (20 mL) over 2 minutes - a small amount of gas evolution was observed. After I hour the reaction was quenched with saturated ammonium chloride (5 mL). The mixture was extracted with ethyl 5 acetate (3 x 25 mL). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography with methanol and dichloromethane as the eluant at a gradient of 0 - 10%. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 5-[(tert-butoxycarbonylmethyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic 10 acid I-tert-butyl ester 2-ethyl ester (601 mg, 1.55 mmol, 47 %). C 19 1-1 34

N

2 0 6 calculated 386.2, observed [M + 1]+ 387.2; rt = 1.61 min. 5-[(tert-Butoxycarbonylmethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-1,2 dicarboxylic acid 1-tert-butyl ester 2-ethyl ester: Methyl chloroformate (0.065 mL, 0.85 15 mmol) was added to a solution of 5-[(tert-butoxycarbonylmethyl-amino)-methyl]-pyrrolidine l,2-dicarboxylic acid I -tert-butyl ester 2-ethyl ester (300 mg, 0.77 mmol) and 4 methylmorpholine (0.12 mL, 1.2 mmol) in dichloromethane (10 mL) at 0 *C. After 15 minutes the mixture was diluted with dichloromethane (30 mL) and washed with water (15 mL), saturated ammonium chloride (15 mL) and saturated sodium chloride (15 mL). The organic 20 phase was dried over sodium sulfate and the solvent was removed under reduced pressure to provide 5-[(tert-butoxycarbonylmethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-I,2 dicarboxylic acid I-tert-butyl ester 2-ethyl ester (304 mg, 0.68 mmol, 88 %). C 2 1

H

3 6

N

2 0 8 calculated 444.3, observed [M + 1] 445.3; rt = 2.58 min. 25 5- I(Carboxymethyl-methoxycarbonyl-amino)-methyl] -pyrrolidine-2-carboxylic acid ethyl ester: 5-[(tert-Butoxycarbonylmethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-1,2 dicarboxylic acid I -tert-butyl ester 2-ethyl ester (304 mg, 0.68 mmol) was added to a solution of hydrogen chloride in dioxane (4N, 15 mL). After 16 hours the solvent was removed under reduced pressure and the resulting residue was azeotroped with toluene to provide 5 30 [(carboxymethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-2-carboxylic acid ethyl ester (224 mg) - assumed 100 % yield. 4-Oxo-hexahydro-pyrrolo[1,2-ajpyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester: HATU (390 mg, 1.03 mmol) was added to solution of 5-[(carboxymethyl 35 methoxycarbonyl-amino)-methyl]-pyrrolidine-2-carboxylic acid ethyl ester (187 mg, 0.68 500 mmol) and 4-methylmorpholine (375 gL, 3.4 mmol) in dimethylformamide (30 mL). After 50 minutes the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (20 mL) which was washed with half saturated sodium chloride (2 x 10 mL), saturated sodium bicarbonate (2 x 10 mL) and dried over sodium sulfate. The aqueous phase 5 also contained product. The water was removed under reduced pressure and the residue was azeotroped with toluene and then stirred with ethyl acetate (50 mL). The mixture was filtered and combined with the organic extracts. The solvent was removed under reduced pressure and the resulting residue was subjected to flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was 10 removed under reduced pressure to provide 4-oxo-hexahydro-pyrrolo[ 1,2-a]pyrazine-2,6 dicarboxylic acid 6-ethyl ester 2-methyl ester (141 mg, 0.52 mmol, 76 %). C 12 H 18

N

2 0 5 calculated 270.1, observed [M + 1]*271.1; rt = 1.54 min. The following (ester hydrolysis) constitutes an example of Method 801 15 4-Oxo-hexahydro-pyrrolo[1,2-alpyrazine-2,6-dicarboxylic acid 2-methyl ester: A solution of lithium hydroxide monohydrate (16.8 mg, 0.38 mmol) in water (0.5 mL) was added to a solution of 4-oxo-hexahydro-pyrrolo[ 1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester (86 mg, 0.32 mmol) in methanol (I mL) and tetrahydrofuran (1 mL). After 2 hours, an 20 aqueous solution of hydrogen chloride (IN, 0.41 mL, 0.41 mmol) was added and the organic solvents were removed under reduced pressure. The resulting aqueous solution was lyophilized for 16 hours to give 4 -oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 2-methyl ester. A yield of 100 % was assumed for the subsequent step. C 1 oH 1 4

N

2 0 5 calculated 242.1, observed [M + 1]+242.9, [M + 1]- 241.1; rt = 1.54 min. 25 The following three steps (amide formation, imidazole cyclization and Suzuki coupling) constitute an example of Method 802 6-{2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[1,2-alpyrazine-2 30 carboxylic acid methyl ester: A solution of 4 -oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6 dicarboxylic acid 2-methyl ester (81 mg, 0.33 mmol), HATU (152 mg, 0.40 mmol), and 4 methyl morpholine (146 gL, 1.33 mmol) in dimethylformamide (4 mL) was stirred at ambient temperature for 5 minutes. 2-Amino-I-(4-bromo-phenyl)-ethanone hydrochloride (91 mg, 0.37 mmol) was added to the reaction mixture. After 1 hour the solvent was removed under reduced 35 pressure and the resulting residue was taken up in ethyl acetate (10 mL). The resulting mixture 501 contained a solid and was filtered. The solvent was removed under reduced pressure from the filtrate. The resulting residue was subjected to flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 6-[2-(4-bromo-phenyl)-2-oxo 5 ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[,2-a]pyrazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol, 75 %). C 18

H

20 BrN 3 0 5 calculated 437.1 observed [M + I]438.1; rt = 1.82 min. 6-15-(4-Bromo-phenyl)-IH-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-alpyrazine-2 carboxylic acid methyl ester: A mixture of 6 -[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-4 10 oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), ammonium acetate (193 mg, 2.5 mmol) and xylenes (8 mL) was heated to 130*C. After 1 hour the mixture was cooled and the xylenes were removed under reduced pressure. Dichloromethane was added to the resulting residue and the mixture was filtered. The solvent was removed under reduced pressure from the filtrate and the resulting residue was subjected to 15 flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide 6-[5-(4-bromo-phenyl)- I H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[ 1,2-a]pyrazine-2 carboxylic acid methyl ester (65 mg, 0.15 mmol, 60 %). C 18 HIgBrN 4 0 3 calculated 418.1observed [M + 1]419.1; rt = 1.50 min. 20 6-[5-(4'-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yll-3H-imidazol 4-yl}-biphenyl-4-yI)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-alpyrazine-2 carboxylic acid methyl ester: A mixture of 6 -[5-(4-bromo-phenyl)-I H-imidazol-2-yl]-4-oxo hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 mmol), [2 25 methyl-I -(2-{5-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl} pyrrolidine-l-carbonyl)-propyl]-carbamic acid methyl ester (77 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol), potassium carbonate (42.8 mg, 0.31 mmol), 1,2-dimethoxyethane (4 mL) and water (I mL) was heated in a microwave reactor at 120'C for 20 minutes. The mixture was cooled and all volatiles were removed under reduced 30 pressure. The resulting residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1 % TFA in water and 0.1 % TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 6-[5-(4'- {2- [1-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)- I H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[ 1,2 35 aJpyrazine-2-carboxylic acid methyl ester (16.8 mg, 0.024 mmol, 15 %). C 38

H

4 4 BrN 8

O

6 502 calculated 708.3 observed [M + l]709.4; rt = 1.39 min. 'H (DMSO-d6): 6= 8.10 (s, 2H), 7.89 (m, 7H), 7.33 (d, J = 9 Hz, I H), 5.03 (t, J= 7.8 Hz, I H), 5.12 (m, I H), 4.30 (m, I H), 4.23 (m, 1H), 4.11 (t,J= 8.1 Hz, 1H), 3.99 (m, 2H), 3.83 (m, 1H), 3.67 (s, 3H), 3.54 (m,3 H), 2.90 (m, I H), 2.41 (m, I H), 2.18 (m, 2H), 2.01 (m,4H), 1.67 (m, I H), 0.82 (m, 6H). 5 Example AUl 0 HATU, NMM HN BrCH 2 COOBn BnOOC N H 2 , Pd/C H) DMIF 07 N~c LHMDS 0 *' -c HO "NHBoc NHBoc NHBoc (3-tert-Butoxycarbonylamino-2 5-Amino-2-tert- (2-Oxo-piperidin-3-yi)- oxo-piperidin-1 -yl)-acetic acid butoxycarbonylami carbamic acid tert-butyl ester benzyl ester no-pentanoic acid HATU, NMM, DMF N O- 0 NH 4 0Ac HOOC N HN O HCI / Br NHBoc Br xylenes, 130 *C NHBoc H 2 N (1-{(2-(4-Bromo-phenyl)-2-oxo (3-terd- 2-Amino-1-(4-bromo- ethylcarbamoyl]-methyl}-2-oxo-piperidin-3-y) Butoxycarbonylamin phenyl)-ethanone carbamic acid tert-butyl ester o-2-oxo-piperidin-1 yl)-acetic acid H Hr N N B 0O N N ) N \ Br 0 NH 0 0 BocHN - Pd(PPh 3

)

4 , K2C03, DME, H 2 0, MW 120 0C {m-[y-(4-Bromo-phenyl)-iH-imidazol- [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl 2-ylmethyl]-2-oxo-piperidin-3-yl- [1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl} carbamic acid tert-butyl ester pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester H H N O N HCI, Dioxane BocHN HN-O 0. {1-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yI]-3H-imidazol-4-yil-biphenyl-4-yl)-1 H-imidazol-2 ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester 503 H H 1. MeOOCCI, NMM, DCM N N - - N N SN N O 2. NaOH, H20, MeOH

H

2 N HN O 0s {1-[2-(5-{4'-[2-(3-Amino-2-oxo-piperidin-1-ylmethyl)-3H imidazol-4-yl]-biphenyl-4-y}-1H-imidazol-2-yl)-pyrrolidine-1 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester H H 7 N N 0 N N O 0 O NH HN O {1 -[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-y}-biphenyl-4-yl)-1 H-imidazol-2 ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester (2-Oxo-piperidin-3-yl)-carbamic acid tert-butyl ester: 4-Methylmorpholine (4.73 mL, 43.0 mmol) was added to a suspension of R-5-amino-2-tert-butoxycarbonylamino-pentanoic acid (5 5 g, 21.5 mmol) and HATU (9 g, 23.6 mmol) in dimethylformamide (100 mL). After 2 hours the solvent was removed under reduced pressure. Saturated sodium bicarbonate (100 mL) was added to the residue and the resulting mixture was extracted with dichloromethane (3 x 75 mL). The combined organic extracts were washed with saturated sodium chloride (50 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue 10 was subjected to flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide (R)-(2-oxo-piperidin-3-yl)-carbamic acid teri-butyl ester (3 g, 14.0 mmol, 66 %). CIOH 18

N

2 0 3 calculated 214.1 observed [M + 1]+215.2; rt = 1.73 min. 15 R-( 3 -tert-Butoxycarbonylamino-2-oxo-piperidin-1-yl)-acetic acid benzyl ester: A solution of lithium bis(trimethylsilyl)amide (1.0 M, 16.8 mL, 16.8 mmol) in tetrahydrofuran was added dropwise to a solution of R-2-oxo-piperidin-3-yl)-carbamic acid tert-butyl ester (3 g, 14.0 mmol) in tetrahydrofuran in a dry flask under an atmosphere of nitrogen. After 30 minutes bromo-acetic acid benzyl ester (2.41 mL, 15.4 mmol) was added dropwise. After an additional 20 30 minutes the mixture was quenched with saturated ammonium chloride (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated sodium chloride (50 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product-containing fractions were 25 combined and the solvent was removed under reduced pressure to provide (R)-(3-tert 504 butoxycarbonylamino-2-oxo-piperidin- I-yl)-acetic acid benzyl ester (2.31 g, 6.37 mmol, 45 %).

C

19

H

26

N

2 0 5 calculated 362.2 observed [M + 1]* 363.1; rt = 2.40 min. The following (benzyl ester cleavage) constitutes and example of Method 803 5 (R)-(3-tert-Butoxycarbonylamino-2-oxo-piperidin-1-yl)-acetic acid: Palladium on carbon (10 %, 500 mg) was added to a solution of (R)-(3-tert-butoxycarbonylamino-2-oxo-piperidin-1 -yl) acetic acid benzyl ester (2.31 g, 6.37 mmol) in ethanol (50 mL). The atmosphere was replaced with hydrogen and maintained with a balloon filled with hydrogen and the above mixture was 10 vigorously stirred. After 16 hours the hydrogen was removed and CELITE was added to the mixture with stirring and then the mixture was filtered though a pad of CELITE. The solvent was removed under reduced pressure and the resulting residue was azeotroped with toluene to provide (R)-(3-tert-butoxycarbonylamino-2-oxo-piperidin- I -yl)-acetic acid (1.65 g, 6.06 mmol, 95 %). C 1 2

H

20

N

2 0 5 calculated 272.3 observed [M + 1]* 271.2; rt = 1.80 min. 15 (R)-i1-15-(4'-(2-1 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yll-3H imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl methyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester: (R)-{ I -[5-(4'-{2-[ I -(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yI)- I H-imidazol-2-yl methyl]-2-oxo-piperidin-3 20 yl}-carbamic acid tert-butyl ester was prepared by Method 802 substituting (3-tert butoxycarbonylamino-2-oxo-piperidin- I -yl)-acetic acid for 4-oxo-hexahydro-pyrrolo[ I,2 a]pyrazine-2,6-dicarboxylic acid 2-methyl ester. C 40 Ho 5

N

8 0 6 calculated 738.4 observed [M + 1] 739.5; rt = 1.83 min; iH (DMSO-d6): 8 =1 1.82 (s, I H), 7.79 (m, 4H), 7.64 (m, 4H), 7.47 (s, I H), 7.25 (d, J= 8.4 Hz, I H), 6.95 (d, J= 8 Hz, I H), 5.05 (m, I H), 4.62 (d, J= 15.6 Hz, I H), 25 4.43 (d, J = 15.2 Hz, I H), 4.03 (m, 2H), 3.77 (m, I H), 3.50 (s, 2H), 3.1 (m, 1 H), 3.28 (s, 3 H), 2.11 (m, 2 H), 1 .93 (m, 4H), 1.74 (m, 3H), 1.37 (s, 9H), 0.850 (m, 6H). H H N N BocHN HN 0s {1-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2 ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester 505 (S)- { 1- [5-(4'- {2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolid in-2-yl] -3H imidazol-4-yl}-biphenyl-4-yI)-1H-imidazol-2-yl methyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester: (S)-{ I-[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3 H-imidazol-4-yl}-biphenyl-4-yl)- IH-imidazol-2-yl methyl]-2-oxo-piperidin-3 5 yl}-carbamic acid tert-butyl ester was prepared following the method described above.

C

40

H

50

N

8 0 6 calculated 738.4 observed [M + 1]*739.5; rt = 1.80 min. ' H (DMSO-d6): 6 = 8.09 (s, 1 H), 7.90 (m, 8H), 7.30 (d, J= 8.4 Hz, I H), 6.97 (d, J= 8.4 Hz, I H), 5.10 (t, J= 7.2 Hz, I H), 7.85 (d, J= 16.4 Hz, I H), 4.56 (d, J= 15.6 Hz, I H), 4.09 (t, J= 8.0 Hz, I H), 3.99 (m, 2H), 3.82 (m, 2H), 3.51 (s, 2H), 3.43 (t, J= 5.6 Hz, I H), 2.20 (m, I H), 2.14 - 1.86 (series m, 9H), 1.34 (s, 10 9H), 0.810 (m, 6H). The following (Boc deportation) constitutes an example of Method 804 (R)-{1-12-(5-{4'-12-(3-Amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol-4-ylI]-biphenyl-4-yl} 15 1H-imidazol-2-yl)-pyrrolidine-I-carbonyll-2-methyl-propyl}-carbamic acid methyl ester: A solution of hydrogen chloride (4N, 8 mL) in dioxane was added to a solution of (R)-{ l-[5-(4' {2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrro idin-2-yl]-3 H-imidazol-4-yl} biphenyl-4-yl)- I H-imidazol-2-yl methyll-2-oxo-piperidin-3-yl} -carbamic acid tert-butyl ester (175 mg, 0.24 mmol) in dichloromethane (2 mL). After I hour the solvent was removed under 20 reduced pressure. The resulting residue was placed on a high vacuum for I hour to provide (R) { 1 -[2-(5-{4'-[2-(3-amino-2-oxo-piperidin-I -ylmethyl)-3H-imidazol-4-yl]-biphenyl-4-y}-1 H imidazol-2-yl)-pyrrolidine-l -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester. The yield was assumed to be 100 % percent. A sample suitable for analysis was obtained by subjection to reverse phase chromatography with an eluent of 0.1 % TFA in water and 0.1 % TFA in 25 acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization. C 35

H

42

N

8 0 4 calculated 638.3 observed [M + 1]* 639.4; rt = 1.41 min. 'H (DMSO-d6): 5 = 8.33 (m, 1 H), 8.12 (m, I H), 7.99 (m, I H), 7.92 (m, 6H), 7.26 (d, J= 8.4 Hz, I H), 5.13 (t, J= 8.0 Hz, 1 H), 4.83 (m, 2H), 4.09 (t J= 8.0 Hz,I H), 4.09 - 3.82 (series m, 6H), 2.36 (m, 2H), 2.14 (m, 2H), 1.96 (m, 4H), 0.76 (m, 6H). 30 506 H H O O N N N N ,

H

2 N HN-O 0- {1-[2-(5-{4'-[2-(3-Amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol 4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2 methyl-propyll-carbamic acid methyl ester (S)-{1-1 2 -(5-14'-12-(3-Amino-2-oxo-piperidin-1-yl methyl)-3H-imidazol-4-yl]-biphenyl-4 yl}-IH-imidazol-2-yI)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl 5 ester: (S)-{1-[2-(5-{4'-[2-(3-Amino-2-oxo-piperidin-I-ylmethyl)-3H-imidazol-4-yl]-biphenyl 4-yl}-I H-imidazol-2-yl)-pyrrolidine-l-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was prepared following the method used for the (R)-isomer with the appropriate substitution described above. C 35

H

42

N

8 0 4 calculated 638.3 observed [M + 1]*639.5; rt = 1.39 min. 'H (DMSO-d6): S= 8.32 (m, 2H), 7.91 (m, 8H), 7.27 (d, J= 8.8 Hz, I H), 5.13 (t, J= 7.2 Hz, I H), 10 4.79 (m, 3H), 4.09 (t, J= 7.2 Hz, I H), 3.89 (m, 4H), 3.51 (s, 3H), 3.45 (m, I H), 3.40 (m, I H), 2.35 (m, 2H), 2.32 (m, 3H), 1 .95 (m, 6H), 0.78 (m, 6H). The following two steps (Carbamate formation and imidazole deprotection) constitute an example of Method 805 15 (R)-{1-[5-(4'-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-biphenyl-4-yi)-1H-imidazol-2-yl methyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester: 4-Methylmorpholine (71 pL, 0.64 mmol) was added to a suspension of (R) {I -[2-(5-{4'-[2-(3-amino-2-oxo-piperidin-I1-yl methyl)-3H-imidazol-4-yl]-biphenyl-4-y }-1 H 20 imidazol-2-yl)-pyrrolidine-I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (137 mg, 0.21 mmol) in dichloromethane (5 mL). Methyl chloroformate (16.5 RL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed under reduced pressure. The residue was taken up in tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, I mL) was added. After 2 hours the organic solvents were 25 removed under reduced pressure and the aqueous phase was decanted. The residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1 % TFA in water and 0.1 % TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide (R)-{1-[5-(4'-{2-[1-(2 methoxycarbonylam ino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl}-biphenyl-4-yl) 30 1 H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester (46.7 mg, 0.67 507 mmol, 32 %). C 37 H44N 8

O

6 calculated 696.3 observed [M + 1] 697.4; rt = 1.58 min. 1 H (DMSO-d6,): 6 = 8.05 (s, I H), 7.87 (m, 8H) 7.30 (m, I H), 5.10 (t, J = 7.2 Hz, I H), 4.85 (d, J 15.6 Hz, I H), 4.53 (d, J= 16.0 Hz, I H), 4.08 (m, 2H), 3.81 (m, 2H), 3.51 (s, 3 H), 3.50 (s, 3H), 2.14 (m, I H), 2.05 - 1.78 (series m, 8H), 0.78 (m, 6H). 5 H H N N HN N {1 -[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-biphenyl-4-y)-1 H-imidazol-2-ylmethy]-2-oxo piperidin-3-yl}-carbamic acid methyl ester (S)-{1 -[5-(4'-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-biphenyl-4-yI)-1H-imidazol-2-ylmethyl-2-oxo-piperidin-3-yl}-carbamic acid 10 methyl ester: (S)-{ I -[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-I H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester was prepared following the method described above for the (R) isomer with the appropriate substitution. C 37

H

4 4

N

8 0 6 calculated 696.3 observed [M + 1]+ 697.4; rt = 1.54 min. 'H (DMSO-d6): 5 = 8.03 (m, I H), 7.86 (m, 8H), 7.03 (m, I H), 5.10 (t, J= 6.4 Hz, I H), 15 4.84 (d, J = 16.8 Hz, I H), 4.52 (d, J = 16.4 Hz, 1 H), 4.08 (m, 2H), 3.80 (m, 3H), 3.51 (s, 3H), 3005 (s, 3H), 2.29 (m, I H), 2.14 - 1.78 (series m, 9H), 0.78 (m, 6H). Example AV1 H H N N HN N _OOs BocHN 0 HN 01~ {3-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl] 5-oxo-octahydro-indolizin-6-yl}-carbamic acid tert-butyl ester 20 {3-[5-(4'-{2-[I-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol 4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid tert butyl ester: {3-[5-(4'-{2-[I-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-biphenyl-4-yl)-l H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic 508 acid tert-butyl ester was prepared following method 802 substituting 6-tert butoxycarbonylamino-5-oxo-octahydro-indolizine-3-carboxylic acid for 4-oxo-hexahydro pyrrolo[l,2-a]pyrazine-2,6-dicarboxylic acid 2-methyl ester. C 4 2

H

52 NsO 6 calculated 764.4 observed [M + 1]* 765.5; rt = 1.86 min. ' H (DMSO-d6): 6 = 7.89 (m, 8H), 7.33 (d, J= 11.2 Hz, 5 1 H), 6.88 (m, I H), 5.12 (m, 2H), 4.09 (m, 2H), 3.84 (m, 2H), 3.60 - 3.45 (series m, 4H), 3.53 (s, 3H), 2.34 (m, 2H), 2.10 (m 8H), 1.79 (m, 31H), 1.37 (s, 9H), 0.81 (dd, J= 8.8 Hz, J= 17.2 Hz, 6H). Example AW1 H H N N - - N N HN O HN O/ 01"0-- {3-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl} 10 carbamic acid methyl ester {3-[5-(4'-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol 4-yI}-biphenyl-4-yl)-l H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid methyl ester: {3-[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 15 3 H-imidazol-4-yl}-biphenyl-4-yl)- IH-imidazol-2-yli]-5-oxo-octahydro-indolizin-6-y}-carbamic acid methyl ester was prepared following method 804 followed by method 805, substituting {3 [5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-ylJ-3H-imidazol-4-yl} biphenyl-4-yl)- I H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-y}-carbamic acid tert-butyl ester for {I -[5-(4'-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H 20 imidazol-4-yl}-biphenyl-4-yl)-l H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester in method 804, and substituting {l-[2-(5-{4'-[2-(6-Amino-5-oxo-octahydro indolizin-3-yI)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-l-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester for {l-[2-(5-{4'-[2-(3-amino-2-oxo-piperidin-1 ylmethyl)-3 H-imidazol-4-yl]-biphenyl-4-yI}-1 H-imidazol-2-yl)-pyrrolidine-l -carbonyl]-2 25 methyl-propyl}-carbamic acid methyl ester in method 805. C 3 9

H

4 6

N

8 0 6 calculated 722.4 observed [M + 1]+ 723.4; rt = 1.62 min. 1 H (DMSO-d6): 6 = 8.10 (m, I H), 7.90 (m, 8H), 7.31 (m, 2H), 5.12 (m, 2H), 4.11 (m, 2H), 3.84 (m 2H), 3.74 (m, 1 H), 3.53 (s, 6H), 2.38 (m, 2H), 2.14 (m, 3H), 2.05 (m, 5H), 1.82 (m 3H), 0.81 (dd,J= 8.8 Hz,J= 17.6 Hz, 6H). 30 509 Example AXI O Br NHBoc 0 NH 0 BO\ Pd(PPh 3

)

4 , K 2

CO

3 , DME, H 2 0 80 "C -0 [2-Methyl-1 -(2-{5-[4-(4,4,5,5-tetramethyl- [2-(4-Bromo-phenyl)-2-oxo [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H- ethyl]-carbamic acid tert-butyl imidazol-2-yi}-pyrrolidine-1 -carbonyl)- ester propyl]-carbamic acid methyl ester H H N 0 HCI, Dioxane - N N NHBoc DCM [1 -(2-{5-[4'-(2-tert-Butoxycarbonylamino-acetyl)-biphenyl-4 yl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2-methyl propyl]-carbamic acid methyl ester 0 HNH2 [1 -(2-{5-[4'-(2-Amino-acetyl)-biphenyl-4-y]-1

H

imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl] carbamic acid methyl ester [1-( 2 -{5-14'-(2-tert-Butoxycarbonylamino-acetyl)-biphenyl-4-yl]-1 H-im idazol-2-yl} 5 pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: A mixture of [2-(4 Bromo-phenyl)-2-oxo-ethyl]-carbamic acid lert-butyl ester (I g, 3.2 mmol), [2-methyl-1-(2-{5 [4-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl } -pyrrolidine- I carbonyl)-propyl]-carbamic acid methyl ester (1.57 g, 3.2 mmol), tetrakis(triphenylphosphine)palladium(O) (183 mg, 0.15 mmol), potassium carbonate (878 mg, 10 6.5 mmol), 1,2-dimethoxyethane (25 mL) and water (2.5 mL) was stirred at 80*C for 16 hours. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dichloromethane (100 mL) and washed with water (25 mL) and saturated sodium chloride (25mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash 15 chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to 510 provide [1-(2-{5-[4'-(2-tert-butoxycarbonylamino-acetyl)-biphenyl-4-yl]-l H-imidazol-2-yl} pyrrolidine-l -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (869 mg, 1.4 mmol, 44

C

33

H

4 1

N

5 0 6 calculated 603.3 observed [M + 1] 604.3; rt = 2.01 min. 'H (DMSO-d6): 8 = 5 11 .82 (s, I H), 8.03 (m, 2H), 7.84 (m 4H), 7.72 (m, 2H), 7.56 (d, J = 1.8 Hz, I H), 7.29 (d, J = 8.7 Hz, I H), 7.08 (m, I H), 5.08 (m, I H), 4.46 (d, J = 5.7 Hz, 2H), 4.03 (m, I H), 3.80 (m, 2H), 3.53 (s, 3 H), 2.14 (m, 2H), 1.95 (m, 2H), 0.86 (dd, J= 6.9 Hz, J= 15.9 Hz, 6H). [1-(2-{5-14'-(2-Amino-acetyl)-biphenyl-4-yli]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2 10 methyl-propyl-carbamic acid methyl ester: [1-(2-{5-[4'-(2-Amino-acetyl)-biphenyl-4-yl] I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared using method 804 substituting [I -(2-{5-[4'-(2-tert-butoxycarbonylamino-acetyl) biphenyl-4-yl]-i H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester for { 1 -[5-(4'- { 2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 15 3 H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-y}-carbamic acid tert-butyl ester. C 28

H

33

N

5 0 4 calculated 503.3 observed [M + 1]+ 504.2; rt = 1.42 min. 511 Example AYI OH"IN 1N'01 0MeNHOMe HCI, NMM 0Boc 2 O, DMAP 0N NH~oc NHBoc

N(BOC)

2 2-tert- 2-tert-Butoxycarbonylamino-4- 22bstr-uoyabnlmn) Butoxycarbonylamino- (methoxy-methyl-carbamoyl)- ,-i(erty-methxyca rbon aml) pentanedioic acid 1- butyrc acid benzyI ester -mtoyehlcab ol) benzyl ester butyric acid benzyl ester DIBAL, THF BnO "-] HCI 1 HN COQEt Pd/C, H 2 -78 OC N(BOC) 2 HN COt BnOOC EtOH 22bstr- NaBH(OAC) 3 N(BoC) 2 Butoxycarbonylamino)-5- 2,2-bis(tert oxo-pentanoic acid Butoxycarbonylamino)-5-(1 benzyl ester ethoxycarbonyl-ethylamino) pentanoic acid benzyl ester HN COQOt HAru, NMM EtOOC~ N HCI, Dioxane HOOC DMF :PDCM N(BOC)2N(BOC) 2 2,2-bis(tert-Butoxycarbonylamino)-5- 2-[3,3-bis(tert-Butoxycarbonylamino) (1 -ethoxycarbonyl-ethylamino)- 2-oxo-piperidin-1 -yl]-propionic acid pentanoic acid ethyl ester EtOOC ~ N OH, H 2 0 HOOC EtOOC N MeQOCCI -: Q 0 N2 NMM, 0CM HN Y MeOH, H 2 0 HN 0 1H0 o0 2-(3-Amino-2-oxo-pipeddin-1 - 2-(3-Methoxycarbonylamino-2- 2-(3-Methoxycarbonylamino yI)-propionic acid ethyl ester oxo-pipeddin-1-yI)-propionic 2-oxo-piperidin-1-yl) acid ethyl ester propionic acid 512 H00C N NH H 0 00

NH

2 HATU, NMM HN 0 - DMF [1-(2-{5-[4'-(2-Amino-acetyl)-biphenyl-4-yl]-1H 2-(3-Methoxycarbonylamino- imidazol-2-y}-pyrrolidine-1-carbonyl)-2-methyl-propy] 2-oxo-piperidin-1-yl)- carbamic acid methyl ester propionic acid HN H O/O NH 4 0Ac 10 0 NH N xylenes, 130 C (1 -{1 -[2-(4'-{2-[1-(2-Methoxycarbonylamino- HN 3-methyl-butyryl)-pyrrolidin-2-yl]-3H- O imidazol-4-yl}-biphenyl-4-yl)-2-oxo- O ethylcarbamoyl]-ethyl}-2-oxo-piperidin-3-yl) carbamic acid methyl ester H 0 H N N -N~ N 0 NN \ NH HN (1-{1 -[4-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-y}-biphenyl-4-y)-1 H-imidazol-2 yl]-ethyl}-2-oxo-piperidin-3-yI)-carbamic acid methyl ester 2 -tert-Butoxycarbonylamino-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester: 4 Methylmorpholine (9.77 mL, 88.9 mmol) was added to a suspension of 2-tert 5 butoxycarbonylamino-pentanedioic acid I -benzyl ester (6 g, 17.7 mmol), and HATU (8.11 g, 21.3 mmol) in dimethylformamide (20 mL). After 5 minutes NO- dimethylhydroxylamine hydrochloride (2.60 g, 26.7 mmol), was added to the solution. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (150 mL), and washed with water (100 mL), aqueous hydrogen chloride (0.5 N, 2 x 100 mL), saturated sodium 10 bicarbonate (100 mL), and saturated sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to yield 2-tert-butoxycarbonylamino-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester (6.8 15 g, 17.8 mmol, 99 %). C 19

H

28

N

2 0 6 calculated 380.2 observed [M + 1] 381.2; rt = 2.48 min. 513 2

,

2 -bis(tert-Butoxycarbonylamino)-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester: Di-tert-butyl dicarbonate (4.20 g, 19.6 mmol) was added to a solution of 2-tert butoxycarbonylam ino-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester (6.8 g, 17.8 5 mmol) and dimethylamino pyridine (436 mg, 3.5 mmol) in acetonitrile (40 mL). After 16 hours starting material remained and di-teri-Butyl dicarbonate (4.20 g, 19.6 mmol) was added again. After 6 days the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (250 mL), washed with water (2 x 100 mL) and saturated ammonium chloride (100 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure. The 10 residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 2,2-bis(tert-butoxycarbonylamino)-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester (8.2 g, 17.0 mmol, 95 %). C 24

H

36

N

2 0 6 calculated 480.3 observed [M + I]* 481.1; rt = 2.83 min. 15 2,2-bis(tert-Butoxycarbonylamino)-5-oxo-pentanoic acid benzyl ester: A solution of DIBAL (1.0 M, 14.7 mL, 14.7 mmol) in hexane was added dropwise to a solution of 2,2-bis(tert butoxycarbonylamino)-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester (4 g, 10.5 mmol) under an atmosphere of nitrogen at -78*C. After 2 hours the mixture was quenched with 20 saturated ammonium chloride (30 mL) and allowed to warm to room temperature. Water (20 mL) was added, and the mixture was extracted with diethyl ether (3 x 50 mL). The combined organic phases were left to stand at room temperature for 15 minutes. The resulting thick gel was filtered through a pad of CELITE. The filtrate was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to provide 2,2-bis(tert-butoxycarbonylamino) 25 5-oxo-pentanoic acid benzyl ester (3.34 g, 7.9 mmol, 75 %). This was used immediately in the next step. 2,2-bis(tert-Butoxycarbonylamino)-5-(1-ethoxycarbonyl-ethylamino)-pentanoic acid benzyl ester: Sodium triacetoxyborohydride (5 g, 23.5 mmol) was added to a solution of 2,2-bis(tert 30 butoxycarbonylamino)-5-oxo-pentanoic acid benzyl ester (3.34 g, 7.9 mmol) and alanine ethyl ester hydrochloride (3.62 g, 23.5 mmol) in dichloromethane (30 mL). After 1 hour saturated ammonium chloride (10 mL) was added and the mixture was stirred for 5 minutes. The aqueous phase was extracted with dichloromethane (2 x 15 mL), and the combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The 35 resulting residue was subjected to flash chromatography with eluent of (10 % methanol in ethyl 514 acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 2,2-bis(teri-butoxycarbonylamino)-5-(I ethoxycarbonyl-ethylamino)-pentanoic acid benzyl ester (1.7 g, 3.3 mmol, 41 %). C 2 7

H

4 2

N

2 0 8 calculated 522.3 observed [M + 1]+ 523.3; rt = 2.08 min. 5 2,2-bis(tert-Butoxycarbonylamino)-5-(1-ethoxycarbonyl-ethylamino)-pentanoic acid: 2,2 bi s(tert-Butoxycarbonylamino)-5-(I -ethoxycarbonyl-ethylamino)-pentanoic acid was prepared using method 803, substituting 2,2-bis(tert-butoxycarbonylamino)-5-(I -ethoxycarbonyl ethylamino)-pentanoic acid benzyl ester for (3-tert-butoxycarbonylamino-2-oxo-piperidin- I-yl) 10 acetic acid benzyl ester. C 20

H

36

N

2 0 8 calculated 432.3 observed [M + 1]*433.1; rt = 1.73 min. 2-13,3-bis(tert-Butoxycarbonylam ino)-2-oxo-piperidin-1 -ylJ -propion ic acid ethyl ester: HATU (1.72 g, 4.5 mmol) was added to a solution of 2,2-bis(tert-butoxycarbonylamino)-5-(1 ethoxycarbonyl-ethylamino)-pentanoic acid (1.31 g, 3.0 mmol) and 4-methylmorpholine in 15 dimethylformamide (50 mL). After 30 minutes the solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 2-[3,3-bis(tert-butoxycarbonylamino)-2-oxo-piperidin- I -yl]-propionic acid ethyl ester (1.11 g, 2.6 mmol, 86 %). C 20

H

34

N

2 0 7 calculated 414.2 observed [M + 1]*415.2; rt 20 = 2.77 min. 2-(3-Amino-2-oxo-piperidin-1 -yl)-propionic acid ethyl ester: 2-(3-Amino-2-oxo-piperidin-1 yl)-propionic acid ethyl ester was prepared using method 804 substituting 2-[3,3-bis(tert butoxycarbonylamino)-2-oxo-piperidin-1-yl]-propionic acid ethyl ester for {1-[5-(4'-{2-[1-(2 25 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl) 1 H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C IOH 1 8

N

2 0 3 calculated 214.2 observed [M + 1]*215.2; rt = 1.21 min. The following (carbamate formation) constitutes an example of Method 806 30 2-(3-Methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester: Methyl chloroformate (192 pL, 2.5 mmol) was added to a solution of 2-(3-amino-2-oxo-piperidin-1-yl) propionic acid ethyl ester (353mg, 1.6 mmol) and 4-methylmorpholine (907 RL, 8.24 mmol) in dichloromethane (10 mL). After 15 minutes the mixture was diluted with dichloromethane (20 35 mL) and washed with water (10 mL), and aqueous hydrogen chloride (0.5 N, 10 mL). The 515 organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to provide 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yI)-propionic acid ethyl ester (332 mg, 1.2 mmol, 75 %). C 12

H

20

N

2 0 5 calculated 272.1 observed [M + 1]+ 273.0; rt = 1.82 min. 5 2-(3-Methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid: 2-(3 Methoxycarbonylamino-2-oxo-piperidin-I-yl)-propionic acid was prepared by method 801 substituting 2-(3-methoxycarbonylamino-2-oxo-piperidin-I-yl)-propionic acid ethyl ester for 4 oxo-hexahydro-pyrrolo[I,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester. 10 CiaH 1 6

N

2 0 5 calculated 244.1 observed [M + 1]+ 245.1; rt = 1.53 min. (1-{1-[2-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yll-3H im idazol-4-yl} -biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-ethyl}-2-oxo-piperidin-3-yl)-carbamic acid methyl ester: A solution of 2-(3-methoxycarbonylamino-2-oxo-piperidin-I-yl)-propionic 15 acid (48.5 mg, 0.20 mmol), HATU (91 mg, 0.24 mmol), and 4-methylmorpholine (109 [tL, 0.99 mmol) in dimethylformamide (5 mL) was stirred at ambient temperature for 5 minutes. [1-(2 {5-[4'-(2-Amino-acetyl)-biphenyl-4-yl]-I H-imidazol-2-yl}-pyrrolidine-l -carbonyl)-2-methyl propyl]-carbamic acid methyl ester (100 mg, 0.20 mmol) was added to the reaction mixture. After 40 minutes the solvent was removed under reduced pressure and the resulting residue was 20 taken up in ethyl acetate (10 mL). The resulting mixture contained a solid and was subjected to flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane followed by 30 % methanol in DCM. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide (1-{1-[2-(4'-{2-[I-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl] 25 ethyl}-2-oxo-piperidin-3-yl)-carbamic acid methyl ester (149 mg, 0.20 mmol, 99%).

C

3 8

H

4 7

N

7 0 8 calculated 729.4 observed [M + 1]+ 730.6; rt = 1.78 min. (1-{1-[4-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yl}-biphenyl-4-yI)-1 H-imidazol-2-ylI-ethyl}-2-oxo-piperidin-3-yl)-carbamic acid 30 methyl ester: A mixture of ammonium acetate (157 mg, 2.0 mmol), (1-{1-[2-(4'-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yI}-biphenyl-4-yl)-2 oxo-ethylcarbamoyl]-ethyl}-2-oxo-piperidin-3-yl)-carbamic acid methyl ester (149 mg, 0.20 mmol) and xylenes (20 mL) was heated at 130*C for 1 hour. The solvent was removed under reduced pressure. The residue was taken up in dichloromethane (15 mL) and filtered. The 35 solvent was removed under reduced pressure. The residue was taken up in dimethylformamide 516 (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1 % TFA in water and 0.1 % TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide (1- {-[4-(4'-{2-[I-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3 H -imidazol-4-yl} -biphenyl-4-yl)- I H-imidazol-2-yl]-ethyl }-2 5 oxo-piperidin-3-yI)-carbamic acid methyl ester (20.5 mg, 0.029 mmol, 15 %). C 38

H

4 6

N

8 0 6 calculated 710.4 observed [M + 1]*711.4; rt = 1.59 min. H (DMSO-d6): 8 = 8.10 (m, I H), 7.88 (m, 8H), 7.33 (d, J= 8.7 Hz, 2H), 5.33 (m, I H), 5.12 (t, J = 6.9 Hz, I H), 4.11 (t, J = 9.0 Hz, I H), 3.97 (m, I H), 3.54 (s, 3H), 3.26 (m, 2H), 2.37 (m, I H), 2.26 - 1.74 (series m, 8H), 1.63 (d, J= 6.3 Hz, 3H), 0.81 (dd, J= 6.9 Hz, J= 13.2 Hz, 6H). 517 Example AZI 0 E.. DCC 0 0 Br 0/NH OH BcOH 0CM KN)_ _____ (teft-Butoxycarbonyl- Boc carboxymethyl-amino)- 2,6-Dioxo-morpholine-4- NMM, DMF acetic acid carboxylic acid tert-butyl ester 2-Amino-i -(4-bromo phenyl)-ethanone BrBxBr 0 0 BocOO

H

2 N COOMe 0 BocK 0 O~ , ,NCOOHHATU, NMM )- ' ACO e H DMFHH ({[2-(4-Bromo-phenyl)-2-oxo- 2-[2-({[2-(4-Bromo-phenyl)-2-oxo ethylcarbamoyl]-methyl)-tert- ethylcarbamoyl]-methyl)-tert-butoxycarbonyl butoxycarbonyl-amino)-acetic acid amino)-acetylamino]-3-methyl-butyric acid U_____H20 0 0 HCI, Dioxane MeOH, THF N Nc NfCOOH H H 0CM 2-[2-({[2-(4-Bromo-phenyl)-2-oxo ethylcarbamoyl]-methyl}-tert-butoxycarbonyl amino)-acetylamino]-3-methyl-butyric acid Br ~ H 0 0 0 N N<N.JQ OH DTMFH~> H H 2-(2-({[2-(4-Bromo-phenyl)-2-oxo- Br etylamoy]-3methyl}-amino)- N-[2-(4-Bromno-phenyl)-2-oxo aey a id-ehy-uyi ethyl]-2-(3-isopropyi-2,5-dioxo acid piperazin-1 -yI)-acetamide 0 H

NH

4 OAc, xylenes ''\ H N N B HN N N -NH 0 NI B 1300 >C Hj/ Zi N/ Br 0 y H N'

-

0 Pd(PPh 3

)

4 , K 2 C0 3 , DME, H 2 0, MW 12000C 1 -[5-(4-Bromo-phenyl)-1 H-imidazol- (2-Methyl-i -(2-{5-[4-(4,4,5, 5-tetramethyl-ji ,3,2]dioxaborolan 2-ylmethyl]-3-isopropyl-piperazine- 2-yl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl) 2,5-dione propyl]-carbamic acid methyl ester H 0\ / N N-j- HN N N - -N I N 0 H HN 0 o {1 -2-(5-{4-[2-(3-Isopropyl-2,5-dioxo-piperazin-1 -yfmethyl)-3H imidazol-4-y]-biphenyl-4-yl)-1 H-imidazol-2-yI)-pyrrolidine-1 -carbonyl] 2-methyl-propyl)-carbamic acid methyl ester 518 2,6-Dioxo-morpholine-4-carboxylic acid tert-butyl ester: A suspension of (tert butoxycarbonyl-carboxymethyl-amino)-acetic acid (5 g, 21.4 mmol) and DCC (4.85 g, 23.6 mmol) in dichloromethane was stirred for 16 hours. The mixture was filtered and the solvent 5 was removed from the filtrate to provide 2,6-dioxo-morpholine-4-carboxylic acid tert-butyl ester (4.86 g, 21.0 mmol, 99 %). ([2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyll -methyl}-tert-butoxycarbonyl-am ino)-acetic acid: 2,6-Dioxo-morpholine-4-carboxylic acid tert-butyl ester (2.5 g, 11.6 mmol) was added to 10 a solution of 2-amino-1 -(4-bromo-phenyl)-ethanone hydrochloride (3.05 g, 12.2 mmol) and 4 methylmorpholine (1.92 mL, 17.4 mmol) in dimethylformamide (15 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and washed with water (50 mL), aqueous hydrogen chloride (0.5 N, 2 x 50 mL), and saturated sodium bicarbonate (2 x 50 mL). The basic extracts were neutralized and extracted 15 with ethyl acetate (2 x 75 mL). The combined organic phases from the second extraction were dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to provide ({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino) acetic acid (4 g, 9.3 mmol, 80 %). C 17

H

2 IBrN 2 0 6 calculated 428.0 observed [M + 1]+431.1; rt = 2.36 min. 20 2-12-({[ 2

-(

4 -Bromo-phenyl)-2-oxo-ethylcarbamoyl-methyl}-tert-butoxycarbonyl-amino) acetylaminol-3-methyl-butyric acid methyl ester: 4-Methylmorpholine (4.1 mL, 37.3 mmol) was added to a suspension of ({[ 2 -(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert butoxycarbonyl-amino)-acetic acid (4 g, 9.3 mmol), and HATU (4.61 g, 12.1 mmol) in 25 dimethylformamide (25 mL). After 5 minutes d-valine methyl ester hydrochloride (1.56 g, 9.3 mmol), was added to the solution. After I hour the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (150 mL), and washed with water (100 mL), aqueous hydrogen chloride (0.5 N, 2 x 100 mL), saturated sodium bicarbonate (100 mL), and saturated sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered 30 and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to yield 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino) acetylamino]-3-methyl-butyric acid methyl ester (4.37 g, 8.1 mmol, 87 %). C 23

H

32 BrN 3 07 35 calculated 541.1 observed [M + 1]* 431.1; rt = 2.65 min. 519 2-[ 2 -({[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino) acetylaminol-3-methyl-butyric acid: 2-(2-({[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl] methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid was prepared using 5 method 801 substituting 2-[2-({{2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl)-tert butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid methyl ester for 4-oxo-hexahydro pyrrolo[l,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester. C 2 2

H

30 BrN 3 07 calculated 527.1 observed [M + 1]* 528.1; rt = 2.39 min. 10 2

-[

2

-({[

2

-(

4 -Bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-amino)-acetylamino]-3 methyl-butyric acid: 2-[2-({[ 2 -(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl} -amino) acetylamino]-3-methyl-butyric acid was prepared using method 804 substituting 2-[2-({[2-(4 bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3 methyl-butyric acid for l-[5-(4'-{2-[l-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 15 2-yl]-3 H-imidazol-4-yl}-biphenyl-4-yl)- IH-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl} carbamic acid tert-butyl ester. C 17

H

2 2 BrN 3 0 5 calculated 427.1 observed [M + 1]+ 428.0; rt = 2.39 min. N-12-(4-Bromo-phenyl)-2-oxo-ethyll-2-(3-isopropyl-2,5-dioxo-piperazin-1-yl)-acetamide: 20 HATU (3.70 g, 9.7 mmol) was added to a solution of 2-[2-({[2-(4-bromo-phenyl)-2-oxo ethylcarbamoyl]-methyl}-amino)-acetylamino]-3-methyl-butyric acid (2.78 g, 6.5 mmol), and 4 methylmorpholine (3.57 mL, 32.5 mmol) in DMF (I0mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (150 mL) and washed with water (50 mL), aqueous hydrogen chloride (0.5 N, 2 x 50 mL), saturated sodium 25 bicarbonate (50 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield N-[2-(4-bromo-phenyl) 2 -oxo-ethyl]-2-(3-isopropyl-2,5-dioxo-piperazin- I -yl)-acetamide (1.56 g, 3.8 mmol, 60 %). 30 C 1 7

H

20 BrN 3 0 4 calculated 409.1 observed [M + 1]*410.1; rt = 2.00 min. {1-12-(5-{4'-[2-(3-Isopropyl-2,5-dioxo-piperazin-1-ylmethyl)-3H-imidazol-4-yI]-biphenyl-4 yl}- 1 H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: {I-[2-(5-{4'-[2-(3-Isopropyl-2,5-dioxo-piperazin-1-ylmethyl)-3H-imidazol-4-yI] 35 biphenyl-4-yl}-1 H-imidazol-2-yl)-pyrrolidine-l -carbonyl]-2-methyl-propyl}-carbamic acid 520 methyl ester was prepared using the imidazole cyclization from method 802, substituting N-[2

(

4 -bromo-phenyl)-2-oxo-ethyl]-2-(3-isopropyl-2,5-dioxo-piperazin- I -yl)-acetamide for 6-[2-(4 bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[ I,2-a]pyrazine-2-carboxylic acid methyl ester and using [2-Methyl-I -(2-{5-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2 5 yl)-phenyl]-l H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-propyl]-carbamic acid methyl ester in the coupling reaction. C 37 H44N 8

O

5 calculated 680.3 observed [M + 1]* 681.4; rt = 1.57 min. 1 H (DMSO-d6): 6 = 8.39 (d, J = 3.0 Hz, I H), 8.11 (m, I H), 8.04 (m, I H), 7.88 (m, 5H), 7.33 (d, J = 8.7 Hz, I H), 8.13 (m, I H), 4.79 (m, I H), 4.65 (d, J= 15.9 Hz, I H), 4.26 - 4.02 (m, 2H), 3.83 (m, 2H), 3.73 (m, I H), 3.54 (s, 3H), 2.38 (m, I H), 2.14 (m, 2H), 2.05 (m, 2H), 8.40 (m, 8H).: 10 521 The following 3 steps (Sonogashira coupling, SEM protection, Boc deprotection) constitute an example of method 807 Example BA Bo0 H~~ N ~N Bo-o Br ~ ~ N HCul, TEA, Pd(PPh 3

)

4 , DMF, 80 0 C (1 -{2-[4-(4-EthynyI-pheny)-1 H-imidazol-2-y] 4-(4-Bromo-phenyl)-3'-(2- pyrrolidine-1 -carbonyl}-2-methy-propy) methoxycarbonylamino-3-methyl-butyryl)- carbamic acid methyl ester 2',3,4',5-tetrahydro-1 H-[2,4']biimidazoyl 1 -carboxylic acid tert-butyl ester Boc N> SEMCI, NaH 10 rH N~ NH DMF 3'-(2-Methoxycarbonyiamino-3-methylbutyryl)j44(4-{2-[1-(2 methoxycarbonyIamino-3-methyl-butyryI)..pyrrolidin2-yl]1H-imidazol-4-y} phenylethynyl)-phenyll-2',3,4',5'tetrahydr&.1 H-[2,4J]biimidazolyl-carboxylic acid tert-butyl ester Boo SEM SEM > N C N H cj 1N0 - HCI, Dioxane 0 0jN\N DCM 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)A-[4-(4-{2(1-(2 methoxycarbonylamino-3-methylkbutyryl)-pyrrolidin-2yl I -(2-tnmethylsilanyl ethoxymethyl)-1 H-imidazol-4-yl}-phenylethynyl)..phenyl]1 -(2-trimethylsilanyl ethoxymethyl)-2,3',4',5-tetrahydro-1 H-[2,4']biimidazoly-l -carboxylic acid tert-butyI 5 ester 522 H SEM SEM -- N 1. MeOOCCI, NMM, O N

-

N 2. TFA, DCM N N N HI C 3. NaOH,

H

2 0 MeOH, THF 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl ethoxymethyl)-1H-imidazol-4-yI}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl ethoxymethyl)-2',3',4',5'-tetrahydro-1 H-[2,4']biimidazole 0O -_O NN O HN" - NH N _ -0 0 0 0 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl} phenylethynyl)-phenyl]-2',3',4',5'-tetrahydro-1H-[2,4']biimidazolyl-1 carboxylic acid methyl ester 3 '-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-IH-imidazol-4-yI}-phenylethynyl)-phenyl]-2',3',4',5' 5 tetrahydro-1H-12,4'lbiimidazolyl-l'-carboxylic acid tert-butyl ester: A mixture of 4-(4 bromo-phenyl)-3'-(2-methoxycarbonylamino-3-methyl-butyryl)-2',3',4',5'-tetrahydro- 1 H [2,4']biimidazolyl- '-carboxylic acid lert-butyl ester (686 mg, 1.74 mmol), (1 -{2-[4-(4-ethynyl phenyl)-l H-imidazol-2-yi]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (800 mg, 1.45 mmol), copper([) iodide (28 mg, 0.14 mmol), 10 tetrakis(triphenylphosphine)palladium(0) (167 mg, 0.14 mmol), triethylamine (2.0 mL, 14.5 mmol) and degassed dimethylformamide (10 mL) was stirred at 80'C for I hour. (1-{2-[4-(4 Ethynyl-phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl} -2-methyl-propyl)-carbamic acid methyl ester (200 mg, 0.57 mmol) was added. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (50 mL) and washed with water 15 (10 mL), saturated ammonium chloride (2 x 10 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to yield 3'-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[ I -(2-methoxycarbonylamino 20 3-methyl-butyryl)-pyrrolidin-2-yl]- I H-imidazol-4-yl}-phenylethynyl)-phenyl]-2',3',4',5' tetrahydro- 1 H-[2,4']biimidazolyl- '-carboxylic acid tert-butyl ester (439 mg, 0.50 mmol, 35%). 523

C

4 6

H

57

N

9 0 8 calculated 863.4 observed [M + 1]+ 864.5; rt = 1.91 min. 'H (DMSO-d6): 5 = 8.07 (m, I H), 7.76 (m, 4H), 7.68 (m, H), 7.56 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 8.8 Hz, I H), 5.37 (m, I H), 5.21 (m, I H), 5.08 (m, 2H), 4.80 (m, I H), 4.07 (t, J= 7.2 Hz, 2H), 3.81 (m, 2H), 3.52 (s, 3H), 3.51 (s, 3H), 2.33 (m, 2H), 2.08 (m, I H), 1.97 (m, 4H), 1.39 (s, 9H), 1.34 (m, 2H), 0.81 (m, 5 12H). H HO 0 H NI N N N -N /O {1-[2-(5-{4-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-phenyl)-buta-1,3-diynyl]-phenyl}-1H-imidazol-2-yl) pyrrolidine-1 -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester {1-[ 2

-(

5

-{

4

-[

4

-(

4

-{

2 -[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 10 imidazol-4-yl}-phenyl)-buta-1,3-diynyl]-phenyl}-1H-imidazol-2-yI)-pyrrolidine-1 carbonyll-2-methyl-propyl}-carbamic acid methyl ester: { I -[2-(5-{4-[4-(4-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-buta 1,3-diynyl]-phenyl}-1 H-imidazol-2-yl)-pyrrolidine-l-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was also isolated in the flash chromatography. The fractions containing this 15 product were combined and the solvent was removed under reduced pressure. The resulting residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1 % TFA in water and 0.1 % TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 20 { 1-[2-(5-{4-[4-(4-{2-[l-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenyl)-buta-1,3-diynyl]-phenyl}-I H-imidazol-2-yl)-pyrrolidine- I -carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (83.2 mg, 0.10 mmol). C 4 4

H

5 oN 8 0 6 calculated 786.4 observed [M + 1]+ 787.6; rt = 2.59 min ' H (DMSO-d6): 6 = 8.06 (s, 2H), 7.79 (m, 4H), 7.72 (m, 4H), 7.28 (d, J = 8.8 Hz, 2H), 5.08 (t, J 25 = 7.2 Hz, 2H), 4.07 (t, J= 8.0 Hz, 2H), 3.80 (m, 4H), 3.51 (s, 6H), 2.32 (m, 2H), 2.11 (m, 2H), 1.99 (m 6H), 0.84 (m, I H), 0.78 (dd, J = 6.8 Hz, J = 17.6 Hz, 12H). 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yIl-1-( 2 -trimethylsilanyl-ethoxymethyl)-1 H-imidazol-4-yl} 30 phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2',3',4',5'-tetrahydro-1H 524 12,4']biimidazolyl-1'-carboxylic acid tert-butyl ester: Sodium hydride (60 % in mineral oil, 27 mg, 0.55 mmol) was added to a solution of 3

'-(

2 -methoxycarbonylamino-3-methyl-butyryl) 4-[4-(4- {2- [1-( 2 -methoxycarbonylamino-3-methyl-butyry)-pyrroidin-2-yl] - H-imidazol-4-yl} phenylethynyl)-phenyl]-2',3',4',5'-tetrahydro- I H-[2,4']biimidazolyl- '-carboxylic acid tert-butyl 5 ester (248 mg, 0.23 mmol) in dimethylformamide (8 mL) under an atmosphere of nitrogen at 0 0 C. After 15 minutes 2-(trimethylsilyl)ethoxymethyl chloride (107.5 RL, 0.48 mmol) was added and the reaction was allowed to warm to ambient temperature. After 2 hours the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (50 mL) washed with water (20 mL), and dried over sodium sulfate and filtered. The solvent was 10 removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10 % methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 3'-(2 methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4- {2-[1 -(2-methoxycarbonylam ino-3-methyl butyryl)-pyrrolidin-2-yl]- I -(2-trimethylsilanyl-ethoxymethyl)- I H-imidazol-4-yl} 15 phenylethynyl)-phenyl]- I -( 2 -trimethylsilanyl-ethoxymethyl)-2',3',4',5'-tetrahydro- I H

[

2 ,4']biimidazolyl-l'-carboxylic acid lert-butyl ester (410 mg, 0.36 mmol). C 5 8

H

85

N

9

O

10 Si 2 calculated 1123.6 observed [M + I] 1124.7; rt = 3.10 min. 3

'-(

2 -Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3 20 methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-4-yl} phenylethynyl)-phenyl]-1-( 2 -trimethylsilanyl-ethoxymethyl)-2',3',4',5'-tetrahydro-1

H

12,4']biimidazole: 3

'-(

2 -Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrol idin-2-yl]- I -(2-trimethylsi lanyl-ethoxymethyl) I H-imidazol-4-yl}-phenylethynyl)-phenyl]-l -(2-trimethylsilanyl-ethoxymethyl)-2',3',4',5' 25 tetrahydro-I H-[2,4']biimidazole was prepared using method 804 substituting 3'-(2 methoxycarbonylam ino-3-methyl-butyryl)-4-[4-(4- { 2-[]-(2-methoxycarbonylam i no-3-methyl butyryl)-pyrrolidin-2-yl]-I-( 2 -trimethylsilanyl-ethoxymethyl)- IH-imidazol-4-yl} phenylethynyl)-phenyl]-I-(2-trimethylsilanyl-ethoxymethyl)-2',3',4',5'-tetrahydro-

IH

[2,4']biimidazolyl- '-carboxylic acid tert-butyl ester for { 1-[5-(4'-{2-[1-(2 30 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl) I H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-y}-carbamic acid tert-butyl ester. C 53

H

77

N

9 0 8 Si 2 calculated 1023.5 observed [M + 1]+ 1024.7; rt = 2.81 min. 525 The following step constitutes an example of method 808. 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-2',3',4',5' 5 tetrahydro-1H-[2,4']biimidazolyl-l'-carboxylic acid methyl ester: Methyl chloroformate (15 gL, 0.19 mmol) was added to a solution of 3'-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4 (4-{2-[ I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl ethoxymethyl)- IH-imidazol-4-yl}-phenylethynyl)-phenyl]- I-(2-trimethylsilanyl-ethoxymethyl) 2',3',4',5'-tetrahydro- IH-[2,4']biimidazole (97 mg, 0.09 mmol), and 4-methylmorpholine (40 pL, 10 0.36 mmol) in dichloromethane (3 mL). After 30 minutes the solvent was removed under reduced pressure and azeotroped with toluene. The residue was taken up in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added. After 16 hours the volatiles were removed under reduced pressure and the residue was taken up in tetrahydrofuran (4 mL) and methanol (2 mL). An aqueous solution of sodium hydroxide (2 N, I mL) was added. After 30 min the 15 organic solvents were removed under reduced pressure and the resulting precipitate was isolated by filtration. The solid was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1 % TFA in water and 0.1 % TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3'-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[I1-(2 20 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]- I H-imidazol-4-yl }-phenylethynyl) phenyl]-2',3',4',5'-tetrahydro- I H-[2,4']biimidazolyl- '-carboxylic acid methyl ester (14.1 mg, 0.017 mmol, 10 %).

C

43

H

5

N

9 0 8 calculated 821.4 observed [M + 1]* 822.8; rt = 1.72 min. 1 H (DMSO-d6): 6 = 8.07 (m, I H), 7.77 (m, 7H), 7.67 (m, 2H), 7.57 (m, 3H), 7.29 (d, J= 8.4 Hz, I H), 5.41 (m, I H), 5.27 25 (d, J= 5.6 Hz, I H), 5.15 (d, J= 5.6 Hz, 1 H), 5.08 (t, J= 7.6 Hz, 2H), 4.07 (t, J= 13.2 Hz, 2H), 3.83 (m, 2H), 3.76 (m, 2H), 3.64 (s, 3H), 3.58 (m, I H), 3.52 (s, 3H), 3.51 (s, 3H), 2.33 (m, 2H), 2.13 (m, I H), 2.03 (m, 5H), 1.90 (m, 2H), 0.805 (m, 18H). 526 Example BB O -N H HO O H N N -- N J N N~ 0 (1-{2-[5-(4-{4-[1'-Acetyl-3'-(2-methoxycarbonylamino-3-methyl-butyryl) 2',3',4',5'-tetrahydro-3H,1'H-[2,4']biimidazolyl-4-yl]-phenylethynyl}-phenyl) 1 H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1 -{2-[5-(4-{4-[ l'-Acetyl- 3

'-(

2 -methoxycarbonylamino-3-methyl-butyryl)-2',3',4',5'-tetrahydro 5 3 H, I'H-[2,4']biimidazolyl-4-yl]-phenylethynyl}-phenyl)- 1 H-imidazol-2-yl]-pyrrolidine- 1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester was prepared following method 808 in Example BA substituting acetic anhydride for methyl chloroformate in the first step of the synthesis. C 43 1H 5

N

9 0 7 calculated 805.4 observed [M + 1]+ 806.5; rt = 1.65 min; 1 H (DMSO d6): 8 = 8.06 (m,l H), 776 (m, 6H), 7.68 (m, 3H), 7.56 (d,J= 7.6 Hz, 3H), 7.29 (d, J= 9.2 Hz, 10 11H), 5.47 (m, I H), 5.38 (m, I H), 5.27 (m,l H), 5.18 (m,l H), 5.08 (t,J= 6.8 Hz, 2H), 4.17 (m,1 H), 4.07 (t, J= 8.0 Hz, 2H), 3.93 (m, 2H), 3.84 (m, 4H), 3.52 (s, 3H), 3.51 (s, 6H), 3.37 (m, I H), 2.34 (m, 2H), 2.13 (m, I H), 1 .99 (m, 12H), 0.81 (m, 1 8H). Example BC Boc N 0 H N N -- N N -Nl/ HN O 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3{5-[4-(4-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl} phenylethynyl)-phenyl]-1 H-imidazol-2-yi}-piperazine-1 -carboxylic acid tert 15 butyl ester 4

-(

2 -Methoxycarbonylamino-3-methyl-butyryl)-3-{ 5-[4-(4- {2-[ I -(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]- I H-imidazol-2-yl} piperazine-I-carboxylic acid tert-butyl ester was prepared following step one of method 807, 20 substituting (I -{2-[4-(4-bromo-phenyl)-t H-imidazol-2-yl]-piperazine- I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester for 4-(4-bromo-phenyl)-3'-(2-methoxycarbonylamino-3 527 methyl-butyryl)-2',3',4',5'-tetrahydro-I H-[2,4']biimidazolyl-l'-carboxylic acid tert-butyl ester in the first step of Example BA. C 4 7

H

59

N

9 0 8 calculated 877.5 observed [M + ]]* 878.5; rt = 1.65 min 'H (DMSO-d6): 8 = 8.08 (m, I H), 7.78 (m, 4H), 7.68 (m, 2H), 7.54 (m, 2H), 7.29 (d, J = 9.2 5 Hz, 2H), 5.54 (m, I H), 5.08 (t, J= 6.0 Hz, I H), 4.32 (m, 2H), 4.07 (t, J= 8.0 Hz, 2H), 3.81 (m, 4H), 3.52 (s, 3H), 3.51 (s, 3H), 3.41 (m, I H), 2.34 (m, I H), 2.14 (m, I H), 2.00 (m, 4H), 1.28 (3, 3H), 1.17 (br s, 3H), 0.80 (m, 12 H). Example BD H H H 7) OO N N -- N N HN0 [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-piperazin-2-yl] 3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1 10 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-piperazin-2-yl]-3H imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyl]-carbamic acid methyl ester was prepared following method 807 15 substituting (1-12-[4-(4-bromo-phenyl)-1H-imidazol-2-yll-piperazine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester for 4-(4-bromo-phenyl)-3'-(2 methoxycarbonylamino-3-methyl-butyryl)-2',3',4',5'-tetrahydro-1 H-[2,4']biimidazolyl l'-carboxylic acid tert-butyl ester. Followed by method 808, substituting [1-(2-{5-[4-(4 {2-[1-( 2 -methoxycarbonylamino-3-methyl-butyryl)-piperazin-2-yl]-1-(2 20 trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2 trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl propyll-carbamic acid methyl ester for 3'-(2-methoxycarbonylamino-3-methyl-butyryl) 4-[4-(4-12-[1-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2 trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2 25 trimethylsilanyl-ethoxymethyl)-2',3',4',5'-tetrahydro-1H-[2,4'lbiimidazole and leaving 528 out methyl chloroformate. C42H51N906 calculated 777.4 observed [M + 1]+ 778.4; rt = 1.58 min. 'H (DMSO-d6): 6 = 9.30 (m, 1H), 7.9 (m, 2H), 7.75 (m, 3H), 7.63 (m, 2H), 7.52 (m 2H), 7.28 (d, J = 8.0 Hz, 1H), 5.96 (1H), 5.07 (m, 1H), 4.49 (m, 1H), 4.28 (m, 2H), 4.06 (m, 2H), 5 3.80 (m, 4H), 3.56 (m, 1H), 3.53 (s, 3H), 3.51 (s, 3H), 3.27 (m, 2.12 (m, 1H), 1.96 (m, 4H), 0.95 (m, 1H), 0.81 (m, 12H). Example BE 40, ,0 H B-B,

NH

2 EtOH N N O O Br N2+ OHC~ N-cMcoae 0G rN o Bis(pinacolato)diboro~n

NH

2 N Microwave, 80 OC Br -0 -N Bo Pd(dPPQ 2

C

2 4-Bromo-benzene- 2-Formyl-pyrrolidine-1- 2-(6-Bromo-1H-benzoimidazol- KOAc, dioxane, 95 0 C benzidazo- 2-yl] -pyrrolidine- [5,5']bi2-yl)-pyrrolidine- n-carboxylic 1,2-diamine carboxylic acid tert-butyl acid tert-butyl ester ester H H HN N N N Boc NB0C oc N N Boc N Boc B HO ON Pd(PPh 3

)

4 , K 2 00 3 U 2-[6-(4,4,5,5-Tetramethy1- 2-2'-(l-Boc-pyrrolidin)2-y-)-3H,3H [1,3,2]dioxaborolan-2-y)-1 p' [5,5]bibenzimidazotyl-2-y]-pyrrolidine-l 100 2(-r-Hbenzoimidazo-2-yl)-pyrrolidine-1- carboxylic acid tert-buty ester : ter-butyl acidtert(2.5u g)y i eser hnl( L a etdi irwv t8* o or itr was cocetatdAn puife Hyfahclm homtgah slc gl0t 0 ty 2. HATU, DIEA N C 3 N 1H 0 N 0 HO 1-(2{2'-[1-(2-Methoxycarbonylamino-3-methy-butyryl) 2-Methoxycarbonylamino-3- pyrrolidin-2-yg-3H,3H1-[5,5]bibenzoimidazoy-2-y)-pyrroidine methyl-butyric acid 1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 10 2-(6-bromo-1 H-benzoimidazol-2-yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester: A mixture of 4-bromo-benzene-I,2-diamine (2.4 g) and 2-formyl-pyrrolidine-I-carboxylic acid tert-butyl ester (2.55 g) in ethanol (5 mL) was heated in microwave at 80 0 C for 1 hour. Mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl 15 acetate/hexane) to give 2-(6-bromo-I H-benzoimidazol-2-yl)-pyrrolidine-l -carboxylic acid tert butyl ester (2.6 g, yield 55%). LCMS-ESIU: calc'd for C 16

H

2 oBrN 3

O

2 : 366.25; Found: 365.8 (M+H*). 529 2-[6-(4,4,5,5-tetramethyl-I1,3,2]dioxaborolan-2-yl)-1 H-benzoimidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester: A mixture of 2-(6-bromo-I H-benzoimidazol-2-yl) pyrrolidine- -carboxylic acid tert-butyl ester (890 mg, 2.43 mmol), bis(pinacolato)diboron(l.36g, 5.35 mmol), [1,1' 5 bis(diphenylphosphino)ferrocene]dichloropalladium(lI)(99 mg, 0.12 mmol) and potassium acetate (620 mg, 6.32 mmol) in 15 mL dioxane was heated to 95*C for 4 hour. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[6-(4,4,5,5-tetramethyl 10 [l,3,2]dioxaborolan-2-yl)-1 H-benzoimidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (588 mg, yield 59%). LCMS-ESI-: calc'd for C 32

H

2 0

BN

3 0 4 : 413.32; Found: 414.0 (M+H*). 2-[2'-(1-Boc-pyrrolidin-2-yI)-3H,3'H-15,5']bibenzoimidazolyl-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester: A mixture of 2-(6-bromo-I H-benzoimidazol-2-yl) 15 pyrrolidine-l -carboxylic acid tert-butyl ester (64 mg, 0.174 mmol), 2-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)- IH-benzoimidazol-2-yl]-pyrrolidine-I-carboxylic acid tert-butyl ester (72 mg, 0.174 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol) and potassium carbonate (48 mg, 0.35 mmol) in 2 ml 1,2-dimethoxyethane and I mL water was heated to II 0C in microwave for 15 minutes. The reaction mixture was cooled and dissolved 20 in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 10% methanol/ethyl acetate) to give 2-[2'-(I-Boc-pyrrolidin-2-yl)-3H,3'H-[5,5']bibenzoimidazolyl-2 yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (15 mg, yield 15%). LCMS-ESI-: calc'd for

C

3 2

H

40

N

6 0 4 : 572.70; Found: 573.1 (M+H+). 25 [1-(2-{2'-[ 1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H,3'H 15,5']bibenzoimidazoly-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: Trifluoroacetic acid (0.5 mL) was added to (2-[2'-(l-Boc-pyrrolidin-2-yl) 3H,3'H-[5,5']bibenzoimidazolyl-2-yl]-pyrrolidine-I -carboxylic acid tert-butyl ester (15 mg, 30 0.0262 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (1.5 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl butyric acid (10 mg, 0.058 mmol), diisopropylethylamine (27 PL), followed by HATU (20 mg). Reaction mixture was stirred at 0 0 C for 60 minutes. The reaction mixture was dissolved in ethyl 35 acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried 530 (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100%

ACN/H

2 0 + 0.1% TFA). Product was lyophilized to give [I-(2-{2'-[l-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H,3'H-[5,5']bibenzoimidazolyl-2 yl}-pyrrolidine-I-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester as the bis-TFA salt 5 (8.1 mg). 'H-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: 8.02 (s, 2H), 7.88 (m, 4H), 5.38 (m, 2H), 4.27(d, 2H), 4.12(m, 2H), 3.96 (m, 2H), 3.62 (s, 6H), 2.62 (m, 2H), 2.40-2.20 (m, 6H), 2.08(m, 2H), 0.95 0.85 (m, 12 H); LCMS-ESI*: calc'd for C 36

H

4 6

N

8 0 6 : 686.80; Found: 687.3 (M+H*). 10 Example BF Hoo N / N + qB //OBBPd(PPh 3

)

4 , K 2 CO3 Br N Boc O O DME, water, microwave Br_6 NBoc t 120 OC 2-(6-Bromo-1H-benzoimidazol- 4,4'-bipheynldiboronic acid 2-yl)-pyrrolidine-1-carboxylic dipinacol ester acid teft-butyl ester Boc N \ B 2-[5-Bromo-1-(2-trmethylsilanyl H I Br ethoxymethy)-1H-imidazo-2-y] N N pyrrolidine-1-carboxylic acid tert o -- -- SEM butyl ester B N Boc Pd(dppf) 2

C

2 , Pd(PPh 3

)

4 , 2-(6-[4'-(4,4,5,5-Tetramethyl- K 2

CO

3 , 90 0 C [1,3,2]dioxaborolan-2-y)-biphenyl-4-y]-1H benzoimidazol-2-yl}-pyrrolidine-1 -carboxylic acid tert-butyl ester H Boc N 1TFA I_ - \ / 0 / N Bc 2.HFATU, DIEA _Z N - \/ \/JI SEM HO HO Ir N 2-(6-{4'-[2-(1-Boc-pyrrolidin-2-yl)-3-(2- 0 H 0 trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]- 2-Methoxycarbonylamino-3 biphenyl-4-y}-1 H-benzoimidazol-2-yl)-pyrrolidine-1- methyl-butyric acid carboxylic acid tert-butyl ester 0 HH, NO N N N N (1-{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-16- [4'-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yi)-bipheny-4-yi]-1 H-benzoimidazol-2 yi}-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-(6-bromo-IH 15 benzoimidazol-2-yi)-pyrrolidine-I-carboxylic acid tert-butyl ester (230 mg, 0.628 mmol), 4,4' bipheynidiboronic acid dipinacol ester (1.28 g, 3.14 mmol), 531 tetrakis(triphenylphosphine)palladium (73 mg, 0.063 mmol) and potassium carbonate (521 mg, 3.77 mmol) in 10 ml 1,2-dimethoxyethane and 5 mL water was heated to 120*C in microwave for 40 minutes. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and 5 purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2 {6-[4'-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-I H-benzoimidazol-2-yl} pyrrolidine-l -carboxylic acid tert-butyl ester (15 mg, yield 15%). LCMS-ESI-: calc'd for

C

34

H

40

BN

3 0 4 : 65.51; Found: 566.1 (M+H*). 10 2-(6-{4'-[2-(1 -Boc-pyrrolidin-2-y)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl] biphenyl-4-yl}-1H-benzoimidazol-2-yl)-pyrrolidine-I-carboxylic acid tert-butyl ester: A mixture of 2- ( 6-[4'-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]- I H benzoimidazol-2-yl}-pyrrolidine-l-carboxylic acid tert-butyl ester (147 mg, 0.26 mmol), 2-[5 bromo-l -(2-trimethylsilanyl-ethoxymethyl)-l H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid 15 tert-butyl ester (116 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol), Pd(dppf)Cl 2 (21 mg, 0.026 mmol) and potassium carbonate (72 mg, 0.52mmol) in 3 ml I,2-dimethoxyethane and I mL water was heated to 90"C for 2.5 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by preparative 20 reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give 2-(6-{4'-[2-(I-Boc-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4 yl]-biphenyl-4-yl}-1 H-benzoimidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (52 mg, yield 25%); LCMS-ESlI: calc'd for C 4 6

H

60

N

6 0 5 Si: 805.09; Found: 805.1 (M+H*). 25 (1-{2-[5-(4'-{2-[1-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yI}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: Trifluoroacetic acid (2 mL)was added to 2-(6-{4'-[2-(l Boc-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-ylJ-biphenyl-4-yl} I H-benzoimidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (52 mg, 0.056 mmol) and 30 the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (1.5 mL) and to this solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (20 mg), diisopropylethylamine (59 sL), followed by HATU (43 mg). Reaction mixture was stirred at 0*C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute 35 sodium bicarbonate solution. The organic layer was dried (MgSO 4 ), concentrated and purified 532 by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (I -{2-[5-(4'-{2-[-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-benzoimidazol-5-yl}I -biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt (4.8 mg). 5 1 H-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: 8.0 (s, I H), 7.92-7.82 (m, I I H), 5.38 (t, I H), 5.24 (t, I H), 4.27(dd, 2H), 4.16(m, 2H), 3.96 (m, 2H), 3.63 (s, 6H), 2.62 (m, 2H), 2.40-2.18 (m, 6H), 2.08(m, 2H), 0.95-0.85 (m, 12 H); LCMS-ESI*: calc'd for C44H 5 2

N

8

O

6 : 788.93; Found: 789.3 (M+H*). Example BG H H N Pd(PPh3)4, Cul, TEA N - I +- M Br N Boc Ethynyl DMF, 800C, o/n TMS - / N Boc 2-(6-Bromo-1H-benzoimidazol- trimethyl-silane 2-(6-Trimethylsilanyethynyl-1H 2-yl)-pyrrolidine-1-carboxylic benzoimidazol-2-y)-pyrrolidine-1 acid tert-butyl ester carboxylic acid tert-butyl ester H NBr N Boc ,BO

K

2

CO

3 - N \ / N N N Boc MeOH \ / Pd(PPh 3

)

4 , Cul, TEA N 2-(6-Ethynyl-1H- OME, 900C, 90min. H e da 2-yl)- DMF,90C,90m2-{6-[2-(1-Boc-2-yl)-1H-benzoimidazol-5 pyrrolidine-1-carboxylic ylethynyl]-1H-benzoimidazol-2-y} acid tert-butyl ester pyrrolidine-1-carboxylic acid tert-butyl ester 0 HZ 0 NH 2.HATU, DIEA OKz( N N N HN O... HO H O O H -O {1-[2-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-y]-3H-benzoimidazol-5-ylethynyl}-1H 2-Methoxycarbonylamino-3- benzoimidazol-2-yl)-pyrrolidine-1-carbony]-2-methyl 10 methyl-butyric acid propyl}-carbamic acid methyl ester 2-(6-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert butylester: A mixture of 2-(6-bromo-IH-benzoimidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (309 mg, 0.84 mmol), ethynyl-trimethyl-silane (1.2 mL, 8.4 mmol), 15 tetrakis(triphenylphosphine)palladium (97 mg, 0.08 mmol), copper(I) iodide (32 mg, 0.16 mmol) and triethylamine (0.7 mL, 5,04 mmol) in 5 ml DMF was heated to 80*C for 8 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(6 533 trimethylsilanylethynyl- I H-benzoimidazol-2-yI)-pyrrolidine-l -carboxylic acid tert-butyl ester (200 mg, yield 62%). LCMS-ESI-: calc'd for C 2 1 1H 29

N

3 0 2 Si: 383.56; Found: 384.1 (M+H*). 2-(6-ethynyl-IH-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: 5 Potassium carbonate (144 mg) was added to 2-(6-trimethylsilanylethynyl-I H-benzoimidazol-2 yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (200 mg, 0.52 mmol) in 6 ml methanol. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2 (6-ethynyl-1 H-benzoimidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (121 mg, yield 10 75%). LCMS-ESI-: calc'd for C, 8

H

21

N

3 0 2 : 311.38; Found: 31 1.8 (M+H4). 2-{6-[2-(1-Boc-2-yl)-IH-benzoimidazol-5-ylethynyl]-1H-benzoimidazol-2-yl}-pyrrolidine-1 carboxylic acid tert-butyl ester: A mixture of 2-(6-bromo-l H-benzoimidazol-2-yl) pyrrolidine-l -carboxylic acid tert-butyl ester (91 mg, 0.24 mmol), 2-(6-ethynyl-I H 15 benzoimidazol-2-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester (77 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (14 mg), copper(l) iodide (5 mg) and triethylamine (138 pL) in 2 ml DMF was heated to 90'C for 2 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 20 0-10% IPA/ DCM: acetone(3:2) mixture) to give 2-{6-[2-(l-Boc-2-yl)-IH-benzoimidazol-5 ylethynyl]-l H-benzoimidazol-2-yl}-pyrrolidine-l -carboxylic acid tert-butyl ester (5.4 mg). LCMS-ESr~: calc'd for C 3 4

H

40

N

6 0 4 : 596.72; Found: 597.0 (M+H 4 ). {1 -[2-(6-{2- [1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 25 benzoimidazol-5-ylethynyl}-1H-benzoimidazol-2-yI)-pyrrolidine-1-carbony]-2-methyl propyl}-carbamic acid methyl ester: Trifluoroacetic acid (I mL)was added to 2-{6-[2-(]-Boc 2-yl)-l H-benzoimidazol-5-ylethynyl]- IH-benzoimidazol-2-yl}-pyrrolidine-l -carboxylic acid tert-butyl ester (5.4 mg, 0.0065 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and dried overnight under vacuum. The 30 residue was dissolved in DMF (1 mL) and to this solution was added 2-methoxycarbonylamino 3-methyl-butyric acid (2.6 mg), diisopropylethylamine (9 PL), followed by HATU (5.5 mg). Reaction mixture was stirred at 0*C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% 35 ACN/H 2 0 +0.1% TFA). Product was lyophilized to give {l-[2-(6-{2-[]-(2 534 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-benzoimidazol-5-ylethynyl}-Il H benzoimidazol-2-yI)-pyrrolidine- I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester as the bis-TFA salt (0.9 mg). 'H-NMR: 300 MHz, (CD 3 0D-d 4 ) 6: 7.82 (s, 2H), 7.68-7.60 (m, 4H), 5.32 (m, 2H), 4.27(dd, 5 2H), 4.1 1(m, 2H), 3.96 (m, 2H), 3.63 (s, 6H), 2.58 (m, 2H), 2.40-2.12 (m, 6H), 2.08(m, 2H), 0.95-0.85 (m, 12 H); LCMS-ES*: calc'd for C 38

H

4 6

N

8 0 6 : 710.82; Found: 711.2 (M+H*). Example BH HH r~J Boc NN N Boc N N I - Pd(PPh 3

)

4 , Cul, TEA N Boc 2-(6-Ethynyl-1H- DMF, 500C, 2hr. ' N benzoimidazol-2-yl) pyrrolidine-1 -carboxylic 2-(6-{4-(2-(1 -Boc-pyrrolidin-2-yl)-1 H-benzoimidazol acid tert-butyl ester 5-yi]-buta-1,3-diynyl}-1 H-benzoimidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester 0 H 1. TFA 0 NH 0N N O-NHN 2. HATU, DIEA N N HO N H\'Jr N:- H 0 S H (1 -{2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl 2-Methoxycarbonylamino-3- butyryl)-pyrrolidin-2-yl]-3H-benzoimidazol-5-yl}-buta-1,3 methyl-butyric acid diynyl)-1 H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester 10 2-(6-{4-12-(1-Boc-pyrrolidin-2-yl)-IH-benzoimidazol-5-yl]-buta-1,3-diynyl}-1H benzoimidazol-2-yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester: A mixture of 2-(6 ethynyl-I H-benzoimidazol-2-yI)-pyrrolidine-I -carboxylic acid teri-butyl ester (88 mg), tetrakis(triphenylphosphine)palladium (16 mg), copper(l) iodide (3 mg) and triethylamine (120 15 p L) in 1.5 ml DMF was heated to 50'C for 2 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA) to give 2-(6-{4-[2-(1-Boc-pyrrolidin-2-yl)-I

H

benzoimidazol-5-yI]-buta-I,3-diynyl}-I H-benzoimidazol-2-yI)-pyrrolidine-I-carboxylic acid 20 tert-butyl ester (12 mg). LCMS-ESI~: calc'd for C 36

H

40

N

6 0 4 : 620.74; Found: 621.0 (M+H*). (1-(2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yl}-buta-1,3-diynyl)-1H-benzoimidazol-2-ylj-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: Trifluoroacetic acid (1 mL)was added to 2-(6 535 {4-[2-(l -Boc-pyrrolidin-2-yl)- I H-benzoimidazol-5-yl]-buta-1,3-diynyl}- I H-benzoimidazol-2 yl)-pyrrolidine-1-carboxylic acid terl-butyl ester (12 mg) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (1 mL) and to this solution was added 2 5 methoxycarbonylamino-3-methyl-butyric acid (5.5 mg), diisopropylethylamine (13 pL), followed by HATU (12 mg). Reaction mixture was stirred at 0 0 C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (1-{2-[6-(4-{2 10 [1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-benzoimidazol-5-yl}-buta 1,3-diynyl)- I H-benzoimidazol-2-yl]-pyrrolidine- I -carbonyl} -2-methyl-propyl)-carbamic acid methyl ester as the bis-TFA salt (4 mg). 'H-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: 7.82 (s, 2H), 7.72-7.62 (m, 4H), 5.32 (m, 2H), 4.27(d, 2H), 4.1 I(m, 2H), 3.90 (m, 2H), 3.63 (s, 6H), 2.54 (m, 2H), 2.38-2.12 (m, 6H), 2.06 (m, 2 H), 15 0.95-0.85 (m, 12 H); LCMS-ESI*: calc'd for C 4 oH 4 6

N

8 0 6 : 734.84; Found: 735.2 (M+H*). 536 Example BI H H N NN Boc + Pd(PPh,) 4 Cul, TEA - Boc - 6 DMF, 100 0 C,l1hr.- - / N Bo 2-(6-Ethynyl-1H benzoimidazol-2-yl)- 1,4-Diiodo-benzene 2-[6-(4-lodo-phenylethynyl)-1H pyrrolidine-1-carboxylic benzoimidazol-2-yl]-pyrrolidine-1 acid tert-butyl ester carboxylic acid tert-butyl ester 2-[5-Bromo-1-(2 Br trimethylsilanyl N N ethoxymethyl)-1H B-B H imidazol-2-yl] 0' O N SEM pyrrolidine-1-carboxylic __ _ _ _ __ _ _ _ K O A C H O ,B - - N B a cid tert-b utyl este r Pd(PPh 3

)

4 , KOAc HO - \ / Pd(dppf) 2

C

2 , Pd(PPh 3

)

4 , dioxane,90 0 C, 5hr. 2-{6-boronic acid)-phenylethynyl]-1H- K 2

CO

3 , 90 0C benzoimidazol-2-yl}-pyrrolidine-1 carboxylic acid tert-butyl ester H Cc IN\ /\ 1. TFA Bo I- Boc N N - 2. HATU, DIEA SEM O-- HO 2-Methoxycarbonylamino 2-(6-{4-[2-(1-Boc-pyrrolidin-2-yl)-3-(2- HO N4. 3-methyl-butydc acid trimethylsilanyl-ethoxymethyl)-3H-imidazol- O H 4-yl]-phenylethynyl-1 H-benzoimidazol-2 yl)-pyrrolidine-1-carboxylic acid tert-butyl ester 0H o N k_ O O HN 0 (1-{2-[5-(4-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 3H-benzoimidazol-5-ylethynyl}-phenyl)-1 H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-[6-(4-Iodo-phenylethynyl)-1H-benzoimidazol-2-yI]-pyrrolidine-1-carboxylic acid tert 5 butyl ester: A mixture of 2-(6-ethynyl- IH-benzoimidazol-2-yI)-pyrrolidine-l-carboxylic acid tert-butyl ester (100 mg, 0.321 mmol), I,4-Diiodo-benzene (529 mg, 1.61 mmol), tetrakis(triphenylphosphine)palladium (37 mg, 0.03 mmol), copper(1) iodide (12 mg, 0.06 mmol) and triethylamine (0.135 mL, 0.96 mmol) in 2 ml DMF was heated to 100 0 C in the microwave for I hour. The reaction mixture was cooled and dissolved in ethyl acetate and 10 washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-[6-(4-lodo-phenylethynyl)- I H-benzoimidazol-2-yl]-pyrrolidine- carboxylic acid tert-butyl ester (123 mg, yield 75%). LCMS-ESI~: calc'd for C 2 4

H

24

IN

3 0 2 : 513.37; Found: 531.8 (M+H*). 15 537 2-{6-[4-boronic acid-phenylethynyl]-1H-benzoimidazol-2-yI}-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-[6-(4-lodo-phenylethynyl)-l H-benzoimidazol-2-yl] pyrrolidine-l -carboxylic acid tert-butyl ester (123 mg, 0.24 mmol), bis(pinacolato)diboron (122 mg, 0.48 mmol), tetrakis(triphenylphosphine)palladium (52 mg, 0.02 mmol) and potassium 5 acetate (52 mg, 0.53 mmol) in 3 ml 1,4-dioxane was heated to 90*C for 5 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) and followed by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA) to give the corresponding 10 boronic acid of 2-{6-[4-(4,4,5,5-Tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenylethynyl]- I H benzoimidazol-2-yl}-pyrrolidine-l -carboxylic acid tert-butyl ester (15 mg). LCMS-ESI~: calc'd for C 24

H

26

BN

3 0 4 : 431.29; Found: 431.9 (M+H*). 2-(6-{4-12-(1-Boc-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl] 15 phenylethynyl}-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-{6-[4-boronic acid-phenylethynyl]-I H-benzoimidazol-2-yl}-pyrrolidine-I carboxylic acid tert-butyl ester (I I mg, 0.025), 2-[5-Bromo-l -(2-trimethylsilanyl ethoxymethyl)-l H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (34 mg, 0.076 mmol), tetrakis(triphenylphosphine)palladium (1.5 mg), Pd(dppf)Cl 2 ( mg) and potassium 20 carbonate (3.5 mg) in I ml DME and 0.3 mL water was heated to 90*C for 30 minutes. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/-1 2 0 + 0.1% TFA) to give 2-(6-{4 [2-(1 -Boc-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl] 25 phenylethynyl}-1 H-benzoimidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (4 mg, yield 21%). LCMS-ESI~: calc'd for C 4 3

H

6 oN 6 0 5 Si; 753.02; Found: 751.4 (M-H*). (1-{2-15-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-ylethynyl}-phenyl)-1H-imidazol-2-yI]-pyrrolidine-1-carbonyl}-2-methyl 30 propyl)-carbamic acid methyl ester: Trifluoroacetic acid (I mL)was added to 2-(6-{4-[2-(1 Boc-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenylethynyl} I H-benzoimidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (4 mg) and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (I mL) and to this solution 35 was added 2-methoxycarbonylamino-3-methyl-butyric acid (2 mg), diisopropylethylamine (6 538 pL), followed by HATU (4 mg). Reaction mixture was stirred at 0*C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to 5 give (1-{2-[5-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-ylethynyl}-phenyl)- I H-imidazol-2-yl]-pyrrolidine- 1 -carbonyl}-2-methyl propyl)-carbamic acid methyl ester as the bis-TFA salt (2.8 mg): 1H-NMR: 300 MHz,

(CD

3 0D-d 4 ) 6: 7.86 (s, I H), 7.82(s, I H), 7.78-7.60 (m, 5H), 5.32 (m, 2H), 4.27(dd, 2H), 4.1 l(m, 2H), 3.96 (m, 2H), 3.63 (s, 6H), 2.58 (m, 2H), 2.40-2.12 (m, 6H), 2.08(m, 2H), 0.95 10 0.85 (m, 12 H); LCMS-ESI*: calc'd for C 40

H

4 6

N

8 0 6 : 736.86; Found: 737.3 (M+H*). Example BJ 00 N NH O NH 0- t NBr -TM Pd(PPh 3

)

4 , CUl 0 ~N N - / TMS - Br + =-TMS TEADMF, N00 0 C N Ethynyl (1 -{2-[5-(4-Bromo-phenyt)-1 H-imidazol-2- trimethyl yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)- silane (2-Methyl-1y-2-[5-(4 carbamic acid methyl ester trimethylsilanylethynyl-phenyl)-1H imidazol-2-yl]-pyrrolidine-1 -carbonyl} O propyl)-carbamic acid methyl ester

K

2

CO

3 -o N\ 0 MeOH (1 -{2-[5-(4-Ethynyl-pheny)-1 H-imidazol 2-yl]-pyrrolidine-i -carbonyl}-2-methyl propyl)-carbamic acid methyl ester 15 (2-Methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-IH-imidazol-2-yII-pyrrolidine-1 carbonyl}-propyl)-carbamic acid methyl ester: A mixture of (1-{2-[5-(4-Bromo-phenyl)-I H imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (364 mg, 0.81 mmol), Ethynyl-trimethyl-silane (0.68mL, 4.9 mmol), Copper(I) iodide (154 mg, 0.81 mmol), tetrakis(triphenylphosphine)palladium (94 mg, 0.08 mmol) and triethylamine (0.67 mL, 20 4.9 mmol) in 5 ml DMF was heated to 70*C overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) and followed by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA) to give (2-Methyl-I-{2-[5-(4-trimethylsilanylethynyl-phenyl) 25 1 H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-propyl)-carbamic acid methyl ester (324 mg). LCMS-ESI~: calc'd for C 2 5

H

3 4

BN

4 0 3 Si: 466.65; Found: 467.1 (M+H). 539 (1 -{2- [5-(4-Ethynyl-phenyl)- 1 H-imidazol-2-yl] -pyrrolid ine-1 -carbonyl}-2-methyl-propyl) carbamic acid methyl ester: Potassium carbonate (192 mg) was added to (2-Methyl-1-{2-[5 (4-trimethylsilanylethynyl-phenyl)- IH-imidazol-2-yl]-pyrrolidine-I-carbonyl}-propyl)-carbamic 5 acid methyl ester (324 mg) in 7 mL MeOH solution. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated down and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give (1 -{2-[5-(4 Ethynyl-phenyl)-I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (234 mg). 10 ' H-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: 7.84 (s, I H), 7.84(d, 2H), 6.98 (d, 2H), 5.22 (t, I H), 4.21 (d, I H), 4.11 (m, 1 H), 3.86 (m, I H), 3.63 (s, 3H), 2.55 (m, I H), 2.31-2.02 (m, 4H), 0.95-0.85 (m, 6 H); LCMS-ESI: calc'd for C 2 2

H

26

N

4 0 3 : 394.47; Found: 395.1 (M+H*). Example BK H TH N N 1. TFA N N -I i N" N Boc 2.HATU, DIEA N 2-(6-Ethynyl-1H- HO O- HN O benzoimidazol-2-yl)- N-k O pyrrolidine-1-carboxylic H 0 {1-[2-(6-Ethynyl-1H-benzoimidazol-2 acid tert-butyI ester 2-Methoxycarbonylamino- yl)-pyrrolidine-1-carbonyl]-2-methyl 15 3-methyl-butyric acid propyl}-carbamic acid methyl ester (1-[2-(6-Ethynyl-I H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl} carbamic acid methyl ester: Trifluoroacetic acid (I mL) was added to 2-(6-Ethynyl-1 H benzoimidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (20 mg) and the reaction 20 mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (I mL) and to this solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (12 mg), diisopropylethylamine (67 pL), followed by HATU (24 mg). Reaction mixture was stirred at 0*C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate 25 solution. The organic layer was dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give { l -[2-(6-Ethynyl-1 H-benzoimidazol-2-yl)-pyrrolidine-l -carbonyl]-2-methyl-propyl} carbamic acid methyl ester as the mono TFA salt (23 mg): 'H-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: 7.82 (s, I H), 7.72(d, I H), 7.62 (d, I H), 5.32 (t, I H), 4.24(d, I H), 4.11 (m, 1 H), 3.90 (m, I H), 540 3.63 (s, 4H), 2.58 (m, I H), 2.38-2.12 (m, 3H), 2.04(m, I H), 0.95-0.85 (m, 6 H); LCMS-ESI*: calc'd for C 2 2

H

26

N

4 0 3 : 368.43; Found: 369.0 (M+H*). Example BL HCbzCI H b (COCI) 2 C TMSCHN 2 -C H - )C-ZNCb -. bo HO HO Piperdine-4-carboxylic Piperidine-1,4-dicarboxylic acid 4-Chlorocarbony-piperidine-1 acid monobenzyl ester carboxylic acid benzyl ester Boc 0 N~J 0 33% HBr 0 OH Nab _) NCbz N-z______ _ -C Nbz - NCbz

N

2 Bir TEA o_ 4-(2-Diazo-acetyl)- 4-(2-Bromo-acetyl)-piperidine- Pyrrolidine-1,2-dicarbaxylic add 2-[2. piperidine- -carboxylic 1 -carboxylic acid benzyl ester (1 1 -rbox ylIc 2 acid benzyl ester oxo-ethyl] ester 1-tert-butyl ester

NH

4 0Ac N SEMI Boc I NCbz H 2 , Pd/C - Bac I NCbz - N N N NNaH SM 4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl) 4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)- 3-(2-trimethylsilanyl-ethoxymethyl) 3H-imidazol-4-yIl-piperidine-1- 3H-imidazol-4-yl]-piperidine carboxylic acid benzyl ester 1-carboxylic acid benzyl ester SEM N Br oc SEM Boc NH N/BoN N \ N N SEM Pd(OAc) 2 , BINAP N NNN - SEM 2-[5-Pipendin-4-yI-1-(2- 2-[3-(2-Trinethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl toxymethylsilan phenyl)-piperidin-4-yl)-1-(2-trimethylsilanyl ethoxymethyl)-ii-imidazol-2- ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-bis-1 ya]-pyrrolidinel-carboxylic carboxylic acid tert-butyl ester acid tert-butyl ester 0 HH 1. TFA OO O \ N 0N N N 0k.

~O N OH H) H 2. HATU, H4 0 [1-(2{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4 3. TFA yl)-piperidin-1-yI)-phenyl]-1 H-imidazol-2-yl)-pyrralidine-1-carbonyl)-2-methyl-propyll-carbamic 5 acid methyl ester Piperidine-1,4-dicarboxylic acid monobenzyl ester: Piperidine-4-carboxylic acid (64.8 g, 0.5 mol) in H 2 0 (50 mL) was treated with NaOH (44.0 g, 1.1 mol). The reaction mixture was cooled to 0*C and treated with CbzCI (93.8 g, 0.55 mol). The reaction mixture was stirred at 10 ambient temperature for 4 hours and the mixture was extracted with Et20 (3 x 1 50 mL). The aqueous phase was acidified with 6 N HCI (140 mL) and extracted with EtOAc (3 x 200 mL). The solution was dried over MgSO4, filtered, and concentrated to afford crude piperidine-1,4 dicarboxylic acid monobenzyl ester (120 g), which was used without further purification: MS (ES I) m/z 262 [M - H]*. 541 4 -Chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester: Piperidine-l,4-dicarboxylic acid monobenzyl ester (40.2 g, 0.15 mol) in dichloromethane (300 mL) was treated with oxalyl chloride (100 g, 0.79 mol). The reaction mixture was stirred at ambient temperature for 4 hours 5 and the mixture was concentrated to afford crude 4 -chlorocarbonyl-piperidine-l-carboxylic acid benzyl ester (43 g), which was used without further purification. 4 -(2-Diazo-acetyl)-piperidine-1-carboxylic acid benzyl ester: 4-Chlorocarbonyl-piperidine- I carboxylic acid benzyl ester (43 g, 0.15 mol) in dichloromethane (300 mL) was treated with 10 (trimethylsilyl)diazomethane (2.0 M in hexanes, 150 mL, 0.31 mol) over 15 min. The reaction mixture was stirred at ambient temperature for 18 hours and the mixture was concentrated to afford crude 4

-(

2 -diazo-acetyl)-piperidine-1 -carboxylic acid benzyl ester (44 g), which was used without further purification. 15 4

-(

2 -Bromo-acetyl)-piperidine-1-carboxylic acid benzyl ester: 4 -(2-Diazo-acetyl)-piperidine 1-carboxylic acid benzyl ester (44 g, 0.15 mol) in EtOAc (300 mL) was cooled to 0*C. The solution was treated with 33% HBr/HOAc (75 mL, 0.42 mol) over 15 min and stirred at ambient temperature for 2 hours. The mixture was slowly treated with saturated NaHCO 3 solution (300 mL) until pH was neutral or slightly basic and filtered. The solution was dried over MgSO 4 and 20 subjected to a 330 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford 4

-(

2 -bromo-acetyl)-piperidine-I-carboxylic acid benzyl ester (38.1 g, 81%): MS (ESI) m/z 341 [M + H]-. Pyrrolidine-1,2-dicarboxylic acid 2-[2-(I-benzyloxycarbonyl-piperidin-4-yl)-2-oxo-ethyl] 25 ester 1-tert-butyl ester: (S)-Proline (13 g, 61 mmol) in MeCN (250 mL) was treated with triethylamine (8.5 mL, 61 mmol). 4

-(

2 -Bromo-acetyl)-piperidine-1-carboxylic acid benzyl ester (19 g, 56 mmol) in MeCN (50 mL) was added dropwise over 15 min and the reaction was stirred for 2 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with H 2 0 (50 mL). The solution was dried over MgSO 4 and subjected to a 330 g SiO 2 30 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford pyrrolidine-1,2 dicarboxylic acid 2-[2-(l -benzyloxycarbonyl-piperidin-4-yl)-2-oxo-ethyl] ester I -tert-butyl ester (20 g, 75%): MS (ESI) m/z 497 [M + Na]f. 4- [2-(1 -tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-im idazol-4-yl I-piperid ine-I -carboxylic 35 acid benzyl ester: Pyrrolidine-1,2-dicarboxylic acid 2

-[

2 -(1-benzyloxycarbonyl-piperidin-4 542 yl)-2-oxo-ethyl] ester 1-tert-butyl ester (20 g, 42 mmol) in xylenes (100 mL) was treated with ammonium acetate (16 g, 210 mmol). The reaction was stirred at 130'C in a sealed tube for 3 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO 3 (50 mL). The solution was dried over MgSO 4 and subjected to a 330 g 5 SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes followed by 0-20% MeOH-EtOAc gradient) to afford 4-[2-(I-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-piperidine- I carboxylic acid benzyl ester (6.8 g, 36%): MS (ESI) m/z 455 [M + HJ. 4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3-(2-trimethylsilany-ethoxymethyl)-3H 10 imidazol-4-yl]-piperidine-1-carboxylic acid benzyl ester: 4-[2-(1 -tert-Butoxycarbonyl pyrrolidin-2-yl)-3H-imidazol-4-yl]-piperidine-I -carboxylic acid benzyl ester (6.8 g, 14.9 mmol) in DMF (115 mL) was treated with NaH (60% dispersion in mineral oil, 655 mg, 16.4 mmol) in one portion. After 5 min, the mixture was treated with SEMCI (2.75 mL, 15.7 mmol) in 0.1 mL portions over 10 min. The reaction was stirred for 3 hours and diluted with saturated NH 4 Cl 15 solution (50 mL) and EtOAc (100 mL). The organic layer was washed with H20 (3 x 50 mL) and brine (50 mL). The solution was dried over MgSO 4 and subjected to a 120 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes followed by 0-20% MeOH-EtOAc gradient) to afford 4-[2-(I-tert-butoxycarbonyl-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H imidazol-4-yl]-piperidine-1-carboxylic acid benzyl ester (2.8 g, 32%): MS (ESI) m/z 585 [M + 20 H]*. 2-[5-Piperidin-4-yl-1-(2-trimethylsilany-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester: 4-[2-(l -tert-Butoxycarbonyl-pyrrolidin-2-y)-3-(2 trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-piperidine- I -carboxylic acid benzyl ester (2.8 25 g, 6.1 mmol) in EtOH (60 mL) was treated with 20% PdOH/C (600 mg) and placed under an atmosphere of H 2 . The reaction was stirred for 18 hours and filtered through a CELITE plug to afford crude 2-[5-piperidin-4-yl-I -(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yl] pyrrolidine- I -carboxylic acid tert-butyl ester (2.0 g), which was used without further purification: MS (ESI) m/z 451 [M + H]*. 30 2-[3-(2-Trimethylsilany--ethoxymethyl)-3H-imidazol-4-yl]-phenyl}-piperidin-4-yl)-1-(2 trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yI]-pyrrolidine-bis-1-carboxylic acid tert butyl ester: 2-[5-Piperidin-4-yl-I-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl] pyrrolidine-l-carboxylic acid tert-butyl ester (170 mg, 0.37 mmol) and 4-Bromophenyl-1-SEM 35 imidazol-2-yl-pyrrolidine-1 -Boc (164 mg, 0.31 mmol, prepared according to WO 2008/021927) 543 in toluene (3.5 mL) were treated with Pd(OAc) 2 (1.4 mg, 0.0064 mmol, via 10% solution in toluene), BINAP (19 mg, 0.03 1 mmol), and NaOtBu (42 mg, 0.44 mmol). The mixture was stirred in a sealed tube at I 10*C for 36 hours. The solution was concentrated, diluted with EtOAc (50 mL), and washed with saturated NaHCO 3 (20 mL), H 2 0 (20 mL), and brine (20 mL). 5 The solution was dried over MgSO 4 and subjected to a 40 g SiO 2 COMBIFLASH column (0 100% EtOAc-hexanes followed by 0-20% MeOH-EtOAc gradient) to afford 2-[3-(2 trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl}-piperidin-4-yl)-1 -(2 trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yl]-pyrrolidine-bis-I -carboxylic acid tert-butyl ester (35 mg, 13%): MS (ESI) m/z 892 [M + H]*. 10 I1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yI)-piperidin-1-yI)-phenyl]-IH-imidazol-2-yI}-pyrrolidine-1-carbonyl)-2 methyl-propyl]-carbamic acid methyl ester: 2-[3-(2-Trimethylsilanyl-ethoxymethyl)-3H imidazol-4-yl]-phenyl}-piperidin-4-yl)-I -(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yi] 15 pyrrolidine-bis-I-carboxylic acid tert-butyl ester (35 mg, 0.04 mmol) in dichloromethane (1.0 mL) was treated with trifluoroacetic acid (0.2 mL) and the mixture was stirred for I hours. The solution was concentrated and the residue was suspended in DMF (1.0 mL) and treated with (S) Moc-Val-OH (15 mg, 0.086 mmol), HATU (32 mg, 0.085 mmol), and N-methyl morpholine (0.034 mL, 0.31 mmol). The mixture was stirred for 2 hours then diluted with EtOAc (25 mL), 20 and washed with saturated NaHCO 3 (3 x 10 mL), H 2 0 (10 mL), and brine (10 mL). The solution was dried over MgSO 4 and suspended in trifluoroacetic acid (1.0 mL) and stirred in a screw-cap vial at 40*C for I hour. The solution was concentrated and subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford [1-(2-{5-[4-(4-{2-[l

(

2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-piperidin-1 25 yl)-phenyl]-l H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (9.5 mg, 33%) as a white solid (TFA salt): H NMR (CD 3 0D, 300 MHz) 7.64 (s, I H), 7.57 (d, J = 9.0 Hz, 2H), 7.29 (s, I H), 7.11 (d, J= 9.0 Hz, 2H), 5.18 (m, 2H), 4.21 (m, 2H), 4.08 (m, 2H), 3.96 (m, 2H), 3.84 (m, 2H), 3.65, (s, 3H), 3.64 (s, 3H), 2.96 (m, 3H), 2.51 (m, 2H), 2.20 (m, 2H), 2.13 (m, 7H), 1.82 (m, 2H), 0.91 (m, 12H); MS (ESI) m/z 746 [M + H]*. 30 544 Example BM H SEM - N *N SEMCI - N IN HN NH Br I /V \. 0 *1'-1B Br O SMC.Pd(OAC) 2 , BINAP 0,. 0 (1 -{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]- (1-{2-[5-(4-Bromo-pheny)-1 pyrrolidine-1-carbonyl}-2-methyl-propyl)- (2-trimethylsilanyl-ethoxymethyl) carbamic acid methyl ester 1 H-imidazol-2-yl]-pyrrolidine-1 -carbonyl} 2-methyl-propyl)-carbamic acid methyl ester O N SEM 0 N N\N N O(N N TFA N N I/ \ SEM H, 0 {1 -(2-(5-{4-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-(2 trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yI)-phenyl)-piperazin-1 -yl]-phenyl}-1 -(2 trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl)-pyrrolidine-1 -carbonyl]-2-methyl-propyl} carbamic acid methyl ester O H O NN N - N N N H 0 {1-[2-(5-{4-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenyl)-piperazin-1-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (1 -{2- [5-(4-Bromo-phenyl)-1 -(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl] 5 pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: (1 -{2-[5-(4-Bromo phenyl)- I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.6 g, 5.8 mmol) in DMF (60 mL) was treated with NaH (60% dispersion in mineral oil, 256 mg, 6.4 mmol) in one portion. After 5 min, the mixture was treated with SEMCI (1.08 mL, 6.1 mmol) in 0.1 mL portions over 10 min. The reaction was stirred for 2 hours and diluted with 10 saturated NH 4 Cl solution (50 mL) and EtOAc (100 mL). The organic layer was washed with

H

2 0 (3 x 50 mL) and brine (50 mL). The solution was dried over MgSO 4 and subjected to a 120 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford (1-{2-[5-(4 bromo-phenyl)-1 -(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yl]-pyrrolidine-1 -carbonyl} 2-methyl-propyl)-carbamic acid methyl ester (2.4 g, 71%). 15 545 {1 -[2-(5-{4-14-(4-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-(2 trimethylsilany--ethoxymethyl)-3H-imidazol-4-y(-phenyl)-piperazin-1-yl]-phenyl}-1-(2 trimethylsilanyl-ethoxymethyl)- 1 H-imidazol-2-yl)-pyrrolidine-1 -carbonyl] -2-methyl propyl)-carbamic acid methyl ester: (1-{2-[5-(4-Bromo-phenyl)-l -(2-trimethylsilanyl 5 ethoxymethyl)- IH-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (222 mg, 0.38 mmol) and piperazine (17 mg, 0.19 mmol) in toluene (3.5 mL) were treated with Pd(OAc) 2 (2.1 mg, 0.0096 mmol, via 10% solution in toluene), BINAP (12 mg, 0.019 mmol), and NaOtBu (64 mg, 0.67 mmol). The mixture was stirred in a sealed tube at 120'C for 4 hours. The solution was concentrated, diluted with EtOAc (50 mL), and washed 10 with saturated NaHCO 3 (20 mL), H 2 0 (20 mL), and brine (20 mL). The solution was dried over MgSO 4 and subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford { I -[2-(5-{4-[4-(4-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yI}-phenyl)-piperazin-l-yl] phenyl}-l -(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yl)-pyrrolidine-l -carbonyl]-2 15 methyl-propyl}-carbamic acid methyl ester (8 mg, 4%): MS (ESI) m/z 1105 [M + Na]*. {1-[2-(5-{4-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yl}-phenyl)-piperazin-1-y]-phenyl}-1 H-imidazol-2-yl)-pyrrolidine-1-carbonyl] 2-methyl-propyl}-carbamic acid methyl ester: { l-[2-(5-{4-[4-(4-{2-[l-(2 20 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-(2-trimethylsilanyl-ethoxymethyl) 3H-imidazol-4-yl}-phenyl)-piperazin-I -yl]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-Il

H

imidazol-2-yl)-pyrrol idine- I -carbonyl]-2-methyl-propyl} -carbamic acid methyl ester (8 mg, 0.007 mmol) in trifluoroacetic acid (1.0 mL) was stirred in a screw-cap vial at 40'C for I hours. The solution was concentrated and subjected to a reverse phase HPLC column (5-95% MeCN 25 H 2 0; 0.1% TFA modifier) to afford { I -[2-(5-{4-[4-(4-{2-[I-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl} -phenyl)-piperazin- I -yl]-phenyl}- I H imidazol-2-yl)-pyrrolidine- I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (1.9 mg, 32%) as a white solid (TFA salt): 'H NMR (CD 3 0D, 300 MHz) 7.66 (s, 2H), 7.60 (d, J= 8.7 Hz, 4H), 7.13 (d, J= 8.7 Hz, 4H), 5.21 (app t, J= 8.1 Hz, 2H), 4.22 (d, J= 7.2 Hz, 2H), 4.09 (m, 30 2H), 3.85 (m, 2H), 3.66 (s, 6H), 3.31 (m, 51H), 2.52 (m, 2H), 2.16 (m, 8H), 0.91 (m, 12H); MS (ESI) m/z 824 [M + H]*. 546 Example BN Br t-BuLi HO 2 C N HNQ_ NH N Boc N Boc HATU SEM 002 SEM 2-[4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1 H- 2-(1 -tert-Butoxycarbonyl-pyrrolidin-2-yl)-1 imidazol-2-yl]-pyrrolidine-1 -carboxylic acid tert- (2-trmethylsilanyl-ethoxymethyl) butyl ester 1 H-imidazole-4-carboxylic acid SEM STFA NVJK N 0O' Boc \ OO B _ 0O 2. HATU, O O SEM 2-[4-{9-[1-(2-Trimethylsilanyl-ethoxymethyl)-1 H imidazole-4-carbonyl-3,9-diaza-spiro[5.5]undecane 3-carbonyl}-1 -(2-trmethylsilanyl-ethoxymethyl)-1 H imidazol-2-yl]-pyrrolidine-1 -carboxylic acid tert-butyl ester H O N NH 0 O'rj N N, N NN H N 0 O N O~ (1 -{2-[4-(9-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1

H

imidazole-4-carbonyl}-3,9-diaza-spiro[5.5]undecane-3-carbonyl)1 H-imidazol-2 yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1

H

imidazole-4-carboxylic acid: 2-[4-Bromo-l -(2-trimethylsilanyl-ethoxymethyl)-l H-imidazol-2 yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (1.0 g, 2.2 mmol) in THF (10 mL) was cooled to -78'C and treated with t-BuLi (1.7 M in pentane, 2.7 mL, 4.6 mmol). The reaction mixture 10 was stirred for I hour and treated with solid CO 2 (500 mg). The mixture was warmed to ambient temperature and mixture was concentrated. The solution was dried over MgSO 4 and subjected to a 120 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes followed by 0 20% MeOH-EtOAc gradient) to afford 2-(1 -tert-butoxycarbonyl-pyrrolidin-2-yl)- 1 -(2 trimethylsilanyl-ethoxymethyl)-IH-imidazole-4-carboxylic acid (200 mg, 22%): MS (ESI) m/z 15 412 [M + H]*. 2-14-{9-[1-(2-Trimethylsilanyl-ethoxymethyl)-1 H-imidazole-4-carbonyl]-3,9-diaza spiro[5.5]undecane-3-carbonyl}-1-( 2 -trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester: 2-(I-tert-Butoxycarbonyl-pyrrolidin-2-yl)-l 20 ( 2 -trimethylsilanyl-ethoxymethyl)-1 H-imidazole-4-carboxylic acid (141 mg, 0.34 mmol) in DMF (1.0 mL) was treated with spiro-diamine (38 mg, 0.16 mmol), HATU (136 mg, 0.36 547 mmol), and N-methyl morpholine (0.90 mL, 0.82 mmol). The mixture was stirred for 2 hours then diluted with EtOAc (25 mL), and washed with saturated NaHCO 3 (3 x 10 mL), H 2 0 (10 mL), and brine (10 mL). The solution was dried over MgSO 4 to afford crude 2-[4-{9-[I-(2 trimethylsilanyl-ethoxymethyl)-I H-imidazole-4-carbonyl]-3,9-diaza-spiro[5.5]undecane-3 5 carbonyl}-l -(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yi]-pyrrolidine-l -carboxylic acid tert-butyl ester which was used without further purification: MS (ESI) m/z 941 [M + H]f. (1-{2-[4-(9-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-1H imidazole-4-carbonyll-3,9-diaza-spiro[5.5]undecane-3-carbonyl)-1H-imidazol-2-yl] 10 pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: 2-[4-{9-[1-(2 Trimethylsilanyl-ethoxymethyl)-I H-imidazole-4-carbonyl]-3,9-diaza-spiro[5.5]undecane-3 carbonyl}-1 -(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yl]-pyrrolidine-I -carboxylic acid tert-butyl ester (153 mg, 0.17 mmol) in trifluoroacetic acid (3.0 mL) was stirred for 18 hours. The mixture was concentrated, suspended in DMF (1.7 mL), and treated with (S)-Moc-Val-OH 15 (64 mg, 0.37 mmol), HATU (140 mg, 0.38 mmol), and N-methyl morpholine (185 mL, 1.66 mmol). The mixture was stirred for 2 hours then diluted with EtOAc (25 mL), and washed with saturated NaHCO 3 (3 x 10 mL), H 2 0 (10 mL), and brine (10 mL). The solution was dried over MgSO 4 and subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford I-{2-[4-(9-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 20 yl]-I H-imidazole-4-carbonyl}-3,9-diaza-spiro[5.5]undecane-3-carbonyl)- I H-imidazol-2-yl] pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3.0 mg, 2%) as a white solid (TFA salt): 'H NMR (CD 3 OD, 300 MHz) 7.77 (s, 2H), 5.18 (app t, J= 6.9 Hz, 2H), 4.22 (d, J= 7.2 Hz, 2H), 4.09 (m, 2H), 3.85 (m, 2H), 3.66 (s, 6H), 3.31 (m, 5H), 2.52 (m, 2H), 2.16 (m, 8H), 0.91 (m, 12H); MS (ESI) m/z 796 [M + H]*. 25 548 Example BO N HN NCbz NH 0~- 0 NO/ Br Pd(O BINAP O\O N NCbz N-A NdOc N SEM SEM (1-{2-[5-(4-Bromo-phenyl)-1-(2 trimethylsilanyl-ethoxymethyl)-1 H- 4-{4-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyry) imidazol-2-yl]-pyrrolidine-1-carbonyl)-2- pyrrolidin-2-yl]-3-(2-trimethylsilanyl-ethoxymethyl)-3H methyl-propyl)-carbamic acid methyl imidazol-4-yl]-phenyl}-piperazine-1-carboxylic acid benzyl ester ester S H HO 2 C

H

2 , 20%PdOH/C -O N O N N SEMBoc NN N H HATU N NNN SEM (2-Methyl-1-{2-[5-(4-piperazin-1-yl-phenyl) 1-(2-trmethylsilanyl-ethoxymethyl) 1H-imidazol-2-yl]-pyrrolidine-1 O carbonyl}-propyl)-carbamic acid methyl ester IN 00 O O N N N OTFA NZj N ~ N N SEM O kM N O') N fyOH SEM BocN 0 2-[4-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)- 2. HATU, l O pyrrolidin-2-yl)-3-methyl-3H-imidazol-4-yl}-phenyl)-piperazinel carbonyll-1-(2-trmethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester 0 H 0 N / 0N N N N N IH N H'N z0 [1 -(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazole-4-carbonyl}-piperazin-1-yl)-phenyl] 1 H-imidazol-2-yl)-pyrrolidine-1 -carbonyl)-2-methyl-propyl] carbamic acid methyl ester 5 4-{4-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3-(2 trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-y]-phenyl}-piperazine-1-carboxylic acid benzyl ester: (1-{2-[5-(4-Bromo-phenyl)-l -(2-trimethylsilanyl-ethoxymethyl)- IH-imidazol-2 yl]-pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1033 mg, 1.8 mmol) 10 and 4-Cbz-piperazine (588 mg, 2.7 mmol) in toluene (9 mL) were treated with Pd(OAc) 2 (20 mg, 0.09 mmol), BINAP (1 10 mg, 0.1 mmol), and NaOtBu (428 mg, 4.45 mmol). The mixture 549 was stirred in a sealed tube at I 10*C for 18 hours. The solution was concentrated, diluted with EtOAc (50 mL), and washed with saturated NaHCO 3 (20 mL), H 2 0 (20 mL), and brine (20 mL). The solution was dried over MgSO 4 and subjected to a 120 g Si0 2 COMBIFLASH column (0 100% EtOAc-hexanes gradient) to afford 4-{4-[2-[I-(2-methoxycarbonylamino-3-methyl 5 butyryl)-pyrrolidin-2-yl]-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl} piperazine-I-carboxylic acid benzyl ester (166 mg, 13%): MS (ES1) m/z 719 [M + H]f. (2-Methyl-1 -{2-15-(4-piperazin-I-yl-phenyl)-1 -(2-trimethylsilanyl-ethoxymethyl)-1 H imidazol-2-yll-pyrrolidine-1 -carbonyl}-propyl)-carbamic acid methyl ester: 4-{4-[2-[1-(2 10 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3-(2-trimethylsi lanyl ethoxymethyl)-3H-imidazol-4-yl]-phenyl} -piperazine- I -carboxyl ic acid benzyl ester (166 mg, 0.23 mmol) in EtOH (2.5 mL) was treated with 20% PdOH/C (60 mg) and placed under an atmosphere of H2. The reaction was stirred for 18 hours and filtered through a CELITE plug to afford crude (2-methyl-I -{2-[5-(4-piperazin- I -yl-phenyl)- I -(2-trimethylsi lanyl-ethoxymethyl) 15 1 H-imidazol-2-yi]-pyrrol idine- I -carbonyl} -propyl)-carbamic acid methyl ester (120 mg), which was used without further purification: MS (ESI) m/z 585 [M + H]+. 2-[4-J4-(4-{2- [1-(2-Methoxycarbonylamino-3-methy-butyryl)-pyrrolidin-2-y]-3-methyl 3H-imidazol-4-yl}-phenyl)-piperazine--carbonyl]-1-(2-trimethylsilanyl-ethoxymethyl)-I

H

20 imidazol-2-yll-pyrrolidine-1-carboxylic acid tert-butyl ester: (2-Methyl-I-{2-[5-(4 piperazin-1-yl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)- IH-imidazol-2-yl]-pyrrolidine-l carbonyl}-propyl)-carbamic acid methyl ester (28 mg, 0.047 mmol) and 2-(1-tert butoxycarbonyl-pyrrolidin-2-yl)-I-(2-trimethylsilanyl-ethoxymethyl)-l-H-imidazole-4 carboxylic acid (20 mg, 0.047 mmol) in DMF (1 mL) were treated with HATU (20 mg, 0.052 25 mmol) and N-methyl morpholine (0.26 mL, 0.23 mmol). The mixture was stirred for 18 hours then diluted with EtOAc (25 mL), and washed with saturated NaHCO 3 (3 x 10 mL), H 2 0 (10 mL), and brine (10 mL). The solution was dried over MgSO 4 to afford crude 2-[4-[4-(4-{2-[I (2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3-methyl-3H-imidazol-4-yl} phenyl)-piperazine-I -carbonyl]-1 -(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yl] 30 pyrrolidine-l-carboxylic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 978 [M + H]*. 550 11 -(2-{5-[4-(4-{2-[-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazole-4-carbonyl}-piperazin--y)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl) 2-methyl-propyl]-carbamic acid methyl ester: 2-[4-[4-(4-{2-[I-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3-methyl-3H-imidazol-4-yl} -phenyl)-piperazine- I -carbonyll- 1 5 (2-trimethylsilanyl-ethoxymethyl)- I H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (47 mg, 0.05 mmol) in trifluoroacetic acid (3.0 mL) was stirred for 18 hours. The mixture was concentrated, suspended in DMF (1.5 mL), and treated with (S)-Moc-Val-OH (9 mg, 0.0.053 mmol), HATU (20 mg, 0.0.053 mmol), and N-methyl morpholine (0.26 mL, 0.24 mmol). The mixture was stirred for 18 hours then diluted with EtOAc (25 mL), and washed 10 with saturated NaHCO 3 (3 x 10 mL), H 2 0 (10 mL), and brine (10 mL). The solution was dried over MgSO 4 and subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford [1 -(2- { 5-[4-(4- {2-[I-(2-methoxycarbonylamino-3-methyl -butyryl) pyrrolidin-2-yl]-3H-imidazole-4-carbonyl}-piperazin-I -yl)-phenyl]-1 H-imidazol-2-yl} pyrrolidine-I-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (6.6 mg, 18%) as a white 15 solid (TFA salt): 'H NMR (CD 3 0D, 300 MHz) 7.67 (s, 2H), 7.59 (d, J= 8.7 Hz, 2H), 7.10 (d, J = 9.3 Hz, 2H), 5.20 (app t, J= 7.2 Hz, 2H), 4.22 (d, J= 7.2 Hz, 2H), 4.01 (m, 5H), 3.85 (m, 2H), 3.66 (s, 6H), 3.38 (m, 2H), 2.52 (m, 2H), 2.16 (m, 8H), 0.91 (m, 12H); MS (ESI) m/z 775 [M + H]*. 20 551 Example BP O HO NHBoc H

NH

3 CI 1 HATU, O 1. 4 N HCI Br 2.NH 4 0Ac Br N c 2-Amino-1-(4-bromo- (1 -[5-(4-Bromo-pheny)- O N OH phenyl)-ethanone HCI 1H-imidazol-2-yl]- . 2 cyclopropyl}-carbamic acid 2. HATU, 0 tert-butyl ester o H OB-jI H H H 0-, / OO Br O Pd(PPh 3

)

4 j B I N0 (1 -{1 -[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]- [2-Methyl- -(1 -{5-[4-(4,4,5,5-tetramethyl cyclopropylcarbamoy)-2-methyl-propyl)- [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2 carbamic acid methyl ester yl}-cyclopropylcarbamoyl)-propy]-carbamic acid methyl ester Br N N / H HO H Pd(PPh 3 O (1 -{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyrylamino) cyclopropyl]-3H-imidazol-4-yl)-biphenyl-4-yl)-1 H-imidazol-2-yll-pyrrolidine-1 carbonyl-2-methyl-propyl)-carbamic acid methyl ester {1-[5-(4-Bromo-phenyl)-1H-imidazol-2-yI]-cyclopropyl)-carbamic acid tert-butyl ester: 2 Amino-1-(4-bromo-phenyl)-ethanone HCI (2.5 g, 10 mmol) in DMF (30 mL) was treated with 5 l-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (1.97 g, 9.8 mmol), HATU (4.02 g, 10.5 mmol), and DIPEA (5.6 mL, 31.1 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (25 mL), and washed with saturated NaHCO 3 (3 x 10 mL), H 2 0 (10 mL), and brine (10 mL). The solution was dried over MgSO 4 and subjected to a 80 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to 10 afford {l -[ 2

-(

4 -bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (3.49 g, 90%). This material (3.49 g, 8.8 mmol) in xylenes (20 mL) was treated with ammonium acetate (3.4 g, 44 mmol). The reaction was stirred at 130*C in a sealed tube for 18 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO 3 (50 mL). The solution was dried over MgSO 4 to afford crude {1-[5-(4 15 bromo-phenyl)-1 H-imidazol-2-yli]-cyclopropyl}-carbamic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 379 [M + H]*. (1-{1-[5-(4-Bromo-phenyl)-1H-imidazol- 2 -yl]-cyclopropylcarbamoyl}-2-methyl-propyl) carbamic acid methyl ester: { -[5-(4-Bromo-phenyl)- IH-imidazol-2-yl]-cyclopropyl} 20 carbamic acid tert-butyl ester (3.3 g, 8.77 mmol) was treated with 4 N HCI/dioxane (40 mL) and 552 stirred for 2 hours. The mixture was concentrated and suspended in DMF (50 mL). The mixture was treated with (S)-Moc-Val-OH (1.69 g, 9.7 mmol), HATU (3.67 g, 9.7 mmol), and N-methyl morpholone (4.8 mL, 43.9 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (100 mL), and washed with saturated NaHCO 3 (3 x 50 mL), 5 H 2 0 (50 mL), and brine (50 mL). The solution was dried over MgSO 4 and subjected to a 120 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford (I-{ I-[5-(4-bromo phenyl)- I H-imidazol-2-yli]-cyclopropylcarbamoyl}-2-methyl-propyl)-carbamic acid methyl ester (3.37 g, 88%): MS (ESI) m/z 436 [M + H]*. 10 [2-Methyl-1-(1-{5-14-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-IH-imidazol-2 yl}-cyclopropylcarbamoyl)-propyll-carbamic acid methyl ester: (I-{ I -[5-(4-Bromo phenyl)- I H-imidazol-2-yl]-cyclopropylcarbamoyl}-2-methyl-propyl)-carbamic acid methyl ester (1.38 g, 3.2 mmol) in I,4-dioxane (25 mL) was treated with bis(pinacolato)diboron (1.69 g, 6.7 mmol), Pd(PPh 3

)

4 (150 mg, 0.13 mmol), and KOAc (810 mg, 8.2 mmol). The mixture was 15 stirred in a sealed tube at 80*C for 18 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was then suspended in dichloromethane (10 mL) and filtered and subjected to a 120 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford [2-methyl-I -(1-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] I H-imidazol-2-yl}-cyclopropylcarbamoyl)-propyl]-carbamic acid methyl ester (1.24 g, 81%): 20 MS (ESI) m/z 483 [M + H]f. (1-{2-15-(4'-{2-[I-( 2 -Methoxycarbonylamino-3-methyl-butyrylamino)-cyclopropyl]-3H imidazol-4-yl)-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester: [2-Methyl-I-(1- { 5-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2 25 yl)-phenyl]-l H-imidazol-2-yl}-cyclopropylcarbamoyl)-propyl]-carbamic acid methyl ester (85 mg, 0.21 mmol) and (1-{2-[5-(4-bromo-phenyl)- IH-imidazol-2-yl]-pyrrolidine- I-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (97 mg, 0.21 mmol) in 3:1 DME/H 2 0 (2.5 mL) were treated with Pd(PPh 3

)

4 (0 mg, 0.0084 mmol) and K 2

CO

3 (2 M solution, 0.42 mL, 0.84 mmol). The mixture was stirred in a sealed tube at 80*C for 3 hours. The mixture was filtered through a 30 fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford (I-{2-[5-(4'-{2-[l-(2 methoxycarbonylamino-3-methyl-butyrylamino)-cyclopropyl]-3H-imidazol-4-yl}-biphenyl-4 yl)-l H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.3 mg, 2%) as a white solid (TFA salt): 'H NMR (CD 3 0D, 300 MHz) 7.93 (s, 2H), 7.84 (m, 35 4H), 5.20 (m, I H), 4.23 (d, J= 7.2 Hz, 2H), 4.01 (m, 2H), 3.83 (m, 4H), 3.70 (s, 3H), 3.66 (s, 553 3H), 3.38 (m, 2H), 2.57 (m, 2H), 2.18 (m, 4H), 2.04 (m, 4H), 1.75 (m, 4H), 1.58 (m, 4H), 0.95 (m, 12H); MS (ESI) m/z 725 [M + H]*. Example BQ . HON NHBoc 1 ,B-B,0ot

NH

3 CI 1. HATU, O 1. / O 2.NH 4 OAc Br Pd(PPh3)4 2. RP HPLC 2-Amino-1-(4-bromo- {1-[5-(4-Bromo-pheny) phenyl)-ethanone HCI 1 H-imidazol 2-yl]-cyclobutyl}-carbamic acid tert-butyi ester N\ Boc IBr NH H H N HBoc HO - N_ NHBac __________ NI B HcN Pd(PPh 3

)

4 N N HOH {1-[1 H-Imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester boronic acid 2-(5-{4'-[2-(1-tert-Butoxycarbonylamino-cyclobutyl) 3H-imidazol-4-yl]-biphenyl-4-yl-1 H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester H O H O 1. 4 N HCI 0 N NO, O NO N N O N OH 2. HATU, H 0 (1 -{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyrylamino) cydlobutyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2-yl] 5 pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester {l-[5-( 4 -Bromo-phenyl)-IH-imidazol-2-yI]-cyclobutyl}-carbamic acid tert-butyl ester: 2 Amino-]-(4-bromo-phenyl)-ethanone HCI (5.8 g, 23 mmol) in DMF (75 mL) was treated with I -tert-butoxycarbonylamino-cyclobutanecarboxylic acid (5.0 g, 23 mmol), HATU (9.7 g, 25 10 mmol), and DIPEA (12.9 mL, 34 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (25 mL), and washed with saturated NaHCO 3 (3 x 10 mL), H 2 0 (10 mL), and brine (10 mL). The solution was dried over MgSO 4 to afford crude {l -[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclobutyl}-carbamic acid tert butyl ester, which was used without further purification. This material (6.54 g, 16 mmol) in 15 xylenes (40 mL) was treated with ammonium acetate (6.1 g, 80 mmol). The reaction was stirred at 130*C in a sealed tube for 18 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO 3 (50 mL). The solution was dried over MgSO 4 to afford crude {l-[5-( 4 -bromo-phenyl)-I H-imidazol-2-y]-cyclobutyl} carbamic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 393 20 [M + H]*. 554 {1-[1H-Imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester boronic acid: {1-[5-(4 Bromo-phenyl)-lH-imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester (110 mg, 0.28) in 1,4-dioxane (2.5 mL) was treated with bis(pinacolato)diboron (150 mg, 0.59 mmol), Pd(PPh 3

)

4 5 (13 mg, 0.011 mmol), and KOAc (71 mg, 0.73 mmol). The mixture was stirred in a sealed tube at 80'C for 18 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford {]-[I H-imidazol-2-yl]-cyclobutyl}-carbamic acid tert-butyl ester boronic acid. 10 2-(5-{4'-12-(1-tert-Butoxycarbonylamino-cyclobutyl)-3H-imidazol-4-yl]-biphenyl-4yl}-1)H imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: 1-[lH-midazol-2-ylJ cyclobutyl}-carbamic acid tert-butyl ester boronic acid (60 mg, 0.17 mmol) and 2-[5-(4-bromo phenyl)-l H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg, 17 mmol) in 15 3:1 DME/H 2 0 (1.5 mL) were treated with Pd(PPh 3

)

4 (10 mg, 0.0084 mmol) and K 2

CO

3 (2 M solution, 0.25 mL, 0.50 mmol). The mixture was stirred in a sealed tube at 80*C for 18 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford 2-(5-{4'-[2-(l -tert-butoxycarbonylamino-cyclobutyl)-3H-imidazol-4-yl]-biphenyl-4-yl} -l H 20 imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (10 mg, 9%): MS (ESI) m/z 625 [M + H]*. (1-{2-15-(4'-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyrylamino)-cyclobutyl]-3H imidazol-4-yl}-biphenyl-4-yI)-1H-imidazol-2-ylI]-pyrrolidine-1-carbonyl}-2-methyl-propyl) 25 carbamic acid methyl ester: 2-(5-{4'-[2-(] -tert-Butoxycarbonylamino-cyclobutyl)-3H imidazol-4-yl]-biphenyl-4-yl}-l H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.8 mg, 0.016 mmol) was treated with 4 N HCI/dioxane (1.5 mL) and stirred for 4 hours. The mixture was concentrated and suspended in DMF (1.5 mL). The mixture was treated with (S) Moc-Val-OH (6.0 mg, 0.032 mmol), HATU (13 mg, 0.034 mmol), and N-methyl morpholone 30 (0.009 mL, 0.080 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford (1-{2-[5-(4'-{2-[ I-( 2 -methoxycarbonylamino-3-methyl-butyrylamino)-cyclobutyl]-3H imidazol-4-yi}-biphenyl-4-yl)-i H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl) carbamic acid methyl ester (2.8 mg, 24%) as a white solid (TFA salt): 'H NMR (CD 3 0D, 300 35 MHz) 7.88 (m, IOH), 5.20 (m, I H), 4.23 (d, J= 7.2 Hz, I H), 4.12 (m, I H), 3.88 (app d, J= 7.2 555 Hz, 2H), 3.66 (s, 3H), 3.63 (s, 3H), 2.85 (br m, 2H), 2.65 (m, 4H), 2.09 (m, 10 H), 0.95 (m, 12H); MS (ESI) m/z 739 [M +H]. Example BR 0 'B L" 1 . 4 N H C I S O M e 0 0 N O N N 0 2-{5-[4-(4,4,5,5-Tetramethy- - . N OH [1,3,2}dioxaborolan-2-yl)-phenyl]-1 H- 0 12-Methanesulfonyl-2-methyl-1 -(2-{5-[4-(4,4,5,5 imidazol-2-yl}-pyrrolidine-1 - 2. HATU, H 0 tetramethyl-[1,3,2]dioxaborolan-2-y)-phenyll-1

H

carboxylic acid tert-butyl ester imidazol-2-yl)-pyrrolidine-1-carbonyl)-propyl]-carbamic O acid methyl ester H 0 0 N, O O Br O H NH Pd(PPh 3

)

4 - N j N SO0 0 (2-Methanesulfonyl-1 -{2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-y)-1 H-imidazol-2-yl] 5 pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester [2-Methanesulfonyl-2-methyl-1-( 2 -{5-14-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-propyl]-carbamic acid methyl ester: 2 {5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-pyrrolidine-1 10 carboxylic acid tert-butyl ester (1.02 g, 1.73 mmol) was treated with 4 N HCI/dioxane (5 mL) and stirred for 4 hours. The mixture was concentrated and suspended in DMF (1.5 mL). The mixture was treated with (S)-Moc-3-methanesulfonyl-2-methoxycarbonylamino-3-methyl butyric acid (460 mg, 1.82 mmol), HATU (772 mg, 2.03 mmol), and N-methyl morpholone (0.950 mL, 8.65 mmol). The mixture was stirred for 18 hours and concentrated. The mixture 15 was diluted with EtOAc (100 mL), and washed with saturated NaHCO 3 (3 x 50 mL), H 2 0 (50 mL), and brine (50 mL). The solution was dried over MgSO 4 and subjected to a 40g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes followed by 0-20% MeOH-EtOAc gradient) to afford [2-methanesulfonyl-2-methyl- I -(2-{5-[4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2 yl)-phenyl]-l H-imidazol-2-yI}-pyrrolidine-l-carbonyl)-propyl]-carbamic acid methyl ester (728 20 mg, 73%): MS (ESI) m/z 575 [M + H]*. (2-Methanesu lfonyl-1 -{2-[5-(4'- {2- [1-( 2 -methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1 carbonyl)-2-methyl-propyl)-carbamic acid methyl ester: [2-Methanesulfonyl-2-methyl- 1 -(2 25 {5-[4-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl} -pyrrolidine- 1 556 carbonyl)-propyl]-carbamic acid methyl ester (700 mg, 1.22 mmol) and (I -{2-[5-(4-bromo phenyl)- I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (565 mg, 1.26 mmol) in 3:1 DME/H 2 0 (15 mL) were treated with Pd(PPh 3

)

4 (56 mg, 0.0050 mmol) and NaHCO 3 (350 mg, 4.15 mmol). The mixture was stirred in a sealed tube at 5 80*C for 24 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN-H20; 0.1% TFA modifier) to afford (2-methanesulfonyl- I-{2-[5-(4'-{2-[I-(2-methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yi}-biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine- carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (150 mg, 15%) as a white solid (TFA 10 salt): 'H NMR (CD 3 0D, 300 MHz) 7.85 (m, I OH), 5.25 (m, 2H), 4.24 (d, J= 7.5 Hz, I H), 4.13 (m, 2H), 3.88 (app d, J= 7.5 Hz, 2H), 3.71 (s, 3 H), 3.66 (s, 3 H), 2.99 (s, 3 H), 2.57 (m, 2H), 2.16 (m, I OH), 1.81 (s, 3 H), 1.79 (s, I H), 0.93 (m, 6H); MS (ESI) m/z 818 [M + H]+. 557 Example BS B-B S Br 2 Br Br S ,,-Br j O ii 'I Br Pd(PPh 3 ) Thianthrene 2,7-Dibromo-thianthrene 2,8-Dibromo-thianthrene Br N B S N Boc S BB BS 0 Pd(PPh 3

)

4 2,7-(4,4,5,5-Tetramethyl- 2,8-(4,4,5,5-Tetramethyl 11,3,2]dioxaborolan-2-yl)-thianthrene [1,3,2]dioxaborolan-2-yl)-thianthrene N N NBoc O . N .-. Bc N H, HI - + N N4\N S C-N N N NI 'C. 2-(5-{7-[3H-Imidazol-4-yl]-thianthren-2-yl}-1H- 2-(5-(8-3H-Imidazol-4-yl]-thianthren-2-yl}-1H-i imidazol-2-yl)-pyrrolidine-bis-1 -carboxylic acid tert- midazol-2-yl)-pyrrolidine-bis-1-carboxylic acid tert butyl ester butyl ester -0 O~N - H 1. 4 N HCI N N ONH 2. HATU, Hi 1 0N N O (1-{2-[5-(7-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yi}-thianthren-2 yl)-1H-imidazol-2-yl]-pyrrolidine--carbonyi}-2-methyl-propyl)-carbamic acid methyl ester 0 N -H \ H, N 0 0 S O O S (1-{2-[5-(8-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl)thianthren-2 yl)-1H-imidazol-2-yl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 2 ,7-(4,4,5,5-Tetramethyl-[1, 3

,

2 ]dioxaborolan-2-yl)-thianthrene and 2,8-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)-thianthrene: Thianthrene (27 g, 125 mmol) in AcOH (150 mL) was treated with bromine (44 g, 275 mmol) and heated at 120*C for 8 hours. The mixture was allowed to stand overnight at ambient temperature, at which time a white solid appeared. The solid was filtered, washed with H 2 0 (3 x 50 mL) and air dried to afford a mixture 558 of 2,7-dibromo-thianthrene and 2,8-dibromo-thianthrene which was carried forward without further purification (42 g). The 2,7-bibromo-thianthrene/2,8-dibromo-thianthrene mixture (1 g, 2.7 mmol) in DMSO (25 mL) was treated with bis(pinacolato)diboron (2.7 g, 10.7 mmol), PdCl 2 dppf(218 mg, 0.27 mmol), and KOAc (2.1 g, 21.4 mmol). The mixture was stirred in a 5 sealed tube at 80'C for 18 hours. The mixture was diluted with EtOAc (100 mL), and washed with saturated NaHCO 3 (3 x 50 mL), H 2 0 (50 mL), and brine (50 mL). The solution was dried over MgSO 4 and subjected to a 40 g SiO 2 COMBIFLASH column (0-50% EtOAc-hexanes gradient) to afford a mixture of 2,7-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yI)-thianthrene and 2,8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thianthrene (1.25 g, 99%): MS (ESI) m/z 10 796 [M + H]. 2-(5-{7-13H-Imidazol-4-yl]-thianthren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-bis-1-carboxylic acid tert-butyl ester and 2-(5-{8-3H-imidazol-4-yl]-thianthren-2-yl}-IH-imidazol-2-yl) pyrrolidine-bis-1-carboxylic acid tert-butyl ester: A mixture of 2,7-(4,4,5,5-Tetramethyl 15 [1,3,2]dioxaborolan-2-yl)-thianthrene and 2,8-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl) thianthrene (1.25 g, 2.67 mmol) and 2-(4-bromo-I H-imidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (1.77 g, 5.6 mmol) in 3:1 DME/H 2 0 (25 mL) were treated with Pd(PPh 3

)

4 (185 mg, 0.160 mmol) and NaHCO 3 (1.12 g, 13.35 mmol). The mixture was stirred in a sealed tube at 90*C for 24 hours. The mixture was filtered through a fritted glass funnel and 20 concentrated. The mixture was diluted with EtOAc (100 mL), and washed with saturated NaHCO 3 (3 x 50 mL), H 2 0 (50 mL), and brine (50 mL). The solution was dried over MgSO 4 and subjected to a 120 g SiO 2 COMBIFLASH column (0-50% EtOAc-hexanes gradient) to afford a mixture of 2-(5-{7-[3H-imidazol-4-yl]-thianthren-2-yl}-I H-imidazol-2-yl)-pyrrolidine bis- I -carboxylic acid terl-butyl ester and 2-(5-{8-3H-imidazol-4-yl]-thianthren-2-yl}-1

H

25 imidazol-2-yl)-pyrrolidine-bis-I -carboxylic acid tert-butyl ester. (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-thianthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester and (1-{2-[5-(8-{2-I1-(2-Methoxycarbonylamino-3 30 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-thianthren-2-yl)-1H-imidazol-2-yl] pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester: A mixture of 2-(5 {7-[3H-Imidazol-4-yl]-thianthren-2-yl}- I H-imidazol-2-yl)-pyrrolidine-bis-I -carboxylic acid terl-butyl ester and 2-(5-{8-3H-imidazol-4-yl]-thianthren-2-yl}-1 H-imidazol-2-yl)-pyrrolidine bis-1 -carboxylic acid tert-butyl ester (150 mg, 0.22 mmol) was treated with 4 N HCI/dioxane 35 (2.5 mL) and stirred for 4 hours. The mixture was concentrated and suspended in DMF (2.5 559 mL). The mixture was treated with (S)-Moc-Val-OH (84 mg, 0.48 mmol), HATU (191 mg, 0.50 mmol), and N-methyl morpholone (120 mL, 1.09 mmol). The mixture was stirred for 2 hours and concentrated. The mixture was diluted with EtOAc (100 mL), and washed with saturated NaHCO 3 (3 x 50 mL), H 2 0 (50 mL), and brine (50 mL). The solution was dried over MgSO 4 5 and subjected to a 40 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes followed by 0 20% MeOH-EtOAc gradient), which gave a pure mixture of 2,7/2,8 products. The 2,7/2,8 mixture was subjected to a reverse phase HPLC column (5-95% MeCN-H 2 0; 0.1% TFA modifier) to afford (1-{2-[5-(7-{2-[I-( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-thianthren-2-yi)- IH-imidazol-2-yl]-pyrrolidine-I-carbonyl}-2-methyl 10 propyl)-carbamic acid methyl ester (26 mg, 15%) as a white solid (TFA salt): 'H NMR

(CD

3 0D, 400 MHz) 7.88 (s, 2H), 7.80 (s, 2H), 7.63 (s, 4H), 5.20 (m, 2H), 4.23 (d, J = 7.5 Hz, 2H), 4.13 (m, 2H), 3.88 (m, 2H), 3.72 (s, 6H), 2.99 (s, 3H), 2.52 (m, 2H), 2.16 (m, 10H), 0.95 (m, 12H); MS (ESI) m/z 818 [M + H]*; and (I-{ 2 -[5-(8-{2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-thianthren-2-yl)-I H-im idazol-2-yl] 15 pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (10 mg, 5%) as a white solid (TFA salt): 'H NMR (CD 3 0D, 400 MHz) 7.86 (s, 2H), 7.80 (s, 2H), 7.63 (s, 4H), 5.20 (m, 2H), 4.23 (d, J = 7.5 Hz, 2H), 4.13 (m, 2H), 3.88 (m, 2H), 3.72 (s, 6H), 2.99 (s, 31H), 2.52 (m, 2H), 2.16 (m, 10H), 0.95 (m, 12H); MS (ESI) m/z 801 [M + H]f. 20 Example BT

H

2 N 1. BnCHO, NaBH4 N 1H HN OH 2. TMSCHN 2 2. CH 2 0 N OHN O OMe ' Al I N OMe 0 1OA\ 0H 0 4\o 0 4 3-Amino-2-tert butoxycarbonylamino- 3-Benzylamino-2-tert- 1 -Benzyl-imidazolidine-4-carboxylic propionic acid butoxycarbonylamino- acid methyl ester propionic acid methyl ester \I1T 1. H 2 -Pd/C0f0 HATU, R-COOH N 2. BOC 2 (N N H N OMe 0 H N OMe N OMe O\ N O'O- O H I >f-N > NO ~ H 0 00 0 0 1-Benzyl-3-(2- 3-(2 1 -Benzyl-imidazolidine-4-carboxylic methoxycarbonylamino-3-methyl- Methoxycarbonylamino-3 acid methyl ester butyryl)-imidazolidine-4-carboxylic . methyl-butyryl) acid methyl ester imidazolidine-1,4 dicarboxylic acid 1-tert butyl ester 4-methyl ester 560 3-Benzylam ino-2-tert-butoxycarbonylamino-propionic acid methyl ester: 3-Amino-2-tert-butoxycarbonylamino-propionic acid (5.0 g, 24.5 mmol) was suspended in methanol (100 mL) and benzaldehyde (5.2 g, 49 mmol) was added, followed by triethylamine (TEA, 10.2 mL, 73.5 mmol). The reaction mixture was stirred at ambient temperature for 90 5 minutes and cooled to 0 'C. Solid sodium borohydride (2.78 g, 73.5 mmol) was added in small portions and the reaction was stirred for additional 60 minutes after addition was complete. All volatiles were removed in vacuo and the crude was dissolved in NaOHaq (0.1 M, 100 mL). The solution was washed with diethyl ether and acidified with HCI aq. The mixture was extracted with chloroform. The organic extracts were washed with brine and dried over sodium sulfate. 10 Filtration and evaporation of solvents in vacuo yielded crude semi-solid (9.0 g). The crude material was dissolved in methanol (40 mL) and toluene (20 mL) and the solution was cooled to 0*C. Trimethysilyl diazomethane solution (2M, in hexanes) was added until the yellow color persisted (-25 mL). The reaction mixture was stirred for additional 60 minutes at room temperature. The volatiles were removed in vacuo and the crude product was purified via silica 15 gel chromatography (eluent: EtOAc / hexanes) to yield the pure product 3-Benzylamino-2-tert butoxycarbonylamino-propionic acid methyl ester (4.09 g): LCMS-ESI*: calc'd for

C

16

H

2 4

N

2 0 4 : 308.3 (M*); Found: 309.2 (M+H*). 1-Benzyl-imidazolidine-4-carboxylic acid methyl ester: 3-Benzylamino-2-tert 20 butoxycarbonylamino-propionic acid methyl ester (4.01 g, 13.02 mmol) was dissolved in dichloromethane (20 mL) and HCI (4M Dioxane, 40 mL) was added. The resultant suspension was stirred at room temperature for 30 minutes, after which all volatiles were removed in vacuo. The crude material was mixed with para-formaldehyde (390 mg, 13.02 mmol), magnesium sulfate (2.6 g), potassium carbonate (2.6 g) and suspended in chloroform (40 mL). 25 Triethylamine (5.07 mL) was added and the reaction was stirred at room temperature for 48 hours. The suspension was filtered and the volatiles were removed in vacuo. The crude material I-Benzyl-imidazolidine-4-carboxylic acid methyl ester (3.5 g) was used in the next step without further analysis. 30 1-Benzyl- 3

-(

2 -methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-4-carboxylic acid methyl ester: Crude I-Benzyl-imidazolidine-4-carboxylic acid methyl ester (3.0 g, 13.6 mmol) was added as a DMF suspension to a premixed solution of N-(methylcarbamoyl)(L)-valine (2.39 g, 13.6 mmol), HATU (5.16g, 13.6 mmol) and diisopropyl ethylamine (DIEA, 3.58 g, 27.2 mmol) at room temperature. After 60 minutes, all volatiles were removed in vacuo and the 35 crude material was taken into dichloromethane. The organic layer was washed with aqueous 561 hydrochloric acid (0.1 M), aqueous lithium chloride solution (5%), saturated aqueous sodium bicarbonate solution, brine and was dried over sodium sulfate. Filtration and evaporation of solvents yielded crude material. Purification via silica gel chromatography (eluent: EtOAc w MeOH 10% / hexanes) yielded the product I -Benzyl-3-(2-methoxycarbonylamino-3-methyl 5 butyryl)-imidazolidine-4-carboxylic acid methyl ester (1.95 g, 5.15 mmol): LCMS-ESlI: calc'd for C 19

H

2 7

N

3 0 5 : 377.4 (M*); Found: 378.4 (M+H*). 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert butyl ester 4-methyl ester: I -Benzyl-3-(2-methoxycarbonylamino-3-methyl-butyryl) 10 imidazolidine-4-carboxylic acid methyl ester (1.0 g, 2.64 mmol) was dissolved in MeOH (30 mL) at room temperature. Pd on carbon (10%, 350 mg) was added and the reaction was stirred under an atmosphere of hydrogen. After three hours the reaction mixture was filtered through CELITE and the volatiles were removed in vacuo. The crude material was dissolved in tetrahydrofuran (10 mL) and Boc 2 0 (576 mg) and diiso-propyl ethylamine (340 mg) were added 15 and the reaction was stirred at room temperature. After 60 minutes all volatiles were removed in vacuo and the crude material was purified via silica gel chromatography (eluent: EtOAc wlO% MeOH / hexanes) and yielded the product (0.812 g): LCMS-ESl*: calc'd for C 1

H

2 9

N

3 0 7 : 387.4 (M+); Found: 388.4 (M+H*). 562 Example BU Br O Of 1. LiOH O O -7 (N 2. HATU, NH 2 -R N O H N OMe H N N) O H N0N 3-(2-Methoxycarbonylamino- 4-[2-(4-Bromo-phenyl)-2-oxo 3-methyl-bury)- ethylcarbamoy]-3-(2 imidazolidine-1bu methoxycarbonylamino-3-methyl dicarboxylic acid 1-tert-butyl butyryl)-imidazolidine-1-carboxyic ester 4-methyl ester acid tert-butyl ester Br O O ONH40Ac, m-XyI 7 N H IN / 135 *C N <(( H N H O H N N N 00 Br 4-(4-Bromo-phenyl)-3-(2 4-[2-(4-Bromo-phenyl)-2-oxo- methoxycarbonylamino-3-methyl methycarboyln-3-mey- butyryl)-2,3',4',5'-tetrahydro-1H methox bonyamio-3-rnethyl- [2,4]biimidazoly l1 -carboxylic acid tert butyryl)-imidazolidine-1-carboxylic butyl ester acid tert-butyl ester 0 0UN O0 N H H Pd(PPh 3

)

4 NN N N Bronate N*y I-.f N O N N H'N O O O N Br O N 0 4-(4-Bromo-pheny)-3'-(2- 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-5.-(42 methoxycarbonylamino-3-methyl- [1-(2-methoxycarbonylamino-3-methyl-butyryl) butyryl)-2i,3id4a,5'-tetrahydro- H- pyrrolidin-2-y]-3H-imidazol-4-yl}-biphenyl-4-y) [24]biimidazolyl-'-carboxylic acid tt 2',3',4',5'-tetrahydro-1H-[2,4']biimidazolyl-1'-carboxylic butyl ester acid tert-butyl ester 4

-[

2

-(

4 -Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2-methoxycarbonylamino-3-methyl 5 butyryl)-imidazolidine-1-carboxylic acid tert-butyl ester: 3-(2-Methoxycarbonylamino-3 methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid I -tert-butyl ester 4-methyl ester (460 mg, 1.18 mmol) was dissolved in THF (3 mL) and MeOH (2 mL). An aqueous solution of LiOH (49.8 mg, 1.18 mmol) was added and stirring at room temperature was continued. After the hydrolysis was complete, the reaction was neutralized with aqueous HCI (1.18 mL, 1 M). The 10 organic solvents were removed in vacuo and the aqueous suspension was frozen and lyophilized. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (4.0 mL) and HATU (448 mg, 1.18 mmol) and DIEA (152 mg, 1.18 563 mmol) were added. The reaction was stirred at room temperature for five minutes, after which the amino-(4'bromo) acetophenone hydrochloride salt (295 mg, 1.18 mmol) was added. Stirring at room temperature was continued. After 90 minutes, all volatiles were removed in vacuo and the crude material was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield 5 the slightly impure product 4-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2 methoxycarbonylam ino-3-methyl-butyryl)-imidazolidine- I -carboxylic acid tert-butyl ester (723 mg): LCMS-ESl: calc'd for C 24

H

33 BrN 4 0 7 : 569.4 (M*); Found: 570.4 / 572.4 (M+H*). 4

-(

4 -Bromo-phenyl)-3'-(2-methoxycarbonylamino-3-methyl-butyryl)-2',3',4',5'-tetrahyd ro 10 1H-12,4']biimidazolyl-1'-carboxylic acid tert-butyl ester: 4-[2-(4-Bromo-phenyl)-2-oxo ethylcarbamoyl]-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-I -carboxylic acid tert-butyl ester (723 mg) was dissolved in m-xylenes (6.0 mL) and heated at 135 *C. Solid ammonium acetate (500 mg, 6.48 mmol) was added and the reaction was stirred at 135 *C. After 45 minutes, the reaction was cooled to room temperature and the volatiles were removed 15 in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w 10% MeOH / hexanes) to yield the product 4

-(

4 -Bromo-phenyl)-3'-(2-methoxycarbonylamino-3 methyl-butyryl)-2',3',4',5'-tetrahydro-I H-[2,4']biimidazolyl- '-carboxylic acid tert-butyl ester (436 mg): LCMS-ESI: calc'd for C 2 4

H

3 2 BrN 5

O

5 : 550.4 (M); Found: 551.2 / 553.2 (M+H*). 20 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4'-{2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yll-3H-imidazol-4-yl}-biphenyl4-yl)-2',3',4',5'-tetrahydro IH-[2,4']biimidazolyl-l'-carboxylic acid tert-butyl ester: 4-(4-Bromo-phenyl)-3'-(2 methoxycarbonylamino-3-methyl-butyryl)-2',3',4',5'-tetrahydro-i H-[2,4']biimidazolyl- ' carboxylic acid tert-butyl ester (75 mg, 0.136 mmol) was combined with [2-Methyl-1-(2-{4-[4 25 (4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-pyrrolidine- I carbonyl)-propyl]-carbamic acid methyl ester (67.6 mg, 0.136 mmol) under an argon atmosphere. Potassium carbonate (37.5 mg, 0.272 mmol) and Pd(PPh 3

)

4 (15.7 mg, 0.014 mmol) were added, followed by DME (3 mL) and water (0.6 mL). The mixture was heated under microwave conditions for 20 minutes at 120 *C. All volatiles were removed in vacuo and the 30 crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product (55 mg): LCMS-ESI*: calc'd for C 44

H

5 7

N

9 0 8 : 839.9 (M*); Found: 840.5 (M+H*); 'H-NMR: 300 MHz, (MeOH-d 4 ) 5: 7.90-7.81 (m, I OH), 5.58 (m,I H), 5.43 (m, I H), 5.25-5.20 (m, 2H), 4.24 (d,J= 7.5Hz, I H), 4.11 (m, I H), 3.99 (m, I H), 3.86 (m,2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.46 (d, J= 7.2Hz, 1 H), 2.59 (m, I H), 2.22-2.10 (m, 5H), 1.53 & 1.44 (s, 9H) 35 1.04-0.89 (m, 12H). 564 Example BV H _N H H ) ! MeOOCCI, NNM, OH N N - N NDCM _ 4 NI/ I/ \/ _~ D - HN-.<O 2. NaOH,

H

2 0, O THF, MeOH {1 -[2-(5-4'-[3'-(2-Methoxycarbonylamino-3-methyl-butyryl) 2',3',4',5'-tetrahydro-3H,1'H-[2,4']biimidazolyl-4-yl]-biphenyl-4-yl} 1 H-imidazol-2-yl)-pyrrolidine-1 -carbonyl]-2-methy-propyl} carbamic acid methyl ester H HO NNN 10 N \/ \ N HN 0 /O 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4'-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} biphenyl-4-yl)-2',3',4',5'-tetrahydro-1H-[2,4']biimidazolyl-1'-carboxylic acid methyl ester 5 3'-(2-Methoxycarbonylamino-3-methyl-butyry)-5-(4'-{2-1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl)-biphenyl-4-yI)-2',3',4',5'-tetrahydro 1H-12,4']biimidazolyl-1'-carboxylic acid methyl ester: 4-Methylmorpholine (31 ltL, 0.28 mmol) was added to a suspension of {1-[2-(5-{4'-[3'-(2-Methoxycarbonylamino-3-methyl 10 butyryl)-2',3',4',5'-tetrahydro-3H,I'H-[2,4']biimidazolyl-4-yi]-biphenyl-4-yl }-I H-imidazol-2-yl) pyrrolidine-I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (41.1 mg, 0.056 mmol) [prepared via reaction of 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4'-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl) 2',3',4',5'-tetrahydro-I H-[2,4']biimidazolyl-l'-carboxylic acid tert-butyl ester with HCI-solution] 15 in dichloromethane (5 mL). Methyl chloroformate (16.5 1L, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed in vacuo. The residue was taken into tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, I mL) was added. After 2 hours the organic solvents were removed in vacuo and the aqueous phase was decanted. The residue was dissolved in dimethylformamide (2 mL) and 20 purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA). The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3'-(2 Methoxycarbonylamino-3-methyl-butyryl)-5-(4'-{2-[I-(2-methoxycarbonylamino-3-methyl 565 butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2',3',4',5'-tetrahydro- I H [2,4']biimidazolyl-l'-carboxylic acid methyl ester (7.5 mg)

C

4 1 Hs IN 9 0 8 calculated 797.4 observed [M + 1]' 798.4; 'H (DMSO-d6): 8 = 8.08 (s, 1 H), 7.83 (m, 8H), 7.58 (d, J = 8.0 Hz, I H), 7.29 (s, J = 8.4 Hz, I H), 5.42 (dd, J = 7.6, 3.6 Hz, I H), 5.26 5 (d, J = 4.8 Hz, I H), 5.18 (d, J = 6.0 Hz, I H), 5.10 (t, J = 7.2 Hz, I H), 4.88 (m, I H), 4.08 (t, J = 7.6 Hz, 2H), 3.94 (m, I H), 3.82 (m, 4H), 3.65 (s, 3H), 3.52 (s, 3H), 3.51 (s, 3H), 2.36 (m, I H), 2.01 (m, 5H), 0.83 (m, 12H). Example BW N 0o 0 7 H 1. HCI N N 2. PhCOCI < N NN 0 HN N 0Br 0 Br 4-(4-Bromo-phenyl)-3'-(2- { [ Bnol4(-rm-hnl- 24-erhdo1H methoxycarbonylamino-3-methyl- (1['Bno--4boopeyl-'2,'5-erhdGl butyryl)-2,3,4',5-tetrahydro-1H- [2azh-bonyl -2-ethr y a ic [2,4']biimidazoyl-1'-carboxylic acid tert- acid methyl ester butyl ester 0 oO N'Y H H N Pd(PPh 3

)

4 0 N < N" $ boronate .fN\ / - N N O N H H'N O0 N z. 0. N- 0 Br O0O (1-[1'-Benzoyl-4-(4-bromo-phenyl) 1',2',4',5'-tetrahydro-IH- [2,4']biimidazolyl-3'-carbony]-2 methyl-propyl}-carbamic acid methyl {1-[1'-Benzoyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl ester butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl)-biphenyl-4-yl)-1',2',4',5' tetrahydro-1H-[2,4']biimidazoyl-3'-carbonyl]-2-methyl-propyl} 10 carbamic acid methyl ester {1-[1'-Benzoyl-4-(4-bromo-phenyl)-1',2',4',5'-tetrahydro-IH-[2,4']biimidazolyl-3' carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: 4-(4-Bromo-phenyl)-3'-(2 methoxycarbonylamino-3-methyl-butyryl)-2',3',4',5'-tetrahydro-I H-[2,4']biimidazolyl-l' 15 carboxylic acid tert-butyl ester (55.6 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL) and HCI (4M dioxane, 0.5 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THIF (I mL) and diisopropyl ethylamine (26.0 mg, 0.202 mmol) was added, followed by benzoyl chloride (15.6 mg, 0.11 mmol). The reaction was stirred at room 20 temperature. After 10 minutes, all starting material was consumed. All volatiles were removed 566 in vacuo and the crude brown solid {1 -[1'-Benzoyl-4-(4-bromo-phenyl)-l',2',4',5'-tetrahydro- I H [2,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was used in the coupling reaction without further analysis or purification: LCMS-ESI*: calc'd for

C

26

H

2 8 BrN 5

O

4 : 554.4 (M*); Found: 554.3 / 556.4 (M+H+). 5 {1-[1'-Benzoyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 3H-imidazol-4-yl}-biphenyl-4-yl)-l',2',4',5'-tetrahydro-1H-[2,4']biimidazolyl-3'-carbonyl] 2-methyl-propyl}-carbamic acid methyl ester: { I -[1'-Benzoyl-4-(4-bromo-phenyl)-l',2',4',5'-tetrahydro-I H-[2,4']biimidazolyl-3'-carbonyl]-2 10 methyl-propyl}-carbamic acid methyl ester (crude, <0.101 mmol) was combined with [2 Methyl-I -(2-{4-[4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I H-imidazol-2-yl} pyrrolidine-1 -carbonyl)-propyl]-carbamic acid methyl ester (45.1 mg, 0.091 mmol) under an argon atmosphere. Potassium carbonate (27.8 mg, 0.202 mmol) and Pd(PPh 3

)

4 (10 mg, 0.009 mmol) were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated 15 under microwave conditions for 20 minutes at 120 *C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product { I-['-Benzoyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yI)-l',2',4',5'-tetrahydro-1

H

[2,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (20.7 mg): LCMS 20 ESI: calc'd for C 46

H

53

N

9 07: 843.9 (M*); Found: 844.3 (M+H*); 1 H-NMR: 300 MHz, (MeOH-d 4 ) &: 7.90-7.84 (m, I OH), 7.66-7.52 (m, 5 H), 5.68 (m,lI H), 5.59 (m, I H), 5.49 (m, I H), 5.26 (m, I H), 4.24 (d,J= 7.5Hz, 1 H), 4.11 (m, 2H), 3.86 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.46 (d, J= 5.7Hz, I H), 2.57 (m, I H), 2.29-2.09 (m, 51H), 1.01-0.85 (m, 12H). 25 567 Example BX 0 0 {CF 3 N 1. HCI N ( N ))2.

CF

3

CH

2 OTf < O H N OMe H N OMe N O O N O O O 3-(2-Methoxycarbonylamino-3-methyl- 3-(2-Methoxycarbonylamino-3-methyl butyryl)-imidazolidine-1,4-dicarboxytic butyryl)-I-(2,2,2-trifluoro-ethyl) acid 1-tert-butyl ester 4-methyl ester imidazolidine-4-carboxylic acid methyl ester Br

CF

3 CF 3 N 1. LiOH N < 2. HATU, NH 2 -R H 0 H N OMe H N N O N O O N O 0 0 3-(2-Methoxycarbonylamino-3-methyl butyryl)-l -(2,2,2-trifluoro-ethy- {1 -[5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3 imidazolidine-4-carboxylic acid methyl ester (2,2,2-trifluoro-ethyl)-imidazolidine-1 -carbonyl]-2 methyl-propyl}-carbamic acid methyl ester Br

CF

3 ( 3 N/ NH 4 0Ac, m-Xyl N H H 135 "C / ( N OH N N H N) I I 0 H N 0 ) N N O O N O0O O Br (1-[4-(4-Bromo-phenyl)-1 -(2,2,2-trifluoro-ethyl) (1-[5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoy)3- 1',2,45-tetrahydro- '-[2,4ubiimidazolyl3' (2,2,2-trifluoro-ethyl)-imidazolidine-1-carbonyll-2- carbonyl]-2-methyl-propyl)-carbamic acid methyl methyl-propyl}-carbamic acid methyl ester ester

CF

3 0 N HPd(PPh 3

)

4 0O1. N' 0 H, H N nronat) N4 O H N N j NO0 O N O N - HH'N O Br 0

CF

3 1 -[4-(4-Bromo-pheny)-1'-(2,2,2-trifluoro-ethyl)- (1 -[5-(4'-(2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrroidin 1,2,4,5'-tetrahydro-1 H-{2,4]biimidazolyl-3'- 2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1'-(2,2,2-trifluoro-ehyl) carbonyl]-2-methyl-propy}-carbamic acid methyl 1',2',4',5'-tetrahydro-1 H-[2,4'biimidazolyl-3'-carbonyl]-2-methyl ester propyl}-carbamic acid methyl ester 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-1 -(2,2,2-trifluoro-ethyl)-imidazolidine-4 5 carboxylic acid methyl ester: 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine I,4-dicarboxylic acid I -tert-butyl ester 4-methyl ester (160 mg, 0.412 mmol) was dissolved in dichloromethane (0.5 mL) and HCI (4M dioxane, 3 mL) was added. The resultant suspension was stirred at room temperature for 60 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in DMF (1.5 mL) and diisopropyl ethylamine (106 mg, 0.824 10 mmol) was added followed by trifluoroethyl triflate (114.7 mg, 0.494 mmol). After 14 hrs additional diisopropyl ethylamine (212 mg, 1.648 mmol) and trifluoroethyl triflate (229.4 mg, 568 0.988 mmol) were added. Stirring at room temperature was continued. After 40 hours, all volatiles were removed in vacuo and the crude material was purified by flash chromatography on silica gel (eluent: EtOAc / hexanes) to yield the product 3-(2-Methoxycarbonylamino-3 methyl-butyryl)- I -(2,2,2-trifluoro-ethyl)-imidazolidine-4-carboxylic acid methyl ester (95 mg, 5 0.257 mmol): LCMS-ESl*: calc'd for C 14

H

2 3

F

3

N

3 0 5 : 369.3 (M*); Found: 369.9 (M 4 ). {1-[5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2,2,2-trifluoro-ethyl)-imidazolidine-1 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: 3-(2-Methoxycarbonylamino-3-methyl-butyryl)- I -(2,2,2-trifluoro-ethyl)-imidazolidine-4 10 carboxylic acid methyl ester (95 mg, 0.257 mmol) was dissolved in THF (1.8 mL) and MeOH (0.9 mL). An aqueous solution of LiOH (10.8 mg, 0.208 mmol) was added and stirring at room temperature was continued. After the hydrolysis was complete, the reaction was neutralized with aqueous HCI (IM). The organic solvents were removed in vacuo and the aqueous suspension was frozen and lyophilized. The crude material was used in the next step without 15 further purification. The crude material was dissolved in DMF (1.5 mL) and HATU (97.6 mg, 0.257 mmol) and DIEA (66.3 mg, 0.514 mmol) were added. The reaction was stirred at room temperature for five minutes, after which the amino-(4'bromo) acetophenone hydrochloride salt (64.2 mg, 0.257 mmol) was added. Stirring at room temperature was continued. After 60 minutes, all volatiles were removed in vacuo and the crude material was purified via silica gel 20 chromatography (eluent: EtOAc / hexanes) to yield the slightly impure product { I -[5-[2-(4 Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2,2,2-trifluoro-ethyl)-imidazolidine- I -carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (148 mg): LCMS-ESI*: calc'd for C 2 iH 26 BrF 3

N

4 0 5 : 551.3 (M*); Found: 551.2 / 553.2 (M*). 25 (1-[4-(4-Bromo-phenyl)-l'-(2,2,2-trifluoro-ethyl)-1',2',4',5'-tetrahydro-1

H

12,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: { I -[5-[ 2

-(

4 -Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2,2,2-trifluoro-ethyl)-imidazolidine-I carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (148 mg, <257 mmol) was dissolved in m-xylenes (4.0 mL) and heated at 135 *C. Solid ammonium acetate (150 mg, 1.9 mmol) was 30 added and the reaction was stirred at 135 'C. After 60 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via RP HPLC (eluent: water / MeCN w 0.1 % TFA) to yield the product (I -[4-(4-Bromo-phenyl)- ' (2,2,2-trifluoro-ethyl)-l',2',4',5'-tetrahydro-I H-[2,4']biimidazolyl-3'-carbonyl]-2-methyl propyl}-carbamic acid methyl ester (15.1 mg) as the TFA salt: LCMS-ESI*: calc'd for 35 C 2 1 H 2 sBrF 3

N

5 0 3 : 532.3 (M*); Found: 532.1 / 534.2 (M*). 569 {1-15-( 4 '-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol 4-yl)-biphenyl-4-yl)-1'-(2,2,2-trifluoro-ethyl)-1',2',4',5'-tetrahydro-1 H-12,4'] biimidazolyl 3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: { I -[4-(4-Bromo-phenyl)-l' 5 (2,2,2-trifluoro-ethyl)- l',2',4',5'-tetrahydro- I H-[2,4']biimidazolyl-3'-carbonyl]-2-methyl propyl}-carbamic acid methyl ester (13.0 mg, 0.0244 mmol) was combined with [2-Methyl-I (2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2-yl)-pyrrolidine I-carbonyl)-propyl]-carbamic acid methyl ester (12.1 mg, 0.0244 mmol) under an argon atmosphere. Potassium carbonate (6.7 mg, 0.048 mmol) and Pd(PPh 3

)

4 (2.7 mg, 0.0024 mmol) 10 were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated under microwave conditions for 20 minutes at 120 'C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product { 1-[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-y}-biphenyl-4-yl)-l'-(2,2,2-trifluoro-ethyl)-I',2',4',5'-tetrahydro 15 1 H-[2,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (6.1 mg, 0.006 mmol) as the TFA salt: LCMS-ESI*: calc'd for C 4 1

H

5 0

F

3

N

9 0 6 : 821.8 (M*); Found: 823.4 (M+H*); 1 H-NMR: 300 MHz, (MeOH-d 4 ) 6: 7.89-7.82 (m, 10 H), 5.39 (dd, J=6.3, 6.3Hz, I H), 5.25 (m, I H), 4.78 (d, J=6.9Hz, 1 H), 4.24 (d, J=7.5Hz, I H), 4.10 (m,I H), 4.00 (d, J=7.5Hz, I H), 3.88 (m, I H), 3.67 (s, 3H), 3.66 (s, 3H), 3.65-3.43 (m, 4H), 2.58 (m, I H), 2.29-2.01 (m, 5H), 20 1.03-0.89 (m, 12H). 570 Example BY O-~ 1. HCI N / K2. Ac 2 O < / H N OMe .AH N OMe O- N O O O N O 3-(2-Methoxycarbonylamino-3- 1 -Acetyl-3-(2-methoxycarbonylamino methyl-butyryl)-imidazolidine- 3-methyl-butyryl)-imidazolidine-4 1,4-dicarboxylic acid I-tert- carboxylic acid methyl ester butyl ester 4-methyl ester Br O 1. LiOH O( I N 2. HATU, NH 2 -R N OH N OMeOH N O N ON , O 0 0 0 00 0 1 -Acetyl-3-(2-methoxycarbonylamino- (1 -{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo 3-methyl-butyryl)-imidazolidine-4- ethylcarbamoyl]-imidazolidine-1 -carbony}-2 carboxylic acid methyl ester methyl-propyl)-carbamic acid methyl ester Br 0

NH

4 0Ac, m-Xyl N H N / 135 OC < i N, 0 H QHy N ~ O H N N N 0 O Br {1-[1'-Acetyl-4-(4-bromo-phenyl) (1-{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo- 1',2',4',5'-tetrahydro-1H ethylcarbamoyl]-imidazolidine-1-carbonyl)-2- [2,4'biimidazolyl-3'-carbonmetyl-eter methyl-propyl)-carbamic acid methyl ester propyl)carbamic acid methyl ester 0 O Pd(PPh 3

)

4 O N'H H H Boronate O <i N N t , N \ O H N I NJN /N7 I N N H H'N O1 O0 N-7 y Br 0 0 {1-[1'-Acetyl-5-(4'-{2-[1 -(2-methoxycarbonylamino-3-methyl {1 -[1'-Acetyl-4-(4-bromo-pheny)- butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1',2',4',5' 1',2',4',5'-tetrahydro-I H- tetrahydro-1 H-[2,4'lbiimidazolyl-3'-carbonyl-2-methyl-propyl} [2,4']biimidazolyl-3'-carbonyl]-2-methyl- carbamic acid methyl ester propyl}-carbamic acid methyl ester 5 1-Acetyl-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-4-carboxylic acid methyl ester: 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine- 1,4-dicarboxylic acid I -tert-butyl ester 4-methyl ester (465 mg, 1.2 mmol) was dissolved in dichloromethane (1 mL) and H CI (4M dioxane, 3 mL) was added. The resultant suspension was stirred at room temperature for 30 minutes, after which all volatiles were removed in vacuo. The crude material 10 was dissolved in THF and diisopropyl ethylamine (154 mg, 1.2 mmol) was added, followed by 571 acetic anhydride (122 mg, 1.2 mmol). The reaction was stirred at room temperature. After 30 minutes, all volatiles were removed in vacuo. The crude material was purified by silica gel chromatography (eluent: DCM / MeOH) to yield the product I -Acetyl-3-(2 methoxycarbonylamino-3-methyl-butyryl)-imidazol idine-4-carboxylic acid methyl ester (273 5 mg, 0.829 mmol): LCMS-ESI*: calc'd for C 14

H

2 3

N

3 0 6 : 329.4 (M*); Found: 330.4 (M+H*). (1 -{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl] -imidazolid ine- 1 -carbonyl} -2 methyl-propyl)-carbamic acid methyl ester: I -Acetyl-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-4-carboxylic acid 10 methyl ester (273 mg, 0.829 mmol) was dissolved in THF (1.8 mL) and MeOH (1.2 mL). An aqueous solution of LiOH (34.8 mg, 0.829 mmol) was added and stirring at room temperature was continued. After the hydrolysis was complete, the reaction was neutralized with aqueous HCI (0.83 mL, I M). The organic solvents were removed in vacuo and the aqueous suspension was frozen and lyophilized. The crude material was used in the next step without further 15 purification. The crude material was dissolved in DMF (3 mL) and HATU (315 mg, 0.829 mmol) and DIEA (106 mg, 0.829 mmol) were added. The reaction was stirred at room temperature for five minutes, after which the amino-(4'bromo) acetophenone hydrochloride salt (207 mg, 0.829 mmol) was added. Stirring at room temperature was continued. After 120 minutes, all volatiles were removed in vacuo and the crude material was dissolved in DCM. The 20 organic layer was washed with aqueous HCI (0.5 M), aqueous lithium chloride solution (5%), brine and was dried over sodium sulfate. Filtration and evaporation of solvents yielded crude product which was purified via silica gel chromatography (eluent EtOAc / hexanes) to yield the product (1-{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-imidazolidine-l-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester (203 mg, 0.397 mmol): LCMS-ESI*: calc'd for 25 C 21

H

27 BrN 4 0 6 : 511.4 (M*); Found: 511.3 / 513.2 (M+H+). {1-[1'-Acetyl-4-(4-bromo-phenyl)-1',2',4',5'-tetrahydro-1H-12,4']biimidazolyl-3'-carbonyl] 2-methyl-propyl}-carbamic acid methyl ester: (1 -{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-imidazolidine-I-carbonyl}-2 30 methyl-propyl)-carbamic acid methyl ester (203 mg, 0.397 mmol) was dissolved in m-xylenes (4 mL) and heated at 135 *C. Solid ammonium acetate (200 mg, 2.58 mmol) was added and the reaction was stirred at 135 *C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w 10% MeOH/hexanes) to yield the product { I -[1 '-Acetyl-4 35 (4-bromo-phenyl)- l',2',4',5'-tetrahydro- I H-[2,4']bi im idazolyl-3'-carbonyl]-2-methyl-propyl} 572 carbamic acid methyl ester (162 mg, 0.329 mmol): LCMS-ESl*: calc'd for C 2 1

H

2 6 BrN 5

O

4 : 492.4 (Mt); Found: 492.3 / 494.3 (M+H*). {1 -[l'-Acetyl-5-(4'-{2-[1 -(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yJ-3H 5 imidazol-4-yl)-biphenyl-4-yl)-1',2',4',5'-tetrahydro-1H-[2,4']biimidazolyl-3'-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester: { i-[l'-Acetyl-4-(4-bromo-phenyl)-l',2',4',5'-tetrahydro-I H-[2,4']biimidazolyl-3'-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (150 mg, 0.304 mmol) was combined with [2 Methyl- I-(2-{4-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-I H-imidazol-2-yl} 10 pyrrolidine-1 -carbonyl)-propyl]-carbamic acid methyl ester (151 mg, 0.304 mmol) under an argon atmosphere. Potassium carbonate (83.9 mg, 0.608 mmol) and Pd(PPh 3

)

4 (34 mg, 0.030 mmol) were added, followed by DME (8 mL) and water (2 mL). The mixture was heated under microwave conditions for 20 minutes at 120 *C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/ MeCN w 0.1% 15 TFA) to yield the product { I -[ '-Acetyl-5-(4'- { 2- [1 -(2-methoxycarbonylam ino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-l',2',4',5'-tetrahydro- I H [2,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (69.8 mg): LCMS ESlI: calc'd for C 41

H

5

IN

9 0 7 : 781.9 (M*); Found: 782.5 (M+H*); 'H-NMR: 300 MHz, (MeOH-d 4 ) 8: 7.91-7.82 (m, IOH), 5.68 (m,I H), 5.59-5.37 (m, 2H), 5.25 (m, I H), 4.34 (m,l H), 20 4.24 (d, J= 7.5Hz, I H), 4.11-4.02 (m, 2H), 3.88 (m, 1 H), 3.66 (s, 6H), 3.47 (d, J= 7.2Hz, I H), 2.60 (m, I H), 2.29-2.10 (m, 8H), 1.05-0.89 (m, 12H). Example BZ 0 O Pd(PPh 3

)

4 O N'HH N H Boronate O O NK N N / N O N NO 0 Br O=S=O 0 {1-[4-(4-Bromo-phenyl)-1'- {1 -[1'-Methanesulfonyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3 methanesulfonyl-1',2',4',5'-tetrahydro- methyl-butyryl)-pyrrolidin-2-yl-3H-imidazol-4-yl}-biphenyl-4-yl) 1 H-[2,4]biimidazolyl-3'-carbonyl]-2- 1',2',4',5'-tetrahydro-1 H-[2,4]biimidazolyl-3'-carbonyl]-2-methyl methyl-propyl)-carbamic acid methyl propyll-carbamic acid methyl ester ester 25 {1-il'-Methanesulfonyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yI}-biphenyl-4-yl)-1',2',4',5'-tetrahydro-1

H

[2,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: {1-[4-(4 Bromo-phenyl)- I'-methanesulfonyl- l',2',4',5'-tetrahydro- I H-[2,4']biimidazolyl-3'-carbonyl]-2 573 methyl-propyl}-carbamic acid methyl ester (62.9 mg, 0.119 mmol) [prepared as described for the synthesis of {1 -[1'-Acetyl-4-(4-bromo-phenyl)-l',2',4',5'-tetrahydro- H-[2,4']biimidazolyl-3' carbonyl (Example BY)]-2-methyl-propyl}-carbamic acid methyl ester substituting the acetic anhydride with methyl sulfonyl chloride] was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5 5 tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-IH-imidazol-2-y}-pyrrolidine-l-carbonyl) propyl]-carbamic acid methyl ester (54.6 mg, 0.110 mmol) under an argon atmosphere. Potassium carbonate (33.1 mg, 0.240 mmol) and Pd(PPh 3

)

4 (12.7 mg, 0.0 11 mmol) were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated under microwave conditions for 20 minutes at 120 *C. All volatiles were removed in vacuo and the crude material 10 was dissolved in DMF and purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product (20.1 mg): LCMS-ESI*: calc'd for C 40

H

5

N

9 0 8 S: 817.9 (M*); Found: 818.6 (M+H*); 'H-NMR: 300 MHz, (MeOH-d 4 ) 6: 7.90-7.81 (m, IOH), 5.69 (d, J=7.5Hz, 1H), 5.48 (dd, J=6.9, 6.9Hz, I H), 5.27 (dd, J=8.1, 8.1 Hz, I H), 5.17 (d, J=8.4Hz, I H), 4.41 (dd, J=1 2.0, 7.8Hz, 1 H), 4.24 (d, J=7.2Hz, I H), 4.11 (m, 2H), 4.00 (d, J=8.1 Hz, 1 H), 3.87 (m, 2H), 3.67 (s, 15 3H), 3.66 (s, 3H), 3.17 (s, 3H), 2.57 (m, I H), 2.29-1.99 (m, 5H), 1.03-0.89 (m, 12H). Example CA -0 N=SkOH H O=S=O Pd(PPh 3

)

4 0 N' OH Boronate . O 0 H N NI NO oN N 'H 'N O Br 0=S O 0 {1-[1'-Benzenesulfonyl-4-(4-bromo phenyl)-1',2',4',5'-tetrahydro-1H- [2,4m]biimidazolyl-3-carbonyl-2- {1-[1'-Benzenesulfonyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3 methyl-propyl}carbamic acid methyl methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-y) ester 1',2',4',5'-tetrahydro-1H-[2,4]biimidazolyl-3'-carbonyl]-2-methyl propyl}-carbamic acid methyl ester 20 {1-[i'-Benzenesulfonyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1',2',4',5'-tetrahydro-1H i2,4'] biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: { 1 -[1' Benzenesulfonyl-4-(4-bromo-phenyl)-l',2',4',5'-tetrahydro- 1H-[2,4']biimidazolyl-3'-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (63.1 mg, 106.9 mmol) [prepared as described for 25 the synthesis of { 1 -[1'-Acetyl-4-(4-bromo-phenyl)-l',2',4',5'-tetrahydro-I H-[2,4']biimidazolyl-3' carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (Example BY)] substituting the acetic anhydride with phenyl sulfonyl chloride] was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5 tetramethyl-[ ,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-pyrrolidine-I -carbonyl) 574 propyl]-carbamic acid methyl ester (53.1 mg, 106.9 mmol) under an argon atmosphere. Potassium carbonate (29.2 mg, 0.212 mmol) and Pd(PPh 3

)

4 (12.2 mg, 0.0106 mmol) were added, followed by DME (2.5 mL) and water (0.8 mL). The mixture was heated under microwave conditions for 20 minutes at 120 *C. All volatiles were removed in vacuo and the 5 crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product { -[l'-Benzenesulfonyl-5-(4'-{2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-l',2',4',5'-tetrahydro- IH [2,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (27.9 mg): LCMS ESI*: calc'd for C 4 5

H

5 3

N

9 0 8 S: 880.2 (M*); Found: 881.5 (M+H+); 'H-NMR: 300 MHz, 10 (MeOH-d 4 ) 8: 8.01 (d, J=7.5Hz, 2H), 7.90-7.76 (m, I I H), 7.65 (t, J=7.8Hz, 2H), 5.59 (d, J=8.7Hz, I H), 5.25 (dd, J=7.5, 7.5Hz, 1H), 5.19 (d, J=8.7Hz, I H), 4.67 (dd, J=7.5, 7.5Hz, I H), 4.32-4.22 (m, 2H), 4.08 (m, 2H), 3.85 (m, I H), 3.68 (s, 3H), 3.66 (s, 3H), 3.44 (d, J= 6.6Hz, I H), 2.57 (m, I H), 2.29-1.99 (m, 5H), 0.99-0.86 (m, 12H). 575 Example CB N1. HCI N N 2. PhB(OH) 2 , CU(lI) < OH N OMe 0 H N OMe 3-(2Methxycabonyammn-3-3-(2-Methaxycarbonylamino-3-methyl methyl-butyryl)-imidazolidine. uyy)1peyliiaoiie4 1 .4-dicarboxylic acid I-tert- carboxylic acdd methyl ester butyl ester 4-methyl ester Br 1.LiOH <N 2. HATU, NH 2 -R N H j OMe OH N N 0 0), 0 3-(2-Methoxycartonylamino-3-methyl- (1 -(5-[2-(4-Bromo-phenyl)-2-oxo-ethycarbamoyl butyryl)- 1-phenyl-i mid azolidinie-4- 3-phenyl-imidazolidine-1 -carbonyl)-methyl carboxylic acid methyl ester propyl)-carbamic acid methyl ester Br9

INH

4 OAc, m-XyI N / 1350 /C < H OH N)<\ 0 0N N -N~4 N 0 0 0 II Br {1-(4-(4-Bromo-phenyl)-1 -phenyl-l',2'.4',5' tetrahydro-1 H-[2,4']biimidazolyl-3'-carbonylj-2 (I {5-[2-(4-Bromo-phenyt)-2-oxo-ethylcarbamoyl] methyl-propyl}-cartbamic acid methyl ester 3-phenyl-imidazalidine-1 -carbonyl)-2-methyl. propyl)-carbamic acid methyl ester 0 qPd(PPh3)4 0 N' / N N N 0 H H NO -NN N N- fB KI {1 -[4-(4-Bromo-phenyl)-1 -phenyl 1',2',4',5'- (1 -[5-(4'-{2-[1 -(2-Methaxycarbonylamino-3-methyl-butyryl) tetrahydro-1 Hl-[2,4']biimidazolyl-3'-carbonyll-2- pyrrolidin-2-yl]-3H-imidazol-4-ylbiphenyl4-yl)-l -phenyl methyl-propyl}-carbamic acid methyl ester 1',2,4,5-tetrahydrG 1 H[2,4biimidazoly-3'-carbonyl.2-methyl propyl)-carbamic acid methyl ester 576 3-(2-Methoxycarbonylamino-3-methyl-butyryl)- 1-phenyl-imidazolidine-4-carboxylic acid methyl ester: 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid I -tert-butyl ester 4-methyl ester (0.20 g, 0.515 mmol) was dissolved in dichloromethane (1.0 mL) and HCI (4M dioxane, I mL) was added. The resultant suspension was stirred at room 5 temperature for 60 minutes, after which all volatiles were removed in vacuo. The crude material was combined with phenyl boronic acid (188 mg, 1.545 mmol) and DCM (15 mL) was added. Triethylamine (1.2 mL, 8.89 mmol) was added, followed by copper(II) acetate and molecular sieves 4 A. The reaction was stirred at room temperature. After 24 hrs, the reaction was quenched with aqueous ammonium hydroxide solution (10%) and the organic layer was isolated. 10 The organic layer was washed with aqueous HCI solution (0.5 M), brine, and was dried over sodium sulfate. Filtration and evaporation gave crude material. Purification via flash chromatography on silica gel (eluent: EtOAc / hexanes) yielded the desired product 3-(2 Methoxycarbonylamino-3-methyl-butyryl)- I -phenyl-imidazolidine-4-carboxylic acid methyl ester (51.0 mg, 0.14 mmol): LCMS-ESI*: calc'd for C 18

H

25

N

3 0 5 : 363.4 (M+); Found: 364.4 15 (M+H*). (1-{5-[ 2 -(4-Bromo-phenyl)-2-oxo-ethylcarbamoyll-3-phenyl-imidazolidine--carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: 3-(2-Methoxycarbonylamino-3-methyl-butyryl) 1-phenyl-imidazolidine-4-carboxylic acid methyl ester (51 mg, 0.14 mmol) was dissolved in 20 TIHF (1.2 mL) and MeOH (0.8 mL). An aqueous solution of LiOH (6.0 mg, 0.14 mmol) was added and stirring at room temperature was continued. After the hydrolysis was complete, the reaction was neutralized with aqueous HCI (IM). The organic solvents were removed in vacuo and the aqueous suspension was frozen and lyophilized. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and 25 HATU (54.3 mg, 0.14 mmol) and DIEA (36.9 mg, 0.28 mmol) were added. The reaction was stirred at room temperature for five minutes, after which the amino-(4'bromo) acetophenone hydrochloride salt (35.7 mg, 0.14 mmol) was added. Stirring at room temperature was continued. After 10 minutes, all volatiles were removed in vacuo and the crude material was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the slightly impure 30 product (95 mg): LCMS-ESI: calc'd for C 2 5

H

2 9 BrN 4 0 5 : 545.4 (M*); Found: 545.2 / 547.4 (M+H*). {1-[4-(4-Bromo-phenyl)-1'-phenyl-l',2',4',5'-tetrahydro-1H-12,4']biimidazolyl-3' carbonyll-2-methyl-propyl}-carbamic acid methyl ester: (1-{5-[2-(4-Bromo-phenyl)-2-oxo 35 ethylcarbamoyl]-3-phenyl-imidazolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl 577 ester (90 mg) was dissolved in m-xylenes (3 mL) and heated at 135 *C. Solid ammonium acetate (100 mg, 1.29 mmol) was added and the reaction was stirred at 135 *C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc / hexanes) to 5 yield the product { I -[4-(4-Bromo-phenyl)- '-phenyl- l',2',4',5'-tetrahydro- I H-[2,4']biimidazolyl 3'-carbonyll-2-methyl-propyl}-carbamic acid methyl ester (40.2 mg, 0.0764 mmol): LCMS ESl*: calc'd for C 25

H

2 8 BrN 5

O

3 : 526.4 (M*); Found: 526.4 / 528.3 (M+H*). 10 {1-[5-(4'-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol 4-yli-biphenyl-4-yl)-1'-phenyl-1',2',4',5'-tetrahydro-1H-[2,4']biimidazolyl-3'-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester: { I -[4-(4-Bromo-phenyl)-l'-phenyl-l',2',4',5'-tetrahydro-I H-[2,4']biimidazolyl-3'-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (40 mg, 0.076 mmol) was combined with [2-Methyl 15 1-(2-{4-[4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2-yl} pyrrolidine- I -carbonyl)-propyl]-carbamic acid methyl ester (37.6 mg, 0.076 mmol) under an argon atmosphere. Potassium carbonate (20.9 mg, 0.152 mmol) and Pd(PPh 3

)

4 (8.7 mg, 0.0076 mmol) were added, followed by DME (1.8 mL) and water (0.3 mL). The mixture was heated under microwave conditions for 20 minutes at 120 *C. All volatiles were removed in vacuo and 20 the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product {I -[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3 H-imidazol-4-yl}-biphenyl-4-yl)- l'-phenyl-l',2',4',5'-tetrahydro-I H

[

2 ,4']biimidazolyl-3'-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (5.4 mg): LCMS ESI*: calc'd for C 4 5

H

53

N

9 0 6 : 815.9 (M*); Found: 816.5 (M+H*); 'H-NMR: 300 MHz, 25 (MeOH-d 4 ) 8: 7.89-7.86 (m, I OH), 7.35 (m, 2H), 7.18 (in, I H), 6.94 (m, 2H), 5.67 (m, I H), 5.37 (m, I H), 5.25 (m, I H), 5.12 (m, I H), 4.31-4.08 (m, 3H), 4.01-3.79 (m, 3 H), 3.67 (s, 3 H), 3.66 (s, 3H), 2.58 (m, I H), 2.29-1.99 (m, 5 H), 0.99-0.89 (m, 12H). 578 Example CD N 1. R-COOH, HATU N 2. HATU, NH 2 -R' H O N OH N N I 0 0 N O- OBO Piperazine-1,3- Y B dicarboxylic acid 1 -tert- O butyl ester 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2 methoxycarbonylamino-3-methyl-butyryl)-piperazine-1 carboxylic acid tert-butyl ester N O

NH

4 0Ac, m-Xyl N H O H B 135 *CO NNB I H 'F1 N13 0 I H B O / Br 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2- 3-[4-(4-Bromo-pheny)-1 H-imidazo-2-yI]-4-(2 methoxycarbonylamino-3-methyl-butyryl)- methoxycarbonylamino-3-methyl-butyryl)-piperazine-1 -carboxylic piperazine-1-carboxylic acid tert-butyl ester acid tert-butyl ester 3-12-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2-methoxycarbonylamino-3-methyl 5 butyryl)-piperazine-1-carboxylic acid tert-butyl ester: N-(Methylcarbamoyl)(L)-valine (2.0 g, 11.4 mmol) was dissolved in DMF (15 mL) at room temperature. HATU (4.34 g, 11.4 mmol) and diisopropyl ethylamine (1.47 g, 11.4 mmol) were added and stirring was continued. After 10 minutes, solid piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (2.62 g, 11.4 mmol) was added. To the resultant suspension was added DMF (10 mL) and diisopropyl ethylamine (1.47 10 g, 11.4 mmol). Stirring at room temperature was continued. After 45 min, HATU (4.34 g, 11.4 mmol) and diisopropyl ethylamine (1.47 g, 1 1.4 mmol) were added to the resultant yellow solution followed by amino-(4'bromo) acetophenone hydrochloride salt (2.85 g, I 1.4 mmol). After 30 minutes all volatiles were removed in vacuo. The crude material was taken into EtOAc and the organic layer was washed with aqueous HCI (I M), aqueous LiCI (5%), aqueous 15 bicarbonate solution, brine and was dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded crude material, which was purified by flash chromatography on silica gel (eluent: EtOAc w MeOH 10%/ hexanes) to yield the product 3-[2-(4-Bromo-phenyl)-2-oxo ethylcarbamoyl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine- I -carboxylic acid tert-butyl ester (3.62 g): LCMS-ESl*: calc'd for C 2 5

H

35 BrN 4 0 7 : 583.4 (M*); Found: 583.2 / 20 585.2 (M+H*). 579 3-[4-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl) piperazine-1-carboxylic acid tert-butyl ester: 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2-methoxycarbonylamino-3-methyl-butyryl) piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 3.43 mmol) was dissolved in m-xylenes (18 5 mL) and heated at 135 *C. Solid ammonium acetate (1.70 g, 22.0 mmol) was added and the reaction was stirred at 135 'C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10% / hexanes) to yield the product 3-[4-(4-Bromo phenyl)- I H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-I 10 carboxylic acid tert-butyl ester (674 mg, 1.19 mmol): LCMS-ESI*: calc'd for C 2 5

H

3 4 BrN 5 Os: 564.5 (M*); Found: 564.2 / 566.2 (M+H*). Example CE 0 0

CF

3 N 1.HCI N0 3Br CH 2 OTf 0 B OH H 0 0 3-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2- {1-[2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4 methoxycarbonylamino-3-methyl-butyryl)- (2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl piperazine-1-carboxylic acid tert-butyl ester propyl}-carbamic acid methyl ester

CF

3 CF3 N 0

NH

4 0Ac, m-Xyl H N O O Br 135 C Br O O {1-[2-[2-(4-Bromo-phenyl)-2-oxo- {1 -[2-[4-(4-Bromo-pheny)-1 H-imidazol ethylcarbamoy]-4-(2,2,2-trifluoro-ethyl)- 2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine piperazine-1-carbonyl]-2-methyl-propyl}- 1-carbonyl]-2-methyl-propyl}-carbamic carbamic acid methyl ester acid methyl ester 580

CF

3 rCF 3 N H Pd(PPh3)4 N H N Cu(I)i, Alkyne H Nl1 0 / N O N /H\ /' O'N Br O [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2,2,2 trifluoro-ethyl)-piperazin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-pheny]-1H {1-(2-[4-(4-Bromo-phenyl)-1H-imidazol- imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid 2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine- methyl ester 1 -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester { 1-[2- [2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl] -4-(2,2,2-trifluoro-ethyl)-piperazine- 1 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: 3-[4-(4-Bromo-phenyl)- I H 5 imidazol-2-ylI]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine- I -carboxylic acid tert-butyl ester (400 mg, 0.686 mmol) was dissolved in dichloromethane (1.0 mL) and HCI (4M dioxane, 2 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in DMF (1.0 mL) / THF (1.0 mL) and diisopropyl ethylamine (88.5 mg, 0.686 mmol) was added 10 followed by trifluoroethyl triflate (114.7 mg, 0.494 mmol). Stirring at room temperature was continued. After 14 hours, all volatiles were removed in vacuo and the crude material was purified by flash chromatography on silica gel (eluent: EtOAc w MeOH 10% / hexanes) to yield the product { I-[2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2,2,2-trifluoro-ethyl) piperazine-I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (192 mg, 0.34 mmol): 15 LCMS-ESI*: calc'd for C 22

H

28 BrF 3

N

4 0 5 : 565.3 (M*); Found: 565.2 / 567.2 (M+H*). {1-12-[4-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: ( -[2-[2-(4-Bromo-phenyl)-2-oxo ethylcarbamoyl]-4-(2,2,2-trifluoro-ethyl)-piperazine- I -carbonyl]-2-methyl-propyl} -carbamic 20 acid methyl ester (192 mg, 0.34 mmol) was dissolved in m-Xylenes (2 mL) and heated at 135 *C. Solid ammonium acetate (128 mg, 1.66 mmol) was added and the reaction was stirred at 135 *C. After 110 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product {l-[2-[4-(4-Bromo-phenyl)-l H-imidazol-2 25 yl]-4-(2,2,2-trifluoro-ethyl)-piperazine- I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol): LCMS-ESI*: calc'd for C 22

H

27 BrF 3

N

5

O

3 : 546.4 (M*); Found: 546.0 / 548.2 (M+H*). 581 [1-(2-{5-14-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2,2,2-trifluoro-ethyl) piperazin-2-yl]-l H-imidazol-4-yI}-phenylethynyl)-phenyl]-1 H-imidazol-2-yi}-pyrrolidine 1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: ( -[2-[4-(4-Bromo-phenyl)- H imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine- I -carbonyl]-2-methyl-propyl}-carbamic acid 5 methyl ester (98.7 mg, 0.181 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1 H imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (71.2 mg, 0.181 mmol) and Pd(PPh 3

)

4 (21.5 mg, 0.018 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (181 mg, 1.8 mmol) and copper() iodide (3.5 mg, 0.018 mmol). The mixture was heated at 80 *C. After 20 minutes, volatiles 10 were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10% / hexanes) and further purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3 methyl-butyryl)-4-(2,2,2-trifluoro-ethyl)-piperazin-2-yl]- I H-imidazol-4-yl} -phenylethynyl) phenyl]- I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-2-methyl-propyl]-carbamic acid methyl 15 ester (12.4 mg): LCMS-ESI*: calc'd for C 4 4

H

52

F

3

N

9 0 6 : 859.9 (M*); Found: 860.5 (M+H*); H-NMR: 300 MHz, (MeOH-d 4 ) 8: 7.91-7.68 (m, IOH), 6.06 (m, 2H), 5.24 (m, I H), 4.43 (m, I H), 4.23 (d, J=7.8Hz, I H), 4.11 (m, 1 H), 3.85 (m, I H), 3.68 (s, 3H), 3.66 (s, 3H), 3.49-3.45 (m, 2H), 3.15-3.02 (m, 3H), 2.77 (m, I H), 2.58 (m, I H), 2.29-2.01 (m, 5H), 1.07-0.83 (m, 12H). 20 Example CF

CF

3

(CF

3 N H H N HPd/Cu(I)N HH O alkyne NNN N O N 0 N H 0 N / 0 {1-[4-(4-Bromo-phenyl)-1'-(2,2,2- [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4N trfluoro-ethyl)-1',2',4',5'-tetrahydro- (2,2,2-trfluoro-ethyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenylethynyl) 1 H-[2,4'Ibiimidazolyl-3'-carbonyl]-2- phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1 -carbony)-2-methy-propy] methyl-propyl)-carbamic acid methyl carbamic acid methyl ester ester [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4N-(2,2,2-trifluoro ethyl)-pyrrolidin-2-yl]-lH-imidazol-4-yl}-phenylethynyl)-phenyl]-IH-imidazol-2-yI} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: { I -[4-(4-Bromo 25 phenyl)-l'-(2,2,2-trifluoro-ethyl)-l',2',4',5'-tetrahydro-l H-[2,4']biimidazolyl-3'-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (55.0 mg, 0.103 mmol) was combined with (1 -{2-[5 (4-Ethynyl-phenyl)-l H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (37.5 mg, 0.095 mmol) and PdC 2 (PPh 3

)

2 (7.0 mg, 0.0 10 mmol) under an argon atmosphere. DMF (2.0 mL, degassed with Argon) was added followed by triethylamine (104 582 mg, 1.03 mmol) and copper(l) iodide (1.9 mg, 0.01 mmol). The mixture was heated at 80 *C. After 240 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10% / hexanes) and further purified via RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product [1-(2-{5-[4-(4-{2-[1-(2 5 Methoxycarbonylamino-3-methyl-butyryl)-4N-(2,2,2-trifluoro-ethyl)-pyrrolidin-2-yl]- I H imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-l -carbonyl)-2-methyl propyl]-carbamic acid methyl ester (4.9 mg): LCMS-ESI*: calc'd for C 43

H

50

F

3

N

9 0 6 : 845.9 (M'); Found: 846.4 (M+H*); 'H-NMR: 300 MHz, (MeOH-d 4 ) 6: 7.91-7.68 (m, IOH), 5.35 (dd, J=6.3, 6.3Hz, 1H), 5.24 (m, IH), 4.76 (d, J=6.9Hz, 11H), 4.23 (d, J=7.5Hz, IH), 4.09 (m,IH), 10 4.00 (d, J=7.8Hz, I H), 3.87 (m, I H), 3.66 (s, 6H), 3.65-3.42 (m, 4H), 2.56 (m, I H), 2.29-2.06 (m, 5H), 0.99-0.88 (m, 12H). Example CG

NNH

2 + HO O EEDQ RT O NOO H X DCM, X 0CM. RI H

H

2 N' H 0 d 4-Amino-N.(4-amidno-phenyI). Pyrrolidine-1 .2-dicarboxytic acid benzamnide 1-tert-butyl ester 2-(4-{4-{(pyrrolidine-1'-carboxylic acid tert-buty ester) phefiyebamoy1-eylarrmoyl) pyrrolidine-l-carboxyic acid tert-buty ester H IFA0 N TFA O a N H DCM, RT N O N , OH H 2-Methoxycarbonytamino Pyrrolidine-2-carboxylic acid 3-methy-butyric acid (4*(pyrroidin-2-y-carbonyt-amino) pheiy2carbamoyJ-pheyl)-amide O0 H O NH O N~ Nr~ HATU. DIEA ,..O 0 N 001-."_ 0 DMF. RT N N JDI H HN-f H O (1-{2(4-4-ff 1 -(2- Methoxycaronylamino3- methyl- butyry) proalidine-2-cartoonylamirno)-phenycarbamyl) phenylcarbamoyl]-pyrrolidine-1 -carbonyl}-2-methyt-propyl) carbamic acid methyl ester 15 2-(4-{4-[(pyrrolidine-l'-carboxylic acid tert-butyl ester)-phenylcarbamoyl} phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: 4-Amino-N-(4-amino phenyl)-benzamide (3.00 g) and pyrrolidine-1,2-dicarboxylic acid I-tert-butyl ester (6.55 g) were dissolved in DCM (90 mL), and 1-ethoxycarbonyl-1,2-dihydroquinoline (7.88 g) was 20 added. The reaction mixture was stirred at ambient temperature for 17 hours and evaporated under vacuum. Oil was dissolved in ethyl acetate, forming a precipitate, which was collected by vacuum filtration and dried under vacuum, giving 2-(4-{4-[(pyrrolidine-l'-carboxylic acid tert 583 butyl ester)-phenylcarbamoyl}-phenylcarbamoyl)-pyrrolidine-l -carboxylic acid tert-butyl ester (7.64 g, 93%) as a white solid. Pyrrolidine-2-carboxylic-acid (4- [4-(pyrrolidin-2'-yl-carbonyl-amino)-phenylcarbamoyl] 5 phenyl}-amide: 2-(4-{4-[(pyrrolidine-l'-carboxylic acid tert-butyl ester)-phenylcarbamoyl} phenylcarbamoyl)-pyrrolidine-I-carboxylic acid tert-butyl ester (2.01 g) was dissolved in DCM (46 mL), and trifluoroacetic acid (6 mL) was added. The reaction mixture was stirred at ambient temperature for 3.5 hours and evaporated under vacuum. Solid was dissolved in DCM and extracted twice with saturated NaHCO 3 solution. Solid was collected by vacuum filtration, 10 washed with ethyl acetate, and dried under vacuum, giving pyrrolidine-2-carboxylic acid {4-[4 (pyrrolidin-2'-yl-carbonyl-amino)-phenylcarbamoyl]-phenyl}-amide (1.18 g, 87%) as a white solid. (1-{2-14-(4-{[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyll 15 amino}-phenylcarbamoyl)-phenylcarbamoyll-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester: Pyrrolidine-2-carboxylic acid {4-[4-(pyrrolidin-2'-yl-carbonyl amino)-phenylcarbamoyl]-phenyl}-amide (0.305 g), 2-methoxycarbonylamino-3-methyl-butyric acid (0.277 g), and HATU (0.621 g) were dissolved in anhydrous DMF (8 mL), and diisopropylethylamine (0.496 mL) was added. The reaction mixture was stirred at ambient 20 temperature for I hour and evaporated under vacuum. The oil was dissolved in DCM and purified by chromatography (0-20% ethyl acetate:hexane), giving (I -{2-[4-(4-{ [1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl]-amino}-phenylcarbamoyl) phenylcarbamoyl]-pyrrolidine-I -carbonyl }-2-methyl-propyl)-carbamic acid methyl ester (0.324 g, 58%) as a white solid: 'H-NMR: 300 MHz, (DMSO-d 6 ) 8:10.3 (s, I H), 10.1 (s, I H), 10.0 (s, 25 1 H), 7.9 (d, J=9.9, 2H), 7.7 (m, 4H), 7.5 (d, J=9.9, 2H), 7.3 (d, J=9.9, 21H), 4.5 (m, 2H), 4.0 (m, 2H), 3.8 (m, 2H), 3.6 (m, 2H), 3.5 (s, 6H), 2.2 (m, 2H), 1.9 (m, 8H), 0.9 (m, 12H); MS (ESI) m/z 736 [M + H]*. 584 Example CH

NH

2 ,R I * HO y EEDQ 0t~ 0- 0 X

H

2 NH 4,4-Ethylenedianifine Pyrrolidine-12-dicartoxyic acid 2-[4-(2-{4-[(1-carboxyic acid tert-butyl ester-pyrolidine-2-carbonyl) I-tet-bt este-aminop h ylphen r mylpyrroliie I-cartbox~c ad teft-buty4 ester TFA H H 0 DCM, RT O Pyrrolidine-2-carboxylic acid (4-(2-[4-(pyrroIidinecarbonyI- 2-Methoxycarbonylamino amino)-phenyl]-ethy}-phenyt)-amide 3-methyi-butyric acid O0 H d-NH NY N HATU, DIEA Y O O O DMF, RT N HN O [1.(24-{4[2-(4-fl (2.Methoxycirbona-drxo-3-methy-bulyri) pyrrcn d 2-cart n }-a n } )pheny yet h nyryebarog pyrrolidine-1 -carbonyl)-2-methyl-propy)-carbamic acid methyl ester 2-14-(2-{4-[(1-carboxylic acid tert-butyl ester-pyrrolidine-2-carbonyl)-amino]-phenyl} 5 ethyl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester: 4,4' Ethylenedianiline (2.98 g) and pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (7.09 g) were dissolved in DCM (90 mL), and I-ethoxycarbonyl-1,2-dihydroquinoline (8.38 g) was added. The reaction mixture was stirred at ambient temperature for 3 hours and evaporated under vacuum. Oil was dissolved in ethyl acetate, forming a precipitate, which was collected by 10 vacuum filtration and dried under vacuum, giving 2-[4-(2-{4-[(I-carboxylic acid tert-butyl ester pyrrolidine-2-carbonyl)-amino]-phenyl}-ethyl)-phenylcarbamoyl]-pyrrolidine-l-carboxylic acid lert-butyl ester (8.30 g, 97%) as a white solid. Pyrrolidine-2-carboxylic acid (4-{2-14-(py rrolidinecarbonyl-amino)-phenyll-ethyl} 15 phenyl)-amide: 2-[4-(2-{4-[(I-carboxylic acid tert-butyl ester-pyrrolidine-2-carbonyl)-amino] phenyl}-ethyl)-phenylcarbamoyl]-pyrrolidine-I -carboxylic acid tert-butyl ester (3.01 g) was dissolved in DCM (45 mL), and trifluoroacetic acid (15 mL) was added. The reaction mixture was stirred at ambient temperature for 4 hours and evaporated under vacuum. Solid was dissolved in DCM and extracted twice with saturated NaHC0 3 solution. Solid was collected by 20 vacuum filtration, washed with ethyl acetate, and dried under vacuum, giving pyrrolidine-2 carboxylic acid (4- {2-[4-(pyrrolidinecarbonyl-amino)-phenyl]-ethyl}-phenyl)-amide (1.86 g, 93%) as a light gray solid. 585 [1 -(2-{4-[2-(4-{[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl] amino)-phenyl)-ethyl]-phenylcarbamoyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl] carbamic acid methyl ester: Pyrrolidine-2-carboxylic acid (4-{ 2-[4-(pyrrolidinecarbonyl amino)-phenyl]-ethyl} -phenyl)-amide (0.299 g), 2-methoxycarbonylamino-3-methyl-butyric 5 acid (0.296 g), and HATU (0.648 g) were dissolved in anhydrous DMF (5 mL), and diisopropylethylamine (0.513 mL) was added. The reaction mixture was stirred at ambient temperature for I hour and evaporated under vacuum. The oil was dissolved in DCM and purified by chromatography (0-100% ethyl acetate:hexane), giving [1 -(2-{4-[2-(4-{[l-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-ethyl] 10 phenylcarbamoyl}-pyrrolidine-I -carbonyl)-2-methyl-propyll-carbamic acid methyl ester (0.254 g, 48%) as a white solid: 'H-NMR: 300 MHz, (DMSO-d 6 ) 8: 9.9 (s, 2H), 8.2 (broad s, 2H), 7.4 (d, J=9.9, 4H), 7.3 (d, J=9.9, 21H), 7.1 (d, J=9.9, 4H), 4.4 (m, 2H), 4.0 (t, J=7.5, 2H), 3.8 (m, 2H), 3.6 (m, 8H), 3.5 (s, 6H), 3.1 (m, 8H), 2.8 (s, 4H), 2.1 (m, 2H), 1.9 (m, 8H), 0.9 (m, 12H); MS (ESI) m/z 721 [M + H]*. 15 Example CI rNNH HO Y N X EEDO 0NN N2~ N + O CM RT X NO HN H 4 4-EthylenedianIine Pyrrolidine-1 2-dicarboylic acid 2h4- 4-(1Aety-py dine-cronyl aminodphen azo) l-tert-buty1 ester phen~ylcafmoyl)-pyrrolidine--caroxyiic acid ter-butyl ester H HO TFA 0 N N O + /ONN -iiOH DCM. RT H N e H Pyrrolidine-2-carboxylic acd {[4-(pyrrolidinecarbonyl- 2-Methoxycarbonylamino amino)-phenylazo]-phenyl)-ande 3-mathA-butyric acd NH NN HATU, DIEA O 0O N O O OMF, RT NN HN _ZO KJH 0 01-42-[4-(4-U 1 -(2-Methoxycrboylamino3mthy.butyy) pyrroldine-2-carbon]-amino)-phenylazo pheny arbamoyq pyrrolidine-1-carbonyf)2-methyl-propyl)-carbamic acid methyl ester 2-(4-{4-[(1-Acetyl-pyrrolidine-2-carbonyl)-amino]-phenylazo}-phenylcarbamoyl) 20 pyrrolidine-1-carboxylic acid tert-butyl ester: 4-(4-aminophenylazo)-phenylamine (3.02 g) and pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (7.00 g) were dissolved in DCM (90 mL), and I -ethoxycarbonyl- 1,2-dihydroquinoline (8.45 g) was added. The reaction mixture was stirred at ambient temperature for 19 hours and evaporated under vacuum. Oil was dissolved in 586 ethyl acetate, forming a precipitate, which was collected by vacuum filtration and dried under vacuum, giving 2-(4- {4-[(1 -carboxylic acid tert-butyl ester-pyrrolidine-2-carbonyl)-amino] phenylazo}-phenylcarbamoyl)-pyrrolidine-I-carboxylic acid tert-butyl ester (9.28 g) as a brown solid. 5 Pyrrolidine-2-carboxylic acid {4-[4-(pyrrolidinecarbonyl-amino)-phenylazo]-phenyl} amide: 2-(4-{4-[(1-carboxylic acid tert-butyl ester-pyrrolidine-2-carbonyl)-amino]-phenylazo} phenylcarbamoyl)-pyrrolidine-I-carboxylic acid tert-butyl ester (9.28 g, crude) was dissolved in DCM (75 mL), and trifluoroacetic acid (25 mL) was added. The reaction mixture was stirred at 10 ambient temperature for 3 hours and evaporated under vacuum. Solid was dissolved in DCM and extracted twice with saturated NaHC0 3 solution. The solution was evaporated under vacuum, giving pyrrolidine-2-carboxylic acid {4-[4-(pyrrolidinecarbonyl-amino)-phenylazo] phenyl}-amide (6.18 g, crude) as a red solid. 15 (1 -2-[4-(4-{[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl] amino}-phenylazo)-phenylcarbamoyll-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Pyrrolidine-2-carboxylic acid {4-[4-(pyrrolidinecarbonyl-amino) phenylazo]-phenyl}-amide (0.302 g), 2-methoxycarbonylamino-3-methyl-butyric acid (0.284 g), and HATU (0.643 g) were dissolved in anhydrous DMF (5 mL), and N-methylmorpholine 20 (0.324 mL) was added. The reaction mixture was stirred at ambient temperature for 2 hours and evaporated under vacuum. The oil was dissolved in DCM and purified by chromatography (0 100% ethyl acetate:hexane), giving (1-{2-[4-(4-{[1-(2-methoxycarbonylamino-3-methyl butyryl)-pyrrolidine-2-carbonyl]-amino}-phenylazo)-phenylcarbamoyl]-pyrrolidine-I carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.158 g, 30%) as a yellow solid: 'H 25 NMR: 300 MHz, (DMSO-d 6 ) 5: 10.4 (s, 2H), 7.8.(m, 8H), 7.4 (d, J=9.9, 2H), 4.5 (m, 2H), 4.0 (t, J=7.5, 2H), 3.8 (m, 2H), 3.6 (m, 8H), 3.5 (s, 6H), 2.2 (m, 2H), 2.0 (m, 8H), 0.9 (m, 12H); MS (ESI) m/z 721 [M + H]*. 587 Example CJ G S 2S N' ,N ., OH S, .V 1 Si..O BI 'l 40'C Cl DCM. OC-RT Br Br Br 4-Bromo-naphthalene-1- 4-Bromo-naphthalene- 1-(4-Bromonaphthalen-1-yl) carboxylic acid 1-carbonyl chloride 2-diazoethanone HBr/HOAc Br + HO - N TEA 0 N EtOAc, 0*C B O 0 ACN, RT B 0" N Br 0d Br 0 O 2-Bromo-1-(4-bromo- Pyrrolidine-1, 2-dicarboxylic Pyrrolidine- 1,2-dicartboxylic acid 2-[2-(4-bromonaphthalen naphthalen-1-yl)-ethanone acid 1-tert-buty ester 1-y)-2-oxo-ethyl]ester 1-tert-butyl ester

NH

4 0Ac TFA H HO Xytenes Br DCM, RT Br N N + 0 N OH 140T N O O N 2-[5-(4-Bromo-naphthalen-1-yl)-1H-imidazol- 5-(4-Bromo-naphthalen-1-yl)- 2-Methoxycarbonylamino 2-yl]-pyrrolidine-1-carboxylic add tert-butyl ester 2-pyrrolidin-2-yi-1 H-imidazole 3-methyl-butyric acid HO H HATU, NMM N'N N N DMF, RT Br N O' 0- U H (1 -{2-[5-(4-Bromo-naphthalen-1 -yl)- 1 H-imidazol-2-yl}-pyrrolidine- [2-Methyl- 1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2] 1-carbony}-2-methyl-propyl)-carbamic acid methyl ester dioxaborolan-2-yl)-phenyl-1 H-imidazol-2-yl}-pyrrolidine 1-carbonyl)-propyl)-carbamic acid methyl ester -~0 Pd(PPh 3

)

4 H)N HNN NaHCO O , N - - N N 0 H H 0 [1 -(2-{5-[4-(4-{2-(1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidiny-2-y3H-imidazoi4-yf}-phenyl)-naphthalen-1-yl-1 H-imidazol-2 yl}-pyrrolidine- I -carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 4-Bromo-naphthalene-1-carbonyl chloride: 4-Bromonaphthalene-1-carboxylic acid (9.80 g) 5 was suspended in thionyl chloride (80 mL) and stirred at 40'C for 16 hours and evaporated under vacuum. Solid was dissolved in DCM (20 mL) and evaporated under vacuum, giving 4 bromonaphthalene-1-carbonyl chloride (13.8 g, crude) as a white solid. 1-(4-Bromonaphthalen-1-yl)-2-diazoethanone: 4-Bromo-naphthalene-l -carbonyl chloride 10 (13.8 g) was dissolved in dichloromethane (130 mL) and cooled to 0 0 C. TMS diazomethane solution (40 mL, 2 M in DCM) was added, and ice bath was removed. Reaction mixture was stirred for 18 hours and evaporated under vacuum, giving ]-(4-bromonaphthalen-l-yl)-2 diazoethanone (13.8 g, crude) as a brown oil. 15 2-Bromo-1-(4-bromo-naphthalen-1-yl)-ethanone: 1-(4-Bromonaphthalen-l-yl)-2 diazoethanone (13.8 g) was dissolved in ethyl acetate (200 mL), and hydrobromic acid solution (8.4 mL, 5.7 M in acetic acid) was added at 0*C. Reaction mixture was stirred 15 minutes, NaHCO 3 solution (100 mL) was added, and mixture was stirred 10 minutes. Ethyl acetate 588 solution was extracted twice with NaHC0 3 solution (50 mL), once with brine (50 mL), and evaporated under vacuum. The oil was dissolved in DCM and purified by chromatography (0 20% ethyl acetate:hexane), giving 2-bromo- I -(4-bromo-naphthalen- 1 -yl)-ethanone (6.67 g, 51%) as a tan solid. 5 Pyrrolidine-1,2-dicarboxylic acid 2-12-(4-bromonaphthalen-1-yl)-2-oxo-ethyl jester 1-tert butyl ester: Pyrrolidine- 1,2-dicarboxylic acid I -tert-butyl ester (4.85 g) was dissolved in acetonitrile (65 mL), and triethylamine (3.09 mL) was added. A solution of 2-bromo-l-(4 bromonaphthalen-l -yl)-ethanone (6.60 g) in acetonitrile (35 mL) was added. Reaction mixture 10 was stirred 90 minutes and evaporated under vacuum. Oil was dissolved in DCM (50 mL), extracted once with water (20 mL) and once with NaHC0 3 solution (20 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-50% ethyl acetate:hexane) and evaporated under vacuum, giving pyrrolidine-1,2-dicarboxylic acid 2-[2-(4 bromonaphthalen- I -yl)-2-oxo-ethyl]ester I -tert-butyl ester (8.95 g, 95%) as a tan solid. 15 2-15-(4-Bromo-naphthalen-1-yl)-lH-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: Pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromonaphthalen- I -yl)-2-oxo-ethyl]ester I tert-butyl ester (8.80 g) and ammonium acetate (7.51 g) were suspended in xylenes. The reaction mixture was stirred at 140*C for 15 hours and evaporated under vacuum. Solid was 20 dissolved in ethyl acetate (50 mL) and extracted twice with water (20 mL) and once with brine (20 mL). The oil was dissolved in DCM, purified by chromatography (0-50% ethyl acetate:hexanes), and evaporated under vacuum, giving 2-[5-(4-bromo-naphthalen- I -yl)- I H imidazol-2-yl]-pyrrolidine-I-carboxylic acid tert-butyl ester (4.34 g, 52%) as a tan solid. 25 5-(4-Bromo-naphthalen-1-yl)-2-pyrrolidin-2-yl-IH-imidazole: 2-[5-(4-Bromo-naphthalen-1 yl)-I H-imidazol-2-yl]-pyrrolidine-l -carboxylic acid lert-butyl ester (1.00 g) was dissolved in DCM (12 mL), and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at ambient temperature for 3 hours and evaporated under vacuum. Solid was dissolved in DCM (10 mL) and extracted with saturated NaHCO 3 solution (30 mL). A solid was collected by 30 vacuum filtration, washed with DCM, and dried under vacuum, giving 5-(4-bromo-naphthalen I -yl)-2-pyrrolidin-2-yl- I H-imidazole (0.940 g, crude) as an off-white solid. (1-{2-15-(4-Bromo-naphthalen-1-yl)-1 H-imidazol-2-ylI-pyrrolidine-l-carbonyl)-2-methyl propyl)-carbamic acid methyl ester: 5-(4-bromo-naphthalen-1-yl)-2-pyrrolidin-2-yl-I H 35 imidazole (0.925 g), 2-methoxycarbonylamino-3-methyl-butyric acid (0.441 g), and HATU 589 (1.00 g) were dissolved in anhydrous DMF (15 mL), and N-methylmorpholine (0.497 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes and evaporated under vacuum. The oil was dissolved in DCM, purified by chromatography (0-100% ethyl acetate:hexanes), and evaporated under vacuum, giving (I-{2-[5-(4-bromo-naphthalen-1-yl)-I H 5 imidazol-2-yl]-pyrrolidine- I -carbonyl } -2-methyl-propyl)-carbamic acid methyl ester (0.814 g, 72%) as an off-white solid. [1-(2-{5-[4-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl1-3H imidazol-4-yI}-phenyl)-naphthalen-1-y]-1H-imidazol-2-yl}-pyrrolidine-l-carbonyl)-2 10 methyl-propyl]-carbamic acid methyl ester: (1- {2-[5-(4-Bromo-naphthalen- 1 -yl)- 1 H imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.115 g), [2-Methyl-I -(2-{5-[4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2 yl}-pyrrolidine-I-carbonyl)-propyl]-carbamic acid methyl ester (0.111 g), and NaHCO 3 (0.0623 g) were dissolved in a mixture of 1,2-dimethoxyethane (3 mL) and water (1 mL). The solution 15 was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0114 g) was added. The reaction mixture was stirred at 85*C for 16 hours and evaporated under vacuum. Solid was dissolved in ethyl acetate (10 mL) and extracted twice with water (10 mL) and once with brine (10 mL). Solution was evaporated, dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving [1 -(2-{ 5-[4-(4- {2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl) 20 pyrrolidin-2-yI]-3H-imidazol-4-yl}-phenyl)-naphthalen-l-yl]-l H-imidazol-2-yl}-pyrrolidine- 1 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.037 g, 21%) as a white solid: '-1 NMR: 300 MHz, (CHCl 3 -d 1 ) 6: 8.9 (m, I H), 7.6 (m, 2H), 7.4 (m, 5H), 7.0 (m, 2H), 6.8 (m, 2H), 5.8 (m, 2H), 5.3 (m, 2H), 4.3 (m, 2H), 4.0 (m, 4H), 3.6 (s, 6H), 2.4 (m, 6H), 2.0 (m, 6H), 0.8 (m, 12H); MS (ESI) m/z 789 [M + H]*. 25 590 Example CJ B-B KOAc B 8 Br Cb \/ B ~ --- - - 'r0 ~ ~~ 2,6Dbromonap th lene bis-(pinocolato)dborane 2 r6-(bishpinocoato) 2-(5 -Br mo-H-imi zo 2-y)-pyrrobud e diarand -phthalen1 - xarboyi axc-d tesyl steer P (PPhr) 4 -H 0 F

H

3 MMON \ -N N h 10 DM, TN Nj N N

DME.

2 N-DN V CM. RT H Y 9*c -H20H N . O 2.(5- { 4-(-((-1-.rbo y2-c aci tes-butyl ester-pyrralidin.2.yQ. 2.6-bis(2-Pyrro2[di-.2-(t2-1 2-Methoxycar yrnmyimmno. 3H-stmidacol-4-ylnaphthaen-2-y4)-IH-imidazo-2y)- imidazole)naphthalene 3-metryt-butyric acid Pyrrctdine-1.lcrboxyic acid tert-butyl ester -~0 HATU. NMM a t>O N - H DMF. RT N.ZN / N N HN (I J2-15-(64{2-1 1-(2-Methtoxycartionyrarmno.3.merny~butyryl pyolin2y3l-mdzo-y)-naputatn-2y) 1 rndazoI.yq-PyrrOI~jne- I-GBMWYo) - rtetypropyl). Carbamrc 8,C4 tethyt ester 2,6-(bis-pinocolato) Diboranonaphthalene: 2,6-Dibromonaphthalene (10.2 g), bis 5 (pinocolato)diborane (37.3 g), and potassium acetate (18.0 g) were dissolved in 1,4-dioxane (250 mL), and solution was degassed with nitrogen. Pd(PPh 3

)

4 (3.13 g) was added, and the reaction mixture was stirred at 80'C for 20 hours. The suspension was vacuum filtered, and the solid was washed with ethyl acetate, giving 2,6-(bis-pinocolato)diboranonaphthalene (7.71 g, 58%) as a yellow solid. 10 2-(5-{6-[2-(l'-carboxylic acid tert-butyl ester-pyrrolidin-2-y)-3H-imidazol-4-yl] naphthalen-2-yl)-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: 2,6-(bis pinocolato)diboranonaphthalene (0.501 g), 2-(5-bromo-I H-imidazol-2-yl)-pyrrolidine-l carboxylic acid tert-butyl ester (0.885 g), and NaHCO 3 (0.562 g) were dissolved in a mixture of 15 1,2-dimethoxyethanedichloromethane (15 mL) and water (5 mL). The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0935 g) was added. The reaction mixture was stirred at 90*C for 16 hours and evaporated under vacuum. Solid was dissolved in DCM (20 mL) and extracted twice with water and once with brine. Solution was evaporated, recrystallized from ethyl acetate, and dried under vacuum, giving 2-(5-{6-[2-(l'-carboxylic acid tert-butyl ester 20 pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-1 H-imidazol-2-yl)-pyrrolidine- I carboxylic acid tert-butyl ester (0.365 g, 46%) as a white solid. 2,6-bis(2-Pyrrolidin-2-yl-1H-imidazole)naphthalene: 2-(5-{6-[2-(l'-carboxylic acid tert butyl ester-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-y}- I H-imidazol-2-yl)-pyrrolidine 25 1 -carboxylic acid tert-butyl ester (0.365 g) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (I mL) was added. The reaction mixture was stirred at ambient temperature 591 for 27 hours, heated to 40*C for 3 hours, and evaporated under vacuum. Solid was dissolved in DCM (10 mL) and extracted with saturated NaHCO 3 solution (30 mL). A solid was collected by vacuum filtration, washed with DCM, and dried under vacuum, giving 2,6-bis(2-pyrrolidin-2-yl I H-imidazole)naphthalene (0.180 g, 74%) as a yellow solid. 5 (1-{ 2 -[5-( 6

-{

2

-[-(

2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl)-naphthalen-2-yI)-1H-imidazol-2-ylI]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: 2,6-bis(2-Pyrrolidin-2-yl-I H-imidazole)naphthalene (0.170 g), 2 -methoxycarbonylamino-3-methyl-butyric acid (0.168 g), and HATU (0.378 g) were 10 dissolved in anhydrous DMF (3 mL), and N-methylmorpholine (0.188 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes and evaporated under vacuum. The oil was dissolved in DMF and purified by reverse phase HPLC (5-70% acetonitrile:water) and lyophilized, giving (1-{2-[5-(6-{2-[I-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-naphthalen-2-yl)- IH-imidazol-2-yl] 15 pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.051 g, 17%) as a white solid: IH-NMR: 300 MIHz, (DMSO-d 6 ) 5: 8.3 (s, 2H), 8.1 (s, 2H), 8.0 (m, 4H), 7.3 (d, J=l 1.2, 2H), 5.1 (m, 2H), 4.1 (m, 2H), 3.9 (m, 4H), 3.5 (s, 6H), 2.4 (m, I H), 2.0 (m, 5H), 0.8 (m, 12H); MS (ESI) m/z 713 [M + H]+. 20 Example CK O H H H +HATU, NMM r N N - N N + 0 N~-.B Br Y I HO DMF. RT \ N'~ N 0HN 2-[5-(4-Bromonaphthalen-1-yI)- 2-Methoxycarbonylamino- 0 1H-imidazol-2-yl]-pyrrolidine-1- 3-methyl-butyric acid carboxylic acid teft-butyl ester (1 -{2-[5-(4-Bromonaphthalen-1 -yl) 1IH-imidazol-2-yl)-pyrrolidine-1-carbonyl) 2-methyl-propyl)-carbamic acid methyl ester ~-0 Bu 3 Sn - SnBu 3 O NH Pd(PPh 3

)

4 d \ {O O N H DMF, 85*C N\ NH N N H '' HNO o {1-[2-(5-{4-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-y}-U3H-imidazol-4-yl}-phenyl)-viny]-phenyl} 1 H-imidazol-2-yl)-pyrrolidine-1 -carbony]-2-methyl-propyl} carbamic acid methyl ester (1-{2-[5-(4-Bromonaphthalen-1-yl)-I H-imidazol-2-yI]-pyrrolidine--carbonyl-2-methyl propyl)-carbamic acid methyl ester: 2-[5-(4-Bromonaphthalen- I -yl)- I H-imidazol-2-yl] 25 pyrrolidine- I -carboxylic acid tert-butyl ester (3.80 g), 2-methoxycarbonylamino-3-methyl 592 butyric acid (2.57 g), and HATU (5.88 g) were dissolved in anhydrous DMF (85 mL), and N methylmorpholine (2.86 mL) was added. The reaction mixture was stirred at ambient temperature for 22 hours and evaporated under vacuum. The oil was dissolved in dichloromethane, purified by chromatography (0-50% ethyl acetate:hexanes), and evaporated 5 under vacuum, giving (I -{2-[5-(4-bromonaphthalen-1-yl)-I H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (6.10 g, crude) as a tan solid. {1-12-(5-{4-12-(4-12-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yli-phenyl)-vinyll-phenyll-IH-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl 10 propyl}-carbamic acid methyl ester: (1-{2-[5-(4-Bromonaphthalen- I -yl)-l-H-imidazol-2-yl] pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.01 g) was dissolved in anhydrous DMF (13 mL), and (E)-bis(tributylstannyl)ethene (0.585 mL) was added. The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0401 g) was added. The reaction mixture was stirred at 85*C for 17 hours and evaporated under vacuum. Solid was dissolved in DMF, 15 purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving { ]-[2-(5-{4 [2-(4-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl} phenyl)-vinyl]-phenyl}- I H-imidazol-2-yl)-pyrrolidine- I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (25 mg, 1.5%) as a white solid: 'H-NMR: 300 MHz, (DMSO-d 6 ) 8: 8.0 (s, 2H), 7.8 (m, 8H), 7.4 (s, 2H), 7.3 (d, J=9.9, 2H), 5.1 (t, J=6.9, 2H), 4.1 (t, J=6.9, 2H), 3.8 (m, 20 4H), 3.8 (m, 2H), 3.5 (s, 6H), 2.4 (m, 2H), 2.0 (m, 6H), 0.8 (m, 12H); MS (ESI) m/z 765 [M + H]*. 593 Example CL - 0 - 0 N' 9 N0 BH 602 Br-D\M. C-RT Br NN 6-Bromo-naphthalene-2. 6-Bromo-naphthalene- 1-(6-Bromo-naphthalen-2-yl) carboxylic acid 2-carbonyl chlonde 2-diazo-ethanone O HBrHOAc Br Br H TA NRT B 0 0 0 N EtOAc. 0*C - roZ?\ AN, RT Br / 2-Bromo-1-(6-bromo-naphthalen- Pyrrolidine-1,2-dicarboxylic Pyrrolidine-11,2-dicarboxyic acd 2-[2-(6-bromo 2-yi)-ethanone acid 1-tert-butyI ester naphthalen-2-yi)-2-oxo-ethyl) ester 1-tert-butyl ester HH H O NHOAc - N N'-N X-F I/ Xytenes - / \ Rj .C-O'_ DTM.RT - / \ 140C Br 0D, Br ON 2-[S-(6-Bromo-naphthalen-2-ylI)-1H-imidazol-2-yl}- 5-(6-Bromo-naphthalen-2-yl)- 2-Methoxycarbonytamino pyrrolidine-1-carboxylic acid tert-butyl ester 2-pyrrolidi-2-yi-1H-imidazole 3-methyl-butyric acid H

:

HATU NMM N O B-B DMF, RT Br N / HN..-f0d 0 0 (1-{2-[5-(6-Bromonaphthalen-2-yl)-1H-imidazo bis(ptnocolato)dibarane -2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester HH Pd(PPh 3

)

4 N N N N KOAc ++ N~~- BN OIB N OC Dio 0o 0 Br0 0 x I ' H N f H N 0- 0 [2-Methyl-l-(2-{5-[6-(4,4,5.5-tetramehyl-{1,3,2] (1-{2-[5-(6-Bromonaphthalen-2-yl)-1H-imidazo dioxabomlan-2-yl)-naphthalen-2-yl)-1H- -2-yI]-pyrrolidine-1-cartonyl}-2-methyl-pmpyl) imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl- carbamic acd methyl ester carbamic acid methyl ester -~0 Pd(PPh 3 )4 0 NH H NaHCO 3 0 0N\ N .N \

OME-H

2 0 ~ \ N.zN N / 0) ~o' 0 85C H O NI 0 (1-{2-[5-(6'-{2-[1-{2-Methoxycarbonylamino-3-methy-butyryl)-pyrroidin-2-yl 3H-imidazol-4-yI}[2.2']binaphthalenyl-6-yl)-1H-imidazol-2-yl)-pyrrolidine 1-carbony)-2-methyl-propyt)-carbamic acid methyl ester 6-Bromo-naphthalene-2-carbonyl chloride: 6-Bromonaphthalene-2-carboxylic acid (25.1 g) was suspended in thionyl chloride (200 mL), stirred at 60 0 C for 16 hours and evaporated under 5 vacuum. Solid was dissolved in dichloromethane (50 mL) and evaporated under vacuum, giving 6-bromonaphthalene-2-carbonyl chloride (27.0 g, crude) as a white solid. 1-(6-Bromo-naphthalen-2-yl)-2-diazo-ethanone: 6-Bromonaphthalene-2-carbonyl chloride (27.0 g, crude) was dissolved in dichloromethane (330 mL) and cooled to 0 0 C. TMS 10 diazomethane solution (100 mL, 2 M in DCM) was added, and ice bath was removed. Reaction mixture was stirred for 16 hours and evaporated under vacuum, giving 1-(6-bromonaphthalen-2 yl)-2-diazoethanone (34.7 g, crude) as an orange solid. 2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone: 1-(6-Bromonaphthalen-2-yl)-2 15 diazoethanone (34.7 g) were dissolved in ethyl acetate (500 mL), and hydrobromic acid solution (21.1 mL, 5.7 M in acetic acid) was added at 0*C. Reaction mixture was stirred 3 hours, 594 NaHC0 3 solution (200 mL) was added, and mixture was stirred 10 minutes. Ethyl acetate solution was extracted twice with NaHCO 3 solution (50 mL), once with brine (50 mL), and evaporated under vacuum, giving 2-bromo-1-(6-bromonaphthalen-2-yl)-ethanone (33.0 g, crude) as a tan solid. 5 Pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl] ester 1-tert butyl ester: Pyrrolidine- 1,2-dicarboxylic acid I -tert-butyl ester (24.0 g) was dissolved in acetonitrile (330 mL), and triethylamine (15.6 mL) was added. A solution of 2-bromo-l-(6 bromonaphthalen-2-yl)-ethanone (33.0 g) in acetonitrile (170 mL) were added. Reaction 10 mixture was stirred over 3 days and evaporated under vacuum. Oil was dissolved in dichloromethane (100 mL), extracted with water (50 mL) and with NaHC0 3 solution (50 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-30% ethyl acetate:hexane) and evaporated under vacuum, giving pyrrol idine- I,2-dicarboxyl ic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl] ester I -tert-butyl 1 5 ester (39.2 g, 84%) as a tan solid. 2-[5-(6-Bromo-naphthalen-2-yl)-1 H-imidazol-2-y I-pyrrolidine-1-carboxylic acid tert-butyl ester: Pyrrolidine- I,2-dicarboxylic acid 2-[2-(6-bromonaphthalen-2-yl)-2-oxo-ethyl] ester I tert-butyl ester (39.0 g) and ammonium acetate (40.1 g) were suspended in xylenes (420 mL). 20 The reaction mixture was stirred at 140*C for 15 hours and evaporated under vacuum. Solid was dissolved in dichloromethane (300 mL), extracted twice with water (50 mL) and once with brine (50 mL), and evaporated under vacuum, giving 2-[5-(6-bromonaphthalen-2-yl)-I H imidazol-2-yl]-pyrrolidine-I-carboxylic acid tert-butyl ester (30.3 g, 81%) as an off-white solid. 25 5-(6-Bromo-naphthalen-2-yl)-2-pyrrolidin-2-yl-1H-imidazole: 2-[5-(6-Bromonaphthalen-2 yl)-l H-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (5.03 g) was dissolved in dichloromethane (75 mL), and trifluoroacetic acid (25 mL) was added. The reaction mixture was stirred at ambient temperature for 5 hours and evaporated under vacuum. Solid was dissolved in dichloromethane (50 mL) and extracted with saturated NaHCO 3 solution (50 mL). 30 Solid was collected by vacuum filtration, washed with dichloromethane, and dried under vacuum, giving 5-(6-Bromo-naphthalen-2-yl)-2-pyrrolidin-2-yl-IH-imidazole (98%) as an off white solid. 595 (1 -{2-[5-(6-Bromonaphthalen-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: 5-(6-Bromo-naphthalen-2-yl)-2-pyrrolidin-2-yl- IH imidazole (3.80 g), 2-methoxycarbonylamino-3-methyl-butyric acid (2.21 g), and HATU (5.06 g) were dissolved in anhydrous DMF (75 mL), and N-methylmorpholine (2.68 mL) was added. 5 The reaction mixture was stirred at ambient temperature for 16 hours and evaporated under vacuum. The oil was dissolved in dichloromethane, purified by chromatography (0-100% ethyl acetate:hexanes), and evaporated under vacuum, giving (1-{2-[5-(6-bromo-naphthalen-2-yl)-I H imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.814 g, 72%) as an off-white solid. 10 [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H imidazol-2-yl)-pyrrolidine-1-carbonyl)-propyll-carbamic acid methyl ester: (1-{2-[5-(6 Bromonaphthalen-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3.02 g), bis-(pinocolato)diborane (3.18 g), and potassium acetate (1.52 g) 15 were dissolved in 1,4-dioxane (40 mL), and solution was degassed with nitrogen. Pd(PPh 3

)

4 (0.285 g) was added, and the reaction mixture was stirred at 80*C for 20 hours and evaporated under vacuum. Solid was dissolved in dichloromethane (50 mL), extracted with saturated NaHCO 3 solution (50 mL), and evaporated under vacuum. The oil was dissolved in dichloromethane, purified by chromatography (0-10% isopropanol:dichloromethane), and 20 evaporated under vacuum, giving [2-Methyl-I -(2-{5-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-propyl] carbamic acid methyl ester (3.65 g, crude) as a yellow solid. (1-{2-15-(6'-{2-1I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H 25 imidazol-4-yl}-[2,2']binaphthalenyl-6-yl)-I H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: (1-{2-[5-(6-Bromonaphthalen-2-yl)- H imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.174 g), [2-Methyl-I -(2- { 5-[6-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]- I H imidazol-2-yl}-pyrrolidine-l-carbonyl)-propyl]-carbamic acid methyl ester (0.202 g), and 30 NaHCO 3 (0.108 g) were dissolved in a mixture of 1,2-dimethoxyethane (6 mL) and water (2 mL). The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0176 g) was added. The reaction mixture was stirred at 85*C for 16 hours and evaporated under vacuum. Solid was dissolved in ethyl acetate (10 mL) and extracted twice with water (10 mL) and once with brine (10 mL). Solution was evaporated, dissolved in DMF, purified by reverse phase HPLC (5-70% 35 acetonitrile:water), and lyophilized, giving (I -{2-[5-(6'-{2-[I-(2-Methoxycarbonylamino-3 596 methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-[2,2']binaphthalenyl-6-yl)-I H-imidazol-2 yl]-pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.050 g, 16%) as a white solid: 'H-NMR: 300 MHz, (MeOH-d 4 ) 8: 8.3 (m, 4H), 8.1 (m, 6H), 8.0 (s, 2H), 7.8 (d, J=9.4, 2H), 5.3 (m, 2H), 4.3 (d, J=9.0, 2H), 4.1 (m, 2H), 3.9 (m, 2H), 3.7 (s, 6H), 2.6 (m, 2H), 5 2.2 (m, 6H), 0.9 (m, 12H); MS (ESI) m/z 839 [M + H]*. Example CM 1. HC, MeOH NHBc Pd(PPh 3

)

4 , NHBoc 2. Boc-Pro-OH, Br + N EtOCOCI, Et3N, NJ- N \ + B- ,QN / THF N H HO 'B0DME/H7 O 3. H 2 . Pd/C. EtOH 85 'C H 4. HC, MeOH 2-[5-(4-Bromo-phenyl)11q- (3-tert- 2-(3'-tet-Butoxycarbonylamino imidazot-2-y)-pyrrofidine-- Butoxy rbonylamrino 2 pheny1-4xyc1H-imidazo-2-y carboxylic acid benzyl ester phenyl)-boronic acd pyrrolidine-1-carboxylic acid benzyl ester 0 HN O H 0 0 N' 0 H H N\ - NH ON OHATU, DIPEA HN I H1 0 DMF 0~ Pyrrolidine-2-aroxylic acid [4'-(2- 2-Methoxycarbonylamino-3-C k pyrrotidin-2-yi-3H cidazo4'-y(- 2 M ethyl-butyric ad (I -{2-{5-(3'-([1-(2-Methoxycarbonylamino-3-methyl-butyry) biphenyl-3-yl}-amide pyrrolidine-2-carbonyl}-amino}-biphenyl-4-y)-1 H-imidazol-2-y1] pyrrolidine-1 -carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 10 2-[5-(3'-tert-Butoxycarbonylamino-biphenyl-4-y)-1H-imidazol-2-ylI]-pyrrolidine-1 carboxylic acid benzyl ester: 2-[5-(4-Bromo-phenyl)- IH-imidazol-2-yI]-pyrrolidine-l carboxylic acid benzyl ester (2.14 g, 5.01 mmol), (3-tert-Butoxycarbonylaminophenyl)-boronic acid (1.19 g, 5.01 mmol), Pd(PPh 3

)

4 (289 mg, 0.251 mmol) and K 2

CO

3 (5.5 mL of 2 M aqueous solution, I 1.02 mmol) were combined with 1,2-dimethoxyethane (20 mL). The suspension was 15 stirred while N 2 was bubbled through the solution for 24 min. A reflux condenser was attached and the suspension was heated to 85'C for 17 hours. It was then cooled, diluted with ethyl acetate (150 mL), washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (25% to 50% EtOAc/hexanes) to provide 2-[5-(3'-terl-Butoxycarbonylamino-biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine-1 20 carboxylic acid benzyl ester (1.73 g, 64%). Pyrrolidine-2-carboxylic acid 14'-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-3-yl] amide: 2-[5-(3'-tert-Butoxycarbonylamino-biphenyl-4-yl)-l H-imidazol-2-yl]-pyrrolidine-1 carboxylic acid benzyl ester (1.75 g, 3.25 mmol) was dissolved in methanol (40 mL) and 25 concentrated HCI (2 mL) was added. The solution was stirred at 50'C for 19 hours before being concentrated to a volume of 10 mL, poured into saturated NaHCO 3 (60 mL). The organic phase was extracted 3 times with 30 mL dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated. A portion of the resulting residue (515 mg, 1.17 mmol) 597 was dissolved in THF (2 mL). In a separate flask, ethylchloroformate (0.134 mL, 1.41 mmol) was added dropwise to a stirred O'C solution of Boc-Pro-OH (303 mg, 1.41 mmol) and triethylamine (0.197 mL, 1.41 mmol) in THF (4 mL). After 10 minutes, the solution of biphenyl compound was added by cannula followed by a 2 mL rinse with THF. Following addition, the 5 mixture was warmed to RT. After 70 min, the mixture was diluted with ethyl acetate (60 mL) and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica column chromatography (25% to 50% EtOAc/hexanes) to provide the Boc-Pro compound (470 mg, 63%). This material was dissolved in ethanol (40 mL) and 10% Pd/C (300 mg) was added before the flask was sealed and a bladder 10 containing hydrogen gas was attached. A venting needle was placed in the septum for 30 s to allow hydrogen to bubble through the solution. After 13 h, the mixture was filtered over CELITE and concentrated. A portion of this residue (177 mg, 0.353 mmol) was dissolved in methanol (20 mL) and concentrated HCI (2 mL) was added. The mixture was stirred at 60"C before being concentrated to provide Pyrrolidine-2-carboxylic acid [4'-(2-pyrrolidin-2-yl-3H 15 imidazol-4-yl)-biphenyl-3-yl]-amide (142 mg, 100%). (1-{2-[5-(3'-{[I-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl] amino}-biphenyl-4-yl)-1 H-imidazol-2-yi]-pyrrolidine-1 -carbonyl}-2-methyl-propyl) carbamic acid methyl ester: Pyrrolidine-2-carboxylic acid [4'-(2-pyrrolidin-2-yl-3H-imidazol 20 4-yl)-biphenyl-3-yl]-amide (142 mg, 0.353 mmol), 2-Methoxycarbonylamino-3-methyl-butyric acid (124 mg, 0.706 mmol) and HATU (295 mg, 0.777 mmol) were suspended in DMF (7 mL) and cooled to O'C before DIPEA (0.615 mL, 3.53 mmol) was added. After 80 min, the mixture was warmed to RT then filtered and purified by reverse phase preparative HPLC, giving (1 -{2 [5-(3'-{[1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl]-amino} 25 biphenyl-4-yl)-I H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (50 mg, 20%): 'H NMR (DMSO-d6, 400 MHz) 10.11 (s, I H), 7.92 (s, I H), 7.83 (d,J = 9.0 Hz, 2H), 7.80-7.56 (m, 3H), 7.41-7.29 (m, 4H), 5.90 (m, I H), 4.47 (m, I H), 4.05 (m, 2H), 3.82 (m, 3H), 3.64 (m, 2H), 3.54 (m, 6H), 2.18 (m, 2H), 2.02-1.92 (m, 6H), 0.96-0.82 (m, 12H); MS (ESI) m/z 716 [M + H]*. 30 598 Example CN Cbz \ -HO -Pd(PPh 3 )1, Y-.N \/ Br H K 2

C

3 Cz B NHB KC3 b /NHBoc H HO DME/H 2 0 N 7N 85*C CH 2-[5-(4-Bromo-pheny1)-1 H- (4-tert-2-5(telBoyarnlmno imidazol-2-yl]-pyrrolidine- - Butoxycarbonylamino 2-[5-(4'-tert-Butoxycarbonylamino carboxylic acid benzyl ester phenyl)-boronic acid pr enrl-4-arox nli id nz yl ester 1. HCI, MeOH 2. Boc-Pro-OH, H EtOCOCI, Et 3 N, H H O THF Hj N\ -HN) N OyN....OH HATU. DIPEA 3. H 2 , Pd/C, EtOH HIA DMF 4. HCI, MeOH H Pyrrolidine-2-carboxylic acid [4'-(2-pyrrolidin 2-yI-3H-imidazol-4-yl)-biphenyl-4-yl)-amide 2-Methoxycar nylacino-3 0 O N' H F HO 0 o NjNN (1-{2-[5-(4'-{{1 -(2-Methoxycarbonylamino-3-methyl-butyry) pyrrolidine-2-carbonyl]-amino}-biphenyl-4-yl)-1 H-imidazol-2-yl] pyrrolidine-1-carbony)-2-methyl-propyl)-carbamic acid methyl ester 2-[5-(4'-tert-Butoxycarbonylamino-biphenyl-4-yl)-1H-imidazol-2-yIl-pyrrolidine-1 5 carboxylic acid benzyl ester: 2-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-pyrrolidine- carboxylic acid benzyl ester (2.31 g, 5.42 mmol), (4-tert-Butoxycarbonylaminophenyl)-boronic acid (1.28 g, 5.42 mmol), Pd(PPh 3

)

4 (313 mg, 0.271 mmol) and K 2

CO

3 (6 mL of 2 M aqueous solution, 11.92 mmol) were combined with 1,2-dimethoxyethane (20 mL). The suspension was stirred while N 2 was bubbled through the solution for 14 min. A reflux condenser was attached 10 and the suspension was heated to 85'C for 15 hours. It was then cooled, diluted with ethyl acetate (150 mL), washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (25% to 50% EtOAc/hexanes) to provide 2-[5-(4'-tert-Butoxycarbonylamino-biphenyl-4-yl)- 1 H-imidazol-2-yl]-pyrrolidine- carboxylic acid benzyl ester (1.20 g, 4 1%). 15 Pyrrolidine-2-carboxylic acid 14'-(2-pyrrolidin-2-y-3H-imidazol-4-y)-biphenyl-4-yll amide: 2-[5-(4'-tert-Butoxycarbonylamino-biphenyl-4-yl)- IH-imidazol-2-yl]-pyrrolidine- 1 carboxylic acid benzyl ester (1.75 g, 3.25 mmol) was dissolved in methanol (40 mL) and concentrated HC1 (2 mL) was added. The solution was stirred at 50'C for 19 hours before being 20 concentrated to a volume of 10 mL, poured into saturated NaHCO 3 (60 mL). The organic phase was extracted 3 times with 30 mL dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated. A portion of the resulting residue (963 mg, 2.20 mmol) 599 was dissolved in THF (4 mL). In a separate flask, ethylchloroformate (0.231 mL, 2.24 mmol) was added dropwise to a stirred O'C solution of Boc-Pro-OH (568 mg, 2.64 mmol) and triethylamine (0.368 mL, 2.69 mmol) in THF (6 mL). After 10 minutes, the solution of biphenyl compound was added by cannula followed by a 2 mL rinse with THF. Following addition, the 5 mixture was warmed to RT. After 70 min, the mixture was diluted with ethyl acetate (60 mL) and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica column chromatography (25% to 50% EtOAc/hexanes) to provide the Boc-Pro compound (470 mg, 63%). This material was dissolved in ethanol (40 mL) and 10% Pd/C (300 mg) was added before the flask was sealed and a bladder 10 containing hydrogen gas was attached. A venting needle was placed in the septum for 30 s to allow hydrogen to bubble through the solution. After 14 h, the mixture was filtered over CELITE and concentrated. A portion of this residue (169 mg, 0.337 mmol) was dissolved in methanol (20 mL) and concentrated HCI (2 mL) was added. The mixture was stirred at 60*C before being concentrated to provide Pyrrolidine-2-carboxylic acid [4'-(2-pyrrolidin-2-yl-3H 15 imidazol-4-yl)-biphenyl-4-yl]-amide (135 mg, 100%). (1-{2-[5-(4'-{[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl] amino)-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester: Pyrrolidine-2-carboxylic acid [4'-(2-pyrrolidin-2-yl-3H-imidazol 20 4-yl)-biphenyl-4-yl]-amide (135 mg, 0.337 mmol), 2-Methoxycarbonylamino-3-methyl-butyric acid (118 mg, 0.674 mmol) and HATU (282 mg, 0.741 mmol) were suspended in DMF (6 mL) and cooled to 0'C before DIPEA (0.470 mL, 2.70 mmol) was added. After 60 min, the mixture was warmed to RT then filtered and purified by reverse phase preparative HPLC, giving (1-{2 [5-(4'-{[1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carbonyl]-amino} 25 biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl} -2-methyl-propyl)-carbamic acid methyl ester (136 mg, 56%). 'H NMR (DMSO-d6, 400 MHz) 10.16 (s, I H), 8.07 (s, I H), 7.80 (d, J= 4.5 Hz, 4H), 7.70 (d, J= 4.5 Hz, 4H), 7.30 (m, I H), 5.09 (m, I H), 4.44 (m, I H), 4.08 (m, H), 4.02 (m, H), 3.85-3.77 (m, 3H), 3.61 (m, 1 H), 3.54 (s, 3H), 3.53 (s, 3H), 2.37 (m, 1 H), 2.16-1.84 (m, 10 H), 0.92 (d, J= 6.7 Hz, 3H), 0.86 (d, 6.5 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H), 0.75 30 (d, J =6.6 Hz, 3H); MS (ESI) m/z 716 [M + H]. 600 Example CO OH OTf Tf 2 O. Pd(PPh3)4 Et 3 N - K1(C 3 __ \,J=\~O~ K 2 0 3 - - + N PhMe OH OTf H 100 *C Naphthalenle-1 .5-diol Trnflumro-methanesuffonic acid 2-{5-(4-(4.4,5.5-TetrameihyI 5-tNluoarmethanesutonytoxy- (1,3,2]dioxaborolan-2-yl)-phenylj-1H midazoi-2 naphthalen-1-yl ester yl}-pyrrolidine-1-carboxylic acid tert-butyl ester N OTf bs(pnacoato)diboron, Br 3 )N\ -\\N Pd(dpl) 2 C1. KOAc N /\ i-Br K 2 C0 3 N-' dioxane N&LN + /,- D+/2 C H "'1 00 *C H H 85 *C 2-{5-{4-(5-Trifluoromethanesufonyloxy- 2-(5-{4-{5-(4,4.5,5-Tetramethyl-{1 .3.2]doxaborolan-2- 2-(5-Bromo1 H-imidazol-2-yl)-vyrrofidine naphithaleri-1 -yt)-pslenytj.1 H~rrvdazoI.2.yI)- yI)-naphthalen-1-yt).phenyl)-lH-imidazol-2-yI). 1 -caroxyi~c acid trn-out ester pyrroidine- 1-Caroxylic cid tert-2utyl ester pyrroYide-1 1-carboxylic acid tert-butyb ester / \ B/ H 0 1. HCI. MeOH No 0 N' 2.HATU, OtPEA N - /\ + O +OH DMF 2-(5-{4-{5-(1H-imidazol-2-yI)-pyrrolidine-1-carboxylic acid 2-Mettoxycarbonylamino-3 tert-butyl ester)-naphthaten-1-y]-pheny}-1H-imidazol-2- methyl-butyric acid yl)-pyrrolidine-1-carboxylic acid tert-butyl ester 0~ H [14-2-{5-{4-(5(2{1 -(2-Methbuxycarbonylamino-3-nethyl-butrl) pyrrolidin-2-yI-3-imidazol-4.yI)-napTthalen 1 I)-phenyII-lH- idazol-2 yl}-pyrrocidne-l -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester Trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy-naphthalen-1-yI ester: 5 Naphthalene-1,5-diol (I g, 6.25 mmol) was dissolved in dichloromethane (25 mL) and triethylamine (2.6 mL, 18.73 mmol) and trifluoromethanesulfonic anhydride (1.58 mL, 9.86 mmol) were added. After stirring for 16 h, the mixture was diluted with ethyl acetate (250 mL) and washed with water, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, concentrated and purified by silica column chromatography (0% to 10 10% EtOAc/hexanes) to provide Trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy naphthalen-1-yl ester (957 mg, 48%). 2-{5-[4-(5-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-phenyl]-1H-imidazol-2-yl} pyrrolidine-1-carboxylic acid tert-butyl ester: 2-{5-[4-(4,4,5,5-Tetramethyl 15 (1,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl }-pyrrolidine- I -carboxylic acid tert-butyl ester (1.30 g, 2.96 mmol), Trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy naphthalen-1 -yl ester (982 mg, 2.31 mmol), Pd(PPh 3

)

4 (134 mg, 0.116 mmol) and potassium carbonate (639 mg, 4.62 mmol) were suspended in toluene. After degassing with nitrogen for 28 min, the stirred suspension was heated to 100'C for 18 hours. The reaction mixture was then 601 cooled to RT, diluted with ethyl acetate (250 mL), washed with water, brine, dried over magnesium sulfate and concentrated. The resulting residue was purified by silica column chromatography (0% to 60% EtOAc/hexanes) to provide 2-{5-[4-(5 Trifluoromethanesulfonyloxy-naphthalen-1-yl)-phenyl]-I H-imidazol-2-yl}-pyrrolidine-l 5 carboxylic acid tert-butyl ester (1.09g, 80%). 2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-1-yl]-phenyl}-IH imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester: 2-{5-[4-(5 Trifluoromethanesulfonyloxy-naphthalen- I -yl)-phenyl]- I H-imidazol-2-yl}-pyrrolidine-1 10 carboxylic acid tert-butyl ester (468 mg, 0.796 mmol), bis(pinacolato)diboron (202 mg, 0.796 mmol), Pd(dppf) 2 Cl 2 (29 mg, 0.0398 mmol) and potassium acetate (234 mg, 2.39 mmol) were suspended in dioxane (4 mL) and heated to I 00'C for 90 min. After cooling to RT, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The resulting residue was purified 15 by silica column chromatography (40% to 60% EtOAc/hexanes) to provide 2-(5-{4-[5-(4,4,5,5 Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-naphthalen-I -yl]-phenyl}-l H-imidazol-2-yl)-pyrrolidine I -carboxylic acid lert-butyl ester (450 mg, 100%). 2-(5-{4-15-(1H-imidazol-2-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester)-naphthalen-l 20 yl]-phenyl}-lH-imidazol-2-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-(5-{4-[5 (4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-1 -yl]-phenyl}-I H-imidazol-2-yl) pyrrolidine-l -carboxylic acid tert-butyl ester (159 mg, 0.281 mmol), 2-(5-Bromo-l H-imidazol 2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (178 mg (0.562 mmol), Pd(PPh 3

)

4 (65 mg, 0.0562 mmol) and K 2

CO

3 (0.281 mL of a 2 M aqueous solution, 0.562 mmol) were combined in 25 1,2-dimethoxyethane (3 mL) and degassed with bubbling N 2 for 12 min. The mixture was then heated to 85'C for 22 hours then cooled to RT, diluted with ethyl acetate (50 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (80% to 100% EtOAc/hexanes) to afford 2-(5-{4-[5-(l H-imidazol-2-yl)-pyrrolidine- I -carboxylic acid tert 30 butyl ester)-naphthalen- I -yl]-phenyl}-I H-imidazol-2-yl)-pyrrolidine- I -carboxylic acid tert butyl ester (42 mg, 22%). [1-(2-{5-14-(5-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yli-naphthalen-1-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 35 methyl-propyll-carbamic acid methyl ester: 2-(5-{4-[5-(] H-imidazol-2-yl)-pyrrolidine- I 602 carboxylic acid tert-butyl ester)-naphthalen-1 -yl]-phenyl}-I H-imidazol-2-yl)-pyrrolidine-1 carboxylic acid tert-butyl ester (41 mg, 0.0607 mg) was dissolved in methanol (5 mL) and concentrated HCI (1 mL) was added. The mixture was stirred at 60'C for 2 hours then cooled and concentrated. To the residue was added 2-Methoxycarbonylam i no-3-methyl-butyric acid 5 (32 mg, 0.182 mmol), HATU (51 mg, 0.133 mmol) and DMF (2 mL). The mixture was cooled to 0*C and DIPEA (0.063 mL, 0.364 mmol) was added. After 30 min, water (I mL) was added and the mixture was filtered and purified by reverse phase preparative HPLC, giving [1-(2-{5 [4-(5-{2-[l-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} naphthalen-I -yl)-phenyl]-I H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-2-methyl-propyl] 10 carbamic acid methyl ester (17.6 mg, 38%). 'H NMR (MeOH-d4, 400 MHz) 8.03 (d, J= 8.6 Hz, I H), 7.98 (d, J= 8.6 Hz, I H), 7.89 (m, 2H), 7.72-7.57 (m, 6H), 7.16 (m, I H), 5.28 (m, 2H), 4.25 (m, 2H), 4.11 (m, 3H), 3.86 (m, 3H), 3.67 (s, 3H), 3.65 (s, 3H), 2.59 (m, 2H), 2.30-2.04 (m, 8H), 0.95-0.89 (m, 12H); MS (ESI) m/z 789 [M + H]. 15 Example CP c 0 c H O BN I N\'~V OJ- H N Br + 0 yN OH H O 2-(5-(4-[5-(4,4.5.5-Tetramethy[1 ,3.2dioxabxrolan-2- 2-[5-(4-Bromo-phenyl)-1H- 2-Methoxycarbonylamino-3 yl)-napthalen-1-yJ-pheny lt}1 -imidazoi-2.yI). imidazol-2-yJ-pyrrolidine-l- metttyl-butyric add pyrrolidine-1-carboxylic acid fert-butyl ester carboxylic acd tert-butyl ester 0~ 1. Pd(PPh) 4 H'

K

2 C0 3 0 NO

DME/H

2 0 I H O 85'C 0 N' / \ _<'N * 2 H.OH N 3I HATU. DIPEA NQN ' DMFN-LN (1 -[2-(5-4-45-(4-{2-[-(2-Metoxycarbonylamino-3-methyl-butyryl)pyrrolidin 2-yI-3H-.imidazol-4-yt)-phenyl).naphthale,-1 -ylJ-pheny)- 1/-imidazol-2-yl) pyroldine- -carbnyJ-methyl-propycarbamic acid methyl ester 11 -12-(5-{4-15-(4-{2-I11-( 2 -Methoxyca rbony lam ino-3-methy-b uty ryl)-pyrrolid in.2-yj -3 H imidazol-4-yl}-phenyl)-naphthalen-1-yll-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1 20 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester: 2 -(5-{4-[5-(4,4,5,5-Tetramethyl [1,3,2]dioxaborolan-2-yl)-naphthalen-I -ylJ-phenyl}- I H-imidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl ester (98 mg, 0.173 mmol), 2-[5-(4-Bromo-phenyl)-I H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester (102 mg, 0.260 mmol), Pd(PPh 3

)

4 (40 mg, 0.035 mmol) and potassium carbonate (0.173 mL of a 2 M aqueous solution, 0.346 mmol) were 25 suspended in 1,2-dimethoxyethane. The mixture was degassed for 10 min then heated to 85*C for 4 hours. The contents were then cooled to RT, diluted with ethyl acetate (50 mL), washed 603 with water and brine, dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (80% to 100% EtOAc/hexanes) to provide {l -[2-(5 {4-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4 yi}-phenyl)-naphthalen- I -y1]-phenyl)- I H-imidazol-2-yl)-pyrrolidine- 1 -carboxylic acid tert butyl 5 ester (28 mg, 22%). The Suzuki product was dissolved in methanol (5 mL) and treated with concentrated HCI (I mL). The mixture was heated to 60"C for 100 min then cooled and concentrated. To the residue was added 2-Methoxycarbonylamino-3-methyl-butyric acid (20 mg, 0.112 mmol), HATU (31 mg, 0.0821 mmol) and DMF (2 mL). The stirred mixture was cooled to O'C then DIPEA (0.033 mL, 0.187 mmol) was added. After 50 min, the reaction 10 mixture was diluted with I mL of water and purified by reverse phase preparative HPLC to provide { l -[2-(5-{4-[5-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y] 3H-imidazol-4-yl}-phenyl)-naphthalen-I-yl]-phenyl}-lH-imidazol-2-yl)-pyrrolidine-l carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (12 mg, 38%). 'H NMR (MeOH-d4, 400 MHz) 7.89-7.87 (m, 4H), 7.80-7.78 (m, 4H), 7.49-7.41 (m, 8H), 5.22 (m, 2H), 4.26 (m, 2H), 15 4.02 (m, 2H), 3.91 (m, 2H), 3.66 (s, 6H), 2.40-2.19 (m, 6H), 2.11-2.03 (m, 4H), 0.96 (d, J= 6.6 Hz, 6H), 0.92 (d, J= 6.6 Hz, 6H); MS (ESI) m/z 865 [M + H]*. 604 Example CQ I N- Br NaH, SEMCI Nl rN n-BuL, DMF N CHO NDMF N2N BrF "N SEM SEM 2-[5-Bromo-1-(2-trimethylsilanyl- 2-[5-Formyl-1-(2-trimethylsilanyl 2-(5-Bromo-1l-imidazol-2-y)-pyrrolidine- ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine- ethoxymethyl)-1H-midazol-2-yl]-pyrrolidine 1-carfoxylic acid tert-butyl ester 1-carboxylic acid tert-butyl ester 1-carboxylic acid tert-butyl ester dimethyl-1-diazo-2- H 0 1. HCI, dioxane oxopropylphosphonate, 2. HATU, DIPEA K2CO3 Boc N O N OH DMF MeOH/THF N N 3. TFA, DCM SEM 2-[5-Ethynyl-1-(2-trimethylsilanyl- 2-Methoxycarbonylamino-3 ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine- methyl-butyric acd 1-carboxylic acid tert-butyl ester 0 O S N'H O N'H 0 O B Pd(PPh 3

)

4 , N+NBr Cul E3N_ N " N Z)L N DMIF -I2-(5-Ethynyl-1 I-f-im dazol-2-y)- (1 -{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2 pyrrolidine-1-carbonyl -2-methy yl]-pyrrolidine-1 -carbonyl)-2-methyl propyly-carbamic acid methyl ester propyl)-carbamic acid methyl ester 0 OH N NN 'HH O HO HO H'-N O s1 0 (1-(2-[5-(4-{2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yI)-phenylethynyl)-1 H-imidazol-2-y] pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-15-Bromo-1 -(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine-1 5 carboxylic acid tert-butyl ester: 2-(5-Bromo- 1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4 g, 12.65 mmol) was dissolved in DMF and cooled to 0"C. NaH (658 mg of 60% mineral oil dispersion, 16.45 mmol) was added and the reaction mixture was aged for 13 min before addition of SEMCI (2.7 mL, 15.18 mmol) and warming to RT. After 16 h, the reaction was quenched by water, diluted with ethyl acetate (300 mL) and washed with water and 10 brine. The organic phase was dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (10% to 30% EtOAc/hexanes) to afford 2-[5-Bromo- I-(2-trimethylsilanyl-ethoxymethyl)- I H-imidazol-2-y1]-pyrrolidine- I-carboxylic acid tert-butyl ester (4.67 g, 83%). 15 2-[5-Formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylJ-pyrrolidine-1 carboxylic acid tert-butyl ester: 2-[5-Bromo- 1 -(2-trimethylsilanyl-ethoxymethyl)- I H 605 imidazol-2-yl]-pyrrolidine-I-carboxylic acid tert-butyl ester (3.804 g, 8.52 mmol) was dissolved in THIF (42 mL) and cooled to -78'C. n-BuLi (3.4 mL of a 2.5 M hexane solution, 8.52 mmol) was added dropwise over 3 min. After 65 min, DMF (4 mL) was added and the reaction mixture was warmed to RT. After stirring at RT for 75 min, a saturated aqueous solution of ammonium 5 chloride (50 mL) was added and the entire content of the flask was poured into saturated aqueous sodium bicarbonate. The aqueous phase was extracted 3 times with diethyl ether. The combined organic layers were dried over magnesium sulfate, concentrated and purified by silica column chromatography (30% to 70% EtOAc/hexanes) to provide 2-[5-Formyl-1-(2 trimethylsilanyl-ethoxymethyl)- IH-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester 10 (1.50 g, 45%). 2-[5-Ethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester: 2-[5-Formyl-I-(2-trimethylsilanyl-ethoxymethyl)-IH imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (1.625 g, 4.11 mmol) and dimethyl 15 1 -diazo-2-oxopropylphosphonate (1.056 g, 5.50 mmol) were dissolved in 1:1 MeOH/THF (10 mL) and potassium carbonate (1.14 g, 8.25 mmol) was added. After stirring for 200 min, more potassium carbonate (1.14 g, 8.25 mmol) was added. 45 min later, the reaction mixture was poured into 100 mL 1:1 water/saturated aqueous sodium bicarbonate. The aqueous phase was extracted 3 times with diethyl ether. The combined organic phases were dried with magnesium 20 sulfate and concentrated. The crude residue was purified by silica column chromatography (20% to 45% EtOAc/hexanes) to afford 2-[5-Ethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1 H imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (1.234 g, 77%). {1-[2-(5-Ethynyl-1 H-imidazol-2-yl)-pyrrolidine-1-carbonyll-2-methyl-propyl)-carbamic 25 acid methyl ester: 2-[5-Ethynyl- I -(2-trimethylsilanyl-ethoxymethyl)- I H-imidazol-2-yl] pyrrolidine-l -carboxylic acid tert-butyl ester (1.002 g, 2.56 mmol) was dissolved in dioxane (5 mL) and 4 M HCI in dioxane (5 mL) was added. The reaction mixture was stirred for 3 hours and concentrated. To the residue was added 2-Methoxycarbonylam ino-3 -methyl-butyric acid (561 mg, 3.20 mmol), HATU (1.22 g, 3.20 mmol) and DMF (15 mL). The stirred reaction 30 mixture was cooled to O'C and DIPEA (2.23 mL, 12.8 mmol) was added). After stirring for 3 h, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (40% to 75% EtOAc/hexanes) to provide the coupled compound (741 mg, 65% over 2 steps). 35 This material was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was 606 added. The stirred reaction mixture was heated to reflux for 4 h, then cooled to RT, and poured into a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted 3 times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (0% to 10% 5 MeOH/DMC) to provide {I -[2-(5-Ethynyl-I H-imidazol-2-yl)-pyrrolidine-I -carbonyl]-2-methyl propyl}-carbamic acid methyl ester (525 mg, 100%). (1-{2-15-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl 10 propyl)-carbamic acid methyl ester: { 1 -[2-(5-Ethynyl- I H-imidazol-2-yl)-pyrrolidine-1 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (46 mg, 0.144 mmol), (1-{2-[5-(4 Bromo-phenyl)-1 H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (78 mg, 0.173 mmol), Pd(PPh 3

)

4 (17 mg, 0.0 144 mmol), CuI (5 mg, 0.0288 mmol) and triethylamine (0.200 mL, 1.44 mmol) were suspended in DMF (1.5 mL). The reaction 15 mixture was stirred at 80*C for 2 hours then I mL of water was added and the mixture was purified by reverse phase preparative HPLC, giving (1 -{2-[5-(4-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl}-phenylethynyl) 1 H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (24 mg, 24%). 'H NMR (MeOH-d4, 400 MHz) 7.65 (d, J= 8.2 hz, 2H), 7.45 (d, J= 8.2 hz, 2H), 20 7.38 (s, 1 H), 7.22 (s, 1 H), 6.98 (m, 1 H), 5.17 (m, I H), 5.11 (m, I H), 4.25-4.20 (m, 2H), 4.01 3.79 (m, 4H), 3.66 (s, 6H), 2.37-2.00 (m, 10H), 0.99-0.89 (m, 12H); MS (ESI) m/z 687 [M + H]. Example CR 0 0 O N'H O N'H oN Pht(OAc) 2 , PdCI. 0 _ N N PPh 3 , Cut. Et 3 N I N- \ N-- N THF .-NO HQH N 0 H' 0 {1-{2-(5-Ethynyl-1H-imidazo-2-yl)- (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methybutyryl) pyrrolidine-l-cartbonylj-.methy- pyrrolidin-2-ytF3H4-imidazo-4-y)-buta-1 .3-diynyl)-1H-imidazo-2yl. 25 prapyl)-cartbami acid rmthyl ester pyrrolidine-1 -cartony)-24nethyl-propyl)-carbamic astd methyl ester (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yi]-3H imidazol-4-yl)-buta-1,3-diynyl)-1H-imidazol-2-yI]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: Triethylamine (0.270 mL, 1.92 mmol) was added to a 30 mixture of {I -[2-(5-Ethynyl-I H-imidazol-2-yl)-pyrrolidine-I -carbonyl]-2-methyl-propyl} carbamic acid methyl ester (61 mg, 0.192 mmol), Phl(OAc) 2 (247 mg, 0.766 mmol), PdCl2 607 (7mg, 0.0389 mmol), PPh 3 (30 mg, 0.115 mmol) and Cul (7 mg, 0.0389 mmol) in THF (2 mL). After 50 min, the reaction mixture was filtered, concentrated and purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[l-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yI]-3H-imidazol-4-yl}-buta-1 ,3-diynyl)-I H-imidazol-2-yl]-pyrrolidine- l 5 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3 mg, 5%). 'H NMR (MeOH-d4, 400 MHz) 7.33 (s, 2H), 6.95 (d, J= 8.3 Hz, 2H), 5.07 (m, 2H), 4.18 (m, 2H), 3.95 (m, 2H), 3.82 (m, 2H), 3.64 (s, 6H), 2.31-1.98 (m, 10H), 1.02-0.87 (m, 12H); MS (ESI) m/z 635 [M + H]*. Example CS 0 0 N H 0 H 0 0 N' Pd(PPh 3

)

4 . N + % N\/ \/Br CuI Et 3 N_ N N OMF (1 -(2-<5-Ethynyyl-1 H-midazol 2 yI)- (I -{2-[6-(4-Bmmo-phenyI)-Il H pyn'olidine -carbonyl]-2-methy- benzomidazot-2-yl]-pyrrvhdine- -carbonyl) propyl}-carbamic acid methyl ester 2-methyt-propyt)-carbamic acid methyl ester 0 0 IkN >.lO O N'H H _00 H' HN O 0 (1-{24r-(4-{2-i -(2-Methoxycarbonylami -3-methyt-butyryI)-pyrrotidin 2-yll-3H-Imidazol-4-ytethynyl)-pheny).1 H-b~enzoimidazo-2-yJ 10 pyrrolidine-l-carbony)-2methy-propy)carbamic acid methyl ester (1-{2-[6-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-ylethynyl}-phenyl)-IH-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: { I -[2-(5-Ethynyl- IH-imidazol-2-yl)-pyrrolidine-1 15 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (62 mg, 0.195 mmol), (l-{2-[6-(4 Bromo-phenyl)- IH-benzoimidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (73 mg, 0.146 mmol), Pd(PPh 3

)

4 (I I mg, 0.00975 mmol), Cul (4 mg, 0.0195 mmol) and triethylamine (0.271 mL, 1.95 mmol) were suspended in DMF (2 mL). The reaction mixture was stirred at 80"C for 3 hours then I mL of water was added and the mixture was 20 purified by reverse phase preparative HPLC, giving (1-{2-[6-(4-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl)-phenyl) I H-benzoimidazol-2-yI]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (12 mg, 11%). 'H NMR (MeOH-d4, 400 MHz) 7.66-7.64 (m, 2H), 7.59-7.50 (m, 4H), 7.24 (s, 1 H), 6.98 (m, I H), 5.28 (m, I H), 5.12 (m, I H), 4.28-4.19 (m, 2H), 4.04-3.82 (m, 4H), 3.66 (s, 25 3H), 3.65 (s, 3H), 2.43-2.01 (m, 10H), 0.99-0.87 (m, 12H); MS (ESI) m/z 737 [M + H]*. 608 Example CT 0 ON N'HBr ,YO Br Pd(PPh3)4, NN + Cul, Et3N NIN B DMF Q H Br {1-[2-(5-Ethynyl-1H-imidazol-2-yl)- 1,4-Dibromo-benzene pyrrolidine-1 -carbonyl]-2-methyl propyl}-carbamic acid methyl ester 0 0 O N' H O N'H O YPd(PPh 3

)

4 , N - Br + N Cul, Et 3 N ~j N N DMF H HDM (1-(2-[5-(4-Bromo-phenylethynyl)-1H- {1-(2-(5-Ethynyl-1H-imidazol-2-y) imidazol-2-yl]-pyrrolidine-1-carbonyl}-2- pyrrolidine-1 -carbonyl]-2-methyl methyl-propyl)-carbamic acid methyl ester propyl}-carbamic acid methyl ester 0 O N'H N __ N N CzH O H' N os0 NO 0 (1-{2-[5-(4-(2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yI]-3H-imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1-{2-[5-(4-Bromo-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl 5 propyl)-carbamic acid methyl ester: { I -[2-(5-Ethynyl- 1 H-imidazol-2-yi)-pyrrolidine- carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (57 mg, 0.179 mmol), 1,4 dibromobenzene (211 mg, 0.895 mmol), Pd(PPh 3

)

4 (10 mg, 0.00895 mmol), Cui (3 mg, 0.0179 mmol) and triethylamine (0.249 mL, 1.79 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80"C for 70 10 min then diluted with 20 mL ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried with magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (0% to 5% MeOH/DCM) to afford (I-{2-[5-(4-Bromo-phenylethynyl)- IH-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl propyl)-carbamic acid methyl ester (43 mg, 51%). 15 (1-{2-15-(4-{2-[1-(2Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: { I -[2-(5-Ethynyl- 1 H-imidazol-2-yi)-pyrrolidine- I carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (49 mg, 0.154 mmol), (1-{2-[5-(4 609 bromo-phenylethynyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (43 mg, 0.0908 mmol), Pd(PPh 3

)

4 (10 mg, 0.00908 mmol), Cui (2 mg, 0.00908 mmol) and triethylamine (0.127 mL, 0.908 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80"C for 4 5 hours then cooled to RT. Formic acid (0.1 mL) and water (I mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethyny} phenylethynyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl } -2-methyl-propyl)-carbamic acid methyl ester (11 mg, 17%). IH NMR (MeOH-d4, 400 MHz) 7.46 (d, J= 3.9 Hz, 4H), 7.25 (s, 10 2H), 6.96 (d, J= 8.4 Hz, 2H), 5.10 (m, 2H), 4.20 (m, 2H), 3.97 (m, 2H), 3.83 (m, 2H), 3.64 (s, 6H), 2.32-2.00 (m, I OH), 0.98-0.88 (m, 12H); MS (ESI) m/z 711 [M + H]*. Example CU 0 0 N'H O OTf Pd(PPh 3

)

4 , + Cul, Et 3 N N DMF OTf {1 -J2-(5-Ethynyl-1 H-imidazol-2-yl)- Trifluoro-methanesulfonic acid pyrrolidine-1 -carbonyl]-2-methyl- 5-trfluoromethanesufonyloxy propyl}-carbamic acid methyl ester naphthalen-1-yi ester 0 o N' N N H __ N N No0 (1-{2-[5-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2- N 0 yll-3H-imidazol-4-ylethynyl}-naphthalen-1-ylethynyl)-1H-imidazol-2-yl]- H' pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester O 15 (1-{2-15-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-ylethynyl}-naphthalen-1-ylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester: { I-[2-(5-Ethynyl- IH-imidazol-2-yl) pyrrolidine-l-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98 mg, 0.207 mmol), 20 trifluoro-methanesulfonic acid 5-trifluoromethanesulfonyloxy-naphthalen-l -yl ester (29 mg, 0.0683 mmol), Pd(PPh 3

)

4 (12 mg, 0.0104 mmol), Cui (2 mg, 0.0104 mmol) and triethylamine (0.144 mL, 1.04 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80'C for 90 min then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse 25 phase preparative HPLC, giving (I -{2-[5-(5-{2-[I-(2-Methoxycarbonylamino-3-methyl 610 butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-ylethynyl} -naphthalen- 1 -ylethynyl)- I H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (30 mg, 58%). 'H NMR (MeOH-d4, 400 MHz) 8.38 (d,J= 8.2 Hz, 2H), 7.71 (d,J 7.2 Hz, 2H), 7.57-7.5 1 (m, 2H), 7.35 (s, 2H), 6.96 (d, J= 8.4 Hz, 2H), 5.13 (m, 2H), 4.20 (m, 2H), 3.95 (m, 2H), 3.83 (m, 2H), 5 3.63 (s, 6H), 2.33-1.98 (m, 1OH), 0.97-0.87 (m, 12H); MS (ESI) m/z 761 [M + H]*. Example CV 0 0 OA N' 0 AN-H O". O 0 Pd(PPh 3

)

4 , N N Br Cu, Et 3 N NH4 NQLN \ Br DMF CzH CH (1-[2-(5-Ethynyl-1H-imidazol-2-yl)- (1-{2-15-(4'-Bromo-biphenyl-4-yl)-1 H pyrrolidine-1 -carbonyl}-2-methyl- imidazoI-2-yl-pyrrolidine-1 -carbony1)-2 propy}-carbamic acid methyl ester methyl-propyl)-carbamic add methyl ester 0 0~~N O N'H (1-{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrroidin- H O1 2-yl]-3H4-imidazol-4-ylethynyl}-biphenyl-4-yl)-1 H-imidazoQ--yl]- O pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 10 (1-{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-ylethynyl}-biphenyl-4-yI)-IH-imidazol-2-yll-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: { I-[2-(5-Ethynyl- IH-imidazol-2-yl)-pyrrolidine-l carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (44 mg, 0.138 mmol), (1-{2-[5-(4' Bromo-biphenyl-4-yI)- I H-imidazol-2-yl]-pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic 15 acid methyl ester (67 mg, 0.128 mmol), Pd(PPh 3

)

4 (15 mg, 0.0128 mmol), Cul (2 mg, 0.0128 mmol) and triethylamine (0.180 mL, 1.28 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80'C for 15 hours then cooled to RT. Formic acid (0.1 mL) and water (I mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4'-{2-[]-(2 20 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-ylethynyl}-biphenyl 4-yI)-I H-imidazol-2-ylI]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (12 mg, 12%). ' H NMR (MeOH-d4, 400 MHz) 7.73 (d, J= 8.4 Hz, 2H), 7.66-7.64 (m, 4 H), 7.52 (d, J= 8.2 Hz, 2H), 7.35 (s, I H), 7.24 (s, I H), 6.98 (m, 2H), 5.18 (m, I H), 5.11 (m, I H), 4.26-4.19 (m, 2H), 4.0 1-3.80 (m, 4H), 3.65 (s, 6H), 2.37-2.01 (m, OH), 1.00-0.88 (m, 12H); MS 25 (ESI) m/z 763 [M + H]*. 611 Example CW 0 0 ON +ON \ _Pd(PPha)4, NQN Br Cul, Et 3 N N,.Q-N + "p Kr - dPh 3 H H _ Br DMF (1-[2-(5-Ethynyl-1H-imidazol-2-yl)- (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H pyrrolidine-1-carbonyI}-2-methyl- imidazol-2-yl-pyrrolidine-1-carbonyl)-2 propyl}-carbamic acid methyl ester methyl-propyl)-carbamic acid methyl ester 0 0H NH (1-{24-(6-(2 - etho yca lamino-3-methl buyryl)-pyrroiidin- H'N o 2-ylI-3H4-imdzo-4ylethyny)-naphthale-2-yl)-l H-imidazol-2-yfl- H, Yi pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 0 (1-{2-[5-(6-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 5 imidazol-4-ylethynyl}-naphthalen-2-y)-1 H-imidazol-2-yll-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: {1-[2-(5-Ethynyl-lH-imidazol-2-yl)-pyrrolidine 1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (53 mg, 0.166 mmol), (1-{2-[5-(6 Bromo-naphthalen-2-yl)- 1H-imidazol-2-yI]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (100 mg, 0.200 mmol), Pd(PPh 3

)

4 (19 mg, 0.0 166 mmol), Cui (3 mg, 0.0 166 10 mmol) and triethylamine (0.230 mL, 1.66 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80"C for I hours then cooled to RT. Formic acid (0.1 mL) and water (I mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(6-{2-[I-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl} 15 naphthalen-2-yl)-i H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (24 mg, 20%). (DMSO-d6, 400 MHz) 12.00-11.85 (m, 2H), 7.99-7.83 (m, 4H), 7.64 (s, I H), 7.48 (m, 1 H), 7.42 (s, I H), 7.29 (m, 2H), 5.10 (m, I H), 5.03 (m, I H), 4.06 (m, 2H), 3.82-3.76 (m, 4H), 3.54 (s, 6H), 2.15-1.97 (m, 10 H), 0.94-0.81 (m, 12H); MS (ESI) m/z 737 [M + H]+. 20 612 Example CX

NH

2 * HCI HO 8cD Cl / + ND 4'-Chtoro-biphenyl-3-ylamine Pyrrolidine-1.2-dicarboxylic hydrochloride acid 1-tert-butyl ester HN 1 HCIdioxane HN 0 7't= 02+ HATU, DIPA0 CI~ Y0 1 oK / 2-4'-Chloro-biphenyl-3- (1-[2-(4'-Chloro-bipheny-3-ylcarbamoy) ytcarbamoyl)-pyrrolidine-l- 2-Methoxycarbonylamino-3- pyrrolidine-1-carblonyll-2-methyl-propy) carboxylic acid tert-butyl ester methyt-butyric acid carbamic acid methyl ester 0 0- 0 NH bis(pinacolato)diboron, 0 0HN Pd 2 (dba)3. P(c-hex) 3 , HN - O KOAc N Br Pd(PPhJ 0 - K2CO dioxsne IB a0 N..,.N DMEIH 2 0 (2-Methyl-1-{2-[4'-(4,4,5,5-tetramethyl-[1,3.2]dioxaborolan. (1-{2-(5-(4-Bromo-phenyl)-1H-imidazol 2-yl)-biphenyl-3-ylcarbamoy]-pyrrolidine-1-carbonyl- 2-yl]-pyrrolidine-1-carbonyl)-2-methyt propyl)-carbamic acid methyl ester propyl)-carbamic acid methyl ester 0 O N'H 0 O HN 0 0 HN_ H NN H (1-[2-(4-{2-[1-(2-Methoxycartonytamino-3-methyl-butyryl)-pyrroidin-2 ylb3H-imidazo-4-yl}-1,1';4'.1']terphenyl-3"-ylcarbamoyl)-pyrrolidineL carbonylj2-methyl-propyl}-carbamic acid methyl ester 2-(4'-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: 4' 5 Chloro-biphenyl-3-ylamine hydrochloride (I g, 4.16 mmol), Pyrrolidine- 1,2-dicarboxylic acid 1 tert-butyl ester (1.08 g, 5.00 mmol) and HATU (2.06 g, 5.41 mmol) were suspended in DMF (20 mL) and DIPEA (2.20 mL, 12.5 mmol) was added. The mixture was stirred for 16 hours before being diluted with ethyl acetate (250 mL) and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The crude residue was purified by silica 10 column chromatography (25% to 45% EtOAc/hexanes) to provide 2-(4'-Chloro-biphenyl-3 ylcarbamoyl)-pyrrolidine- I -carboxylic acid tert-butyl ester (1.66g, 99%). ( -12-(4'-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolid ine-I -carbonyl] -2-methyl-propyl} carbamic acid methyl ester: 2

-(

4 '-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine-I -carboxylic 15 acid tert-butyl ester (1.66 g, 4.14 mmol) was dissolved in methanol (20 mL) and concentrated HCI (4 mL) was added. The mixture was stirred at 50'C for 80 min then cooled and concentrated. The residue was treated with 2-methoxycarbonylamino-3-methyl-butyric acid (870 mg, 4.97 mmol) and HATU (2.05 g, 5.38 mmol) and brought up in DMF (20 mL). The mixture was cooled to O'C and DIPEA (3.60 mL, 20.7 mmol). After 100 min, the reaction 20 mixture was diluted with ethyl acetate (250 mL) and washed with water and brine. The organic 613 phase was dried over magnesium sulfate and concentrated. The resulting residue was purified by silica column chromatography (50% to 80% EtOAc/hexanes) to afford { I -[2-(4'-Chloro biphenyl-3-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (1.83 g, 96% over 2 steps). 5 (2-Methyl-1-{2-[4'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-ylcarbamoyl] pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester: { I -[2-(4'-Chloro-biphenyl-3 ylcarbamoyl)-pyrrolidine- I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (409 mg, 0.893 mmol), bis(pinacolato)diboron (249 mg, 0.982 mmol), Pd 2 (dba) 3 (20 mg, 0.0223 mmol), 10 tris(cyclohexyl)phosphine (30 mg, 0.107 mmol) and potassium acetate (131 mg, 1.34 mmol) were suspended in dioxane (5 mL) and degassed with nitrogen for 4 min. The stirred suspension was heated to 80'C for 14 hours before being cooled to RT, diluted with ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica column chromatography (55% to 85% 15 EtOAc/hexanes) to afford (2-Methyl-I - {2-[4'-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl) biphenyl-3-ylcarbamoyl]-pyrrolidine- I -carbonyl}-propyl)-carbamic acid methyl ester (491 mg, 100%). {1 -12-(4-{2-1I-(2-Methoxycarbonylamino-3-methyl-butyry)-pyrrolidin-2-yl]-3H-imidazoll 20 4-yl}-[ 1,1';4',1 "]terphenyl-3"-ylcarbamoyl)-pyrrolidine-1 -carbonyll -2-methyl-propyl} carbamic acid methyl ester: (2-Methyl-I -{2-[4'-(4,4,5,5-tetramethyl-[ ,3,2]dioxaborolan-2 yl)-biphenyl-3-ylcarbamoyl]-pyrrolidine-l -carbonyl}-propyl)-carbamic acid methyl ester (135 mg, 0.246 mmol), (1-{2-[5-(4-Bromo-phenyl)- IH-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (1 10 mg, 0.246 mmol), Pd(PPh 3

)

4 (14 mg, 0.0 123 25 mmol) and a 2 M aqueous solution of potassium carbonate (0.246 mL, 0.492 mmol) were degassed in 1,2-dimethoxyethane (2.5 mL) for 13 min. The stirred suspension was heated to 85'C for 3 hours then concentrated, brought up in DMF/water and purified by reverse phase preparative HPLC to provide {1 -[2-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1';4',"I ]terphenyl-3"-ylcarbamoyl)-pyrrolidine-I 30 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (10 mg, 5%). (MeOH-d4, 400 MHz) 7.90 (s, I H), 7.82-7.66 (m, 8H), 7.54-7.51 (m, I H), 7.40-7.37 (m, 2H), 4.59 (m, I H), 4.24 (m, IH), 4.02-3.73 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 2.36-2.02 (m, IOH), 1.15-0.88 (m, 12H); MS (ES I) m/z 792 [M + H]*. 614 Example CY - Pd(PPh 3

)

4 . K 2 C0 3

(HO)

2 B -& NHBoc + Br Br PdP h2C Br - NHBoc 4-tert- 1 ,4-Dibromo-benzene (4'-Bromo-biphenyl-4-yl) Butoxycarbonylamino- ' or4amic acid tert-butyl ester phenylboronic acid 1. HCI, MeOH 2. Boc-Pro-OH, Boq H H A T U , i P r 2 E t N , 0 N O 1 H A T U , H P B C &0 H- OH 2.HATU DIPEA - - DMF 2-(4'-Bromo-biphen y-4 ylcarbamoyl)-pyrrolidine-1- 2-Methoxycarbonylamino-3 carboxylic acid tert-butyl ester methyl-butyric acid O --O HN bis(pinaolato)diboron, O Pd(dppf) 2 Cl 2 , KOAc dioxane Br/ NH (1-[2-(4'-Bmmo-biphenyl-4-ylcarbamoyl) py rrolidine-1-carbonyl)-2-methyl-propyl} carbamic acid methyl ester 0 =O~N BN +Br Pd(PPh 3

)

4 , K 2

CO

3 0 B NH I /N DME/H,0 (2-Methyl-1 -(2-4'-(4,4,5,5-tetramethyl-{1,3,2]dioxaborolan- (1-{2-{5-(4-Bromo-phenyl)-1 H 2-yI)-biphenyl-4-ylcarbamoy]-pyrrolidine-1 -carbonyl}- imidazol-2-yj-pyrrolidine-1 -carbonyl} propyl)-carbamic acid methyl ester 2-methyl-propyl)-carbamic acid methyl este r o H N O N 0 N NNH (1-[2-(4"-{2-i1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl}-3H-in idazol-4-yl)-[1,1'4',1"]terphenyl-4 ylcarbamoyl)-pyrro lidine-1 -carbon yl]-2-methyl-propyl}-carbamic acid methyl ester (4'-Bromo-biphenyl-4-yl)-carbamic acid tert-butyl ester: 4-tert-Butoxycarbonylamino 5 phenylboronic acid (500 mg, 2.11 mmol), 1,4-dibromo-benzene (2.00 g, 8.44 mmol) Pd(PPh 3

)

4 (122 mg, 0.106 mmol) and a 2 M aqueous solution of potassium carbonate (4.2 mL, 8.44 mmol) were degassed in 1,2-dimethoxyethane (20 mL) for 10 min. The stirred suspension was heated to 80*C for 3 hours then diluted with ethyl acetate (60 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was 10 purified by silica column chromatography (0% to 20% EtOAc/hexanes) to provide (4'-Bromo biphenyl-4-yl)-carbamic acid tert-butyl ester (430 mg, 59%). 615 2-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester: (4' Bromo-biphenyl-4-yl)-carbamic acid tert-butyl ester (407 mg, 1.17 mmol) was dissolved in methanol (10 mL) and concentrated HCI (2 mL) was added. The solution was stirred at 60"C for 5 1 hour then concentrated. The crude residue was treated with Boc-Pro-OH (302 mg, 1.40 mmol) and HATU (578 mg, 1.52 mmol) and suspended in DMF (6 mL). DIPEA (1.02 mL, 5.85 mmol) was added and the reaction mixture was stirred at RT for 4 hours after which it was diluted with ethyl acetate (200 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica column 10 chromatography (30% to 55% EtOAc/hexanes) to afford 2-(4'-Bromo-biphenyl-4-ylcarbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester (496 mg, 95% over 2 steps). {1-[2-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl} carbamic acid methyl ester: 2-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine- I -carboxylic 15 acid tert-butyl ester (496 mg, 1 .11 mmol) was dissolved in methanol and concentrated HCI (2 mL) was added. The solution was stirred at 60"C for 30 min then concentrated. The resulting residue was treated with 2-methoxycarbonylamino-3-methyl-butyric acid (233 mg, 1.33 mmol), HATU (549 mg, 1.44 mmol) and DMF (10 mL). After cooling this mixture to O'C, DIPEA (0.970 mL, 5.55 mmol) was added. The reaction mixture was Stirred for 5 hours then diluted 20 with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The resulting residue was purified by silica column chromatography (70% to 90% EtOAc/hexanes) to afford { 1-[2-(4'-Bromo-biphenyl-4 ylcarbamoyl)-pyrrolidine- I -carbonyl]-2-methyl-propyl } -carbamic acid methyl ester (520 mg, 93% over 2 steps). 25 2-Methyl-1-{2-14'-(4,4,5,5-tetramethyl-[1,3,21dioxaborolan-2-yI)-biphenyl-4-yicarbamoyl] pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester: { I -[2-(4'-Bromo-biphenyl-4 ylcarbamoyl)-pyrrolidine-l-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (154 mg, 0.307 mmol), bis(pinacolato)diboron (156 mg, 0.613 mmol), Pd(dppf) 2 Cl 2 (I I mg, 0.0 154 30 mmol) and potassium acetate (90 mg, 1.21 mmol) were suspended in dioxane and degassed for 15 min. The stirred reaction mixture was heated to I 00"C for 2 hours then cooled to RT, diluted with ethyl acetate (100 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica column chromatography (70% to 90% EtOAc/hexanes) to afford (2-Methyl-1 -{2-[4'-(4,4,5,5 616 tetramethyl-[ I,3,2]dioxaborolan-2-yl)-biphenyl-4-ylcarbamoyl]-pyrrolidine- I -carbonyl} propyl)-carbamic acid methyl ester (127 mg, 75%). { -[2-(4"-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-ylI]-3H-imidazol 5 4-yl}-[1,1';4',1 "Iterphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl} carbamic acid methyl ester: (2-Methyl-i-{2-[4'-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2 yl)-biphenyl-4-ylcarbamoyl]-pyrrolidine- I -carbonyl}-propyl)-carbamic acid methyl ester (102 mg, 0.227 mmol), (1-{2-[5-(4-Bromo-phenyl)-l H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (125 mg, 0.227 mmol), Pd(PPh 3

)

4 (13 mg, 0.0114 10 mmol) and a 2 M aqueous solution of potassium carbonate (0.227 mL, 0.454 mmol) were degassed in 1,2-dimethoxyethane (2mL) for 15 min. The stirred suspension was heated to 85'C for 4 hours then concentrated, brought up in DMF/water and purified by reverse phase preparative HPLC to provide {1-[2-(4"-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1';4',1"]terphenyl-4-ylcarbamoyl)-pyrrolidine-I 15 carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (49 mg, 27%). (DMSO-d6, 400 MHz) 11.78 (s, I H), 10.14 (s, I H), 7.82-7.67 (m, I I H), 7.52 (d, J = 1.8 Hz, 1 H), 7.34-7.28 (m, 2H), 5.08 (m, I H), 4.49 (m, I H), 4.05 (m, 2H), 3.81 (m, 3H), 3.64 (m, I H), 3.54 (s, 3H), 3.53 (s, 3H), 2.17-1.88 (m, 1 OH), 0.97-0.85 (m, 12H); MS (ES I) m/z 792 [M + H]*. 20 Example CZ Br BacN B CN Pd(PPh 3

)

4 , K2CO3 Boc No BOC.- DME/H2 N\ H 01- 2H NC 2-{5-[4-(4,4,5,5-Tetramethy- 2 2-[5-(4'-Chloro-2'-cyano-biphenyl-4 [1,3.2]dioxaborolan-2-y)-phenyl-1H-imidazol-2- 2-Bromo-5-chloro-benzonitrile yl)-1H-imidazol-2-yl}-pyrrolidine-1 yl)-pyrrolidine-1-carboxylic acid tert-butyl ester carboxylic acid tert-butyl ester bis(pinacolato)diboron, H 0 dioxane N \j/ \ / B H NC O N 2-{5-[2'-Cyano-4'-(4,4,5,5-tetramethyl- 2-(5-Bromo-1H-imidazol-2- 2-Methoxycarbonylamino-3 [1,3,2}dioxaborolan-2-yl)-biphenyl-4-y-1H-imidazol- yl)-pyrrolidine-1-carboxylic methyl-butyric acd 2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester acid tert-butyl ester 0 Pd(dppf)C1 2 , 0 N,

K

2 C0 3 - 0

DMEIH

2 O )I \ -r N N-, N 2. HCI, MeOH/H 2 0 N ,4 N / N 3. HATU, DIPEA H NC O y OMF (1-{2-5-2'-Cyano-4'-{2-1-(2-methoxycarbonylamino-3-methy-butyryl)- H'N ON pyrrolidin-2-yl}-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl} pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 0 617 2-[5-(4'-Chloro-2'-cyano-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-{5-[4-(4,4,5,5-Tetramethyl-[I,3,2]dioxaborolan-2-yI)-phenyl]- IH-imidazol 2-yl}-pyrrolidine-I-carboxylic acid tert-butyl ester (2 g, 4.55 mmol), 2-Bromo-5-chloro benzonitrile (985 mg, 4.55 mmol), Pd(PPh 3

)

4 (263 mg, 0.228 mmol) and a 2 M aqueous solution 5 of potassium carbonate (4.6 mL, 9.2 mmol) were suspended in 1,2-methoxyethane (20 mL) and degassed for 10 min. The stirred reaction mixture was heated to 85'C for 21 hours then poured into a saturated aqueous solution of NaHCO 3 (250 mL). The aqueous phase was extracted 3 times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (65% to 90% 10 EtOAc/hexanes) to afford 2-[5-(4'-Chloro-2'-cyano-biphenyl-4-y)- H-imidazol-2-yl] pyrrolidine-1 -carboxylic acid tert-butyl ester (1.65 g, 81%). 2-{5-[2'-Cyano-4'-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yi)-biphenyl-4-yl]-1H imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-[5-(4'-Chloro-2'-cyano 15 biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (1.68 g, 3.74 mmol), bis(pinacolato)diboron (1.43 g, 5.61 mmol), Pd 2 (dba) 3 (86 mg, 0.0935 mmol), x-phos (214 mg, 0.449 mmol) and potassium acetate (1.10 g, 11.22 mmol) were suspended in dioxane (20 mL) and degassed for 10 min with nitrogen. The stirred reaction mixture was heated to 90"C for 15 h, then cooled and filtered over a bed of silica, eluting with ethyl acetate until all 20 desired product was removed. The liquid was concentrated and the resulting residue was purified by silica column chromatography (55% to 80% EtOAc/hexanes) to afford 2-{5-[2' Cyano-4'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-I H-imidazol-2-yl} pyrrolidine-1 -carboxylic acid tert-butyl ester (1.57 g, 78%). 25 (1-{2-15-(2'-Cyano-4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: 2-{5-[2'-Cyano-4'-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1 H-imidazol-2-yl)-pyrrolidine-I -carboxylic acid tert butyl ester (1.60 g, 2.96 mmol), 2-(5-Bromo-I H-imidazol-2-yl)-pyrrolidine-I -carboxylic acid 30 tert-butyl ester (935 mg, 2.96 mmol), Pd(PPh 3

)

4 (171 mg, 0.148 mmol), Pd(dppf)Cl 2 (121 mg, 0.148 mmol) and a 2 M aqueous solution of potassium carbonate (3 mL, 6 mmol) were suspended in 1,2-dimethoxyethane and degassed for I1 min. The stirred reaction mixture was heated to 85"C for 100 min, then poured into a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted 3 times with ethyl acetate. The combined organic layers were dried over 35 magnesium sulfate and concentrated. The crude residue was purified by silica column 618 chromatography (5% to 10% MeOH/DCM) to afford the Suzuki coupled product (438 mg, 23%). This material (174 mg, 0.268 mmol) was treated with 4 M HCI in dioxane (4 mL). Solubility was poor so 2 mL dichloromethane and 4 mL DMF were added. After stirring for 40 min, the mixture was concentrated. The crude residue was treated with 2 5 Methoxycarbonylamino-3-methyl-butyric acid (103 mg, 0.590 mmol), HATU (255 mg, 0.670 mmol) and DMF (5 mL) and cooled to O'C. DIPEA (0.470 mL, 2.68 mmol) was added and the reaction mixture was stirred for 4 hours then poured into a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted 3 times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The crude residue was brought up in 10 DMF and water and purified by reverse phase preparative HPLC, giving (1-{2-[5-(2'-Cyano-4' {2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-y} biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (75 mg, 37%). (MeOH-d4, 400 MHz) 8.19-7.35 (m, I I H), 5.18 (m, 2H), 4.24 (m, 2H), 4.03-4.86 (m, 4H), 3.65 (s, 6H), 2.37-2.00 (m, I OH), 1 .00-0.90 (m, 12H); MS (ESI) m/z 15 764 [M + H]*. 619 Example DA and DB Hf. HATU, DMF H EtOH Br NH +NH BrcN N 2 HOOC N 4-methylmorpholine B30 Boc 0 Boc 4-Bromo-benzene- 2-Aza- 3-(2-Amino-4-bromo 1 -diamine bicyclo[22. 1]heptane- phenytcartbamoyl)-2-aza 2,3-dicarboxylic acid bicyclo[2.2+1]heptane-2 2-tert-butyl ester carboxylic acid tert-butyl ester H HB HZB INQ N d0 0- .- *i~ B r - N b~ Pd(PPh 3

)

4 , K 2 C0 3 , DMEIH 2 O dk ! ~ o 3-(6Bmm-1Hbenzimiazo-2-3-{6-14-(4,4,5,5-Tetramethy yl)-2-aza-bicyclo[2.2. 1 Iheptane- 1,32doaooa--I-hn~-1H 2-carboxylic acid tert-butyl ester benzoimidazol-2-yI}-2-aza bicydo[2.2.1]heptane-2-arboxylic acid tert butyt ester imidazol-2-yI]-pyrrolidine-1- i carboxylic acid tert-butyl ester ( H 3-(6-.{4'-[2-(l -tert-Butoxyca rbonyl-pyrrolidi n-2-y)-3H No Br imid azol -4-yt]-bipheny-4-yI}- 1 H-benzoimnidazol-2-yI)-2.aza Boc \ Brbicyclo[2.2. 1]heptane-2-carboxylic acid tert-butyl ester ( H H H Pd(PPh 3

)

4 , K 2 C0 3 , DME/H 2 0 N I N \/ \/ \/ \/ Boc HI Boc. N6 N 3-(6-{4'-[2-(2-Boc-2-aza-bicydo[2.2.1 ]hept-3-y)-3H Hbenzoimidazol-5-y]-biphenyl-4-y}-1 H-benzoimidazol-2-yI)-2 aza-bicyclo[2.2. 1]heptane-2-carboxylic acid ter-butyl ester 0 N. H __ 0 ~ 0 N \N N N N - \ \/ 0 0 (1 -{2-5-(4-{2-[2-(2-Methoxycarbonylamino-3-nmethyl-butyryl)-2-aza 1. 4N HCI/dioxane, 0CM bicycio[2.2. 1]hept-3-yl]-3H-benzoimidazol-5-y}-biphenyl-4-y)- H-imidazol-2-YI] _______________pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2. HATU, DIEA + N H H0- ~ 0 0 N \/\ ~ N 2-Metrhoxycarbonylamino-3- HNOY methyl-butyric acid 0 (1 -{3-[6-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryt)-2-aza-bicycio[2.2.1]hept 3-yI]-3H-benzoimidazol-5-y}-biphenyl-4y)-1 H-benzoimidazol-2-yI]-2-aza bicycio[2.2.l]heptane-2-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 3-(2-Amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo [2.2.11 heptane-2-carboxylic acid tert 5 butyl ester: To a solution of 2-Aza-bicyclo[2.2.1]Iheptane-2,3-dicarboxylic acid 2-tert-butyl ester (0.327 g, 1.36 mmol, I eq.), 4-Bromo-benzene-I ,2-diamine (0.507 g, 2.71 mmol, 2 eq.) and 4-methylmorpholine (0.299 mL, 2 eq.) in 10 mL DMF was added HATU (0.543g, 1.05 eq.). The reaction mixture was stirred at room temperature for I hour then concentrated down. The 620 reaction mixture was diluted with ethyl acetate and washed with diluted NaHCO3 aqueous solution and brine. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give a mixture of regioisomer 3 (2-Amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl 5 ester. 3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert butyl ester: The above mixture of regioisomer 3-(2-Amino-4-bromo-phenylcarbamoyl)-2-aza bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester was dissolved in ethanol and heated to 10 130*C in sealed tube overnight and continue heating at 170'C for 3 days. LC-MS showed desired product and Boc cleaved product (about 1:1 ratio). The mixture was concentrated down and dissolved DCM. Di-tert-butyl dicarbonate (0.6 eq.) was added and reaction was stirred overnight at room temperature. The reaction mixture was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 3-(6-Bromo 15 1 H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (0.383 g, 72%) as an orange foam. 3-{6-[4-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-benzoimidazol-2-yl}-2 aza-bicyclo[2.2.lheptane-2-carboxylic acid tert-butyl ester: A mixture of 3-(6-Bromo- H 20 benzoimidazol-2-yI)-2-aza-bicyclo[2.2.I]heptane-2-carboxylic acid tert-butyl ester (264 mg, 0.673 mmol), Benzene-1,4-diboronic acid dipinocal ester (5 eq., 3.36 g, 6.95 mmol), tetrakis(triphenylphosphine)palladium (5%, 39 mg) and 2M potassium carbonate aqueous solution (3 eq., 1.01 mL) in 5 mL DME was heated to 90*C under Ar for 4 hours. The reaction mixture was cooled down and diluted in ethyl acetate and washed with saturated sodium 25 bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 60% ethyl acetate/hexane) to give 3-{6-[4-(4,4,5,5 Tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I H-benzoimidazol-2-yl}-2-aza bicyclo[2.2. I]heptane-2-carboxylic acid tert-butyl ester (295 mg, yield 85%). LCMS-ESI-: calc'd for C 3 0

H

38

BN

3 0 4 : 515.45; Found: 516.1 (M+H*). 30 3-(6-{4'-12-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-bipheny-4-yl}-1H benzoimidazol-2-yl)-2-aza-bicyclo[2.2.11heptane-2-carboxylic acid tert-butyl ester and 3-(6 {4'-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-ylI]-biphenyl-4-yli-IH benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: A 35 mixture of 2-[5-(4-Bromo-phenyl)-I H-imidazol-2-yi]-pyrrolidine-I -carboxylic acid tert-butyl 621 ester(295 mg, 0.573 mmol, I eq.), 3-{6-[4-(4,4,5,5-Tetramethyl-[I,3,2]dioxaborolan-2-yl) phenyl]-1 H-benzoimidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (269 mg, 0.687 mmol), tetrakis(triphenylphosphine)palladium (5%, 33 mg) and 2M potassium carbonate aqueous solution (5 eq., 1.43 mL) in 5 mL DME was heated to 90'C under Argon 5 overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexane) to give 3 (6-{4'-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}- I H benzoimidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (163 mg, 10 yield 40%) and trace amount of byproduct 3-(6-{4'-[2-(2-Boc-2-aza-bicyclo[2.2.l ]hept-3-yl) 3H-benzoimidazol-5-yl]-biphenyl-4-yl}-1 H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2. I]heptane-2 carboxylic acid tert-butyl ester. LCMS-ESIUof 3-(6-{4'-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2 yl)-3 H-imidazol-4-yl]-biphenyl-4-yl}-1 H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1 Iheptane-2 carboxylic acid tert-butyl ester: calc'd for C 4 2

H

4 8

N

6 0 4 : 700.87; Found: 701.1 (M+H*). 15 (1-{2- [5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyry)-2-aza-bicyclo[2.2. 11 hept-3 yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yI]-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (Example DA) and (1-{3-[6-(4'-{2-[2-(2 Methoxycarbonylamino-3-methyl-butyry)-2-aza-bicyclo12.2. 11 hept-3-yl] -3H 20 benzoimidazol-5-yl}-biphenyl-4-yl)-I H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DB): 4N HCI in dioxane (3 mL)was added to 3-(6-{4'-[2-(I-Iert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl] biphenyl-4-yl}-1 H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert butyl ester and 3-(6-{4'-[2-(2-Boc-2-aza-bicyclo[2.2. I ]hept-3-yl)-3H-benzoimidazol-5-yl] 25 biphenyl-4-yl}- I H-imidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester mixture (163 mg, 0.233 mmol) in 3 mL DCM and the reaction mixture was stirred at room temperature for 2hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (3 mL) and to this solution was added 2 Methoxycarbonylamino-3-methyl-butyric acid (2.1 eq., 85 mg), 4-methylmorpholine (6 eq., 0.15 30 mL), followed by HATU (2 eq., 181 mg). Reaction mixture was stirred at 0 0 C for 50 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% MeCN/H 2 0 + 0.1% TFA). Product was lyophilized to give (1-{2-[5-(4'- { 2

-[

2

-(

2 -Methoxycarbonylamino-3-methyl-butyryl)-2-aza 35 bicyclo[2.2. I ]hept-3-yl]-3 H-benzoimidazol-5-yl} -biphenyl-4-yi)- I H-im idazol-2-yl]-pyrrolidine 622 l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DA) (102 mg) and byproduct (1-{3-[6-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2. I ]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)- I H-benzoimidazol-2-yl]-2-aza bicyclo[2.2. I ]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DB) 5 (10.6 mg). Example DA: I H-NMR: 300 MHz, (DMSO-d 6 ) 6: 8.13 (s, I H), 7.95-7.80 (m, 12H), 7.40-7.20 (m, 2H), 5.18-5.10 (m, I H), 4.76(m, I H), 4.55(m, I H), 4.20-4.10 (m, 3H), 3.92-3.78 (m, 3H), 3.55(d, 6H), 2.76 (m, I H), 2.40-1.55 (m, I OH), 0.95-0.78 (m, 12 H). 10 LCMS-ESI*: calc'd for C 4 6

H

54

N

8 0 6 : 814.97; Found: 815.4 (M+H*). Example DB (byproduct): 'H-NMR: 300 MHz, (DMSO-d 6 ) 8: 7.95-7.72 (m, 14H), 7.38-7.24 (m, 2H), 4.75 (m, 2H), 4.55(m, 2H), 4.24-4.16 (m, 3H), 3.55(d, 6H), 2.76 (m, 2H), 2.40-1.55 (m, 9H), 0.95-0.78 (m, 12 H). 15 LCMS-ESI+: calc'd for C 52

H

5 8

N

8 0 6 : 891.07; Found: 891.4 (M+H*). 623 Example DC O O~p 9 1 2 , Ag 2

SO

4 0 - - 0 KOH -H - S -O O 0 1 / Biphenyl-4,4'-dicarboxylic 2,2'-Diiodo-biphenyl-4,4' acid dimethyl ester dicarboxylic acid dimethyl ester S O - - 0 Na 2 S, Cui OO0 1.oxalyl chloride HO OH K 2

CO

3 , DMF HO OH 2. TMSCH 2

N

2 I Dibenzothiophene-3,7- 3. HBr 2,2'-Diiodo-bipheny-4,4'- dicarboxylic acid dicarboxylic acid Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester Boc S - 1 .COOH H

________NH

4 OAc Boc N\ - N N Br Br DIEA MeCN xyenes N cN N\ h Boc 2-Bromo-1-[7-(2-bromo-acety)- H dibenzothiophen-3-yl]-ethanone 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4 yI]-dibenzothiophen-3-yl}-1 H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester O, N.H S H 1. 4N HCIldioxane, DCM O N 2. HATU, DIEA N I -4\N>\N 0"~ ~ H H NO HO 040 (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 0 2-yl]-3H-imidazol-4-yl}-dibenzothiophen-3-yl)-1 H-imidazol-2-yl] 2-Methoxycarbonytamino-3- pyrrolidine-1-carbony}-2-methyl-propyl)-carbamic acid methyl ester methyl-butyric acid 5 2,2'-Diiodo-biphenyl-4,4'-dicarboxylic acid dimethyl ester: Biphenyl-4,4'-dicarboxylic acid dimethyl ester(5g, 18.5 mmol) and silver sulfate (17 g, 54.5 mmol) were dissolved in 60 mL concentrated sulfuric acid with vigorous stirring. Iodine (I Ig, 43.3 mmol) was added portion wise to give a purple solution which was stirred at room temperature for 1 hour. The reaction mixture was heated to 80*C for overnight. The reaction mixture was cooled down, poured into 10 ice water and sodium thiosulfate solution. Brown solid was formed, filtered and dried over vacuum at 80*C. The brown solid was extracted using a Soxhlet extraction with methanol in two batches. The product crystallized during extraction. Crystal was collected and dried to give a yellow solid 2,2'-Diiodo-biphenyl-4,4'-dicarboxylic acid dimethyl ester (5.7 g, 59%). 15 2,2'-Diiodo-biphenyl-4,4'-dicarboxylic acid: 2,2'-Diiodo-biphenyl-4,4'-dicarboxylic acid dimethyl ester (3.24 g, 6,21 mmol) was dissolved in 20 mL THF and KOH (1.02g, 2.5eq.) was added, followed by 5 mL water. The reaction was stirred at room tempature overnight. The 624 reaction was heated to 50'C for 7 hours. The reaction was cooled to room temprature. Organic solvent was removed by rotovap. The aqueous layer was acidified with concentrated HCI to give pale white solid. The solid was filtered and dried on vacuum overnight to give the product 2,2'-Diiodo-biphenyl-4,4'-dicarboxylic acid (2.74 g, yield 89%). 5 Dibenzothiophene-3,7-dicarboxylic acid: A mixture of 2,2'-Diiodo-biphenyl-4,4'-dicarboxylic acid (450 mg, 0.912 mmol, I eq.) and potassium carbonate (189 mg, 1.5 eq.) in 5 mL DMF was heated to 100*C to give a reddish brown mixture. Sodium sulfide (36 mg, 0.5 eq.) and copper(l) iodide (17 mg, 0.1 eq.) were added and reaction mixture was heated to 150'C under a slow 10 stream of Ar. Cul (100 mg) was added and followed by sodium sulfide (100 mg). The reaction was kept at 150*C overnight. The reaction mixture was diluted with 25 mL water and active carbon ( 10 g) was added. The mixture was refluxed for 10 minutes then filtered through CELITE pad into 6N HCL (50 mL) and washed with water. The solid was formed and cooled to room tempature and filtered and washed with and dired to give product Dibenzothiophene-3,7 15 dicarboxylic acid (179 mg, 72%). 2 -Bromo-1-17-(2-bromo-acetyl)-dibenzothiophen-3-yl]-ethanone: A mixture of dibenzothiophene-3,7-dicarboxylic acid (179 mg, 0.644 mmol), oxalyl chloride (0.56 mL, 6.44 mmol) and I drop of DMF in 6 mL DCM was stirred at room tempature overnight. The 20 resulting cloudy yellow solution was concentrated and co-evaporated with toluene. The residue was suspended in 6 mL DCM and cooled to 0 0 C. TMS diazomethane (I ml, 3 eq.) was added to the reaction mixture dropwise. The reaction was stirred at 0 0 C for I hour and then warmed to room temperature overnight. The mixture was concentrated to give a brown solid. The solid was suspended in 5 mL ethyl acetate and treated with 5.7 M HBr in HOAc (0.28 mL, 2.5 eq.) at 25 0 0 C. The mixture was warmed to room temprature over 2 hours. And then stirred at room temprature for I hour. Solid sodium bicarbonate was added and stirred for 30 minutes. The mixture was diluted with sodium bicarbonate solution and extracted with ethylacetate 3 times. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give impure product 2-Bromo- I -[7-(2-bromo-acetyl) 30 dibenzothiophen-3-yl]-ethanone. 625 2-(5-{7-12-(1 -Boc-pyrrolidin-2-yl)-3H-imidazol-4-yI]-dibenzothiophen-3-yl}-1 H-imidazol-2 yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: The mixture of above impure 2-Bromo- I -[7-(2-bromo-acetyl)-dibenzothiophen-3-yl]-ethanone, Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.1 eq.), and DIEA (2.07 eq.) in 5 mL 5 MeCN was stirred at room temperature overnight. The reaction mixture was concentrated down and diluted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated down. The residue was dissolved in 1.5 mL xylenes and ammonium acetate (65 mg, 15 eq.) was added. The reaction was heated to I I 0C for 2 days. The mixture was diluted with EtOAc and washed with sat.NaHCO3 aqueous solution. The organic layer was concentrated down and purified by 10 preparative reverse phase HPLC (GEMINI, 5 to 100% MeCN/H 2 0 + 0.1% TFA). Product was lyophilized to give 2-(5-{7-[2-(I-Boc-pyrrolidin-2-yI)-3H-imidazol-4-yl]-dibenzothiophen-3 yl}-l H-imidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (12.4 mg). LCMS-ESI~: calc'd for C 3 6

H

42

N

6 0 4 S: 654.82; Found: 655.0 (M+H*). 15 (1-{2-15-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yI}-dibenzothiophen-3-yl)-1 H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester (Example DC): 4 N HCI in dioxane (I mL)was added to 2-(5-{7-[2-(1 -Boc-pyrrolidin-2-yl)-3 H-imidazol-4-yl]-dibenzothiophen-3-yl}-I H-imidazol-2 yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (12.4 mg, 0.014 mmol) and the reaction 20 mixture was stirred at room temperature for I hour. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (I mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (2.08 eq., 5.1 mg), 4 methylmorpholine (6 eq., 9.2 piL), followed by HATU (2.04 eq., 10.9 mg). Reaction mixture was stirred at 0 0 C for 90 minutes. The reaction mixture was diluted with ethyl acetate and 25 washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% MeCN/H 2 0 + 0.1% TFA). Product was lyophilized to give (1-{2-[5-(7-{2-[I-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-y}-dibenzothiophen-3-yl)-I H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DC) (8.1 mg, 30 58%). 'H-NMR: 300 MHz, (CD 3 0D-d 4 ) : 8.41-8.25 (m, 4H), 7.92-7.78 (m, 4H), 5.22(m, 2H), 4.22(m, 2H), 4.08(m,2H), 3.86 (m, 2H), 3.62 (d, 6H), 2.60-2.50 (m, 2H), 2.30-1.92 (m, 8H), 0.97-0.82 (m, 12 H). LCMS-ESI*: calc'd for C 4 0

H

4 8

N

8 0 6 S: 768.92; Found: 769.3 (M+H*). 35 626 Example DD 0 O N S H N O O\NmCPBA, DCM N N -\ N H H.N (1 -{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-dibenzothiophen-3-y)-1 H-imidazol-2-yl] pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester N' HN N0 N

-

H 0 O NN (1 -{2-[5-(7-{2-[1 -(2-Methoxycarbonylamino-3-methy-butyryl)-pyrrolidin-2-yl] 3H-imidazol-4-yl}-5-oxo-5H-5X 4 -dibenzothiophen-3-y)-1 H-imidazol-2-yI] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1-{2- [5-(7-{2-[ 1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrroidin-2-yl]-3H 5 imidazol-4-yl}-5-oxo-5H-5X 4 -dibenzothiophen-3-yl)-1 H-imidazol-2-yIJ-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DD): (I-{2-[5-(7-{2-[l (2-Methoxycarbonylami no-3-methyl-butyryl)-pyrrol idin-2-yl]-3 H-imidazol-4-yl } dibenzothiophen-3-yl)- I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.0041 mmol., 4 mg) was dissolved in I mL DCM and cooled to -40 0 C. 10 mCPBA(0.4 mg, 0.9 eq.) was added. The reaction mixture was stirred at -40'C for 2 hours and warmed up to 0 0 C over 2 hours, then warmed up to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give a yellow I 5 powder (I - {2-[5-(7-{2- [1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrro idin-2-yl]-3H imidazol-4-yl}-5-oxo-5 H-5X 4 -dibenzothiophen-3-yl)-I H-imidazol-2-yl]-pyrrolidine- I carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DD) (0.6 mg). 1 H-NMR: 300 MHz, (CD 3 0D-d 4 ) 6: 8.36 (m, 2H), 8.18-7.90 (m, 6H), 5.22(m, 2H), 4.19(m, 2H), 4.05(m,2H), 3.84(m, 2H), 3.61 (d, 6H), 2.56-1.96 (m, 10H), 0.97-0.84 (m, 12 H). LCMS 20 ESl*: calc'd for C 40

H

48

N

8 0 6 S: 768.92; Found: 769.3 (M+H*). 627 Example DE 0 0 1S1 11 - mCPBA 02HNN 3 N H 2 , Pd/C - 0x){ H 2

S

4 0 2 N -O/ ) /NO 2 Dibenzothiophene Dibenzothiophene 3,7-Dinitro-dibenzothiophene 5-oxide 5-oxide OEt Sn(Bu) 3 S S 1. Pd(PPh 3

)

4

H

2 N NH 2 HBrN , HCI_ Br Br PdCl 2 (PPh 3

)

2 2. NBS/H 2 0 Dibenzothiophene-3,7-diamine 3,7-Dibromo-dibenzothiophene 3. Boc-L-Proline DIEA, DMF S O Br NH 4 OAc Bo Br N 0 \ Br xylenes N Boc 0 Pyrrolidine-1,2-dicarboxylic acid 2-[2- 2-[5-(7-Bromo-dibenzothiophen-3-yl) (7-bromo-dibenzothiophen-3-yl)-2-oxo- 1 H-imidazol-2-yl]-pyrrolidine-1 ethyl] ester 1-tert-butyl ester carboxylic acid tert-butyl ester I H Pd(PPh 3

)

4 H N N PdCI 2 (dppf) 2 SN N +e NBoc K 203, DME/H 2 0 BocN N Boc 3-[6-(4,4,5,5-Tetramethyl (1,3,2]dioxaborolan-2-yl)-1 H- 3-(6-{7-[2-(1 -tert-Butoxycarbonyl-pyrrolidin-2-yl) benzoimidazol-2-yl]-2-aza- 3H-imidazol-4-yl]-dibenzothiophen-3-yl-1 H bicyclo[2.2.1 ]heptane-2- benzoimidazol-2-yl)-2-aza-bicyclo[2.2. 1 ]heptane carboxylic acid tert-butyl ester 2-carboxylic acid tert-butyl ester 1. 4N HCVdioxane, DCM >-NH N 2. HATU, DIEA O

N

0 O 0- H HO O H0 H 0 O H (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl 2-Methoxycarbonylamino-3- butyryl)-2-aza-bicyclo[2.2. 1 ]hept-3-yl]-3H-benzoimidazol-5 methyl-butyric acid yl)-dibenzothiophen-3-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 Dibenzothiophene 5-oxide: A solution of mCPBA (8.27 g, 36.9 mmol) in 71 mL chloroform was added dropwise over 30 minutes to a solution of dibenzothiophene in 89 mL chloroform at 35'C. The reaction mixture was stirred at -35'C for 1 hour and then warmed up to room. The reaction was quenched with saturated sodium bicarbonate aqueous solution. The organic layer was washed with saturated sodium bicarbonate solution twice and dried over MgSO4, 628 concentrated down to give an off-white solid. The solid was dissolved in refluxing ethanol and slowly cooled to room temperature to give a white crystalline solid Dibenzothiophene 5-oxide (5.65g, 76%). LCMS-ESI-: calc'd for C 12

H

8 0S: 200.26; Found: 200.9 (M+H*). 5 3,7-Dinitro-dibenzothiophene 5-oxide: A solution of Dibenzothiophene 5-oxide (5.34g, 26.7 mmol) in concentrated sulfuric acid (120 mL) was cooled to 6*C. Nitric acid (108 mL) was added slowly so that the internal temperature stayed at I 0 0 C. The reaction was stirred at 1 0 0 C for 30 minutes then warmed up to room temperature over 30 minutes. The reaction mixture was poured into ice and formed precipitate. The precipitate was washed with water and dried to give 10 a yellow solid 3,7-Dinitro-dibenzothiophene 5-oxide (7.8 g, still containing some water and inorganic material). Dibenzothiophene-3,7-diamine: Two batches of the above solid 3,7-dinitro-dibenzothiophene 5-oxide was hydrogenated at 45 psi in ethanol (250 mL for each batch) with 10% Pd on carbon 15 (0.46 g each batch) for 2 hours. Two batches were combined and filtered through CELITE to give an orange solution. Hydrogen chloride gas was bubbled into the solution to form precipitate (at pH 1). The precipitate was filtered and washed with small amount of ethanol and dried on vacuum to give an orange solid Dibenzothiophene-3,7-diamine (2.46 g). LCMS-ESI~: calc'd for C 1 2 H ION 2 S: 214.29; Found: 215.0 (M+H*). 20 3,7-Dibromo-dibenzothiophene: A suspension of Dibenzothiophene-3,7-diamine (2.46 g, 8.57 mmol) in water (16 mL) and concentrated HCI (4.3 mL) was cooled to 5'C (internal temperature). A solution of sodium nitrite (1.54 g, 25.67 mmol) in water (5 mL) was added dropwise so that the internal temperature didn't exceed to 10 C. After I hour the reaction 25 mixture was poured into a solution of CuBr (1.8 g, 12.55 mmol) in 48% HBr (18 mL). The mixture was transferred into a I L 3 neck flask using water (100 mL) and refluxed for 2 hours. The reaction mixture was cooled down and poured into ice water mixture. Precipitate formed and collected by filtration, dried and purified by flash column chromatography (silica gel, 0 to 10% MeOH/ethyl acetate) to give a white solid 3,7-Dibromo-dibenzothiophene (1.6 g, 55%). 30 Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzothiophen-3-yl)-2-oxo-ethyl] ester 1-tert-butyl ester: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)(3%, 69 mg, 0.098 mmol) and tetrakis(triphenylphosphine)palladium (3%, 113 mg, 0.098 mmol) were added to the mixture of 35 3,7-Dibromo-dibenzothiophene (1.12 g, 3.27 mmol) and tributyl(l -ethoxyvinyl)tin (1.2 eq., 1.33 629 mL) in 25 mL dioxane. The reaction was heated to 80'C under Ar overnight. The reaction was cooled to room temprature. 8 mL water was added and followed by NBS (leq., 699 mg). The reaction was stirred at room for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), 5 concentrated down and dried on vacuum to give a residue which was used in next step. The residue was dissolved in 20 mL anhydrous DMF. Boc-L-Pro-OH (4 eq., 2.815 g) was added, followed by DIEA (3.5 eq., 1.60 mL) in 20 mL MeCN and 15 mL DMF dropwise. The reaction was stirred at room temperature overnight. The reaction crude was diluted with EtOAc 10 and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexane) to give Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzothiophen-3-yl) 2-oxo-ethyl] ester 1 -tert-butyl ester (593 mg, yield 33%) and bis product. LCMS-ESr: calc'd for C 24

H

24 BrNO 5 S: 518.42; Found: 541.9(M+Na+). 15 2-15-(7-Bromo-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert butyl ester: 10 mL Xylenes was added to the mixture of Pyrrolidine-1,2-dicarboxylic acid 2-[2 (7-bromo-dibenzothiophen-3-yl)-2-oxo-ethyl] ester I -tert-butyl ester (514 mg, 0.99 mmol) and ammonia acetate (20eq., 1.53 g). The mixture was heated in microwave at 140'C for 60 20 minutes. The mixture was diluted with EtOAc and washed with sat.NaHC03 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(7-Bromo-dibenzothiophen-3-yl)- I H-imidazol 2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (391 mg, yield 79%). LCMS-ESr: calc'd for C 24

H

24 BrN 3 0 2 S: 498.44; Found: 499.9(M+Na*). 25 3-(6-17-12-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-dibenzothiophen-3 yl}- 1 H-benzoimidazol-2-yI)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: A mixture of 2-[5-(7-Bromo-dibenzothiophen-3-yl)- IH-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (300 mg, 0.48 mmol, I eq.), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan 30 2-yl)-l H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2. I]heptane-2-carboxylic acid tert-butyl ester (1.1 eq., 530 mg), [1,1 '-bis(diphenylphosphino)ferrocenedichloropal ladium(l I)(3%, 12 mg), tetrakis(triphenylphosphine)palladium (3%, 17 mg) and 2N potassium carbonate aqueous solution (3.3 eq., 0.8 mL) in 2 mL DME was heated to 80'C under Argon for 5 hours. The reaction mixture was cooled and diluted in ethyl acetate and washed with saturated sodium 35 bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash 630 column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give a yellow foam 3 (6-{7-[2-(l -tert-Butoxycarbonyl-pyrrolidin-2-yl)-3 H-imidazol-4-yl]-dibenzothiophen-3-yl}-I H benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (245 mg, yield 70%). LCMS-ESI~: calc'd for C 42

H

46

N

6 0 4 S: 730.92; Found: 731.2(M+H*). 5 (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3 yl]-3H-benzoimidazol-5-yI}-dibenzothiophen-3-y)-1H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DE): 4N HCI in dioxane (3 mL) was added to 3-(6-{7-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl] 10 dibenzothiophen-3-yl} -l H-benzoimidazol-2-yl)-2-aza-bicyclo [2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (141 mg, 0.194 mmol) in 3 mL DCM. The reaction mixture was stirred at room temperature for I hour. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (4 mL) and to this solution was added 2 Methoxycarbonylamino-3-methyl-butyric acid (2.08 eq., 71 mg), 4-methylmorpholine (6 eq., 15 0.12 mL), followed by HATU (2.04 eq., 150 mg). Reaction mixture was stirred at 0 0 C for 30 minutes. The reaction mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 20% MeOH/ethyl acetate), followed by preparative reverse phase H PLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to 20 give (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2. I ]hept 3-yl]-3 H-benzoimidazol-5-yl}-dibenzothiophen-3-yl)- I H-imidazol-2-yl]-pyrrolidine-I carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DE) (121 mg, 59%). ' H-NMR: 300 MHz, (DMSO-d 6 ) 8: 8.60-8.40 (m, 4H), 8.16(m, I H), 8.01 (m, I H), 7.90(m, 2H), 7.76(m, lI H), 7.33 (m, 2H), 5.15(m, I H), 4.76(m,l H), 4.56(d, I H), 4.22-4.08(m, 3H), 25 3.85(m, 2H), 3.55 (d, 6H), 2.76(m,I H), 2.30-1.50 (m, 9H), 0.96-0.75 (m, 12 H). ' 9 F-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: -112.88. LCMS-ESl*: calc'd for C 4 6

H

52

N

8 0 6 S: 845.02; Found: 845.4 (M+H*). 631 Example DF OEt 0 - Sn(Bu) 3 O ~ Br O--~- 0 0 Boc CN 3- r2. NBS/H 2 0 B 0 0 6 Boc 0 Boc O Pyrrolidine-1,2-dicarboxylic acid 2-[2- 3. DIEA, DMF 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid (7-bromo-dibenzothiophen-3-yl)-2- 3.-(2-{7-[2-(1 -tert-butoxycarbonyl-pyrrolidine-2 oxo-ethyl] ester 1-tert-butyl ester H carbonyloxy)-acetyl]-dibenzothiophen-3-y}-2-oxo HOOC ethyl) ester 2-tert-butyl ester Boc 2-Aza-bicyclo[2.2.1]heptane 2,3-dicarboxylic acd 2-tert butyl ester H H S H 1. 4N HCI/dioxane, DCM

NH

4 OAc BoN xylenes BoN N o/c 2. HATU, 4-methylmorpholine H H- 3-(5-{7-[2-(1 -tert-Butoxycarbonyl-pyrrolidin-2-yl)- 0 H O 3H-imidazol-4-yI]-dibenzothiophen-3-yl}-1 H imidazol-2-yl)-2-aza-bicyclo[2.2. 1]heptane-2- 2-Methoxycarbonylamino carboxylic acid tert-butyl ester propionic acid 0 O N N O* H N (2-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-dibenzothiophen-3-yl)-1H-imidazol 2-yI]-pyrrolidin-1-yl-l-methyl-2-oxo-ethyl)-carbamic acid methyl ester 5 2-Aza-bicyclol2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl pyrrolidine-2-carbonyloxy)-acetyl]-dibenzothiophen-3-yl]-2-oxo-ethyl) ester 2-tert-butyl ester: [1,1 '-Bis(triphenylphosphine) dichloropal ladium(1I)(3%, 14 mg, 0.02 mmol) and tetrakis(triphenylphosphine)palladium (3%, 23 mg, 0.02 mmol) were added to the mixture of 10 Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzothiophen-3-yl)-2-oxo-ethyl] ester 1 tert-butyl ester (345 mg, 0.665 mmol) and tributyl(I -ethoxyvinyl)tin (1.2 eq., 0.269 mL) in 5 mL dioxane. The reaction was heated to 80*C under Are for 4 hours. The reaction was cooled to room temperature. 1.5 mL water was added and followed by NBS (Ieq., 142 mg). The reaction was stirred at room for I hour. The reaction mixture was diluted with ethyl acetate and 15 washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated down and dried on vacuum to give residue which was used in next step. 632 The residue was dissolved in 4 mL anhydrous DMF. 2-Aza-bicyclo[2.2. I heptane-2,3 dicarboxylic acid 2-tert-butyl ester (2 eq., 321 mg, 1.33 mmol g) was added, followed by TEA (2.2 eq., 204 mg) in 4 mL MeCN and 3 mL DMF dropwise. The reaction was stirred at room temperature overnight. The reaction crude was diluted with EtOAc and washed with saturated 5 sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexane) to give 2-Aza bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(I-tert-butoxycarbony-pyrrolidine-2 carbonyloxy)-acetyl]-dibenzothiophen-3-yl]-2-oxo-ethyl) ester 2-tert-butyl ester as a yellow residue (92.5 mg, yield 19%). LCMS-ESI~: calc'd for C 38

H

44

N

2 0 1 0 S: 720.83; Found: 743.2 10 (M+Na'). 3-(5-{7-12-(I-tert-Butoxycarbonyl-pyrrolidin-2-yI)-3H-imidazol-4-yl]-dibenzothiophen-3 yl}-1H-imidazol-2-yI)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: 3 mL Xylenes was added to 2-Aza-bicyclo[2.2.l ]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(] -tert 15 butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzothiophen-3-yl]-2-oxo-ethyl) ester 2 tert-butyl ester (92.5 mg, 0.128 mmol) and ammonia acetate (20eq., 198 mg). The mixture was heated in microwave at 140'C for 60 minutes. The mixture was diluted with EtOAc and washed with sat.NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 3-(5-{7-[2-(l 20 tert-Butoxycarbonyl-pyrrolidin-2-yI)-3 H-im idazol-4-yl]-dibenzothiophen-3-yl}- I H-imidazol-2 yl)-2-aza-bicyclo[2.2.lheptane-2-carboxylic acid tert-butyl ester (62 mg, yield 71%). LCMS ESI~: calc'd for C 3 8

H

44

N

6 0 4 S: 680.86; Found: 681.2 (M+H*). (2-{2-[5-(7-{2-12-(2-Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H 25 imidazol-4-yI)-dibenzothiophen-3-yI)-1H-imidazol-2-yl]-pyrrolidin-1-yI}-1-methyl-2-oxo ethyl)-carbamic acid methyl ester (Example DF): 4N HCI in dioxane (I mL) was added to 3 (5-{7-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-y]-dibenzothiophen-3-y}-I

H

imidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (62 mg, 0.091 mmol) in 2 mL DCM. The reaction mixture was stirred at room temperature for 1 hour. The 30 reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (2 mL) and to this solution was added 2-Methoxycarbonylamino-propionic acid (2.08 eq., 28 mg), 4-methylmorpholine (6 eq., 0.06 mL), followed by HATU (2.04 eq., 71 mg). Reaction mixture was stirred at 0 0 C for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was 35 dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 20% 633 MeOH/ethyl acetate), followed by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/-1 2 0 + 0.1% TFA). Product was lyophilized to give (2-{2-[5-(7-{2-[2-(2 Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2. I ]hept-3-yl]-3H-imidazol-4-yl} dibenzothiophen-3-yl)- IH-imidazol-2-yI]-pyrrolidin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid 5 methyl ester (Example DF) (52.7 mg, 60%). 1 H-NMR: 300 MHz, (DMSO-d 6 ) 6: 8.60-8.40 (m, 4H), 8.12(m, 2H), 8.01 (m, I H), 7.92(m, 2H), 7.57-7.40 (m, 2H), 5.15(m, I H), 4.70 (m,I H), 4.50-4.30(m, 3H), 3.54 (d, 6H), 2.76(m,I H), 2.42-1.50 (m, 6H), 1.30 -1.10 (m, 12 H). LCMS-ESI*: calc'd for C 4 2

H

4 4

N

8 0 6 S: 738.86; Found: 739.3 (M+H*). 10 Example DG Hi ISN / N B1. 4N HCI/dioxane, DCM Boc N N Boc N NH 2. HATU, DIEA U HO 3-(6-{7-[2-(1 -terf-Butoxycarbonyl-pyrrolidin-2-yl)- HO N 3H-imidazol-4-yl]-d ibenzothiophen-3-yl}-1 H- O H 0 benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane- 2-Methoxycarbonylamino 2-carboxylic acid tert-butyl ester propionic acid 0 O N N N N -' ' H 0 (2-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza bicyclo[2.2. 1 ]hept-3-yI]-3H-benzoimidazol-5-yl}-dibenzothiophen-3-yl)-1 H imidazol-2-yl]-pyrrolidin-1-yl}-l-methyl-2-oxo-ethyl)-carbamic acid methyl ester 15 (2-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H benzoimidazol-5-yI}-dibenzothiophen-3-y)-1H-imidazol-2-yl]-pyrrolidin-1-yl}-1-methyl-2 oxo-ethyl)-carbamic acid methyl ester (Example DG): 4N HCI in dioxane (2 mL) was added to 3-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-dibenzothiophen-3 yl}- 1 H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (103 20 mg, 0.141 mmol) in 3 mL DCM. The reaction mixture was stirred at room temperature for I hour. The reaction mixture was concentrated and dried overnight under vacuum. The residue 634 was dissolved in DMF (2 mL) and to this solution was added 2-Methoxycarbonylamino propionic acid (2.08 eq., 43 mg), 4-methylmorpholine (6 eq., 0.093 mL), followed by HATU (2.04 eq., 109 mg). Reaction mixture was stirred at 0*C for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The 5 organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 20% MeOH/ethyl acetate), followed by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (2-{2-[5-(7-{2 [2-(2-Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3H-benzoimidazol-5 yl}-dibenzothiophen-3-yl)-l H-imidazol-2-yl]-pyrrolidin-I -yl}- I -methyl-2-oxo-ethyl)-carbamic 10 acid methyl ester (Example DG) (91.3 mg, 80%). ' H-NMR: 300 M4Hz, (DMSO-d 6 ) 8: 8.60-8.52 (m, 2H), 8.44(m, 2H), 8.15 (m, I H), 8.05(m, I H), 7.92 (m, 21-1), 7.80 (m, 2H), 7.56-7.42(m, 2H), 5.15(m, I H), 4.70 (m,l H), 4.50-4.30(m, 3H), 3.54 (d, 6H), 2.76(m,l H), 2.42-1.50 (m, 12H), 1.30 -1.10 (m, 6 H). LCMS-ESI*: calc'd for C 42

H

44

N

8 0 6 S: 788.91; Found: 789.4 (M+H*). 15 635 Example DH +HATU, DIEA N Br + HOOC DMF 00 N 0 -< NH 2 Bac - Boc 2-Amino-1-(4-bromo- 5-Aza-spiro[2.4]heptane- 6-[2-(4-Bromo-phenyI)-2-oxo phenyl)-ethanone 5,6-dicarboxylic acid 5- ethylcarbamoyll-5-aza-spiro[2.4]heptane tert-butyl ester 5-carboxylic add tert-butyl ester H H No , Br +Bo

NH

4 0AC NH % B ziB\&6/N Bac 3-{6-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) phenyl]-1H-benzoimidazol-2-yl)-2-aza 6-[5-(4-Bromo-pheny)-1 H-imidazol- bicyclo[2.2.1]heptane-2-carboxylic acid tert-buLyl ester 2-yI]-5-aza-spiro[2.4]heptane-5 carboxylic acid tert-butyl ester N N Pd(PPh 3

)

4 BocN N Boc 1. 4N HC/dioxane, DCM PdCI 2 (dPpt 2 11 /k .4 Cdoae C

K

2 Co0, OME/H 2 0 2. HATU, DIEA 90 *C - - 3-(6-{4'-[2-(5-tert-Butoxycarbonyl-5-aza- HO or spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-biphenyl-4-yl)- 0 1 H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2. 1]heptane- 2-Methoxycarbonylamino-3 2-carboxylic acid tert-butyl ester methyl-butyric acid O N O ON 0 kN N H 0 (1 -{6-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl butyryl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3H-benzoimidazol-5 yl)-biphenyl-4-yl)-1 H-imidazol-2-yl]-5-aza-spiro[2.4]heptane 5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 6-12-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyll-5-aza-spiro[2.41heptane-5-carboxylic acid 5 tert-butyl ester: 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-tert-butyl ester (350 mg, 1.45 mmol) was mixed with HATU (551 mg, 1.45 mmol) in DMF (5 mL) and the mixture was stirred at room temperature for 30 minutes. 2-Amino-l-(4-bromo-phenyl)-ethanone bis HCI salt (416 mg, 1.45 mmol) in 2 mL DMF was added, followed by DIEA (3.5 eq., 0.88 mL) dropwise at 0 0 C. The reaction was stirred at 0CC for 40 minutes. The reaction mixture was diluted in ethyl 10 acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 67%). LCMS-ESI-: calc'd for

C

2 0

H

2 5 BrN 2 0 4 : 437.33; Found: 460.1 (M+Na'). 636 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-ylI-5-aza-spiro[2.4]heptane-5-carboxylic acid tert butyl ester: 15 mL Xylenes was added to 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5 aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 0.97 mmol) and ammonium 5 acetate (20eq., 1.5 g). The mixture was heated in microwave at 140'C for 60 minutes. The mixture was diluted with EtOAc and washed with sat.NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 6-[5-(4-Bromo-phenyl)-I H-imidazol-2-yl]-5-aza spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (249 mg, yield 61%). LCMS-ESI~: calc'd 10 forC 2 0

H

24 BrN 3 0 2 : 418.33; Found: 418. (M+H*). 3-(6-{4'-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-y]-biphenyl-4 yl}-lH-benzoimidazol-2-yI)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: A mixture of 6-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic 15 acid tert-butyl ester (101 mg, 0.243 mmol, I eq.), 3-{6-[4-(4,4,5,5-Tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-I H-benzoimidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2 carboxylic acid tert-butyl ester (150 mg, 0.291 mmol, 1.2 eq.), tetrakis(triphenylphosphine)palladium (5%, 17 mg) and 2M potassium carbonate aqueous solution (5 eq., 0.73 mL) in 1.5 mL DME was heated to 90*C under Are overnight. The reaction 20 mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexane) to give 3-(6-{4'-[2-(5-tert Butoxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3 H-imidazol-4-yl]-biphenyl-4-yl}-1 H benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (53 mg, yield 25 26%). LCMS-ESI~: calc'd for C 44

H

5

N

6 0 4 : 726.91; Found: 727.2 (M+H*). (1-{6-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1ihept-3 yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yI)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DH): 4N HCI in dioxane 30 (2 mL)was added to 3-(6-{4'-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol 4-yl]-biphenyl-4-yl}-1 H-benzoimidazol-2-y)-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (53 mg, 0.073 mmol) in 2 mL DCM and the reaction mixture was stirred at room temperature for 2hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (1 mL) and to this solution was added 2 35 Methoxycarbonylamino-3-methyl-butyric acid (2.1 eq., 26.6 mg), 4-methylmorpholine (6 eq., 637 0.048 mL), followed by HATU (2 eq., 56 mg). Reaction mixture was stirred at 0 0 C for 50 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was 5 lyophilized to give (1-{6-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.l]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-I H-imidazol-2-yl]-5-aza spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DH) (41.6 mg, 53%). ' H-NMR: 300 MHz, (DMSO-d 6 ) 5: 8.13 (s, I H), 7.95-7.80 (m, 9H), 7.69 (m, 2H), 7.40-7.24 10 (m, 2H), 5.25 (m, I H), 4.76(m, I H), 4.55(m,1 H), 4.20-3.80 (m, 3H), 3.55(d, 6H), 2.74 (m, 2H), 2.40-1.55 (m, 10 H), 0.95-0.65 (m, 12 H). LCMS-ESI*: calc'd for C 46

H

54

N

8 0 6 : 841.01; Found: 841.5 (M+H*). Example DI 15 Br /

/NH

4 0Ac ' BH xylenes B o N microwave 140 *C Boc 90 min. 2-[5-(7-Bromo-9,10-dihydro-phenanthren Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7- 2-yl)-1H-imidazol-2-yl]-pyrrolidine-1 bromo-9,10-dihydro-phenanthren-2-yl)-2- carboxylic acid tert-butyl ester oxo-ethyl] ester 1 -tert-butyl ester HH N N SBoc Pd(PPh 3 )K2CO3 Boc N C H 2-[6-(4,4,5,5-Tetramethyl [1,3,2]dioxaborolan-2-yl)-1H- 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl] benzoimidazol-2-yl]-pyrrolidine-1- 9,10-dihydro-phenanthren-2-y}-1H-imidazol-2-yl) carboxylic acid tert-butyl ester pyrrolidine-1-carboxylic acid tert-butyi ester 1. 4N HCl/dioxane, DCM 0 H ___________ N N 2. HATU, DIEA O NNO O O . 0- \/ \I N N H" 0 HO 2-Methoxycarbonylamino-3- (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 methyl-butyric acid yU-3H-benzoimidazol-5-yl)-9, 10-dihydro-phenanthren-2-y)-1 H-imidazol-2 yi]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yi)-1H-imidazol-2-yI]-pyrrolidine-1-carboxylic acid tert-butyl ester: 10 mL Xylenes and 10 ml DME were added to the mixture of pyrrolidine 20 1,2-dicarboxyl ic acid 2-[2-(7-bromo-9, I 0-dihydro-phenanthren-2-yl)-2-oxo-ethyl] ester I -tert 638 butyl ester (480 mg, 0.935 mmol) and ammonia acetate (20eq., 1.44 g). The mixture was heated in microwave at 140*C for 90 minutes. The mixture was diluted with EtOAc and washed with sat.NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(7-bromo-9,10 5 dihydro-phenanthren-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (246 mg, yield 53%). LCMS-ESI-: calc'd for C 26

H

2 sBrN 3 0 2 : 494.42; Found: 495.5 (M+H*). 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-9,10-dihydro-phenanthren-2 yI}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-[5-(7 10 bromo-9,1 0-dihydro-phenanthren-2-yl)-l H-imidazol-2-yl]-pyrrolidine-I-carboxylic acid tert butyl ester (246 mg, 0.497 mmol), 2-[6-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-I H benzoimidazol-2-yi]-pyrrolidine-l -carboxylic acid tert-butyl ester (I eq., 206 mg), [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(Il)(5%, 20 mg), tetrakis(triphenylphosphine)palladium (5%, 29 mg) and potassium acetate (2 eq., 137 mg) in 5 15 mL DME and I mL water was heated to 80*C for 100 minutes. The reaction mixture was cooled and diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H benzoimidazol-5-yl]-9,1 0-dihydro-phenanthren-2-yl}- I H-imidazol-2-yl)-pyrrolidine- 1 20 carboxylic acid tert-butyl ester (220 mg, yield 63%). LCMS-ESI-: calc'd for C 4 2

H

4 8

N

6 0 4 : 700.87; Found: 701.LI(M+H*). (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yl}-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yI]-pyrrolidine-1 25 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example A): 4N HCI in dioxane (2 mL)was added to 2-(5-{7-[2-(l -Boc-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-9, 1 0-dihydro phenanthren-2-yl}- I H-imidazol-2-yl)-pyrrolidine- I -carboxylic acid tert-butyl ester (220 mg, 0.314 mmol) in I mL DCM and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue 30 was dissolved in DMF (3 mL) and to this solution was added 2-Methoxycarbonylamino-3 methyl-butyric acid (2.1 eq., 16 mg), diisopropyl ethylamine (5 eq., 270 pL), followed by HATU (2 eq., 239 mg). Reaction mixture was stirred at 0 0 C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC 35 (GEMINI, 5 to 100% ACN/-1 2 0 + 0.1% TFA). Product was lyophilized to give (1-{2-[5-(7-{2 639 [I -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-benzoimidazol-5-y}-9,10 dihydro-phenanthren-2-yl)- I H-imidazol-2-yl]-pyrrolidine- 1 -carbonyl}-2-methyl-propyl) carbamic acid methyl ester (Example DI) (115 mg, 45%). 1 H-NMR: 300 MHz, (CD 3 0D-d 4 ) 6: 8.02-7.95 (m, 3H), 7.95-7.80 (m, 3H), 7.66-7.62 (m, 4H), 5 5.40-5.23(m, 2H), 4.22(m, 2H), 4.16(m,2H), 3.96-3.82 (m, 2H), 3.62 (s, 6H), 3.00(s, 4H), 2.60 (m, 2H), 2.40-2.18 (m, 6H), 2.08(m, 2H), 0.95-0.85 (m, 12 H). LCMS-ESI*: calc'd for C 4 6

H

4

N

8 0 6 : 814.97; Found: 815.4 (M+H*). Example DJ QEt IDeoxofluor, F F 1. n(Buh) 3 F - - drops of EtOH P.P2(PPh 3 )2 B Br B BN - BS n(u)3 0 B 90 OC2dr \ j r0 \/~ / B 2,7-DObromo 2. NBSIH 2 O 2,7-Dibromo- 2,7-Dibromo-9,9- Boc O fluoren-9-one difluoro-9H-fluorene 3. Bo -Prone Pyrrolidine-1,2-dicarboxylic acid 2-[2 (7-bromo-9,9-difluoro-9H-fluoren-2-yl) 2-oxo-ethyl] ester 1-tert-butyl ester

NH

4 Ac Boc N \ Br . O, Boc ___ ___ / -N Xylenes, microwave ( O 140 oC, 90min \ 2- 5-(7-Bromo-9,9-difluoro-9H-fluoren-2- 2-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan yl)-H-mao-2-l-pyrro-9Hfldnen2- 2-yl)-1H-benzoimidazol-2-y]-pyrrolidine-1 yl-H-imidazol-2-yI].pyrrolidine-1- carboxylic acid tert-butyl ester carboxylic acid tert-butyl ester FF Pd(PPh 3

)

4 N N PdCl 2 (dppf) 2 Boc N N Boc

K

2

CO

3 , DME/H 2 0 NH 90 *C 2-(5-{9,9-Difluoro-7-[2-(1 -Boc-pyrrolidin-2-yl)-3H benzoimidazol-5-yl]-9H-fluoren-2-yl)-1 H-imidazol-2 yl)-pyrrolidine-1-carboxylic acid tert-butyl ester 1. TFA - N' \ N 2HATU, DIEA N N HO O H N O 6 H 00 ~f 2-Methoxycarbonylamino-3- (1 -{2-5-(9,9-Difluoro-7-2-[1-(2-methoxycarbonylamino methyl-butyric acid 3-methyl-butyryl)-pyrrolidin-2-yl]-3H-benzoimidazol-5 yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyn-olidine-1 10 carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 640 2,7-Dibromo-9,9-difluoro-9H-fluorene: Deoxofluor (bis(2-methoxyethyl)aminosulfur trifluoride, 12 mL) was added to 2,7-dibromo-fluoren-9-one (3 grams, 8.87 mmol), followed by 2 drops of ethanol. The reaction mixture was heated to 90'C. The reaction progress was monitored by analytical HPLC and TLC (in pure hexane). The product is more non-polar than 5 the starting material. The reaction was complete after 2 days. The reaction mixture was cooled down, poured into ice water and neutralized by saturated sodium bicarbonate solution, then was extracted using ethyl acetate and washed with saturated sodium bicarbonate solution twice. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexane) give product 2,7-dibromo-9,9-difluoro-9H-fluorene 10 (3.1 gram, yield 97%). ' H-NMR: 300 MHz, (CDCl 3 ) 6: 7.76 (s, 2H), 7.62 (d, 2H), 7.42 (d, 2H). F-NMR: 300 MHz,

(CDC

3 ) 6: -111.57. Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-y)-2-oxo-ethyl] 15 ester 1-tert-butyl ester: [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropal ladium(l 1)(5%, 82 mg) and tetrakis(triphenylphosphine)palladium (5%, 115 mg) were added to the mixture of 2,7 dibromo-9,9-difluoro-9H-fluorene (720 mg, 3 mmol) and tributyl(1 -ethoxyvinyl)tin (I eq., 0.677 mL) in 12 mL dioxane. The reaction was heated to 70'C under Argon for 4 hours. The reaction was cooled to room temprature. 3 mL water was added and followed by NBS (Ieq., 356 mg). 20 The reaction was stirred at room temprature overnight. The reaction mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated down. The residue was dissolved in 15 mL anhydrous DMF. Boc-L Pro-OH (4 eq., 1.72 g) was added, followed by DIEA (3.5 eq., 1.22 mL) in 5 mL MeCN and 5 mL DMF dropwise. The reaction was stirred at room temperature for 3 hours. The reaction 25 crude was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give pyrrolidine- 1,2-dicarboxylic acid 2-[2-(7-bromo 9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl] ester 1 -tert-butyl ester (363 mg, yield 34%). LCMS ESI~: calc'd for C 25

H

2 4 BrF 2

NO

5 : 536.36; Found: 560.0(M+Na t ), 535.9 (M-H). 30 641 2- [5-(7-Bromo-9,9-d ifluoro-9H-fluoren-2-yi)- 1 H-imidazol-2-yli -pyrrolidine- 1 -carboxylic acid tert-butyl ester: 10 mL Xylenes was added to the mixture of pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl] ester I -tert-butyl ester (363 mg, 0.677 mmol) and ammonia acetate (20eq., 1.04 g). The mixture was heated in microwave at 5 140'C for 90 minutes. The mixture was diluted with EtOAc and washed with sat.NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(7-Bromo-9,9-difluoro 9H-fluoren-2-yl)-l H-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (324 mg, yield 81%). LCMS-ESI~: calc'd for C 2 5

H

2 4 BrF 2

N

3 0 2 : 516.38; Found: 517.9 (M+H*). 10 2-(5-{9,9-Difluoro-7-12-(1-Boc-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl} 1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-[5-(7 Bromo-9,9-difluoro-9H-fluoren-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (137 mg, 0.265 mmol), 2-[6-(4,4,5,5-Tetramethyl-[ I,3,2]dioxaborolan-2-yl)- I H 15 benzoimidazol-2-yl]-pyrrolidine-I-carboxylic acid tert-butyl ester (1 eq., 10 mg), [1,1' bis(diphenylphosphino)ferrocene]dichloropal ladium(l l)(5%, 11 mg), tetrakis(triphenylphosphine)palladium (5%, 16 mg) and potassium carbonate (2 eq., 73 mg) in 4 mL DME and 2 mL water was heated to 90'C for 2 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic 20 layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{9,9-Difluoro-7-[2-(I -Boc-pyrrolidin-2-yl)-3H benzoimidazol-5-y]-9H-fluoren-2-yl}-I H-imidazol-2-yl)-pyrrolidine-I -carboxylic acid tert butyl ester (83 mg, yield 43%). LCMS-ESI~: calc'd for C 4 jH 4 4

F

2

N

6 0 4 : 722.82; Found: 723.1 (M+H*). 25 (I -{2-15-(9,9-Difluoro-7-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-I H-imidazol-2-yi]-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (Example DJ): TFA (2 mL)was added to 2-(5 {9,9-Difluoro-7-[2-(I -Boc-pyrrolidin-2-yl)-3 H-benzoimidazol-5-yl]-9H-fluoren-2-yl}- I H 30 imidazol-2-yl)-pyrrolidine-I-carboxylic acid tert-butyl ester (83 mg, 0.115 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (3 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (2 eq., 40 mg), diisopropyl ethylamine (6 eq., 120 pL), followed by HATU (2 eq., 88 mg). Reaction mixture 35 was stirred at 0 0 C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and 642 washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (1-{2-[5-(9,9-Difluoro-7-{2-[I-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-benzoimidazol-5-yl}-9H 5 fluoren-2-yI)- IH-imidazol-2-yl]-pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DJ) (37 mg, 39%). 'H-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: 8.05-7.82 (m, 9H), 5.40-5.22(m, 2H), 4.22(m, 2H), 4.16(m,2H), 4.00-3.82 (m, 2H), 3.62 (s, 6H), 2.60 (m, 2H), 2.42-2.18 (m, 6H), 2.08(m, 2H), 0.95-0.85 (m, 12 H). ' 9 F-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: -112.88. LCMS-ESI*: calc'd for 10 C 4 5

H

50

F

2

N

8 0 6 : 836.93; Found: 837.3 (M+H*). Example DK F F Pd(PPh 3

)

4 N %CPdCI 2 (dPpf 2 Boc N Br + oc K 2

C

3 , DME/H 2 0 N I NH - A /90 O0 2-[5(7-rom-9,-diluoo-9-flore-2-3-[6-(4,4,5,5-Tetramethyl 2l)- H-(midazol-2-I]-pyrroenuoren-2- 13,2]dioxaborolan-2-yl)- H-benzoimidazol carboxylc acid tert-butyl ester 2-yl]-2-aza-bicyclo[2.2.1]heptane-2 carboxylic acid tert-butyl ester FF P 1. HCI BocN N Boc 2.HATU DIEA N NH H-0 HO O 2-(5-{9,9-Difluoro-7-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3- H yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2- 2-Methoxycarbonylamino-3 yl)-pyrrolidine-1-carboxylic acid tert-butyl ester methyl-butyric acid *'-0 HH N . 00 C -H H. N O 1 O (1-{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3 methyl-butyryl)-2-aza-bicyclo[2.2. 1 ]hept-3-yl]-3H-benzoimidazol 5-yl}-9H-fluoren-2-yl)-1 H-imidazol-2-yl]-pyrrofidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester 2-(5-{9,9-Difluoro-7-[2-(2-Boc-2-aza-bicyclo 12.2.11 hept-3-yI)-3H-benzoimidazol-5-ylI -9H 15 fluoren-2-yl)-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (324 mg, 0.627 mmol), 3-[6-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)- 1 H 643 benzoimidazol-2-yl]-2-aza-bicyclo[2.2. I 1heptane-2-carboxylic acid tert-butyl ester (1 .1 eq., 304 mg), [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(I1)(3%, 15 mg), tetrakis(triphenylphosphine)palladium (3%, 22 mg) and potassium carbonate (3.3 eq., 285 mg) in 10 mL DME and 3 mL water was heated to 90*C under Argon for 3 hours. The reaction 5 mixture was cooled and diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{9,9-Difluoro-7-[2-(2 Boc-2-aza-bicyclo[2.2. I ]hept-3-yl)-3 H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-I H-imidazol-2 yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (361 mg, yield 77%). LCMS-ESr: calc'd for 10 C 4 3

H

4 6

F

2

N

6 0 4 : 748.86; Found: 749.2(M+H*). (1-{2-15-(9,9-Difluoro-7-{2-12-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yI)-9H-fluoren-2-yl)-lH-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DK): 4N 15 HCI in dioxane (2 mL) was added to 2-(5-{9,9-Difluoro-7-[2-(2-Boc-2-aza-bicyclo[2.2.l]hept 3-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-I H-imidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (361 mg, 0.482 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (5 mL) and to this solution was added 2 20 Methoxycarbonylamino-3-methyl-butyric acid (2 eq., 169 mg), diisopropyl ethylamine (6 eq., 0.5 mL), followed by HATU (2 eq., 367 mg). Reaction mixture was stirred at 0*C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 20% MeOH/ethyl acetate), followed by preparative 25 reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (I -{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2. I ]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-I H-imidazol-2-yl] pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (285 mg, 59%). ' H-NMR: 300 MHz, (CD 3 0D-d 4 ) 5: 8.05-7.82 (m, 9H), 5.40-5.22(m, 2H), 4.72(m, I H), 4.39(d, 30 1 H), 4.239d, I H), 4.17(m, I H), 3.91(m, 2H), 3.62 (d, 6H), 2.98(m, I H), 2.58 (m, I H), 2.37-2.18 (m, 4H), 2.18-l.92(m, 4H), 1.80(m, 2H), 1.09-0.85 (m, 12 H). ' 9 F-NMR: 300 MHz, (CD 3 0D d 4 ) 6: -112.88. LCMS-ESl*: calc'd for C 4 7

H

52

F

2

N

8 0 6 862.96; Found: 863.5 (M+H*). 644 Example DL ' H ~ F FHZ 0 - N NUV light N, \\/TFA, MeCN/water N NL nQ/ H H, N O s1 0 (1 -{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3 methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol 5-yl}-9H-fluoren-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 -carbonyl)-2 methyl-propyl)-carbamic acid methyl ester H H.N O -O 0 N N N 0. 0 (1 -{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.1 ]hept-3-yl]-3H-benzoimidazol-5-yl}-9-oxo-9H-filuoren-2-yl)- 1 H imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1 -{2- [5-(7-{2- [2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo 12.2.11 hept-3 yl]-3H-benzoimidazol-5-yl}-9-oxo-9H-fluoren-2-y)-1H-imidazol-2-yl]-pyrrolidine-1 5 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DL): (1-{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2. I]hept-3-yl]-3 H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-I H-imidazol-2-yl] pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (10 mg) is dissolve in MeCN (ImL) and water (I mL). I drop of TFA was added. The mixture was treated with long 10 wavelengh UV light at room temprature for 2 hours. The reaction crude was concentrated down and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give (I - {2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl) 2-aza-bicyclo[2.2.1 ]hept-3-yl]-3 H-benzoimidazol-5-yl}-9-oxo-9H-fluoren-2-yl)-I H-imidazol-2 yl]-pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DL) (3.7 15 mg). H-NM R: 300 MHz, (CD 3 0D-d 4 ) 8: 8.05-7.82 (m, 9H), 5.27(m, 2H), 4.72 (m, I H), 4.37(d,I H), 4.23(d, I H), 4.19(m, I H), 3.91(m, 2H), 3.62 (d, 6H), 2.98(m,I H), 2.58 (m, 2H), 2.37-2.18 (m, 4H), 2.18-l.92(m, 4H), 1.80(m, 2H), 1.09-0.85 (m, 12 H). LCMS-ESI*: calc'd for

C

47

H

52

F

2

N

8 0 6 840.97; Found: 841.6 (M+H*). 20 645 Example DM Oc N\ - Pd(PPh 3

)

4 BBr +B O PdC(pf) 2 H o

K

2 C0 3 , DME/H2 2-[5-(4-Bromo-phenyl)-1H- 110 0 C imidazol-2-ylj-pyrrolidine-1- Naphthalene-2,6-diboronic carboxylic acid tert-butyl ester acid dipinocal ester I H.J 3-(6-Bromo-1H N N benzoimidazol-2-yl)-2-aza N II oc bicyclo[2.2.1]heptane-2 Bo Br - N carboxylic acid tert-butyl N, N B ester H - 0\ Pd(PPh 3

)

4

K

2 C0 3 , DME/H 2 0 2-(5-{4-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan- PdCl 2 (dppf) 2 110 *C 2-yl)-naphthalen-2-yll-phenyl)-1 H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester Boc N 1 1. TFA D E H - 0 3-[6-(6-(4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}- N naphthalen-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic o H 0 acid tert-butyl ester 2-Methoxycarbonylamino-3 methyl-butyric acid ~-0 o_ N,H Q~NN N NN \ HH 0 [1 -(3-{6-{6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl phenyl)-naphthalen-2-yl}-1 H-benzoimidazol-2-yI}-2-aza-bicyclo[2.2. 1]heptane-2-carbonyl)-2-methyl propyll-carbamic acid methyl ester 2-(5-{4-[6-(4,4,5,5-Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-naphthalen-2-y]-phenyl}-1 H 5 imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-[5-(4-Bromo phenyl)-I H-imidazol-2-yl]-pyrrolidine-1 -carboxylic acid tert-butyl ester (1.079g, 2.737 mmol), Naphthalene-2,6-diboronic acid dominical ester (5 eq., 5.2 g, 13.68 mmol), [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(lI)(5%, 96 mg), tetrakis(triphenylphosphine)palladium (5%, 158 mg) and potassium carbonate (5 eq., 757 mg) in 10 40 mL DME and 10 mL water was heated to I 10*C under Argon for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{4-[6-(4,4,5,5 Tetramethyl-[I,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-phenyl}-I H-imidazol-2-yl)-pyrrolidine 15 1 -carboxylic acid tert-butyl ester (730 mg, yield 47%). LCMS-ESr~: calc'd for C 3 4

H

40

BN

3 0 4 : 565.51; Found: 566.1 (M+H*). 646 3-16-(6-{4-12-(1 -tert-Butoxycarbonyl-pyrrolidin-2-y)-3H-imidazol-4-y]-phenyl} naphthalen-2-yI)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: A mixture of 2-(5-{4-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) 5 naphthalen-2-yl]-phenyl}-l H-imidazol-2-yl)-pyrrolidine-I-carboxylic acid tert-butyl ester (216 mg, 0.382 mmol), 3-(6-Bromo- 1 H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane-2 carboxylic acid tert-butyl ester (I eq., 150 mg, 0.382 mmol), [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(II)(5%, 16 mg), tetrakis(triphenylphosphine)palladium (5%, 22 mg) and potassium carbonate (2 eq., 106 mg) in 10 4 mL DME and I mL water was heated to 90'C under Argon for 5 hours. The reaction mixture was cooled and diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 3-[6-(6-{4-[2-(l-tert-Butoxycarbonyl pyrrolidin-2-yl)-3 H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-I H-benzoimidazol-2-yl]-2-aza 15 bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (100 mg, yield 35%). LCMS-ESI-: calc'd for C 46 HsoN 6 0 4 : 750.93; Found: 751.2 (M+H*). [1-(3-{6-16-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-benzoimidazol-2-yl}-2-aza 20 bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example DM): TFA (2 mL) was added to 3-[6-(6-{4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1 H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane 2-carboxylic acid tert-butyl ester (100 mg, 0133 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and dried overnight under 25 vacuum. The residue was dissolved in DMF (2 mL) and to this solution was added 2 Methoxycarbonylamino-3-methyl-butyric acid (2 eq., 47 mg), diisopropyl ethylamine (6 eq., 0.14 mL), followed by HATU (2 eq., 10 1 mg). Reaction mixture was stirred at 0*C for 30 minutes. The reaction mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by 30 preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give [1 -(3-{6-[6-(4-{2-[ I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-y }-phenyl)-naphthalen-2-y]- IH-benzoimidazol-2-yl}-2-aza bicyclo[2.2. I ]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example DM) (19.7 mg, 17%). 647 I H-NMR: 300 MHz, (CD 3 OD-d 4 ) 6: 8.13-7.82 (in, 14H), 5.40-5.22(m, 2H), 4.98(m, IH), 4.72(m, I H), 4.38(d, I H), 4.22(m, I H), 4.l10(m, 2H), 3.92 (in, 2H), 3.66(d, 6H), 2.98(m,1I H), 2.58 (in, I1-H), 2.37-2.18 (mn, 4H), 2.18-1.92(m, 4H), 1.80(m, 2H), 1.09-0.85 (in, 12 H). LCMS ESl+: calc'd for C 50

H

56

N

8

O

6 : 865.03; Found: 866.3 (M+H+). 5 Example DN Boc 0~\ Pd(PPh 3

)

4 N N Br + I ~ 'flPdCI 2 (dPP0 2 (4 -. 0t K 2 C0 3 , DMEIH 2 0 2-[5-(6-Bromo-naphthalen-2-y)-lH- Benzene- 1,4-d iboron ic90O imidazol-2-yI]-pyrrolidine-l- acid dipinacal ester c a rb o x y lic a c id te t-b u ty l e s te rH q -6 B o -1 -b n i m d z l 2 IN N yI)-2-aza-bicyclo[2.2. 1]heptane-2 No N 6 0BrN carboxylic acid tert-butyl ester H -0 Pd(PPh 3

)

4

K

2 C0 3 , DMEH 2 O 2-(5-{6-[4-(4,4,5,5-Tetrametl-[1 ,3,2]dioxaborolan- PdCI 2 (dPpf 2 90 0 C 2-yl)-phenyl]-naphthalen-2-ylH-imidazol-2-yl) pyrrolidine-l-carboxylic acid tert-butyl ester 1. HCI Boc N j 0 -6 N 6C2. HATU, DIEA H -0 3-[6-(4-{6-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H- HO 'N im idazol-4-yI].naphthaIen-2-y})-p henyl)- 1 H-be nzoim idazol-2-yg- 0 H 0 2-aza-bicyclo[2.2. 1]heptane-2-carboxylic acid tert-butyl ester 2-Methoxycarbonylamino-3 methyl-butyric acid o 0 \ N / N N' N KiH - / \/ O 0 [1-(3-{6-[4-(6{2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y] 3H-imidazol-4-yI}-naphthalen-2-y)-phenylH-benzoimidazol-2-yl)-2-aza bicyclo[2.21]heptane-2-carbonyl)-2-methyl-propy]-carbamic acid methyl ester 10 2-(5-16-14-(4,4,5,5-Tetramethyl-II ,3,2]dioxaborolan-2-yI)-phenyll-naphthalen-2-yI-1

H

imidazol-2-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester: A mixture of 2-[5-(6-lBromo naphthalen-2-yi)- I H-imidazol-2-yt]-pyrrolidine- I -carboxylic acid tert-butyl ester (615 mg, 1 .39 inmol), Benzene-1I,4-diboronic acid dipinocal ester (5 eq., 2.3 g, 6.95 inmol), [1,1' bi s(d iphenyl phosph ino)ferrocene] dich loropal lad ium( 1I)(5 %, 57 ing), 15 tetrak is(tri phenyl phosph ine)pal lad ium (5%, 80 mng) and potassium carbonate (3 eq., 576 mng) in 648 20 mL DME and 10 mL water was heated to 90'C under Ar for 1 hour. The reaction mixture was cooled and diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{6-[4-(4,4,5,5-Tetramethyl 5 [1,3,2]dioxaborolan-2-yl)-phenyl]-naphthalen-2-y}- IH-imidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (488 mg, yield 62%). LCMS-ESI~: calc'd for C 3 4

H

40

BN

3 0 4 : 565.51; Found: 566.2 (M+H*). 3-16-(4-{6-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-y)-3H-imidazo-4-y]-naphthalen-2-yl) 10 phenyl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: A mixture of 2-(5-{6-[4-(4,4,5,5-Tetramethyl-[ ,3,2]dioxaborolan-2-yl)-phenyl] naphthalen-2-yl}-l H-imidazol-2-yl)-pyrrolidine-l -carboxylic acid tert-butyl ester (248 mg, 0.438 mmol, 1.1 eq.), 3-(6-Bromo- I H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.l ]heptane-2 carboxylic acid tert-butyl ester (I eq., 156 mg, 0.399 mmol), [1,1' 15 bis(diphenylphosphino)ferrocene]dichloropalladium(II)(3%, 10 mg), tetrakis(triphenylphosphine)palladium (3%, 14 mg) and potassium carbonate (3.3 eq., 182 mg) in 4 mL DME and 2 mL water was heated to 90'C under Argon for 1 hour. The reaction mixture was cooled and diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column 20 chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 3-[6-(4-{6-[2-(-tert Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)- I H benzoimidazol-2-yl]-2-aza-bicyclo[2.2. 1 ]heptane-2-carboxyl ic acid tert-butyl ester (178 mg, yield 59%). LCMS-ESr: calc'd for C 4 6

H

5

N

6 0 4 : 750.93; Found: 751.3 (M+H+). 25 [1-(3-{6-14-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-benzoimidazol-2-yl)-2-aza bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example DN): 4N HCI in dioxane (1 mL) was added to 3 -[6-(6-{4-[2-(1-tert-Butoxycarbonyl-pyrrolidin 2-yl)-3 H-im idazol-4-yl]-phenyl}-naphthalen-2-yl)-I H-benzoimidazol-2-yl]-2-aza 30 bicyclo[2.2.l]heptane-2-carboxylic acid tert-butyl ester (100 mg, 0133 mmol) in 2 mL DCM and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (2 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (2 eq., 83 mg), diisopropyl ethylamine (6 eq., 0.25 mL), followed by HATU (2 eq., 180 mg). Reaction mixture 35 was stirred at 0*C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and 649 washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product was lyophilized to give [I -(3-{6-[4-(6-{2-[I-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yI}-naphthalen-2-yl)-phenyl]-

IH

5 benzoimidazol-2-yl}-2-aza-bicyclo[2.2. I ]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example DN) (102 mg, 50%). 'H-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: 8.13-7.82 (m, 14H), 5.40-5.22(m, 2H), 4.98(m,I H), 4.72(m, I H), 4.38(d, I H), 4.22(m, I H), 4.1 0(m, 2H), 3.92 (m, 2H), 3.66(d, 6H), 2.98(m, 1 H), 10 2.58 (m, 1H), 2.37-2.18 (m, 4H), 2.18-1.92(m, 4H), 1.80(m, 2H), 1.09-0.85 (m, 12 H). LCMS ESI+: calc'd for C 5 0

H

56

N

8 0 6 : 865.03; Found: 866.4 (M+H*). 650 Example DO 0 y0 N H H Pd(PPh 3

)

4 HN Cu(I)I O NNN. N 0 0I - B r0 A0 (1-{2-[5-(4-Ethynyl-pheny)-1 H 3-[4-(4-Bromo-phenyl)-l1H-imidazol-2- imidazol-2-yI]-pyrrolidine-1 yI]-4-(2-methoxycarbonylamino-3- carbonyl)-2-methyl-propyl) methyl-butyryl)-piperazine-1 - carbamnic acid methyl ester carboxylic acid tert-butyl ester 0 y0 NH ~1N H ) N~\ N N SEM-CI. NaH O ~ \ DMF O - H 4-(2-Methoxycarbonyfamino-3-methyl-butyryl)-3- 0 {4-[4-(4-{2-(1 -(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yI} phenylethynyl)-phenyl]-1 H-imidazol-2-y} piperazine-1-carboxylic acid tert-butyl ester CN ,SEM SEM HCI in Dioxane /0CM NID N ~N HN N 0 0 N N SMSEM, 1. Ac 2 O, NMM, 0CM N N- N 2. TFA DCM 0 NH N N \/ y H' IN 01 N H NH \ NN A 0 [1 -(2-{5-(4-(4-{2-[4-Acetyl-1 -(2-methoxycarbonylamino-3-methyl-butrl) piperazin-2-y]-1 H-imidazol-4-yI}-phenylethynyl)-phenyl]-1 H-imidazo-2-yi] pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 651 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3-{4-[4-(4-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} phenylethynyl)-phenyl]-1H-imidazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester: 3 [4-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl) 5 piperazine- I-carboxylic acid tert-butyl ester (600 mg, 1.06 mmol) was combined with (1-{2-[5 (4-Ethynyl-phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (503 mg, 1.27 mmol) and Pd(PPh 3

)

4 (122 mg, 0.106 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (1.47 mL, 10.6 mmol) and copper(I) iodide (20.0 mg, 0.106 mmol). The mixture was heated at 80 *C. After 10 20 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent: EtOAc w MeOH 10% / hexanes) to yield the product 4 (2-Methoxycarbonylamino-3-methyl-butyryl)-3-{4-[4-(4-{ 2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} -phenylethynyl)-phenyl]- I H-imidazol-2-yl} piperazine-l-carboxylic acid tert-butyl ester (542 mg). LCMS-ESl*: calc'd for C 47

H

59

N

9 0 8 : 15 878.0 (M*); Found: 878.5 (M+H+). SEM protected imidazole intermediate: 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3 {4-[4-(4-f{2- [1 -( 2 -methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4 yl}-phenylethynyl)-phenyl]-I H-imidazol-2-yl}-piperazine-l-carboxylic acid tert-butyl ester 20 (512 mg, 0.586 mmol) was dissolved in DMF (10 mL). Sodium hydride (60 % in mineral oil, 56 mg) was added at 0 *C, followed by SEM-Cl (0.217 mL). After two hours, the solvents were removed in vacuo and the crude material was partitioned between DCM and water. The organic layer was dried and the crude material was purified by flash chromatography in silica gel to yield 591 mg of the SEM protected imidazole product. 25 LCMS-ESI*: calc'd for C 59

H

8 7

N

9

O

0 oSi 2 : 1138.6 (M*); Found: 1138.7 (M+H+). de-Boc piperazine material: The above SEM protected imidazole material was dissolved in DCM (2.5 mL) at room temperature. HCI (4M in dioxane, 5 mL) was added and stirring of the resultant suspension at room temperature was continued. After 60 minutes all volatiles were 30 removed in vacuo and the crude material was used in the next reaction without further purification. 652 [1 -( 2

-{

5

-[

4

-(

4

-{

2

-[

4 -Acetyl-1-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazin-2-y] 1 H-imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyl]-carbamic acid methyl ester (Example A): The above de-Boc piperazine material (139 mg, 0.129 mmol) was dissolved in DCM (3 mL) containing NMM (0.057 mL) at 5 room temperature. Acetic anhydride (0.0183 mL) was added and stirring at room temperature was continued. After 60 minutes all volatiles were removed in vacuo and the crude material was dissolved in a micture of DCM (5 mL) and TFA (5 mL). Stirring at room temperature was continued. After 16 hours, the volatiles were removed in vacuo and the material was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA). The product-containing fractions were 10 combined and lyphilized to yield the product [I-(2-{5-[4-(4-{2-[4-Acetyl-1-(2 methoxycarbonylamino-3-methyl-butyryl)-piperazin-2-yl]- I H-imidazol-4-yl} -phenylethynyl) phenyl]- I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example DO) as a TFA salt (15.7 mg). LCMS-ESI*: calc'd for C44H 5 3

N

9 0 7 : 819.9 (M+); Found: 820.4 (M+H*). 15 1 H-NMR: 300 MHz, (dmso-d 6 ) 6: 8.07 (m, 2 H), 7.91-7.68 (m, IOH), 7.28 (m, 2H), 5.64 (m, I H), 5.38 (m, I H), 5.17 (m, 2H), 4.23 (d, J=7.8Hz, 1 H), 4.11 (m, I H), 3.85 (m,I H), 3.68 (s, 3H), 3.66 (s, 3H), 3.49-3.45 (m, 2H), 3.15-3.02 (m, 3H), 2.77 (m, 1 H), 2.58 (m, I H), 2.29-2.01 (m, 5H), 1.07-0.83 (m, 12H) ppm. 20 Example DP 0 N ,SEM C 0 SEM* I ) 1. NMM, DCM O N 2. TFA DCM N H NJO

-

IN 0 0O O INN N N N I H N N 0 N~- 0 O H'N O 0 A0 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3-{4-[4-(4-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} phenylethynyl)-phenyl]-1H-imidazol-2-yI}-piperazine-1-carboxylic acid methyl ester 653 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3-{4-14-(4-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} phenylethynyl)-phenyl]-1H-imidazol-2-yl)-piperazine-1-carboxylic acid methyl ester (Example DP): It was prepared in a similar fashion to [1-(2-{5-[4-(4-{2-[4-Acetyl-I-(2 5 methoxycarbonylamino-3-methyl-butyryl)-piperazin-2-yl]- 1H-imidazol-4-yl}-phenylethynyl) phenyl]-I H-imidazol-2-yl}-pyrrolidine-l-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example DO) replacing the acetic anhydride with methylchloro formate. LCMS-ESI*: calc'd for C 4 4

H

5 3

N

9 0 8 : 835.4 (M*); Found: 835.9 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 6: 8.08 (m, 1 H), 7.76-7.54 (m, 10H), 7.30 (m, 2H), 5.58 (m, 10 1 H), 5.08 (m, I H), 4.36 (m, I H), 4.26 (m, I H), 4.03 (m, 2H), 3.95 - 3.75 (m, 4H), 3.50 (m, 9H), 2.29 (m, I H), 2.13-1.95 (m, 4H), 0.87-0.68 (m, 12H) ppm. 15 Example DQ H N ,SEM -N=C=O SEMI 1. NMM, DCM O N -N- N2. TFA DCM O H'N \ / H NO A 0 H O NN N N I H i N N O H'N N A 0 [1 -(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylcarbamoyl piperazin-2-yl]-1 H-imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl} pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester [1 -(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylcarbamoyl piperazin-2-yl]-1 H-imidazol-4-yl}-phenylethynyl)-phenyll-1 H-imidazol-2-yl}-pyrrolidine 20 1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example DQ): It was prepared in a similar fashion to [1 -(2-{5-[4-(4-{2-[4-Acetyl- I -(2-methoxycarbonylamino-3-methyl butyryl)-piperazin-2-yl]- I H-imidazol-4-yl} -phenylethynyl)-phenyl]- I H-imidazol-2-yl} 654 pyrrolidine-I-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example DO), replacing the acetic anhydride with isocyanatomethane. LCMS-ES+: calc'd for C 44

H

54 NIO0 7 : 834.9 (M*); Found: 835.4 (M 4 ). H-NMR: 300 MHz, (dmso-d 6 ) 6: 8.08 (m, I H), 7.77-7.36 (m, I OH), 7.36 - 7.24 (m, 2H), 5 5.51 (m, I H), 5.07 (m, I H), 4.36 (m, I H), 4.07 (m, I H), 4.06 (m, 2H), 3.95 - 3.75 (m, 4H), 3.52 - 3.48 (m, 9H), 2.34 (m, I H), 2.13-1.96 (m, 4H), 0.90-0.78 (m, 12H) ppm. Example DR SEM

CISO

2 NMe 2 KN _ _MSE SSEMi N 1.NMM,DCM NN N 2.TFADCM O N NO 00 00 N 0 H'NON O 00 [1 -(2-{5-[4-(4-{2-[4-Dimethylsulfamoyl-1 -(2-methoxycarbonylamino-3-methyl butyryl)-piperazin-2-yl]-1 H-imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl} pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 10 [1 -(2-{5-[4-(4-{2-[4-Dimethylsulfamoyl-1-(2-methoxycarbonylamino-3-methyl-butyryl) piperazin-2-yl]-1 H-imidazol-4-yl}-phenylethynyl)-phenyll-1 H-imidazol-2-yI}-pyrrolidine 1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example DR): It was prepared in a similar fashion to [1 -(2-{ 5-[4-(4-{2-[4-Acetyl-1I-(2-mnethoxycarbonylamnino-3-mnethyl-butyryl) piperazin-2-yl]- I H-imnidazol-4-yl }-phenylethynyl)-phenyl]- 1 H-imidazol-2-yl }-pyrrol idine- 1 1 5 carbonyl)-2-mnethyl-propyl]-carbamnic acid methyl ester (example DO), replacing the acetic anhydride with N,N-dimethyl sulfurylamido chloride. LCM4S-ESl*: calc'd for C 44

H

56

N

1 o0sS: 885.0 (M4*); Found: 885.4 (M*). 'H-NMR: 300 M Hz, (dmso-d 6 ) 6: 8.05 (in, I H), 7.91-7.52 (mn, I0H), 7.32 -7.28 (mn, 2H), 5.72 (s, I H), 5.07 (mn, I H), 4.39 - 4.06 (mn, 4H), 3.95 - 3.75 (mn, 4H), 3.52 - 3.48 (mn, 6H-), 2.86 20 46 (mn, 6H-), 2.12-1 .95 (mn, 4H), 0.94-0.76 (in, 1 2H) ppm. 655 Example DS OyON 0N O HrN N O O H'Y 0 3-{4-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H imidazol-2-yl}-4-(2-methoxycarbonylamino-propionyl) piperazine-1-carboxylic acid methyl ester 3-{4-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yI)-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-4-(2-methoxycarbonylamino 5 propionyl)-piperazine-1-carboxylic acid methyl ester (example DS) was prepared in a similar fashion to 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3-{4-[4-(4-{2-[ 1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl}-phenylethynyl) phenyl]-l H-imidazol-2-yl}-piperazine-1-carboxylic acid methyl ester (example DP), replacing the valine derived carbamate with the corresponding alanine derived carbamate. 10 LCMS-ESl*: calc'd for C 40

H

49

N

9 0 8 : 783.8 (M*); Found: 784.3 (M+H*). ' H-NMR: 300 MIHz, (dmso-d 6 ) 6: 8.08 (m, I H), 7.95-7.80 (m, I0 H), 7.47 (m, I H), 7.30 (m, I H), 5.72 (s, I H), 5.55 (s, I H), 5.09 (m, I H), 4.58 (m, I H), 4.09 (m, I H), 3.89 - 3.80 (m, 5H), 3.50 - 3.30 (m, 9H), 2.29 (m, I H), 2.09-1.98 (m, 4H), 1.21 (m, 3H) 0.81-0.75 (m, 6H) ppm. 15 Example DT H

N

O=( N N H H 7 N O H' N O11 0 Ay A 0 (1 -{2-[5-(4-{4-[3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-1'-methylcarbamoyl 2',3',4,5'-tetrahydro-1 H, 1'H-[2,4']biimidazolyl-4-yl]-phenylethynyl}-phenyl)-1 H-imidazol 2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1-{2-[5-(4-{4-13'-(2-Methoxycarbonylamino-3-methyl-butyry)- '-methylcarbamoyl 2',3',4',5'-tetrahydro-1 H,1'H-[2,4'] biimidazolyl-4-yl]-phenylethynyl}-phenyl)-1 H-imidazol 2-ylI]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (example DT) 20 was prepared in a similar fashion to [1-(2-{5-[4-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl butyryl)-4-methylcarbamoyl-piperazin-2-yl]-I H-imidazol-4-y }-phenylethynyl)-phenyl]-1 H 656 imidazol-2-yl}-pyrrolidine-l-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example DQ), replacing the piperazine carboxylic acid with the corresponding 4-amino-pyrrolidine derivative, using methodology described under examples BU and DO. LCMS-ESI*: calc'd for C 4 3

H

52 NiO 0 7 : 820.9 (M*); Found: 821.4 (M*). 5 1 H-NMR: 300 MHz, (dmso-d 6 ) 6: 8.05 (m, I H), 7.91 (s, I H), 7.77-7.50 (m, 10H) 7.32 (m, I H), 6.54 (m, I H), 5.51 (m, I H), 5.36 (m, I H), 5.21 (m, 2H), 4.51 (m, I H), 4.07 (m, I H), 3.95 3.75 (m, 2H), 3.51 (s, 6H), 2.57 (m, 3H), 2.13 (m, I H), 2.05-1.95 (m, 4H), 0.94-0.77 (m, 12H) ppm. 10 Example DU N 3j7 Pd(PPh 3

)

4 / N+ - NH'KCO /B / Bc K 3 h), 2,6-Diiodo-1,5-dithia-s-indacene 2-[5-(4,4,5,5-Tetramethyl [1,3,2]dioxaborolan-2-y)-1 H benzoimidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester NyA 1. 4N HCI/dioxane, DCM Boc /\ / - NH HN Boc 2. HATU, DIEA CIN S N 0 HO N 2-(5-{6-[2-(1 -boc-pyrrolidin-2-yl)-1 H-benzoimidazol-5- O H yl]- 1,5-dithia-s-indacen-2-yl}-1 H-benzoimidazol-2-y1)- 0 pyrrolidine-1-carboxylic acid tert-butyl ester 2-Methoxycarbonylamino-3 methyl-butyric acid 0 N <3 ON, 1) 0S N H 1 H HN (r/ \/ 0N N O C" N 0 (1 -{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-1 H-benzoimidazol-5-yl}-1,5-dithia-s-indacen-2-yl)-1 H-benzoimidazol-2 yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-(5-{6-[2-(1-boc-pyrrolidin-2-yl)-1 H-benzoimidazol-5-yl]-1,5-dithia-s-indacen-2-yl}-1 H benzoimidazol-2-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester: 2,6-Diiodo-1,5-dithia-s indacene (117 mg, 0.263 mmol), 2-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-l H 15 benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (109 mg, 0.263 mmol) , Pd(PPh 3

)

4 (9.1 mg), K 2

CO

3 (69 mg, 0.52 mmol), were dissolved in toluene (5 mL) / water (I 657 mL) under an argon atmosphere. The mixture was heated for 30 minutes at 130 IC (microwave) and 30 minutes at 140 *C. Removed all volatiles in vacuo and purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product 2-(5-{6-[2-(l -Boc-pyrrolidin-2 yl)-I H-benzoimidazol-5-yl]-1,5-dithia-s-indacen-2-yl}-1 H-benzoimidazol-2-yl)-pyrrolidine-I 5 carboxylic acid tert-butyl ester (36.3 mg). LCMS-ESl*: calc'd for C 4 2 H44S 2

N

6 0 4 : 760.3 (M*); Found: 761.3 (M+H*). (1-{2-15-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-1H benzoimidazol-5-yI}-1,5-dithia-s-indacen-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1 10 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DU): 2-(5-{6-[2-(1 -Boc pyrrolidin-2-yl)-i H-benzoimidazol-5-yl]- I,5-dithia-s-indacen-2-yl}-i H-benzoimidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (36 mg) was dissolved in DCM (3 mL) and HCI in dioxane (4M, 4 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step 15 without further purification. The above crude material was dissolved in DMF (3 mL) and NMM (0.025 mL) was added. A solution of 2- (L) Methoxycarbonylamino-3-methyl-butyric acid (17 mg, 0.094 mmol), HATU (36 mg, 0.094 mmol) and NMM (0.025 mL) in DMF (I mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was 20 washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water/ MeCN w/ 0.1% TFA) to yield the product (1-{2-[5 (6-{2- [1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrol idin-2-yl]-I H-benzoimidazol-5 yl }-,5-dithia-s-indacen-2-yl)-l H-benzoimidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl 25 propyl)-carbamic acid methyl ester (3.8 mg). LCMS-ESI*: calc'd for C 4 6

H

50

N

8 0 6

S

2 : 875.1 (M*); Found: 875.4 (M+H*). H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.41 (s, 2 H), 7.94 - 7.91 (m, 4H), 7.73-7.67 (m, 4H), 7.31 (m, 2H), 5.19 (m, 2H), 4.09 (m, 2H), 3.85 (m, 4H), 3.51 (s, 6H), 2.31-1.82 (m, 10H), 0.94-0.77 (m, 12H) ppm. 30 658 Example DV O H NC N* FE H O -NH HN 0 (1-{3-[6-(7-{2-[4-Cyano-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yI}-9,9-difluoro-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane 2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1-{3-[6-(7-{2-[4-Cyano-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 3H-imidazol-4-yl}-9,9-difluoro-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza 5 bicyclo[2.2.llheptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DV) was prepared in a similar fashion to (I-{2-[5-(9,9-Difluoro-7-{2-[2-(2 methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3H-benzoimidazol-5 yl}-9H-fluoren-2-yl)- 1 H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DK), replacing the proline derivative with the corresponding 4 10 cyano-proline derivative. LCMS-ESl+: calc'd for C 48

H

51

F

2

N

9 0 6 : 887.9 (M*); Found: 888.3 (M+H*). ' H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.10-7.95 (m, 8H), 7.70 (s, 2H), 7.34 (m, I H), 7.26 (m, I H), 5.12 (dd, J = 8.4 Hz, I H), 4.72 (s, I H) 4.52 (s, I H), 4.42 (m, I H), 4.16 (m, I H), 4.05 (m, I H), 3.94 (m,l H), 3.74 (m, I H), 3.53 (s, 3 H), 3.52 (s, 3H), 2.85 (m, I H), 2.73 (m, I H), 2.39 (m, I H), 15 2.25 (m, I H), 2.03 - 1.72 (m, 6H), 1 .54 (m, 2H), 0.94 - 0.77 (m, 15H) ppm. 1 9 F-NMR: 282 MHz, (dmso-d 6 ) 6: -108.6 ppm [-74.3 ppm TFA]. Example DW 0 0O11 N' H H ONN N H H'N 2-: 0 (1-{6-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 20 (1-{6-15-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl)-biphenyl-4-yl)-1 H-imidazol-2-yl]-5-aza-spiro[2.41 heptane-5-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (Example DW) was prepared in a similar fashion to (1-{2-[5-(4'-{2-[2-Hydroxy-I-(2-methoxycarbonylamino-3-methyl-butyrylamino)-ethyl]-3H 659 imidazol-4-yl}-biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl) carbamic acid methyl ester, replacing the oxazolidine derived carboxylic acid with the corresponding 4-cyclopropyl-proline derivative and using HCI in dioxane for the Boc deprotection. 5 LCMS-ESI*: calc'd for C 4 2

H

52

N

8 0 6 : 764.9 (M*); Found: 765.3 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.08 (m, 2 H), 7.91-7.84 (m, 10H) 7.33 (m, 2H), 5.23 (m, I H), 5.11 (m, I H), 4.10 (m, I H), 4.01 (m, I H), 3.95 - 3.75 (m, 4H), 3.53 (s, 6H), 2.40 (m, I H), 2.23 (m, I H), 2.05-1.95 (m, 4H), 0.94-0.80 (m, 12H), 0.63 (m, 4H) ppm. 10 Example DX 0 ON H S N'H N N H H' N O 1 O 0 (1 -{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4 yl)-1H-imidazol-2-yl]-thiazolidine-3-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1-{2-15-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-biphenyl-4-yI)-1H-imidazol-2-yll-thiazolidine-3-carbonyl}-2-methyl propyl)-carbamic acid methyl ester (Example DX) was prepared in a similar fashion to (1-{6 15 [5-(4'-{2-[l-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl} biphenyl-4-yl)-l H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl) carbamic acid methyl ester (Example DW), replacing the cyclopropyl proline carboxylic acid with the corresponding thiazolidine derivative. LCMS-ESI*: calc'd for C 3 9

H

4 8

N

8 0 6 S: 756.9 (M*); Found: 757.0 (M*). 20 1 H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.06 (m, 2 H), 7.86-7.70 (m, IOH), 7.45 (m, I H), 7.22 (m, I H), 6.33 (s, 1 H), 5.09 (m, I H), 4.18 - 4.08 (m, 4H), 3.80 (m, 2H), 3.56 (s, 6H), 3.30 (m, 2H), 2.40 (m, I H), 2.05-1.95 (m, 5H), 0.94-0.75 (m, 12H) ppm. 660 Example DY -N4 .A O-O 0 : O F F HHA -NHI N 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl)-9H-fluoren-2-yl)-1 H-benzoimidazol-2-yi]-2-aza bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 1. HCI Dioxane /DCM 2. HATU, DIEA, DMF \ 0 N 1 yO F F o N OH H / 0N/ H (1 -{6-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2. 1 ]hept-3-yI]-3H benzoimidazol-5-yl}-9H-fluoren-2-yl)-1 H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl propyl)-carbamic acid methyl ester (1-{6-15-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-propionyl)-2-aza 5 bicyclo[2.2.1]hept-3-yll-3H-benzoimidazol-5-yI}-9H-fluoren-2-y)-1H-imidazol-2-yl]-5-aza spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3 H-imidazol-4-yl}-9H-fluoren-2-yI)-I H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2 carboxylic acid tert-butyl ester (57.6 mg, 0.068 mmol) was dissolved in DCM (1 mL) and HCI 10 in dioxane (4M, I mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.0 mL) and DIEA (26.4 mg, 0.204 mmol) was added. A solution of 2- (L) methoxycarbonylamino-propionic acid (9.95 mg, 0.068 mmol), HATU (25.9 mg, 0.068 mmol) and DIEA (8.8 mg, 0.068 mmol) in 15 DMF (I mL) was added. The reaction was stirred at room temperature. After 45 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCI solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (I -{6-[5-(9,9-Difluoro-7-(2-[2-(2-methoxycarbonylamino 20 propionyl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3 H-benzoimidazol-5-yl}-9H-fluoren-2-yl)- I H imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (25.4 mg) as a TFA salt. LCMS-ESl*: calc'd for C 47 HsoF 2

N

8 0 6 : 860.9 (M*); Found: 861.8 (M+H*). 661 H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.20-7.99 (m, 8H), 7.73 (s, 2H), 7.37 - 7.27 (m, 2H), 5.24 (dd, J = 7.2 Hz, I H), 4.76 (s, I H) 4.50 (s, I H), 4.41 (m,I H), 4.02 (m, 1 H), 3.85 (m, I H), 3.74 (m, I H), 3.55 (s, 3H), 3.53 (s, 3H), 2.77 (m, I H), 2.25 (m, 2H), 2.09 - 2.04 (m, 2H), 1.88 - 1.79 (m, 2H), 1.54 (in, I H), 1 .25 (d, J= 7.8 Hz, 3H), 0.94 - 0.77 (m, 9H) 0.63 (m, 4H) ppm. 5 ' 9 F-NMR: 282 MHz, (dmso-d 6 ) 6: -109.1 ppm [-74.8 ppm TFA]. Example DZ ?N: o F F N S NH 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[22.1]heptane-2 carboxylic acid tert-butyl ester 1. HCI Dioxane / DCM 2. HATU, DIEA, DMF 0 100 (1-{6-[ -(9 (,9Difuoro-7-{2-[2-(2-methoxycarb~lmfony-lamno4-eysufyllffy-~trI-z -b utyryl)-2-aza-pt biyl[..]t3-yI]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1 H-imidazol-2-yll-5-aza-spr[4hpae5croy)2 spir[2.4hepane--cabony}-2methyl-propyl)-carbamic acid methyl ester : 10H (1 -{6-[5-(9,9-Difluoro-7-(2-[2-(2-methoxycarbonylamino-4-methylsulfonyl-butyryl)-2-aza-biyl[..]et biccll2..11h-3--3H-benzoim idazol-5-yl-9H-fluoren-2-yl)- I H-imidazol-2-yl5-zspr[.]etn5cabyI-5a spir [241 hptae-5carbnyl -2methyl-propyl)-carbamic acid methyl ester : 3-[6-(9,9-Difluoro-7- {2-[5-(2-methoxycarbonylam ino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 1 5 yI]-3 H-imidazol-4-yl}-9H-fluoren-2-yl)-I H-benzoimidazol-2-yli]-2-aza-bicyclo[2.2.I ]heptane-2 carboxylic acid tert-butyl ester (55.6 mg, 0.067 mmol) was dissolved in DCM (1 mL) and HCI in dioxane (4M, I mL) was added and stirring at room temperature was continued. After 30 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.0 mL) and DIEA 20 (25.8 mg, 0.201 mmol) was added. A solution of 2- (L) methoxycarbonylamino-4-methyl sulfonyl-butyric acid (15.9 mg, 0.067 mmol), HATU (25.4 mg, 0.067 mmol) and DIEA (8.6 mg, 0.067 mmol) in DMF (I mL) was added. The reaction was stirred at room temperature. After 662 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (1-{6-[5-(9,9-Difluoro-7-{2-[2-(2 5 methoxycarbonylamino-4-methylsulfonyl-butyryl)-2-aza-bicyclo[2.2.l]hept-3-yl]-3H benzoimidazol-5-yl}-9H-fluoren-2-yl)-I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester (23 mg) as a TFA salt. LCMS-ESI*: calc'd for C 4 9

H

54

F

2

N

8 0 8 S: 953.1 (M*); Found: 954.0 (M+H*). 1 H-NMR: 300 MHz, (dmso-d 6 ) 6: 8.20-7.99 (m, 8H), 7.77 (s, 2H), 7.65 (m, I H), 7.35 (m, I H), 10 5.25 (dd, J = 7.2 Hz, I H), 4.79 (s, I H) 4.56 (s, I H), 4.53 (m, I H), 4.02 (m, I H), 3.88 (m,I H), 3.72 (m, I H), 3.56 (s, 3H), 3.53 (s, 3H), 3.27 (m, 2H), 3.01 (s, 3H), 2.78 (m, I H), 2.25 (m, 2H), 2.09 - 2.04 (m, 2H), 1.88 - 1.79 (m, 4H), 1.56 (m, I H), 0.94 - 0.77 (m, 9H) 0.63 (m, 4H) ppm.

'

9 F-NMR: 282 MHz, (dmso-d 6 ) 6: -109.1 ppm [-74.8 ppm TFA]. 15 Example EA 0 F FF H H O N NHN 3-[6-(9,9-Difluoro-7-{2-{5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl] 3Himidazol4-y)l}9-9-fluoren-2-yy))1 H-benzoimidazol-2-yI-2-azabicyclo[2.2. 1]heptane-2 carboxylic acid tert-butyl ester 1. HCI Dioxane /0CM 2. HATU, DIEA, DMF 0 0 CN- I 1 F F HON~O $ NH I NH ~ \ / N NO 0 ON 3H-imidazol-4-yI)-9H4-fluoren-2y).1 H-benzoimidazol.2.yl].2-aza-bicyclo[2.2. 1]heptane-2-carbonyl-propyl) carbamic acid methyl ester (3-Cyano-1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-ylI-2-aza bicyclo[2.2.1]heptane-2-carbonyl}-propyl)-carbamic acid methyl ester: 20 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylam ino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3 H-imidazol-4-yl}-9H-fluoren-2-yl)-I H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.l]heptane-2 carboxylic acid tert-butyl ester (61.9 mg, 0.074 mmol) was dissolved in DCM (I mL) and HCI in dioxane (4M, I mL) was added and stirring at room temperature was continued. After 30 663 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.0 mL) and DIEA (28.5 mg, 0.186 mmol) was added. A solution of 2- (L) Methoxycarbonylamino-3-cyano butyric acid (13.8 mg, 0.074 mmol), HATU (28.3 mg, 0.074 mmol) and DIEA (9.5 mg, 0.074 5 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 30 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (3-Cyano-1-{3-[6-(9,9-difluoro-7-{2-[5-(2 10 methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H fluoren-2-yl)- IH-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.l]heptane-2-carbonyl}-propyl) carbamic acid methyl ester (33.1 mg) as a TFA salt. LCMS-ESI*: calc'd for C 4 9

H

5 1

F

2

N

9 0 6 : 899.9 (M*); Found: 900.4 (M+H*). ' H-NMR: 300 MHz, (dmso-d 6 ) 5: 8.20-7.99 (m, 8H), 7.76 (s, 2H), 7.59 (m, I H), 7.36 (m, I H), 15 5.25 (dd, J = 7.2 Hz, I H), 4.79 (s, I H) 4.55 (s, I H), 4.41 (m, I H), 3.99 (m, I H), 3.86 (m,I H), 3.74 (m, I H), 3.56 (s, 3H), 3.54 (s, 3H), 2.77 (m, I H), 2.62 (m, 2H), 2.25 (m, 2H), 2.14 (m, 2H), 1 .88 - 1.79 (m, 4H), 1.54 (m, I H), 0.94 - 0.77 (m, 9H) 0.63 (m, 4H) ppm. 1 9 F-NMR: 282 MHz, (dmso-d 6 ) 6: -109.1 ppm [-74.7 ppm TFA]. 20 Example EB 1. HATU, DIEA, DMF 0 0 N OH H O sI H O N N NH 4 0Ac, m-Xyl O 2. HATU, DIEA, DMF HN 0 O Br O O Br NH 2 Is -N-, N K S< H O 0 ' N N NO H N Br H N O 00 (1-{4-[5-(4-Bromo-phenyl)-1H- O H H thiazohdine-3-carbonyI}2-methyl- N propyl)-carbamic acid methyl ester HN O N 'N O 0 [1-(4-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3 carbonyl)-2-methyl-propyl-carbamic acid methyl ester 664 (1-{4-15-(4-Bromo-phenyl)-1 H-imidazol-2-ylI-5,5-dimethyl-thiazolidine-3-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: 5,5-Dimethyl-thiazolidine-4-carboxylic acid (1.1 g, 6.91 mmol) and DIEA (891 mg, 6.91 mmol) were added as a DMF (5 mL) suspension to a premixed solution of N 5 (methylcarbamoyl)(L)-valine (1.21 g, 6.91 mmol), HATU (2.26g, 6.91 mmol) and DIEA (891 mg, 6.91 mmol) at room temperature. After 20 minutes, additional HATU (2.26g, 6.91 mmol) and DIEA (891 mg, 6.91 mmol) were added and stirring at room temperature was continued. After 5 minutes, as suspension of amino-(4'bromo) acetophenone hydrochloride salt (1.72 g, 6.91 mmol) and DIEA (891 mg, 6.91 mmol) in DMF (3 mL) was added. Stirring at room 10 temperature was continued. After 10 minutes, all volatiles were removed in vacuo and the crude material was taken into EtOAc. The organic layer was washed with aqueous hydrochloric acid (0.1 M), aqueous lithium chloride solution (5%), saturated aqueous sodium bicarbonate solution, brine and was dried over sodium sulfate. Filtration and evaporation of solvents yielded crude material. Purification via silica gel chromatography (eluent EtOAc / hexanes) yielded the 15 product (3.46 g, 6.73 mmol). LCMS-ESI*: calc'd for C 21 H2 8 BrN 3 0 5 S: 514.3 (M*); Found: 515.4 / 513.4 (M+H*). The product of the previous step (1.04mg, 1.94 mmol) was dissolved in m-xylenes (9.0 mL) and heated at 135 *C. Solid ammonium acetate (700 mg, 9.07 mmol) was added and the reaction was stirred at 135 *C. After 240 minutes, the reaction was cooled to room temperature and the 20 volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product (1-{4-[5-(4-Bromo-phenyl)-IH-imidazol-2-yl] 5,5-dimethyl-thiazolidine-3-carbonyl} -2-methyl-propyl)-carbamic acid methyl ester (190 mg). LCMS-ES*: calc'd for C 2 1

H

2 8 BrN 4 0 3 S: 495.4 (M*); Found: 496.4 / 494.4 (M+H*). 25 [1 -(4- (5-14-(4-12-11-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolid in-2-yl] -3H imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: (I-{4-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-5,5-dimethyl-thiazolidine-3-carbonyl}-2-methyl propyl)-carbamic acid methyl ester (83 mg, 0.167 mmol) was combined with (I-{2-[5-(4 30 Ethynyl-phenyl)-l H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (66.0 mg, 0.167 mmol) and PdCI 2 (PPh 3

)

2 (11.7 mg, 0.017 mmol) under an argon atmosphere. DMF (2.0 mL degassed with Argon) was added followed by triethylamine (168 mg, 1.67 mmol) and copper(l) iodide (3.2 mg, 0.017 mmol). The mixture was heated at 80 *C. After 20 hours, volatiles were removed in vacuo and the crude material was semi-purified via 35 chromatography on silica gel (eluent EtOAc w MeOH 10% / hexanes) and further purified via 665 RP-HPLC (eluent: water/ MeCN w 0.1% TFA) to yield the product (1-(4-{5-[4-(4-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl) phenyl]-] H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (32.1 mg) as a TFA salt. 5 LCMS-ESI*: calc'd for C 4 3

H

52

N

8 0 6 S: 808.9 (M*); Found: 809.9 (M+H*). H-NMR: 300 MHz, (dmso-d 6 ) 5: 8.09 (m, 2H), 7.83 - 7.69 (m, 12H), 7.56 (m, 1 H), 7.34 (m, I H), 5.33 (s, I H), 5.12 (m, 2H), 5.01 (m, 1 H) 4.01 (m, 2H), 3.83 (m, 2H), 3.55 (s, 3H), 3.53 (s, 31H), 2.37 (m, I H), 2.09 - 2.04 (m, 3H), 1.55 (s, 3H), 1.11 (s, 3H), 0.92 - 0.76 (m, 12H) ppm. 10 Example EC 1. HATU, DIEA, DMF H

H

2 N N 0H N OH HCI H N O 2. NH 4 0Ac, m-Xyl 2,2-Dimethyl-oxazolidine-4- 2. HATU, DIEA, DMF carboxylic acid Y -N HIN I 0 N COOH H' 4-[5-(4'-{2-[1-(2- 0 Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-imidazol 4-yl}-biphenyl-4-yl)-1 H-imidazol-2-yl]- HO H 2,2-dimethyl-oxazolidine-3- 0 0 H carboxylic acid tert-butyl ester H O N N NN ON 0 (1-{2-[5-(4'-{2-[2-Hydroxy-1-(2-methoxycarbonylamino-3-methyl butyrylamino)-ethyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2 yI]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 4-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol 15 4-yI}-biphenyl-4-yI)-1 H-imidazol-2-yli-2,2-dimethyl-oxazolidine-3-carboxylic acid tert butyl ester: 2,2-Dimethyl-oxazolidine-4-carboxylic acid (350 mg, 1.02 mmol) was dissolved in DMF (2.5 mL) and HATU (387 mg, 0.102 mmol) and DIEA (129.0 mg, 1.02 mmol) were added. The reaction was stirred at room temperature for five minutes, after which [l-(2-{5-[4'-(2-Amino 20 acetyl)-biphenyl-4-yl]-l H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester hydrochloride salt (503 mg, 1.0 mmol) and DIEA (129.0 mg, 1.02 mmol) were added. Stirring at room temperature was continued. After 18 hours, all volatiles were 666 removed in vacuo and the crude material was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product (323 mg). The material was dissolved was dissolved in m-xylenes (5.0 mL) and heated at 135 *C. Solid ammonium acetate (280 mg, 3.63 mmol) was added and the reaction was stirred at 135 *C. After 180 minutes, the reaction was cooled to 5 room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product 4-[5-(4'-{2-[l-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl) I H-imidazol-2-yl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (123 mg, 0.172 mmol). 10 LCMS-ESI*: calc'd for C 3 9

H

4 9

N

7 0 6 : 711.8 (M*); Found: 712.7 (M+H*). (1-{2- [5-(4'- {2-2-Hydroxy-1-(2-methoxycarbonylamino-3-methyl-butyrylamino)-ethyl 3H-imidazol-4-yl)-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: 15 4-[5-(4'-{2-[I-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4 yl}-biphenyl-4-yl)-l H-imidazol-2-yl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (61 mg, 0.086 mmol) was dissolved in DCM (1 mL) and TFA (4M, 0.2 mL) was added and stirring at 0 *C was continued. After 30 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was 20 dissolved in DMF (1.5 mL) and DIEA (33.0 mg, 0.255 mmol) was added. A solution of 2- (L) Methoxycarbonylamino-3-methyl-butyric acid (15.2 mg, 0.086 mmol), HATU (32.5 mg, 0.086 mmol) and DIEA (11.0 mg, 0.086 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCI solution (5%), brine, and was dried over 25 sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water/ MeCN w/ 0.1% TFA) to yield the product (1-{2-[5-(4' {2-[2-Hydroxy-l -(2-methoxycarbonylamino-3-methyl-butyrylamino)-ethyl]-3H-imidazol-4-yl} biphenyl-4-yl)- IH-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (11.2 mg) as a TFA salt. 30 LCMS-ESI*: calc'd for C 3 8

H

4 8

N

8 0 7 : 728.8 (M*); Found: 729.7 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.62 (m, I H), 8.11 (m, 2H), 7.95 - 7.86 (m, 8H), 7.34 (m, I H), 7.22 (m, I H), 5.10 (m, 2H), 4.78 (s, I H) 4.13 (m, I H), 3.94 (m, I H), 3.83 (m, 4H), 3.54 (s, 3H), 3.53 (s, 3H), 2.37 (m, I H), 2.09 - 2.04 (m, 5H), 0.88 - 0.75 (m, 12H) ppm. 35 667 Example ED Preparation of Intermediate 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-methyl ester , Boc Cbz N0 1. HC, MeOH N..CO 2 Me Et 2 Zn, TFA,

CO

2 H 2. Cbz-CI, NMM CH

C

2 1 2 lo DCM 4-Methylene-pyrrolidine-1,2- 4-Methylene-pyrrolidine-1,2 dicarboxylic acid 1-tert-butyl ester dicarboxylic acid 1-benzyl ester 2 methyl ester Cbz Cbz ICbz NMO, OsO4 N 0M .C~ H/ No-. P 1 ).COMe + <~.IOM CO2Me bICO 2 Me THF/H 2 0/acetone .O2 -. & MH" 5-Aza-spiro[2.4]heptane-5,6 dicarboxylic acid 5-benzyl ester 6-methyl ester LIOH, THF, MeOH, H 2 0 Cbz N .CO2H 5-Aza-spiro[2.4]heptane 5,6-dicarboxylic acid 5 5 benzyl ester 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester: 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (10.0 g, 44 mmol) was dissolved in MeOH (75 mL) at room temperature and HCI (4M in dioxane, 75 mL) was added. 10 Stirring at room temperature was continued for 4 hours. All volatiles were removed in vacuo and a beige solid was obtained. The crude material was suspended in DCM (100 mL) and N-Methyl morpholine (13.3 g, 132 mmol) was added. The mixture was cooled to 0 *C and benzyl chloroformate (8.26 g, 48.4 mmol) was added while stirring. After 30 minutes, the reaction was warmed to room 15 temperature and the solution was washed with water and aqueous HCI (I M). The solution was dried over sodium sulfate. Filtration and evaporation of solvents gave crude product, which was purified by silica gel chromatography (eluent: EtOAc / hexanes) to yield the product (10.2 g). LCMS-ESI*: calc'd for C 15

H

17

NO

4 : 275.3 (M*); Found: 276.4 (M+H*). 668 5-aza-spiro 12.41 heptanes-5,6-dicarboxylic acid benzyl ester: An oven-dried 3-neck round bottom flask was equipped with a nitrogen inlet adaptor and a 250 mL addition funnel. The third neck was sealed with a septum. The flask was charged with a stir bar, diclorormethane (120 mL) and diethyl zinc (1.0 M in hexane, 118 mL, 118 mmol) then cooled to 0 *C in an ice 5 bath. The addition funnel was charged with dichloromethane (40 mL) and trifluoroacetic acid (9.1 mL, 118 mmol). After the diethyl zinc solution had cooled to 0 "C (about 25 minutes), the trifluoroacetic acid solution was added dropwise over 20 minutes to the stirred reaction mixture. After stirring for another 20 minutes at 0 'C, diiodomethane (9.5 mL, 118 mmol) was added slowly over 4 minutes. After another 20 minutes, 4-methylene-pyrrolidine-1,2-dicarboxylic acid 10 1 -benzyl ester 2-methyl ester (8.10 g, 29.4 mmol) was added in 30 mL dichloromethane by cannula. The flask containing 4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2 methyl ester was then rinsed with another 10 mL dichloromethane and this solution was also transferred to the reaction mixture by cannula. The reaction mixture was allowed to warm to RT and stirred for I 10 hours (about 5 days) after which the reagents were quenched with saturated 15 aqueous ammonium chloride (-150 mL). The contents of the flask were slowly poured into a 2 L sep funnel containing saturated aqueous sodium bicarbonate (-800 mL). The aqueous phase was extracted three times with 300 mL ethyl acetate. The combined organics were dried over magnesium sulfate and concentrated to provide the crude material. The crude material was dissolved in 3:1:1 TH F/water/acetone (165 mL) then treated with N-methylmorpholine-N-oxide 20 (3.45 g, 29.4 mmol) and osmium tetroxide (4 wt% in water, 5 mL, 0.818 mmol). After stirring at RT for 7 h, the reagents were quenched with 1 M aqueous sodium thiosulfate (-100 mL). The contents of the flask were then poured into a I L sep funnel containing water (-300 mL). The aqueous phase was extracted three times with 300 mL dichloromethane. The combined organics were dried over magnesium sulfate and concentrated. The crude residue was purified by silica 25 column chromatography (5% to 45% EtOAc/hexane) to provide 5-aza-spiro[2.4]heptane-5,6 dicarboxylic acid 5-benzyl ester 6-methyl ester as a clear oil (5.54g, 19.15 mmol, 65%) as a clear oil. 'H NMR (CDCl 3 ) 8 7.36-7.29 (m, 5H), 5.21-5.04 (m, 2H), 4.56-4.47 (m, I H), 3.75 (s, 1.5H), 3.60 (m, 1.5 H), 03.51-3.37 (m, 2H), 2.32-2.25 (m, I H), 1.87-1.80 (m, I H), 0.64-0.51 (m, 4H). 30 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester: 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-methyl ester (244 mg, 0.840 mmol) was dissolved in THF (2.0 mL)/MeOH (1.5 mL). An aqueous solution of LiOH (35.5 mg, 0.84 mmol) was added and stirring at room temperature was continued. After 3 hours, the 35 reaction was neutralized with aqueous HCI (IM) and the organic solvents were removed in 669 vacuo. The crude mixture was diluted with water and EtOAc and the organic layer was collected. All volatiles were removed in vacuo and the crude acid was used without further purification. LCMS-ESI*: calc'd for C 15

HI

7

NO

4 : 275.3 (M *); Found: 276.3 (M+H*). 670 Example ED' 0 F F 1. Pd(PPh 3

)

4 (2.5%), SnBu 3 OEt deoxofluor PdC1 2 (PPh 3

)

2 (2.5%) Br / \ / Br - Br & Br Dioxane 80 "C 3 h 2. NBS (1x) H 2 0 2,7-Dibromo-fluoren-9-one 2,7-Dibromo-9,9-difluoro- 3. N-Cbz-4-cydopropy (L) Proline, DIEA, 9H-fluorene DMF, MeCN, rt N'Cbz F 'Cbz F 00

NH

4 0Ac, m-Xyl, N YBr Br 0 - - - !l - 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5- 6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1 H benzyl ester 6-[2-(7-bromo-9,9-difluoro-9H- imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic fluoren-2-yl)-2-oxo-ethyl] ester acid benzyl ester 1. HBr / HOAc O 0 2. HATU, DIEA, DMF N'Cbz F F )O O 4 H 0/N~ F F 0 Br NN N" - Br O Br (1 -{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1 H imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 methyl-propyl)-carbfamic acid methyl ester O NH FH F /N H\ / \ Pd(PPh 3

)

4 (10%), 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza

K

2

CO

3 (3x) spiro[2.4]hep-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1 H-benzoimidazol-2-yl] DME / H 2 0 2-aza-bicydo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 1. HCI Dioxane /DCM 2. HATU, DIEA, DMF NLO F F H QXO OH NHNHO ON HN 0 0~ OH N (1 -{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl-9H-fluoren-2-y)-1 H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 2,7-Dibromo-9,9-difluoro-9H-fluorene: 2,7-Dibromo-fluoren-9-one (4.0 g, 11.8 mmol) was suspended in deoxofluor (12 mL) at room 5 temperature and EtOH (4 drops) was added. The stirred suspension was heated at T = 90* C for 24 hours (CAUTION: Use of deoxofluor at elevated temperatures, as described above, is strongly discouraged as rapid and violent exotherms may occur). The reaction was cooled to room temperature and poured onto ice containing sodium bicarbonate. A solid formed and was collected via filtration. The crude material was taken into EtOAc and was washed with 671 aqueous HCI (I M) and brine. The solution was dried over sodium sulfate. Filtration and evaporation of solvents gave crude product, which was purified by silica gel chromatography (eluent: EtOAc / hexanes) to yield the product 2,7-Dibromo-9,9-difluoro-9H-fluorene (3.2 g). 19 F-NMR: 282 MHz, (dmso-d 6 ) 8: -111.6 ppm. 5 Before using the material in the next step, it was exposed as a solution in EtOAc to charcoal. 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-9,9-difluoro 9H-fluoren-2-yl)-2-oxo-ethylJ ester: 2,7-Dibromo-9,9-difluoro-9H-fluorene (372 mg, 1.04 mmol), Pd(PPh 3

)

4 (30.0 mg, 0.026 mmol), 10 PdCl 2 (PPh 3

)

2 (18.2 mg, 0.026 mmol), As(PPh 3

)

3 (5.0 mg) were dissolved in dioxane (10 mL) under an argon atmosphere. Ethoxyvinyl-tributyl tin (376.4 mg, 1.04 mmol) was added. The mixture was heated for 140 minutes at 85'C (oil bath). The reaction was cooled to room temperature. N-bromo succinimide (177 mg, 1.0 mmol) was added followed by water (2 mL). The reaction was stirred at room temperature for 3 hours, after which the majority of the dioxane 15 was removed in vacuo. The crude reaction mixture was diluted with EtOAc and was washed with water. All volatiles were removed in vacuo. Toluene was added and all volatiles were removed in vacuo for a second time. The crude material was dissolved in DMF / MeCN (2 mL, 1:1) at room temperature. A solution of N-Cbz-4-cyclopropyl (L) Proline (0.84 mmol) and DIEA (268 mg, 2.08 mmol) in MeCN (2 mL) was added and stirring at room temperature was 20 continued. After 14 hours, most of the MeCN was removed in vacuo and the crude reaction mixture was diluted with EtOAc. The mixture was washed with aqueous HCI (IM), aqueous LiCI solution (5%), brine, and was dried over sodium sulfate. Filtration and evaporation of solvents gave the crude reaction product, which was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5 25 benzyl ester 6-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl] ester (176 mg). LCMS ESl*: calc'd for C 30

H

24 BrF 2

NO

5 : 596.4 (M *); Found: 595.2 / 597.2 (M+H*). 6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yll-5-aza-spiro[2.4]heptane-5 30 carboxylic acid benzyl ester: 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-9,9-difluoro-9H fluoren-2-yl)-2-oxo-ethyl] ester (172 mg, 0.293 mmol) was dissolved in m-xylenes (6.0 mL). Ammonium acetate (226 mg, 2.93 mmol) was added and the reaction was stirred at 140'C for 60 minutes under microwave conditions. The reaction was cooled to room temperature and all 35 volatiles were removed in vacuo. The crude material was purified via silica gel chromatography 672 (eluent: EtOAc / hexanes) to yield the product 6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl) I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (80.3 mg). LCMS ESI: calc'd for C 30

H

2 4 BrF 2

N

3 0 2 : 576.4 (M *); Found: 575.2 / 577.2 (M+H*). 5 (1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: 6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)- I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5 carboxylic acid benzyl ester (800 mg, 1.38 mmol) was dissolved in DCM (15 mL) and HBr in 10 AcOH (37%, 2 mL) was added and stirring at room temperature was continued. After 180 minutes, the suspension was diluted with hexanes and the solid was collected via filtration and was washed with hexanes and subjected to vacuum. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (4.0 mL) and DIEA (356 mg, 2.76 mmol) was added. A solution of 2-(L)-Methoxycarbonylamino-3-methyl-butyric 1 5 acid (242 mg, 1.38 mmol), HATU (524 mg, 1.38 mmol) and DIEA (178 mg, 1.38 mmol) in DMF (I mL) was added. The reaction was stirred at room temperature. After 50 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by silica gel chromatography (eluent: 20 EtOAc / hexanes) to yield the slightly impure product (1-{6-[5-(7-Bromo-9,9-difluoro-9H fluoren-2-yl)-1 H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl) carbamic acid methyl ester (878 mg). LCMS-ESI: calc'd for C 2 9

H

2 9 BrF 2

N

4 0 3 : 599.5 (M *); Found: 598.5 / 600.5 (M+H*). 25 3 -1 6 -(9,9-Difluoro-7-{2-5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yI)-9H-fluoren-2-yl)-1 H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: (I -{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)- I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (840 mg, 1.4 mmol), 3-[6-(4,4,5,5 30 Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)- I H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2 carboxylic acid tert-butyl ester (615 mg, 1.4 mmol), Pd(PPh 3

)

4 (161 mg, 0.14 mmol), K 2 CO3 (579 mg, 4.2 mmol), were dissolved in DME (15 mL) / water (3 mL) under an argon atmosphere. The mixture was heated for 120 minutes at 85 - 90'C (oil bath). After 120 minutes additional boronate ester (61 mg, 0.14 mmol) was added and heating was continued. After 3 35 hours, the reaction was cooled to room temperature. Most of the DME was removed in vacuo 673 and the crude reaction mixture was diluted with EtOAc. The mixture was washed with brine and was dried over sodium sulfate. Filtration and evaporation of solvents gave the crude reaction product, which was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5 5 aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-I H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.I]heptane-2-carboxylic acid tert-butyl ester (878 mg). LCMS-ESI*: calc'd for

C

47

H

5 1

F

2

N

7 0 5 : 831.9 (M *); Found: 832.7 (M+H*). (1-{ 3

-[

6 -(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza 10 spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3 H-imidazol-4-yl}-9H-fluoren-2-yI)-I H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2. 1 ]heptane-2 carboxylic acid tert-butyl ester(l 15 mg, 0.138 mmol) was dissolved in DCM (2 mL) and HCI in 15 dioxane (4M, 2 mL) was added and stirring at room temperature was continued. After 20 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and DIEA (53.4 mg, 0.414 mmol) was added. A solution of 2- (L) Methoxycarbonylamino-3-methyl butyric acid (24.2 mg, 0.138 mmol), HATU (52.4 mg, 0.138 mmol) and DIEA (17.8 mg, 0.138 20 mmol) in DMF (I mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCI solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (1-{3-[6-(9,9-Difluoro-7-{2-[5-(2 25 methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H fluoren-2-yl)-l H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carbonyl)-2-methyl propyl)-carbamic acid methyl ester (76 mg). LCMS-ESI*: calc'd for C 49

H

54

F

2

N

8 0 6 : 888.9 (M ); Found: 890.0 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.20-7.99 (m, 8H), 7.73 (s, 2H), 7.37 - 7.27 (m, 2H), 5.25 30 (dd, J = 7.2 Hz, I H), 4.78 (s, 1 H) 4.54 (s, I H), 4.16 (m, I H), 4.02 (m, I H), 3.87 (m, I H), 3.74 (m, I H), 3.55 (s, 3H), 3.53 (s, 3H), 2.75 (m, I H), 2.25 (m, 2H), 2.09 - 2.04 (m, 2H), 1.88 - 1.79 (m, 2H), 1 .54 (m, I H), 0.94 - 0.77 (m, 15H) 0.63 (m, 4H) ppm. 1 9 F-NMR: 282 MHz, (dmso d 6 ) 8: -109.1 ppm [-74.8 ppm TFA] 35 674 Example EE -oc Noc ;4 H 4 &N BOC 245 7-Brmo-,1 Dd hyro.NaHCO3 2-[5-(7-Bromo-9,10-dihydro- 3-{6-{4.4.5,5-TetramethyI- OME 3-(6-{7-{2-(1 -tert-8utoxycarbonyt-pyrrolidin-2-yl)-3H phenianthren-2-yi -1 H-im idazo k (C1, 3,2jdioxaboroan2yI)-1 H- im idazol -4-ylI-9 1 O-dihydro-phe,,anthren-2-y)- 1 H 2-yI] -pyrrol idine- I-carboxyl ic benzoimidazol-2-yt)-2-aza. berizoanhidazo-2-yI)-2-aza-icyclo[2.2. 1 ]hoptane-2 acid tert-butyt ester bicyclo[22 1] heptane-2 -carboxytic carboxylic acid tert-butyl ester acid ter-Lqtyl ester /ON O N HK_0__ N \.- H H TFA HATU

CH

2 Cl 2 DIPEA (1 -3-[6-(7-{2{1-(2-Methoxycarbonylamino-3-methy-butyryt). DMF pyrrol'din-2-ytJ-3H-imidazol-4-yI)-9 1 O-diydro-phenanttiren-2 Yi).l H-benzoimidazoI-2-yt]-2-aza-bicycb[2.2 Iljhepterle-2. carboy)-2-methy-propy)-carbamic acid methyl ester 3-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-y)-3H-imidazol-4-yl]-9,10-dihydro 5 phenanthren-2-yl}-1H-benzoimidazol-2-yI)-2-aza-bicyclo[2.2.1Iheptane-2-carboxylic acid tert-butyl ester. Pd(Ph 3

)

4 (20 mg, 0.0 17 mmol) was added to a mixture 2-[5-(7-bromo-9,10 dihydro-phenanthren-2-yl)-i H-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (173 mg, 0.35 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 H-benzoimidazol-2-yl] 2-aza-bicyclo[2.2.I]heptane-2-carboxylic acid tert-butyl ester (154 mg, 0.35 mmol), NaHCO 3 10 (103 mg, 1.22 mmol) in 1,2-dimethoxyethane (5 mL) and water (1 mL). The reaction mixture was flushed with nitrogen, heated at 80'C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 3-(6-{7-[2-(1-tert 15 Butoxycarbonyl-pyrrolidin-2-yl)-3 H-imidazol-4-yl]-9,l 0-dihydro-phenanthren-2-yl} - I -1 benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester as a white solid (150 mg, 59%). m/z 727.4 (M+H)*. (1-{3-[6-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yll-3H 20 imidazol-4-yl}-9,1 O-dihydro-phenanthren-2-y)-1 H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.1]heptane-2-carbonyll-2-methyl-propyl)-carbamic acid methyl ester: To a solution of 3-(6-{7-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yIJ-9,10-dihydro phenanthren-2-yl}- I H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert butyl ester (135 mg, 0.19 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 25 mL, excess). The mixture was stirred for 2 hours at ambient temperature and concentated under reduced pressure. The residue was treated with ether to remove excess trifluoroacetic acid. The 675 obtained white solid was dissoved in DMF (5 mL), to the solution was added 2 methoxycarbonylamino-3-methyl-butyric acid (65 mg, 0.37 mmol), HATU (156 mg, 0.41 mmol) and NN-diisopropylethylamine (0.32 mL, 1.86 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was 5 dissolved in ethyl acetate (100 mL), washed with I N NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (I -{3-[6-(7-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-9,1 0-dihydro-phenanthren-2-yl)-l H-benzoimidazol-2-yl]-2 aza-bicyclo[2.2.l]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as a TFA 10 salt (57 mg, 36%). 'H-NMR (300 MHz, CD 3 0D) 8 8.05-7.60 (m, 10H), 5.25 (t, I H), 4.40-4.05 (m, 3 H), 3.95-3.60 (m, 8H), 3.10-2.90 (m 6H), 2.65-2.50 (m, I H), 2.40-1.70 (m, I I H), 1.05-0.90 (m, 12H); m/z 839.2 (M+H)*. 676 Example EF OEt Boc B S n(Bu) 3 Boc N B oc N \ - ,I'-- N B r 1. Pd(PPh 3

)

4 H PdCl 2 (PPh 3

)

2 2-[5-(7-Bromo-9,10-dihydro- 2. NBS/H 2 0 2-{5-[7-(2-Bromo-acetyl)-9,10-dihydro phenanthren-2-yl)-1 H-imidazol- phenanthren-2-yl]-1 H-imidazol-2-yl} 2-yl]-pyrrolidine-1-carboxylic pyrrolidine-1-carboxylic acid tert-butyl ester acid tert-butyl ester 1Boc N. N N 0L2 H- H Boc HOOC N Boc 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic 2-Aza-bicyclo[2.2.1 ]heptane- acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidin-2 2,3-dicarboxylic acid 2-tert- yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2 butyl ester yI}-2-oxo-ethyl) ester 2-tert-butyl ester DIEA, MeCN Boc N NN NN o NH40Ac xylene 3-(5-{7-[2-(1 -tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol 4 -yl]-9, 1 0-dihydro-phenanthren-2-y}-1 H-imidazol-2-yl)-2 aza-bicyclo[2.2. 1 ]heptane-2-carboxylic acid tert-butyl ester O O HO NH O N 0 N'~ N N / \ N -11 N N N 0 TFA HATU H

CH

2

CI

2 DIPEA H-N DMF 0 -O (2-{3-[5-(7-{2-[1-(2-Methoxycarbonylamino-propionyl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-9, 10-dihydro-phenanthren 2-yI)-1 H-imidazol-2-yl]-2-aza-bicyclo[2.2. 1 ]hept-2-yl}-1 methyl-2-oxo-ethyl)-carbamic acid methyl ester 5 2-{5-[7-(2-Bromo-acetyl)-9,10-dihydro-phenanth ren-2-yl]-1 H-imidazol-2-yl}-pyrrolidine-1 carboxylic acid tert-butyl ester. Pd(Ph 3

)

4 (15 mg, 0.015 mmol) and PdC 2 (Ph 3

)

2 (10 mg, 0.0 15 mmol) were added to a mixture 2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)- H-imidazol-2 yl]-pyrrolidine-I-carboxylic acid tert-butyl ester (180 mg, 0.37 mmol) and tributyl(l 10 ethoxyvinyl)tin (0.15 mL, 0.44 mL) in 5 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 80*C for 16 hours, then cooled to ambient temperature. Water (1.5 mL) and NBS (78 mg, 0.44 mmol) was added and the mixture was stirred at room temperature for 40 677 minutes, then diluted with ethyl acetate (100 mL). Washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was carried on to next step reaction without purification. 5 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl pyrrolidin-2-yl)-3H-imid azol-4-y]-9,10-dihydro-phenanthren-2-yl}-2-oxo-ethyl) ester 2 tert-butyl ester. A mixture of 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (167 mg, 0.69 mmol) and DIPEA (0.11 mL, 0.67 mmol) was added to a solution of 2-{5 [7-(2-bromo-acetyl)-9, I 0-dihydro-phenanthren-2-yl]- I H-imidazol-2-yl}-pyrrolidine-1 10 carboxylic acid tert-butyl ester (0.37 mmol, crude) in acetonitrile (5 mL). The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO 3 solution and water, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2-aza-bicyclo[2.2. I ]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert 15 butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,1 0-dihydro-phenanthren-2-yl}-2-oxo ethyl) ester 2-tert-butyl ester as a brown solid (132 mg, 51% over two steps). m/z 697.2 (M+H)*. 3-(5-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-y)-3H-imidazol-4-yl]-9,10-dihydro 20 phenanth ren-2-yl}-1 H-imidazol-2-yi)-2-aza-bicyclo[2.2.11 heptane-2-carboxylic acid tert butyl ester. A mixture of 2-aza-bicyclo[2.2.I]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-terl butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,1 0-dihydro-phenanthren-2-yl}-2-oxo ethyl) ester 2-tert-butyl ester (132 mg, 0.19 mmol) and ammonium acetate (292 mg, 3.8 mmol) in xylene (10 mL) was heated in a sealed tube at 140*C for 1.5 hours under microwave 25 condition. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (100 mL), washed with NaHC0 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 3-(5-{7-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-y)-3H-imidazol 4-yl]-9,10-dihydro-phenanthren-2-yl}-I H-imidazol-2-yl)-2-aza-bicyclo[2.2.l]heptane-2 30 carboxylic acid tert-butyl ester as a white solid (36 mg, 28%). m/z 677.4 (M+H)*. (2-{3-[5-(7-{2-[1-(2-Methoxycarbonylamino-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} 9,10-dihydro-phenanthren-2-yl)-H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]hept-2-yl}-1-methyl 2-oxo-ethyl)-carbamic acid methyl ester. To a solution of 3-(5-{7-[2-(l-tert-Butoxycarbonyl 35 pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl}-1 H-imidazol-2-yl)-2-aza 678 bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (36 mg, 0.053 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL, excess). The mixture was stirred for 2 hours at ambient temperature and concentated under reduced pressure. The residue was treated with ether to remove excess trifluoroacetic acid. The obtained white solid was dissoved 5 in DMF (5 mL), to the solution was added 2-methoxycarbonylamino-propionic acid (17 mg, 0.12 mmol), HATU (50 mg, 0.13 mmol) and NN-diisopropylethylamine (0.09 mL, 0.53 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with I N NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue 10 was purified by HPLC to provide the desired product (2-{3-[5-(7-{2-[1-(2 Methoxycarbonylamino-propionyl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-9,1 0-dihydro phenanthren-2-yl)-1 H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]hept-2-yl}-1 -methyl-2-oxo-ethyl) carbamic acid methyl ester as a TFA salt (5.5 mg, 14%). 'H-NMR (300 MHz, CD 3 OD) 8 8.05 7.60 (m, 8H), 5.35-5.25 (m, I H), 4.65-4.40 (m, 3H), 4.05-3.80 (m, 2H), 3.75-3.50 (m, 7H), 3.00 15 (s, 4H), 2.87 (s, I H), 2.65 (m, I H), 2.30-1.70 (m, 9H), 1.45-1.20 (m, 6H); m/z 735.3 (M+H)*. 679 Example EG 0/ O 'N N ~ / - Br 0 K 0 BocN N O O N-OBr HHCI HATU I MeOH DIPEA H 2-[5-(7-Bromo-9,10-dihydro- DMF (1-{2-[5-(7-Bromo-9,10-dihydro-phenanthren phenanthren-2-yl)-1H-imidazol- 2 -yl)-lH-imidazol-2-yl)-pyrrolidine-1-carbonyl) 2-yl]-pyrrofidine-1 -carboxylic 2-methyl-propyl)-carbamic acid methyl ester acid tort-butyl ester OEt H Sn(Bu) 3 DIEA, DMF O- N 0 0 H N N 1. Pd(PPh 3

)

4 Boc' PdCI 2 (PPh 3

)

2 Hf H HOC HOOC N 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-fert 2. NBS/H 2 0 Boc butyl ester 3-[2-(7-{2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl)-9,1 0 dihydro-phenanthren-2-yl)-2-oxo-ethyl] ester 0 - /\ 1 ~N NH40Ac N N Boc xylene e; 3-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrroidin-2 yl]-3H-imidazol-4-yl}-9,1 0-dihydro-phenanthren-2-y)-1 H-imidazol-2 y]-2-aza-bicydo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 0 O/ O TFA HATU N N

CH

2 Cl 2 DIPEA - H-N DMF O -o (1 -{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza bicydo[2.2.1]hept-3-y]-3H-imidazol-4-yl)-9,10-dihydro phenanthren-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester 5 (1-{2-[5-(7-Bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. To a solution of 2-[5-(7-bromo 9,10-dihydro-phenanthren-2-yl)- IH-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (187 mg, 0.38 mmol) in methanol (5 mL) was added 4.0 M solution of HCI in dioxane (2 mL, excess). The mixture was stirred for 3 hours at 50'C and concentated under reduced pressure. 10 The residue was treated with ether to remove excess HCL. The obtained white solid was dissoved in DMF (5 mL), to the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (70 mg, 0.40 mmol), HATU (173 mg, 0.46 mmol) and NN-diisopropylethylamine (0.66 mL, 3.8 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with I N 680 NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (I-{2-[5 (7-bromo-9,1 0-dihydro-phenanthren-2-yl)- I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester as an oil (200 mg, 95%). m/z 551.2, 553.2 (M+H)*. 5 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-[2-(7-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y-3H-imidazol-4-yl}-9,10 dihydro-phenanthren-2-y)-2-oxo-ethyl] ester: Pd(Ph 3

)

4 (15 mg, 0.015 mmol) and PdCl 2 (Ph 3

)

2 (10 mg, 0.015 mmol) were added to a mixture of (1-{2-[5-(7-bromo-9,10-dihydro 10 phenanthren-2-yl)- IH-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (200 mg, 0.37 mmol) and tributyl(1 -ethoxyvinyl)tin (0.15 mL, 0.44 mL) in 5 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 80'C for 16 hours, then cooled to ambient temperature. Water (1.5 mL) and NBS (78 mg, 0.44 mmol) was added and the mixture was stirred at room temperature for 40 minutes, then diluted with ethyl acetate (100 15 mL). Washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was disolved in acetonitrile (3 mL). To it was added a solution of 2-aza bicyclo[2.2.I]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (167 mg, 0.69 mmol) and DIPEA (0.11 mL, 0.67 mmol) in 2 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO 3 20 solution and water, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2-Aza bicyclo[2.2.1 ]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-[2-(7-{2-fl-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-9,1 0-dihydro phenanthren-2-yi)-2-oxo-ethyl] ester as a brown oil (130 mg, 47% over two steps). m/z 754.3 25 (M+H)*. 3-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4 yl}-9,10-dihydro-phenanthren-2-yI)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2 carboxylic acid tert-butyl ester. A mixture of 2-Aza-bicyclo[2.2.l]heptane-2,3-dicarboxylic 30 acid 2-tert-butyl ester 3-[2-(7-{2-[l-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3 H-imidazol-4-yl}-9,1 0-dihydro-phenanthren-2-yl)-2-oxo-ethyl] ester (130 mg, 0.17 mmol) and ammonium acetate (292 mg, 3.8 mmol) in xylene (10 mL) was heated in a sealed tube at 140*C for 1.5 hours under microwave condition. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, 35 water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue 681 was purified by flash chromatography to provide the desired product 3-[5-(7-{2-[I-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-y}-9, I 0-dihydro phenanthren-2-yl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester as a white solid (38 mg, 28%). m/z 734.4 (M+H)*. 5 (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H imidazol-4-yl}-9,10-dihydro-phenanthren-2-y)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester. To a solution of 3-[5-(7-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl-3H-imidazol-4-yl}-9,10-dihydro 10 phenanthren-2-yl)-i H-imidazol-2-yl]-2-aza-bicyclo[2.2.l]heptane-2-carboxylic acid tert-butyl ester (38 mg, 0.052 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL, excess). The mixture was stirred for 2 hours at ambient temperature and concentated under reduced pressure. The residue was treated with ether to remove excess trifluoroacetic acid. The obtained white solid was dissoved in DMF (5 mL), to the solution was added 2 15 methoxycarbonylamino-propionic acid (9 mg, 0.06 mmol), HATU (30 mg, 0.08 mmol) and NN diisopropylethylamine (0.09 mL, 0.53 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with I N NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired 20 product (I -{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2. I ]hept-3-yl] 3 H-imidazol-4-yl}-9,1 0-dihydro-phenanthren-2-yl)-l H-imidazol-2-yl]-pyrrolidine- I -carbonyl} 2-methyl-propyl)-carbamic acid methyl ester as a TFA salt (15 mg, 39%). 'H-NMR (300 MHz,

CD

3 0D) 8 8.10-7.60 (m, 8H), 5.35-5.25 (m, I H), 4.70-4.45 (m, 3H), 4.30-3.80 (m, 3H), 3.67 (s, 6H), 2.70-1.60 (m, 12H), 1.41 (d, 3H), 1.05-0.80 (m, 6H); m/z 763.3 (M+H)*. 25 682 Example EH OEt - -'-EBr Br SnB Br Br2 1. Pd(PPh 3

)

4 0I >/ 9.10-Dihydro-phenanthrene 2,7-Dibromo-9,10- PdCl 2 (PPh 3

)

2 HOOC'N Pyrrolidine-1,2-dicarboxylic acid 2-{2-(7 dihydro-phenanthrene 2. NBS/H 2 0 Boc bromo-9,10-dihydro-phenanthren-2-yl)-2 DIEA, DMF oxo-ethyll ester 1-tert-buty ester OEt 1. dSn(Bu) 3 POc Iq 00 00 H 1. Pd(PPh 3 ) C C l -, PdCI 2 (PPh 3

)

2 H Bc' HOOC 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-{2-(1-tert 2. NBS/H 2 0 Boc butoxycarbonyl-pyrrolidine-2-carbonytoxy)-acetyl}-9,10-dihydro DIEA,MeCN phenanthren-2-yi)-2-oxo-ethyl) ester 2-tert-buty ester HH 110c N\ - / \1 I j \ / \ 1" NH40Ac Bo cc xylene H 3-(5-{7-{2-(1-tert-Butoxycarbonyt-pyrrolidin-2-yl)-3H-imidazol4 ylI- 9 ,10-dihydro-phenanthren-2-yl-1H-imidazol-2-yl)-2-aza bicyclo[2.2. lheptane-2-carboxylic acid tert-butyl ester ON HCI HATU MeOH DIPEA H-N DMF O -0 (1-{3-{5-(7-{2-{1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl}3H imidazol-4-yl}-9,10-dihydro-phenanthren-2-y)-1 H-imidazol-2-yl}-2-aza bicydo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 5 2,7-Dibromo-9,10-dihydro-phenanthrene. Bromine (6.13 mL, 19.3 mmol) was added slowly to a solution of 9,10-dihydro-phenanthrene (10 g, 55.5 mmol) in trimethylphosphate (100 mL). The mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was recrystallized from chloroform to give product 2,7-Dibromo-9,1 0-dihydro phenanthrene as a white crystal (9.45g, 5 1%). 10 Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-9,10-dihydro-phenanthren-2-yl)-2-oxo ethyl] ester 1-tert-butyl ester. Pd(Ph 3

)

4 (347 mg, 0.3 mmol) and PdC 2 (Ph 3

)

2 (210 mg, 0.3 mmol) were added to a mixture 2,7-dibromo-9,10-dihydro-phenanthrene (2.5 g, 7.4 mmol) and tributyl(1 -ethoxyvinyl)tin (2.5 mL, 7.4 mL) in 70 mL dioxane. The reaction mixture was 15 flushed with nitrogen, heated at 80'C for 16 hours, then cooled to ambient temperature. Water (20 mL) and NBS (1.39 g, 7.8 mmol) were added and the mixture was stirred at room temperature for 40 minutes, then diluted with ethyl acetate (300 mL). Washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was 683 suspended in acetonitrile (70 mL). To it was added a solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.2 g, 14.9 mmol) and DIPEA (2.4 mL, 14.1 mmol) in 20 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (300 mL). The organic layer was washed with NaHCO 3 solution and water, dried over 5 Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo 9,10-dihydro-phenanthren-2-yl)-2-oxo-ethyl] ester 1-tert-butyl ester as a white solid (1.76 g, 46% over two steps). m/z 514.2, 516.2 (M+H)*. 10 2-Aza-bicyclo[2.2.11heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl pyrrolidine-2-carbonyloxy)-acetyl]-9,10-dihydro-phenanthren-2-yl}-2-oxo-ethyl) ester 2 tert-butyl ester. Pd(Ph 3

)

4 (37 mg, 0.03 mmol) and PdC 2 (Ph 3

)

2 (22 mg, 0.03 mmol) were added to a mixture of pyrrolidine- 1,2-dicarboxylic acid 2-[2-(7-bromo-9,1 0-dihydro-phenanthren-2 yl)-2-oxo-ethyl] ester 1-tert-butyl ester (410 mg, 0.8 mmol) and tributyl(1 -ethoxyvinyl)tin (0.32 15 mL, 0.96 mmol) in 8 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 80'C for 16 hours, then cooled to ambient temperature. Water (2 mL) and NBS (171 mg, 0.96 mmol) were added and the mixture was stirred at room temperature for 40 minutes, then diluted with ethyl acetate (100 mL). Washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. Half of the obtained residue was suspended in acetonitrile (5 mL). To it 20 was added a solution of 2-aza-bicyclo[2.2.l]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.41 mmol) and DIPEA (0.068 mL, 0.39 mmol) in 2 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO 3 solution and water, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide 25 the desired product 2-aza-bicyclo[2.2. I ]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(l -tert butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-9,1 0-dihydro-phenanthren-2-yl}-2-oxo ethyl) ester 2-tert-butyl ester as a white solid (171 mg, 60% over two steps). m/z 717.2 (M+H)*. 3-(5-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yll-9,10-dihydro 30 phenanthren-2-yl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert butyl ester. A mixture of 2-aza-bicyclo[2.2.1 ]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(l -tert butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-9,1 0-dihydro-phenanthren-2-yl}-2-oxo ethyl) ester 2-tert-butyl ester (171 mg, 0.24 mmol) and ammonium acetate (800 mg, 10.2 mmol) in xylene (5 mL) was heated in a sealed tube at 140*C for 1.5 hours under microwave condition. 35 The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate 684 (100 mL), washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product of 3-(5-{7-[2-(l -tert-butoxycarbonyl-pyrrolidin-2-yl)-3 H-imidazol-4-yl] 9,1 0-dihydro-phenanthren-2-yl} -l H-imidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic 5 acid tert-butyl ester as a white solid (100 mg, 62%). m/z 677.9 (M+H)*. (1-{3-[5-(7-{2-11-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-2-aza bicyclo[2.2.11heptane-2-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester. To a 10 solution of 3-(5- {7-[2-(] -tert-butoxycarbonyl-pyrrolidin-2-y)-3 H-imidazol-4-yl]-9,l 0-dihydro phenanthren-2-yl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.l]heptane-2-carboxylic acid tert-butyl ester (100 mg, 0.15 mmol) in methanol (5 mL) was added 4.0 M solution of HCI in dioxane (2 mL, excess). The mixture was stirred for 3 hours at 50'C and concentated under reduced pressure. The residue was treated with ether to remove excess HCL. The obtained white solid 1 5 was dissoved in DMF (5 mL), to the solution was added 2-methoxycarbonylamino-3-methyl butyric acid (54 mg, 0.31 mmol), HATU (141 mg, 0.37 mmol) and NN-diisopropylethylamine (0.2 mL, 1.2 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with I N NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. 20 The obtained residue was purified by HPLC to provide the desired product (I-{3-[5-(7-{2-[I-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} -9,01 -dihydro phenanthren-2-yl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carbonyl }-2-methyl propyl)-carbamic acid methyl ester as TFA salt (67 mg, 57%). 'H-NMR (300 MHz, CD 3 0D) 6 8.05-7.65 (m, 8H), 5.35-5.20 (m, I H), 4.40-4.05 (m, 3H), 3.95-3.80 (m, I H), 3.67 (d, 6H), 3.05 25 2.80 (m, 5H), 2.70-2.50 (m, I H), 2.40-1.60 (m, 13 H), 1.10-0.85 (m, 12H); m/z 791.3 (M+H)*. 685 Example EI Br Br Br BBr O B Mel 0 \ KOH Pd(PPh 3

)

4 2 .7 -D ib ro m o -9 H -flu o re n e D M S O 2 .7 .D ib ro m o -9 .- K O Ac n e 5xa n e1 t2] m eox a b -2 y ) 9 d, te y l dimetyi-SH-flurene 1,4-dioxane ,,,-erm ty2[7(4,.tta ehy dimehyl9H-luoene[1 ,3,2]dioxaborolan-2-yl)-9.9-dimrethy-9H-fluoren-2 ylF[1,3,2]dioxaborolane Br BH Boc Pd(PPh 3

)

4 NaHC 3 2-(5-{7-[2-(1-Boc-pyrrolidin-2-y)-3H-imidazol-4-yy DMEtwater 9,9-dimethyl-9H-fluoren-2-y-1 H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester OH H N- HN HCI HATU H 0 MeOH DIPEA L DMF (1 -{2-[5-(7-{2-[1-(2-Methoxycarbonyamino-3-methyl butyryl)-pyrdin-2-yk3H-imidaz-4-y} 9,9-dimethy-9H fluoren-2-yl)-1i-imidazol-2-yl-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic add methyl ester 2,7-Dibromo-9,9-dimethyl-9H-fluorene. To a stirred solution of 2,7-dibromo-9H-fluorene (1.0 5 g, 3.1 mmol), KI (50 mg, 0.3 mmol) and KOH (750 mg, 13.3 mmol) in DMSO was added methyl iodide (0.42 mL, 6.8 mmol). The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2,7-Dibromo-9,9-dimethyl-9H-fluorene as 10 a white solid (I.1 g, 100%). 4,4,5,5-Tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,9-dimethyl-9H fluoren-2-yl]-[1,3,2]dioxaborolane. Pd(PPh 3

)

4 (347 mg, 0.3 mmol) was added to a flask containing a mixture of 2,7-dibromo-9,9-dimethyl-9H-fluorene (1.0 g, 2.9 mmol), 15 bis(pinacolato)diboron (2.9 g, 11.6 mmol), potassium acetate (1.4 g, 14.5 mmol) and 1,4 dioxane (30 mL). The reaction mixture was flushed with nitrogen, heated at 80*C for 16 hours, then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL), washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 20 4,4,5,5-Tetramethyl-2-[7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-9,9-dimethyl-9H fluoren-2-yl]-[1,3,2]dioxaborolane as a white solid (0.8 g, 62%). 686 2-(5-{7-12-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,9-dimethyl-9H-fluoren-2-yl}-1H imidazol-2-yI)-pyrrolidine-1-carboxylic acid tert-butyl ester. Pd(Ph 3

)

4 (55 mg, 0.05 mmol) was added to a mixture 4,4,5,5-Tetramethyl-2-[7-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl) 9,9-dimethyl-9H-fluoren-2-yl]-[ 1,3,2]dioxaborolane (205 mg, 0.48 mmol), 2-(4-bromo- I H 5 imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (309 mg, 0.98 mmol), NaHCO 3 (282 mg, 3.4 mmol) in 1,2-dimethoxyethane (8 mL) and water (I mL). The reaction mixture was flushed with nitrogen, heated at 80*C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained 10 residue was purified by HPLC to provide the desired product 2-(5-{7-[2-(1 -Boc-pyrrolidin-2 yl)-3H-imidazol-4-yl]-9,9-dimethyl-9H-fluoren-2-yl}- I H-imidazol-2-yl)-pyrrolidine- 1 carboxylic acid tert-butyl ester as a TFA salt (45 mg, 14%). m/z 665.4 (M+H)*. (1-{2-15-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yll-3H 15 imidazol-4-yl}-9,9-dimethyl-9H-fluoren-2-y)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2 methyl-propyl)-carbamic acid methyl ester. To a solution of 2-(5-{7-[2-(1-Boc-pyrrolidin-2 yl)-3 H-imidazol-4-yl]-9,9-dimethyl-9H-fluoren-2-yl}-1 H-imidazol-2-yl)-pyrrolidine- I carboxylic acid tert-butyl ester (45 mg, 0.07 mmol) in methanol (5 mL) was added 4.0 M solution of HCI in dioxane (1 mL, excess). The mixture was stirred for 3 hours at 50*C and 20 concentated under reduced pressure. The residue was treated with ether to remove excess HCL. The obtained white solid was dissoved in DMF (5 mL), to the solution was added 2 methoxycarbonylamino-3-methyl-butyric acid (25 mg, 0.14 mmol), HATU (65 mg, 0.17 mmol) and NN-diisopropylethylamine (0.09 mL, 0.54 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in 25 ethyl acetate (100 mL), washed with I N NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (1 -{2-[5-(7-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-imidazol-4-yl} -9,9-dimethyl-9H-fluoren-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as TFA salt (15 mg, 28%). 'H-NMR 30 (300 MHz, CD 3 0D) 8 8.05-7.70 (m, 8H), 5.35-5.20 (m, 2H), 4.30-3.80 (m, 6H), 3.67 (s, 6H), 2.65-2.00 (m, 10H), 1.61 (s, 6H), 1.05-0.85 (m, 12H); m/z 779.4 (M+H)*. 687 Example EJ 00 Br Br rBr LiBH H 3 PO Br Br

H

2 0 2 -urea THF 27Dboofurn-oeCH 2

CI

2 3,8-Dibromo- TF3,8-Dibrum-6H 2,7-Dibromo-fluoren-9-one Cbenzo[c] romen-6-one benzo[c]chromene OEt "Sn(B) 3 O0 0 1. Pd(PPh 3

)

4 O/ 0 N PdCl 2 (PPh 3

)

2 HOOC'N Boc Boc Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2 2. NBS/H 2 0 DIPEA, DMF (2-{8-[2-(1 -Boc-pyrrolidine-2-carbonyloxy)-aoetyl]-6H benzo[c]chromen-3-yl)-2-oxo-ethyl) ester 0 _______ Bc N -N No NH40Ac N N xylene H 2-(5-{8-[2-(1-Boc-pyrrolidin-2-y)-3H-imidazol-4-yl] 6H-benzo[c]chromen-3-yl}-1H-imidazol-2-yl) OH0 pyrrolidine-1-carboxylic acid tert-butyl ester 0 0~N N N TFA HATU 0 H O H DCM OIPEA HO DMF <J/0 (1 -{2-[5-(3-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yI)-6H-benzo[c]chromen-8-yl)-1 H-imidazo-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 3,8-Dibromo-benzo[clchromen-6-one. A solution of TFAA (2.1 mL, 3.15 mmol) in 5 dichloromethane (5 mL) was added dropwise to a suspension of 2,7-dibromo-fluoren-9-one (3.3 g, 10 mmol) and H 2 0 2 -urea (1.4 g, 15 mL) in dichloromethane (50 mL). The mixture was stirred at room temperature for 48 hours, a second portion of H 2 0 2 -urea was added, and stirring was continued at room temperature for a further 72 hours. The mixture was filtered, the organic phase was extracted with water (50 mL), and dried over Na 2

SO

4 . After removal of solvent, the 10 residue was heated with 2N NaOH at 80*C for 10 minutes, filtered, the cooled filtrate extracted with ether. The aqueous phase was acidified with 2N HCI and extracted with ethyl acetate (200 mL). HCI (2 mL 4M solution) was added to the ethyl acetate and heated for 2 hours. The solvent was removed under vacuum, the residue was recrystallized from ethyl acetate/ethanol to give the final product 3,8-Dibromo-benzo[c]chromen-6-one as a white solid (1.5 g, 40%). 15 3,8-Dibromo-6H-benzo[cjchromene. To a solution of 3,8-dibromo-benzo[c]chromen-6-one (650 mg, 1.85 mmol) in THF (20 mL) was added 2 M solution of LiBH 4 in THF (3.7 mL, 7.4 mmol). The mixture was stirred for 3 hours at room temperature. Quenched slowly with ammonium chloride solution. The mixture was extracted with ethyl acetate, dried over Na 2

SO

4 , 688 filtered and concentrated in vacuo. The obtained residue was suspended in 85% phosphoric acid (20 mL) and heated at 160'C for 4h. The mixture was extracted with ethyl acetate, washed with water, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 3,8-Dibromo-6H-benzo[c]chromene as a 5 white solid (539 mg, 86%). Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-(2-{8-12-(1-Boc-pyrrolidine-2 carbonyloxy)-acetyl] -6H-benzo [c] ch romen-3-yl}-2-oxo-ethyl) ester. Pd(PPh 3

)

4 (74 mg, 0.064 mmol) and PdC 2 (Ph 3

)

2 (45 mg, 0.064 mmol) were added to a mixture 3,8-dibromo-6H 10 benzo[c]chromene (539 mg, 1.6 mmol) and tributyl(I-ethoxyvinyl)tin (1.2 mL, 3.5 mL) in 20 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 80'C for 16 hours, then cooled to ambient temperature. Water (7 mL) and NBS (623 mg, 3.5 mmol) were added and the mixture was stirred at room temperature for 40 minutes, then diluted with ethyl acetate (300 mL). The solid was filtered and kept separately. The ethyl acetate layer was washed with water 15 and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue conbine with the solid collected before was suspended in acetonitrile (20 mL) and DMF (10 mL). To it was added a solution of pyrrolidine-I,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol) and DIPEA (1.2 mL, 7.1 mmol) in 5 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (300 mL). The organic layer was 20 washed with NaHCO 3 solution and water, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product Pyrrolidine- I,2-dicarboxylic acid I -tert-butyl ester 2-(2-{8-[2-(l -Boc-pyrrolidine-2 carbonyloxy)-acetyl]-6H-benzo[c]chromen-3-yl}-2-oxo-ethyl) ester as a white solid (602 mg, 54% over two steps). m/z 715.2 (M+Na)*. 25 2-(5-{8-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-6H-benzolclchromen-3-yl}-1

H

imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester. A mixture of pyrrolidine-1,2 dicarboxylic acid I -tert-butyl ester 2-(2-{8-[2-(] -Boc-pyrrolidine-2-carbonyloxy)-acetyl]-6H benzo[c]chromen-3-yl}-2-oxo-ethyl) ester (168 mg, 0.24 mmol) and ammonium acetate (374 30 mg, 4.8 mmol) in xylene (10 mL) was heated in a sealed tube at 140'C for 1.5 hours under microwave condition. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2-(5-{8-[2-(l -Boc-pyrrolidin-2-yl)-3H-imidazol 689 4-yl]-6H-benzo[c]chromen-3-yl } - H-imidazol-2-yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester as a white solid (100 mg, 64%). m/z 653.4 (M+H)*. (1-{2-15-(3-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyry)-pyrrolidin-2-yl]-3H 5 imidazol-4-yIl-6H-benzolclchromen-8-yl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester. To a solution of 2-(5-{8-[2-(l-Boc-pyrrolidin-2 yl)-3H-imidazol-4-yl]-6H-benzo[c]chromen-3-yl}- I H-imidazol-2-yl)-pyrrolidine- 1 -carboxylic acid teri-butyl ester (300 mg, 0.46 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.5 mL, excess). The mixture was stirred for 2 hours at ambient temperature and 10 concentrated under reduced pressure. The residue was treated with ether to remove excess trifluoroacetic acid. The obtained white solid was dissolved in DMF (10 mL), to the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (161 mg, 0.92 mmol), HATU (437 mg, 1.2 mmol) and NN-diisopropylethylamine (0.64 mL, 3.7 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was 15 dissolved in ethyl acetate (100 mL), washed with I N NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (1 -{2-[5-(3-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-6H-benzo[c]chromen-8-yl)- I H-imidazol-2-yl]-pyrrolidine l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as a TFA salt (130 mg, 37%). 'H 20 NMR (300 MHz, CD 3 0D) 8 7.80-7.20 (m, 8H), 5.40-5.05 (m, 4H), 4.65-3.80 (m, 6H), 3.75-3.40 (m, 6H), 2.40-1.90 (m, lOH), 1.05-0.80 (m, 12H); m/z 767.3 (M+H)*. 690 Example EK O NH NH N '/ H- {1-[6-(5-{7-[2-(2-Aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-y] 9,9-difluoro-9H-fluoren-2-yl}-1 H-imidazol-2-yl)-5-aza-spiro[2.4]heptane 5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester 0 O=0 H NH O M ONH FNF N N N - 0 HATU HHN \ DI PEA H DMF - N -O (1 -{6-[5-(7-{2-[2-(3-Cyano-2-methoxycarbonylamino-propionyl)-2 aza-bicyclo[2.2.1 ]hept-3-yl]-3H-benzoimidazol-5-yl}-9,9-difluoro 9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1-{6-[5-(7-{2- [2-(3-Cyano-2-methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.11 hept 3-yl]-3H-benzoimidazol-5-yl}-9,9-difluoro-9H-fluoren-2-y)-1 H-imidazol-2-yl]-5-aza 5 spiro[2.4lheptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. To a solution of {l -[6-(5-{7-[2-(2-aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-yl]-9,9-difluoro-9H fluoren-2-yl}-l H-imidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl} carbamic acid methyl ester (30 mg, 0.037 mmol) in DMF (2 mL) was added 3-cyano-2 methoxycarbonylamino-propionic acid (8 mg, 0.045 mmol), HATU (20 mg, 0.052 mmol) and 10 NN-diisopropylethylamine (0.051 mL, 0.3 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with 1 N NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (1-{6-[5-(7-{2-[2-(3-Cyano-2-methoxycarbonylamino-propionyl)-2-aza 15 bicyclo[2.2. I ]hept-3-yl]-3 H-benzoimidazol-5-yl}-9,9-difluoro-9H-fluoren-2-yl)-I H-imidazol-2 yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester as a TFA salt (18 mg, 54%). 'lH-NMR (300 MHz, DMSO-d 6 ) 6 8.30-7.70 (m, I OH), 7.45-7.30 (m, I H), 5.26 (t, I H), 5.00-4.80 (m, 2H), 4.60-4.45 (m, I H), 4.10-3.70 (m, 4H), 3.63 (s, 3H), 3.54 (s, 3H), 3.00-2.65 (m, 4H), 2.30-1.10 (m, 12H), 1.00-0.60 (m, 8H); m/z 886.4 (M+H)*. 691 Example EL t '0 O N N H7 N {1 -[6-(5-{7-[2-(2-Aza-bicyclo[2.2.1 ]hept-3-yl)-3H-benzoimidazol-5-y] 9,9-difluoro-9H-fluoren-2-yl}-1 H-imidazol-2-yl)-5-aza-spiro[2.4]heptane 5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester HO SO 2

CH

3 N O DIPE pH HN SO 2

CH

3 DMFO -o (1 -{6-[5-(7-{2-[2-(3-Methanesulfonyl-2-methoxycarbonylamino propionyl)-2-aza-bicyclo[2.2. 1]hept-3-yl]-3H-benzoimidazol-5-yl}-9, 9 difluoro-9H-fluoren-2-yl)- 1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 (1 -{6- [5-(7-{2-[12-(3-Methanesulfonyl-2-methoxycarbonylam ino-propionyl)-2-aza bicyclo [2.2.11]hept-3-yl] -3H-benzoimidazol-5-yl} -9,9-difluoro-9H-fluoren-2-yl)-1 H im idazol-2-yl] -5-aza-spiro [2.4] heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. To a solution of { Il-[6-(5-{7-[2-(2-aza-bicyclo[2.2. I]hept-3-yI)-3H 10 benzoimidazol-5-yl]-9,9-difluoro-9H--fluoren-2-yl }-1 H-imidazol-2-yl)-5-aza-spiro[2.4]heptane 5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (30 mg, 0.037 mmol) in DMF (2 mL) was added 3-methanesulfonyl-2-methoxycarbonylamino-propionic acid (8 mg, 0.045 mmol), H ATU (20 mg, 0.052 mmol) and N,N-diisopropylethylamine (0.05 1 mL, 0.3 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in 1 5 vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with I N NaOH- solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (1-{6-[5-(7-{2-[2-(3-M~ethanesulfonyl-2 methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2. I]hept-3-yl]-3 H-benzoimidazol-5-y } -9,9 difluoro-9H-fluoren-2-yl)- I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl})-2-methyl 20 propyl)-carbamic acid methyl ester as a TFA salt (18 mg, 54%). 'H--NMR (300 MHz, DM4SO 692 d 6 ) 8 8.30-7.70 (m, I OH), 7.40-7.30 (m, I H), 5.26 (t, 1 H), 5.00-4.80 (m, 2H), 4.60-4.45 (m, I H), 4.10-3.70 (m, 5H), 3.63 (s, 3H), 3.54 (s, 3H), 3.00-2.65 (m, 4H), 2.30-1.10 (m, 12H), 1.00-0.60 (m, 10H); m/z 939.4 (M+H)*. 5 A. Example EM 02N H2N Br Br Cu/DMF B 2 B r

B

r NH 2

NH

2 Br Br 13 C ' \/r 2 ~ /\ /r5%RuC - /Br N0 2 -OMe W~e 1,4-Dibrormo-2-nitro- NO 2 4,4-Dibromo-2-methoxy- 4,4'-Dibromo-2'-methoxy benzene 4,4'-Dibromo-2,2 -dinitro-b pheny 2-nitro-biphenyl biphenyl-2-ylamine 1. NaNH 2 Br/s - 1. CH 2 =C(OEt)SnBU 3 Br Br Br 0 2.NICOH -~ /Br PdI(~ 3

)

2 /80 C; - r- \/ Br -02. NBS/H 2 0 00 2-Bromno-1 -(7-bromno- 2-Bromo(-1 -(7-(2-bromno-acety) 3,7-Dibromo-dibenzofuran dibenzofuran-3-y thanone dibenzofuran-3-y}-ethanone _______ Br -1 -- - 0k BocPrOEt Br oc 0 Boc Pyrrolidine-1,2-dicarboxylic acid Diketoester 2-{2-(7-bromo-dibenzofuran-3-yl)-2-oxo-ethyl} ester 1-tert-butyl ester 10 1,4-Dibromo-2-nitro-benzene: The compound was bought from Sigma-Aldrich Co. 4,4'-Dibromo-2,2'-dinitro-biphenyl: The mixture of 1,4-dibromo-2-nitro-benzene (25 g, 89 mmol) and copper powder (12.5 g, 197 mmol) in DMF (150 ml) was heated at 137 C for 2 hours. The mixture was cooled to 25'C and was quenched with water. The mixture was 15 extracted with EtOAc (2x). The combined organic solution was washed with water and brine and was dried with Na 2

SO

4 . Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4'-dibromo-2,2'-dinitro-biphenyl (13.6 g). 4

,

4 '-Dibromo-2-methoxy-2'-nitro-biphenyl: To the solution of 4,4'-dibromo-2,2'-dinitro 20 biphenyl (6.58 g, 16.5 mmol) in DMF (50 ml) at 0 0 C was added a solution of sodium methoxide in Methanol (4.4 M, 4.5 ml, 19.8 mmol). The mixture was stirred at 25*C for 12 hours and was poured into ice-water (140 ml). The mixture was extracted with EtOAc (2x). The combined organic phase was washed with water and brine and dried with Na2SO4. Concentration under 693 reduced pressure gave pale solid. The re-crystallization from CH3CN/MeOH gave 4,4' dibromo-2-methoxy-2'-nitro-biphenyl as a white solid (3.76 g). 4,4'-Dibromo-2'-methoxy-biphenyl-2-ylamine: To a suspension of 4,4'-dibromo-2-methoxy 5 2'-nitro-biphenyl (3.76 g, 9.8 mmol) and 5%Ru/C (400 mg) in ethanol (37 ml) at 65-70*C was added dropwise a solution of hydrazine (4.6 ml, 59 mmol) in ethanol (5 ml). The mixture was refluxed for 7 hours and filtered through a pad of CELITE. The CELITE pad was washed with ethanol. The combined solution was concentrated under reduced pressure. Coevaporation with ethanol, EtOAc and DCM gave 4,4'-dibromo-2'-methoxy-biphenyl-2-ylamine as yellow solid 10 (3.5 g). 3,7-Dibromo-dibenzofuran: To a suspension of 4,4'-Dibromo-2'-methoxy-biphenyl-2-ylamine (3.5 g, 9.8 mmol) in H2SO4 (2.4 g) and water (8.5 ml) at 0*C was added slowly a solution of NaNO2 (682 mg, 9.8 mmol) in water (9 ml). The mixture was stirred at 0*C for 2 hours. Urea 15 (1.2 g, 20 mmol) was added and the mixture was stirred for 12 hours. The mixture was diluted with water and was heated at 70*C for 24 hours. The mixture was cooled to 25*C and was filtered. The collected solid was re-crystallized from benzene/methanol to give 3,7-dibromo dibenzofuran (2.27 g). 20 2-Bromo-1-(7-bromo-dibenzofuran-3-yl)-ethanone and 2-Bromo-1-17-(2-bromo-acetyl) dibenzofuran-3-yl]-ethanone: To the solution of 3,7-dibromo-dibenzofuran (972 mg, 3 mmol) and tributyl(ethoxyvinyl)stannane (1.22 ml, 3.6 mmol) in dioxane (20 ml) was added PdCl 2 (PPh 3

)

2 (90 mg) and Pd(PPh3)4 (90 mg). The mixture was heated at 80'C for 16 hours and was cooled to 0*C. Water (7 ml) was added, followed by slow addition of NBS (641 mg, 25 3.6 mmol) over 5 minutes period. The mixture was stirred at 0 0 C for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration under reduced pressure gave a mixture of 2-bromo-l -(7-bromo-dibenzofuran-3-yl)-ethanone and 2-Bromo-1 [7-(2-bromo-acetyl)-dibenzofuran-3-yl]-ethanone, which was used directly for the next step. 30 Pyrrolidine-1,2-dicarboxylic acid 2-12-(7-bromo-dibenzofu ran-3-yl)-2-oxo-ethylj ester 1 tert-butyl ester and Diketoester: To the solution of (s)Boc-PrOH (2.58 g, 12 mmol) and triethylamine (1.46 ml, 10.5 mmol) in acetonitrile (20 ml)/DMF (15 ml) was added a solution of 2-bromo- I -(7-bromo-dibenzofuran-3-yl)-ethanone and 2-bromo- I -[7-(2-bromo-acetyl) 35 dibenzofuran-3-yl]-ethanone in DMF (20 ml). The mixture was stirred for 10 hours, and the 694 solvent was evaporated. The mixture was diluted with EtOAc, and washed with 0.5 N NaOH solution, water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7 bromo-dibenzofuran-3-yl)-2-oxo-ethyl] ester I -tert-butyl ester (630 mg) and Diketoester (620 5 mg). Example EN H 0 %' o Bc Boc oc NH 4 0AcJ14O C; Boc Diketoester 3,7- bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl) 3H-imidazol-4-yl]-dibenzofuran 0 a. TFA/DCM; O N b. RCOOH/HATU/iPr 2 NEt IN /\ O L N N H 0 HN O 0 (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-dibenzofuran-3-yl) 1 H-imidazol-2-yll-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 3,7- bis-{2-(1 -tert-butoxycarbonyl-pyrrolid in-2-yI)-3H-imidazol-4-yI]-dibenzofu ran: The 10 mixture of diketoester (600 mg, 0.89 mmol) and ammonium acetate (I.72g) in xylene (10 ml) was heated at 140*C for 80 minutes under microwave. The mixture was quenched with water, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/EtOAc) gave 3,7- bis-[2-(I-tert-butoxycarbonyl-pyrrolidin-2-yl)-3 H-imidazol-4-yl] 15 dibenzofuran (330 mg). m/z: 639.1 (M+l), 637.3 (M-l), 320.0 (M+2)/2. (1-{2-[5-(7-{2-[l-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yli]-3H-imidazol-4-yl}-dibenzofuran-3-y) 1 H-imidazol-2-ylI]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: 20 To the solution of 3,7- bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yI] dibenzofuran (330 mg, 0.51 mmol) in DCM (4 ml) was added TFA (2 ml). The mixture was stirred for 60 minutes, and the solvent and reagent were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give brown powder. To the solution of above powder (0.51 mmol) and MeOCO-Val-OH (179 mg, 1.02 mmol) in 25 DMF (15 ml) was added HATU (407 mg, 1.07 mmol), followed by diisopropylethylamine (0.9 ml, 5.1 mmol). The mixture was stirred for 60 minutes and was evaporated and then diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was 695 dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. I %TFA/H 2 0) gave (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-y}-dibenzofuran-3-yl)- I H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (130 mg). m/z: 753.4 5 (M+1), 751.3 (M-1), 377.3 (M+2)/2. 'H NMR (CD 3 0D, 300 MHz) 6 8.23 (2 H, d, J = 7.9 Hz), 8.0 (2 H, s), 7.98 (2 H, s), 7.78 (2 H, d, J = 7.9 Hz), 5.27 (2 H, m), 4.24 (2 H, d, J = 7.0 Hz), 4.15 (2 H, m), 3.90 (2 H, m), 3.67 (6 H, s), 2.60 (2 H, m), 2.35-2.0 (8 H, m), 1.0-0.8 (12 H, m). B. Example EO 10 0B CH=C(OEt)SnBu Br RCOOHE3N BrPdCI 2 (PPh 3

)

2 /EW C, -N 0 rROHE 3 00 0 b.NBSrI 2 0 00 0 Pyrrolidifle-1 .2-dicarboxylrc acid 2-[2-{7-brorrto- Pyrrohidine-1 ,2-C6carfloxyfic acid 2-{2-{7 dibenzfuran-3-y)2-oxo-ehy] ester 1-tert-butyl ester (2-bromo-a tyl)-d benzofuran3yI]-2oxo-ethyl) ester 1-tert-butyl ester 0 NH 4 0Ac/140 C - \ \ -Aza-bicyclo[2.2 1]heptane-23-dicarboxylic acd 3-(2-{7-12-{1 -tet-butoxycarbolyl-pyrrolrine-2-carbonyloxy)- 3-(5-{7-{2-(-tedl-Butoxcycrony-pyrrolicn-2-y) aetyll-dlbenzoluran-3-y}-2-cxo-etiyl) ester 2-teit-butyl este3H-imidazo-4-yl]-dibenzofursn3-yl}1 H-imidazoI2-yl)-2-aza-b cyc(2 1]Jheptane-2-carboxylic ad tert-butyl ester a TFAIDCM, b. RCOOH/HATU/iPr 2 NEt NH H N k\h kNO H 0 HN 0 0 (1 -3-{5-(7-{ 2--(2-Methoxycarbonylamino-3-methyl butyryl) pyrrolicin-2-yI-3-mdazo4y}-dibenzofuran3y) 1 H-~midazot-2-lJ-2-aza-bicylo(2 2. 1 iheptane 2-cartonyl}-2-methyl-propyl)-carbamic acid methyl ester Pyrrolidine-1,2-dicarboxylic acid 2-{2-17-(2-bromo-acetyl)-dibenzofu ran-3-ylj -2-oxo ethyl}ester 1-tert-butyl ester: To the solution of Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7 15 bromo-dibenzofuran-3-yl)-2-oxo-ethyl] ester I -tert-butyl ester (250 mg, 0.5 mmol) and tributyl(ethoxyvinyl)stannane (188 pl, 0.55 mmol) in dioxane (3.3 ml) was added PdCl 2 (PPh 3

)

2 (15 mg). The mixture was heated at 80'C for 16 hours and was cooled to 0 0 C. Water (1.1 ml) was added, followed by slow addition of NBS (98 mg, 0.55 mmol) over 5 minutes period. The mixture was stirred at 0 0 C for additional 40 minutes, and the solvent was removed under 20 reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave Pyrrolidine-1,2-dicarboxylic acid 2-{2-[7-(2-bromo-acetyl)-dibenzofuran 3-yl]-2-oxo-ethyl}ester 1-tert-butyl ester (205 mg). 696 2-Aza-bicyclo[2.2.11heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl pyrrolidine-2-carbonyloxy)-acetyl] -dibenzofu ran-3-yl}-2-oxo-ethyl) ester 2-tert-butyl ester: To the solution of 2-Aza-bicyclo[2.2.l]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (155 mg, 0.64 mmol) and triethylamine (77 pl, 0.55 mmol) in acetonitrile (3 ml) was added a solution of 5 Pyrrolidine-1,2-dicarboxylic acid 2-{2-[7-(2-bromo-acetyl)-dibenzofuran-3-yl]-2-oxo ethyl}ester l-tert-butyl ester (200 mg, 0.37 mmol) in DMF (6 ml). The mixture was stirred for 10 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-Aza bicyclo[2.2. I ]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(l -tert-butoxycarbonyl-pyrrolidine-2 10 carbonyloxy)-acetyl]-dibenzofuran-3-yl}-2-oxo-ethyl) ester 2-tert-butyl ester (243 mg). m/z: 703.3 (M-1), 727.2 (M+Na) 3-(5-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-y)-3H-imidazol-4-yl dibenzofuran-3-yl) 1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: The 15 mixture of 2-Aza-bicyclo[2.2.I]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzofuran-3-yl}-2-oxo-ethyl) ester 2 tert-butyl ester (243 mg) and ammonium acetate (860 mg, I I mmol) in xylene (5 ml) was heated at 140'C for 80 minutes under microwave. The mixture was quenched with water, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium 20 sulfate. Concentration and purification by flash column chromatography (DCM/EtOAc) gave 3 (5-{7-[2-(] -tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]dibenzofuran-3-yl}-1

H

imidazol-2-yl)-2-aza-bicyclo[2.2.I]heptane-2-carboxylic acid tert-butyl ester (170 mg). m/z: 665.0 (M+l), 663.4 (M-l), 333.0 (M+2)/2. 25 (1-{3-[5-(7-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl)-dibenzofuran-3-yl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane 2 -carbonyl)-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 3-(5-{7-[2-(1 tert-Butoxycarbonyl-pyrrolidin-2-yl)-3 H-imidazol-4-yl]dibenzofuran-3-yl}-I H-imidazol-2-yl) 2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (170 mg) in DCM (6 ml) was 30 added TFA (3 ml). The mixture was stirred for 60 minutes, and the solvent and reagent were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give brown powder. To the solution of above powder (0.256 mmol) and MeOCO-Val-OH (90 mg, 0.51 mmol) in DMF (7.5 ml) was added HATU (204 mg, 0.54 mmol), followed by diisopropylethylamine (0.45 ml, 2.56 mmol). The mixture was stirred for 90 35 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, 697 water, and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1%TFA/CH 3

CN/O.I%TFA/H

2 0) gave (1-{3-[5-(7-{2-[I-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-y}-dibenzofuran-3-yI)- IH-imidazol-2-yl]-2 aza-bicyclo[2.2.I]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (127 mg). 5 m/z: 779.3 (M+1), 777.3 (M-1), 390.2 (M+2)/2. 'H NMR (CD 3 0D, 300 MHz) 5 8.23 (2 H, d, J = 8.2 Hz), 8.03 (2 H, s), 7.98 (2 H, m), 7.88 (2 H, d, J = 8.2 Hz), 5.25 (1 H, m), 4.85 (1 H, m), 4.33 (1 H, d, J = 6.1 Hz), 4.24 (1 H, d, J = 7.0 Hz), 4.15 (1 H, m), 3.88 (1 H, m), 3.69 (3 H, s), 3.67 (3 H, s), 3.45 (1 H, m), 2.89 (1 H, m), 2.60 (1 H, m), 2.35-1.6 (11 H, m), 1.05-0.8 (12 H, m). 10 C. Example EP Yo N\ /\ Br NH 4 0Ac N 0~ 0 H 0 No Pyrmlidine-1 2-dicarboxyfic acid 2-[2-(7-bromo- 2-15-(7-Bmmo-dibenzokiran-3-y)- 2-[6-(4.4,5,5-Tetramety-[1,3.21 diberizofuran-3-yi)-2.axo-ethyt] ester 1 -tert-butyl 1 I4.imidazoI.2.-tj-pyrrolidine- 2-6-44,,-tab m et - [12.yI ester 1-carboxylic acid tert-butyl ester 1Hx-bezomda-2-pyldne 1-carboxyliC acid tert-butyl ester N PdC(plhf) N Boc a. TFA/DCM; b. RCOOH/HATUiPr 2 NEt H O 2-(5{7-12-(1-t-butoxycarbonyl-pyrrolidin-2yI) 3H4benzoimidazol-5ylJ-dibenzofuran-3-yt) 1H-imidazol-2-yt)-pyrrolidine-1-carboxylic acid talt-buty ester H N - ~ HN 0" H 0 0 (1 -{2-[5-(7-{2-[1-(2-Mthoxycartbanylamino-3-methy-butyry)-pyrrlidin-2-ytJ.3H benzo midazol-5-y-ibenzofurn-3y)-1 H-midazol-2-yt]-pyrrolidine-l.carbony) 2-methyl-propyl)-carbamic acd methyl ester 15 2- [5-(7-Bromo-d ibenzofu ran-3-yi)-1 H-imidazol-2-yl]-pyrrolidine- 1 -carboxylic acid tert butyl ester: The mixture of Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzofuran-3 yl)-2-oxo-ethyl] ester I-tert-butyl ester (200 mg) and ammonium acetate (860 mg, 1 Immol) in xylene (5 ml) was heated at 140'C for 80 minutes under microwave. The mixture was quenched with water, and extracted with EtOAc. The organic phase was washed with water and brine, and 20 was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/EtOAc) gave 2-[5-(7-Bromo-dibenzofuran-3-yl)- I H-imidazol-2-yi]-pyrrolidine- carboxylic acid tert-butyl ester (124 mg). m/z: 481.9 (M+1), 480.2 (M-I). 698 2-(5-{7-12-(1 -t-butoxycarbonyl-pyrrolid in-2-yl)-3H-benzoim idazol-5-yl] -dibenzofu ran-3 yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: To the solution of 2-[5 (7-Bromo-dibenzofuran-3-yi)-l H-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (124 mg, 0.26 mmol) and 2-[6-(4,4,5,5-Tetramethyl-[ ,3,2]dioxaborolan-2-yl)- 1 H 5 benzoimidazol-2-yI]-pyrrolidine 1-carboxylic acid tert-butyl ester (107 mg, 0.26 mmol) in DME (2.25 ml) and water (0.75 ml) was added potassium carbonate (72 mg, 0.52 mmol), followed by Pd(PPh 3

)

4 (15 mg) and PdCl 2 (dppf)CH 2

CI

2 (15 mg). The mixture was heated at 90*C for 6 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. 10 Concentration and purification by flash column chromatography (EtOAc) gave 2-(5-{7-[2-(i-t butoxycarbonyl-pyrrolidin-2-yl)-3 H-benzoimidazol-5-yl]-dibenzofuran-3-yl}-1 H-imidazol-2 yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester (83 mg). m/z: 689.1 (M+l), 687.3 (M-1), 345.0 (M+2)/2. 15 (1-{2-15-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yl}-dibenzofuran-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: To the solution of 2-(5-{7-[2-(l-t butoxycarbonyl-pyrrolidin-2-yI)-3 H-benzoimidazol-5-yl]-dibenzofuran-3-yl}-I H-imidazol-2 20 yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (82 mg, 0.12) in DCM (4 ml) was added TFA (2 ml). The mixture was stirred for 60 minutes, and the solvent and reagent were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give brown powder. To the solution of above powder (0.12 mmol) and MeOCO-Val-OH (42 mg, 0.24 mmol) in DMF (3.5 ml) was added HATU (95 mg, 0.25 mmol), followed by 25 diisopropylethylamine (0.21 ml, 1.2 mmol). The mixture was stirred for 90 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. I %TFA/H 2 0) gave (I -{2-[5-(7-{2-[I-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3 H-benzoimidazol-5-yl}-dibenzofuran-3-yl)- I H-imidazol-2 30 yli]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (79 mg). m/z: 803.4 (M+I), 801.1 (M-1), 402.2 (M+2)/2. 'H NMR (CD 3 0D, 300 MHz) 8 8.25 (2 H, m), 8.1-7.9 (5 H, m), 7.9-7.75 (3 H, m), 5.4-5.2 (2 H, m), 4.25 (2 H, m), 4.2-3.8 (4 H, m), 3.67 (6 H, s), 2.60 (2 H, m), 2.4-2.0 (8 H, m), 1.05 -0.8 (12 H, m). 699 D. Example EQ MeO 2 C / Br bis(pinacolato)diboron MeO 2 C / B ( NBS/AlBN MeO 2 C B O HO 4-Bromo-3-methyl- 3-Methyl-4-(4,4,5,5-tetramethyl Br NO 2 benzoic acid methyl -[1.3,2]dioxaborolan-2-yl)-benzoic 3-Bromomethyl-4-(4,4,5,5-tetramethyl ester acid methyl ester [1,3,2]dioxaborolan-2-yi) 2-lodo-5-nitro benzoic acid methyl ester phenol MeO 2 C / B'

K

2

CO

3 O Pd(PPh 3

)

4 DMF I Pd(dppf)Cl 2 MeO 2 C NO2 Zn/HOAc MeO2C NH2 0 3-Nitro-6H-benzo[c]chromene- 3-Anino6H-benzo[c]chromene-8

NO

2 8-carboxylic acid methyl ester carboxylic acid methyl ester 3-(2-lodo-5-nitro-phenoxymethyl)-4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-benzoic acid methyl estermethane; 1. CICOCOCI t-BuONO - 1. NaOH - 2. TMSCHN 2 0 / CuBr N MeO 2 C Br N HB HO 2 C 3. HBrBHOAc 0 0 0 3-Bromo-6H-benzo[c]chromene- 3-Bromo-6H-benzo[c]chromene- 2-Bromo-1-(3-bromo-6H 8-carboxylic acid methyl ester 8-carboxylic acid benzo[c]chromen-8-yl)-ethanone Boc rOH B O r Br NHN0Ac-cHBr Nt3N _______ .N N N /B EtN0 0 HO H 0$ / N Boc Pyrr olid ine- 1, 2- dicarboxy lic ac id 2-45- (3-B romro- 6H- ben zo c~chrome n-8 yl) 2-[2-3-bromo-6H-benzo cchromen-8-yl) -1 H - b idazol-2-y+pyrrolid ne- 2-[6-(4,4,5,5-Tetramethyl-{1 ,321 -2-oxo-ethyll ester 1-tert-butyl ester 1-carboxylic acid tert-butyl ester dioxaborolan-2-yl) 1 H-benzoimidazo-2-yl]-pyrrolidine 1-carboxyic acid tert-butyl ester N Pd(PPh 3

)

4 N /\ PdC 2 (dppf) B N Boc a. TFA/DCM; b. RCOOH/HATU/iPr 2 NEt 2-(5-{3-[2-(1-t-butoxycarbony-pyrrolidin-2-y) 3H-benzoimidazol-5-yl]-6H-benzolcjchromen-8-yl} 1H-imidazol-2-yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester H ON N O - - N 0 ~N NN HN 0o 0 (1-(2-[5-(2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-benzoimidazol-5-yl)-6H benzo[clchromen-8-yl)-1 H-midazol-2-yl]-pyrrlidine-1 -carbonyl}2 -methyl-propyl)-carbamic acid methyl ester 4-Bromo-3-methyl-benzoic acid methyl ester: The chemical was bought from Sigma-Aldrich 5 Co. 3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester: To the solution of 4-Bromo-3-methyl-benzoic acid methyl ester (4.56 g, 20 mmol) and bis(pinacolato)diboron (10.2 g, 40 mmol) in 1,4-dioxane (160 ml) was added potassium acetate 10 (5.0 g, 51 mmol), followed by Pd(PPh 3

)

4 (924 mg). The mixture was heated at 80*C for 16 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography 700 (hexanes/EtOAc) gave 3-Methyl-4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (4.8 g). 3-Bromomethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester: 5 The solution of 3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (3.71 g, 13.4 mmol), NBS (2.39 g, 13.4 mmol), and AIBN (235 mg) in CC 4 (20 ml) was heated at 80*C for 14 hours. The mixture was cooled to 25*C, and was filtered and washed with

CCI

4 . The solution was concentrated under reduced pressure, and was diluted with EtOAc. The solution was washed with water and brine and was dried with Na2SO4. Concentration gave 3 10 Bromomethyl-4-(4,4,5,5-tetramethyl-[ l,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (4.9 g). 3-(2-Iodo-5-nitro-phenoxymethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl estermethane: The mixture of 3-Bromomethyl-4-(4,4,5,5-tetramethyl 15 [1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (3.63 g, 10.3 mmol), 2-Iodo-5-nitro-phenol (2.72 g, 10.3 mmol), and potassium carbonate (2.26 g, 16.4 mmol) in DMF (21 ml) was heated at 75"C for 3 hours. The mixture was cooled to 25*C, and DMF was removed under reduced pressure. The mixture was diluted with EtOAc, and was acidified with 0.5 N HCI until pH=4. More water (total volume of water 100 ml) was added and the mixture was stirred for 5 minutes. 20 The mixture was filtered and washed with water. The solid was collected and dried under reduced pressure. 3-(2-lodo-5-nitro-phenoxymethyl)-4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-benzoic acid methyl estermethane was obtained as solid (1.8 g). 3-Nitro-6H-benzolclchromene-8-carboxylic acid methyl ester: To the solution of 3-(2-lodo 25 5-nitro-phenoxymethyl)-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-benzoic acid methyl estermethane (2.7 g, 5 mmol) in l,2-dimethoxyether (75 ml) and water (25 ml) was added sodium bicarbonate (1.26 g, 15 mmol), followed by Pd(PPh 3

)

4 (250 mg) and Pd(dppf)C1 2 (250 mg). The mixture was heated at 80'C for 16 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and 30 purification by flash column chromatography (DCM/hexanes) gave 3-Nitro-6H benzo[c]chromene-8-carboxylic acid methyl ester (690 mg). 3-Amino-6H-benzo[clchromene-8-carboxylic acid methyl ester: To the solution of 3-Nitro 6H-benzo[c]chromene-8-carboxylic acid methyl ester (690 mg) in THF/DMF (5 ml/5 ml) was 35 added acetic acid (10 ml), followed by slow addition of Zinc (800 mg). The mixture was stirred 701 for 12 hours and solvents were removed under reduced pressure. The mixture was diluted with EtOAc, and 0.2 N sodium hydroxide solution was added until pH=10. The organic layer was separated and was washed with water and brine and dried with Na2SO4. Concentration and purification by flash column chromatography (DCM/EtOAc) gave 3-Amino-6H 5 benzo[c]chromene-8-carboxylic acid methyl ester (300 mg). 3-Bromo-6H-benzo[clchromene-8-carboxylic acid methyl ester: To a solution of copper (II) bromide (315 mg, 1.42 mmol) and t-butyl nitrite (233 pl, 1.77 mmol) in CH 3 CN (4 ml) at 65*C was added dropwise a suspension of 3-Amino-6H-benzo[c]chromene-8-carboxylic acid methyl 10 ester (300 mg, 1.18 mmol) in CH 3 CN (5 ml). The mixture was heated at 65'C for 3 hours. Concentration and purification by flash column chromatography (DCM/EtOAc) gave 3-Bromo 6H-benzo[c]chromene-8-carboxylic acid methyl ester (160 mg). 3-Bromo-6H-benzolclchromene-8-carboxylic acid: The solution of 3-Bromo-6H 15 benzo[c]chromene-8-carboxylic acid methyl ester (160 mg, 0.5 mmol) and sodium hydroxide (1.0 N, I ml, I mmol) in THF/MeOH (2 ml/2 ml) was heated at 50'C for 3 hours. The mixture was cooled to 25*C and was acidified with 2 N HCI (0.6 ml). The solvents were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give 3-Bromo-6H-benzo[c]chromene-8-carboxylic acid as brown powder. 20 2-Bromo-1-(3-bromo-6H-benzoclchromen-8-yl)-ethanone: To 3-Bromo-6H benzo[c]chromene-8-carboxylic acid (0.5 mmol) was added a solution of oxalyl chloride in DCM (2.0 N, 5 ml, 10 mmol). The mixture was heated at 45'C for 2 hours and cooled to 25'C. Excess reagents and solvent were removed under reduced pressure and co-evaporated with 25 toluene. To the solution of above residue in DCM (5 ml) at 0 0 C trimethylsilyldiazomethane (2.0 N, 0.75 ml, 1.5 mmol) was added dropwise. The mixture was stirred at 25'C for 12 hours and was concentrated. The residue was dissolved in EtOAc and was cooled to 0 0 C. To above solution HBr/HOAc (0.28 ml, 1.5 mmol) was added dropwise. The mixture was stirred at 25*C for I hour. Solid sodium bicarbonate was added and the mixture was stirred for 30 minutes. 30 The mixture was diluted with EtOAc, and was washed with water and brine and was dried with Na 2

SO

4 . Concentration gave 2-Bromo-l -(3-bromo-6H-benzo[c]chromen-8-yl)-ethanone, which was used for next step without purification. Pyrrolidine-1,2-dicarboxylic acid 2-[2-(3-bromo-6H-benzo[cichromen-8-yl) -2-oxo-ethyll 35 ester 1-tert-butyl ester: To the solution of (s)Boc-PrOH (1.07 g, 5 mmol) and triethylamine 702 (0.63 ml, 4.5 mmol) in acetonitrile (20 ml) was added a solution of 2-Bromo-l-(3-bromo-6H benzo[c]chromen-8-yl)-ethanone (0.5 mmol) in DMF (10 ml). The mixture was stirred for 10 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with 0.5 N NaOH solution, water and brine, and was dried with sodium sulfate. Concentration gave 5 Pyrrolidine-I,2-dicarboxylic acid 2-[2-(3-bromo-6H-benzo[c]chromen-8-yl)-2-oxo-ethyl] ester 1-tert-butyl ester, which was used for the next step without further purification. 2-15-(3-Bromo-6H-benzolclchromen-8-y)-1H-imidazol-2-yI]-pyrrolidine-1-carboxylic acid tert-butyl ester: The mixture of Pyrrolidine-l,2-dicarboxylic acid 2-[2-(3-bromo-6H 10 benzo[c]chromen-8-yl) -2-oxo-ethyl] ester I -tert-butyl ester (0.5 mmol) and ammonium acetate (860 mg, I I mmol) in xylene (5 ml) was heated at 140'C for 80 minutes under microwave. The mixture was quenched with water, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. I %TFA/H 2 0) gave 2-[5-(3-Bromo-6H-benzo[c]chromen-8-yl)- I H 15 imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (8 mg). m/z: 496.0 (M+l), 494.1 (M-l). 2-(5-{3-[2-(1-t-butoxycarbonyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-6H benzolclchromen-8-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: To 20 the solution of 2-[5-(3-Bromo-6H-benzo[c]chromen-8-yl)-l H-imidazol-2-yl]-pyrrolidine- 1 carboxylic acid tert-butyl ester (9 mg, 0.02 mmol) and 2-[6-(4,4,5,5-Tetramethyl [l,3,2]dioxaborolan-2-yl)-I H-benzoimidazol-2-yl]-pyrrolidine-I -carboxylic acid tert-butyl ester (9.6 mg, 0.02 mmol) in DME (0.75 ml) and water (0.25 ml) was added potassium carbonate (10 mg, 0.07 mmol), followed by Pd(PPh 3

)

4 (2 mg) and PdCl 2 (dppf)CH 2

CI

2 (2 mg). The mixture 25 was heated at 90*C for 6 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 2-(5- (3-[2-(] -t-butoxycarbonyl-pyrrolidin-2-yl)-3H benzoimidazol-5-yl]-6H-benzo[c]chromen-8-yl}I-l H-imidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (4.2 mg). m/z: 729.2 (M+l), 727.3 (M-l), 365.2 (M+2)/2. 30 (1-{2-15-(3-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yl}-6H-benzo[cjchromen-8-yl)-1 H-imidazol-2-yli]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 2-(5-{3-[2-(1-t 35 butoxycarbonyl-pyrrolidin-2-y)-3H-be'nzoimidazol-5-y]-6H-benzo[c]chromen-8-y}- I H 703 imidazol-2-yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester (4.2 mg, 0.006) in DCM (2 ml) was added TFA (I ml). The mixture was stirred for 60 minutes, and the solvent and reagent were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give brown powder. To the solution of above powder (0.006 mmol) and 5 MeOCO-Val-OH (2 mg, 0.0 12 mmol) in DMF (1 ml) was added HATU (4.6 mg, 0.0 12 mmol), followed by diisopropylethylamine (10 si, 0.058 mmol). The mixture was stirred for 90 minutes and was diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. I %TFA/H 2 0) gave (1 -{2-[5-(3-{2-[I-(2-Methoxycarbonylamino-3 10 methyl-butyryl)-pyrrolidin-2-yl]-3 H-benzoimidazol-5-yl }-6H-benzo[cjchromen-8-yl)- I H imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.5 mg). m/z: (M+l), (M-l), (M+2)/2. 'H NMR (CD 3 0D, 300 MHz) 8 8.07-7.7 (7 H, m), 7.62 (1 H, s), 7.45 (1 H, m), 7.38 (1 H, s), 5.25 (4 H, m), 4.35 (1 H, m), 4.22 (1 H, m), 4.15 (2 H, m), 3.85 (2 H, m), 3.65 (6 H, m), 2.98 (1 H, s), 2.6 (1 H, m), 2.3-1.7 (8 H, m), 1.05-0.85 (12 H, m). 15 Example ER O o Br TFA N Br + o H N 1 NDCM. RT N N o _ H U:H G" H O0 2-(6-Bromo-1H-benzoimidazol-2-yl)- 6-Bromo-2-pyrrolidin-2-yl- 2-Methoxycarbonylamino-3 pyrrolidine-1-carboxylic acid tert-butyl ester 1H-benzoimidazole methyl-butyric acid _~*0 NHH H HATU, NM M o Br B N DMFRT N ) dB Ni 0 H"-,

HN

0 0 {1-[2-(6-Bromo-1H-benzoimidazol-2-yl)- [2-Methytl-(3-{5-[6-(4,4,5,5-tetramethyl pyrrolidine-1-carbonyl]-2-methyl-propyl}- [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl] carbamic acid methyl ester 1 H-imidazol-2-yl}-2-aza-bicyclo[2.2. 1]heptane 2-carbonyl)-methyl]-carbamic acid methyl ester o H N Pd(PPh 3

)

4 H P NaHC0 3 0 KNH o0 B5*C N AN0 H o (1-{2-[6-(6-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1]hept-3-yl] 3H-imidazol-4-yl)-naphthalen-2-yl)-1 H-benzoimidazol-2-yl}-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester 20 6-Bromo-2-pyrrolidin-2-yl-1H-benzoimidazole: Prepared by the same method as (1-{2-[5-(4 Bromo-phenyl)- IH-imidazol-2-yl]-pyrrolidine-l 704 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, except that 2-(6-Bromo-l H benzoimidazol-2-yl)-pyrrolidine-I-carboxylic acid tert-butyl ester was used as the substrate. 120 mg light yellow solid (66% yield). 5 {1-[2-(6-Bromo-lH-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl} carbamic acid methyl ester: Prepared by the same method as (l-{2-[5-(4-Bromo-phenyl)-l H imidazol-2-yl]-pyrrolidine- 1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester but using 6-bromo-2-pyrrolidin-2-yl-l H-benzoimidazole as the substrate. 193 mg crude solid were used for the next step. 10 12-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl-11,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H imidazol-2-yl}-2-aza-bicyclo[2.2.I]heptane-2-carbonyl)-methyl]-carbamic acid methyl ester: This compound was made using the same procedure as for [2-Methyl-I-(2-{5-[6 (4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine 15 1 -carbonyl)-propyl]-carbamic acid methyl ester, except that 2-Aza-bicyclo[2.2. I ]heptane-2,3 dicarboxylic acid 2-tert-butyl ester was used in place of Pyrrolidine-1,2-dicarboxylic acid 1-tert butyl ester and 2-Methoxycarbonylamino-propionic acid was used in place of 2 Methoxycarbonylamino-3-methyl-butyric acid 2-Methoxycarbonylamino-propionic acid. 20 (1-{2-[6-(6-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H imidazol-4-yl}-naphthalen-2-yl)-1 H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: { I -[2-(6-Bromo- I H-benzoimidazol-2-yl)-pyrrolidine- I carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.193 g), [2-Methyl-1 -(3-{5-[6 (4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]- I H-imidazol-2-yl} -2-aza 25 bicyclo[2.2.1 ]heptane-2-carbonyl)-methyl]-carbamic acid methyl ester (0.241 g), and NaHCO 3 (0.123 g) were dissolved in a mixture of 1,2-dimethoxyethane (6 mL) and water (2 mL). The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0219 g) was added. The reaction mixture was stirred at 85*C for 2 days and evaporated under vacuum. Solid was dissolved in ethyl acetate (15 mL) and extracted twice with water (10 mL) and once with brine (10 mL). The 30 resulting oil was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0-5% MeOH:DCM. The fractions containing product were combined and the solvent was removed under reduced pressure. Oil was dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving (I -{2-[6-(6-{2-[2-(2 Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2. I ]hept-3-yl]-3 H-imidazol-4-yl} 705 naphthalen-2-yl)- I H-benzoimidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.039 g, 12%) as a white solid. ' H-NMR: 300 MHz, (DMSO-d 6 ) 8: 11.8 (s, I H), 8.2 (d, J = 27 Hz, 2H), 7.9 (m, 4H), 7.6 (m, 3H), 7.3 (m, 2H), 5.3 (m, 2H), 4.1 (m, 2H), 3.8 (m, 2H), 3.5 (s, 6H), 2.5 (s, 6H), 2.8 (m, I H), 2.1 5 (m, 4H), 2.0 (m, 4H), 0.9 (m, 1 2H); MS (ESI): m/z 763 [M + H]f. Example ES 0 0 H 2 , PtO 2 H 0 N

H

2 N, O AcOH N AcOH N 0 + Br H Acetone H EtOH, RT H H H 0 RT N 0OR Hydrazinecarboxylic acid NI-isopropylidene-hydrazine- et0propylhyydrie- ter -(4-Bromo-phenyl)-2-pyrrolidin methyl ester carboxylic acid methyl ester carboxylic acid methyl ester 21-Brfl-fyl)-pyni lidifl 2 -yl-1 H-imidazole Triphosgene 0 N O Pd(PPh 3

)

4 DIPEA ,ABr N O N N + O,-B, KOAc DCM N H 0 o Dioxane O'C-RT H 80*C NA-{2-[5-(4-Bromo-phenyl)-1H-imidazo-2-y]- 4,4,5,5,4',4',5',5'-Octamethyl-[2,2] pyrrolidine-1-carbonyl}-A-isopropyl-hydrazine- bi[[1,3,2]dioxaborolanyl} carboxylic acid methyl ester 0 0 -NH B N H N Br H H 0 A-IsopropykN-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan- (1-{2-[5-(6-Bromonaphthalen-2-yl)-1 H-imidazol 2-yl)-phenyl)-1H-imidazok2-yl)-pyrrolidine-1-carbonyl)- -2-yl]-pyrrolidine-1-carbony}-2-methyl-propyl) hydrazinecarboxylic acid methyl ester carbamic acid methyl ester Pd(PPh 3

)

4 NH H NaHC0 3 0 .

0 N\- N N O

DMIE-H

2 0 N -N 0 ''~ 85"C H HN O NA-Isopropy-{2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyry) pyrrolidin-2-yl)-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl] pyrrolidine-1-carbony}-hydrazinecarboxylic acid methyl ester 10 N'-Isopropylidene-hydrazine-carboxylic acid methyl ester: Hydrazinecarboxylic acid methyl ester (5.01 g) were dissolved in acetone (28 mL), and acetic acid (0.0636 mL) was added. The reaction mixture was stirred at room temperature for 24 hours. Water (50 mL) was added, and mixture was extracted three times with DCM (50 mL) and evaporated under vacuum, giving N' 15 Isopropylidene-hydrazine-carboxylic acid methyl ester (6.45 g, 89%). N'-Isopropyl-hydrazine-carboxylic acid methyl ester: N'-Isopropylidene-hydrazine carboxylic acid methyl ester (6.45 g) were dissolved in ethanol (50 mL) and acetic acid (50 mL). PtO 2 (0.231 g) was added, and reaction was stirred at room temperature for 22 hours under an 20 atmosphere of hydrogen. Mixture was evaporated under vacuum, giving N'-Isopropyl hydrazine-carboxylic acid methyl ester (5.08 g, 77%) as a white solid. 706 N'-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-N'-isopropyl hydrazine-carboxylic acid methyl ester: Triphosgene (1.05 g) was dissolved in DCM (17 mL) and stirred at 0*C. N'-Isopropyl-hydrazine-carboxylic acid methyl ester (1.00 g) and DIPEA 5 (1.5 mL) were dissolved in DCM (25 mL), and mixture was added to triphosgene solution and stirred for 10 minutes. 5-(4-Bromo-phenyl)-2-pyrrolidin-2-yl-IH-imidazole (2.65 g) was added. Reaction was stirred at room temperature for 1 hour and extracted twice with water (10 mL), once with brine (10 mL), and evaporated under vacuum. The resulting oil was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0-100% ethyl 10 acetate:hexanes. The fractions containing product were combined and the solvent was removed under vacuum, giving N'-{2-[5-(4-Bromo-phenyl)-l H-imidazol-2-yl]-pyrrolidine-I -carbonyl} N'-isopropyl-hydrazine-carboxylic acid methyl ester (533 mg, 16%). N'-Isopropyl-N'-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H 15 imidazol-2-yl}-pyrrolidine-1-carbonyl)-hydrazinecarboxylic acid methyl ester: N'-{2-[5-(4 Bromo-phenyl)- I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-N'-isopropyl-hydrazine-carboxylic acid methyl ester (0.533 g), 4,4,5,5,4',4',5',5'-Octamethyl-[2,2']-bi[[1,3,2]dioxaborolanyl] (0.644 g), and KOAc (0.309 g) were dissolved in dioxane (8 mL). The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0562 g) was added, and reaction was stirred at 80'C for 2 days. Solid 20 was removed by vacuum filtration, and solvent was removed under vacuum. The resulting oil was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0-5% MeOH:DCM. The fractions containing product were combined and the solvent was removed under vacuum, giving N'-Isopropyl-N'-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) phenyl]- I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-hydrazinecarboxylic acid methyl ester 25 (0.564 g, 96%) as a yellow solid. 707 N'-Isopropyl-N'-{2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-I H-imidazol-2-yll-pyrrolidine-1 -carbonyl} hydrazinecarboxylic acid methyl ester: N'-Isopropyl-N'-(2-{5-[4-(4,4,5,5-tetramethyl [I ,3,2]dioxaborolan-2-yl)-phenyl]- 1 H-imidazol-2-yl}-pyrrolidine- I -carbonyl) 5 hydrazinecarboxylic acid methyl ester (0.295 g), (1-{2-[5-(6-Bromophenyl-2-yl)- I H-imidazol-2 yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.280 g), and NaHCO 3 were dissolved in DME (9 mL) and water (3 mL). The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0282 g) was added, and reaction was stirred at 85'C for 19 hours. Solvent was removed under vacuum. Solid was dissolved in DMF, purified by reverse phase 10 HPLC (5-70% acetonitrile:water) two times, and lyophilized, giving N'-Isopropyl-N'-{2-[5-(4' {2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} biphenyl-4-yl)-l H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-hydrazinecarboxylic acid methyl ester (0.017 g, 4%) as a white solid. ' H-NMR: 300 MHz, (CH 3 0H-d 4 ) 6: 7.9 (m, 12H), 5.3 (m, 2H), 4.4 (m, I H), 4.2 (d, J = 7 Hz, 15 2H), 4.1 (m, I H), 3.9 (m, 4H), 3.6 (m, 6H), 3.3 (s, 3H), 2.6 (m, 2H), 2.0 (m, 8H), 1.L (m, 6H), 0.9 (m, 6H); MS (ESI): m/z 740 [M + H]*. Example ET -~0 Q.-NHHH N 'N Br + I

-

HNPO 0 (1-{2-[5-(6-Bromonaphthalen-2-y)-1H-imidazol [2-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl -2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)- [1,3.2]dioxaborolan-2-yl)-naphthalen-2-yl] carbamic acid methyl ester 1H-imidazol-2-yl}-2-aza-bicyclo[2.2. 1 Iheptane 2-carbonyl)-methyl]-carbamic acid methyl ester -0 H H Pd(PPh 3

)

4 4YNH NaHCO 3 . O - - / _t4 N\

DME-H

2 0 N N HN 80*C H O [1-(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl)-phenyl)-naphthalen-2-yl] 1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl) 20 2-methyll-carbamic acid methyl ester [1-(3-15-16-(4-12-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenyl)-naphthalen-2-y]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2 carbonyl)-2-methyll-carbamic acid methyl ester: (1 -{2-[5-(6-Bromonaphthalen-2-yl)-I H 708 imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.226 g), [2-Methyl-I -(3-{5-[6-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]- I H imidazol-2-yl} -2-aza-bicyclo[2.2. I]heptane-2-carbonyl)-methyl]-carbamic acid methyl ester (0.297 g), and NaHCO 3 (0.154 g) were dissolved in a mixture of 1,2-dimethoxyethane (9 mL) 5 and water (3 mL). The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0263 g) was added. The reaction mixture was stirred at 80'C for 19 hours and evaporated under vacuum. Solid was dissolved in DCM (15 mL) and extracted twice with water (10 mL) and once with brine (10 mL). The resulting oil was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0 -5 % MeOH:DCM. The fractions containing product were combined 10 and the solvent was removed under reduced pressure. Oil was dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving [1 -(3-{5-[6-(4-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl) naphthalen-2-yl]-1 H-imidazol-2-yl}-2-aza-bicyclo[2.2.1 ]heptane-2-carbonyl)-2-methyl] carbamic acid methyl ester (0.138 g, 32%) as a white solid. 15 ' H-NMR: 300 MHz, (CH 3 0H-d 4 ) 6: 8.3 (d, J= 9 Hz, 2H), 8.1 (m, 2H), 8.0 (m, 4H), 7.9 (m, 4H), 5.3 (t, J= 7 Hz, 2H), 4.6 (s, 2H), 4.5 (m, 2H), 4.2 (d, J= 7 Hz, 2H), 4.1 (m, 2H), 3.9 (m, 2H), 3.6 (s, 6H), 3.3 (s, 2H), 2.9 (s, I H), 2.8 (m, I H), 2.0 (m, 8H), 1.8 (m, I H), 1.4 (d, J 7 Hz, 3H), 0.9 (m, 6H); MS (ESI): m/z 787 [M + H]f. 20 Example EU * ~0 N N ''Br + B N N N - HN (2-{2-(5-(4-Bromo-pheny)-1 H-imidazol-2-yl]- (2-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl pyrrolidin-1 -y}-1 -methyl-2-oxo-ethyl)- [1,3,2]dioxaborolan-2-yl)-naphthalen-2-y] carbamic acid methyl ester 1 H-imidazol-2-yl}-2-aza-bicyclo[2.2.1lheptane 2-carbonyl)-methyl]-carbamic acid methyl ester 0 HH Pd(PPh 3

)

4 O NH - N N NaHCO 3 0 N \ - - / \ N O

DME-H

2 0 N N HN O 80*C H (2-(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-propionyl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl] 1 H-imidazol-2-yl}-2-aza-bicyclo[2.2. 1 ]hept-2-yl) 1 -methyl-2-oxo-ethyl]-carbamic acid methyl ester 12-(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4 yI}-phenyl)-naphthalen-2-yl]-lH-imidazol-2-yI}-2-aza-bicyclo[2.2.1]hept-2-yI)-1-methyl-2 oxo-ethyl]-carbamic acid methyl ester: (2-{2-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl] 709 pyrrolidin- I-yl} - I -methyl-2-oxo-ethyl)-carbamic acid methyl ester (0.241 g), [2-Methyl-I -(3 { 5-[6-(4,4,5,5-tetramethyl-[ ,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]- I H-imidazol-2-yl} -2-aza bicyclo[2.2. I]heptane-2-carbonyl)-methyl]-carbamic acid methyl ester (0.303 g), and NaHCO 3 (0.164 g) were dissolved in a mixture of 1,2-dimethoxyethane (9 mL) and water (3 mL). The 5 solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0263 g) was added. The reaction mixture was stirred at 80'C for 19 hours and evaporated under vacuum. Solid was dissolved in DCM (15 mL) and extracted twice with water (10 mL) and once with brine (10 mL). The resulting oil was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0-5 % MeOH:DCM. The fractions containing product were combined and the solvent was removed 10 under reduced pressure. Oil was dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving [2-(3-{5-[6-(4-{2-[I-(2-Methoxycarbonylamino propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-2 aza-bicyclo[2.2.l]hept-2-yl)-l -methyl-2-oxo-ethyl]-carbamic acid methyl ester (0.159 g, 38%) as a white solid. 15 'lH-NMR: 300 MHz, (CH 3 0H-d 4 ) 6: 8.3 (d, J = 9 Hz, 2H), 8.1 (m, 2H), 8.0 (m, 4H), 7.9 (m, 4H), 5.3 (in, 2H), 4.6 (s, 2H), 4.5 (m, 4H), 4.0 (m, 2H), 3.9 (m, 2H), 3.7 (d, J= 7 Hz, 6H), 3.3 (m, 2H), 2.9 (s, I H), 2.8 (s, I H), 2.6 (m, I H), 2.0 (m, 8H), 1 .8 (m, 2H), 1 .4 (m, 6H); MS (ESI): m/z 759 [M + H]. 20 Example EV -~0 P hN N BrC3 N - 0 / \ / D 0 N N HN 8H*C H 0 (1 -{2-[5-(4-Brmo-phenyl)-11-imidazol-2-y]- [2-Methyl- -(3-{5-[6-(4,4,5,5-tetramethyl pyrrolidine-1 -carbonyl}-2-methyl-propyl)- [1 ) 3,2]dioxaboroan-2-yl)-naphthalen-2-yo carbamic acid methyl ester 1 H-imidazol-2-y}c-2-aza-bicyclo[2.2. 1 ]heptane-2-carbonyl) propyl]-carbamic acid methyl ester Pd(PPh 3

)

4 ~ NH N N NaHCO 3 N - - / \N

DME-H-

2 0 N/ \/

H

80*C N N 0 [1 -(3-{5-[6-(4-{2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl) pyrro lid in-2-yl-3H-imidazol-4-yl}-phenyl)-naphtha len-2-y] 1 H-imidazaI-2-yl}-2-aza-bicyc~o[2.2. 1 ]heptane-2-carbonyl)-2-methyl-propyl] carbamic acid methyl ester 710 [2-Methyl-1 -(2- {5-16-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-naphthalen-2-y] -1 H imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester: This compound was made using the same procedure as for [2-Methyl-I-(2-{5-[6-(4,4,5,5-tetramethyl [I ,3,2]dioxaborolan-2-yI)-naphthalen-2-yI]- I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-propyl] 5 carbamic acid methyl ester, except that 2-Aza-bicyclo[2.2.l]heptane-2,3-dicarboxylic acid 2 tert-butyl ester was used in place of Pyrrolidine-1,2-dicarboxylic acid I-tert-butyl ester as described in example CL. [1-(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) 10 pyrrolidin-2-yl]-3H-imidazol-4-yli-phenyl)-naphthalen-2-yl] 1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyll carbamic acid methyl ester: (1-{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl] pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.251 g), [2-Methyl-l -(3 {5-[6-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yI)-naphthalen-2-yl]- IH-imidazol-2-yl}-2-aza 15 bicyclo[2.2.1 ]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester (0.301 g), and NaHCO 3 (0.162 g) were dissolved in a mixture of 1,2-dimethoxyethane (9 mL) and water (3 mL). The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0254 g) was added. The reaction mixture was stirred at 80*C for 21 hours and evaporated under vacuum. Solid was dissolved in DCM (20 mL) and extracted twice with water (10 mL) and once with brine (10 mL). The resulting oil 20 was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0-5 % MeOH:DCM. The fractions containing product were combined and the solvent was removed under reduced pressure. Oil was dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitri le:water), and lyophilized, giving [I -(3-{5-[6-(4-{2-[I-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2 25 yl }-2-aza-bicyclo[2.2. I ]heptane-2-carbonyl)-2-methyl-propyl]-carbam ic acid methyl ester (0.187 g, 44%) as a white solid. 1 H-NMR: 300 MHz, (CH 3 0H-d 4 ) 8: 8.3 (d, J= 9 Hz, 2H), 8.1 (in, 2H), 8.0 (m, 4H), 7.9 (m, 4H), 5.3 (m, 2H), 4.7 (s, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.9 (m, 2H), 3.7 (d, J= 7 Hz, 6H), 3.3 (m, 2H), 2.9 (s, I H), 2.6 (m, 2H), 2.1 (m, 8H), 1.8 (m, 2H), 1.4 (m, 12H); MS (ESI): m/z 815 30 [M + H]-. 711 Example EW ~-0 H H N N N N AN 01fB 0 U H d0 (2-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]- [2-Methyl-1-(3-{5-(6-(4,4,5,5-tetramethyl pyrrolidin-1-yl}-l-methyl-2-oxo-ethyl)- [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl] carbamic acid methyl ester 1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl) propyl]-carbamic acid methyl ester Pd(PPh 3

)

4 'NH N N NaHICO 3 N

OME-H

2 0 N - N ""/~ /HN-f 0 80"C H Os [1 -(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-propionyl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl] 1 H-imidazol-2-yl}-2-aza-bicyclo[2.2. 1 ]heptane-2-carbonyl)-2-methyl-propyl] carbamic acid methyl ester [1-(3-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4 5 yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2 methyl-propyl-carbamic acid methyl ester: (2-{2-[5-(4-Bromo-phenyl)-l H-imidazol-2-yl] pyrrolidin-1-yl}- I-methyl-2-oxo-ethyl)-carbamic acid methyl ester (0.235 g), [2-Methyl-I-(3 {5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-l H-imidazol-2-yl}-2-aza bicyclo[2.2.l ]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester (0.310 g), and NaHCO 3 10 (0.145 g) were dissolved in a mixture of 1,2-dimethoxyethane (9 mL) and water (3 mL). The solution was degassed with nitrogen, and Pd(PPh 3

)

4 (0.0260 g) was added. The reaction mixture was stirred at 80'C for 24 hours and evaporated under vacuum. Solid was dissolved in DCM (20 mL) and extracted twice with water (10 mL) and once with brine (10 mL). The resulting oil was subjected to silica gel chromatography using a 40 g ISCO column and effluent of 0-5 % 15 MeOH:DCM. The fractions containing product were combined and the solvent was removed under reduced pressure. Oil was dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving [1 -(3-{ 5-[6-(4-{2- [1 -(2-Methoxycarbonylamino propionyl)-pyrrol idin-2-yl]-3H-imidazol-4-yl} -phenyl)-naphthalen-2-yl]- I H-imidazol-2-yl}-2 aza-bicyclo[2.2. I ]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.150 g, 20 36%) as a white solid. I H-NMR: 300 MHz, (CH 3 0H-dI) 5: 8.3 (d, J= 9 Hz, 2H), 8.1 (m, 2H), 8.0 (m, 4H), 7.9 (m, 4H), 5.3 (m, 2H), 4.7 (s, 2H), 4.5 (m, I H), 4.3 (d, J= 7 Hz, I H), 4.0 (m, 2H), 3.7 (d, J= 7 Hz, 712 6H), 3.3 (s, 6H), 2.9 (s, I H), 2.3 (m, 2H), 2.1 (m, 8H), 2.0 (m, 2H), 1 .8 (m, 2H), 1 .3 (d, J= 7 Hz, 3H)1.0 (m, 6H); MS (ESI): m/z 787 [M + H]*. Example EX 5 Pd(PPh 3

)

4 , Cui, Et 3 N, 0 H 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza N' bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl o) N ester H DMF, 80 *C (1-{2-[5-(4-Ethynyl-phenyl)-1 H-imidazol-2-yl]-pyrrolidine-1-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester H 1) HCI, Dioxanes H 2) HATU, NMM, DMF NN Boc 70 N 3-{5-.[4-(4-{2-[1-(2-Methoxyaronylamino-3-mthyl-buyr)pyr~oidin2yl]-3Himidazol-4 yI}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl}-2-aza-bicyclo[ 2.2.1|jheptane-2-carboxylic 2-Methoxycarbonylamino-3 acid tert-butyl ester methyl-butyric acid OH H N 0 V- ' N~ /\o H- N N N- 1'0 /

--

0 Q H H' ~ [1-(3-{5-[4-(4-{2-[1-(2-Methoxcarbonyamino-3methyl-butyry)-pyrrolidin-2-y]-3H-imidazol-4-y) phenylethynyl)-phenyl]-1 H-imidazol-2-yI}-2-aza-bicyclo[2.2.1 heptane-2-carbonyl)-2-methy-propyl] carbamic acid methyl ester 3-{5-[4-(4-{2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H 10 imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]jheptane-2 carboxylic acid tert-butyl ester: A solution of (1 -{ 2-[5-(4-Ethynyl-phenyl)- I H-imidazol-2-yI] pyrrolidine-1 -carbonyl}-2-mnethyl-propyl)-carbamic acid methyl ester (500 ing, 1.27 inmol), 3 [5-(4-Bromno-phenyl)-lI H-imidazol-2-yI]-2-aza-bicyclo[2.2.l1]heptane-2-carboxylic acid tert butyl ester (530 mg, 1.27 minol), and triethylainine (531 [IL, 3.81 minol) in DMF (6.4 mL) was 15 degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (150 mg, 0.13 minol) and CuI (25 mg, 0.13 minol). The pressure flask was sealed then heated at 80*C overnight. After cooling to room temperature, the reaction was quenched with AcOH then purified by reverse phase preparative H-PLC (10-70% MeCN-H 2 0; 0.1% formic acid modifier) then silica gel chromatography (0-10% MeOH-EtOAc gradient) to afford 3-{5-[4-(4-{2-[1-(2 713 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl} -phenylethynyl) phenyl]- IH-imidazol-2-yl}-2-aza-bicyclo[2.2.l]heptane-2-carboxylic acid tert-butyl ester (500 mg, 0.68 mmol, 54% yield). LCMS-ESI*: calc'd for C 4 2

H

50

N

7 0 5 : 732.4 (M+H*-1); Found: 732.2 (M+H*). 5 [1 -(3-{5-[4-(4- {2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] -3H imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.11heptane-2 carbonyl)-2-methyl-propyll-carbamic acid methyl ester: To 3-{5-[4-(4-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl) 10 phenyl]-I H-imidazol-2-yl}-2-aza-bicyclo[2.2.I]heptane-2-carboxylic acid tert-butyl ester (150 mg, 0.20 mmol) in dioxanes (2 mL) was added 4N HCI in dioxanes (250 0 L). The suspension was stirred for 2 hours then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (4 mL) was added N-methylmorpholine (330 0 L, 0.30 mmol). After all material dissolved, 2-methoxycarbonylamino-3-methyl-butyric acid (53 mg, 0.30 mmol) and HATU (76 15 mg, 0.20 mmol) were added. After stirring for overnight the reaction was quenched with AcOH then purified by reverse phase preparative HPLC (5-45% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product [1 -(3-{5-[4-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-phenylethynyl)-phenyl]-I H-imidazol-2-yl}-2-aza bicyclo[2.2. I]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (83 mg, 0.11 20 mmol, 53% yield). 'H-NMR: 400 MHz, (DMSO-d 6 ) 8: 7.59-7.55 (m, 4H), 7.41-7.38 (m, 4H), 7.17 (s, I H), 7.15 (s, I H), 6.16 (m, 2H), 5.15 (m, I H), 4.63 (s, I H), 4.50 (s, I H), 4.34-4.24 (m, 2H), 3.88-3.72 (m, 2H), 3.63 (s, 3H), 3.61 (s, 3H), 2.88 (m, I H), 2.25-2.15 (m, I H), 2.27-2.16 (m, 2H), 2.05-1.80 (m, 5H), 1.54 (d, 2H), 1 .00-0.887 (m, 12H). LCMS-ESl*: calc'd for

C

44

H

5 3

N

8 0 6 : 789.4 (M+H*); Found: 789.5 (M+H*). 25 714 Example EY -~ Pd(PPh 3

)

4 ~i PdCl 2 dpp 2 - N- IN K 2 C0 3 OcC p ME Br + B N C H-H

O

3-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-2-aza-bicydo[2.2. 1]heptane-2- [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl carboxytic acid tert-butyl ester [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yi-1H-imidazol-2-yl} pyrrolidine-1-carbonyl)-propyl}-carbamic acid methyl ester 1) HCI, Dioxanes H -2) HATU, NMM, DMF \- IT// 0 NH 1 O0 N O OHN HH 2-Methoxycarbonylamino-3 3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2- methyl-butyric acid yi}3H-imidazol-4-yl)-naphthalen-2-yl)-phenyl-1 H-imidazol-2-yl}-2-aza bicydo[2.2. 1 ]heptane-2-carboxylic acid tert-butyl ester -O H N N 1r N ,'\ N N 0 H O [1-(2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicycol2.2.1]hept-3-y ]-3--imidazol-4-yI}-phenyl)-naphthalen-2-yl]-1H-imidazol-2 yl)-pyrrolidine-1-carbonyl)-2-methy-propyll-carbamic acid methyl ester 5 3-15-[4-(6-{2-{1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yll-3H imidazol-4-yl}-naphthalen-2-yI)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2 carboxylic acid tert-butyl ester: A solution of [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl [l,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine-I-carbonyl)-propyl] carbamic acid methyl ester (500 mg, 0.92 mmol), 3-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-2 10 aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (383 mg, 0.92 mmol) and aq K 2 CO3 (920 si of a 2M solution, 1.84 mmol) in DME (9 mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (106 mg, 0.092 mmol) and PdCl 2 dppf (75 mg, 0.092 mmol) and then the reaction was heated to 80'C overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The 15 crude product was purified by reverse phase preparative HPLC (5-50% MeCN-H 2 0; 0.1% formic acid modifier) to afford 3-{5-[4-(6-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]- I H-imidazol-2-yl}-2-aza bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (112 mg, 0.15 mmol, 16% yield). LCMS-ESI*: calc'd for C 4 4

H

5 2

N

7 0 5 : 758.4 (M+H*); Found: 758.0 (M+H*). 20 715 [1-(2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2. 1 hept 3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-pyrrolidine-1 carbonyl)-2-methyl-propyll-carbamic acid methyl ester: To 3-{5-[4-(6-{2-[l-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl }-naphthalen-2 5 yl)-phenyl]- I H-imidazol-2-yl} -2-aza-bicyclo[2.2.l ]heptane-2-carboxylic acid tert-butyl ester (60 mg, 0.092 mmol) in dioxanes (3 mL) was added 4N HCI in dioxanes (I mL). The suspension was stirred overnight then concentrated to afford the HCI salt of the crude amine, which was purified by reverse phase preparative HPLC (5-45% MeCN-H 2 0; 0.1% formic acid modifier) and concentrated. The formate salt was dissolved in MeOH then passed through an 10 ion-exchange column (StratoSpheres SPE PL-HCO 3 MP SE) to afford the free amine (30 mg, 0.046 mmol, 58%). To the amine (30 mg, 0.046 mmol) in DMF (1 mL) was added N methylmorpholine (10 0 L, 0.092 mmol). After all material dissolved, 2 methoxycarbonylamino-3-methyl-butyric acid (12 mg, 0.068 mmol) and HATU (19 mg, 0.051 mmol) were added. After stirring for 3 hours the reaction was quenched with AcOH then 15 purified by reverse phase preparative HPLC (5-45% MeCN-H 2 0; 0.1% formic acid modifier) to afford [1 -(2-(5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.I]hept-3-yl]-3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]- IH-imidazol-2-yl} pyrrolidine-l -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (29 mg, 0.036 mmol, 77% yield). ' H-NMR: 400 MHz, (DMSO-d 6 ) 6: 8.04 (s, I H), 7.86 (s, I H), 7.71 (d, 2H), 7.63-7.58 20 (m, 4H), 7.52 (d, 2H), 7.26 (s, I H), 7.14 (s, I H), 6.17 (m, 2H), 5.21 (m, I H), 4.67 (s, 1 H), 4.52 (s, I H), 4.35-4.26 (m, 2H), 3.86 (m, I H), 3.79 (m, I H), 3.64 (s, 6H), 2.90 (m, I H), 2.43 (m, I H), 2.30-2.1.82 (m, 9H), 1.55 (d, 2H), 1.02-0.87 (m, 12H). LCMS-ESI*: calc'd for C 4 6

H

55

N

8 0 6 : 815.3 (M+H); Found: 815.4 (M+H*). 25 716 Example EZ H H Pd(PPh 3

)

4 O H}PdCl2dppf2

K

2 C0 3 -k- N N N-j 0 Br, + B OI8F (1-3-f5-(4-Bromo-phenyl) H- midazol-2-yl}-2aza- [2-MethIy-l-(6-{5-[6-(4,4,5,5-tetramethyl-( 3.2]dioxabarolan-2-yl) bicydlo[2.2.1 Iheptane-2-carbonyl).2-methy-pmopyl)- naplltlalen-2-yIJ-lH-~midazo-2-yl)5aza-spiro[2+4Jheptane-5 carbamic acid methyl ester carbonyl)-propyl}-carbamic acid methyl ester -N- N V 0 I HH [1-(6-{ 5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicydo[22llhept-3-ii3Hmidazol-4-y-phenyl)-naphthalen-2.yl)lH-imidazol-2-yl)-5 aza-spiro[2 4]heptane-5-carbonyn2-methyl-propyj-carbamic ad methyl ester 5 3-ylI-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl-1 H-imidazol-2-yl}-5-aza spiro[2.4]heptane-5-carbonyl)-2-methyl-propylj-carbamic acid methyl ester: A solution of (1 -{3-[5-(4-Bromo-phenyl)-I H-imidazol-2-yI]-2-aza-bicyclo[2.2. I ]heptane-2-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (151 mg, 0.32 mmol), [2-Methyl-I-(6-{5-[6-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-y]-HI -imidazol-2-yl}-5-aza 10 spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (200 mg, 0.35 mmol) and aq

K

2

CO

3 (438 pl of a 2M solution, 0.88 mmol) in DME (4 mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (40 mg, 0.035 mmol) and then the reaction was heated to 80'C overnight. After cooling to room temperature, the reaction was quenched with acetic acid, filtered, and then concentrated. The crude product was purified by 15 reverse phase preparative HPLC (5-50% MeCN-H 2 0; 0.1% formic acid modifier) to afford [I (6-{5-[ 6

-(

4

-{

2 -[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.I ]hept-3-yl] 3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]- I H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (40 mg, 0.047 mmol, 14% yield). 'H NMR: 400 MHz, (DMSO-d 6 ) 8: 11.75 (s, I H), I11.72 (s, I H), 8.24 (s, 1 H), 8.15 (d, I H), 7.93 20 7.74 (m, 8H), 7.63 (s, I H), 7.54 (s, I H), 7.30 (d, I H), 7.16 (d, I H), 5.22 (t, I H), 4.52-4.50 (m, 21-), 4.16 (t, I H), 4.00 (t, I H), 3.81 (d, I H), 3.75 (d, I H), 3.72 (s, 3H), 3.31 (s, 31-), 2.55 (m, IH), 2.32-1.41 (m, 10H), 1.01-0.57 (m, 16H). LCMS-ESI*: calc'd for C 4 8

H

5 7

N

8 0 6 : 841.4 (M+H*); Found: 842.1 (M+H*). 25 717 Example FA and FB Br 0 0 NHOAc Br N C OBr HO HKL 13O*C, 75 min o Hu., N N 2-Bromo-l1-(6-bromo- N-Boc-ds-4cno-L- 4-Cyano-pyrralidine-1 .2-dicarboxylic naphthalen-2-yi)-ethanone praline methyl ester acdd 2-[2-(6-bromo-naphthalen-2-y)-2 oxo-ethyl] ester 1 -tert-butyl ester Br - N 0 Br - /N 0 J 0 NH OAc N ~ ' N N Xylenes H H< _________4h_ H H -L 130C, 7 mm //~ 2. HIATU, DIPEAIf N DMF. RT N 2-[5-(6-Bromo-naphthalen-2-yl)-1 H- 0 (1 -2-[5-(6-Bromo-naphthalen-2-yl)-1 H-midazol imidazol-2-yI]-4-cyano-pyrrolidine?-1- H2-yl]-4-cyano-pyrrolidine-1 -carbonyl}-2-methyl carbaxylic acdd tert-butyl ester -OH propyl)-carbamic acid methyl ester 0 -K 0 B\ -o N 0 - N 'IH H o___ N IN r 0' . 4 rN Br Pd(dPpfCl 2 1CH 2 Cl 2 H _01 KOAc. 1,4-Dioxane Hr 1 90-C, 16h N [1 -(4-Cyano-2-{5-[6-(4,4,5,5-tetramethyl- (1-{6-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-5-aza [11,3,2]dioxaborolan-2-y)-naphthalen-2-y]-1 H- spiro[2.4]heptane-5-carbonyl)-3-methanesufonyl imidazol.2-y)-pyrrolidine.1 -carbonyl)-2- propyl)-carbamic ad methyl ester methyl-propyl]-carbamic acid methyl ester Pd(PPh 3

)

4 H~S H H 0 2M K 2 C0 3 /' N N - - H/ \0 /

DMEIH

2 0 N. 'UN 85*C, 18hi N H N N [1-(4-Cyano-2-5[6-(4-{2-(5-(4-methanesulfonyl-2-methoxycarbonylamino butyryl)-5-aza-spiro[2.4]hept-6-yl-3H-imidazol-4-yl)-phenyl)-naphthalen-2 ylil H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 718 4-Cyano-pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl] ester 1-tert-butyl ester: Title compound was prepared according to the method employed to prepare pyrrolidine-1,2 5 dicarboxylic acid 2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl] ester 1-tert-butyl ester in Example CL, substituting pyrrolidine- 1,2-dicarboxylic acid I -tert-butyl ester with N-Boc-cis-4 cyano-L-proline methyl ester (643 mg, 67%) 2-[5-(6-Bromo-naphthalen-2-yl)-1 H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid 10 tert-butyl ester: Title compound was prepared according to the method employed to prepare 2-[5-(6-Bromo naphthalen-2-yl)- IH-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester: in Example CL, changing the reaction temperature to 130'C and the reaction time to 75 minutes. (396 mg, 15 64%) MS (ESI) m/z 468.99 [M + H]*. (1-{2-15-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: 20 Title compound was prepared according to the method employed to prepare (I-{2-[5-(7-{2-[1 (2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-thianthren-2 yl)-I H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester and (1 -{ 2-[5-(8-{2- [1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazo-4 yl}-thianthren-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl} -2-methyl-propyl)-carbamic acid 25 methyl ester in Example BS, substituting N-methylmorpholine with five equivalents of diisopropylethylamine. (430 mg, 97%) MS (ESI) m/z 525.94 [M + H]*. [1-(4-Cyano-2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1

H

imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: 30 Title compound was prepared according to the method employed to prepare 2-[6-(4,4,5,5 Tetramethyl-[1,3,2]dioxaborolan-2-y)-1 H-benzoimidazol-2-yl]-pyrrolidine-I -carboxylic acid tert-butyl ester in Example CL, replacing N-Boc Proline with N-Boc-4-cyano-proline. (407 mg, 87%) MS (ESI) m/z 572.46 [M + H]f. 35 719 (1-{6-15-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-3 methanesulfonyl-propyl)-carbamic acid methyl ester: HBr O's O NH H HBr O OH NH 4 0Ac N H H N - O Xyenes . O N N N ~130C,75 min N O O- H 0 0 6-[5-(4-Bromo-phenyl)-1 H-imidazol- 4-Methanesulfonyl-2- (1 -{6-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-5-aza 2-yI}-5-aza-spiro[2.4]heptane X2 methoxycarbonylami spiro[2.4]heptane-5-carbonyl)-3-methanesulfonyl hydrogen bromide salt no-butyric acid propyl)-carbamic acid methyl ester 5 Title compound was prepared according to the method employed to prepare (1-{2-[5-(4 Bromonaphthalen-l-yl)-I H-imidazol-2-yl]-pyrrolidine-I -carbonyl} 2-methyl-propyl)-carbamic acid methyl ester in Example CK, substituting N-methylmorpholine with five equivalents of diisopropylethylamine.(99%) 10 Example FA: l1-(4-Cyano-2-{5-[6-(4-{2-15-(4-methanesulfonyl-2-methoxycarbonylamino butyryl)-5-aza-spiro[2.4] hept-6-yli]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H imidazol-2-yl}-pyrrolidine-I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester \O 0S HH N NH -O O N Br 0 \ (1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl}-5-aza spiro[2.4]heptane-5-carbonymethanesufonyl- Pd(PPh 3

)

4 0 ) H H H, 0 propyl)-carbamic acid methyl ester 2M K 2 C0 3 N N N _ O N O O DME/H20 .. O NN N 85*C, 18h O H N N N N [1-(4-Cyano-2-{5-[6-(4-{2-[5-(4-methanesulfonyl-2-methoxycarbonyamino H butyryl)-5-aza-spiro[2.4]hept-6-y)-3H-imidazol-4-yf-phenyl)-naphthalen-2 H yl]- H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyt}-carbamic acid methyl ester N [1 -(4-Cyano-2-{5-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-naphthalen-2-y)-1 H-imidazol 2-yl}-pyrolidine-1-carbonyl)-2-methy-propy] 15 carbamic acid methyl ester Title compound was prepared according to the method employed to prepare (I-{2-[5-(6'-{2-[1 (2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 3 H-imidazol-4-yl}-[2,2']binaphthalenyl-6-yl)-I H-imidazol-2-yl]-pyrrolidine 20 1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester in Example CL. (30%) 720 :I H-NMR: 400 MHz, (CD 3 0D) 8 8.14 (s, 2H), 8.09 (d, J= 5.6 Hz, I H), 7.92 (d, J= 7.6 Hz, 2H), 7.85 - 7.78 (m, 5H), 7.46 (s, 1 H), 7.41 (s, I H), 5.33 (dd, J= 5.6 Hz, 7.6 Hz, 1 H), 5.21 (t, J= 8.4 Hz, I H), 4.63 - 4.58 (m, 2H), 4.17 - 4.13 (m, I H), 4.05 (t, J= 10.4 Hz, I H), 3.83 (s, 2H), 3.65 (d, J= 5.2 Hz, 6H), 3.48 - 3.42 (m, 3H), 3.21 (t, J= 7.6 Hz, 2H), 2.98 (s, I H), 2.95 (s, 2H), 2.92 5 - 2.84 (m, I H), 2.64 - 2.55 (m, I H), 2.35 - 2.27 (m, 2H), 2.14 - 1.92 (m, 4H), 0.98 - 0.87 (m, 7H), 0.79 - 0.59 (m, 4H). MS (ESI) m/z 904.58 [M + H]*. Example FB: [1-(4-Cyano-2-{5-[6-(4-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2 10 aza-bicyclo[2.2.1]hept-3-yll-3H-imidazol-4-yl)-phenyl)-naphthalen-2-yl]-1 H-imidazol-2 yl}-pyrrolid ine- 1 -carbonyl)-2-methyl-propyl] -carbam ic acid methyl ester: 0 O H [1-.(4-Cyano -{6-(4,4,5,5-tetramethyl- ) NH mId0 2- yprroldine -ca Bny)-2 et N N N propyl]-carbamic acid methyl ester + O85 8 2 Ha H 0 N Br N Nb o2 21 he p y m o phenaphh -y mi o H2 }razN2 pi-O-yy r iyo}-rhne-r-caroonyli-2d - r )- p yc b ci m es methyl-ppyl)-car bami c acid methyl este r 15 Title compound was prepared according to the method employed to prepare (1-{2-[5-(6'-{2-[1 (2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 3 H-imnidazol-4-yl }-[2,2']binaphthalenyl-6-yI)- H-imidazol-2-yl]-pyrrolidine 1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester in Example CL. (35%) 20 : 1 H-NMR: 400 MHz, (CD 3 0D) 8 8.22 (s, I H), 8.15 (s, I H), 8.07 (s, I H), 7.92 (dd, J= 2 Hz, 8.4 Hz, 2H), 7.85 - 7.76 (m, 6H), 7.44 (s, I H), 7.33 (s, I H), 5.21 (t, J= 8.8 Hz, I H), 4.71 (s, I H), 4.62 - 4.55 (m, 2H), 4.33 - 4.27 (m, I H), 4.16 (d, J= 7.6 Hz, I H), 4.05 (t, J= 10.4 Hz, I H), 3.65 (d, J= 5.6 Hz, 4H), 3.51 (m, 2H), 2.90 (m, I H), 2.76 (s, I H), 2.64 (m, I H), 2.29 (d, J= 9.6 Hz, I H), 2.19 - 2.10 (m, I H), 2.00 - 1.84 (m, 4H), 1.65 - 1.56 (m, 2H), 1.31 (m, I H), 1.02 (d, J= 6.8 25 Hz, 2H), 0.971 - 0.86 (m, 8H). MS (ESI) m/z 840.64 [M + H]+. 721 Example FC HATU, Br- NH3CI .+ HO 2 C N 0 Loc DMF 2-Amino-1 -(4-bromo-phenyl)- Morpholine-3,4-dicarboxylic ethanone hydrochloride acid 4-tert-butyl ester 'O 1. HCI H 2. carboxcylic acid, BN - NH40Ac_ HATU, DIPEA o o ,N xylenes \..-N DMF Boc 3-[5-(4-Bromo-phenyl)-1

H

3-[2-(4-Bromo-phenyl)-2-oxo- imidazol-2-yl]-morpholine-4 ethylcarbamoy]-morpholine-4- carboxylic acid tert-butyl ester carboxylic acid tert-butyl ester : 0Cul, H O Pd(PPh 3

)

4 N -- jr NEtN Br + HN N N0 NI ODMF 0OyrNH

-

(1 -{3-[5-(4-Bromo-phenyl)-1 H-imidazol- (1 -{2-[5-(4-Ethynyl-phenyl)-1 H-imidazol-2 2-yl]-morpholine-4-carbonyl}-2-methyl- yl]-pyrrolidine-1 -carbonyl}-2-methyl propyl)-carbamic acid methyl ester propyl)-carbamic acid methyl ester 0/0 HN H H 0 NH -o [1 -(2-{5-[4-(4-{2-[4-(2-Methoxycarbonylamino-3-methyl-butyryl) morpholin-3-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2 yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-morpholine-4-carboxylic acid tert-butyl 5 ester: Title compound was prepared according to the method employed to prepare 3-[2-(4 Bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AE), substituting Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester for 2-aza bicyclo[2.2.l ]heptane-2,3-dicarboxylic acid 2-tert-butyl ester. 10 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-morpholine-4-carboxylic acid tert-butyl ester: Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo phenyl)- 1 H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (Example AS), substituting 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-morpholine-4 722 carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester. (1-{3-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-morpholine-4-carbonyl}-2-methyl-propyl) 5 carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare ( -[2-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-l -carbonyl]-2-methyl-propyl} carbamic acid methyl ester (Example CY), substituting 3-[5-(4-Bromo-phenyl)-1 H-imidazol-2 yl]-morpholine-4-carboxylic acid tert-butyl ester for 2-(4'-Bromo-biphenyl-4-ylcarbamoyl) pyrrolidine- I -carboxylic acid tert-butyl ester. 10 [1-(2-(5-14-(4-{2-[4-(2-Methoxycarbonylamino-3-methyl-butyryl)-morpholin-3-yl]-3H imidazol-4-yI}-phenylethynyl)-phenyl]-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H 15 imidazol-4-ylethynyl}-phenylethynyl)-I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester (Example CT), substituting (I -{3-[5-(4-Bromo-phenyl)-l H imidazol-2-yl]-morpholine-4-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1 -{2 [5-(4-bromo-phenylethynyl)-I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl) carbamic acid methyl ester. 1H-NMR: 400 MHz, (DMSO-d 6 ) 8 12.05 (s, I H), 11.84 (s, I H), 20 7.81 - 7.74 (m, 4H), 7.69 (s, I H), 7.56 (s, I H), 7.50 - 7.47 (m, 4H), 7.32 - 7.27 (m, 2H), 4.42 4.34 (m, 2H), 4.08 - 3.95 (m, 2H), 3.85 - 3.79 (m, 3H), 3.72 - 3.68 (m, 2H), 3.56 (d, J= 7.6 Hz, 5H), 3.46 - 3.40 (m, 2H), 2.2 - 2.07 (m, 3H), 2.01 - 1.90 (m, 4H), 1.02 - 1.00 (d, J= 6.4 Hz, 2H), 0.953 - 0.837 (m, 12H); MS (ESI) m/z 779 [M + H]*. 25 723 Example FD Pd(PPh 3

)

4 , N OHC Pd(dppf)C 2 -DCM, OHC oBr HoB CI

K

2

CO

3 N / H HO DME/H 2 0 N 2-(5-Bromo-1H-imidazol-2- 4-Chloro-2-formyl yi)-pyrrolidine-1 -carboxylic phenylboronic acid 2-[5-(4-Chloro-2-formyl-phenyl) acid tert-butyl ester 1 H-imidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester / NC 1. HCI HNC 1. H 2 NOH, EtOH N \ Cl 2. carboxcylic acid, N I 2. TBSCI, Im., DMF N N HATU, DIPEA N DMF (&H 2-[5-(4-Chloro-2-cyano-phenyl)- (1 -{2-(5-(4-Chloro-2-cyano-phenyl)-1 H 1 H-midazol-2-yl]-pyrrolidine-1 - imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2 carboxylic acid tert-butyl ester methyl-propyl)-carbamic acid methyl ester 0 H/ Bis(pinacolato)diboron, NC Pd 2 (dba)3, x-phos, KOAc r N o H dioxane (JH OH N H O< 3-Cyano-4-(2-[1-(2-methoxycarbonylamino- (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2 3-methyl-butyryl)-pyrrolidin-2-yl]-3H- yl]-pyrrolidine-1 -carbonyl}-2-methyl imidazol-4-yl}-phenylboronic acid propyl)-carbamic acid methyl ester Pd(PPh 3

)

4 , HNo NC H

K

2 C0 3 N V N N yNI

DME/H

2 0 N/N N N H NH O=< /0 (1-{2-[5-(3-Cyano-4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 2-[5-(4-Chloro-2-formyl-phenyl)-1H-imidazol-2-yI]-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-(5-Bromo-l H-imidazol-2-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (2.00 g, 6.32 mmol), 4-Chloro-2-formyl-phenylboronic acid (1.17 g, 6.32 mmol), Pd(PPh 3

)

4 (365 mg, 0.316 mmol), Pd(dppf)C1 2 -DCM (258 mg, 0.316 mmol) K 2

CO

3 (2 M, 6.3 mL, 12.6 mmol) and DME (30 mL) were combined in a round bottom flask. The stirred suspension was degassed for 10 10 minutes with bubbling N 2 then heated to 85 'C. After 4 h, the reaction mixture was poured into saturated aqueous NaHCO 3 . The aqueous phase was extracted 3x with EtOAc and the combined organics were dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (25% to 75% EtOAc/Hexane) to afford the title compound 2-[5-(4-Chloro-2-formyl-phenyl)- I H-imidazol-2-yl]-pyrrolidine- 15 carboxylic acid tert-butyl ester (1.85 g, 78%). 724 2-15-(4-Chloro-2-cyano-phenyl)-1H-imidazol-2-yI]-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-[5-(4-Chloro-2-formyl-phenyl)- IH-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert butyl ester (985 mg, 2.62 mmol) was dissolved in ethanol (20 mL) and hydroxylamine (50% 5 w/w in H 2 0, 642 pL, 10.48 mmol) was added. After stirring at room temperature for 15 h, the solution was concentrated. To the crude oxime was added TBSCI (474 mg, 3.14 mmol), imidazole (357 mg, 5.24 mmol) and DMF (10 mL). The reaction mixture was stirred at 120 "C for 80 minutes at which point more TBSC (237 mg, 1.58 mmol) and imidazole (177 mg, 2.60 mmol) were added. The reaction mixture was stirred an additional 17 hours at 120 *C then 10 cooled to room temperature, diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO 3 and brine then dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (25% to 50% EtOAc/Hexane) to afford the title compound 2-[5-(4-Chloro-2-cyano-phenyl)-1 H-imidazol-2 yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 5 1%). 15 (1-{2-[5-(4-Chloro-2-cyano-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare { I -[2-(4'-Chloro-biphenyl-3-ylcarbamoyl)-pyrrol idine- I -carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (Example CX), substituting 2-[5-(4-Chloro-2-cyano 20 phenyl)-1 H-imidazol-2-yli]-pyrrolidine-1-carboxylic acid tert-butyl ester for 2-(4'-Chloro biphenyl-3-ylcarbamoyl)-pyrrolidine- I -carboxylic acid tert-butyl ester. 3-Cyano-4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yi}-phenylboronic acid: Title compound was prepared according to the method 25 employed to prepare 2-{5-[2'-Cyano-4'-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl 4-yl]-1 H-imidazol-2-yl}-pyrrolidine-I -carboxylic acid tert-butyl ester (Example CZ), substituting (I -{2-[5-(4-Chloro-2-cyano-phenyl)- I H-imidazol-2-yl]-pyrrolidine-1 -carbonyl)-2 methyl-propyl)-carbamic acid methyl ester for 2-[5-(4'-Chloro-2'-cyano-biphenyl-4-y)- H imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester. 30 (1-{2-[5-(3-Cyano-4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-ylI 3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [1 -(2-{ 5-[6-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) 35 pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine-l 725 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting 3-Cyano-4 {2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-im idazol-4-yl} phenylboronic acid for [2-methyl-I -(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-propyl]-carbamic acid methyl 5 ester. 'H-NMR: 400 MHz, (DMSO-d 6 ) 8 12.13 (s, I H), 8.13 - 8.04 (m, 2H), 7.85 - 7.75 (m, 4H), 7.57 (s, I H), 7.31 (dd, J= 3.6 Hz, 8.4 Hz, I H), 5.13 - 5.10 (m, 2H); MS (ESI) m/z 764 [M + H]+. Example FE 10 NC NC HHATU, -H NH CI N 3HO,, N DIPEA Br NH3 + Boc DMF 00 BrN 2-Amino-1 -(4-bromo-phenyl)- 4-Cyano-pyrrolidine-1,2- 2-[2-(4-Bromo-phenyl)-2-oxo ethanone hydrochloride dicarboxylic acid 1-ted-butyl ester ethylcarbamoyl]-4-cyano-pyrrolidine 1-carboxylic acid tert-butyl ester NC - H 1. HCI NN 2. carboxcylic acid, NH4A Br - ilBoc HATU, DIPEA xylenes 2-[5-(4-Bromo-phenyl)-1H- DMF imidazol-2-yl]-4-cyano-pyrrolidine 1-carboxylic acid ted-butyl ester NC H H/O N-- HN Br + ( o 0 (1 -{2-[5-(4-Bromo-pheny)-1 H-imidazol-2- [2-Methyl-1 -(2-{5-[6-(4,4,5,5-tetramethyl yl]-4-cyano-pyrrolidine-1 -carbonyl}-2- (1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1 H-imidazol-2 methyl-propyl)-carbamic acid methyl ester yl)-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester NC Pd(PPh 3

)

4 , HN 0 H

K

2 C0 3 \N IN/

DMEIH

2 0 , H N NH 0=( /0 [1 -(2-{5-[6-(4-{2-[4-Cyano-1 -(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl-1 H-imidazol-2 yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert butyl ester: Title compound was prepared according to the method employed to prepare 3-[2 15 (4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert 726 butyl ester (Example AE), substituting 4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for 2-aza-bicyclo[2.2.l]heptane-2,3-dicarboxylic acid 2-tert-butyl ester. 2-15-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl 5 ester: Title compound was prepared according to the method employed to prepare 3-[5-(4 Bromo-phenyl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (Example AS), 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-I carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza bicyclo[2.2. I Iheptane-2-carboxylic acid tert-butyl ester. 10 (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare { -[2-(4'-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine-l-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (Example CX), substituting 2-[5-(4-Bromo-phenyl) 15 1 H-imidazol-2-yl]-4-cyano-pyrrolidine-l-carboxylic acid tert-butyl ester for 2-(4'-Chloro biphenyl-3-ylcarbamoyl)-pyrrolidine- I -carboxylic acid tert-butyl ester. [1-(2-{5-[6-(4-{2-14-Cyano-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 20 methyl-propyll-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [I -(2-{5-[6-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]- IH-imidazol-2-yl}-pyrrolidine-l carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (I -{2-[5-(4 Bromo-phenyl)-l H-imidazol-2-yl]-4-cyano-pyrrolidine-I -carbonyl } -2-methyl-propyl)-carbamic 25 acid methyl ester for [2-methyl-I -(2-{5-[6-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl) naphthalen-2-yl]- 1 H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-propyl]-carbamic acid methyl ester. ' H-NMR: 400 MHz, (DMSO-d 6 ) 8 11.98 (s, I H), 11.82 (s, 1 H), 8.22 (m, 2H), 7.92 - 7.77 (m, 6H), 7.62 (m, 2H), 7.44 (d, J= 7.6 Hz, 1 H), 7.31 (d, J= 8.0, 1 H), 5.24 (t, J= 5.2 Hz, I H), 5.12 (d, J= 4.0, 1 H), 4.22 - 4.19 (m, I H), 4.09 - 4.0 (m, 4H), 3.89 - 3.83 (m, 4H), 3.56 (d, J= 5.6 Hz, 30 6H), 2.17 (brs, 2H), 2.06 - 1.90 (m, 4H), 0.95 - 0.84 (m, 14H); MS (ESI) mlz 814 [M + H]f. 727 Example FF 0 /1. TMS-acetylene, Cul, Pd(PPh 3

)

4 , HN Et 3 N, DMF 0N 1 B 2. K 2

CO

3 , MeOH (H (1 -{2-[5-(6-Bromo-naphthalen-2-yl)-1 H imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester 0/ O>=o H HN N 00 (1 -{2-[5-(6-Ethynyl-naphthalen-2-yl)-1 H- {1 -[3-(6-Bromo-1 H-benzoimidazol-2-yl)-2 imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2- aza-bicyclo[2.2.1 ]heptane-2-carbonyl]-2 methyl-propyl)-carbamic acid methyl ester methyl-propyl}-carbamic acid methyl ester Cul, Pd(PPh 3

)

4 HN O H H Et3N 0 N DMF T2 H N 0=O (1 -{2-[5-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.1 ]hept-3-yl]-3H-benzoimidazol-5-ylethynyl}-naphthalen-2-yl)-1 H imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 (1-{2-15-(6-Ethynyl-naphthalen-2-yl)-I H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2-methyl propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (1- { 2-[5-(4-Ethynyl-phenyl)- I H-imidazol-2-yl]-pyrrol idine- I -carbonyl} -2 methyl-propyl)-carbamic acid methyl ester from (I -{2-[5-(4-bromo-phenyl)- I H-imidazol-2-yl] pyrrolidine-I-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example AY), 10 substituting (I -{2-[5-(6-Bromo-naphthalen-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl} -2 methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)- I H-imidazol-2-yl] pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. (1-{2-15-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3 15 yl]-3H-benzoimidazol-5-ylethynyl)-naphthalen-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared 728 according to the method employed to prepare Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3 H-imidazol-4-ylethynyl}-phenylethynyl)-I H-imidazol-2-yl]-pyrrolidine-I carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example CT), substituting {I-[3-(6 Bromo-l H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carbonyl]-2-methyl-propy} 5 carbamic acid methyl ester for (1 -{2-[5-(4-bromo-phenylethynyl)-l H-imidazol-2-yl] pyrrolidine-l -carbonyl }-2-methyl-propyl)-carbamic acid methyl ester and (I -{2-[5-(6-Ethynyl naphthalen-2-yI)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl } -2-methyl-propyl)-carbamic acid methyl ester for { 1-[2-(5-Ethynyl- I H-imidazol-2-yl)-pyrrol idine- I -carbonyl]-2-methyl-propyl} carbamic acid methyl ester. NMR (MeOH-d4, 400 MHz) 6: 8.19-8.11 (m, 1IH), 8.01-7.99 (m, 10 1 H), 7.86-7.71 (m, 3H), 7.57-7.39 (m, 3H), 7.02-6.99 (m, I H); MS (ESI) m/z 813 [M + H]*. Example FG H H )_ CN -HC HO N HATU, H +BrNHCIH DIP D Br 0 Boc DMVF 00 0 Boc 13 2-Amino-1 -(4-bromo-phenyl)- 4-Cyano-pyrrolidine-1,2- 2-[2-(4-Bromo-phenyl)-2-oxo ethanone hydrochloride dicarboxylic acid 1-tert-butyl ester ethylcarbamoyl]-4-cyano-pyrrolidine 1-carboxylic acid tert-butyl ester H 1. HCI N 2. carboxcylic acid, NH40A Brioc HATU, DIPEA xylenes N DMVF 2-[5-(4-Bromo-phenyl)-1 H imidazol-2-yl]- 4 -cyano-pyrrolidine 1-carboxylic acid terf-butyl ester H -CN H )jN / HHN Br VO1+H NH< H O' /0 (1 -{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2- [2-Methyl-1 -(2-{5-[6-(4,4,5,5-tetramethyl yl]-4-cyano-pyrrolidine-1 -carbonyl}-2- [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1 H-imidazol-2 methyl-propyl)-carbamic acid methyl ester yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester 0/H O4H C Pd(PPh2 3 ) HN

K

2 C0 3 fN&H- IN'~'

DMVIE/H-

2 0 H N - &H /0 [1 -(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-3-methy-butyry) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2 yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 15 729 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert butyl ester: Title compound was prepared according to the method employed to prepare 3-[2 (4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert butyl ester (Example AE), substituting 4-Cyano-pyrrolidine- 1,2-dicarboxylic acid I -tert-butyl 5 ester for 2-aza-bicyclo[2.2. I ]heptane-2,3-dicarboxylic acid 2-tert-butyl ester. 2-15-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester: Title compound was prepared according to the method employed to prepare 3-[5-(4 Bromo-phenyl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl 10 ester (Example AS), and substituting 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano pyrrolidine- I-carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl] 2-aza-bicyclo[2.2. I]heptane-2-carboxylic acid tert-butyl ester. (1 -{2-15-(4-Bromo-phenyl)-1 H-imidazol-2-y1]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl 15 propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare { -[2-(4'-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine- I -carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (Example CX), substituting 2-[5-(4-Bromo-phenyl) I H-imidazol-2-yl]-4-cyano-pyrrolidine-l-carboxylic acid tert-butyl ester for 2-(4'-Chloro biphenyl-3-ylcarbamoyl)-pyrrolidine- I -carboxylic acid tert-butyl ester. 20 [1-(2-{5-16-(4-{2-[4-Cyano-1 -(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y] 3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [1 -(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) 25 pyrrolidin-2-yl]-3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yi]-I H-imidazol-2-yl}-pyrrolidine- I carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (I-{2-[5-(4 Bromo-phenyl)-l H-imidazol-2-yl]-4-cyano-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for [2-methyl-I -(2-{5-[6-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl) naphthalen-2-yl]- I H-imidazol-2-yi}-pyrrolidine-I -carbonyl)-propyl]-carbamic acid methyl 30 ester. NMR (MeOH-d4, 400 MHz) 6: 8.12-8.03 (m, 2H), 7.89-7.74 (m, 6H), 7.48-7.36 (m, 2H), 5.20 (m, 2H), 4.60 (m, I H), 4.28-3.88 (m, 6H), 3.66 (s, 6H), 2.86 (m, I H), 2.60 (m, I H), 2.40 2.19 (m, 3H), 2.11-1.97 (m, 3H), 1.00-0.88 (m, 12H); MS (ESI) m/z 814 [M + H]*. 730 Example FH 0 0 C1CO 2 Me, NC OH NaOH NH -- *1 H OH NC -Y OH THF/H 2 0 W HN Os

NH

2 0 2-Amino-3-cyano-propionic acid 3-Cyano-2-methoxycarbonylamino propionic acid 0/ O 1. HCI H 2. carboxcylic acid, N N-j r HATU. DIPEA am CN 'FH H I DMF 3-{5-[6-(4,4,5.5-Tetramethyl-{1,3,2]dioxaborolan-2-yl)- [2-Cyano-1-(3-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y) naphthalen-2-y]-1 H-imidazol-2-yl}-2-aza- naphthalen-2-yl]-1 H-imidazol-2-yl}-2-aza-bicyclo[2.2. 1]heptane-2 bicyclo[2.2. 1)heptane-2-carboxylic acid tert-butyl ester carbonyl)-ethyll-carbamic acid methyl ester / )0 Pd(PPh 3

)

4 , HN

I(

2 C0 3 N 0 H NH 0= /0 [1 -(2-{5-[4-(6{2-[2-(3-Cyano-2-methoxycarbonylamino-propionyl)-2-aza bicycio(2.2.1]hept-3-yl]-3H-imidazol-4-y}-naphthalen-2-y)-phenyl]-1 H-imidazol 2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 3-Cyano-2-methoxycarbonylamino-propionic acid: Methyl chloroformate (0.81 mL, 10.51 5 mmol) was added dropwise to a stirred suspension of 2-Amino-3-cyano-propionic acid ( 1.00g, 8.76 mmol) and NaOH (5 N in H 2 0, 4.2 mL, 21.0 mmol) in THF (20 mL). After stirring at room temperature for 7h, the reaction mixture was poured into 10% HCI and the aqueous phase was extracted 3x with diethyl ether. The combined organics were dried over MgSO 4 , filtered and concentrated to afford 3-Cyano-2-methoxycarbonylamino-propionic acid (295 mg, 20%). 10 [2-Cyano-1-(3-{5-16-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-IH imidazol-2-yl}-2-aza-bicyclo[2.2.11heptane-2-carbonyl)-ethyll-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare { I -[2-(4'-Chloro biphenyl-3-ylcarbamoyl)-pyrrolidine- I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester 15 (Example CX), substituting 3-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen 2-yl]-1 H-imidazol-2-yl}-2-aza-bicyclo(2.2. I]heptane-2-carboxylic acid tert-butyl ester for 2-(4' Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine- I -carboxylic acid tert-butyl ester and 3-Cyano-2 methoxycarbonylamino-propionic acid for 2-methoxycarbonylamino-3-methyl-butyric acid. 20 [1-(2-{5-[4-(6-{2-[2-(3-Cyano-2-methoxycarbonylamino-propionyl)-2-aza bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl)-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-propyll-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [1-(2-{5-[6-(4-{2-[1-(2 731 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl} -phenyl) naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine- 1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting [2-Cyano-l-(3-{5-[6-(4,4,5,5-tetramethyl [1 ,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]- 1 H-imidazol-2-yl}-2-aza-bicyclo[2.2. 1 ]heptane-2 5 carbonyl)-ethyl]-carbamic acid methyl ester for [2-methyl-I-(2-{5-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine-l -carbonyl)-propyl] carbamic acid methyl ester. 1H NMR (DMSO-d6, 400 MHz) 8: 8.24-8.18 (m, 2H), 7.99-7.79 (m, 6H), 7.63-7.54 (m, 2H), 5.09 (m, I H), 4.84 (m, I H), 4.53 (s, I H), 4.41 (s, I H), 4.07 (m, I H), 3.82 (m, 2H), 3.62 (s, 3H), 3.54 (s, 3H), 2.92-2.87 (m, I H), 2.79-2.75 (m, I H), 2.72-2.67 (m, 10 1 H), 2.16-1.42 (m, 9H), 0.91-0.87 (m, 12H); MS (ESI) m/z 812 [M + H]*. Example FI o 0/ Cul, HN HN Pd(PPh 3

)

4 +. A.

0 N ~ Et3N B DMF F Nd (1 -{2-[5-(4-Ethynyl-pheny)-1 H-imidazol-2- (1 -{2-[5-(4-Bromo-pheny)-1 H-imidazol-2 yl]-4,4-difluoro-pyrrolidine-1 -carbonyl}-2- yl]-4-cyano-pyrrolidine-1 -carbonyl)-2 methyl-propyl)-carbamic acid methyl ester methyl-propyl)-carbamic acid methyl ester 0 / F -0 HN - H NH [1-(4-Cyano-2-{5-[4-(4-{2-[4,4-difluoro-1-(2-methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yI]-3H-imidazol-4-y}-phenylethynyl)-phenyl]-1 H-imidazol 2-yI}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 15 [l-(4-Cyano-2-{5-14-(4-{2-4,4-difluoro-1-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl)-phenylethynyl)-phenyl]-1 H-imidazol-2-yl}-pyrrolidine 1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [I -(2-{5-[4-(4-{2-[4,4-Difluoro-l-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl}-phenylethynyl) 20 phenyl]-I H-imidazol-2-yl}-pyrrolidine-l-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AB 1) substituting (1 -{2-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-4-cyano pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (I -{2-[5-(4-bromo phenyl)- IH-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl 732 ester (400 mg, 0.89 mmol), and (1-{2-[5-(4-ethynyl-phenyl)- I H-imidazol-2-yl]-4,4-difluoro pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-ethynyl phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl } -2-methyl-propyl)-carbamic acid methyl ester. 'IH NMR (MeOH-d4, 400 MIHz) 6: 7.71-7.61 (m, 4H) 7.46-7.34 (m, 4H), 5.30 (m, I H), 5 5.14 (m, I H), 4.55-4.45 (m, 2H), 4.20-3.94 (m, 5 H), 3.61 (s, 6H), 3.47-3.40 (m, 2H), 2.84-2.76 (m, 3H), 2.52 (m, I H), 1.96-1.91 (m, 2H), 0.96-0.83 (m, 12H); MS (ESI) m/z 824 [M + H]*. Example FJ 1. HCI, HO2C' N' MeOH/dioxane WM2C)N Et 2 Zn, CH 2 1 2 , TFA B. 2. CbzCl, Cbz DCM/hexane 4-Methylene-pyrrolidine-1,2- DIPEA, DCM 4-Methylene-pyrrolidine-1,2 dicarboxylic acid 1-tert-butyl ester dicarboxylic acid 1-benzyl ester 2-methyl ester Cbz 1. LiOH, N HN Meo 2 C' H 2 0/MeOH rN> -\//- Br NH 4 OAc, Cbz 2. 2-Amino-1-(4-bromo-phenyl)- V xylene 5-Aza-spiro[2.4]heptane-5,6- ethanone hydrochloride, 6-[2-(4-Bromo-phenyl)-2-oxo dicarboxylic acid 5-benzyl ester HATU, ethylcarbamoyl]-5-aza-spiro[2.4]heptane DIPEA, DMF 5-carboxylic acid benzyl ester 0/ 0 1. HBr/AcOH HN Cbz Br 2. carboxcylic acid, r N ~HATU, DIPEA Y DMF H 6-[5-(4-Bromo-phenyl)-1 H-imidazol-2- (1 -{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-y] y]-5-aza-spiro(2.4]heptane-5- 5-aza-spiro[2.4]heptane-5-carbonyl}-2 carboxylic acid benzyl ester methyl-propyl)-carbamic acid methyl ester 0/ 0/ 1. TMS-acetylene, )=o = Cul, Pd(PPh 3

)

4 , HN HN EtN, DMVF 0+ \ 2. K 3 , MeOH NjH 2COH NC H Nd (1 -{6-[5-(4-Ethynyl-phenyl)-1 H-imidazol-2- (1 -{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2 yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2- yl]-4-cyano-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester methyl-propyl)-carbamic acid methyl ester Cul, 0 Pd(PPha) 4 HN H Et DMF Q H NH N [1-(4-Cyano-2-{5-[4-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1 H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 10 733 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester: 4-Methylene pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (12.00 g, 52.80 mmol) was dissolved in MeOH (200 mL) and treated with 4.0 M HCI/dioxane (50 mL). After stirring for 3.5 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The crude 5 residue was dissolved in DCM (200 mL) and treated with DIPEA (22 mL, 127 mmol) and BnOCOCI (9.64 mL, 63.4 mmol). After stirring for I hours at room temperature, the reaction mixture was poured into H20. The aqueous layer was extracted 3x with DCM. The combined organics were dried over MgSO 4 , filtered and concentrated. The residue was purified by silica column chromatography (10% to 25% EtOAc/hexane) to provide 4-Methylene-pyrrol idine- 1,2 10 dicarboxylic acid I -benzyl ester 2-methyl ester (8.20 g, 56%). 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester: Diethyl zinc (1.0 M in hexane (118 mL, 118 mmol) was added to a 3-neck round bottom flask containing a stir bar, DCM (120 mL) and equipped with an addition funnel and an Argon inlet adaptor. The solution was cooled 1 5 to 0 'C before TFA (9.5 mL, 118 mmol) in DCM (40 mL) was added dropwise by addition funnel over 22 minutes. 20 minutes after completion of the addition, CH 2 1 2 was added slowly over 4 minutes. 20 minutes after completion of addition, 4-Methylene-pyrrolidine-1,2 dicarboxylic acid I-benzyl ester 2-methyl ester (8.10 g, 29.4 mmol) in DCM (30 mL) was added by cannula followed by a rinse with DCM (10 mL). 10 minutes later, the reaction mixture was 20 warmed to room temperature and stirred for 1 10 hours. The reaction was quenched by addition of 100 mL saturated aqueous NH 4 Cl. The entire contents of the flask were poured into saturated aqueous NaHCO 3 and the aqueous phase was extracted 3x with EtOAc. The combined organics were dried over MgSO 4 , filtered and concentrated. The residue was dissolved in THF (100 mL), acetone (33 mL) and H 2 0 (33 mL) and N-methylmorpholine-N-oxide (3.45 g, 29.41 mmol) and 25 osmium tetroxide (4 wt% in H20, 5 mL, 0.818 mmol) were added sequentially. The reaction mixture was stirred 7 hours at room temperature then quenched with 100 mL saturated aqueous Na 2

S

2 0 3 . The entire contents of the flask was poured into H 2 0 and the aqueous layer was extracted 3x with DCM. The combined organics were dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by silica column chromatography (10% to 25% 30 EtOAc/hexane) to provide 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (5.54 g, 65%). 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester: 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (361 mg, 1.25 35 mmol) was dissolved in MeOH (10 mL) and LiOH (I M in H 2 0, 5 mL, 5 mmol) was added. 734 After stirring for 15 hours at room temperature, the reaction mixture was poured into 10% HCI and the aqueous phase was extracted 3x with DCM. The combined organics were dried over MgSO 4 , filtered and concentrated. The residue was treated with 2-Amino-l -(4-bromo-phenyl) ethanone hydrochloride (344 mg, 1.38 mmol), HATU (525 mg, 1.38 mmol) and DMF (14 mL). 5 The suspension was stirred at 0 "C for 21 minutes before DIPEA (0.72 mL, 4.1 mmol) was added dropwise. Immediately after addition, the reaction mixture was warmed to room temperature. 40 minutes later the mixture was diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO 3 and brine, then dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (30% to 50% 10 EtOAc/hexane) to afford 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza spiro[2.4]heptane-5-carboxylic acid benzyl ester (589 mg, 100%). 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester: Title compound was prepared according to the method employed to prepare 3-[5-(4 15 Bromo-phenyl)-I H-imidazol-2-yl]-2-aza-bicyclo[2.2.I ]heptane-2-carboxylic acid tert-butyl ester (Example AS), substituting 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza spiro[2.4]heptane-5-carboxylic acid benzyl ester for 3-[2-(4-bromo-phenyl)-2-oxo ethylcarbamoyl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid terl-butyl ester. 20 (1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: 6-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-5 aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (478 mg, 1.04 mmol) was treated with DCM (5 mL) then HBr (33 wt% in AcOH, 5 mL). The mixture was stirred for 160 minutes at room temperature, concentrated under reduced pressure then coevaporated 2x with toluene to 25 remove excess AcOH. The crude residue was treated with 2-Methoxycarbonylamino-3-methyl butyric acid (274 mg, 1.56 mmol), HATU (435 mg, 1.14 mmol) and DMF (10 mL). The stirred mixture was cooled to 0 "C and DIPEA (0.91 mL, 5.2 mmol) was added before the warming to room temperature. After Ih, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 , filtered and 30 concentrated and the crude residue was purified by silica column chromatography (75% to 100% EtOAc/hexane) to yield (1-{6-[5-(4-Bromo-phenyl)-I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane 5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (297 mg, 60%). 735 (1-{6-[5-(4-Ethynyl-phenyl)-1 H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (1 -{2-[5-(4-Ethynyl-phenyl)- I H-imidazol-2-yl]-pyrrolidine- I carbonyl}-2-methyl-propyl)-carbamic acid methyl ester from (1-{2-[5-(4-bromo-phenyl)-IH 5 imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example AY), substituting (I -{6-[5-(4-Bromo-phenyl)-I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1 -{2-[5-(4-bromo-phenyl)-I H imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. 10 [1 -(4-Cyano-2-{5- [4-(4-{2- [5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyll-1H-imidazol-2-yI} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [I-(2-{5-[4-(4-{2-[4,4-Difluoro-1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl) 15 phenyl]-I H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AB 1) , substituting (I -{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-cyano pyrrolidine-I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (I -{2-[5-(4-bromo phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl }-2-methyl-propyl)-carbamic acid methyl ester (400 mg, 0.89 mmol), and (I -{6-[5-(4-Ethynyl-phenyl)-l H-imidazol-2-yl]-5-aza 20 spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (I -{2-[5-(4 Ethynyl-phenyl)-I H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-I -carbonyl }-2-methyl-propyl) carbamic acid methyl ester. ' H NMR (MeOH-d4, 400 MHz) 6: 7.78-7.66 (m, 4H), 7.52-7.37 (m, 4H), 5.29 (m, I H), 5.17 (m, 1 H), 4.59 (m, 1 H), 4.17-4.09 (m, 3 H), 4.01 (m, I H), 3.93-3.80 (m, 2H), 3.65 (s, 6H), 3.50-3.42 (m, 2H), 2.88-2.81 (m, I H), 2.66-2.52 (m, 2H), 2.36-2.31 (m, 25 1 H), 2.18-2.13 (m, 1H), 2.05-1.94 (m, 31H), 1.01-0.87 (m, 12H), 0.82-0.63 (m, 4H); MS (ESI) m/z 814 [M + H]*. 736 Example FK Cbz 1 LiOH,b HN MeO 2 C H 2 0IMeOH Br NH40AC, Cbz 2. 2-Bromo-1-(6-bromo- xylene 5-Aza-spiro[2.4]heptane-5,6- naphthalen-2-yl)-ethanone, 6-[2-(6-Bromo-naphthalen-2-yl)-2-oxo dicarboxylic acid 5-benzyl ester Et 3 N, MeCN ethylcarbamoyl]-5-aza-spiro[2.4]heptane 5-carboxylic acid benzyl ester 1. HBr/AcOH N N H 2. carboxcylic acid, Bis(pinacolato)diboron, N- N HATU, DIPEA rp Br N Cbz DMF 0-( dioxane 6-[5-(6-Bromo-naphthalen-2-yl)-1 H- (1 -{6-[5-(6-Bromo-naphthalen-2-yl)-1 H-imidazol imidazol-2-yl]-5-aza-spiro[2.4]heptane- 2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl}-2 5-carboxylic acid benzyl ester methyl-propyl)-carbamic acid methyl ester 0/ H - 0 NH OO= /0 NC [2-Methyl-1-(6-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- (1 -2-[5-(4-Bromo-phenyl)-1 H-imidazol-2 yl)-naphthalen-2-yl]-1 H-imidazol-2-yl-5-aza-spiro[2.4]heptane- yl]-4-cyano-pyrrolidine-1 -carbonyl}-2 5-carbonyl)-propyl]-carbamic acid methyl ester methyl-propyl)-carbamic acid methyl ester Pd(PPh) 4 H= KC0 3 )4 HN 0 N - irN NN

DME/H

2 O ,- NhN H = /0 NC [I -(4-Cyano-2-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2 yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 6-12-(6-Bromo-naphthalen-2-yl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.41heptane-5 5 carboxylic acid benzyl ester: 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (2.217 g, 7.66 mmol) was dissolved in MeOH (30 mL) and LiOH (1 M in H 2 0, 15 mL, 15 mmol) was added. After stirring for 15 hours at room temperature, the reaction mixture was poured into 10% HCI and the aqueous phase was extracted 3x with DCM. The combined organics were dried over MgSO 4 , filtered and concentrated. The residue was treated with MeCN 10 (40 mL), Et 3 N (1.2 mL, 8.4 mmol) and 2-Bromo-1 -(6-bromo-naphthalen-2-yl)-ethanone and the mixture was stirred at room temperature for 20 hours before being filtered over CELITE and concentrated. The resulting oil was dissolved in the minimum amount of DCM and EtOAc (30 mL) was added causing the product to precipitate. The mixture was cooled to 0 "C then the solid was filtered off and rinsed with EtOAc giving clean product (4.00g, 100%). 15 6-[5-(6-Bromo-naphthalen-2-yl)-1 H-imidazol-2-ylI]-5-aza-spiro12.41 heptane-5-carboxylic acid benzyl ester: Title compound was prepared according to the method employed to prepare 737 3-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert butyl ester (Example AS), substituting 6-[2-(6-Bromo-naphthalen-2-yl)-2-oxo-ethylcarbamoyl] 5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester for 3-[2-(4-bromo-phenyl)-2-oxo ethylcarbamoyl]-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester. 5 (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (I - {6-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-5 aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, substituting 6 10 [5-(6-Bromo-naphthalen-2-yl)-i H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester for 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5 carboxylic acid benzyl ester according to example FJ. 12-Methyl-I -(6-{5-16-(4,4,5,5-tetramethyl-[ 1,3,2 ]dioxaborolan-2-yl)-naphthalen-2-yl]-1 H 15 imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare Methyl-I-{2-[4' (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-ylcarbamoyl]-pyrrolidine-l carbonyl}-propyl)-carbamic acid methyl ester (Example CY), substituting (1 -{6-[5-(6-Bromo naphthalen-2-yl)-l H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl) 20 carbamic acid methyl ester for { l-[2-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-l carbonyl]-2-methyl-propyl}-carbamic acid methyl ester. [1-(4-Cyano-2-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl} 25 pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [1-(2-{5-[6-(4-{2-[l-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl}-phenyl) naphthalen-2-yl]- IH-imidazol-2-yl}-pyrrolidine-I-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (I -{2-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-4 30 cyano-pyrrolidine- I -carbonyl }-2-methyl-propyl)-carbamic acid methyl ester for (I -{2-[5-(4 bromo-phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester and [2-Methyl-I -(6-{5-[6-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl) naphthalen-2-yl]- 1 H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester for [2-methyl-I -(2-{5-[6-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl) 35 naphthalen-2-yl]- I H-imidazol-2-yl }-pyrrolidine- I -carbonyl)-propyl]-carbamic acid methyl 738 ester. 'H NMR (DMSO-d6, 400 MHz) 5: 8.20-8.10 (m, 2H), 7.90-7.68 (m, 6H), 7.60-7.55 (m, 2H), 7.33-7.30 (m, 2H), 5.18 (m, I H), 5.07 (m, I H), 4.44 (m, I H), 4.04-3.69 (m, 6H), 3.40-3.38 (m, I H), 3.30 (s, 6H), 2.71 (m, I H), 2.40-1.90 (m, 5H), 0.90-0.79 (m, 12H), 0.70-0.54 (m, 4H); MS (ESI) m/z 841 [M + H]f. 5 Example DL 1. LiOH, H20/MeOH 2. 4-Bromo Br NH Cbz +NH Cbz OMe Cbz benzene-1,2- BrN" NH2 5-Aza-spiro[2.4]heptane- diamine, HATU, NH 2 NH2 5,6-dicarboxylic acid 5- DIPEA, DMF 6-(2-Amino-5-bromo- 6-(2-Amino-4-bromo benzyl ester 6-methyl ester phenylcarbamoyl)-5-aza- phenylcarbamoyl)-5-aza spiro[2.4]heptane-5- spiro[2.4]heptane-5 carboxylic acid benzyl ester carboxylic acid benzyl ester Bis(pinacolato) 1. HBr/AcOH H diboron, 2. carboxcylic acid, N N Pd(dppf)C 2 AcOH HATU, DIPEA - NB DCM,KOAc NDMF Br-sx- NH dioxane Br N Cbz 0 O 6-(6-Bromo-1 H-benzoimidazol- {1 -[6-(6-Bromo-1 H-benzoimidazol-2-yl)-5 2-yl)-5-aza-spiro[2.4]heptane-5- aza-spiro[2.4]heptane-5-carbonyl]-2 carboxylic acid benzyl ester methyl-propyl}-carbamic acid methyl ester B / N MN 0==< /0 Nd (2-Methyl-1-{6-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan- (1 -{2-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl) 2 -yl)-1 H-benzoimidazol-2-yl]-5-aza-spiro[2.4]heptane-5- 1 H-imidazol-2-yl]-4-cyano-pyrrolidine-1 -carbonyl) carbonyl}-propyl)-carbamic acid methyl ester 2-methyl-propyl)-carbamic acid methyl ester K O Pd(PPh 3

)

4 , I KC0 3 MN N\N IyN

DMVE/H

2 0 eNH06 H O O NC (1 -{4-Cyano-2-[5-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl) 5-aza-spiro[2.4]hept-6-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-y)-1 H-imidazol-2 yl]-pyrrolidine-1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 6-(2-Amino-5-bromo-phenylcarbamoyl)-5-aza-spiro[2.41heptane-5-carboxylic acid benzyl ester and 6-(2-Amino-4-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic 10 acid benzyl ester: 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6 methyl ester (987 mg, 3.41 mmol) was dissolved in EtOH (10 mL) and LiOH (1 M in H 2 0, 5 mL, 5 mmol) was added. After stirring for 2 hours at 50 "C, the reaction mixture was poured into 10% HCI and the aqueous phase was extracted 3x with DCM. The combined organics were dried over 739 MgSO 4 , filtered and concentrated. The residue was treated with 4-Bromo-benzene-l,2-diamine (1.60 g, 8.53 mmol), HATU (1.43 g, 3.75 mmol) and DMF (17 mL) then cooled to 0 *C. DIPEA (0.712 mL, 4.09 mmol) was added and the reaction mixture was allowed to warm to room temperature slowly overnight. The reaction mixture was then diluted with EtOAc and the 5 organic layer was washed with saturated aqueous NaHCO 3 and brine then dried over MgSO 4 , filtered and concentrated. The crude material was purified by silica column chromatography to afford a mixture of 6-(2-Amino-5-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5 carboxylic acid benzyl ester and 6-(2-Amino-4-bromo-phenylcarbamoyl)-5-aza spiro[2.4]heptane-5-carboxylic acid benzyl ester (1.47 g, 97%). 10 6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.41heptane-5-carboxylic acid benzyl ester: A mixture of 6-(2-Amino-5-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5 carboxylic acid benzyl ester and 6-(2-Amino-4-bromo-phenylcarbamoyl)-5-aza spiro[2.4]heptane-5-carboxylic acid benzyl ester (1.446 g, 3.25 mmol) was dissolved in AcOH 15 (20 mL) and the reaction mixture was stirred at 40 *C for 18 hours then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO 3 . The aqueous layer was extracted 2x with EtOAc and the combined organics were dried over MgSO 4 , filtered and concentrated to provide 6-(6-Bromo-l H-benzoimidazol-2-yl)-5 aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (1.385 g, 100%). 20 {1-[6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyll-2-methyl propyl}-carbamic acid methyl ester: 6-(6-Bromo- I H-benzoimidazol-2-yl)-5-aza spiro[2.4]heptane-5-carboxylic acid benzyl ester (301 mg, 0.706 mmol) was dissolved in DCM (10 mL) and HBr (33 wt% in AcOH, 5 mL) was added. After 2h the reaction mixture was 25 concentrated and placed under hi-vac. The residue was co-evaporated with PhMe, MeOH, then again with PhMe and MeOH and placed under hi-vac. The residue was treated with 2 Methoxycarbonylamino-3-methyl-butyric acid (130 mg, 0.741 mmol, HATU (282 mg, 0.741 mmol) and DMF (7 mL). The reaction mixture was cooled to 0 "C then DIPEA (0.615 mL, 3.53 mmol) was added before warming to room temperature. After 30 minutes, the reaction mixture 30 was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO 3 and brine, then dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (50% to 80% EtOAc/hexane) to afford {1 -[6-(6-Bromo- H benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (238 mg, 75%). 35 740 (2-Methyl-i -{6-[6-(4,4,5,5-tetramethyl-I 1,3,2]dioxaborolan-2-yl)-1 H-benzoimidazol-2-ylJ-5 aza-spiro[2.4]heptane-5-carbonyl}-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare Methyl-1-{2-[4'-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-ylcarbamoyl]-pyrrolidine- 1-carbonyl} 5 propyl)-carbamic acid methyl ester (Example CY), substituting {I -[6-(6-Bromo-I H benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester for { I -[2-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine- I -carbonyl]-2-methyl propyl}-carbamic acid methyl ester. 10 (1-{4-Cyano-2-[5-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-benzoimidazol-5-yl)-9H-fluoren-2-yl)-1 H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [1 -(2-{5-[6-(4-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl I -phenyl) 15 naphthalen-2-yl]- I H-imidazol-2-yl}-pyrrolidine- 1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (I -{2-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yI)- I H imidazol-2-yl]-4-cyano-pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)-1 H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl-propyl) carbamic acid methyl ester and (2-Methyl-I-{6-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 20 yl)-I H-benzoimidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-propyl)-carbamic acid methyl ester for [2-methyl-I-(2-{5-[6-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yi)-naphthalen-2-yl] I H-imidazol-2-yl}-pyrrolidine-l -carbonyl)-propyl]-carbamic acid methyl ester. 'H NMR (DMSO-d6, 400 MHz) 5: 8.07-7.55 (m, 9H), 7.34 (m, 2H), 5.31 (m, 1 H), 5.11 (m, 1 H), 4.45 (m, I H), 4.08-3.87 (m, 6H), 3.63-3.54 (m, 9H), 3.41-3.28 (m, 4H), 2.73 (m, I H), 2.40-2.25 (m, 2H), 25 2.15-2.13 (m, I H), 1.95 (m, 3H), 0.93-0.83 (m, 12H), 0.74-0.57 (m, 4H); MS (ESI) m/z 889 [M + H]*. 741 Example FM 0 o CICO 2 Me, Ho SO2Me HO - SO2Me NaOH HN OMe

NH

2

THF/H

2 0 0 2-Amino-4-methanesulfonyl- 4-Methanesulfonyl-2 butyric acid methoxycarbonylamino-butyric acid BOC -Br ,N H 1. HCI, dioxane 2. 4-Methanesulfonyl-2 NC methoxycarbonylamino 2-[5-(4-Bromo-phenyl)-1 H- butyric acid, HATU, DIPEA imidazol-2-yl]-4-cyano-pyrrolidine 1-carboxylic acid tert-butyl ester 0 HN H <& H- NH MeO2S o Br B&O Nd (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4- [2-Methyl-1-(6-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 cyano-pyrrolidine-l-carbonyl}-3-methanesulfonyl- yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane propyl)-carbamic acid methyl ester 5-carbonyl)-propyl]-carbamic acid methyl ester 0 / Pd(PPh 3

)

4 , ')==o/ K 2 C0 3 HN - / " N MeO 2 S H o O NC [1 -(6-{5-[6-(4-{2-[4-Cyano-1 -(4-methanesufonyl-2-methoxycarbonylamino-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-y]-1H-imidazol-2-yl}-5-aza spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 4-Methanesulfonyl-2-methoxycarbonylamino-butyric acid: Methyl chloroformate (2.6 mL, 5 33 mmol) was added dropwise to a stirred suspension of 2-Amino-4-methanesulfonyl-butyric acid (5.03 g, 27.8 mmol) and NaOH (5 N in H20, 13.3 mL, 66.6 mmol) in THF (50 mL). After stirring at room temperature for 9h, additional methyl chloroformate (5.2 mL, 66.6 mmol) and NaOH (5 N in H 2 0, 30 mL, 150 mmol) were added. After another 14 h, the reaction mixture was poured into H 2 0. The aqueous phase was washed with DCM 2x then acidified to pH I with 10 10% HCl. The acidified aqueous phase was extracted 3x with EtOAc. The combined organics were dried over MgSO 4 , filtered and concentrated to provide 4-Methanesulfonyl-2 methoxycarbonylamino-butyric acid (970 mg, 15%). 742 (1-{2-15-(4-Bromo-phenyl)-1 H-imidazol-2-yll-4-cyano-pyrrolidine-1-carbonyl}-3 methanesulfonyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare { I-[2-(4'-Chloro-biphenyl-3-ylcarbamoyl) pyrrolidine-I-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (Example CX), 5 substituting 2-[5-(4-Bromo-phenyl)-I H-imidazol-2-yl]-4-cyano-pyrrolidine-I -carboxylic acid tert-butyl ester for 2-(4'-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine- I -carboxylic acid tert butyl ester and 4-Methanesulfonyl-2-methoxycarbonylamino-butyric acid for 2 methoxycarbonylamino-3-methyl-butyric acid. 10 [1-(6-{5-[6-(4-(2-[4-Cyano-1-(4-methanesulfonyl-2-methoxycarbonylamino-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yI}-5-aza spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [I-(2-{5-[6-(4-{2-[l-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-y}-phenyl) 15 naphthalen-2-yl]-l H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (I-{2-[5-(4-Bromo-phenyl)-IH-imidazol-2-yl]-4 cyano-pyrrolidine- I -carbonyl} -3-methanesulfonyl-propyl)-carbamic acid methyl ester for (I -{2 [5-(4-bromo-phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl }-2-methyl-propyl)-carbamic acid methyl ester and [2-Methyl-I-(6-{5-[6-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl) 20 naphthalen-2-yl]- IH-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester for [2-methyl-I -(2- {5-[6-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl) naphthalen-2-yl]- I H-imidazol-2-yl} -pyrrolidine- I -carbonyl)-propyl]-carbamic acid methyl ester. 'H NMR (MeOH-d4, 400 MHz) 8: 8.09-8.07 (m, 2H), 7.92-7.22 (m, 8H), 7.42-7.38 (m, 2H), 5.33 (t, J = 7.5 Hz, I H), 5.21 (t, J = 8.0 Hz, I H), 4.65 (m, I H), 4.49 (m, I H), 4.17-4.11 (m, 25 2H), 3.95 (d, J = 9.6 Hz, I H), 3.83 (d, J = 10.2 Hz, I H), 3.66 (s, 6H), 3.55-3.49 (m, 3H), 3.19 3.15 (m, 3H), 2.94 (s, 3H), 2.89-2.03 (m, 10 H), 1.03-0.64 (m, 14H); MS (ESI) m/z 904 [M + H]. 743 Example FN 0 ,OH B OH Br H BO Br 0 0 .OH H O CS 2

CO

3 0 N NH 4 0Ac Br IN Boc 2-Bromo-1-(4-bromo- Boc 110 OC phenyl)-ethanone 4-Hydroxy-pyrrolidine-1,2-dicarboxylic 2-[S-(4-Bromo-phenyl)-1H-imidazol acid 2-[2-(4-bromo-pheny)-2- 2-yl}-4-hydroxy-pyrrolidine-1 oxo-ethyl] ester 1-tert-butyl ester carboxylic acid teft-butyl ester NaH NO M-CI Br r Oc a Br c/ \ N, Bo \E / \NNa SEM HCI 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl- 2-[4-(4-Bromo-pheny)-1-(2-trimethylsilanyl ethoxymethyl)-1H-imidazol-2-yl}-4-hydroxy- ethoxymethyl)-1H-imidazo-2-yl)-4-(2-methoxy pyrrolidine-1-carboxylic acid tert-butyl ester ethoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester / O ONH N\ 0H 0 0N -K N- -N N Nr Br B---HB N__ HN-f0BB,0 HATU 0- KOAC, Pd(dppf)C1 2

K

3

PO

4 (1-(2-(S-(4-Bromo-pheny)-1H-imidazol-2-yl]-4 (2-methoxy-ethoxy)-pyrrolidine-1-carbonyl]-2 methyl-propyl}-carbamic acid methyl ester O O~N~ O \N 0 -N H [1-(6-(-[6-(4-(2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) N NN N 4-(2-methoxy-ethoxy)-pyrrolidin-2-yl]-3H-imidazol-4-y}-phenyl) H- N naphthalen-2-yl}-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5 HN O 0 carbonyl)-2-methyl-propy]-carbamic acid methyl ester Os 4-Hyd roxy-pyrrolidine-1,2-dicarboxylic acid 2-12-(4-bromo-phenyl)-2-oxo-ethyl] ester 1 tert-butyl ester: 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.0 g) was 5 dissolved in methanol (87 mL), and Cs 2

CO

3 (3.5 g ) in water (56 mL) was added. The mixture was stirred over 10 min. and evaporated under vacuum. The solid was dissolved in DMF (100 mL), and 2-bromo-l -(4-bromo-phenyl)-ethanone (6.0 g) was added. Reaction mixture was stirred over 3 hours and evaporated under vacuum. The crude solid was used for the next step. 10 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yll-4-hydroxy-pyrrolidine-1-carboxylic acid tert butyl ester: The crude 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2 oxo-ethyl] ester 1-tert-butyl ester (10.8 g) and ammonium acetate (13.3 g) were suspended in toluene (80 mL). The reaction mixture was stirred at I0I 0C for 80 min. and evaporated under reduced pressure and resulting residue was taken up in ethyl acetate (200 mL). The organic 15 phase was washed with saturated sodium bicarbonate (I x 150 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 50 -90 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-[5-(4 744 Bromo-phenyl)- 1 H-imidazol-2-yl]-4-hydroxy-pyrrolidine- I -carboxylic acid tert-butyl ester (2.3 g, 32 % over 2 steps) as an off-white solid. 2-14-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylI-4-hydroxy 5 pyrrolidine-1-carboxylic acid tert-butyl ester: 2-[5-(4-Bromo-phenyl)- IH-imidazol-2-yl]-4 hydroxy-pyrrolidine-l -carboxylic acid tert-butyl ester (500 mg) was dissolved in DMF (8 mL), and NaH (54 mg ) was added. The mixture was stirred over 10 min. and SEM-Cl was added slowly, and then stirred for 2 hours. The mixture was quenched with 3 mL of sat. NH 4 Cl and was taken up in ethyl acetate (100 mL). The organic phase was washed with saturated sodium 10 bicarbonate (I x 100 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 20 -50 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-[4-(4-Bromo-phenyl)- 1 -(2-trimethylsilanyl-ethoxymethyl) 1 H-imidazol-2-yl]-4-hydroxy-pyrrolidine- I -carboxylic acid tert-butyl ester (648 mg, 98 %) as 15 an off-white solid. 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-(2 methoxy-ethoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-[4-(4-Bromo-phenyl)-l (2-trimethylsilanyl-ethoxymethyl)- IH-imidazol-2-yl]-4-hydroxy-pyrrolidine-l -carboxylic acid 20 tert-butyl ester (222 mg) was dissolved in DMF (4 mL), and NaH (25 mg ) was added. The mixture was stirred over 20 min. and I -bromo-2-methoxy-ethane was added slowly, and then stirred for 2.5 hours. The mixture was quenched with 3 mL of sat. NH 4 CI and was taken up in ethyl acetate (50 mL). The organic phase was washed with saturated sodium bicarbonate (I x 50 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was 25 subjected to silica gel chromatography using effluent of 20 -60 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-[4-(4-Bromo-phenyl)- 1 -(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2 yl]-4-(2-methoxy-ethoxy)-pyrrolidine-I -carboxylic acid tert-butyl ester (209 mg, 85 %) as a clear oil. 30 {1-[2[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1 carbonyll-2-methyl-propyl}-carbamic acid methyl ester: To 2-[4-(4-Bromo-phenyl)-1-(2 trimethylsilanyl-ethoxymethyl)- IH-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1 carboxylic acid tert-butyl ester (209 mg) in DCM (3 mL) was added 4N HCI in dioxane (2.6 35 mL). The suspension was stirred for 16 hours then concentrated to afford the HC salt of the 745 crude amine. To the crude amine in DMF (3 mL) was added N-methylmorpholine (193 p.L). After all material dissolved, 2-methoxycarbonylamino-3-methyl-butyric acid (123 mg) and HATU (267 mg) were added. After stirring for 30 min. the reaction was purified by a preparative HPLC (10-60% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product 5 (169 mg, 92%). [1-(6-{5-16-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2-methoxy-ethoxy) pyrrolidin-2-yli]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yll-1H-imidazol-2-yl}-5-aza spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: A mixture of 10 { -[2[5-(4-Bromo-phenyl)-l H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-I -carbonyl]-2 methyl-propyl}-carbamic acid methyl ester (169 mg), bis(pinacolato)diboron(107 mg), [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(lI)(24 mg) and potassium acetate (95 mg) in 1.6 mL of dioxane was heated to 90 0 C for 1.5 hour. (1-{6-[5-(6-Bromo-naphthalen-2-yl)-I H imidazol-2-yl]-5-aza-spiro[2.4] heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl 15 ester (170 mg) in ImL of dioxane and 2M tripotassium phosphate (565 pl) were added and stirred at 90 0 C for ovemight. The mixture was purified by a preparative HPLC (10-60% MeCN

H

2 0; 0.1% formic acid modifier) to afford the title product (119 mg, 41%). '1 H NMR (DMSO d6, 400 MHz) 6: 8.20-8.10 (m, 2H), 7.90-7.68 (m, 6H), 7.60-7.55 (m. 2H), 7.33-7.30 (m, 2H), 5.18 (m, I H), 5.07 (m, Il H), 4.44 (m, I H), 4.04-3.69 (m, 6H), 3.80-3.38 (m, 5H), 3.30 (m, 9H), 20 2.71 (m, I H), 2.40-1.90 (m, 5H), 0.90-0.79 (m, 12H), 0.70-0.54 (m, 4H); MS (ESI) mlz 889.5 [M + H]-. 746 Example FO OH N O NJ Br KNaHCl Br NHI N N, EN I NaH Br BO8C HCI SEM SEM 2-!4-(4-Bromo-phenyl)-1-(2.thmethysIanyl- 2-[4-(4.Bromo-phenyl)-1-(2-tnmethylsilany ethoxymethyl)- IH-imidazol-2-yIH--hydroxy- ethaxymethyl)-l H-irdazol-2-yI]-4-(pyrazin-2 pyrrolidine-1-carboxylic acid tert-butyl ester ytoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester N O/ N d- 0 O ONH N\ H O) NO N Br Br B-BH 0Br IC _ 0 0 __ _ __ _ __ _ __ _ HATU O- KOAc, Pd(dppf)C1 2

K

3

PO

4 (1-[2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4 (pyrazin-2-yloxy)-pyrrolidine-1-carbonyl]-2-methy propyl}-carbamic acid methyl ester O / NH 0N H N [1-(6-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) 0NL

O

9 N N 4-(pyrazin-2-yloxy)-pyrrolidin-2-yI3H-imidazol-4-y|-phenyl) -Ii 'N \/ naphthalen-2-y]- IHimidazol-2-yi)-5-aza-spiro[2.4]heptane-5 H N N O carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 0 2-14-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylI-4-(pyrazin 2-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester: Title compound was prepared 5 according to the method employed to prepare 2-[4-(4-Bromo-phenyl)-I-(2-trimethylsilanyl ethoxymethyl)-I H-imidazol-2-yI]-4-(2-methoxy-ethoxy)-pyrrolidine-l -carboxylic acid tert-butyl ester (Example 1), substituting 2-chloro-pyrazine (50 ptl) for I -bromo-2-methoxy-ethane (94 mg, 40%). 10 {1-[215-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(pyrazin-2-yloxy)-pyrrolidine-1-carbonyl] 2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare { I -[2-[5-(4-Bromo-phenyl)-l H-imidazol-2-yl]-4-(2-methoxy ethoxy)-pyrrolidine-l-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (Example 1), substituting 2-[4-(4-Bromo-phenyl)-I-(2-trimethylsilanyl-ethoxymethyl)-I H-imidazol-2-yl]-4 15 (pyrazin-2-yloxy)-pyrrolidine-I -carboxylic acid tert-butyl ester (94 mg) for 2-[4-(4-Bromo phenyl)- 1 -(2-trimethylsilanyl-ethoxymethyl)- I H-imidazol-2-yl]-4-(2-methoxy-ethoxy) pyrrolidine-I-carboxylic acid tert-butyl ester (88 mg, 99%). 11 -(6-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyry)-4-(pyrazin-2-yloxy) 20 pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl-1 H-imidazol-2-yl)-5-aza spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare [1-(6-{5-[6-(4-{2-[1-(2 747 Methoxycarbonylam ino-3 -methyl-butyryl)-4-(2-methoxy-ethoxy)-pyrrolidi n-2-yl 1-3 H-i m idazol 4-yl}-phenyl)-naphthalen-2-yl]- 1 H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2 methyl-propyl]-carbamic acid methyl ester (Example 1), substituting { I -[2[5-(4-Bromo-phenyl) I H-imidazol-2-yl]-4-(pyrazin-2-yloxy)-pyrrolidine- 1 -carbonyl]-2-methyl-propyl}-carbamic acid 5 methyl ester (88 mg) for ( -[2[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-(2-methoxy-ethoxy) pyrrolidine-I-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (38 mg, 26 %). 'H NMR (MeOH-d4, 400 MHz) 8: 8.20-8.10 (m, 3H), 7.90-7.68 (m, 8H), 7.60-7.55 (m. 2H), 7.33-7.30 (m, 2H), 5.68 (m, IH), 5.39 (m, 1H), 4.44 (m, IH), 4.04-3.69 (m, 6H), 3.80-3.38 (m, IH), 3.30 (m, 6H), 2.71 (m, I H), 2.40-1.90 (m, 5H), 0.90-0.79 (m, 12H), 0.70-0.54 (m, 4H); MS (ESI) m/z 10 910.5 [M + H]*. Example FP HO Cl O'' HO O NH 2 NaOH, Na 2

CO

3 0 HN _ 0 2-Amin phenyl 2-Methoxycarbonylamino 3-phenyl-propionic acid O d- NH 0 H O \oc HCI HATU 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yI-3H-imidazol-4-yl)-naphthalen-2-yl)-phenyl-1H imidazol-2-yi}-pyrrolidine-1 -carboxylic acid teft-butyl ester 0 O _N \~ 0 N \ -N -N HN 0 [1 -{2-{5-[6-{4-{2-[1-(2-Methoxycarbonylamino3-phnyl-proponyl) pyrrolidin-2-yI-3-imidazol-4-yI)-phenyl}-naphthalen-2-y]-1H-imidazo 2-yI}-pyrrolidine-1 -arbanyl)-2-methyl-propylycarbamic acdd methyl ester 2-Methoxycarbonylamino-3-phenyl-propionic acid: 2-A mino-3-phenyl-propionic acid (1.65 15 g) was dissolved in I N NaOH (10 mL), and Na 2

CO

3 (530 mg) was added. The mixture was cooled to 0*C and methyl chlorofornate was added slowly, and then stirred for overnight at room temperature. The mixture was washed with DCM and acidified with 3 mL of 2N HCI, and then was taken up in ether (200 mL). The organic phase was dried over sodium sulfate. Removing the solvent to give 2-Methoxycarbonylamino-3-phenyl-propionic acid (1.95 g, 87 %) 20 as an off-white solid. 748 [I -(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-phenyl-propionyl)-pyrrolidin-2-yl]-3H imidazol-4-yI}-phenyl)-naphthalen-2-y]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester: To 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 5 imidazol-4-yl}-naphthalen-2-yl]-IH-imidazol-2-yI}-pyrrolidine-l-carboxylic acid tert-butyl ester (40 mg) in methanol (0.5 mL) was added 4N HCI in dioxanes (0.5 mL). The mixture was stirred for 1.5 hours then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (2 mL) was added N-methylmorpholine (30 pL). After all material dissolved, 2 methoxy carbonylamino-3-phenyl-propionic acid (24 mg) and HATU (42 mg) were added. 10 After stirring for 30 min. the reaction was purified by a preparative HPLC (10-60% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product (34 mg, 37%). 'H NMR (MeOH-d4, 400 MHz) 8: 8.22-8.03 (m, 4H), 7.89-7.74 (m, 8H), 7.54-7.05 (m, 5H), 5.20 (m, 2H), 4.63 (m, I H), 4.48(m, I H), 4.25 (m, I H), 4.15-3.88 (m, 4H), 3.69-3.51 (m, 8H), 3.45-3.15 (m, 4H) 3.10 (m, 1 H), 2.95 (m, I H), 2.86 (m, I H), 2.45-2.04 (m, 7H), 1 .00-0.88 (m, 6H); MS (ESI) m/z 837.4 [M 15 + H] . Example FQ HO 0 0 HO Cl 0 HO 0 2-Aminophenyl- 2-Methoxycarbonylamino 3-phenyl-propionic acid 0 NH H N -- N No Hoc HCI HATU 2-{5-(4-(6-{2-[1 -(2-Methoxyr-arbonylamino-3-methlbutyryl) pyrro idin-2-y] 3HA midaz ol -4yI}nap hthale n-2-y)-pheny]-1 t imidazol-2-yl)-pyrrolidine-1 -carboxylic acid tert-butyl ester 0 N HN N N N NN -0 N 0 [1 -(2-{5-16-(4-{2-1 -C2-Methoxycarbanylamino-3-pheny-propionyl) pyrralidin-2-yI|}3H-imidazol-4-y)-phenyl)-naphthalen-2-y)-1 H-imidazol 2-yl)-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 20 [1-(2-{5-[6-(4-{2-11-(2-Methoxycarbonylamino-3-phenyl-propionyl)-pyrrolidin-2-yll-3H imidazol-4-yl}-phenyl)-naphthalen-2-y]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester: Title compound was prepared according to the 749 method employed to prepare [1 -(2-{ 5-[6-(4- {2-[l-(2-Methoxycarbonylamino-3-phenyl propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]- IH-imidazol-2-yl} pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example 3), (33 mg, 36%). 'H.NMR (MeOH-d4, 400 MHz) 8: 8.22-8.03 (m, 4H), 7.89-7.74 (m, 9H), 7.54-7.05 (m, 5 4H), 5.20 (m, 2H), 4.63 (m, I H), 4.48(m, I H), 4.25 (m, I H), 4.15-3.88 (m, 4H), 3.69-3.51 (m, 8H), 3.45-3.15 (m, 4H) 3.10 (m, I H), 2.95 (m, I H), 2.86 (m, I H), 2.45-1.97 (m, 5 H), 1.80 (m, I H), 1.63 (m, I H), 1.00-0.88 (m, 6H); MS (ESI) m/z 837.4 [M + H]*. Example FR F or ,,OH O OH O F F 0 N N F Boc Cu(I)l Boc Br N oc 4-Hydroxy-pyrroltne .2-dicrboxyed xic 4-Odf 2-or 2et byrpyr hdine- .2- 2 (S-(4-o-"henyfI Hy ridazoo acid 242-(4-brot hrro-ey[-2- drcartboeyc most 2-12.44-bromo-phenyo 2-yq-4-drftoramthosy-prohi* ceo-ethy] ester 1-terd-butyl ester -2-oxo-ethy ester 14ert-butyl ester 1-carboxylic acid teff-butyl ester F HO N O H F \ - *- N N + NB B r II O \ H - ' O P d K(d be ) HC ATU ~ N -'"\ P Xantthos. K 5 PO, 0-. 2-{5-[-(4,4,5.5-Tetrame thyl(1.3,21dioxaborolan (1-{2-5-4-Broms-phenyl-1 ieda o2-y]-4- 2.yl).npttalen2-yQ-l H-riaot-2-yf difluootetoy-tryrroi~ rneI a yl- pyr difle-l -rboeyo aid tert-Ordtyl ester 2-methy-propyf)-carbarrsc acd methyl ester F F F F 0 ~NH Boc N\ NO Z~ yN L ' 0 \ .~ - -\ NH H - \ N 0 0 0 H / - H N \ 'PHN-. 0-. 24-h-IB-(42.I44thioooridhoxy-l-(2-rsthoycortosylarrns3- (1-(4-Onorsthoy-2-5-4-(-(241-(2rrthoxyomrbonylanins-2-preny methyl-adryl-py] -3Ho rid azo -ay l}-ph eny -naphtlen- ace ) rmin-2-y-3H rduol-4-ya)-nmtdthe -2-yt)- l H4.dazo 10 -y]-1 H ideze&2-yt)- oidioe-1-orbcetrc acid tert-butyt ester 2-yroidn 1ol r2-m thy prol-o rbrso ead methyIeter 4-Difluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 2-12-(4-bromo-phenyl)-2-oxo-ethyl] ester 1-tert-butyl ester : To 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo phenyl)-2-oxo-ethyl] ester I -tert-butyl ester (500 mg) and Cu(I)l (45 mg) in MeCN (8 mL) at 45 OC was added 242 pl of difluoro-fluorosulfonyl-acetic acid in 2 mL of MeCN dropwise for 60 15 min. The reaction mixture was stirred at 45'C for 60 min. and evaporated under reduced pressure, and resulting residue was taken up in ethyl acetate (100 mL). The organic phase was washed with brine (I x 100 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 10 -50 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was 20 removed under reduced pressure to provide 4-Difluoromethoxy-pyrrolidine-I,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl] ester I -tert-butyl ester (339 mg, 61 %) as a clear oil. 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl-4-difluoromethoxy-pyrrolidine-1-carboxylic acid tert-butyl ester : Title compound was prepared according to the method employed to prepare 2 750 [5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-4-hydroxy-pyrrolidine- 1 -carboxylic acid tert-butyl ester (Example 1), substituting 4-Difluoromethoxy-pyrrolidine- 1,2-dicarboxylic acid 2-[2-(4 bromo-phenyl)-2-oxo-ethyl] ester 1-tert-butyl ester (305 mg) for 4-Hydroxy-pyrrolidine-1,2 dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl] ester I-tert-butyl ester (244 mg, 83 %). 5 (1-{2-15-(4-Bromo-phenyl)-1 H-imidazol-2-yl-4-difluoromethoxy-pyrrolidine-1-carbonyl}-2 methoxy-propyl)-carbamic acid methyl ester: To 2-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl-4 difluoromethoxy-pyrrolidine-1 -carboxylic acid tert-butyl ester (244 mg) in DCM (4 mL) was added 4N HCI in dioxanes (1.3 mL). The mixture was stirred for I hours then concentrated to 10 afford the HCI salt of the crude amine. To the crude amine in DMF (2.7 mL) was added N methylmorpholine (234 pL). After all material dissolved, 2-methoxycarbonylamino-3-methyl butyric acid (103 mg) and HATU (263 mg) were added. After stirring for 60 min. the reaction was evaporated under reduced pressure, and resulting residue was taken up in ethyl acetate (100 mL). The organic phase was washed with saturated sodium bicarbonate (I x 100 mL) and dried 15 over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 80 -100 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide (I-{2 [5-(4-Bromo-phenyl)-l H-imidazol-2-yl-4-difluoromethoxy-pyrrolidine-I -carbonyl}-2-methoxy propyl)-carbamic acid methyl ester (166 mg, 61 %) as a clear oil. 20 2-{5-16-(4-{2-[4-Difluoromethoxy-1-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl)-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl} pyrrolidine-1-carboxylic acid tert-bytyl ester: To (1-{2-[5-(4-Bromo-phenyl)-l H-imidazol-2 yl-4-difluoromethoxy-pyrrolidine- I -carbonyl}-2-methoxy-propyl)-carbamic acid methyl ester 25 (166 mg) and 2-{5-[6-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-I H imidazol-2-yl}-pyrrolidine-l-carboxylic acid tert-butyl ester (237 mg) in DME (1.6 mL) were added Pd 2 (dba) 3 (15 mg), Xanphos (19 mg), and 2M K 3

PO

4 (483 pl). After stirring for overnight at 80*C, the mixture was filtered and evaporated under reduced pressure, and resulting residue was subjected to silica gel chromatography using effluent of 10 -15 % MeOH and DCM. 30 The fractions containing product were combined and the solvent was removed under reduced pressure to provide the title product (30 mg, 12 %) as a clear film. [1-(4-Difluoromethoxy-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl) pyrrolidin-2-ylI-3H-imidazol-4-yli-naphthalen-2-y)-phenyl]-1H-imidazol-2-yl} 35 pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: Title compound was 751 prepared according to the method employed to prepare (I-{2-[5-(4-Bromo-phenyl)-IH imidazol-2-yl-4-difluoromethoxy-pyrrolidine- I -carbonyl } -2-methoxy-propyl)-carbamic acid methyl ester (Example 5), substituting methoxycarbonylamino-phenyl-acetic acid (30 mg) for 2 methoxycarbonylamino-3-methyl-butyric acid (22 mg, 58 %). 'H NMR (MeOH-d4, 400 MHz) 5 8: 8.20-8.05 (m, 3H), 7.95-7.72 (m, 5H), 7.56-7.35 (m. 8H), 7.15 (m, I H), 6.71-6.35 (m, I H), 5.55 (m, I H), 5.30-5.20 (m, 3H), 5.05-4.90 (m, 3H), 4.36 (m, I H), 4.20 (m, I H), 4.12-3.82 (m, 2H), 3.65 (m, 6H), 3.50 (m, I H), 2.75 (m, I H), 2.45 (m, I H), 2.35-1.90 (m, 2H), 0.98-0.85 (m, 6H); MS (ESI) m/z 889.3 [M + H]*. 10 Example FS 0 / H 0 *S O / Ny 1. HCI 2. HATU, DIEA COH 2.yt)-1H.~midazoI.2.yI).5-aza-spiro[2 41heptane.5-cartoony-methyI. propy}-carbam c acd methyl ester 0 H - - 0 N

NH

4 0Ac, m- Xylenes 135 "C 226-(245-2-Mtoycartenyamin-3-mety-buyrl)-5-aza spiro[2 4Jhept-6-yI- 1H mdazo-4-yI)iaphthalen-2-yt)ph }nyl-2-oxo ethylcarbamoy)-thazolidine-3-carboxylic ead tert-buty ester [OH o H Ny-N)L 1. HCI 2. HATU. DIEA MWc [ ] 2-{24-(26-{2-[-2-Methoxycarbonylamino-3-methyl-butyry)-5azaspio[2.]het-6y y15 1H-imidazo4-yl)-nathale-2-yl-phenyl en1H-iidzo-2-y)-theaz n]2one-3- 0 H y}ne3 carboxylic acid tert-butyl ester 0 ' N N K /0 { l-[-(-{-[-(-trtBuoxcaboylmio-ceyl-phenyl]6-naph2-thlerbnm--myl-yl -azl-2 sptqro(2 4jhept-6-ylH-imidazol-A-yI)-naphtthaet,2-y)phenyl-1H-,mldazol 2-yI}-thiazolidins-3-carbonyI}-2-metthyl-propyI-arbetic sad methyl ester 2-{2-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4J hept-6-yll 15 1 H-imid azol-4-yl )-nap hthalen -2-yl)-ph enylj -2-oxo-ethylca rba moyl) -th iazolid ine-3 carboxylic acid tert-butyl ester: ( ] -[6-(4- {6-[4-(2-tert-Butoxycarbonylainino-acetyl)-phenyl]-naphthalen-2-y) - -I H-imidazol-2 yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (395.0 mg, 0.581 mmol) was dissolved in DCM (4 mL) and HCI in dioxane (4M, 4 mL) was added and 20 stirring at room temperature was continued. After 60 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude 752 material was dissolved in DMF (2.0 mL) and DIEA (110.8 mg, 0.860 mmol) was added. A solution of N-Boc (S) thiazolidine -2-carboxylic acid (100.0 mg, 0.430 mmol), HATU (163.0 mg, 0.430 mmol) and DIEA (55.4 mg, 0.430 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was 5 washed with brine, sodium hydroxyl solution (1 M), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material (350 mg), which was used in the next step without further purification. LCMS-ESI+: calc'd for C 4 3

H

5 oN 6 0 7 S: 794.9 (M *); Found: 795.8 (M+H*). 10 2-{5-[4-(6-{2-15-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl] 1H-imidazol-4-yl)-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-thiazolidine-3-carboxylic acid tert-butyl ester: 2-{2-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-I H imidazol-4-yl}-naphthalen-2-yl)-phenyl]-2-oxo-ethylcarbamoyl}-thiazolidine-3-carboxylic acid 15 lert-butyl ester (350 mg, 0.44 mmol) was dissolved in m-xylenes (3.0 mL) and heated at 135 *C. Solid ammonium acetate (400 mg, 9.07 mmol) was added and the reaction was stirred at 135 *C. After 45 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was partitioned between chloroform and water. The organic layer was collected and dried over sodium sulfate. Filtration and evaporation of solvents 20 gave the crude product. The crude material was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product (151.3 mg, 0.195 mmol). LCMS-ESl*: calc'd for C 4 3

H

4 9

N

7 0 5 S: 775.9 (M *); Found: 776.8 (M+H*). [1-(2-{5-14-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 25 yl]-1 H-imidazol-4-yI}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl}-thiazolidine-3 carbonyl)-2-methyl-propyll -carbamic acid methyl ester: 2- {5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]- I H imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl}-thiazolidine-3-carboxylic acid tert butyl ester (49.9 mg, 0.064 mmol) was dissolved in DCM (0.33 mL) and HCI in dioxane (4M, 30 0.33 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.5 mL) and DIEA (24.6 mg, 0.191 mmol) was added. A solution of 2- (L) methoxycarbonylamino-3-methyl-butyric acid (11.2 mg, 0.064 mmol), HATU (24.1 mg, 0.064 mmol) and DIEA (8.2 mg, 0.064 mmol) in DMF (0.5 mL) 35 was added. The reaction was stirred at room temperature. After 18 hrs all volatiles were 753 removed in vacuo. The crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (8.5 mg) as a TFA salt. LCMS-ESI*: calc'd for C 4 5

H

52

N

8 0 6 S: 833.0 (M *); Found: 833.7 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 6: 8.35-7.88 (m, 14H), 7.36 - 7.33 (m, 2H), 6.36 (m, I H), 5.28 5 (dd, J = 7.2 Hz, I H), 4.24 (m, I H) 4.16 (m, I H), 4.03 - 3.74 (m, 6H), 3.55 (s, 3H), 3.54 (s, 3H), 2.27 (m, 2H), 2.08 (m, 2H), 0.90 - 0.76 (m, 12H) 0.65 (m, 4H) ppm. Example FT 10 0 ~OMe 0 H N-,.f'-N)L 1 HCI 2 HATU. DIEA MeO N O O O, H0 ~ /-H />(0 yI]-1H-Imidazol-4-y)-naphthalen-2-yI)-phenyl)-lH-rnidazol.2y}-thazoidine-3- 0 i HN N carboxylic acid terl-butyI ester 0 N a I N C /> 0/ [1 -( 4-[6-(4-(2{3 (4-Metoxy-2-methoxycartonyaMino-6utyry).thiazodidin 2-yIJ-3H-~midazo[-4.yI)-phenyI)-rnaphthalen-2ylj.1 -c-midazol-2-yI)-aza. spiro[2.4lheptane-5-earbonyl).2-metlyl-popyjcabamc acid mnetyl ester [1-(6-{4-[6-(4-{2-13-(4-Methoxy-2-methoxycarbonylamino-butyryl)-thiazolidin-2-yl]-3H imidazol-4-yl)-phenyl)-naphthalen-2-yl]-iH-imidazol-2-yl}-5-aza-spiro[2.41heptane-5 carbonyl)-2-methyl-propyl] -carbamic acid methyl ester: 15 2- { 5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yI]- I H imidazol-4-yl}-naphthalen-2-yi)-phenyl]- IH-imidazol-2-yl}-thiazolidine-3-carboxylic acid tert butyl ester (49.9 mg, 0.064 mmol) was dissolved in DCM (0.33 mL) and HCI in dioxane (4M, 0.33 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further 20 purification. The crude material was dissolved in DMF (0.5 mL) and DIEA (24.6 mg, 0.191 mmol) was added. A solution of (L) 4-methoxy-2-methoxycarbonylamino-butyric acid (12.1 mg, 0.064 mmol), HATU (24.1 mg, 0.064 mmol) and DIEA (8.2 mg, 0.064 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 3 hrs all volatiles were removed in vacuo. The crude material, which was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% 25 TFA) to yield the product (21.3 mg) as a TFA salt. LCMS-ESI*: calc'd for C 45

H

52

N

8 07S: 849.0 (M *); Found: 849.7 (M+H*). H-NMR: 300 MHz, (dmso-d 6 ) 5: 8.37 (m, 2H), 8.20 - 8.14 (m, 2H), 8.06 - 7.88 (m, I OH), 7.36 - 7.33 (m, 2H), 6.36 (m, 1 H), 5.30 (dd, J = 7.2 Hz, I H), 4.45 (m, I H) 4.06 (m, 1 H), 4.06 - 3.69 754 (m, 6H), 3.55 (s, 3H), 3.54 (s, 3H), 3.36 (m,2H), 3.25 (m, 3H), 2.26 (m, 2H), 2.02 (m, 2H), 1.81 (m,I H), 0.90 - 0.76 (m, 6H) 0.65 (m, 4H) ppm. Example FU 5 0 00 o H - /1. HCI. 2. HAiTU, DIEA MeO N OH 2{5-[4-(-{ 6-[5-(2-M{thoxycarb yamino-3-methyo-butyryb)-5-aza-spo lami24nhept -a yt H-iaoidazo-4-y)apalen-2-yi)-pmenylmIHmidazol--yl)-thiazoeidinl3- a H - - -iN roxy.ic an- d tet-a tyl] -ster aci ehy He st 01-[64(4--M4o-(x3-2-MctamoXyCarnyamno-2(tetrahyo2 ro.pyran-4-y)- H ai}tyhthaz olidin-2-y)-3Hidazol-y)-p3nl-aphaen2-ylc tH imdzol-2-y)-5-aza-spiro[2 4heptane. -caronyll2-met es-propyll carvomic ad methyl ester (ml w6-(4-a6- 14-(2-a3-s 2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-y)-acetyli thiazolidin-2-yl}-3H-imidazol-4-yl)-phenylj-naphthalen-2-y}-1 H-imidazol-2-yl)-5-aza spiro[2.41 heptane-5-carbonyll-2-methyl-propyl)-carbamic acid methyl ester: 10 2- {5-[4-(6- {2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-y]- I H imidazol-4-yl }-naphthalen-2-yl)-phenyl]- IH-imidazol-2-yl }-thiazolidine-3-carboxylic acid tert butyl ester (49.9 mg, 0.064 mol) was dissolved in DCM (0.33 ml) and HCI in dioxane (4M, 0.33 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further 15 purification. The crude material was dissolved in DMF (0.5 mL) and DIEA (24.6 mg, 0. 191 mmol) was added. A solution of 2- (L) methoxycarbonylam ino-(tetrahydro-pyran-4-yl)-acetic acid (13.8 mg, 0.064 minol), HATU (24.1 mg, 0.064 minol) and DIEA (8.2 mg, 0.064 mmol) in DMF (0.5 ml) was added. The reaction was stirred at room temperature. After 18 hrs all volatiles were removed in vacuo. The crude material, which was purified by RP-HPLC (eluent: 20 water / MeCN w/ 0.1% TFA) to yield the product (6.2 mg) as a TFA salt. LCMS-ESl*: calc'd for C 47

H

52

N

8 0 7 S: 875.0 (M '); Found: 875.7 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 6: ' H-NMR: 300 MHz, (dmso-d 6 ) 6: 8.31 - 7.89 (m, 14H), 7.36 7.33 (m, 2H), 6.34 (m, I H), 5.27 (m, I H), 4.30 (m, I H) 4.03 (m, I H), 4.06 - 3.69 (m, 6H), 3.57 (s, 3H), 3.54 (s, 3H), 3.28 - 2.95 (m, 4H), 2.26 (m, 2H), 2.02 (m, 2H), 1.50-1.32 (m,4H), 0.85 25 0.73 (m, 6H) 0.65 (m, 4H) ppm. 755 Example FV Ph, N / O 0 H 1. HCI. 2. HATU, DIEA COOH Ph N A r 1C 0 BOO {12 486 2-tefl-utoyca r oam yl)-nypap 2-tHlen 2y)Hmiao2)pyrroidine--carbo y ac d t ertyl estroy carbamic acid m rethyl ester / H Ph pyr Hi NH 4 Ac . r m e Xylenes, 135 aC 2-{2- 4-({6-{ 2-[2-Met -oxycaryyonycaminoa3- r3mthyb-butyryl)-py lamiino2.y -p.IHy imidazo-4-yI) }-apt a phlen-2-y)-plenyIl2-oxo-ethylcerbemoy)-4-phenyl pycoidne-1 -broxylic acid tert-utyl ester y oH 1ao ]-m h HCI 2 HATU. DIEA Me eNerOH 0o H N N 0 O0 >Oj\ - N N -0/ 25462-[l-(2-Methoxycreonylasmino-n-methyinuerryt)-pyrro9idin-2-yi-nH midazom4- alphhalen-2-yi)-uheny1 H-midt-2-y4phex pyi-yrr ithdIne - e d m roli -ca rboxylic acid tert-butyl ester ( m U- /0N -/\ (1 -(2-(5-4-(-2{1 -(2-Methxycarbonytamino-3methyl-utyryl)-pyrrolidr-2 y5-mH0idazo4-y)npn.ale-2-y)-phyl-lHmiaddezoT-2-yI-4henyt pyrrodine-1 -croy)2-rethyl-propyll-cramic ad methyl ester 5 2-w2-i4-(6-12- -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yinia-I imidazol-4-yl}-naphthalen-2-yl)-phenyl]-2-oxo-ethylcarbamoyl}-4-phenyl-pyrrolidine-I carboxylic acid tert-butyl ester: (I1 -[2-(4- {6-[4-(2-tert-Butoxycarbonylamino-acetyl)-phenyl]-naphthalen-2-yl - -1 H-imidazol-2 yl)-pyrrolidine- I-carbonyl]-2-methyl-propyl-carbamic acid methyl ester (61.0 mg, 0.095 10 mmol) was dissolved in DCM (I ml-) and HCI in dioxane (4M, I ml-) was added and stirring at room temperature was continued. After 90 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.0 mL) and DIEA (23.7 mg, 0.183 mmol) was added. A solution of 4 Phenyl-pyrrolidine-I,2-dicarboxylic acid I7-tert-butyl ester (17.8 mg, 0.061 mmol), HATU (23.3 15 mg, 0.061 mmol) and DIEA (7.9 mg, 0.061 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with brine, saturated sodium bicarbonate solution, brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material (88 mg), which was used in the next step without further purification. 20 LCMS-ESI+: calc'd for C 48

H

54

N

6 0 7 : 826.9 (M4 +); Found: 827.7 (M+H+). 756 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1 H imidazol-4-yl}-naphthalen-2-y)-phenyl]-1 H-imidazol-2-yl}-4-phenyl-pyrrolidine-1 carboxylic acid tert-butyl ester: 2-{2-[4-(6- {2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]- I H-imidazol-4 5 yl}-naphthalen-2-yl)-phenyl]-2-oxo-ethylcarbamoyl}-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (88 mg) was dissolved in m-xylenes (1.0 mL) and heated at 135 *C. Solid ammonium acetate (100 mg, 1.2 mmol) was added and the reaction was stirred at 135 'C. After 180 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was partitioned between chloroform and water. The organic 10 layer was collected and dried over sodium sulfate. Filtration and evaporation of solvents gave the crude product. The crude material was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product (51.0 mg, 0.195 mmol). LCMS-ESl*: calc'd for C 4 8

H

53

N

7 0 5 : 807.9 (M *); Found: 808.4 (M+H*). 15 [1-(2-{5-4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-1 H imidazol-4-yl}-naphthalen-2-yl)-phenyll-1H-imidazol-2-yl}-4-phenyl-pyrrolidine-1 carbonyl)-2-methyl-propyl -carbamic acid methyl ester: 2- { 5-[4-(6- {2-[]-(2-Methoxycarbonylam ino-3-methyl-butyryl)-pyrrolidin-2-yl]- H-imidazol-4 yl}-naphthalen-2-yl)-phenyl]-l H-imidazol-2-yl}-4-phenyl-pyrrolidine-1 -carboxylic acid tert 20 butyl ester (51.0 mg, 0.063 mmol) was dissolved in DCM (1.0 mL) and HCI in dioxane (4M, 1.0 mL) was added and stirring at room temperature was continued. After 30 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.5 mL) and DIEA (24.3 mg, 0.190 mmol) was added. A solution of 2- (L) methoxycarbonylamino-3-methyl-butyric acid (11.1 mg, 25 0.063 mmol), HATU (24.0 mg, 0.063 mmol) and DIEA (8.1 mg, 0.063 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 60 minutes, the crude reaction was quenched with aqueous hydrochloric acid (0.1 mL, 2 M) and was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (12.1 mg) as a TFA salt. LCMS-ESl*: calc'd for C 50

H

56

N

8 0 6 : 865.0 (M *); Found: 865.4 (M+H 4 ). 30 1 H-NMR: 300 MHz, (dmso-d 6 ) 5: 8.31 - 8.30 (d, J = 3 Hz, 2H), 8.08 (d, J = 6.6 Hz, 2h), 7.98 7.86 (m, IOH), 7.34 - 7.21 (m, 7H), 5.28 (dd, J = 6.0 / 2.7 Hz, I H), 5.10 (dd, J = 6.0 / 5.7 Hz, I H), 4.26 (m, I H) 4.11 (m, I H), 4.06 (in, I H) 3.85 - 3.73 (in, 3 H), 3.48 (s, 3 H), 3.47 (s, 3 H), 2.27 (m, 2H), 2.14 - 2.09 (in, 7H), 0.89 - 0.72 (m, 12H) ppm. 757 Example FW Ph 0/ - 1. HCI. 2. HATU, DIEA Meo N OH NN 7NN 25-(24-56-[2-[1 -(2(-Metho2ycaronyam no3-metho-buyry)-pyrronidn-2-yla-21 H- m imidazol4-y4aphtha~en.2-yI)-henyi1H.imidazoln-2-yl)-phenyyl-pyrroidin-e11 0 OH a - / \/ carbony)-2-methoxylacid-opyl] -crbai acid methyle I1~[1-(2-t5-[4-(6-{22I[l-(2-Methoxycar~onylamino.4-methyl-butyryl)-pyrrolidir-2-1 i~~~~y11Hmidazol4-yI}-naphthalen-2-yl)-henylj-1 H-imidazol-2-yl}-4-phenyl-pyrldn carbonyl)-2-methyl-propyll -carbam ic acid methyl ester: 2-{5-[4-(6-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-I H-imidazol-4 10 yl}-naphthalen-2-yl)-phenyl]-i H-imidazol-2-yl}-4-phenyl-pyrrolidine-I -carboxylic acid tert butyl ester (88.mg, 0.107 mmol) was dissolved in DCM (1.0 mL) and HCI in dioxane (4M, 1.0 mL) was added and stirring at room temperature was continued. After 40 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.4 mL) and DIEA (40.8 mg, 0.321 15 mmol) was added. A solution of 2- (L) methoxycarbonylamino-3-methyl-butyric acid (18.7 mg, 0.107 mmol), HATU (40.6 mg, 0.107 mmol) and DIEA (13.6 mg, 0.107 mmol) in DMF (0.4 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the crude reaction was quenched with aqueous hydrochloric acid (0.1 mL, 2 M) and was purified by RP HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (38.7 mg) as a TFA salt. 20 LCMS-ESI+: calc'd for C 50

H

56

N

8 0 6 : 865.0 (M *); Found: 865.4 (M+H*). H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.37 - 8.35 (m, 2H), 8.16 - 7.91 (m, 12H), 7.47 - 7.28 (m, 7H), 5.24 (dd, J = 7.8 / 5.4 Hz, I H), 5.16 (dd, J = 4.8 / 4..8 Hz, I H), 4.44 (dd, J = 6.3 / 6.3 Hz, I H) 4.16 - 4.09 (m, 2H) 3.85 - 3.80 (m, 3H), 3.57 (s, 3H), 3.56 (s, 3H), 2.78 (m, I H), 2.30 - 1.96 (m, 8H), 0.90 - 0.75 (m, 12H) ppm. 25 758 Example FX H P1 HCI 2. HATU, DIEA MeO N H N H O \ - y ) 1 m d N o yro n-.cron -ety op e 0ccimty1se 4-Be nyzyl.2-(6-{41-(2-metho4 { -mxonylaminxb3ymethylcbutamne)tpyhb-din2y H yl]-H-imidazol-4-yI)naphthafen-2-yI)-phtnyJ.1h-4midazol-2-y l )mpy -2oidine-- hId car2oxylicaad tert-butyl ester met H hy este o N\4 H N N~ 0 H'/0 [1 -44-8enzyI-2{5{4-{62{1 -{2-methoxycarbornylamino-3.,etyI-buyry). pyrroidin2-y1Hmidazo-4-y-napthaln-2y)pheny1H4mdazo-2-y) 5 pyrrolidine-l-carbonyl)-2-methyI-pmpyIl-certamic adid rnettll ester [1-(4-Benzyl-2-{5-[4-(6-2-[-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl-H-imidazol-4-yI-naphthalen-2-yl)-phenyl- H-imidazo-2-y-y-pyrrolidine-1-carbonyl) 2-methyl-propyll-carbamic acid methyl ester: 4-Benzyl-2- {5-[4-(6- {2-[ I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]- IH 10 imidazol-4-yl }-naphthalen-2-yl)-phenyll]IH-imidazol-2-yl }-pyrrol idine-lI-carboxylic acid tert butyl ester (58.0 mg, 0.071 mmol) was dissolved in DCM (1.0 mL) and HCI in dioxane (4M, 1.0 mL) was added and stirring at room temperature was continued. After 30 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.5 mL) and DIEA (27.3 mg, 0.211 15 mmol) was added. A solution of 2- (L) methoxycarbonylamino-3-methyl-butyric acid (12.3 mg, 0.071 mmol), HATU (26.8 mg, 0.071 mmol) and DIEA (9.1 mg, 0.071 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 30 minutes, the crude reaction was quenched with aqueous hydrochloric acid (0.1 mL, 2 M) and was purified by RP-HPLC (eluent: water/ MeCN w/ 0.1% TFA) to yield the product (25.1 mg) as a TFA salt. 20 LCMS-ESI+: calc'd for C 5 1

H

57

N

8 0 6 : 878.0 (M *); Found: 879.6 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 5: 8.36 (s, 2H), 8.16 - 7.89 (m, 12H), 7.38 - 7.19 (m, 7H), 5.29 (dd, J = 5.7 / 3.9 Hz, I H), 5.16 (dd, J = 5.1 / 5.1 Hz, I H), 4.18 - 4.05 (m, 2H), 3.93 - 3.86 (m, 2H), 3.56 (s, 3H), 3.53 (s, 3H), 3.52 (m, 2H), 2.79 (m, I H), 2.48 (m, 2H), 2.39 (m, 1 H), 2.18 2.01 (m, 7H), 0.91 - 0.77 (m, 12H) ppm. 25 759 Example FY 0 i. n-BuLi, THF. -78"C 1. MeMgCI, THF. i 0 O S 2 . S n C 1 2 , H C I C I N 'o S S _ _ _ _ 0 1,5-Dithia-s-indacene-4,8-dione 4.8-Dimethyl-1.5-dithia-s-indacene -COOH C11 / 0 BOC S CISNH 4 0Ac, m- Xylenes, 135 *C 2-Chloro-1-[6-(2-chloro-acetyl)-4.8-dimethy-1.5-dithia s-indacen-2-yl-ethanone 0 N\0/ N N 1. HCI. 2. HATU,DIEA MeO N N N S N 0/> 1-{2-[5-(6-(2-{1-carbamic acid tert. buty ester-pyrrolidin-2-y-3--imidazol 4-yl)-4,8-dimethyl-1,5-dithia-s-indacen-2-y)-1H-imidazol-2-yl-pyrrolidine 1-carbamic acid tert.butyl ester O NH H ( N N - S N 1 N K.f H 0 (1 -(2-[5-(6-{2-{1-(2-Methoxycarbonylamino-3-methyl-butyry)-pyrrolidin-2-y)3H imidazol-4-yl)-4,8-dimethyl-1,5-dithia-s-indacen-2-yl)-1 H-imidazol-2-yl]-pyrrclidine 1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 4,8-Dimethyl-1,5-dithia-s-indacene: 1,5-Dithia-s-indacene-4,8-dione (2.0 g, 9.17 mmol) was added to a methyl magnesium chloride solution (60 mmol) in THF (80 mL) [Org. Lett., 2008, 10:4421-4424]. The reaction mixture was heated at 550 C (oil bath). After 14 hrs, a solution of tin(II)chloride (10 g) in aqueous HCI (2M, 50 mL) was added carefully and the heating was continued for 4 additional hours. The reaction 10 was cooled to room temperature and the THF was removed in vacuo. The crude mixture was partitioned between chloroform and brine. The resultant thick suspension was filtered and the solid was discarded. The organic layer was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was via silica gel chromatography (eluent: EtOAc / hexanes) to yield the product (355.0 mg, 1.63 mmol). 15 'H-NMR: 300 MHz, (CDCl 3 ) 5: 7.49 (d, J = 4.2 Hz, 2H), 7.46 (d, J = 4.2 Hz, 2H), 2.81 (s, 6H)ppm. 760 2-Ch loro-1 -[6-(2-chloro-acetyl)-4,8-d imethyl-1,5-dithia-s-indacen-2-yII -ethanone: 4,8-Dimethyl-1,5-dithia-s-indacene (61.0 mg, 0.095 mmol) was dissolved in THF (9 mL) and was cooled to -78* C. A solution of n-BuLi (1.6 M hexanes, 0.946 mL) was added and stirring at -78* C was continued for 90 minutes. To the resultant suspension was added a solution of N 5 Methyl, N-Methoxy-2-chloroacetate (209 mg, 1.51 mmol) in THIF (I mL). Stirring at -78* C was continued for 45 minutes. The reaction was quenched with ammonium chloride solution and methanol and was warmed to room temperature. The bright yellow solid was collected and used in the next step without further purification. 10 1-{2-15-(6-{2-[1-carbamic acid tert. butyl ester-pyrrolidin-2-yl]-3H-imidazol-4-yI}-4,8 dimethyl-1,5-dithia-s-indacen-2-yl)-1 H-imidazol-2-yI]-pyrrolidine-1-carbamic acid tert butyl ester 2-Chloro-l -[6-(2-chloro-acetyl)-4,8-dimethyl-I,5-dithia-s-indacen-2-yl]-ethanone (crude solid from previous step)) was combined and with (L)-N-Boc Proline carboxylic acid (324 mg, 1.51 15 mmol), potassium carbonate (304 mg, 2.2 mmol), sodium iodide (21.6 mg) and was heated in acetone (10 mL) at -78* C. After 120 minutes, all volatiles were removed in vacuo. The reaction was diluted with chloroform and was washed with brine, saturated sodium bicarbonate solution, brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material (580 mg, 0.797 mmol), which was used in the next step without further 20 purification. The crude product from the previous step (580.1 mg, 0.797 mol) was dissolved in m-xylenes (7.0 mL) and heated at 140 *C. Solid ammonium acetate (500 mg, 6.41 mmol) was added and the reaction was stirred at 140 *C. After 240 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was 25 partitioned between chloroform and aqueous sodium bicarbonate solution. The organic layer was collected, washed with brine and dried over sodium sulfate. Filtration and evaporation of solvents gave the crude product (303.0 mg, 0.440 mmol). LCMS-ESI+: calc'd for C 3 6

H

4 4

N

6 0 4

S

2 : 688.9 (M *); Found: 688.3 (M+H*). 30 (1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yI)-4,8-dimethyl-1,5-dithia-s-indacen-2-yl)-1 H-imidazol-2-ylj-pyrrolidine-1 carbonyl)-2-methyl-propyl)-carbamic acid methyl ester: 1-{2-[5-(6-{2-[ I-carbamic acid tert-butyl ester-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-4,8 dimethyl- 1,5-dithia-s-indacen-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carbamic acid lert-butyl 35 ester (51.0 mg, 0.073 mmol) was dissolved in DCM (0.67 mL) and HCI in dioxane (4M, 0.67 761 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.8 mL) and DIEA (37.6 mg, 0.292 mmol) was added. A solution of 2- (L) methoxycarbonylamino-3-methyl-butyric acid (25.5 mg, 5 0.146 mmol), HATU (55.5 mg, 0.146 mmol) and DIEA (18.8 mg, 0.146 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 30 minutes, the reaction was quenched with aqueous hydrochloric acid (0.2 mL, 2 M) and was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (5.1 mg) as a TFA salt. LCMS-ESl*: calc'd for C 4 aH 5 oNsO 6

S

2 : 803.0 (M *); Found: 803.2 (M+H*). 10 1 H-NMR: 300 MHz, (dmso-d 6 ) 8: 7.88 (s, 4H), 7.30 (m, 2H), 5.10 (m, 2H), 4.12 (dd, J = 8.1 / 8.1 Hz, 2H), 3.83 (m, 4H) 3.53 (s, 6H), 2.73 (s, 6H), 2.27 (m, 2H), 2.14 - 1.98 (m, 8H), 0.89 0.80 (m, 12H) ppm. Example FZ 0 H H N\ / | S N N N N N _,O H 0 HN O (2-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-4,8-dimethyl-1,5-dithia-s-indacen-2-yl)-1H-imidazol-2-yl]-pyrrolidin 15 1-yl}-2-oxo-1-phenyl-ethyl)-carbamic acid methyl ester (2-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol 4-yl}-4,8-dimethyl-1,5-dithia-s-indacen-2-yl)-1 H-imidazol-2-yll-pyrrolidin-1-yl}-2-oxo-1 phenyl-ethyl)-carbamic acid methyl ester 20 1-{2-[5-(6-{2-[1-carbamic acid tert-butyl ester-pyrrolidin-2-yl]-3H-imidazol-4-yl}-4,8 dimethyl- 1,5-dithia-s-indacen-2-yl)-l H-imidazol-2-yl]-pyrrolidine- I -carbamic acid tert-butyl ester (51.0 mg, 0.073 mmol) was dissolved in DCM (0.67 mL) and HCl in dioxane (4M, 0.67 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further 25 purification. The crude material was dissolved in DMF (0.8 mL) and DIEA (37.6 mg, 0.292 mmol) was added. A solution of 2- (D) methoxycarbonylamino-2-phenyl-acetic acid (30.5 mg, 0.146 mmol), HATU (55.5 mg, 0.146 mmol) and DIEA (18.8 mg, 0.146 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 30 minutes, the reaction was quenched with aqueous hydrochloric acid (0.2 mL, 2 M) and was purified by RP-HPLC 762 (eluent: water / MeCN w/ 0.1% TFA) to yield the product (6.7 mg) as a mixture of isomers and in the form of the TFA salt. LCMS-ESI*: calc'd for C 4 0

H

5

ON

8 0 6

S

2 : 871.0 (M*); Found: 871.7 (M+H*). H-NMR: 300 MHz, (dmso-d 6 ) 8: 7.95 - 7.66 (m, 6H), 7.40 - 7.34 (m, 8H), 7.06 (m, 2H), 5.51 5 (m, 2H), 5.13 (m, 2H), 3.91 (m, 2H), 3.54 and 3.52 (2x s, 6H), 3.16 (m, 2H), 2.76 (s, 6H), 2.19 - 1.98 (m, 8H) ppm. Example GA O O H H / ~ S NI -N / 17, >.0j N N 0 (2-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-2-tetrahydropyranyl-acetyl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-4,8-dimethyl-1,5-dithia-s-indacen-2-y)-1 H-imidazol-2-yl] 10 pyrrolidin-1-yl}-2-oxo-l-tetrahydropyranyl-ethyl)-carbamic acid methyl ester (2-{2-[5-(6-12-[1-(2-Methoxycarbonylamino-2-tetrahydropyranyl-acetyl)-pyrrolidin-2-yll 3H-imidazol-4-yl}-4,8-dimethyl-1,5-dithia-s-indacen-2-yl)-1H-imidazol-2-yI]-pyrrolidin-1 yl}-2-oxo-1 -tetrahyd ropyranyl-ethyl)-carbamic acid methyl ester: 15 1-{2-[5-(6-{2-[I-carbamic acid tert-butyl ester-pyrrolidin-2-yl]-3H-imidazol-4-yl}-4,8 dimethyl- 1,5-dithia-s-indacen-2-yl)- I H-imidazol-2-yl]-pyrrol idine- 1 -carbamic acid tert-butyl ester (51.0 mg, 0.073 mmol) was dissolved in DCM (0.67 mL) and HCI in dioxane (4M, 0.67 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further 20 purification. The crude material was dissolved in DMF (0.8 mL) and DIEA (37.6 mg, 0.292 mmol) was added. A solution of 2- (L) methoxycarbonylamino-2-(4-tetrahydropyranyl)-acetic acid (31.6 mg, 0.146 mmol), HATU (55.5 mg, 0.146 mmol) and DIEA (18.8 mg, 0.146 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was quenched with aqueous hydrochloric acid (0.2 mL, 2 M) and was purified by 25 RP-H PLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (8.1 mg) as a TFA salt. LCMS-ESI+: calc'd for C 4 4

H

54

N

8 0 8

S

2 : 887.0 (M +); Found: 887.9 (M+H*). 1 H-NMR: 300 MHz, (dmso-d 6 ) 8: 7.81 (s, 4H), 7.39 (m, 2H), 5.08 (m, 2H), 4.18 (m, 2H), 3.85 (m, 8H) 3.53 (s, 6H), 3.22 (m, 4H), 2.72 (s, 6H), 2.27 (m, 2H), 2.14 - 1.98 (m, 8H), 1 .58 - 1.25 (m, 8H) ppm. 763 Example GB 0 O NH 0 "1_ O N \ /S N N L N, N g N O O 'H HO H , O0 (1-{2-[5-(4,8-Dimethoxy-6-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-1,5-dithia-s-indacen-2-yl)-1H-imidazol-2-yI] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 (1 -{2-[5-(4,8-Dimethoxy-6-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-1,5-dithia-s-indacen-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 carbonyl)-2-methyl-propyl)-carbamic acid methyl ester: 1-{2-[5-(6-{2-[1 -carbamic acid tert-butyl ester-pyrrolidin-2-yl]-3H-imidazol-4-yl}-4,8 10 dimethoxy-1,5-dithia-s-indacen-2-yl)-I H-imidazol-2-yl]-pyrrolidine-I -carbamic acid tert-butyl ester (49.3 mg, 0.070 mmol) was dissolved in DCM (0.67 mL) and HICI in dioxane (4M, 0.67 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.8 mL) and DIEA (36.0 mg, 0.280 15 mmol) was added. A solution of 2- (L) methoxycarbonylamino-3-methyl-butyric acid (24.5 mg, 0.140 mmol), HATU (53.2 mg, 0.140 mmol) and DIEA (18.0 mg, 0.140 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 45 minutes, the crude reaction was quenched with aqueous hydrochloric acid (0.2 mL, 2 M) and was purified by RP HPLC (eluent: water/ MeCN w/ 0.1% TFA) to yield the product (5.1 mg) as a TFA salt. [The 20 required starting material for the modified sequence was described in Org. Lett., 2008, 10:442 1 4424.] LCMS-ESI: calc'd for C 4 0

H

5

ON

8 0 8

S

2 : 835.0 (M *); Found: 835.2 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 6: 7.95 (s, 2H), 7.85 (s, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.09 (dd, J = 4.8 / 4.8 Hz, 2H), 4.10 - 4.07 (m, 8H), 3.82 (m, 4H) 3.57 (s, 6H), 2.30 (m, 2H), 2.15 - 1.96 25 (m, 8H), 0.87 - 0.80 (m, 12H) ppm. 764 Example GC H 0 H 0 S NT *N N N S - H

HI

H 0-= (2-{2-[5-(4,8-Dimethoxy-6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-1,5-dithia-s-indacen-2-yl)-1 H-imidazol-2-yl] pyrrolidin-1-yl}-2-oxo-1-phenyl-ethyl)-carbamic acid methyl ester 5 (2-{2-15-(4,8-Dimethoxy-6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2 yl]-3H-imidazol-4-yI}-1,5-dithia-s-indacen-2-yl)-1H-imidazol-2-ylI]-pyrrolidin-1-yl}-2-oxo 1-phenyl-ethyl)-carbamic acid methyl ester: I- {2-[5-(6-{2-[l -carbamic acid tert-butyl ester-pyrrolidin-2-yl]-3H-imidazol-4-y}-4,8 10 dimethoxy- I,5-dithia-s-indacen-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-I -carbamic acid tert-butyl ester (49.3 mg, 0.070 mmol) was dissolved in DCM (0.67 mL) and HCI in dioxane (4M, 0.67 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.8 mL) and DIEA (36.0 mg, 0.280 15 mmol) was added. A solution of 2- (D) methoxycarbonylamino-2-phenyl-acetic acid (29.3 mg, 0.140 mmol), HATU (53.2 mg, 0.140 mmol) and DIEA (18.0 mg, 0.140 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 45 minutes, the crude reaction was quenched with aqueous hydrochloric acid (0.2 mL, 2 M) and was purified by RP HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (6.7 mg) as a mixture of 20 isomers and in the form of the TFA salt. LCMS-ESl+: calc'd for C 40

H

50

N

8 0 6

S

2 : 871.0 (M +); Found: 871.7 (M+H*). 1 H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.01 - 7.67 (m, 6H), 7.39 - 7.35 (m, 8H), 7.06 (m, 2H), 5.51 (m, 2H), 5.13 (m, 2H), 4.13 (s, 6H), 3.91 (m, 2H), 3.54 and 3.52 (2x s, 6H), 3.16 (m, 2H), 2.19 - 1.87 (m, 8H) ppm. 25 765 Example GD O0 O N,H H -, O N\ / S N N NN C /N OH HN 0-1 (2-{2-[5-(4,8-Dimethoxy-6-{2-[1-(2-methoxycarbonylamino-2 tetrahydropyranyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-1,5-dithia-s indacen-2-yl)-1 H-imidazol-2-yl]-pyrrolidin-1 -yl}-2-oxo-1 -tetrahydropyranyl ethyl)-carbamic acid methyl ester 5 (2-{2-[5-(6-{2- [1-(2-Methoxycarbonylamino-2-tetrahyd ropyranyl-acetyl)-pyrrolidin-2-yl] 3H-imidazol-4-yl}-4,8-dimethyl-1,5-dithia-s-indacen-2-yl)-1H-imidazol-2-yI]-pyrrolidin-1 yl}-2-oxo-1 -tetrahyd ropyranyl-ethyl)-carbamic acid methyl ester: 1-{2-[5-(6-{2-[ I -carbamic acid tert-butyl ester-pyrrolidin-2-yl]-3H-imidazol-4-y1}-4,8 dimethoxy-1,5-dithia-s-indacen-2-yI)-1 H-imidazol-2-yl]-pyrrolidine-I -carbamic acid tert-butyl 10 ester (49.3 mg, 0.070 mmol) was dissolved in DCM (0.67 mL) and HCI in dioxane (4M, 0.67 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.8 mL) and DIEA (36.0 mg, 0.280 mmol) was added. A solution of 2- (L) methoxycarbonylamino-2-(4-tetrahydropyranyl)-acetic 15 acid (30.4 mg, 0.140 mmol), HATU (53.2 mg, 0.140 mmol) and DIEA (18.0 mg, 0.140 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was quenched with aqueous hydrochloric acid (0.2 mL, 2 M) and was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (8.1 mg) as a TFA salt. LCMS-ESl*: calc'd for C 44

H

54

N

8 0 8

S

2 : 919.0 (M*); Found: 919.6 (M+H*). 20 1 H-NMR: 300 MHz, (dmso-d 6 ) 8: 7.86 (s, 2H), 7.74 (s, 2H), 7.39 (m, 2H), 5.07 (m, 2H), 4.18 (m, 2H), 4.08 (s, 6H), 3.84 (m, 8H), 3.53 (s, 6H), 3.21 (m, 4H), 2.26 (m, 2H), 2.15 - 1.92 (m, 8H), 1.64 - 1.27 (m, 8H) ppm. 766 Example GE OMe /-NH 0 N Ph O hHN NN Nh SJ ~NH 0a S OMe O (2-{2-[4-(4,8-Dimethoxy-6-{2-[3-(2-methoxycarbonylamino-2-phenyl-acetyl) th iazolidin-2-yl]-1 H-imidazol-4-yl}-1, 5-dithia-s-indacen-2-yl)-1 H-imidazol-2-yl] thiazolidin-3-yl}-2-oxo-1-phenyl-ethyl)-carbamic acid methyl ester 5 (2-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-ylI-3H-imidazol 4-yl}-4,8-dimethyl- 1,5-dith ia-s-indacen-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1 -yl}-2-oxo-1 phenyl-ethyl)-carbamic acid methyl ester (2-{ 2-[5-(6- {2- [1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrro idin-2-yl]-3H-im idazol-4 10 yl}-4,8-dimethyl-1,5-dithia-s-indacen-2-yl)- I H-imidazol-2-yl]-pyrrolidin-l -yl}-2-oxo- I -phenyl ethyl)-carbamic acid methyl ester was prepared following method used for (2-{2-[5-(4,8 Dimethoxy-6-{2-[I-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol 4-yl}-1,5-dithia-s-indacen-2-yl)- I H-imidazol-2-yl]-pyrrolidin- I-yl}-2-oxo-I -phenyl-ethyl) carbamic acid methyl ester substituting L- thiazolidine-2,3-dicarboxylic acid 3-tert-butyl ester 15 for L-pyrrolidine- 1,2-dicarboxylic acid I -tert-butyl ester. LCMS-ESl*: calc'd for C 4 4

H

4 2

N

8 0 8

S

4 : 938.2 (M*) found: 939.1 (M + H*) 'H-NMR: 300 MHz, (dmso-d 6 ) 8: 7.85 - 7.63 (m 2H), 7.46 -7.29 (m I 0H), 7.08 -7.01 (m, 2H), 6.31 (m, 2H), 5.60 (d, J= 7.6 Hz, 2H), 4.24 (m 2H), 4.13 (s, 6H), 4.06 - 3.76 (m 2H), 3.54 (m, 6H), 3.28 (m, 2H), 3.15 (m, 2H). 20 767 Example GF H O O pTsOH, Acetone, H 2 0 BrN 60 "C, 3 days Br 0HN HN 0- 0 (1-{8-(5-(4-Bmmo-phenyl)-1H-imidazol-2-yl]-1,4- (1-{2-[5-(4-Bmmo-phenyl)-1H-imidazol-2-yl] dioxa-7-aza-spro[ 4]nonane-7-carb eyI}2-methyl- 4-ox yrrolidine-1 -carbonyl-2-methy1 propyl)-catamic acid methyl ester propyl)-cartamic acid Methyl ester 0 0/H Pd(PPh3) 4 , NaHCO,,. N O 0 N N D ME, 110 OC, Brs N~ N U 0 (2-Methyl-1-{2-{4-[6-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan- ( 4 yrrd-1 y)e1 H dazoyl 2-y)-napht len-2yI H midazol-2-yl}-pyrroidine-1- propyl)-carbamic acid methyl ester carbonyl)-propyll-carbarmc aad Methyl ester 0 O O 0 H N NH 0 H*/0 1 -(2-5-{4-(1-(2l -(2-Methoxyoar onytamiro-3-methy -butyryl)-pyrro]idin-2-yI]-IH imidazol-4-yI)-naphthlen-2-yi) -phenyh-1fAM idazol2-yI4aso-py rrofidine-1.

carbny)-2-methyl.pmpy}-carbamic acid methyl ester 5 (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester: (I -{8-[5-(4-Bromo-phenyl)-I H-imidazol-2-yl]- I,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (230.0 mg, 0.453 mmol) was dissolved in acetone 10 (10 mL) and water (0.2 mL) and p-TsOH - H20 (53 mg, 0.278 mmol) were added. The reaction was heated at 60 *C for 20 hours, after which additional p-TsOH o H 2 0 (53 mg, 0.278 mmol) was added heating at 60 *C was continued. After three days, all volatiles were removed in vacuo. The crude material was taken into EtOAc and was washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of solvents in 15 vacuo gives the crude product. The crude material was purified via silica gel chromatography (eluent: EtOAc containing I0%MeOH / hexanes) to yield the product (93.9 mg, 0.202 mmol). LCMS-ESI*: calc'd for C 20

H

23 BrN 4 0 4 : 463.3 (M *); Found: 463.6 (M+H*). 'H-NMR: 300 MHz, (dmso-d 6 ) 6: 7.92 (m, I H), 7.64 (m, 5H), 7.49 (d, J = 6.5 Hz, I H), 5.56 (dd, J = 7.5 / 3.6 Hz, I H), 4.34 (m, 2H), 3.91 (dd, J = 6.3 / 6.3 Hz, I H), 3.52 (s, 3H), 3.20 (dd, J = 20 14.4 / 7.8 Hz, I H), 2.82 (br-d, J = 14.4 Hz, I H), 1.87 (m, I H), 0.78 (d, J= 5.1 Hz, 3H), 0.71 (d, J = 4.8 Hz, 3 H) ppm. 768 11 -(2-{5-14-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1

H

imidazol-4-yI)-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl)-4-oxo-pyrrolidine-1-carbonyl) 2-methyl-propyl]-carbamic acid methyl ester: 5 (1 -{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-oxo-pyrrolidine-1-carbonyl}-2-methyl-propyl) carbamic acid methyl ester (46.0 mg, 0.1 mmol), [2-Methyl-I -(2-{4-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine-l -carbonyl)-propyl] carbamic acid methyl ester (54 mg, 0.1 mmol), and Pd[PPh 3

]

4 (11.5 mg, 0.0 1 mmol) were dissolved in DME (2 mL) under an atmosphere of argon. Saturated, aqueous sodium bicarbonate 10 solution (0.3 mL) was added and the reaction was heated under microwave conditions at 120 'C for 20 minutes. The solids were discarded and the volatiles were removed in vacuo. The crude reaction mixture was purified by RP-HPLC (eluent: water / MeCN w/ 0.1% TFA) to yield the product (4.0 mg) as a TFA salt. LCMS-ESI+: calc'd for C 4 4

H

5 0

N

8 0 7 : 802.9 (M *); Found: 803.4 (M+H*). 15 H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.32 (m, 2H), 8.12 - 7.84 (m, 1 OH), 7.52 (d, J = 7.8Hz, I H), 7.32 (d, J = 8.4Hz, I H), 5.61 (m, I H), 5.14 (m, I H), 4.39 (m, 2H), 4.12 (dd, J = 7.5 Hz, I H), 3.94 (dd, J = 8.4 / 8.4 Hz, I H), 3.85 (m, 2H), 3.54 (2x s, 6H), 3.26 (m, I H), 2.90 (m, I H), 2.13 1.90 (m, 6H), 0.86 - 0.74 (m, I 2H) ppm. 769 Example GG o H -COOH 1 HCI. 2 HATU, DIEA midazal-2-y}pyrdine-1 -ca tonyl)-2-methyl-propyl]-caitamic acd methyl ester 0 H O

NH

4 0Ac, m- Xylenes, 135 OC N NN F 1 -{2-4-(21 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrro idin-2ylI 1 N-imidazol-4-yt-bphenyl-4-yI)-2-oxo-ethytcarbamoyl.1 .3-dihydro isoindole-2-carboxylic acd tert-butyl ester / H H 1 HCL. 2 HATU, DIEA MeO N'iOH 0NN N 1-[5-(4{2-1 -(2-Methoxycino1nyamno-3-mehyl-butyry)-pyrrolidin-2-J1H- 0 H H imidazoI-4.yI)-bipbtenyt-yilt imidazol-2yl-1 3-drhydro-isoindole-2- L carboxylic acid teft-butyl ester ' N N L 6N O NJ>0N No H/0 (1-q1 -[5-(4{-2-[-2-Methoccarbnylamino-3-methyl-buyryl)-pyrroldin-2-y)-1 H midazo-4-yl} bpheny4-yI)-I H-iidazol-2-y1 ,3-dihydro soindole-2-carboyl 2-methyl-propyl)-carbamic acid methyl ester 5 1-12-(4'-(2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl-1 H-imidazol 4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyll-1,3-dihyd ro-isoindole-2-carboxylic acid tert butyl ester: 10 [1 -(2-{4-[4'-(2-tert-Butoxycarbonylamino-acetyl)-biphenyl-4-yl]-I H-imidazol-2-yl} pyrrolidine-I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (107.0 mg, 0.177 mmol) was dissolved in DCM (1 mL) and HCI in dioxane (4M, I mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved 15 in DMF (0.6 mL) and DIEA (68.4 mg, 0.531 mmol) was added. A solution of racemic 1,3 dihydro-isoindole- 1,2-dicarboxylic acid 2-tert-butyl ester (46.6 mg, 0.177 mmol), HATU (67.3 mg, 0.177 mmol) and DI EA (22.8 mg, 0.177 mmol) in DMF (0.4 mL) was added. The reaction was stirred at room temperature. After 15 minutes, the reaction was diluted with EtOAc and was washed with brine, saturated sodium bicarbonate solution, brine, and was dried over sodium 770 sulfate. Filtration and removal of solvents in vacuo gave the crude material (147.8 mg), which was used in the next step without further purification. LCMS-ESI*: calc'd for C 4 2

H

48

N

6 0 7 : 748.8 (M +); Found: 749.2 (M+H*). 5 1-[5-(4'-{2-I1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol 4-yI}-biphenyl-4-yI)-1H-imidazol-2-yl]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester: 1-[2-(4'-{2-[I -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-I H-imidazol-4 yl }-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]- 1,3-dihydro-isoindole-2-carboxylic acid tert-butyl 10 ester (147.8 mg) was taken into m-xylenes (2.0 mL) and heated at 135 *C. Solid ammonium acetate (120 mg, 1.5 mmol) was added and the reaction was stirred at 135 *C. After 180 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was partitioned between EtOAc and water. The organic layer was collected and dried over sodium sulfate. Filtration and evaporation of solvents gave the crude product (142 15 mg). LCMS-ESI: calc'd for C 42

H

4 7

N

7 0 5 : 729.8 (M *); Found: 730.4 (M+H*). H-NMR: 300 MHz, (dmso-d 6 ) 8: 8.07 (m, 2H), 7.90 - 7.85 (m, 8H), 7.49 - 7.27 (m, 5H), 6.31 (s, I H), 5.12 (dd, J = 6.9 / 6.9 Hz, I H), 4.95 - 4.70 (m, 2H), 4.11 (dd, J = 7.5 / 7.5 Hz, I H), 3.83 (m, 2H), 3.53 (s, 3H), 2.41 (m, I H), 2.13 - 1.95 (m, 4H), 1.45 and 1.22 (2 x s, 9H), 0.88 - 0.78 20 (m, 6H) ppm. (1-{1-[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H imidazol-4-yI}-biphenyl-4-yI)-IH-imidazol-2-yl]-1,3-dihydro-isoindole-2-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: 25 1 -[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-I H-imidazol-4 yl}-biphenyl-4-yl)-i H-imidazol-2-yl]-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (71.0 mg, 0.086 mmol) was dissolved in DCM (1.0 mL) and HCI in dioxane (4M, 0.5 mL) was added and stirring at room temperature was continued. After 5 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The 30 crude material was dissolved in DMF (0.5 mL) and DIEA (30.9 mg, 0.24 mmol) was added. A solution of 2- (L) methoxycarbonylamino-3-methyl-butyric acid (14.0 mg, 0.080 mmol), HATU (30.4 mg, 0.08 mmol) and DIEA (10.3 mg, 0.08 mmol) in DMF (0.4 mL) was added. The reaction was stirred at room temperature. After 120 minutes, the crude reaction was quenched with aqueous hydrochloric acid (0.1 mL, 2 M) and was purified by RP-HPLC (eluent: water/ 771 MeCN w/ 0.1% TFA) to yield the two diastereomeric products (1.5 mg and 2.4 mg) as TFA salts. Compound A (faster eluding material on RP-HPLC) LCMS-ESI*: calc'd for C 4 4

H

5 oN 8 0 6 : 786.9 (M *); Found: 787.4 (M+H*). 5 1 H-NMR: 300 MHz, (dmso-d 6 ) 8: 7.90 - 7.75 (m, 1 OH), 7.50 - 7.27 (m, 6H), 6.42 (m, I H), 5.39 - 5.21 (m, 2H), 5.09 (m, I H), 4.16 - 4.08 (m, 2H), 3.81 (m, 2H), 3.52 (s, 6H), 2.41 (m, I H), 2.13 - 1.95 (m, 5H), 0.91 - 0.79 (m, 12H) ppm. Compound B (later eluding material on RP-HPLC) LCMS-ESI+: calc'd for C44H 50

N

8

O

6 : 786.9 (M *); Found: 787.4 (M+H*). 10 'H-NMR: 300 MHz, (dmso-d 6 ) 8: 7.80 - 7.58 (m, I OH), 7.40 - 7.13 (m, 6H), 6.29 (m, I H), 5.09 - 4.70 (m, 3H), 4.06 (m, I H), 3.91 (m, I H), 3.65 (m, 2H), 3.34 (s, 3H), 3.33 (s, 3H), 2.18 (m, 1 H), 1.98 - 1.82 (m, 5H), 0.75 - 0.59 (m, 12H) ppm. 772 Example Gil 0 0 80J r K 2 C0 3 , DMVF 4N / 0 H Nan 0 H N + 1 Br rt, 1§8h ~4 ~lix X (S)-2-benzyl 1 -tert-butyt 4 oxopyrrolidine-1,2 (S)-1-(tert-butoxycarbony)-4- dicarbaxylate oxopyrrolidine-2-carboxylic acid 0 00 0 0 H11 N r HATU, DIPEA /C 0 H H '+ (S)-benzyl 4-oxopyrralidine-2- (S)-2-(mnethoxycrarbanylamino)- 0 carboxylate hydrochloride 3-methyl butanoic acid S nz 1(Y2mthxcroyalY 3-methylbutanoyl-4-xopyrrolidine-2 carboxylate HO OH /- 0 H t p-TsOHH1- 2 0

H

2 , pd/c H L Toluene, reflux H'~sO EtO H' N Y 01 0 0 (S)-benzyl 7-((S)-2-(methoxycarbonylaminvo)- (S)-7-((S)-2-(methoxycarbonyfamino)-3 3-methylbutanoyl)-1,4-dioxa-7- methylbutanoyl)-1,4-dioxa-7 azaspiro[4.4]nonane-8-carboxylate azaspira[4.4]nonane8-carboxyic acid Br 0 0'> O 0\- 0 00 H H TEA, ACN 0 H N N N rt. 18h NH4OAc Br / \N Br /Br H'N Ol Toluene-HN1 0r reflux 0 0 methyi (S-1 -((SW--5-(4-bromaopheny)-1 H (S)-2-(4-bmomophenyl)-2-oxoethyl 7-((S)-2- imidazol-2-yl)-1 ,4-dioxa-7-azaspirof4.4]nonan (methoxycarbonyfamino)-3-methylbutanoyl)- 7-yI)-3-methyi-1 -oxabutan-2-ylcarbamate 1 ,4-dioxa-7-azaapiro[4.4]nonane-8-carboxylate 773 0 O B 1)0 4 m - B- OC ~ NH- - NN mehy--oobtn--ycrbmae KO ,. 90t ISh N HN \ 1,4-Oloxane jH H-. + 2) Pd( H H DMSO, 100'C,04h (s 4 2 S) s) 2 me a

)

H N I 4 a-. spfole4zas44Inon-hlt)-3-meth N1 oxobuten-2-ytcarbamate (S)-2-benzyl 1-tert-butyl 4-oxopyrrolidine-1 ,2-dicarboxylate 5 To a stirring solution of a mixture of(S)-l-(ert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (2.85 g, 12.43 mmol) and potassium carbonate (4.33 g, 24.87 mmol) in anhydrous N,N dimethylformamide (60 mL) was added benzyl bromide (4.25 g, 24.87 mmol). The mixture was stirred at room temperature overnight. The resulting crude mixture was diluted with ethylacetate and the organic layer was washed with 10 10% sodium carbonate and brine. The organic layer was dried over sodium sulfate and volatile were removed in-vacuo. The residue was purified on normal phase column to yield 2.82 g (7 1%) of desired product. (S)-benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride 15 To a stirring solution of(S)-2-benzyl 1-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (2.82 g, 8.8 mmol) in anhydrous tetrahydrofuran (44 mL) was added 4N HC in ,4-dioxane (9.3 mL) at room temperature. The mixture was stirred for 18 hours at room temperature. The product was then three times with toluene on rotovap to dryness to remove all the excess acid and further 20 dried on a high vacuum overnight and used as is in the next step. Quantitative yield. (S)-benzyl 1 -((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopy rrolid ine-2 carboxylate 25 Following the procedure used to prepare compound (S)-benzyl -((S)-2 (methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate, except that (S) benzyl 4-oxopyrrolidine-2-carboxylate and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid were used instead of 2-{ 5-[4-(4,4,5,5-tetramethyl-[ ,3,2]dioxaborolan-2-yl)-phenyl]- 774 imidazol-2-yl}-pyrrolidine-I-carboxylic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)-l H imidazol-2-yi]-pyrrolidine- 1 -carboxylic acid tert-butyl ester. (S)-benzyl 7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7 5 azaspiro[4.4]nonane-8-carboxylate (S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2 carboxylate (2.45 g, 6.51 mmol) in a round bottom flask was dissolved in anhydrous toluene (200 mL) and p-toluene sulfonic acid monohydride (124 mg, 0.1 mmol) and ethylene glycol (808 mg, 13.02 mmol) were added and the mixture was refluxed for 18 hours, removing the 10 generated byproduct water with a Dean-Stark apparatus. The crude mixture was then diluted with ethyl acetate and washed, respectively, with 10% citric acid, saturated ammonium chloride, 10% sodium carbonate and finally with brine. The organic layers were combined and dried over sodium sulfate and concentrated down on rotovap. The crude residue was then purified on normal phase column chromatography with 5% MeOH/DCM. (2.3 g, 84%) 15 (S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.41 nonane 8-carboxylic acid (S)-benzyl 7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7 azaspiro[4.4]nonane-8-carboxylate (2.3 g, 5.47 mmol) was dissolved in ethyl alcohol (55 mL) 20 and under Argon charged with 10% Pd/C in a round bottom flask. The flask was then sealed with a rubber septa and the air was removed by vacuum and replaced with H2 from a balloon. This process repeated three times and the mixture was stirred under H2 atmosphere for 18 hours. The resulting mixture was then passed through a elite plug and concentrated down on rotovap to yield 1.76 g, 98% desired product. 25 (S)-2-(4-bromophenyl)-2-oxoethyl 7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl) 1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate Title compound was prepared according to the method employed to prepare (S)-2-(4 bromophenyl)-2-oxoethyl 5-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5 30 azaspi ro[2.4]heptane-6-carboxylate (2.07g, 74%) 775 Methyl (S)-i-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan 7-yl)-3-methyl-1 -oxobutan-2-ylcarbamate Title compound was prepared according to the method employed to prepare methyl (S)- 1 -((S)-6 (5-(4-bromophenyl)-1 H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-l -oxobutan-2 5 ylcarbamate (1.64 g, 82.2%) (S)-1 -((S)-6-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)- 1,4 dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-y)-1H-imidazol 2-yl)-5-azaspiro[2.4] heptan-5-yl)-3-methyl-1-oxobutan-2-yl-carbamic acid methyl ester: 10 Methyl (S)-I -((S)-8-(5-(4-bromophenyl)- I H-imidazol-2-yl)- 1,4-dioxa-7-azaspiro[4.4]nonan-7 yl)-3-methyl-l -oxobutan-2-ylcarbamate (200 mg, 0.39 mmol), bis(pinacolato)diboron (130 mg, 0.51 mmol), potassium acetate (116 mg, 1.18 mmol), and Pd(dppf)Cl 2 (29 mg, 0.039 mmol) were all weighed out in a glass pressure vessel and anhydrous 1,4-Dioxane (2 mL) was added. The mixture was bubbled with nitrogen gas for about 5 min. The vessel was then capped and 15 sealed and heated in an oil bath at 90*C overnight with continuous stirring. The reaction vessel was cooled down to room temperature and methyl (S)-I -((S)-6-(5-(6 bromonaphthalen-2-yl)-l H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-I -oxobutan-2 ylcarbamate (215 mg, 0.41 mmol), 2M K 2

CO

3 , and Pd(PPh3)4 (46 mg, 0.04 mmol) were all added along with 2 mL of DMSO and the mixture was bubbled with nitrogen gas for 5 minutes. 20 The vessel, again, was capped, sealed and placed in an oil bath at I 00 0 C for 4 hours. The resulting crude mixture was diluted with ethyl acetate and washed, respectively, with brine, 10% Na 2

CO

3 , 10% citric acid, saturated solution of NH 4 Cl, and brine. The organic layer was then dried over Na 2

SO

4 and the volatiles were removed on rotovap. The residue was first purified on normal phase chromatography and then on prep H PLC. Yield= 205 mg (60%). IH 25 NMR: 400 MHz, (CDC 3 ) 8 8.18 - 7.97 (m, I H), 7.83 - 7.6 (m, 8H), 7.82 - 7.22 (m, 3H), 5.47 5.34 (m, 4H),4.33 - 4.26 (m, I H), 4.08 - 4.03 (m, 4H), 3.94 - 3.89 (m, I H), 3.78 - 3.69 (m, 8H), 3.22 (brs, I H), 2.96 - 2.94 (m, I H), 2.49 - 2.46 (m, I H), 2.22 - 2.17 (m, I H), 1.99 (brs, I H), 1.08 - 1.04 (m, 2H), 0.94 - 0.79 (m, 12H), 0.71 (m, 4H). MS (ESI) mlz 873.79 [M + H]*. 30 776 Example GI H HO KHCO,, DMVF 0 E>BF. "- KOH ONTBrI rt, 18h 'HO_,_______O : NHBoc: + 015 Ph Prdn (S)-2-(tert- NHBoc: Dichioromethane butoxycarbonylamino)-4- (S)-benzyl 2-(tert- rt, 1 8h hydroxybutanoic acid butoxycarbonylamino) 4-hydroxybutanoate 0y NIS H yDrn FyF 0 30% TFAJOCM 00 Ph -35C 1h 0 Ph rt,l1h then rt, 18h NHBac: NHBoc: (S)-benzyt 4-(benzo~d][1 ,3Jdithiol- (S)-benzyl 2-(tert 2-yloxy)-2-(tert-butoxycarbony butoxycarbonytamino)-4 amino) butanoate (dlfluoromethoxy)butanoate F F 0 FF "1' ,r 0 1- MeO 1 ~CI FyF 0 H 2 , 10%Pd/C 0 Ph 0 -Y O, Ph tH-

NH-

2 TEA, DCM HN 0 EO TFA 0*C, then rt, 18h (S)-benzyl 2-amlnD-4 (difluoromethoxy)butanoate (S)-baenzyl 4-(difluoromethoxy)-2 (methoxycarbonylamino)butancate ~~-0 F yF 0 f-NH 0 H~ EDC.HCI, HOBt 0 N H 2 N M M HN ~"+\ N N P H - \ /O*C to rt, 4h HI HOI HCI HCI NM II (S)-4-{difluoromethoxy)-2- methyl (S)-1 -((S)-6-{5-(6-{4-(2-((1 R,3S.4S)-2 (methoxycarbonytamino) azabicyclo[2.2. ljheptan-3-y)-1 H-imidazal-5-yl)phenyl)naphthalen butanoic acid 2-yt)-l H-imldazol-2-y-Y5-azaspiro[2.4]heptan-5-yI-3-methyl-1 oxobutan-2-ylcarbamate tetrahydrochionde HHI (S)-1-((S)-6-(5-(6(4-(2-((1 R,3S,4S-2-((S)4-difluoromethoxy)-2 imidazol-5-yl)phenyl)naphthalen-2-y)-1 H-imidazol-2-yl)-5-azaspiro[2.4]heptan 5-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester 777 (S)-benzyl 2-(tert-butoxycarbonylamino)-4-hydroxybutanoate: N-t-Boc-L-homoserine (5.14 g, 23.45 mmol) and potassium bicarbonate (2.46g, 24.6 mmol) was weighed out in a round bottom flask and to it was added anhydrous N,N-dimethylformamide (100 mL) and benzyl bromide (4.2 g, 24.6 mmol). The mixture was stirred at room temperature 5 for 18 hours. The crude mixture was then diluted with ethyl acetate and washed, respectively, with brine, saturated NaHCO 3 and brine, and dried over Na 2

SO

4 . The organic layer was then concentrated down on rotovap and purified on normal phase column chromatography. Yield= 7.27 g (100%). 10 (S)-benzyl 4-(benzoId l[1,3]dithiol-2-yloxy)-2-(tert-butoxycarbonyl amino) butanoate: (S)-Benzyl 2-(tert-butoxycarbonylamino)-4-hydroxybutanoate (5.76 g, 18.62 mmol) and 1,3 benzodithiol-2-ylium tetrafluoroborate (4.69 g, 19.55 mmol) were dissolved in dichloromethane (186 mL) and pyridine (4.42 g, 55.86 mmol) was added at room temperature. The mixture was stirred overnight. Upon completion of the reaction, it was quenched with triethylamine (11.5 g, 15 113.5 mmol) and diluted with dichloromethane. The organic layer was then washed with saturated NaHCO 3 and brine. The organic layer was dried over MgSO4 and concentrated down in vacuo. The residue was then purified on normal phase column to obtain a clear oil. 7.6 g (88%). 20 (S)-Benzyl 2-(tert-butoxycarbonylamino)-4-(difluoromethoxy)butanoate: N-lodosuccinimide (783 mg, 3.48 mmol) was suspended in anhydrous dichloromethane (10 mL) and at -35'C was slowly added HF.pyridine (70% HF)(50 pl, 1.91 mmol) and the mixture was stirred for 5 - 10 min. At this temperature was then dropwise added a solution of (S)-benzyl 4 (benzo[d][1,3]dithiol-2-yloxy)-2-(tert-butoxycarbony amino) butanoate (400 mg, 0.87 mmol) in 25 dichloromethane (3 mL). The reaction content was then stirred for I hour at - 35*C and 1 hour at room temperature. To the reaction mixture was added ice-cold saturated NaHCO 3 and extracted with dichloromethane. The organic layer was washed with a saturated solution of sodium thiosulfate and washed with brine and dried over sodium sulfate. The volatiles were removed in vacuo and 30 the residue was purified on normal phase column. 161 mg (52%). (S)-benzyl 2-amino-4-(difluoromethoxy)butanoate: (S)-benzyl 2-(tert-butoxycarbonylamino)-4-(difluoromethoxy)butanoate (161 mg, 0.448 mmol) was stirred in 30% TFA in dichloromethane (5 mL) for Ih. The resulting mixture was 35 concentrated down on rotovap and redissolved and concentrated down with toluene three times, 778 and finally the residue was dried on high vacuum pump. The desired product was used as-is in the next step. (S)-benzyl 4-(difluoromethoxy)-2-(methoxycarbonylamino)butanoate: 5 (S)-Benzyl 2-amino-4-(difluoromethoxy)butanoate (116 mg, 0.448 mmol) was dissolved in anhydrous dichloromethane (2.5 mL) and cooled down to 0 0 C and TEA (181 mg, 1.79 mmol) and methylchloroformate (51 mg, 0.538 mmol) were added respectively. The mixture was stirred for 30 minutes and then it was stirred at room temperature overnight. The resulting product mixture was quenched with saturated NaHCO 3 and extracted with dichloromethane. The 10 organic layer was washed with saturated NH 4 CI solution and brine and dried over Na 2

SO

4 . The volatiles were removed in vacuo to afford 56 mg (40%) of desired product after column purification. (S)-4-(Difluoromethoxy)-2-(methoxycarbonylamino) butanoic acid: 15 (S)-Benzyl 4-(difluoromethoxy)-2-(methoxycarbonylamino)butanoate (56 mg, 0.176 mmol) was dissolved in ethyl alcohol (3.5 mL) and under Argon charged with 10% Pd/C (19 mg). The flask was sealed with a rubber septa and the air atmosphere was replaced with H 2 from a balloon by applying vacuum and then releasing H 2 and repeating this three times. The mixture was stirred for 4 hours at room temperature. Upon completion, the crude mixture was passed through a Elite 20 plug, concentrated down on rotovap and used as-is in the next step. 40 mg (100%). (S)-1-((S)-6-(5-(6-(4-(2-((1R,3S,4S)-2-((S)-4-(difluoromethoxy)-2 (methoxycarbonylamino)butanoyl)-2-azabicyclo[2.2.1 Iheptan-3-yl)-1 H-imidazol-5 yl)phenyl)naphthalen-2-yl)-1 H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1 25 oxobutan-2-ylcarbamic acid methyl ester: Methyl (S)- I -((S)-6-(5-(6-(4-(2-((1 R,3S,4S)-2-azabicyclo[2.2. I ]heptan-3-yl)- 1 H-imidazol-5 yl)phenyl)naphthalen-2-yl)- 1 H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl- 1 oxobutan-2-ylcarbamate tetrahydrochloride (66 mg, 0.096 mmol), (S)-4-(difluoromethoxy)-2 (methoxycarbonylamino) butanoic acid (20 mg, 0.088 mmol), N-(3-dimethylaminopropyl)-N' 30 ethylcarbodiimide hydrochloride (24 mg, and hydroxybenzotriazole hydrate (HOBt)( 17 mg, 0.125 mmol) were all weighed out in a flask and anhydrous N,N-dimethylformamide (1 mL) was added. The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(58 mg, 0.576 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on 35 reverse phase prep. HPLC. 37 mg, (43%). 'H-NMR: 400 MHz, (CD 3 0D) 6 8.08 (s, I H), 8.01 (d, 779 J= 16 Hz, I H), 7.86 - 7.66 (m, I OH), 7.38 (s, I H), 7.27 (s, I H), 7.03 (d, J= 8.4 Hz, I H), 6.58 (t, J= 75.6 Hz, I H), 5.32 (t, J= 7.2 Hz, I H), 4.70 (s, I H), 6.66 - 6.25 (m, I H), 4.51 (s, I H), 4.14 (m, I H), 3.98 - 3.78 (m, 4H), 3.63 (s, 6H), 3.50 - 3.46 (m, I H), 2.70 (brs, I H), 2.39 - 1.78 (m, 7H), 1.71 - 1.40 (m, 2H), 0.99 - 0.90 (m, 5H), 0.82 - 0.60 (m, 4H). MS (ESI) m/z 894.16 [M + H]*. 5 Example GJ F YF 0 O -I OH HN 0 EN\H t-O NH O FH H~~ H N0 (S)04-(difluormetoxy)-2 - E(S - (5 6( 4 - , 2( 2 t c no butanolc acid m O-C tor.I M-L 4h 0 \ F 15 Ttlecompundwas repredaccodin to he ethd empoydtoprpar 4(W-6(4-2(R3S)--((S)2-6(- N\ - H2S - l (meothoxyonjamrno-butnao4ylazabtnoyl) azbcyl[221]eta - -)- H-imidazol-5-yl)phernyl)naphthae-2-yl- Imdzl2y)5 s p 2Ir.]2.4]tptan-55y)l1)-xob3t-nmt2ythucarbamic acid me" er es + H]* ( HA HCI N HCI HNd 0 780 A7 cco2.2.]heptan2-i1)eTyt--oxobuta-2-ycarbbumate t.ehydroctdomide 10 (S)-4-(d ifluoromethoxy)- 1-((S)-6-(5-(6-(4-(2-((1 R,3S,4S)-2-((S)-2-(methoxycarbonylamino) 3-methylbutanoyl)-2-azabicycloj2.2.l1 heptan-3-yl)-1 H-imidazol-5-yl)phenyl)naphthalen-2 yl)-l H-imidazol-2-yl)-5-azaspiro j2.41 heptan-5-yI)-1 -oxobutan-2-ylcarbamic acid methyl ester 15 Title compound was prepared according to the method employed to prepare (S)-1I-((S)-6-(5-(6 (4-(2-((I R,3S, 4 S)-2-((S)-4-(difluoroinethoxy)-2-(methoxycarbonylamino)butanoyl)-2 azabicyclo[2.2. 1 ]heptan-3-yl)- 1 H-imidazol-5-yl)phenyl)naphthalen-2-yl)- I H-iinidazol-2-yl)-5 azaspiro[2.4]heptan-5-yl)-3-methyl- I-oxobutan-2-ylcarbamic acid methyl ester. IH-NMR: 400 MHz, (CD 3 OD) 6 8.13 (s, I H), 8.03 (in,I H), 7.91 - 7.85 (in, 2H), 7.80 - 7.71 (in, 6H), 7.42 (s, 20 1 H), 7.31 (s, I H), 6.97 (in, I H), 6.56 (t, J= 76 Hz, I H), 5.40 - 5.35 (in, I H), 4.83 (in, I H), 4.71 (s, I H), 4.56 (in, I H), 4.44 - 4.33 (in, I H), 3.93 (brs, 2H), 3.82 (in, 2H), 3.76 - 3.66 (mn, 5H), 3.51 - 3.42 (in, I N), 2.80 - 2.64 (in, I H), 2.32 - 2.25 (in, I H), 2.17 -2.12 (mn, 2H), 2.07 - 1.86 (in, 5H), 1 .73 - 1.57 (mn, 2H), 1.03 - 0.9 (in, 4H), 0.77 - 0.57 (in, 4H). MIS (ESI) m/z 894.00 [M + [1J+. 25 780 Example GK H H N NW a 1 methyl (S)-1-(S)--5-{4-bromopheilyl)IH- j B-B Imidazol-2-y9-1 ,4-dloxa-7-azaspiro[4.4]noflian- -0 '~ 7-yt)-3-metthyt-1-oxobutan-2-ylcarbamato Pd(dppf)C 2 -X H H K0A, B0*C I Sh N ~ = / ' N N + N N j\ a. 2) Pd(PPhi 3

)

4 H H 2M K 2 C0 3 H DMSO, 100-C. 4h 0 H H N (S)-tert-butyl 2--(4'-(2-(S)-7-((S)-2-(methoxycronylamino)-3 Nr rMthylbutanoy-1 ,4-diox&-7-azaq fr[4.4nonan-8-y)-1H-lmidazo-5 -Q \ -o y)bphenyyl-lH1mazt-2-l)pyrr~ldine-l-carboxytate yl~yrroldine-1-carboxylate 3%TFAIDCM NN 01 0- - H HH' 0 (S)-tert-butyl 2-(4-(2-(S-((S)-2-(Meuoixycnylamiln)-3- methYl (S)-3-mthyt-l-oxo-l-((S-85-(4-(2((S-pyrrvldn-2 medybutanoyl-dioxa-7-azaspir(4.4]anan-8-yl)-lHlmidazo-5 y9)-1H-1mkaok-y)biphny-4-y)-1Hmidazci-2-yl-1.4 yl)blphenyt-4-y)-1 H-mkdazol-2-yl)pyrrwlldlne-l-carboxytate dioxa-7-azaspi4.4non-7-y)butn-2-ytcarbamate 0 0 1,NH N 0 0'~ H L 6 0 0' 'NHHH NH N __ _ N0~ \ ~ ~ o 0 DMF, rt 0 methyl (S) 3-t-1-1(S)--(5-4-(2-((Spyretdi2-lIH- (S).1-(S).2-(4-(2(S)-7-((S).2-(metxycabylan~mo)-I-metylbubanoy)-.4 ImdaZo4--ylet-1H~da zcl-2yl .4.Iox-- diox-7-zas(r4.4]nonayl.1Hmc 51ay)hlhe -ylHmdazo-2. 5 azespiro[4.4)nnan-7-l"uta-2-lcvfmte Iproll y h--xtf -mbn acd methyl esta (S)- Tert-butyl 2-(5-(4'-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1 ,4 dioxa-7-azaspiro[4.41 nonan-8-yl)-1 H-imidazol-5-yl)biphenyl-4-yl)-1 H-imidazol-2 yl)pyrrol id ine- I -ca rboxy late: 10 Title compound was prepared according to the method employed to prepare (S)-1 -((S)-6-(5-(6 (4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)- I ,4-dioxa-7 azaspiro[4.4]nonan-8-yl)- I H-imidazol-5-yl)phenyl)naphthalen-2-yI)- I H-im idazol-2-yl)-5 azaspiro[2.4]heptan-5-yI)-3-methyl- I -oxobutan-2-yl-carbamic acid methyl ester, except instead of methyl (S)- I -((S)-6-(5-(6-bromonaphthalen-2-yl)- I H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5 15 yl)-3-methyl- I -oxobutan-2-ylcarbamate and methyl (S)- I -((S)-8-(5-(4-bromophenyl)-I H imidazol-2-yi)- I ,4-dioxa-7-azaspiro[4.4] nonan-7-yI)-3 -methyl- I -oxobutan-2-ylcarbamate, methyl (S)- I -((S)-8-(5-(4-bromophenyl)- I H-imidazol-2-yI)- I ,4-dioxa-7-azaspiro[4.4]nonan-7 yl)-3-methyl- I -oxobutan-2-ylcarbamate (600 mg, 1. .182 mmol) and (S)-tert-butyl 2-(5-(4 781 bromophenyl)-I H-imidazol-2-yl)pyrrolidine-1-carboxylate (510 mg, 1.3 mmol). The amount for all the other reagents were adjusted accordingly. 489 mg (56%). Methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5 5 yl)biphenyl-4-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2 ylcarbamate: Title compound was prepared according to the method employed to prepare (S)-benzyl 2-amino 4-(difluoromethoxy)butanoate, except it was freebased as follows: The volatiles were removed and the residue was taken up in EtOAc and washed with water to get the desired product in 10 aqueous layer. The organic layer was again washed with some more water and the aqueous layers were combined and basified with 50% NaOH solution to adjust the pH to 9. The desired product was then back-extracted into EtOAc layer and the aqueous layer was extracted three times with EtOAc. The organic phase was dried over Na 2

SO

4 and concentrated down on rotovap to afford 290 mg (69%) of desired compound as free base. 15 (S)-1-((S)-2-(5-(4'-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7 azaspiro[4.41 nonan-8-yl)-I H-imidazol-5-yl)biphenyl-4-yl)-1 H-imidazol-2-yl)pyrrolidin-I yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester: Title compound was prepared according to the method employed to prepare 1-{2-[5-(9-{2-[1-(2 20 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-6-methyl-6,7 dihydro-5H-dibenzo[c,e]azepin-3-yl)-I H-imidazol-2-yi]-pyrrolidine-I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester. 'H-NMR: 400 MHz, (CD 3 0D) 8 7.80 (d, J= 8.0 Hz, I H), 7.74 - 7.70 (m, 4H), 7.66 - 7.62 (m, 5H), 7.36 - 7.31 (m, 2H), 7.02 (t, J=7.6 Hz, I H), 5.24 (m, 2H), 4.25 (d, J= 7.2 Hz, I H), 4.17 (d, J= 7.6 Hz, I H), 4.11 - 3.85 (m, 8H), 3.66 (s, 5H), 3.50 25 3.45 (m, I H), 2.56 - 2.44 (m, 2H), 2.36 - 2.17 (m, 3H), 2.09 - 1.99 (m, 3H), 1.01 - 0.86 (m, 12H). MS (ESI) m/z 797.84 [M + H]*. 782 Example GL 0> O YF F 0 ($(-4dIuoromUoxy-2(mUfxycarbonyamlno)butomlc acid 0IIN HATU. DIPEA H 0 N OMF. rt N FF 0 ... CS) -diuorometthoxy)-1-(S)-2-(5 4'-(2-((S)7-((S)2 HH - (meoatyronaino-medbutaoo)1 .4-dcixa-7 N W asaao[44nan-8)-1Haz-5-y)blphny 4-I)-Hnilao4-2 O yl)pyrwdIdn-1.-1)-1-oxobutan-2-ykwafmic acid metho4 ester azDs-5-Yl)biPIhnO-1-ldMazo-2-)1)-1 ,4-doyxn azaapiroC4.4]nor.7.y4)butan .- yicarbamata (S)-4-(difluoromethoxy)-1 -((S)-2-(5-(4'-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3 5 methy lbu tanoyl)-1 ,4-d ioxa-7-azaspi ro14.41 non an -8-yl)- I H-im idazol-5-yl)biphenyl-4-yl)-1I H imidazol-2-yl)pyrrolidin-1 -yl)-1-oxobutan-2-ylcarbamic acid methyl ester: Title compound was prepared according to the method employed to preparel1-(2-[5-(9-12-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrol idin-2-yl]-3 H-imidazol-4-yl }-6-methyl-6,7 dihydro-5 H-dibenzo[c,e]azepin-3-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carbonyl)}-2-methyl 10 propyl)-carbamic acid methyl ester. IH-NMR: 400 MHz, (CD 3 OD) 8 7.69 (d, J= 8.0 Hz, I H), 7.61 - 7.57 (in, 4H), 7.56 - 7.52 (in, 5H), 7.28 - 7.24 (in, 2H), 6.46 (t, J=7.6 Hz, I H), 5.14 (in, 2H), 4.62 (in, I H), 4.24(m, I11 H), 3.64 (s, 5H), 2.54 - 2.43 (in, 2H), 2.36 - 1.81 (in, 8H), 099 - 0.84 (in, 6H). MS (ESI) m/z 849.76 [M4 + H]+. 15 Example GM H 0 . O Y N 'AUOH 0 (S>2-<mewbtioxyrboymIno-2-(tftmhydru-2H-pymn4 yf)acotlc acid 0r-0 HAkTI. OIPEA OIN HH DMF. rt NI N IN HH H -' ,~ 0 UoH pya-4)ethcabaric add "mtyl ester methyl (S)-mayl-l1xo1-((S8-5-4-(2{(S-py,'oidlr,-.)-lH Imlaocbphel)-yIH-lm daz-2-yl-t 4-dioxs-7 azaspro4.4Inonan-7-y1)butan-2-ylcarbamate 783 (S)-2-((S)-2-(5-(4'-(2-((S)-7-((S)-2-(Methoxycarbonylam ino)-3-methylbutanoyl)-1,4-d ioxa 7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1 yl)-2-oxo-1 -(tetrahyd ro-2H-pyran-4-yl)ethylcarbamic acid methyl ester: Title compound was prepared according to the method employed to preparel -{2-[5-(9-{2-[1-(2 5 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4-yl}-6-methyl-6,7 dihydro-5 H-dibenzo[c,e]azepin-3-yl)-I H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl propyl)-carbamic acid methyl ester. 1 H-NMR: 400 MHz, (CD 3 0D) 5 7.68 (d, J= 8.0 Hz, I H), 7.63 - 7.50 (m, 8H), 7.25 - 7.19 (m, 2H), 5.13 - 5.05 (m, 2H), 4.22 (d, J= 8.4 Hz, I H), 4.07 (d, J= 7.2 Hz, I H), 4.01 - 3.80 (m, I OH), 3.56 (s, 5H), 3.36 (s, I H), 3.29 - 3.18 (m, 3H), 2.46 - 2.34 10 (m, 2H), 2.27 - 2.07 (m, 3H), 1.99 - 1.87 (m, 4H), 1.54 - 1.19 (m, 5H), 0.85 - 0.76 (m, 6H). MS (ESI) m/z 839.84 [M + H]*. Example GN H H N N Br 11 H 'N_1 imidazol-2- )-1,4-dloxa-7-azasp-ro[4.4Bn-nan ) OO]' 0 O 0 7-yl)-3-methyl-1 -oxobutan-2-ylcarbamate Pd(dppf)Cl2 O NH H H KOAc, 90*C, 1Sh 0 N N 2 ) P ( P P h H H N 0/12M K 2 C0 3 H H 0 DMSO. 100'C. 4h 0 0 H H B N N (S)--((S)-(5-04-(2 (S)-7-((S)2-(meoxycarony mino)-3 N rnthiybutanoyI)-1 .4-dioxa-7-aaspiro[4.4]nonan-&4)-1H-midaz4-5 HN Oy)biphen 1-4-A)H-mldazl-2-yl14-dio xa-7-azspiro(4.4]nonan-7 H yi)-3methy--oxobutn-2-)lcarbamc acid mpethl ester 0 mirnkazo-2-V4)-1 ,4-dioxa-7-azaspiro[4.4]nonan 15 7-y')3-methyl-1-oxobutan-2-yicarbamate (S)-1-((S)-8-(5-(4'-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7 azaspiro[4.41 nonan-8-yl)-1 H-imidazol-5-yi)biphenyl-4-yl)-1 H-imidazol-2-yl)-1,4-dioxa-7 azaspiro[4.41 nonan-7-yI)-3-methyl-1 -oxobutan-2-ylcarbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (S)-tert-butyl 2-(5 20 (4'-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7 azaspiro[4.4]nonan-8-yl)- I H-imidazol-5-yl)biphenyl-4-yl)-I H-imidazol-2-yl)pyrrolidine- I carboxylate. 'H-NMR: 400 MHz, (CD 3 0D) 6 7.78 (d, J= 8.0 Hz, I H), 7.71 - 7.69 (m, 4H), 7.65 - 7.61 (m, 5 H), 5.23 (t, J= 8.4 Hz, 2H), 4.17 (d, J= 7.6 Hz, I H), 4.10 (m, 14H), 3.65 (s, 5H), 784 3.46 (s, I H), 2.65 (s, I H), 2.55 - 2.44 (m, 4H), 2.04 - 1.96 (m, 2H), 1.00 (d, J= 6.8 Hz, I H), 0.95 - 0.85 (m, 12H). MS (ESI) m/z 855.80 [M + H]*. Example GO 5 F YF O 0 OH HN O O0 0 F (S)-4-(dfluoromethoxy)-2- 04 NH F O (methoxyaronyian~no) I buthnoic add EDC.HCI, HOBt H O' NMM. DMF - - N O N \ 5 -~~~V~ n \t y - - - r a i H~~ -1 N Acdmeh-0se HC\ I\/ \ 0 (S)-1-((S)-6-(5-(6-(4-(2-((S)-1-((S)-4-(Difluoromethoxy)-2--2 ( t(hmooxxo iybonyatmIno)butano-yl)pyrr hedlny-2.yl) n t H-bhieaznl 0 ) H-imidazo -2-y ) azasp-ro52-4ahepzi 2-5ny1-xeUy1--o butan-2-yfcarbamiic H mtN dd mttyestr HCI HOJ HO HC4 thytl (S3 tu1- -1-((S5r(6e(4-(2-((S) odin-2-yi) h lH~mIdazo5 y)nmaale2-1Hldazol2-y4).5 azasplro[2.4Jhep5-l)butn-2-ycabamate trahydmdoh1do (S)-1-((S)-6-(5-(6-(4-(2-((S)--((S)-4-(Difluoromethoxy)-2 (methoxycarbonylamino)butanoyl)pyrrolidin-2-y)-H-imidazol-5-yl)phenyl)naphthalen-2 10 yl)-l H-imidazol-2-y1)-5-azaspiro2.41 heptan-5-yI)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (S)- I -((S)-6-(5-(6 (4-(2-((1 R,3S,4S)-2-((S)-4-(difluoroinethoxy)-2-(inethoxycarbonylamino)butanoyl)-2 azabicyclo[2.2. I ]heptan-3-yl)- I H-imidazol-5-yl)phenyl)naphthalen-2-y)- I H-imidazol-2-yl)-5 15 azaspiro[2.4]heptan-5-yl)-3-methyl-1 -oxobutan-2-ylcarbamic acid methyl ester. 'H-NMR: 400 MHz, (CD 3 0D) 6 8.00 - 7.98 (m, I H), 7.91 - 7.84 (m, 1 H), 7.78 - 7.55 (m, 8H), 7.37 - 7.20 (m, 2H), 6.49 (t, J= 75.6 Hz, I H), 5.25 - 5.20 (m, I H), 5.14 (m, I H), 4.57 (m, I H), 4.12 - 4.01 (m, I H), 3.89 - 3.81 (m, 4H), 3.75 - 3.66 (m, I H), 3.58 (s, 5H), 3.42 - 3.39 (m, I H), 2.33 - 1.77 (m, 9H), 0.94 - 0.83 (m, 6H), 0.72 - 0.52 (m, 4H). MS (ESI) m/z 867.86 [M + H]+. 20 785 Example GP and GQ -O Br methyl 4-(4 -O bromophenyl)bicyclo[2.2. Br AIC1 3 2joctane-1-carboxylate O bromobenzene methyl 4- 0*C, 30 min -o bromobicyclo[2.2.2]oct then rt, 18h ane-1-carboxylate O Br methyl 4-(3 bromophenyl)bicyclo[2.2. 2]octane-1-carboxylate 5 Mixture of methyl 4-(4-bromophenyl)bicyclo[2.2.2]octane-I-carboxylate and methyl 4-(3 bromophenyl)bicyclo[2.2.21 octane-I -carboxylate: A solution of methyl 4-bromobicyclo[2.2.2]octane-1 -carboxylate (1 g, 4.05 mmol) in anhydrous bromobenzene (6.75 mL) was added dropwise to an ice-water cooled suspension of aluminum chloride (2.16 g, 16.2 mmol) in bromobenzene (3.25 mL) under nitrogen. The resulting reaction 10 mixture was allowed to stir in the ice bath for 30 min and then at ambient temperature overnight. The mixture was cautiously poured onto ice (100 g) and concentrated HCI (3.3 mL) and the mixture was extracted into ether (4 x 100 mL). The ether extracts were combined, washed with brine (100 mL), separated, and dried over MgSO4 to leave a-brown solid. Purification by silica chromatography (5% ethyl acetate / hexane) gave a mixture of para- and meta substituted 15 derivatives. (970 mg, 74%). (For a more detailed procedure see J. Med. Chem., 2009, 52, 6, 1563). Br HO ~ Br methyl 4-(4- ]cae bromophenyl)bicyclo[2.2. 4-(-bromophenyl)bicycl[2.2.2]octane 2]octane-1-carboxylate 2.5M1-carboxylic acid 7 6HO Br P Br Br methyl 4-(3- 4(-rmpey~iyl[..]cae bromophenyl)bicyclo[2.2. 4-(3bromphe ylic cid222]cae 2]octa ne-I -carboxylate1-rbxlcai 786 Mixture of 4-(4-bromophenyl)bicyclo[2.2.2]octane- 1 -carboxylic acid and 4-(3 bromophenyl)bicyclo12.2.2]octane-1-carboxylic acid: A mixture of the title compounds were prepared according to the method employed to prepare (1-{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-imidazolidine-l-carbonyl}-2 5 methyl-propyl)-carbamic acid methyl ester. (638 mg, 94%) Brr H 1. Oxalyl Chloride B DMF (2 drops) 4-(4-bromophienyblclo[22.2]octane- 6h, r N, DCM 2-bromo-1-(4-(4-bronaphenyl)bicydo[2.2.2]octan 1-carboxylic acid 2. TMVSCHAN, Anh. DCM IMhnn O'C, 15 min then rt 2 days 3. HBr/AcOH HO EtOAc. O'c then rt,1h B O QBr Br 4-(3-bromophenyl)bicyclo[2.2.2]octane- 2-bromo-1-(4-(3 1-carboxylic acid bromopheny)bicyclo[2.2.2]octan-1-y)ethanone Mixture of 2-bromo-1-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)ethanone and 2-bromo 10 1-(4-(3-bromophenyl)bicyclo[2.2.2]octan-1-yl)ethanone: A mixture of the title compounds were prepared according to the method employed to prepare 2 Bromo-I-{4-[3-(2-bromo-acetyl)-phenoxy]-phenyl}-ethanone.(290 mg, 43%) Bra BrBr ,Boc 2-bromo-1-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)ethanone r 0 (S)-2-(2-(4-(4-bromopheny)bicyclo[2.2.2]octan + 1-yI)-2-oxoethyt) 1-tert-buty pyrrolidine-1,2 dicarboxylate Br 8 2-bromo-1-(4-(3-bromophenyl)bicydo[2.2.2]octan-1-yl)ethanone HO Br + (S)-2-(2-(4-(3-bromophenyl)bicyclo[2.2.2]octan Boc 1-yl)-2-oxoethyl) 1-tert-butyl pyrrolidine-1,2 N OH dicarboxylate N OH (S)-i-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid 15 787 Mixture of (S)-2-(2-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)-2-oxoethyl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate and (S)-2-(2-(4-(3-bromophenyl)bicyclo[2.2.2]octan-1-yl)-2 oxoethyl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate: A mixture of the title compounds were prepared according to the method employed to prepare 2 5 Aza-bicyclo[2.2.l ]heptane-2,3-dicarboxylic acid 3-(2-{9-[2-(] -tert-butoxycarbonyl-pyrrolidine 2-carbonyloxy)-acetyl]-5,7-dihydro-dibenzo[c,e]oxepin-3-yl}-2-oxo-ethyl) ester 2-tert-butyl ester. (365 mg, 94%). Boc Bo Br Br N N L. i H HH (S)-2-(2-(4-(4-bromophenyl)bicyclo[2.2.2]octan- (S)-tert-butyl 2-(5-(4-(4 1-yI)-2-oxoethy) 1-tert-buty pyrrolidine-1.2- bromaphenyl)bicyclo[2.2.2]octan-1-yl)-1H dicarboxylate NH40AC imidazol-2-yl)pyrrolidine-1 -carboxylate + Toluene, reflux Bac 18h N' H 0 0Boc, N Br Br H (S)-2-(2-(4-(3-bromophenyl)bicyclo[2.2.2]octan 1-yI)-2-oxoethyl) 1-tert-butyl pyrrolidine-1,2- (S)-tert-butyl 2-(5-(4-(3 dicarboxylate bromopheny)bicyclo[2.2.2]octan-1-y)-1

H

imidazol-2-yI)pyrrolidine-1-carboxylate 10 Mixture of (S)-tert-butyl 2-(5-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)-lH-imidazol-2 yl)pyrrolidine-1-carboxylate and (S)-tert-butyl 2-(5-(4-(3-bromophenyl)bicyclo[2.2.2]octan 1-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate: A mixture of the title compounds were prepared according to the method employed to prepare methyl (S)- I -((S)-6-(5-(4-bromophenyl)- I H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3 15 methyl-I -oxobutan-2-ylcarbamate. (298 mg, 85%). 788 N~ 4 \H N, N. N \\ - ' 1) N-9 B BocBr J) OB-B NN F B-B'Th H H (S)-tert-butyl 2-(5-(4-(4- O O(S)-tert-butyi 2-(5-(4-(4-(2-((S)-1-(tert bromopheny)bicyclo[2.2.2]octan-1-y)-1 H- butoxycarbonl)pyrroidin-2-y)-1H-imidazol imidazo$-2-yi)pyrralidine-1-carboxylata Pd(dPPf)C1 2 5-yibicyclo(2.2.2Jactan-1-yl)pheiy-H KOA, 90-C. 18h midazoI-2-y)pyrrolidine-l-carboxylate + 1,4-Dioxane 2) Pd(PPh 3

)

4 + 2M K 2 C0 3 N DMSO, 100C, 4h NH Br N HN\ N NH N (S)-tert-butyl 2-(5-(4-(3- H bromophenyl)bicyclo[2.2.2]octan-1-yl)-1 H- N H N imidazol-2-yl)pyrrolidine-1-carboxylate / + (S)-tert-butyl 2-5-(3-(4-(2-((S)-1-(tert butoxycarbonyl)pyrrolidin-2-y)-1H-imidazot 5-yl)bicyco[2.2.2]octan-1-yl)phenyl)-1H imidazol-2-yl)pyrrolidine-1-carboxyate H Br INH (S)-tert-butyl 2-(5-bromo-1H-imidazol 2-yl)pyrrolidine-1-carboxytate Mixture of (S)-tert-butyl 2-(5-(4-(4-(2-((S)-1-(tert-butoxycarbonyl)py rrolid in-2-yI)-1H imidazol-5-yl)bicyclo[2.2.2]octan-1-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 5 and (S)-tert-butyl 2-(5-(3-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yI)-1H-imidazol-5 yl)bicyclo[2.2.2]octan-I-yl)phenyl)-1 H-imidazol-2-yI)pyrrolidine-1 -carboxylate A mixture of the title compounds were prepared according to the method employed to prepare (S)-tert-butyl 2-(5-(4'-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-I,4-dioxa-7 azaspiro[4.4]nonan-8-yI)-1 H-imidazol-5-yI)biphenyl-4-yI)-I H-imidazol-2-yi)pyrrolidine-1 10 carboxylate. (287 mg, 73%). BH NN N (-7 H C H HCI HC H (S)-tert-btyt 2-(5-(4-(4-(2-((S)-1 -(ert-butoxycarbonlyl)pyrrlidin-2-y) yl)pyrrelldlne-1-carboxylate 2-yi-1H-Idazo-5-y lyd(.2ja 4N HCI/Dioxane - /N N NH N H N HHFHa Ho HCI HCJH4 H (S)-tert-buy 2-(5-(3-(4-(2-((S-1-(tert-butoxycarbonyl)pynrolidin-2HCI H 2-yl)-1H-midazo 5-yl)bicydo2.2.2octan-1 yl)phenyl)-1H- 2() din-Sp n azI--1)pyrroidne-1 -carboxyate 2-I H-irnldazo l -ido[2.2.2oct-lrrnl-1 Imidazoe tetrahydrochlortde 789 Mixture of 2-((S)-pyrrolidin-2-yl)-5-(4-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5 yl)bicyclo[2.2.2]octan-1-yl)phenyl)-1H-imidazole tetrahydrochloride and 2-((S)-pyrrolidin 2-yI)-5-(3-(4-(2-((S)-pyrrolidin-2-yI)-1H-imidazol-5-yl)bicyclo[2.2.2]octan-1-yI)phenyl)-1H imidazole tetrahydrochloride 5 A mixture of the title compounds were prepared according to the method employed to prepare (S)-benzyl 4-oxopyrrol idine-2-carboxylate hydrochloride. H H 0~ O OH NH H N O 00 N H )Ano cNo (S)-2-(methoycarbonytamino- N H 0 (S)-1-((S)-2-(5-(4-(4-(2-((S)-1-((S)-2-(methoxycarbonyamino-3 mntyvbtn~yrol -2-yl)-IHmldaol5 yl)phenyt)bicy }o[2.2.2octda-1- H.4mdazo4-2- dn)pyrrofdm-1.yl)-3 H NHmethylt-I-oxobjtan-2-*larbamlc acdd methyl ester H EDC.HC, HOBI HH HIH HC HIOC r.4h 0 NN H NC C C C - or,4 + N- HN N N\ N HH H C H HC (meto ycarbamicamthylbutenpy ldin mhb n pri 2-ydn2yH)1mHmazoz-5oyypn iyc2.22)octan-1-yl i d oi N-1 Hy)m-Ia3o--2-ymtphaiyn-1y-y-y3-cc mthyl-eoxbutar Ho Ht HCc H H 2-ylcarbamc acid meth ester (2-(( 1 Raii--y)3,4S-2((S)-yrid2-- dif oo eh x )--m tox cro ylmn5utn y)2 yclo[2.22 .. n-1-y])pheny) - 3deH--mida l Hye tetrHhydro- i z y5de 10 (S)-I-((S)-2-(5-(4-(4-(2-((S)-I -((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)pyrrolidin-2-yI)-1 H-imidazol-5-yl)phenyl)bicyclo2.2.2]octan- -yl)-l H imidazol-2-yl)pyrrolidin-1-yI)-3-methyl--oxobutan-2-ycarbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (S)- I -((S)-6-(5-(6 (4-(2-(( 1 R,3 S,4S)-2-((S)-4-(difluoromethoxy)-2-(metboxycarbonylam ino)butanoyl)-2 15 azabicyclo[2.2. 1 ]heptan-3-yI)- I H-imidazol-5-yl)phenyl)naphthalen-2-y1)- I H-imidazol-2-y1)-5 azaspiro[2.4]heptan-5-yl)-3-methyl- 1 -oxobutan-2-ylcarbamic acid methyl ester and separated from (S)-1I -((S)-2-(5-(4-(3-(2-((S)- I -((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)pyrrol idin-2-yl)- I H-imidazol-5-yl)phenyl)bicyclo[2.2.2]octan- I -yl)- I H imidazol-2-yl)pyrrolidin- I -yI)-3-methyl- I -oxobutan-2-ylcarbamic acid methyl ester by prep 20 HPLC. (41 mg, 23%) 'H-NMR: 400 MHz, (CD 3 0D) 8 7.63 (d, J= 8 Hz, I H), 7.55 (d, J= 8.4 Hz, 2H), 7.42 (s, I H), 7.34 (d, J= 8.4 Hz, 2H), 7.20 (s, I H), 7.01 - 6.95 (m, I H), 5.17 - 5.11 (m, 2H), 4.24 - 4.19 (m, 2H), 4.00 - 3.96 (m, 2H), 3.88 - 3.81 (m, 2H), 3.64 (s, 5H), 3.54 - 3.48 (m, I H), 2.34 - 1.96 (m, IOH), 1.91 (brs, 12H), 1.01 - 0.88 (m, 12H). MS (ESI) m/z 772.56 [M + H]*. 790 (S)- 1 -((S)-2-(5-(4-(3-(2-((S)- 1 -((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)bicyclo[2.2.2]octan-1-yl)-I H imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (S)-I-((S)-6-(5-(6 5 (4-(2-((1 R,3S,4S)-2-((S)-4-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)-2 azabicyclo[2.2. 1 ]heptan-3-yl)-1 H-imidazol-5-yl)phenyl)naphthalen-2-yl)- I H-imidazol-2-yl)-5 azaspiro[2.4]heptan-5-yl)-3-methyl-1 -oxobutan-2-ylcarbamic acid methyl ester and separated from (S)-I -((S)-2-(5-(4-(4-(2-((S)-I -((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)pyrrolidin-2-yl)- I H-imidazol-5-yl)phenyl)bicyclo[2.2.2]octan- l-yl)-l H 10 imidazol-2-yl)pyrrolidin- I -yl)-3-methyl- I -oxobutan-2-ylcarbamic acid methyl ester by prep HPLC. (54 mg, 30%). ' H-NMR: 400 MHz, (CD 3 0D) 8 7.66 (s, I H), 7.43 (d, J= 8 Hz, 2H), 7.28 - 7.21 (m, 3 H), 7.01 - 6.95 (m, I H), 5.17 - 5.11 (m, 2H), 4.25 - 4.20 (m, 2H), 3.99 - 3.94 (m, 2H), 3.89 - 3.81 (m, 2H), 3.64 (s, 5H), 3.57 - 3.45 (m, I H), 2.34 - 1.88 (m, 22H), 1.02 - 0.89 (m, 12H). MS (ESI) m/z 772.96 [M + H]*. 15 Example GR HO 10 0 N-? 0 O N.H HN 0 H aE H I HO B '~rN I N AD.CHB VY HCI HC HCI HCI H N O. 0 phen ddzpyrrolodln-2-y)lH zo.5-)phen )naphthren-2-y)-1H- (methxycartamino) ano- - 1pyrroidin-2-yl)-1H Imidazot-2-yl)pyrrolldin-1-yl)butan-2-ylcarbama te ahydroch ide Imidaza)ph a alen-2-y IH4 mdaz o-2-)pyrr Idin 1.yy)q h-3. l-oxo1,uten-2-yiArtan*i add rmthlyl sti 20 (S)-1 -((S)-2-(5-(6-(4-(2-((2S,5R)-1 -((S)-2-(methoxycarbonylamino)propanoyl)-5 phenylpyrrolidin-2-yI)-1H-imidazol-5-yl)phenyl)naphthalen-2-y)-1H-imidazol-2 yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester Title compound was prepared according to the method employed to prepare (S)-I -((S)-6-(5-(6 (4-(2-((I R,3S,4S)-2-((S)-4-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)-2 25 azabicyclo[2.2.1 ]heptan-3-yl)- I H-imidazol-5-yl)phenyl)naphthalen-2-yl)- I H-imidazol-2-yl)-5 azaspiro[2.4]heptan-5-yI)-3-methyl- I -oxobutan-2-ylcarbamic acid methyl ester. 1 H-NMR: 400 MHz, (CD 3 0D) 5 8.13 (s, I H), 8.08 (s, I H), 7.94 - 7.77 (m, 8H), 7.50 - 7.42 (m, 3H), 7.36 - 7.25 (m, 2H), 7.17 - 6.99 (m, 2H), 5.49 - 5.36 (m, 2H), 5.23 (d, J= 5.2 Hz, I H), 4.27 - 4.21 (m, 2H), 4.04 - 3.99 (m, I HN, 3.93 - 3.87 (m, I H), 3.70 (s, I H), 3.66 (s, 4H), 2.68 791 2.48 (m, 2H), 2.39 - 2.20 (m, 4H), 2.11 - 2.03 (m, 2H), 1.39 (d, J= 6.8 Hz, I H), 1.04 - 0.96 (m, 4H), 0.93 (d, J= 6.8 Hz, 2H), 0.70 (d, J= 6.8 Hz, 2H). MS (ESI) m/z 837.92 [M + H]*. Example GS 0 C ON -0 - HO 0 OH TEA, DMAP N- 0 Hydroxy-phenyl-acetic acid methyl ester Dimethylcarbamoyloxy-phenyl- Dimethylcarbamoyloxy acetic acid methyl ester phenyl-acetic acid / ~NH 0~ oc HC COMU 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-pheny]-1 H imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester O 0 / N N H N y\/ N N 0~ 0_ / [1-(2-{5-[6-(4-(2-[1-(2-Dimethylcarbamoyloxy-2-phenyl-acetyl)-pyrrolidin 2-yl]-3H-imidazol-4-yl)-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl} 5 pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester Dimethylcarbamoyloxy-phenyl-acetic acid: To hydroxyl-phenyl-acetic acid methyl ester (500 mg) in THF (10 mL) were added dimethylcarbamoyl chloride (304 pl), TEA (503 pl), and DMAP (37 mg). After stirring for overnight at room temperature, the mixture was taken up in 10 ethyl acetate (150 mL). The organic phase was washed with I N HCI (I x 100 mL) and saturated sodium bicarbonate (1 x 100 mL), and dried over sodium sulfate. After the solvent was removed, the resulting solid was dissolved in THF (6 mL). To the solution was added 2 M LiOH (3 mL). After stirring for 90 min. at room temperature, the reaction mixture was acidified with 2 N HCI (3.2 mL). The mixture was extracted with ethyl acetate (50 mL). The organic phase was 15 dried over sodium sulfate. The solvent was removed under reduced pressure to provide dimethylcarbamoyloxy-phenyl-acetic acid (561 mg, 83 %) as an off-white solid. [1-(2-{5-16-(4-{2-[1-(2-Dimethylcarbamoyloxy-2-phenyl-acetyl)-pyrrolidin-2-y]-3H imidazol-4-yl)-naphthalen-2-yl]-lH-imidazol-2-yl}-pyrrolidine-l-carbonyl)-2-methyl 20 propyll-carbamic acid methyl ester: To 2-{5-[4-(6-{2-[l-(2-Methoxycarbonylamino-3 792 methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-naphthalen-2-yl]-I H-imidazol-2-yl} pyrrolidine-1 -carboxylic acid tert-butyl ester (40 mg) in methanol (0.5 mL) was added 4N HCI in dioxanes (0.5 mL). The mixture was stirred for 2 hours then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (1 mL) was added DIEA (14 pl). After all 5 material dissolved, dimethylcarbamoyloxy-phenyl-acetic acid (12 mg) and (1-cyano-2-ethoxy-2 oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU, 23 mg) were added. After stirring for 30 min. the reaction was purified by a preparative HPLC (10-60% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product (22 mg, 48%). 'H NMR (MeOH-d4, 400 MHz) 8: 8.22-8.05 (m, 2H), 7.92-7.69 (m, 9H), 7.56-7.44 (m, 6H), 6.08 10 5.92 (d, I H), 5.27-5.20 (m, 2H), 4.28-4.24 (m, I H), 4.13-4.00 (m, 2H), 3.90-3.68 (m, 2H), 3.66 (s, 3H), 3.45-3.38 (m, 2H), 2.92-2.90 (m, 6H), 2.47-1.96 (m, 10H), 1.05-0.91 (m, 6H); MS (ESI) m/z 837.3 [M + H]*. Example GT 15 -0OC1 AN -O HO OO ' O O O OH TEA, DMAP N-

N

Hydroxy-phenyl-acetic acid methyl ester Dimethylcarbamoyloxy-phenyl- Dimethylcarbamoyloxy acetic acid methyl ester phenyl-acetic acid o \N/,0 N\ H : COMU OO SN oc HCC 2-{5-[4-(6-(2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H imidazol-2-yl}-pyrrolidine-1 -carboxylic acid tert-buty ester O O NH

-

H N-. / N [1-(2-{5-[6-(4-{2-[1-(2-Dimethylcarbamoyloxy-2-phenyl-aetyl)-pyrrolidin 2-yl]-3H-imidazol-4-yl)-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl} pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester [1-(2-{5-[6-(4-{2-1l-(2-Dimethylcarbamoyloxy-2-phenyl-acetyl)-pyrrolidin-2-ylI]-3H imidazol-4-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl 20 propyll-carbamic acid methyl ester: Title compound was prepared according to the method 793 employed to [1-(2-{5-[6-(4-{2-[I-(2-Dimethylcarbamoyloxy-2-phenyl-acetyl)-pyrrolidin-2-y] 3H-imidazol-4-yl)-naphthalen-2-yl]- IH-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl propyl]-carbamic acid methyl ester (Example 6), (20 mg, 43%). 1 H NMR (MeOH-d4, 400 M Hz) 5: 8.21-8.04 (m, 2H), 7.93-7.89 (m, 3H), 7.81-7.68 (m, 5H), 7.53-7.41 (m, 7H), 6.10-5.78 (d, 5 1 H), 5.28-5.21 (m, 2H), 4.28-4.26 (m, 1 H), 4.03-3.81 (m, 4H), 3.66 (s, 3H), 3.62-3.45 (m, 2H), 2.92-2.85 (m, 6H), 2.42-1.90 (m, 10 H), 1.01-0.89 (m, 6H); MS (ESI) m/z 837.5 [M + H]*. Example GU 0 ON H0 H Pd(PPh 3

)

4 , +\ BB r b N Bc DME/H 2 0 [2-Methyl-1 -(6-{5-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H- 2-[5-(6-Bromo-naphthalen-2-y)-1 H imidazol-2-yl}-5-aza-spiro[2.4]heptane-5- imidazol-2-yl]-4-cyano-pyrrolidine-1 carbonyl)-propyl]-carbamic acid methyl ester carboxylic acid tert-butyl ester 0 0 Jk N'HCN O N. ,CN ON \ / \ / HCI, dioxane/DCM N N -N ^ H

-

N Boc 4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl) naphthalen-2-y]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic O acid tert-butyl ester O N.H 3HCI ,CN

&HCO

2 Me - H 2-Methoxycarbonylamino N N - \ / N N 3-methyl-butyric acid - N H EDC-HCI, HOBt, NMM DMF (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen 2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride 0 H 0 N. N N O NO [1 -(6-{5-[4-(6-{2-[4-Cyano-1 -(2-methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yi]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl}-5 aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 794 4-Cyano-2-15-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4] hept-6-yl]-3H-imidazol-4-yI)-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl} pyrrolidine-1-carboxylic acid tert-butyl ester: [2-Methyl-I-(6-{5-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl) 5 propyl]-carbamic acid methyl ester (997 mg, 1.91 mmol), 2-[5-(6-Bromo-naphthalen-2-yl)-I H imidazol-2-yl]-4-cyano-pyrrolidine-l-carboxylic acid lerl-butyl ester, Pd(PPh 3

)

4 (184 mg, 0.159 mmol), and K 2

CO

3 (2 M in H 2 0, 1.9 mL, 3.8 mmol) were combined in 1,2-dimethoxyethane (16 mL). The reaction mixture was degassed with bubbling N 2 for 10 minutes then heated to reflux for 3.5 h. After heating, the reaction mixture was cooled to RT, diluted with EtOAc and washed 10 with H 2 0 and brine. The organic phase was dried over MgSO 4 , then filtered and concentrated. The resulting residue was purified with silica column chromatography 0% to 100% (10% MeOH/DCM)/EtOAc to afford the title compound (641 mg, 51%). (1-{6-15-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl) 15 1 H-imidazol-2-yli]-5-aza-spiro[2.41 heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride: 4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3 methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H imidazol-2-yl}-pyrrolidine-l-carboxylic acid tert-butyl ester (639 mg, 0.816 mmol) was dissolved in DCM (8 mL) and 4.0 M HCI in dioxane (2 mL, 8 mmol) was added. After stirring 20 for 37 min, the solid was filtered off and rinsed with EtOAc, affording the title compound (597 mg, 92%). [1-(6-{5-[4-(6-{2-[4-Cyano--(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yI}-5-aza-spiro[2.4|heptane-5 25 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: 2-Methoxycarbonylamino-3 methyl-butyric acid (40 mg, 0.227 mmol) EDC-HCI (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (I -{6-[5-(4-{6-[2-(4 Cyano-pyrrol idin-2-yl)-3 H -im idazol-4-yl]-naphthalen-2-yl }-phenyl)- I H-imidazol-2-yl]-5-aza spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride 30 (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0 "C and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO 3 , then 1:1 brine/5M NaOH. The organic phase was dried over MgSO 4 , then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (18 mg, 11%). MS (ESI) m/z 840 [M + H]*. 35 795 Example GV 0 O HO) O) N'H 3HCI QN

NHCO

2 Me -H F 7 2-Methoxycarbonylamino N N NN _)butyric acid N H EDC-HCI, HOBt, NMM DMF (1 -{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen 2-yl}-phenyl)-1 H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride 0 0' N' H O N H H N._,C H. O' NO H' Nhf T N 0 [1-(6-{5-[4-(6-{2-[4-Cyano-1-(2-methoxycarbonylamino-butyryl)-pyrrolidin-2-yl]-3H-imidazol 4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2 methyl-propyl]-carbamic acid methyl ester 5 1 -(6-{5-[4-(6-{2-[4-Cyano-1-(2-methoxycarbonylamino-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yl}-naphthalen-2-yl)-phenyll-1 H-imidazol-2-yI)-5-aza-spiro[2.4]heptane-5 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: 2-Methoxycarbonylamino-butyric acid (37 mg, 0.227 mmol) EDC-HCI (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were 10 combined in DMF (2 mL) and stirred for 20 min at RT. (I-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin 2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)- I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane 5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0 'C and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5h, the reaction mixture was warmed to RT. 30 min later, the mixture 15 was diluted with EtOAc and washed with NaHCO 3 , then 1:1 brine/5M NaOH. The organic phase was dried over MgSO 4 , then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (85 mg, 54%). MS (ESI) m/z 826 [M + H]*. 796 Example GW 0 HO O N.H 3HCI CN

NHCO

2 Me - H 2-Methoxycarbonylamino-3,3 N - \ / N' dimethyl-butyric acid - H N H EDC-HCI, HOBt, NMM DMF (1 -{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen 2-yl}-phenyl)-1 H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride 0 O I N.H ,CN H 0 ON H N Y 0 [1-(4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl ester 5 [1-(4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.41hept-6-yll-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl ester: 2 Methoxycarbonylamino-3,3-dimethyl-butyric acid (37 mg, 0.227 mmol) EDC-HCl (44 mg, 10 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yi)-3H-imidazol-4-yl]-naphthalen-2-yl} phenyl)-I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0 'C and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5h, the reaction 15 mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO 3 , then 1:1 brine/5M NaOH. The organic phase was dried over MgSO 4 , then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (77 mg, 48%). MS (ESI) m/z 855 [M + H]+. 20 797 Example GX / \bis(pin nacolato)di boron, BocN- \ Br Pd(dPpf 2 C1 2 , KOAc N N --- __ _ NC 2-[5-(4-Bromo-phenyl)-1 H-imidazol 2-yI]-4-cyano-pyrrolidine-1 carboxylic acid tert-butyl ester BocN-\ / \ + r\ \ 1 NJ+ /b,_\, N NHOM Nk 0 NC' 4-Cyano-2-{5-[4-(4,4,5, 5-tetramethyl- (1 -{6-[5-(6-Bromo-naphthalen-2-y)-1 H-imidazol [1 ,3,2]dioxaborolan-2-y)-phenyl]-1 H-imidazol-2- 2-yI]-5-aza-spiro[2 .4]heptane-5-carbony}-2 yl}-pyrrolidine-1-carboxylic acid tert-butyl ester methyl-propyl)-carbamic acid methyl ester Pd(PPh 3

)

4 , BocN H / \ - HCI,

K

2 C0 3 IN NJ-N - \ N-11/j dioxane/DCM..

DMEIH

2 O \C 04-"'N HCOU 2 me NC' 4-Cyano-2-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl) 5-aza-spiro[2.4]hept-6-y]-3H-imidazol-4-yl}-naphthalen-2-y)-phenyl] 1 H-imidazol-2-yI}-pyrrolidine-1 -carboxylic acid tert-butyl ester 0 3HCI NJN - N ~ NHCO 2 Me I'- No NHCO 2 Me 2-Methoxycarbonylamino oz butyric acid NC' EDC-HCI, HOBt, NMM (I -(6-[5-(6-{4-[2-(4-Cyano-pyrrolidin-2-yI)-3H-imidazol-4-ylI-phenyl}- DMF naphthalen-2-y)-1 H-imidazol-2-yI]-5-aza-spiro[2.4]heptane-5-carbonyl-2 methyl-propyl)-carbamic acid methyl ester tris-hydrochionide 0 0 N! NN /Y\ \S N 1 N Nc N O Nd H N 0 (1 -(6-{5-[6-(4-{2-[4-Cyano-1 -(2-methoxycarbonylamino-butyryl)-pyrrolidin-2-y] 3H-imidazol-4-yI}-phenyl)-naphthalen-2-yI]-l1H-imidazol-2-yl}-5-aza spiro[2.4Jheptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 4-Cyano-2-{5-14-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenyl 1-1H-imidazol-2-yl} pyrrolidine-l -carboxylic acid tert-butyl ester: 2-[5-(4-Bromno-phenyl)- I H-imidazol-2-yi]-4 cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (2.895 g, 6.94 mmol), bis(pinacolato)diboron (2.64 g, 10.41 mmol), Pd(dppf) 2

CI

2 (254 mg, 0.347 mnmol) and KOAc 798 (2.04 g, 20.82 mmol) were combined in dioxane and degassed for 12 min with bubbling N 2 . The reaction mixture was then stirred at 90 'C for 18h, cooled to RT and diluted with EtOAc. The organic mixture was washed with saturated aqueous NaHCO 3 and brine before being dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column 5 chromatography (50% to 100% EtOAc/Hex) to provide the title compound (1.56 g, 48%). 4-Cyano-2-{5-14-(6-(2-15-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-y)-phenyl]-1 H-imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester: 4-Cyano-2-{5-[4-(4,4,5,5-tetramethyl 10 [1,3,2]dioxaborolan-2-yl)-phenyl]-lH-imidazol-2-yl}-pyrrolidine-I-carboxylic acid tert-butyl ester (0.990 g, 2.13 mmol), (1-{6-[5-(6-Bromo-naphthalen-2-yl)- IH-imidazol-2-yl]-5-aza spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.007 g, 1.92 mmol), Pd(PPh 3

)

4 (222 mg, 0.192 mmol) and K 2

CO

3 (2.0 M in H 2 0, 2.1 mL, 4.2 mmol) were combined in 1,2-dimethoxymethane. The mixture was degassed for 10 min with bubbling N 2 15 then heated to reflux for 4h then cooled. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO 3 and brine before being dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (EtOAc, then 2% MeOH/DCM, then 4% MeOH/DCM) to provide the title compound (1.028 g, 68%). 20 (1-{6-[5-(6-{4-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl) 1H-imidazol-2-yli-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester tris-hydrochloride: A solution of 4-Cyano-2-(5-[4-(6-{2-[5-(2 methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-y]-3H-imidazol-4-yl} naphthalen-2-yI)-phenyl]- I H-imidazol-2-yl}-pyrrolidine-l-carboxylic acid tert-butyl ester 25 (l.000g, 1.28 mmol) in DCM (16 mL) was treated with HCI (4.0 M in dioxane, 3.2 mL, 12.8 mmol). After 2.5 h, the solid was filtered off and rinsed with EtOAc to provide the title compound (1.004 g, 99%). [1-(6-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-butyryl)-pyrrolidin-2-yl]-3H 30 imidazol-4-yl)-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yIl-5-aza-spiro2.4]heptane-5 carbonyl)-2-methyl-propyl] -carbamic acid methyl ester: 2-2-Methoxycarbonylamino-butyric acid (37 mg, 0.227 mmol) EDC-HCI (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1 -{6-[5-(6-{4-[2-(4-Cyano-pyrrolidin 2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane 35 5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester tris-hydrochloride (150 mg, 0.189 mg) 799 was added, the reaction mixture was cooled to 0 'C and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO 3 , then brine. The organic phase was dried over MgSO 4 , then filtered and concentrated. The resulting residue was purified by HPLC to 5 afford the title compound (78 mg, 49%). MS (ESI) m/z 826 [M + H]*. Example GY 3HCI HO N)L.N - ~ \ N<>.JNHCO 2 Me

NHCO

2 Me 2-Methoxycarbonylamino NC H 3,3-dimethyl-butyric acid EDC-HCI, HOBt, NMM (1-{6-[5-(6-{4-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}- DMF naphthalen-2-y)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester tris-hydrochloride 0 H 0 N. 0 N H O'lr Nd H' 0Os 0 [1 -(4-Cyano-2-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yI]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2 yl}-pyrrolidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl ester 10 11 -(4-Cyano-2-{5-14-(6-{2-15-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.41hept-6-yli-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl-IH-imidazol-2-yl} pyrrolidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl ester: 2 Methoxycarbonylamino-3,3-dimethyl-butyric acid (43 mg, 0.227 mmol) EDC-HCl (44 mg, 15 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (I -{6-[5-(6-{4-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl } -naphthalen 2-yl)- I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl} -2-methyl-propyl)-carbamic acid methyl ester tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0 'C and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 20, the reaction mixture 20 was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHC0 3 , then brine. The organic phase was dried over MgSO 4 , then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (73 mg, 45%). MS (ESI) m/z 854 [M + H]*. 800 Example GZ Mel, AgOTf, BocO BocO BH 3 -SMe 2 , BocO 2,6-di-tert-butyl- * OMe NaOH, H202 OMe 4-methylpyridine N OMe THF HO DCM MeO 4-Methylene-pyrrolidine- 4-Hydroxymethyl-pyrrolidine- 4-Methoxymethyl-pyrrolidine 1,2-dicarboxylic acid 1 -tert- 1,2-dicarboxylic acid 1-tef- 1,2-dicarboxylic acid 1-tedt butyl ester 2-methyl ester butyl ester 2-methyl ester butyl ester 2-methyl ester Boc BocO0 0 N o Bo Br NHOcN Br 1. LiOH, H 2 0/MeOH O0NH40Ac ( N 2. 2,4'-dibromoacetophenone, MeOPh MeO triethylamine, MeCN 4-Methoxymethyl-pyrrolidine-1,2- 2-[5-(4-Bromo-phenyl)-1H-imidazol dicarboxylic acid 2-[2-(4-bromo-phenyl)- 2-yl]-4-methoxymethyl-pyrrolidine 2-oxo-ethyl] ester 1-tert-butyl ester 1-carboxylic acid tert-butyl ester 0 O N.H bis(pinnacolato)diboron, 1. HCI, dioxane/DCM . O Pd(dppf) 2 Cl 2 , KOAc 2. HATU, DIPEA, DMF N Br O N OH MeO-'

NHCO

2 Me (1-{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl] 2-Methoxycarbonylamino-3- 4-methoxymethyl-pyrrolidine-1-carbonyl}-2 methyl-butyric acid methyl-propyl)-carbamic acid methyl ester 0 0 N.HH BN +Br NN2LNN 0t

-

H s MeO-" 0 [1 -(4-Methoxymethyl-2-{5-[4-(4,4,5,5-tetramethyl- (1 -{6-[5-(6-Bromo-naphthalen-2-yl)-1 H-imidazol [1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine- 2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester methyl-propyl)-carbamic acid methyl ester 0 0 N.H Pd(PPh3)4, 0

H

2 0,DME NJ-N/\ MeO-' H 0, 0 [1 -(2-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl}-4 methoxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: 4 Methylene-pyrrolidine-1,2-dicarboxylic acid l -tert-butyl ester 2-methyl ester (4.48 g, 19.71 mmol) was dissolved in THF (100 mL) and the stirred solution was cooled to 0 'C. Borane dimethylsulfide complex (1.9 mL, 19.7 mmol) was added and the reaction mixture was allowed to warm to RT o/n. After 16h, water was added dropwise until no bubbling was observed. The 801 stirred mixture was then cooled to 0 'C. Aqueous NaOH (5M in H20, 5.3 mL, 26.6 mmol), then H202 (30 wt% in H 2 0, 6.0 mL, 58.5 mmol) were added dropwise. The reaction was then warmed to 50 "C. After 30 min, the mixture was diluted with ethyl ether and washed with water and brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The crude 5 residue was purified by silica column chromatography (25% to 75% EtOAc/Hex) to afford the title compound (2.08 g, 4 1%). 4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: 4 Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (861 mg, 3.32 10 mmol) was dissolved in DCM (6.6 mL) then 2,6-di-tert-butyl-4-methylpyridine (1.023 g, 4.98 mmol) and AgOTf (938 mg, 3.65 mmol) were added. The reaction mixture was cooled to 0 "C and iodomethane (0.25 mL, 3.98 mmol) was added. After 4 min, the reaction mixture was diluted with DCM and it was filtered over elite. The filtrate was concentrated to a residue which was dissolved in diethyl ether. The organic solution was washed with 10% HCI and brine, then 15 dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 80% EtOAc/Hex) to afford the title compound (479 mg, 53%). 4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-12-(4-bromo-phenyl)-2-oxo-ethyl] ester 1-tert-butyl ester: 4-Methoxymethyl-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester 20 2-methyl ester (461 mg, 1.68 mmol) was dissolved in MeOH (17 mL) and LiOH (1 M in H 2 0, 8.5 mL, 8.5 mmol) was added. After stirring at RT for Sh, the MeOH was removed under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with I M HCI (9 mL, 9 mmol) and extracted with DCM (3x). The combined organics were dried over MgSO 4 , filtered and concentrated. The residue was dissolved in MeCN (17 mL) and treated 25 with 2,4'-dibromoacetophenone (514 mg, 1.85 mmol), and triethylamine (0.258 mL, 1.85 mmol). After stirring for 2 h, the solvent was removed and the solid was suspended in EtOAc. The organic layer was washed with saturated aqueous NaHCO 3 and brine then dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (15% to 35% EtOAc/Hex) to afford the title compound (746 mg, 97%). 30 2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester: 4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2 oxo-ethyl] ester I -tert-butyl ester (746 mg, 1.63 mmol) was dissolved in PhMe (16 mL) and treated with NH40Ac (2.52 g, 32.7 mmol). The stirred mixture was refluxed for 19 h then 35 cooled to RT and diluted with EtOAc. The organic phase was washed with saturated aqueous 802 NaHCO 3 and brine then dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (35% to 65% EtOAc/Hex) to afford the title compound (334 mg, 47%). 5 (1-{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-methoxymethyl-pyrrolidine-1-carbonyl)-2 methyl-propyl)-carbamic acid methyl ester: 2-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-4 methoxymethyl-pyrrolidine-I-carboxylic acid tert-butyl ester (334 mg, 0.765 mmol) was dissolved in DCM (4 mL) and treated with HCI (4.0M in dioxane, 0.960 mL, 3.83 mmol). After 2.5 h, the solution was concentrated and the residue was treated with 2-Methoxycarbonylamino 10 3-methyl-butyric acid (146 mg, 0.832 mmol) and HATU (316 mg, 0.832 mmol). The solids were suspended in DMF (4 mL) and the reaction mixture was cooled to 0 *C before triethylamine (0.67 mL, 3.83 mmol) was added in a dropwise fashion. After 30 min, the mixture was warmed to RT. After another I h, it was diluted with EtOAc and washed with saturated aqueous NaHCO 3 and brine. Then it was dried over MgSO 4 , filtered and concentrated. The crude residue 15 was purified by silica column chromatography (80% to 100% EtOAc/Hex) to afford the title compound (369 mg, 98%). [1-(4-Methoxymethyl-2-{5-14-(4,4,5,5-tetramethyl-11,3,2]dioxaborolan-2-yl)-phenyll-1H imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: (1 20 {2-[5-(4-Bromo-phenyl)-l H-imidazol-2-yl]-4-methoxymethyl-pyrrolidine-I -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (348 mg, 0.705 mmol), bis(pinacolato)diboron (269 mg, 1.06 mmol), Pd(dppf) 2 Cl 2 (52 mg, 0.0705 mmol) and KOAc (208 g, 2.12 mmol) were combined in dioxane and degassed for 12 min with bubbling N 2 . The reaction mixture was then stirred at 90 'C for 18h, cooled to RT and diluted with EtOAc. The organic mixture was washed 25 with saturated aqueous NaHCO 3 and brine before being dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (80% to 100% EtOAc/Hex) to provide the title compound (297 mg, 78%). [1-(2-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 30 ylI-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methoxymethyl pyrrolidine-1-carbonyl)-2-methyl-propyll-carbamic acid methyl ester: [1 -(4 Methoxymethyl-2-{5-[4-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2 yl}-pyrrolidine-I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (132 mg, 0.244 mmol), (I -{6-[5-(6-Bromo-naphthalen-2-yl)- I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5 35 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (154 mg, 0.293 mmol) Pd(PPh 3

)

4 (28 803 mg, 0.0244 mmol) and K 2

CO

3 (2M in H 2 0, 0.488 mL, 0.976 mmol) were combined in 1,2 dimethoxyethane (5 mL). The mixture was degassed with bubbling N 2 for 12 min then heated to 85 *C for 4 h. After cooling to RT, the reaction mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over MgSO 4 , filtered and concentrated. The 5 crude residue was purified by HPLC to provide the title compound (118 mg, 56%). MS (ESI) m/z 859 [M + H]*. Example HA SEM N \ + B H ~N )-N Br /\ - N Boc 2-[4-Ethynyl-1 -(2-trimethylsilanyl- 2-[5-(6-Bromo-naphthalen-2-yI) ethoxymethyl)-1 H-imidazol-2-yl]-pyrrolidine- 1 H-imidazol-2-yl]-pyrrolidine-1 1-carboxylic acid tert-butyl ester carboxylic acid tert-butyl ester 1. Pd(PPh 3

)

4 , Cul Et 3 N, DMF 2. TFA, DCM MeO 2 CHN N _H 3. HATU, DIPEA, DMF N)N N N ON NHCO2Me :0 0 OH

NHCO

2 Me 2-Methoxycarbonylamino-3- (1 -{2-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-pentanoyl)-pyrrolidin methyl-pentanoic acid 2-y]-3H-imidazol-4-yl)-naphthalen-2-ylethynyl)-1H-imidazol-2-yl] pyrrolidine-1 -carbonyl}-2-methyl-butyl)-carbamic acid methyl ester 10 (1-{2-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-pentanoyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-naphthalen-2-ylethynyl)-1 H-imidazol-2-yll-pyrrolidine-1-carbonyl}-2 methyl-butyl)-carbamic acid methyl ester: 2-[4-Ethynyl- I -(2-trimethylsilanyl-ethoxymethyl) I H-imidazol-2-yl]-pyrrol idine- I -carboxylic acid tert-butyl ester (192 mg, 0.490 mmol), 2-[5-(6 15 Bromo-naphthalen-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (260 mg, 0.588 mmol), Pd(PPh 3

)

4 (57 mg, 0.0490 mmol), Cul (19 mg, 0.0980 mmol) and Et 3 N (0.683 mL, 4.90 mmol) were combined in DMF (5 mL). The stirred reaction mixture was degassed for 10 min, then heated to 80 'C for 3h, after which it was diluted with EtOAc, washed with H 2 0 and brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The crude 20 residue was purified by silica column chromatography (45% to 75% EtOAc/Hex) to provide the naphthyl alkyne compound (147 mg, 40%). This product was dissolved in DCM (10 mL) and treated with TFA (5 mL). After stirring for 20h, the mixture was concentrated. The residue was free-based then treated with 2-Methoxycarbonylamino-3-methyl-pentanoic acid (52 mg, 0.276 mmol), HATU (84 mg, 0.222 mmol) and DMF (2 mL). The stirred mixture was cooled to 0 'C 804 and DIPEA (0.160 mL, 0.923 mmol) was added dropwise. The reaction was allowed to come to RT slowly o/n. After 30h, 6 drops of 5 M NaOH were added and the mixture was stirred for 20 min, after which it was diluted with EtOAc and washed with I M LiOH and brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The crude residue was purified by 5 HPLC to afford the title compound (33 mg, 22%). MS (ESI) m/z 765 [M + H]*. Example HB FF Br Br HO2C F Et 3 N Br O 0o Br HO 2 C'N MeCN 0- O Boc O 2-Bromo-1-(6- 4,4-Difluoro-pyrrolidine- 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic bromo-naphthalen- 1,2-dicarboxylic acid 1- acid 2-[2-(6-bromo-naphthalen-2-yl)-2 2-yl)-ethanone tert-butyl ester oxo-ethyl] ester 1-tert-butyl ester F SEM

NH

4 0Ac H F Boc 'N PhMe Br oc / . N 1\ N Boc C 2-[5-(6-Bromo-naphthalen-2-y)-1H- 2-[4-Ethynyl-1-(2-trimethylsilanyl imidazol-2-yl]-4,4-difluoro-pyrrolidine-1- ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine carboxylic acid tert-butyl ester 1-carboxylic acid tert-butyl ester 1. Pd(PPh 3

)

4 , Cul Et 3 N, DMF F 2. TFA, DCM MeO 2 CHN 0 - F Me2H4 HN\- H 3. HATU, DIPEA, DMF NN N -- \ / N 0 _ _ N NHCO 2 Me OH

NHCO

2 Me (1-{2-[4-(6-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-3-methyl-butyryl) 2-Methoxycarbonylamino-3- pyrrolidin-2-yl]-3H-imidazol-4-yl)-naphthalen-2-ylethynyl)-1H-imidazol-2 methyl-butyric acid yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 10 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 2-12-(6-bromo-naphthalen-2-yI)-2-oxo-ethyl] ester 1-tert-butyl ester: 2-Bromo-1 -(6-bromo-naphthalen-2-yl)-ethanone (I g, 3.07 mmol) and 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (849 mg, 3.38 mmol) were suspended in MeCN (15 mL) and treated with Et 3 N (0.45 mL, 3.22 mmol). After stirring o/n, the reaction mixture was concentrated. The resulting residue was dissolved in EtOAc and washed I 5 with water, saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 , filtered and concentrated. The crude material was purified by silica column chromatography (0% to 20% EtOAc/Hex) to provide the title compound (1.27 g, 83%). 2-15-(6-Bromo-naphthalen-2-yI)-1 H-imidazol-2-ylI-4,4-difluoro-pyrrolidine-1-carboxylic 20 acid tert-butyl ester: 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 2-[2-(6-bromo-naphthalen 805 2-yl)-2-oxo-ethyl] ester 1-tert-butyl ester (1.2 g, 2.41 mmol) was treated with NH 4 0Ac (3.72 g, 96.4 mmol) and PhMe (48 mL). The reaction mixture was refluxed with stirring for 18 h. After this period, it was cooled to RT, diluted with EtOAc and washed with saturated aqueous NaHC0 3 and brine. Filtration and concentration provided a crude residue that was purified by 5 silica column chromatography (20% to 60% EtOAc/Hex) to provide the title compound (803 mg, 70%). (1-{2-[4-(6-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-naphthalen-2-ylethynyl)-1 H-imidazol-2-yi]-pyrrolidine-1-carbonyl} 10 2-methyl-propyl)-carbamic acid methyl ester: 2-[4-Ethynyl- I -(2-trimethylsilanyl ethoxymethyl)-I H-imidazol-2-yl]-pyrrolidine-I -carboxylic acid tert-butyl ester (199 mg, 0.508 mmol), 2-[5-(6-Bromo-naphthalen-2-yl)- I H-imidazol-2-yl]-4,4-difluoro-pyrrolidine- carboxylic acid tert-butyl ester (364 mg, 0.762 mmol), Pd(PPh 3

)

4 (118 mg, 0.102 mmol), Cul (19 mg, 0.102 mmol) and triethylamine (0.71 mL, 5.08 mmol) were suspended in DM F (5 mL). 1 5 The reaction mixture was degassed with bubbling N 2 then heated to 80 "C for 4h. Following this period, the mixture was cooled to RT, diluted with EtOAc and washed with water, saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 , filtered and concentrated. The crude material was purified by silica column chromatography (50% to 100% EtOAc/Hex) to provide the naphthyl alkyne (284 mg, 71%). A fraction of this material (123 mg, 0.156 mg) was 20 dissolved in EtOH (4 mL) and treated with conc. HCL. The reaction mixture was stirred at reflux for 18h. The solution was then concentrated. The resulting residue treated with 2 Methoxycarbonylamino-3-methyl-butyric acid (60 mg, 0.343 mmol) and HATU (130 mg, 0.343 mmol), suspended in DMF (3 mL) and cooled to 0 'C. DIPEA (0.272 mL, 1.56 mmol) was added dropwise. After stirring for 4h, NaOH (5M in H 2 0, 0.300 mL, 1.5 mmol) was added. This 25 mixture was stirred for 3h then diluted with EtOAc and washed with I M LiOH (2x) then brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The crude residue was then purified by HPLC to afford the title compound (53 mg, 44%). MS (ESI) m/z 773 [M + H]*. 806 Example HC 0 HO'2' S N' H 3HCI ,CN NHCO2Me O H 2-Methoxycarbonylamino N - N N^ 3-methyl-pentanoic acid N H HATU, DIPEA DMF (1 -{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen 2-yl}-phenyl)-1 H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride 0 0 N'H CN NH. OsN S H IF H' N Y(1 0 [1-(4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-butyl]-carbamic acid methyl ester [1-(4-Cyano-2-{5-16-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza 5 spiro[2.4]hept-6-yl]-3H-imidazol-4-yI}-phenyl)-naphthalen-2-y]-1H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-butyl]-carbamic acid methyl ester: (1 -{6-[5-(4-{6-[2-(4 Cyano-pyrrol idin-2-yl)-3 H-imidazol-4-yl]-naphthalen-2-yl } -phenyl)- I H-imidazol-2-yl]-5-aza spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (148 mg, 0.187 mmol), 2- 2-Methoxycarbonylamino-3-methyl-pentanoic acid (42 mg, 0.224 10 mmol) and HATU (78 mg, 0.206 mmol) were combined in DMF (2 mL) and cooled to 0 'C. DIPEA (0.163 mL, 0.935 mmol) was added dropwise. The reaction mixture was allowed to warm to RT slowly. Afterl2 h, it was diluted with EtOAc and washed with saturated aqueous NaHCO 3 , then brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The crude residue was purified by HPLC to afford the title compound (80 mg, 50%). MS (ESI) m/z 15 854 [M + H]*. 807 Example HD BocO Difluoro-fluorosulfonyl- BocO e 1. LOH, H20/MeOH OMe MeCN ' F-( 2. 2,4'-dibromoacetophenone, HO O triethylamine, MeCN 4-Hydroxymethyl-pyrrolidine- 4-Difluoromethoxymethyl 1,2-dicarboxylic acid 1-tert- pyrrolidine-1,2-dicarboxylic acid butyl ester 2-methyl ester 1-tert-butyl ester 2-methyl ester BocO0 0 -Boc B O Br NH40Ac F Br F ,NJ O PhMe F-( H F--- 0 F 4-Difluoromethoxymethyl-pyrrolidine-1,2- 2-[5-(4-Bromo-phenyl)-1 H-imidazol-2 dicarboxylic acid 2-[2-(4-bromo-phenyl)- yl]-4-difluoromethoxymethyl-pyrrolidine 2-oxo-ethyl] ester 1-tert-butyl ester 1-carboxylic acid tert-butyl ester 1. HCI, dioxane/DCM 2. HATU, DIPEA, DMF 0 OH

NHCO

2 Me 2-Methoxycarbonylamino-3 O methyl-butyric acid O AN.H H o0 B Br + F-( H '('Os O- 0 (1 -{2-[5-(4-Bromo-pheny)-1 H-imidazol- [2-Methyl-1 -(2-{5-[4-(4,4,5,5-tetramethyl 2-yl]-4-difluoromethoxymethyl- [1,3,2]dioxaborolan-2-yl)-phenyl]-1

H

pyrrolidine-1 -carbonyl}-2-methyl- imidazol-2-yl}-pyrrolidine-1 -carbonyl) propyl)-carbamic acid methyl ester propyll-carbamic acid methyl ester 0 N.H Pd(PPh 3

)

4 , 0 0

K

2

CO

3 F N N H20, DME F N N - 0 0 F-( H 0 (1 -{4-Difluoromethoxymethyl-2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol 2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 5 4-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: 4-Hydroxymethyl-pyrrolidine- 1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (584 mg, 2.25 mmol) and Cul (86 mg, 0.45 mmol) were suspended in MeCN (10 mL). The reaction mixture was heated to 45 *C and difluoro-fluorosulfonyl-acetic acid (0.465 mL, 4.5 mmol) was added dropwise over the course of 30 min. Stirring was continued for another 3h, after which the 808 reaction mixture was cooled to RT and concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO 3 and brine then dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (19% to 40% EtOAc/Hex) to afford the title compound (394 mg, 57%). 5 4-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo ethyl] ester 1-tert-butyl ester: 4-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid I tert-butyl ester 2-methyl ester (398 mg, 1.29 mmol) was dissolved in MeOH (8 mL) and LiOH (I M in H 2 0, 2mL, 2 mmol) was added. After stirring at RT for 5h, the MeOH was removed 10 under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with 1 M HCI (2 mL, 2 mmol) and extracted with DCM (3x). The combined organics were dried over MgSO 4 , filtered and concentrated. The residue was dissolved in MeCN (4 mL) and treated with 2,4'-dibromoacetophenone (200 mg, 0.719 mmol), and triethylamine (0.100 mL, 0.719 mmol). After stirring for 15 h, the solvent was removed. The crude residue was purified by silica 15 column chromatography (10% to 35% EtOAc/Hex) to afford the title compound (303 mg, 94%). 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yll-4-difluoromethoxymethyl-pyrrolidine-1 carboxylic acid tert-butyl ester: 4-Difluoromethoxymethyl-pyrrolidine-l,2-dicarboxylic acid 2 [2-(4-bromo-phenyl)-2-oxo-ethyl] ester I -tert-butyl ester (303 mg, 0.615 mmol) was dissolved 20 in PhMe (12 mL) and treated with NH 4 0Ac (948 mg, 12.3 mmol). The stirred mixture was refluxed for 23 h then cooled to RT and diluted with EtOAc. The organic phase was washed with saturated aqueous NaHC0 3 and brine then dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (25% to 50% EtOAc/Hex) to afford the title compound (130 mg, 45%). 25 (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: 2-[5-(4-Bromo-phenyl)-I H imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-I -carboxylic acid tert-butyl ester was dissolved in DCM (4 mL) and treated with HCI (4.OM in dioxane, I mL, 4 mmol). After 2.5 h, 30 the solution was concentrated and the residue was treated with 2-Methoxycarbonylamino-3 methyl-butyric acid (55 mg, 0.315 mmol) and HATU (120 mg, 0.315 mmol). The solids were suspended in DMF (3 mL) and the reaction mixture was cooled to 0 'C before triethylamine (0.25 mL, 1.43 mmol) was added in a dropwise fashion. After 30 min, the mixture was warmed to RT. After another I h, it was diluted with EtOAc and washed with saturated aqueous 35 NaHCO 3 and brine. Then it was dried over MgSO 4 , filtered and concentrated. The crude residue 809 was purified by silica column chromatography (60% to 100% EtOAc/Hex) to afford the title compound (92 mg, 61%). (1-{4-Difluoromethoxymethyl-2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl) 5 pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: (1-{2-[5-(4-Bromo-phenyl)- I H imidazol-2-yI]-4-difluoromethoxymethyl-pyrrolidine- I -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (42 mg, 0.174 mmol), [2-Methyl-I -(2-{5-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-pyrrolidine- 1 -carbonyl)-propyl]-carbamic 10 acid methyl ester (95 mg, 0.191 mmol), Pd(PPh 3

)

4 (20 mg, 0.0174 mmol) and K 2

CO

3 (2M in

H

2 0, 0.191 mL, 0.383 mmol) were combined in 1,2-dimethoxyethane (2 mL). The mixture was degassed with bubbling N 2 for 12 min then heated to 85 "C for 4 h. After cooling to RT, the reaction mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over MgSO 4 , filtered and concentrated. The crude residue was purified by HPLC to 15 provide the title compound (42 mg, 30%). MS (ESI) m/z 819 [M + H]*. 810 Example HE MeNHOMe-HCI, O S \ e 0 r O S HOBt, EDCI, DIPEA N MeMgBr HO S DMF 6 THF/PhMe -1 -(3a,6a-Dihydro 3a,6a-Dihydro- 3a,6a-Dihydro-thieno[3,2- thieno[3,2-b]thiophen thieno[3,2- b]thiophene-2-carboxylic 2-yl)-ethanone b]thiophene-2- acid methoxy-methyl-amide carboxylic acid BocO S Br s3B3. triethylamine,. S B PhNMe 3 Bra _Bre_ aBo NBS THF MeCN DMF 2-Bromo-1-(3a,6a-dihydro- Pyrrolidine-1,2-dicarboxylic acid 1-ter thieno[3,2-b]thiophen-2- butyl ester 2-[2-(3a,6a-dihydro-thieno[3,2 yl)-ethanone b]thiophen-2-yI)-2-oxo-ethyl] ester bis(pinnacolato) B diboron, BcO S Br OCN Br Pd(dPpf) 2 Cl 2 , Br HO 'N " KOAc PhMe H Pyrrolidine-1,2-dicarboxylic acid 2-[2-(5- 2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2 bromo-3a,6a-dihydro-thieno[3,2-b]thiophen- b]thiophen-2-yl)-1 H-imidazol-2-yl] 2-yl)-2-oxo-ethyl] ester 1-tert-butyl ester pyrrolidine-1-carboxylic acid tert-butyl ester Boc S S B Br /oc H 2-[5-(4-Bromo-phenyl)-1H 2-{5-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)- imidazol-2-yl]-pyrrolidine-1 3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl]-1H-imidazol- carboxylic acid tert-butyl ester 2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester 0 1. Pd(PPh 3

)

4 , O N.H

K

2

CO

3 ; H 2 0/DME - H 2. HCI, dioxane/DCM S N N 3. HATU, DIPEA, DMF S OH H'N Os 0

NHC

2 Me [1-(2-{5-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 2-Methoxycarbonylamino- 3H-imidazol-4-yl}-phenyl)-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl]-1H-imidazol 3-methyl-butynic acid 2-yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 3a,6a-Dihydro-thieno[3,2-blthiophene-2-carboxylic acid methoxy-methyl-amide: 3a,6a Dihydro-thieno[3,2-b]thiophene-2-carboxylic acid (2g, 10.86 mmol) MeNHOMe-HCI (1.06 g, 10.86 mmol), HOBt (1.47 g, 10.86 mmol) and DIPEA (5.9 mL, 33.67 mmol) were combined in DMF (40 mL). To the stirred mixture was added EDCI (2.72 g, 14.12 mmol). After 5h, EtOAc (100 mL) was added and the organics were washed with saturated aqueous NaHCO 3 and brine 10 then dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 45% EtOAc/Hex) to afford the title compound (1.98 g, 80%). 1-(3a,6a-Dihydro-thienol3,2-blthiophen-2-yl)-ethanone: 3a,6a-Dihydro-thieno[3,2 b]thiophene-2-carboxylic acid methoxy-methyl-amide (1.955 g, 8.60 mmol) was dissolved in 811 THF. The stirred solution was cooled to 0 C before methylmagnesium bromide (1.4 M in PhMe, 8.6 mL, 12.04 mmol) was added. The reaction was allowed to gradually warm to RT o/n, then it was quenched by addition of 10% HCL. The aqueous phase was extracted with diethyl ether. The organic phase was washed with brine then dried over MgSO 4 , filtered and 5 concentrated to afford the title compound (1.98 g, 80%). 2-Bromo-1-(3a,6a-dihydro-thieno[3,2-bthiophen-2-yl)-ethanone: 1-(3a,6a-Dihydro thieno[3,2-b]thiophen-2-yl)-ethanone (453 mg, 2.48 mmol) was dissolved in THF (12 mL) and phenyltrimethylammonium tribromide (932 mg, 2.48 mmol) was added. After stirring for I h, the 10 suspension was filtered over CELITE. The filtrate was diluted with diethyl ether, then washed with saturated aqueous NaHCO 3 and brine then dried over MgSO 4 , filtered and concentrated to afford the title compound which was carried on without purification. Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-[2-(3a,6a-dihydro-thieno[3,2 15 bjthiophen-2-yl)-2-oxo-ethylj ester: Crude 2-Bromo- I -(3a,6a-dihydro-thieno[3,2-b]thiophen 2-yl)-ethanone (2.48 mmol assuming complete conversion from starting material) was treated with Boc-proline and MeCN (25 mL). Triethylamine was added and the solution was stirred at RT for lh then concentrated. The crude residue was purified by silica column chromatography (14% to 35% EtOAc/Hex) to afford the title compound (595 mg, 61%). 20 Pyrrolidine-1,2-dicarboxylic acid 2-12-(5-bromo-3a,6a-dihydro-thieno[3,2-blthiophen-2 yl)-2-oxo-ethyl] ester 1-tert-butyl ester: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2 [2-(3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-2-oxo-ethyl] ester (595 mg, 1.5 mmol) was dissolved in DMF (7.5 mL) and treated with N-bromosuccinimide (295 mg, 1.65 mmol). The 25 reaction mixture was stirred for 4d at RT then diluted with EtOAc and washed with saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/Hex) to afford the title compound (469 mg, 66%). 30 2-15-(5-Bromo-3a,6a-dihydro-thieno[3,2-blthiophen-2-y)-1H-imidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester: Pyrrolidine-1,2-dicarboxylic acid 2-[2-(5-bromo-3a,6a dihydro-thieno[3,2-blthiophen-2-yl)-2-oxo-ethyl] ester 1-tert-butyl ester (480 mg, 1.0 1 mmol) was treated with PhMe (10 mL) and ammonium acetate (1.56 g, 20.24 mmol). The reaction mixture was refluxed while stirring for 16h, then cooled to RT. EtOAc was added and the 35 organic phase was washed with saturated aqueous NaHCO 3 and brine. After it was dried over 812 MgSO 4 , it was filtered and concentrated. The crude residue was purified by silica column chromatography (25% to 60% EtOAc/Hex) to afford the title compound (378 mg, 82%). 2-{5-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3a,6a-dihydro-thieno[3,2 5 bjthiophen-2-yl]-1H-imidazol-2-yI}-pyrrolidine-1-carboxylic acid tert-butyl ester: 2-[5-(5 Bromo-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-I H-imidazol-2-yl]-pyrrolidine- I-carboxylic acid tert-butyl ester (273 mg, 0.598 mmol), bis(pinacolato)diboron (0.228 mg, 0.897 mmol), Pd(dppf) 2

C

2 (44 mg, 0.0598 mmol) and KOAc (176 mg, 1.79 mmol) were combined in dioxane and degassed for 12 10 min with bubbling N 2 . The reaction mixture was then stirred at 85 'C for 2.5h, cooled to RT and diluted with EtOAc. The organic mixture was washed with saturated aqueous NaHCO 3 and brine before being dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (25% to 60% EtOAc/Hex) to provide the title compound (0.159 g, 53%). The product was contaminated with an equimolar amount of a byproduct which 15 was believed to be the proteodebrominated starting material. [1-( 2 -15-15-(4-{2-[-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yil-3H imidazol-4-yl}-phenyl)-3a,6a-dihydro-thieno[3,2-bthiophen-2-yl]-1H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-propyll-carbamic acid methyl ester: 2-{5-[5-(4,4,5,5 20 Tetramethyl-[ l,3,2]dioxaborolan-2-yl)-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl]- I H-imidazol 2-yl}-pyrrolidine-l -carboxylic acid tert-butyl ester (159 mg, 0.317 mmol), 2-[5-(4-Bromo phenyl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxyl ic acid tert-butyl ester (124 mg, 0.317 mmol), Pd(PPh 3

)

4 (37 mg, 0.0317 mmol) and K 2

CO

3 (2 M in H 2 0, 0.32 mL, 0.64 mmol) were combined in 1,2-dimethoxyethane (3 mL) and degassed with bubbling N 2 for 10 min. The stirred reaction 25 mixture was warmed to 85 *C for 3.5h then cooled to RT and diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO 3 and brine before being dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (EtOAc then 5% MeOH/DCM) to afford the Suzuki-coupled product (89 mg, 41%). This material was dissolved in DCM (4 mL) and treated with HCI (4 M in dioxane, I mL, 4 mmol). 30 After stirring for 73min, the reaction mixture was diluted with EtOAc and the solid was filtered off and rinsed with EtOAc. The solid was dried, then combined with 2-Methoxycarbonylamino 3-methyl-butyric acid (37 mg, 0.212 mmol), HATU (81 mg, 0.212 mmol) and DMF (2 mL). The stirred reaction mixture was cooled to 0 'C and DIPEA (0.17 mL, 0.96 mmol) was added dropwise. After 15min, it was warmed to RT. 17h later, the reaction mixture was diluted with 35 EtOAc. . The organic phase was washed with saturated aqueous NaHCO 3 and brine before being 813 dried over MgSO 4 , filtered and concentrated. The crude residue was purified by HPLC to afford the title compound (23 mg, 22%). MS (ESI) m/z 801 [M + H]*. Example HF 5 H \ \Br +B H O 2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2- (2-Methyl-1-{2-[6-(4,4,5,5-tetramethyl-(1,3,2]dioxaborolan b]thiophen-2-yl)-1H-imidazol-2-yl]- 2-yl)-lH-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl} pyrrolidine-1-carboxylic acid tert-butyl ester propyl)-carbamic acid methyl ester 1. Pd(PPh 3

)

4 , O

K

2

CO

3 ; H 2 0/DME 0 N. H 2. HCl, dioxane/DCM , O N -N 3. HATU, DIPEA, DMF N'NO NjN S OH H.N O0 _Y 0

NHCO

2 Me (1 -{2-[5-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 2-Methoxycarbonylamino- benzoimidazol-5-yl}-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1 H-imidazol-2-yl] 3-methyl-butyric acid pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1-{2-[5-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H benzoimidazol-5-yl)-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1H-imidazol-2-yl] 10 pyrrolidine-1-carbonyll-2-methyl-propyl)-carbamic acid methyl ester: 2-[5-(5-Bromo 3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert butyl ester (100 mg, 0.219 mmol), (2-Methyl-I-{2-[6-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan 2-yl)-l H-benzoimidazol-2-yl]-pyrrolidine-I -carbonyl}-propyl)-carbamic acid methyl ester (117 mg, 0.283 mmol), Pd(PPh 3

)

4 (51 mg, 0.0438 mmol) and K 2

CO

3 (2 M in H 2 0, 0.33 mL, 0.66 15 mmol) were combined in 1,2-dimethoxyethane (4 mL) and degassed with bubbling N 2 for 10 min. The stirred reaction mixture was warmed to 85 'C for 3.5h then cooled to RT and diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO 3 and brine before being dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (EtOAc) to afford the Suzuki-coupled product (71 mg, 49%). This 20 material was dissolved in DCM (4 mL) and treated with HCI (4 M in dioxane, I mL, 4 mmol). After stirring for 97min, the reaction mixture was concentrated. The solid was dried, then combined with 2-Methoxycarbonylamino-3-methyl-butyric acid (39 mg, 0.225 mmol), HATU (86 mg, 0.225 mmol) and DMF (4 mL). The stirred reaction mixture was cooled to 0 "C and DIPEA (0.18 mL, 1.07 mmol) was added dropwise. After 30min, it was warmed to RT. 12min 814 later, the reaction mixture was diluted with EtOAc. . The organic phase was washed with saturated aqueous NaHCO 3 and brine before being dried over MgSO 4 , filtered and concentrated. The crude residue was purified by HPLC to afford the title compound (32 mg, 39%). MS (ESI) m/z 775 [M + H]*. 5 Example HG Boc s WBr 1. HCI, dioxane/DCM S 2. HATU, DIPEA, DMF 0 2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2- OH b]thiophen-2-yl)-1 H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester NHCO 2 Me 2-Methoxycarbonylamino 3-methyl-butyric acid H O N-(^'N MeO 2 CHN N \Br + SN NHCO 2 Me N 0 (1 -{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2- {1 -[2-(5-Ethynyl-1 H-imidazol-2-yl) b]thiophen-2-yI)-1 H-imidazol-2-yl]-pyrrolidine-1 - pyrrolidine-1 -carbonyl]-2-methyl carbonyl}-2-methyl-propyl)-carbamic acid methyl propyl}-carbamic acid methyl ester ester Pd(PPh 3

)

4 , Cul, 0H?7 t tyh u' MeO 2 CHN ON__ NN triethylamine M 2CN N\ S - ,I- N DMF N S NO NHCO 2 Me JH0 (1-{2-[5-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-ylethynyl}-3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-1 H-imidazol-2 yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1 -{2-15-(5-Bromo-3a,6a-dihydro-thieno[3,2-bthiophen-2-y)-1 H-imidazol-2-yl] 10 pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: 2-[5-(5-Bromo 3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert butyl ester (250 mg, 0.548 mmol) was dissolved in DCM (4 mL) and treated with HCI (4 M in dioxane, I mL, 4 mmol). After stirring for 1.5h, the reaction mixture was concentrated. The solid was dried, then combined with 2-Methoxycarbonylamino-3-methyl-butyric acid (106 mg, 15 0.603 mmol), HATU (229 mg, 0.603 mmol) and DMF (6 mL). The stirred reaction mixture was cooled to 0 "C and DIPEA (0.48 mL, 2.74 mmol) was added dropwise. After 50min, it was warmed to RT. 12min later, the reaction mixture was diluted with EtOAc. . The organic phase was washed with saturated aqueous NaHCO 3 and brine before being dried over MgSO 4 , filtered 815 and concentrated. The crude residue was purified by silica column chromatography to afford the title compound (252 mg, 90%). (1-{2-15-(5-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H 5 imidazol-4-ylethynyl)-3a,6a-dihydro-thieno[3,2-blthiophen-2-yl)-I H-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: (1-{2-[5-(5-Bromo 3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)- 1 H-imidazol-2-yl]-pyrrolidine- I -carbonyl} -2-methyl propyl)-carbamic acid methyl ester (140 mg, 0.440 mmol), {1 -[2-(5-Ethynyl-I H-imidazol-2-yl) pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (130 mg, 0.254 mmol), 10 Pd(PPh 3

)

4 (29 mg, 0.0254 mmol), Cul (10 mg, 0.0508 mmol) and triethylamine (0.354 mmol, 2.54 mmol) were combined in DMF (2.5 mL) and degassed with N 2 for 17min. The reaction was heated to 85 'C for 4h then cooled to RT, diluted with EtOAc and washed with saturated aqueous NaHCO 3 (2x) and brine. The organic layer was dried over MgSO 4 , filtered and concentrated. The crude residue was purified by HPLC chromatography to afford the title 15 compound (34 mg, 18%). MS (ESI) m/z 749 [M + H]f. Example HH _. N 1. HCI, dioxane/DCM 0 N Boc 2. HATU, K 3

PO

4 , DCM O 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2- Ph yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1- 3 OH carboxylic acid tert-butyl ester NHCO 2 Me Methoxycarbonylamino phenyl-acetic acid I H?7 IR.B \NHCO2e + MeO 2 CHN Br Ph C H [2-Oxo-1 -phenyl-2-(2-{5-[4-(4,4,5,5-tetramethyl- (1 -{2-[5-(5-Bromo-3a,6a-dihydro-thieno[3,2 [1,3,2]dioxaborolan-2-y)-phenyl]-1 H-imidazol-2-yl}- b]thiophen-2-y)-1 H-imidazol-2-yl]-pyrrolidine-1 pyrrolidin-1-yl)-ethyl]-carbamic acid methyl ester carbonyl}-2-methyl-propyl)-carbamic acid methyl ester Pd(PPh 3

)

4 , 0 H

K

2

CO

3 ; H 2 0/DME MeO 2 CHN N N N N S NO NHCH 2 0 2 Me Ph {2-Methyl-1-[2-(5-{5-[4-(2-{1-[2-(methylperoxymethyl-amino)-2-phenyl-acetyl] pyrrolidin-2-yl}-3H-imidazol-4-y)-phenyl]-3a,6a-dihydro-thieno[3,2-b]thiophen-2 yI}-1 H-imidazol-2-yl)-pyrrolidine-1 -carbonyl]-propyl}-carbamic acid methyl ester 20 816 [2-Oxo-1-phenyl-2-(2-{5-[4-(4,4,5,5-tetramethyl-I1,3,2]dioxaborolan-2-yl)-phenyl]-1

H

imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamic acid methyl ester: 2-{5-[4-(4,4,5,5 Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]- IH-imidazol-2-yI}-pyrrolidine-l -carboxylic acid tert-butyl ester (530 mg, 1.21 mmol) was dissolved in DCM (4 mL) and treated with HCI (4M in 5 dioxane, I mL, 4 mmol). The reaction mixture was stirred at RT for 19h then the solid was filtered off and rinsed with DCM. After being thoroughly dried (461 mg, 92%), a portion of this solid (200 mg, 0.485 mmol) was combined with Methoxycarbonylamino-phenyl-acetic acid (122 mg, 0.582 mmol) and HATU (221 mg, 0.582 mmol)were suspended in DCM (5 mL) and

K

3

PO

4 (309 mg, 1.455 mmol) was added. After stirring 24h, the reaction mixture was diluted 10 with EtOAc and washed with I M LiOH and brine. The organic layer was dried over MgSO 4 , filtered and concentrated. The crude residue was purified by silica column chromatography (75% to 100% EtOAc) to provide the title compound (204 mg , 79%). {2-Methyl-1-[2-(5-{5-[4-(2-{1-12-(methylperoxymethyl-amino)-2-phenyl-acetyll-pyrrolidin 15 2-yl}-3H-imidazol-4-yl)-phenyll-3a,6a-dihydro-thieno[3,2-bthiophen-2-yl}-1 H-imidazol-2 yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester: [2-Oxo- I -phenyl-2-(2-{5 [4-(4,4,5,5-tetramethyl-[ l,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl }-pyrrolidin- I -yl) ethyl]-carbamic acid methyl ester (204 mg, 0.385 mmol), (I -{2-[5-(5-Bromo-3a,6a-dihydro thieno[3,2-b]thiophen-2-yl)-1 H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl) 20 carbamic acid methyl ester (137 mg, 0.268 mmol), Pd(PPh 3

)

4 (31 mg, 0.0268 mmol) and K 2 CO3 (2M in H 2 0, 0.4 mL, 0.8 mmol) were combined in 1,2-dimethoxyethane (2.7 mL). After 10 min of degassing with bubbling N 2 , the reaction mixture was heated to 85 'C for 19h. After this period, it was cooled and diluted MeOH. The suspension was filtered over a thiol SPE cartridge to remove the palladium, then concentrated. The crude residue was purified by HPLC to afford 25 the title compound (103 mg, 46%). MS (ESI) m/z 835 [M + H]f. 817 Example HI 0 00 0 Br 0 - NBS CCu 0 O LiAIH 4 O 0O 3,5-Dimethoxy-benzoic 2-Bromo-3,5-dimethoxy- 4,6,4',6'-Tetramethoxy-biphenyl-2, acid methyl ester benzoic acid methyl ester 2'-dicarboxylic acid dimethyl ester OH Br Br 0 0 OH O O O O HO6'- / OH 0 PBr 3 O BBr 3 HO HO Br Br (6'-Hydroxymethyl-4,6,2',4'-tetra 6,6-Bis-bromomethyl-2,4, 6,6'-Bis-bromomethyl methoxy-biphenyl-2-yl)-methanol 2',4'-tetramethoxy-biphenyl biphenyl-2,4,2',4'-tetrao 0 0 HO \ \ OH Tf2O TfO \/ OTf Cs 2

CO

3 O Pyridine O 5,1 0-Dihydro-chromeno Trifluoro-methanesulfonic acid 7-trifluoro [5,4,3-cde]chromene-2,7-dio methanesulfonyloxy-5, 1 0-dihydro chromeno[5,4,3-cde]chromen-2-y ester // N 0 N N N 0 ~ H o HN (1 -{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y] 3H-imidazo-4-y}-5,1 0-dihydro-chromeno[5,4,3-cde]chromen-2-yl)-1 H-imidazol 2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 2-Bromo-3,5-dimethoxy-benzoic acid methyl ester: 3,5-Dimethoxy-benzoic acid methyl ester 5 (4.0 g) was dissolved in MeCN (28 mL), and NBS (4.4 g ) was added at 0*C. After stirring at room temperature for 3 hours, saturated Na 2

SO

3 (15 mL) was added. The mixture was evaporated under vacuum and extracted with ether (lx, 500 mL). After the solvent was removed, the crude material was subjected to silica gel chromatography using effluent of 10 -40 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was 10 removed under reduced pressure to provide 2-bromo-3,5-dimethoxy-benzoic acid methyl ester (5.2 g, 93 %) as a clear oil. 4,6,4',6'-Tetramethoxy-biphenyl-2,2'-dicarboxylic acid dimethyl ester: 2-Bromo-3,5 dimethoxy-benzoic acid methyl ester (5.2 g) was dissolved in DMF (16 mL), and Cu powder 15 (2.4 g ) was added . After stirring at 150'C for 3 days, the mixture was filtered and evaporated under vacuum. The crude material was subjected to silica gel chromatography using effluent of 818 30 -60 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 4,6,4',6'-tetramethoxy-biphenyl-2,2' dicarboxylic acid dimethyl ester (2.5 g, 68 %) as a clear oil. 5 (6'-Hydroxymethyl-4,6,2',4'-tetramethoxy-biphenyl-2-yl)-methanol : 4,6,4',6' tetramethoxy-biphenyl-2,2'-dicarboxylic acid dimethyl ester (2.5 g) was dissolved in THIF (96 mL), and I M LiAlH 4 in THF (9.6 mL) was added . After stirring at room temperature for overnight, the mixture was quenched with water and 2N HCI (24 mL) was added. The mixture was evaporated under vacuum and partitioned with DCM (300 mL) and water (200mL). The 10 organic layer was dried over Na 2

SO

4 and crystallized with DCM to provide (6'-hydroxymethyl 4,6,2',4'-tetramethoxy-biphenyl-2-y)-methanol (1.7 g, 77 %) as a pale blue white triclinic crystals. 6,6'-Bis-bromomethyl-2,4,2',4'-tetramethoxy-biphenyl : (6'-hydroxymethyl-4,6,2',4' 15 tetramethoxy-biphenyl-2-yl)-methanol (779 mg) was dissolved in DCM (5.8 mL), and PBr 3 (527 pl) was slowly added at 0*C. After stirring at 0 0 C for 30 min. and at room temperature for I hour, H 2 0 (40 mL) was added. The mixture was extracted with ether (lx, 50 mL). After the solvent was removed, the crude material was subjected to silica gel chromatography using effluent of 10 -40 % ethyl acetate and hexanes. The fractions containing product were combined 20 and the solvent was removed under reduced pressure to provide 6,6'-bis-bromomethyl-2,4,2',4' tetramethoxy-biphenyl (700 mg, 65 %) as a thick oil. 6,6'-Bis-bromomethyl-biphenyl-2,4,2',4'-tetraol : 6,6'-bis-bromomethyl-2,4,2',4' tetramethoxy-biphenyl (685 mg) was dissolved in DCM (3.0 mL), and IM BBr 3 in DCM (16.4 25 mL) was slowly added. After stirring for 2 days, the mixture was poured on to ice and concentrated. The crude material was used for the next step without a further purification. 5-1-Dihydro-chromeno[5,4,3-cdejchromene-2,7-diol : The crude 6,6'-bis-bromomethyl biphenyl-2,4,2',4'-tetraol was dissolved in DMF (30 mL), and Cs 2

CO

3 (1.9 g ) was added. After 30 stirring at room temperature for 1 hour, the mixture was partitioned with I N HCI (100 mL) and ethyl acetate (100 mL), and extracted with ethyl acetate (3X, 100 mL). After the solvent was removed, the crude material was subjected to silica gel chromatography using effluent of 10 -15 % methanol and DCM. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 5-1 0-dihydro-chromeno[5,4,3-cde]chromene-2,7 35 diol (301 mg, 84 %) as a white solid. 819 Trifluoro-methanesulfonic acid 7-trifluoromethanesulfonyloxy-5,10-dihydro chromeno[5,4,3-cdelchromen-2-yl ester: 5-10-Dihydro-chromeno[5,4,3-cde]chromene-2,7 diol (290 mg) was dissolved in DCM (12 mL), and Tf 2 O (1.2 mL) and pyridine (969 PI) were added. After stirring at room temperature for overnight, the mixture was partitioned with 2 N 5 HCI (50 mL) and DCM (50 mL), and washed with 2 N HCI (2 x 50 mL) and saturated sodium bicarbonate (1 x 50 mL). After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 0 -30 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide trifluoro-methanesulfonic acid 7-trifluoromethanesulfonyloxy-5,10-dihydro 10 chromeno[5,4,3-cde]chromen-2-yl ester (472 mg, 78%) as an off-white solid. (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H imidazol-4-yI}-5,10-dihydro-chromeno[5,4,3-cdelchromen-2-yl)-IH-imidazol-2-yl] pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was 15 prepared according to the method employed to prepare (1 -{2-[5-(2-{2-[1-(2 Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-6-H dibenzo[c,h]chromen-8-yl)-i H-imidazol-2-yl]-pyrrolidine-I -carbonyl}-2-methyl-propyl) carbamic acid methyl ester, substituting trifluoro-methanesulfonic acid 7-trifluoromethane sulfonyloxy-5, I 0-dihydro-chromeno[5,4,3-cde]chromen-2-yl ester for trifluoro-methanesulfonic 20 acid 2-trifluoromethanesulfonyloxy-6-H-dibenzo[c,h]chromen-8-yl ester. 820 Example HJ N\ Boc I qBr HH H H 3-[5-(6-Bromo-naphthalen-2-yl)-1 H-imidazol-2-yl]-2-aza N N bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester HN,..// Pd(PPh 3

)

4

K

2

CO

3 0- DME, H 2 0 [2-Methyl-1 -(6-{5-[4-(4,4,5,5-tetramethyl-[1, 3,2]dioxaborolan 2-yl)-phenyl]-1 H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5 carbonyl)-propyl]-carbamic acid methyl ester 1) HCI, dioxanes B H MeOH BocN N N N / I L N / O 2) HATU, NMM YHO HO N OH 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza- O spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2- O yl}-2-aza-bicyclo[2.2. 1]heptane-2-carboxylic acid tert-butyl ester 0 /)_NH 0 H H ~-0 N{ IN\ HI - N 0 [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl} 5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl] 3H-imidazol-4-yl}-phenyl)-naphthalen-2-yI]-I H-imidazol-2-yi}-2-aza bicyclo[2.2.lheptane-2-carboxylic acid tert-butyl ester. To a solution of [2-Methyl-l-(6-{5 [4-(4,4,5,5-tetramethyl-[ I,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-5-aza spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (0.95 g, 1.82 mmol) and 3-[5 10 (6-Bromo-naphthalen-2-yl)- I H-imidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert-butyl ester (0.96 g, 1.82 mmol, I equiv.) in DME (20 mL) was added K 2

CO

3 (aqueous, 2 M, 3.6 mL, 7.2 mmol, 4 equiv.) and Pd(PPh 3

)

4 (0.11 g, 0.09 mmol, 0.05 equiv.). The slurry was degassed with argon for 5 minutes and heated to 80 'C for 12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was back-extracted 15 with EtOAc and the combined organic layers were dried over Na 2

SO

4 and concentrated. The crude oil was purified by column chromatography (SiO 2 , 50--100% EtOAc in Hexanes) to 821 provide 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-2-aza bicyclo[2.2.I]heptane-2-carboxylic acid tert-butyl ester (0.53 g, 37%) as a yellow powder. LCMS-ESI': calc'd for C 4 6

H

53

N

7 0 5 : 783.4 (M *); Found: 784.3 (M+H*). 5 [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza bicyclo[2.2.1Ihept-3-yl]-3H-imidazol-4-yI)-naphthalen-2-yI)-phenyl]-1H-imidazol-2-yl}-5 aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester. To a slurry of 3- {5-[6-(4- {2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 10 yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-l H-imidazol-2-yl}-2-aza bicyclo[2.2.I]heptane-2-carboxylic acid tert-butyl ester (0.05 g, 0.06 mmol) in MeOH (0.1 mL) was added HCI in dioxanes (4 M, 0.6 mL). The resulting solution was stirred at room temperature for I hour and the concentrated to dryness. Cyclopropyl-methoxycarbonylamino acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) and CH 2 Cl 2 (0.6 mL) were then added, followed by 15 HATU (0.03 g, 0.08 mmol, 1.25 equiv.) and NMM (0.05 mL, 0.45 mmol, 5 equiv.). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative HPLC (Gemini, 15-40% MeCN in H20 (0.1% formic acid)) and lyophilized to provide [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2 methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2 20 yl)-phenyl]-l H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 49%) as a white powder. LCMS-ESI*: calc'd for C 4 8

H

54

N

8 0 6 : 838.4 (M *); Found: 839.9 (M+H*). 'IH-NMR: 400 MHz, (CDCl 3 ) 8: (mixture of rotomers) 8.22 (s, 2H), 7.81-7.96 (m, 10 H), 7.63 (d, I H), 7.29 (d, I H), 5.18 (t, I H), 4.56 (d, I H), 3.96 (t, 1 H), 3.74 (m, IH), 3.51 (s, 6H), 3.12 (t, IH), 2.48 (s, IH), 1.93-2.29 (m, 6H), 1.58-1.77 (m, 5H), 0.85 (d, 25 3H), 0.80 (d, 3H), 0.58 (m, 4H), 0.34 (m, I H), 0.26 (m, I H), 0.03 (m, I H), -0.12 (m, I H). 822 Example HK 5 0 1) HCI, dioxanes NH 0MeOH N N ~ - N N O O Boc 2) HATU, NMM H H N H 0 6-{5-[4-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl- O butyryl)-2-aza-bicyclo[2.2. 1 ]hept-3-yI]-3H-imidazol-4- 0 yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl}-5-aza spiro[2.4]heptane-5-carboxylic acid tert-butyl ester 0 NHH ON N N NN HH -NO 0 [1-(3-{5-[6-(4-{2-[5-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-2 aza-bicyclo[2.2. 1 ]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester [1-(3-15-16-(4-{2-[5-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-5-aza-spiro[2.4] hept 6-yl]-3H-imidazol-4-yI)-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza 10 bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester. This compound was prepared following the procedure for [I-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2 methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2 yl)-phenyl]-l H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using 6-{5-{4-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza 15 bicyclo[2.2. I ]hept-3-yI]-3H-imidazol-4-yI}-naphthalen-2-yI)-phenyl]-I H-imidazol-2-yl}-5-aza spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (0.05 g, 0.06 mmol) to provide [l-(3-{5-[6 (4-{ 2 -[5-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-5-aza-spiro[2.4]hept-6-yl]-3H imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-2-aza-bicyclo[2.2. I ]heptane-2 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.02 g, 46%) as a white powder. 20 LCMS-ESI: calc'd for C 48

H

54

N

8 0 6 : 838.4 (M *); Found: 839.9 (M+H*). 'H-NMR: 400 MHz, (CDCl 3 ) 6: (mixture of rotomers) 8.18 (s, 2H), 7.80-7.91 (m, 10H), 7.58 (s, IH), 7.14 (d, IH), 5.19 (d, I H), 4.50 (d, I H), 4.13 (t, I H), 3.57 (m, I H), 3.51 (s, 6H), 3.28 (m, I H), 2.48 (s, I H), 1.94-2.04 (m, 2H), 1.71-1.83 (m, 5H), 1.42-1.49 (m, 4H), 0.97 (d, 3H), 0.87 (d, 3H), 0.52-0.68 (m, 4H), 0.33 (m, I H), 0.23 (m, I H), 0.03 (m, I H), -0.12 (m, I H). 823 Example HL Boc /, Br IN IN B / N NJ 2-[5-(4-Bromo-phenyl)-l H-imidazol-2-yl] 7~0 / ~ " pyrrolidine-1-carboxylic acid tei't-butyl ester HN 0 [2-Methyl-I -(2-{5-[6-(4,4,5, 5-tetramethyl-[l 3,2]dioxaborolan- dba Xnpo 2-yl)-naphthalen-2-yI]-1 H-imidazol-2-yl}-pyrrolidine-1 -Pdbaanho carbonyl)-propyl]-carbamic acid methyl ester 0 NI 0 H IHCI, dioxanes I N N N MeOH N\ Boc 2-{5-[4-(6-{2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-ylJ-3H-imidazol-4-yl-naphthalen-2-yl)-phenyl]- H imidazol-2-yl}-pyrrolidine-1 -carboxylic acid tert-butyl ester 0 NH 0H HATU, K 3 P0 4 n N N -NI H/ N HH _ \/ \ N OH-1 00 {2-Methyl-l1-[2-(5-{6-[4-(2-pyrrolidin-2-yl.3H-imidazol-4-yl) phenylJ-naphthalen-2-yl-1H-imidazol-2-yl)-pyrrolidine-I - Methoxycarbonylamino carbonyl]-propyl}-carbamic acid methyl ester phenyl-acetic acid 0 )~NN N IN - N N HH IN O \k - -{ 0 [1 -(2-{5-[6-(4-{2-[1 -(2-Methoxycarbonylamino-2-phenyl- 0 acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yI}-phenyl) naphthalen-2-yl]-1 H-imidazol-2-yI}-pyrrolidine-1 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 2-{5-[4-(6-{2-[1 -(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-ylj-3H imidazol-4-yI)-naphthalen-2-yl)-phenyl-1 H-imidazol-2-yl}-pyrrolidine-1 -carboxylic acid tert-butyl ester. To a solution of 2-[S-(4-Bromo-phenyl)-Il--imidazol-2-yl]-pyrrolidine-I 824 carboxylic acid tert-butyl ester (1.00 g, 2.5 mmol) and [2-Methyl-1-(2-{5-[6-(4,4,5,5 tetramethyl-[I,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-IH-imidazol-2-yl}-pyrrolidine-1 carbonyl)-propyl]-carbamic acid methyl ester (1.97 g, 3.6 mmol, 1.5 equiv.) in DME (12.5 mL) was added K 3

PO

4 (aqueous, 2 M, 3.9 mL, 7.8 mmol, 3 equiv.), Pd 2 dba 3 (0.12 g, 0.13 mmol, 0.05 5 equiv.), and Xantphos (0.15 g, 0.26 mmol, 0.1 equiv.). The slurry was degassed with argon for 5 minutes and heated to 80 *C for 18 hours. The resulting reaction mixture was diluted with EtOAc/MeOH (10:1) and filtered through CELITE. The solution was washed with water and brine. The aqueous layer was back-extracted with EtOAc and the combined organic layers were dried over Na 2

SO

4 and concentrated. The crude oil was purified by column chromatography 10 (SiO 2 , 50-100% EtOAc in Hexanes) to provide 2-{5-[4-(6-{2-[l-(2-Methoxycarbonylamino-3 methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-y}-naphthalen-2-yl)-phenyl]-IH-imidazol-2 yl}-pyrrolidine-l-carboxylic acid Iert-butyl ester (0.93 g, 49%) as a yellow powder. LCMS ESI*: calc'd for C 42

H

49

N

7 0 5 : 731.4 (M *); Found: 732.9 (M+H*). 15 {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1 H imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester. To a slurry of 2-{5-[4-(6-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4 yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-I-carboxylic acid tert-butyl ester (0.1 g, 0.14 mmol) in MeOH (0.15 mL) was added HCI in dioxanes (4 M, 0.7 mL). The 20 resulting solution was stirred at room temperature for I hour and diluted with Et 2 0. The resulting precipitate was filtered and dried to provide {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2 yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1 H-imidazol-2-yl)-pyrrolidine-l-carbonyl] propyl}-carbamic acid methyl ester trihydrochloric acid salt (0.09 g, 87%) as a white powder. LCMS-ESl*: calc'd for C 37

H

41

N

7 0 3 : 631.3 (M *); Found: 632.7 (M+H*). 25 [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H imidazol-4-yI}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester. To a slurry of {2-Methyl-1-[2-(5-{6-[4-(2 30 pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1 H-imidazol-2-yl)-pyrrolidine-l carbonyl]-propyl}-carbamic acid methyl ester (0.045 g, 0.06 mmol) and (S) methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) in CH 2 Cl 2 (0.6 mL) was added HATU (0.03 g, 0.08, 1.25 equiv.) and K 3

PO

4 (0.05 g, 0.22 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for 18 hours and diluted with CH 2 Cl 2 . The 35 salts were filtered and the filtrate was concentrated. The crude oil was purified by preparative HPLC (Gemini, 15-40% MeCN in H 2 0 (0.1% formic acid)) and lyophilized to provide [1-(2 825 {5-[6-(4-{2-[I-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-y]-3 H-imidazol 4-yl}-phenyl)-naphthalen-2-y]- I H-imidazol-2-yi}-pyrrolidine- I -carbonyl)-2-methyl-propyl] carbamic acid methyl ester (0.03 g, 65%) as a white powder. LCMS-ESl*: calc'd for

C

4 7

H

5 oN 8 0 6 : 822.4 (M *); Found: 823.5 (M+H*). 'H-NMR: 400 MHz, (CDCl 3 ) 6: (Mixture of 5 rotomers) 7.64-8.03 (m, 9H), 7.20-7.40 (m, 6H), 7.17 (s, 2H), 6.14 (m, I H), 5.53 (dd, 2H), 5.25 5.33 (m, 2H), 4.33 (t, I H), 3.85 (m, I H), 3.73 (m, I H), 3.68 (s, 3H), 3.66 (s, 3H), 3.27 (m, I H), 2.86-2.96 (m, 3 H), 2.35 (m, I H), 1.94-2.23 (m, 6H), 0.87-0.90 (m, 6H). Example HM 10 0 NH 0 H HATU, K 3 PO4 110

-

N 0__ N N\

-

r" H N0 N H O O OH -3HCI O {2-Methyl-1 -[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl) phenyl]-naphthalen-2-yl}-1 H-imidazol-2-yl)-pyrrolidine-1 - Methoxycarbonylamino carbonyl]-propyl}-carbamic acid methyl ester phenyl-acetic acid 0 N N N I H N 0/ 0 [1 -(2-{5-[6-(4-{2-[1 -(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 1 -(2-{5-[6-(4-{2-[1-(2R)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrroidin-2-y1]-3H 15 imidazol-4-yI}-phenyl)-naphthalen-2-y1]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyl]-carbamic acid methyl ester. This compound was prepared following the procedure for [I -(2-{5-[6-(4-{2-[I-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin 2-yI]-3 H-imidazol-4-yl } -phenyl)-naphthalen-2-yl]- I H-imidazol-2-yl } -pyrrol idine- I -carbonyl) 2-methyl-propyl]-carbamic acid methyl ester using (R)-methoxycarbonylam ino-phenyl -acetic 20 acid (0.02 g, 0.09 mmol, 1.5 equiv.) to provide [1 -(2-{5-[6-(4-{2-[1-(2R)-(2 Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-y]-3H-imidazol-4-y }-phenyl) naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 65%) as a white powder. LCMS-ESI*: calc'd for C 4 7 Ho 5

N

8 0 6 : 822.4 (M *); Found: 823.8 (M+H*). 'H-NMR: 400 MHz, (CDC1 3 ) 8: (Mixture of rotomers) 7.62-8.02 (m, 25 9H), 7.36-7.43 (m, 6H), 7.22 (s, 2H), 6.01 (s, I H), 5.29-5.53 (m, 4H), 4.35 (t, I H), 3.73-3.87 (m, 826 2H), 3.68 (s, 3H), 3.63 (s, 3H), 3.22 (q, 2H), 2.82-2.96 (m, 2H), 2.37 (m, I H), 2.23 (m, 2H), 1.90-2.11 (m, 4H), 0.87-0.93 (m, 6H). Example HN 5 0 NNH SBr N N HHk 0, 1 H (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl] ,pyrrolidine-1 -carbonyl}-2-methyl-propyl) O 1 Boc carbamic acid methyl ester 2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan- Pd 2 dba 3 , Xantphos 2-yl)-naphthalen-2-yl]-1 H-imidazol-2-yl} pyrrolidine-1-carboxylic acid tert-butyl ester H HCI, dioxanes N N H MeOH N NHN HH HN-c 2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-O pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester O\ -'HHATU, K 3

PO

4 H N N N0 N HN N NN -' \k;'-\ OH 0 -3HCI O {2-Methyl-1 -[2-(5-{4-[6-(2-pyrrolidin-2-yl-3H-imidazol-4-y) naphthalen-2-yl]-phenyl}-1 H-imidazol-2-yl)-pyrrolidine-1 carbonyl]-propyl}-carbamic acid methyl ester 0 NH ~~ N>~~ 0 1 N O N HH r4 HN 0 [1 -(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-naphthalen-2-yI)-phenyl]-1 H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 827 [1 -(2-{5-14-(6-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-naphthalen-2-yl)-phenyll-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2 methyl-propyll-carbamic acid methyl ester. This compound was prepared following the procedure for [I -(2-{5-[6-(4-{2-[l -(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin 5 2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-I-carbonyl) 2-methyl-propyl]-carbamic acid methyl ester using (1-{2-[5-(4-Bromo-phenyl)- IH-imidazol-2 yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.0 g, 2.2 mmol) and 2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]- IH-imidazol-2-yI} pyrrolidine-l -carboxylic acid tert-butyl ester (1.6 g, 3.4 mmol, 1.5 equiv.) to provide [1-(2-{5 10 [4-(6-{2-[l-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-y]-3H-imidazol-4-yl} naphthalen-2-yl)-phenyl]- I H-im idazol-2-yl} -pyrrolidine- I -carbonyl)-2-methyl-propyl] carbamic acid methyl ester (0.03 g, 54%) as a white powder. LCMS-ESI*: calc'd for

C

4 7

H

5 oN 8 0 6 : 822.4 (M *); Found: 823.9 (M+H*). 'H-NMR: 400 MHz, (CDC 3 ) 8: (Mixture of rotomers) 7.52-7.93 (m, 9H), 7.27-7.42 (m, 6H), 7.16 (s, 2H), 6.08 (m, I H), 5.48-5.56 (m, 2H), 15 5.34 (s, I H), 5.24 (s, I H), 4.35 (t, I H), 3.93 (m, I H), 3.73 (m, I H), 3.68 (s, 3 H), 3.66 (s, 3 H), 3.38 (m, I H), 2.78-2.83 (m, 3H), 2.36 (m, I H), 2.04-2.23 (m, 6H), 0.86-0.97 (m, 6H). Example HO H HATU, K 3

PO

4 HI H/~ - N NH N N N ON HH '' ,' 0-... OH -3HCI H 0 {2-Methyl-1 -[2-(5-{4-[6-(2-pyrrolidin-2-yl-3H-imidazol-4-yl) naphthalen-2-yl]-phenyl}-1 H-imidazol-2-yl)-pyrrolidine-1 carbonyl]-propyl}-carbamic acid methyl ester 0 _NH 0 N 11N N I N HN 0 [1 -(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 20 [1-(2-{5-[4-(6-{2-[1-(2R)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H imidazol-4-yl)-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yi)-pyrrolidine-1 -carbonyl)-2 methyl-propyll-carbamic acid methyl ester. This compound was prepared following the procedure for [1-(2-{5-[4-(6-{2-[I-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin 828 2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]- 1 H-imidazol-2-yl } -pyrrolidine- I -carbonyl) 2-methyl-propyl]-carbamic acid methyl ester using (R)-methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) to provide [1-(2-{5-[4-(6-{2-[I-(2-Methoxycarbonylamino 2-phenyl-acetyl)-pyrrolidin-2-y]-3H-imidazol-4-yl}-naphthalen-2-y1)-phenyl]-I H-imidazol-2 5 yI}-pyrrolidine-l-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 58%) as a white powder. LCMS-ESI+: calc'd for C 4 7

H

5 oN 8 0 6 : 822.4 (M *); Found: 823.8 (M+H*). IH NMR: 400 MHz, (CDC 3 ) 6: (Mixture of rotomers) 7.62-7.87 (m, 9H), 7.29-7.43 (m, 6H), 7.18 (s, 2H), 6.09 (m, 1 H), 5.46 (m, 2H), 5.33 (s, I H), 5.27 (s, I H), 4.33 (t, I H), 3.84 (m, I H), 3.71 (m, I H), 3.68 (s, 3H), 3.61 (s, 3H), 3.24 (m, I H), 2.83-2.93 (m, 3H), 2.35 (m, I H), 1.92-2.23 (m, 10 6H), 0.86-0.97 (m, 6H). Example HP O O 1) 'B-B Bcc Br N N Pd(dppf)Cl 2 H H 2) 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]- Br- / _ N N pyrrolidine-1-carboxylic acid tert-butyl ester IN Boc 2-[5-(6-Bromo-naphthalen-2-yl)-1 H imidazol-2-yl]-pyrrolidine-1 carboxylic acid tert-butyl ester 1) HCI, dioxanes H MeOH I Bc 2) DEBT, NaHCO 3 NO N 2-[5-(6-{4-[2-( 1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-3H-O imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1 H-imidazol-2 yI]-pyrrolidine-1-carboxylic acid tert-butyl ester O NH HN OH [2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl) pyrrolidin-2-yl]-3H-imidazol-4-yI}-naphthalen-2-y)-phenyl]-1 H-imidazol 2-yl}-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-carbamic acid methyl ester 829 2- [5-(6-{4-12-(1 -tert-butyloxycarbonyl-pyrrolid in-2-yl)-3H-im idazol-4-yl]-phenyl} naphthalen-2-yl)-1H-imidazol-2-yI]-pyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of 2-[5-(4-Bromo-phenyl)-IH-imidazol-2-yI]-pyrrolidine-l-carboxylic acid tert-butyl ester (0.39 g, 1.0 mmol) and bis(pinacolato)diborane (0.31 g, 1.2 mmol, 1.2 equiv.) in dioxane 5 (5 mL) was added KOAc (0.30 g, 3.0 mmol, 3 equiv.) and Pd(dppf)C1 2 (0.04 g, 0.05 mmol, 0.05 equiv.). The slurry was degassed with argon for 5 minutes and heated to 85 'C for 2.5 hours. The resulting solution was cooled to room temperature and 2-[5-(6-Bromo-naphthalen-2-yl)-I H imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 1.0 mmol, I equiv.) and

K

3

PO

4 (aqueous, 2 M, 1.75 mL, 3.5 mmol, 3.5 equiv.) was added. The reaction mixture was 10 heated to 85 *C for 6 hours. The slurry was filtered through CELITE and concentrated. The crude product was purified by column chromatography (SiO 2 , 50--100% EtOAc in Hexanes (2% MeOH)) and preparative HPLC (Gemini, 15-40% MeCN in H 2 0 (0.1% formic acid)) to provide 2-[5-(6-{4-[2-(I-tert-butyloxycarbonyl-pyrrolidin-2-y)-3H-imidazol-4-yl]-phenyl} naphthalen-2-yl)- IH-imidazol-2-yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (0.07 g, 10%) 1 5 as a white powder. LCMS-ESI*: calc'd for C 40

H

46

N

6 0 4 : 674.4 (M *); Found: 675.6 (M+H*). [2-(2-{5-14-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yli]-3H imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1 phenyl-ethyll-carbamic acid methyl ester. To a slurry of 2-[5-(6-{4-[2-(1-tert 20 butyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl)-naphthalen-2-yl)-1 H-imidazol-2 yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (0.07 g, 0.09 mmol) in MeOH (0.1 mL) was added HCI in dioxanes (4 M, 1.5 mL). The resulting solution was stirred at room temperature for 2 hour and basified with NaOH (2 N). The crude product was extracted with CH 2

CI

2 . The organic extracts were combined, dried over Na 2

SO

4 and concentrated. (R) 25 Methoxycarbonylamino-phenyl-acetic acid (0.08 g, 0.4 mmol, 4.4 equiv.) and DMF (1.0 mL) were then added, followed by DEPBT (0.12 g, 0.4, 4 equiv.) and NaHCO 3 (0.04 g, 0.43 mmol, 4 equiv.). The resulting slurry was stirred at room temperature for 7 days. The reaction mixture was purified by preparative HPLC (Gemini, 15-40% MeCN in H 2 0 (0.1% formic acid)) and lyophilized to provide [2-(2-{5-[4-(6-{2-[I-(2-Methoxycarbonylamino-2-phenyl-acetyl) 30 pyrrolidin-2-yl]-3 H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]- IH-imidazol-2-yl}-pyrrolidin-I yl)-2-oxo-l-phenyl-ethyl]-carbamic acid methyl ester (0.04 g, 49%) as a white powder. LCMS ESI*: calc'd for C 5 0

H

4 8

N

8 0 6 : 856.4 (M *); Found: 858.1 (M+H*). 'H-NMR: 400 MHz, (CDCl 3 ) 8: (Mixture of rotomers) 10.32-10.45 (m, 2H), 8.26 (s, I H), 8.00 (s, I H), 7.72-7.98 (m, 8H), 7.19-7.50 (m, 12H), 6.07 (m, 2H), 5.28-5.55 (m, 4H), 3.73 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 35 3.22 (m, 2H), 2.86-2.96 (m, 2H), 2.22 (m, 2H), 2.04 (m, 2H), 1.92 (m, 2H). 830 Example HQ 0 O NH H HATU, K 3

PO

4 N N - N N H 0 HH-I H ~ 0 N O H~ O OH -3HCI 0 {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl) phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1- Methoxycarbonylamino carbonyl]-propyl}-carbamic acid methyl ester o-tolyl-acetic acid 0 -I N\ N N 0N Ozz /O [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl} pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2-yl1-3H 5 imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine- -carbonyl)-2 methyl-propyll-carbamic acid methyl ester. This compound was prepared following the procedure for [1-(2-{5-[6-(4-{2-[I-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yI]-IH-imidazol-2-yl}-pyrrolidine-I-carbonyl) 2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-o-tolyl-acetic acid 10 (0.03 g, 0.12 mmol, 1.75 equiv.) to provide [1-(2-{5-[6-(4-{2-[l-(2-Methoxycarbonylamino-2-o tolyl-acetyl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl} pyrrolidine-l-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 50%) as a white powder. LCMS-ESI: calc'd for C 48

H

52

N

8 0 6 : 836.4 (M *); Found: 837.4 (M+H*). 'H-NMR: 400 MHz, (CDC 3 ) 8: (Mixture of diastereomers) 7.61-8.00 (m, 16H), 7.18-7.41 (m, 12H), 7.10 15 (s, 2H), 5.28-5.63 (m, IOH), 4.36 (t, 2H), 3.72-3.86 (m, 4H), 3.68 (s, 6H), 3.66 (s, 6H), 2.79 3.07 (m, 8H), 2.50 (s, 31H), 2.44 (s, 31H), 2.38 (m, 4H), 1 .86-2.28 (m, 8H), 0.88-0.94 (m, 12H). 831 Example HR 0 NH COMU, K 3

PO

4 ~-N Y N\ H H___ _ N N oO O OH I HCI0 N 11 -3HClO {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl) phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1- Methoxycarbonylamino-(2 carbonyl]-propyl}-carbamic acid methyl ester methoxy-phenyl)-acetic acid 0 NH N 1 NN HH -N 0 NH Ozz X0 /O {1 -[2-(5-{6-[4-(2-{1 -[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl] pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}- 1H-imidazol-2-yl) pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester 5 {1 -[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2 yl)-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1 H-imidazol-2-yi)-pyrrolidine-1-carbonyl] 2-methyl-propyl}-carbamic acid methyl ester. To a solution of {2-Methyl-l-[2-(5-{6-[4-(2 pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1 H-imidazol-2-yl)-pyrrolidine-l carbonyl]-propyl}-carbamic acid methyl ester (0.04 g, 0.05 mmol) and (S) 10 Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid (0.02 g, 0.08 mmol, 1.5 equiv.) in

CH

2 Cl 2 (0.5 mL) was added K 3

PO

4 (0.03 g, 0.15 mmol, 3 equiv.). The slurry was cooled to 0 'C and COMU (0.03 g, 0.06 mmol, 1.25 equiv.) and the reaction was stirred at 0 'C for I hour. The slurry was diluted with CH 2 C1 2 and filtered. The filtrate was concentrated and the crude product was purified by preparative HPLC (Gemini, 15-40% MeCN in H 2 0 (0.1% formic 15 acid)) and lyophilized to provide ( -[2-(5-{6-[4-(2-{ I-[2-Methoxycarbonylamino-2-(2 methoxy-phenyl)-acetyl]-pyrrol idin-2-yl } -3 H-imidazol-4-yl)-phenyl]-naphthalen-2-yl} -l H imidazol-2-yl)-pyrrolidine- I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.02 g, 50%) as a white powder. LCMS-ESI*: calc'd for C 48

H

52

N

8 0 7 : 852.4 (M *); Found: 853.6 (M+H*). 'H-NMR: 400 MHz, (acetone-d 6 ) 8: (Mixture of rotomers) 10.96-11.01 (m, 2H), 8.29 20 (s, I H), 8.07 (s, I H), 7.73-7.89 (m, 7H), 7.35-7.48 (m, 4H), 7.33 (t, I H), 7.05 (d, I H), 6.96 (t, I H), 6.36 (d, I H), 5.91 (d, I H), 5.21-5.26 (m, 31H), 4.29 (t, I H), 3.90 (s, 3H), 3.78-3.93 (m, 2H), 832 3.60 (s, 3H), 3.58 (s, 3H), 3.30 (q, 2H), 2.59-2.65 (m, 2H), 2.36 (m, I H), 1.90-2.21 (m, 6H), 0.85-0.93 (m, 6H). Example HS 5 (1-{2-15-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-naphthalen-2-yl)-1H-benzoimidazol-2-yl]-azetidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester 10 H N N N N' H N N 0~ 0 H i N'H 0.._. 10 N (1 -{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-naphthalen-2-yl)-1H-benzoimidazol-2-yl]-azetidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (1 -{2-[5-(6-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol-4 yl}-naphthalen-2-yl)-l H-benzoimidazol-2-yl]-azetidine- I -carbonyl}-2-methyl-propyl)-carbamic 15 acid methyl ester was prepared following method YYY substituting azetidine-1,2-dicarboxylic acid I -tert-butyl ester for pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. C 4 1

H

4 8

N

8 0 6 calculated 748.4 observed [M + 1]* 749.4; rt = 1.59 min. 1 H (DMSO-d6): 8 = 8.31 (d, J = 6.4 Hz, 2H), 8.16 (m, 2H), 8.04 (m, 2H), 7.98 (m, I H), 7.90 (d, J = 8.8 Hz, I H), 7.78 (s, 2H), 7.42 (d, J= 7.6 Hz, I H), 7.32 (d, J= 8.8 Hz, I H), 5.49 (t, J= 6.8 Hz, I H), 5.15 (t, J= 6.8 Hz, I H), 20 4.41 (m, 2H), 4.12 (t, J= 8.0 Hz, 2H), 3.85 (m, I H), 3.78 (t, J= 8.0 Hz, I H), 3.55 (s, 3H), 3.53 (s, 3 H), 2.76 (m, I H), 2.65 (m, I H), 2.41 (m,I H), 2.17 - 2.08 (m, 2H), 2.03 (m, 2H), 1.86 (m, I H), 0.83 (m, 6H). 833 Example HT (1-{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-azetidin-2-yl]-3H benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl propyl)-carbamic acid methyl ester 5 O H * ~-0 N

N

4 PN - N N H N N N N H (1 -{2-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-azetidin-2-yl]-3H benzoimidazol-5-yl}-biphenyl-4-y)-1 H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (I -{2-[5-(4'-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-azetidin-2-yl]-3H 10 benzoimidazol-5-yl}-biphenyl-4-yl)- I H-imidazol-2-yl]-pyrrolidine-l -carbonyl}-2-methyl propyl)-carbamic acid methyl ester was prepared following method YYY substituting azetidine 1,2-dicarboxylic acid 1-tert-butyl ester for pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.

C

43

H

so

N

8 0 6 : calculated 774.4 observed [M + 1] 775.8; rt = 1.66 min. 1 H (DMSO-d6): 8 = 8.11 (s, I H), 7.91 (m, 3H), 7.86 (m, 5H), 7.72 (d, J= 8.0 Hz, I H), 7.65 (d, J= 8.4 Hz, I H), 7.42 (d, J 15 = 7.6 Hz, I H), 7.32 (d, J= 8.4 Hz, I H), 5.47 (t, J= 6.4 Hz, I H), 5.12 (t, J= 7.2 Hz, I H), 4.40 (m, 2H), 4.11 (t, J= 7.6 Hz, I H), 3.84 (m, 2H), 3.69 (m, 2H), 3.55 (s, 3H), 3.53 (s, 3H), 2.75 (m, I H), 2.63 (m, I H), 2.39 (m, 1 H), 2.18 - 2.03 (m, 2H), 2.01 (m, 2H), 1 .86 (m, I H), 0.83 (m, 6H). 834 Example HU O N TO n-Bui, THF, -78 "C: N O25M HCI(8, RT H 0 N Br- CF3 O N '' CF 3 F N Br 3CF3 2-sopropy-3,6-dimethoxy- THF, RT 2-isopropyl-3,6-dimethoxy-5- 2-Amino-5,5,5-tnfluoro 2,5-dihydro-pyrazine (3,3,3-tinfluoro-propyl) 2.5-dhydro-pyrazine Pentafloic ad methyl ester H 0 H 0H CIC02Me, TEA OO L O O + H N N>No DCM, RT CF 3 MeOH, RT CF 3 H 5,5,5-Trifluoro-2-methoxy- 5,5,5-Trifluoro-2-methoxy 2-(5-[4'-(2-Pyrrolidin-2-yl-3H-imidazoi-4-yl) carbonylamino-pentanoic acid carbonylamino-pentanoic acid bipheny-4-yl]-1H-imidazol-2-yl}-pyrrolidine methyl ester 1-carboxylic acid tert-buty ester ~-0 HATU, DIPEA, O>NH H TFA, DCM, RT N\ -- 0 N N __ ____ DMF, RT F 3 C NO N O d / N. H 2-[5-(4'-{2-[1-(5,5,5-Trfluoro-2-methoxycarbonylamino pentanoyl)-pynnlidin-2-yl-3H-imidazol-4-y}-biphenyl-4-yl)-1 H imidazol-2-yI}-pyrrolidine-1-carboxylic acid tert-butyl ester ~-0 H 0 NH H O O N\- - - N N0 FC NO N H HATU, DIPEA. DMF, RT [4,4.4-Trfluoro-1-(2-{5-[4'-(2-pyrrolidin-2-yl-3H-imidazol-4-y)-biphenyl-4-yl 1 H-imidazol-2-yl)-pyrrolidine-1-carbonyl)-butyU-carbamic acid methyl ester NH H N\I /

F

3 C NO NN H HN 0 (4,4,4-Trfluoro-1-{2-(5-(4'-{2-[1-(2-methoxycarbonylamino 3-methyl-butyry)-pyrrolidin-2-y}t3H-irmidazol-4-y-bipheny-4-yl)-1 H imidazol-2-yl}-pyrrolidine-1-carbonyl}-butyt)-carbamic add methyl ester 5 2-Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine: To a stirred solution of 2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (I mL, 5.58 mmol) in TH F (13.5 mL) under argon at -78* C was added a solution of n-butyllithium (2.5 M, 2.3 mL, 5.75 mmol). The solution was stirred at -78' C for 30 minutes. A solution of I -lodo-3,3,3-trifluoropropane 10 (925 p L, 5.87 mmol) in THF (11.5 mL) was added slowly. The resulting solution was stirred at -78* C for 5 hours, warmed to room temperature and diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NH 4 Cl solution, water and brine. The organic layer was then dried (MgSO 4 ), concentrated and purified by flash chromatography to yield 2-Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine (915 mg, 15 59%). 'H-NMR: 400 MHz, (CDC 3 ) 8: 4.04-3.99 (m, H), 3.98-3.95 (m, I H), 3.71 (s, 3H), 3.68 835 (s, 3 H), 2.29-2.20 (m, I H), 2.18-2.04 (in, 3 H), 1.94-1.84 (m, I H), 1.03 (d, J = 6.9 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H) ppm. 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid methyl ester: A solution of 2 5 Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine (725 mg, 2.59 mmol) in 0.25N HCI was stirred at room temperature for 3 hours. The aqueous solution was washed once with ethyl acetate. The ethyl acetate rinsing was discarded and the aqueous layer was basified to pH-1l with saturated aqueous NaHCO 3 . The aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO 4 ) and 10 concentrated to give crude (2S)-amino-5,5,5-trifluoro-pentanoic acid methyl ester contaminated with D-valine methyl ester. The crude material was dissolved in dichloromethane (20 mL) and cooled to 0 C. Triethylamine (1.75 mL, 12.6 mmol) and methyl chloroformate (480 p L, 6.2 mmol) were successively added to the solution. After I hour the reaction was concentrated and purified by flash chromatography to yield 5,5,5-Trifluoro-2-methoxy-carbonylamino-pentanoic 15 acid methyl ester (465 mg, 74%). 1 H-NMR: 400 MHz, (CDCl 3 ) 8: 5.27 (br, I H), 4.42 (br, I H), 3.79 (s, 3H), 3.70 (s, 3H), 2.29-2.09 (m, 3H), 1.94-1.84 (m, I H) ppm. 2-15-(4'-12-[I-(5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yI]-pyrrolidine-l-carboxylic acid tert-butyl 20 ester: To a solution of 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid methyl ester (194 mg, 0.80 mmol) in methanol (3 mL) was added an aqueous LiOH solution (I M, 2 mL, 2 mmol). The resulting solution was stirred at room temperature for 45 minutes and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCL. The acidified aqueous layer was extracted twice with ethyl acetate. The 25 combined organics were washed with brine, dried (MgSO 4 ), and concentrated to give clean 5,5,5-Trifluoro-2-methoxy-carbonylamino-pentanoic acid. To a solution of the pentanoic acid in dimethylformamide (2 mL) was added HATU (300 mg, 0.79 mmol). After stirring for 5 minutes, a solution of 2-{5-[4'-(2-pyrrolidin-2-yl-3 H-imidazol-4-yl)-biphenyl-4-yl]-I H imidazol-2-yl}-pyrrolidine-I-carboxylic acid tert-butyl ester (412 mg, 0.79 mmol) in 30 dimethylformamide (1.9 mL) was added to the reaction, followed immediately by diisopropylethylamine (275 pL, 1.58 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO 4 ), concentrated and purified by flash chromatography to yield 2-[5-(4'-{2-[1 (5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-y]-3H-imidazol-4-yl} 836 biphenyl-4-yl)-Il H-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (340 mg, 59%). LCMS-ESI: calculated for C 38 14 4

F

3

N

7 0 5 : 735.34; observed [M+1]+: 736.05. [4,4,4-Trifluoro-1-(2-{5-[4'-(2-pyrrolidin-2-yI-3H-imidazol-4-yl)-biphenyl-4-y]-1 H 5 imidazol-2-yl}-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester: To a solution of 2-[5-(4'- {2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-biphenyl-4-yi)- I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (340 mg, 0.46 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (I mL). The reaction was stirred at room temperature for 3 hours and then thoroughly concentrated. The 10 resulting residue was dissolved in dichloromethane and washed three times with saturated aqueous NaHCO 3 solution. The organic layer was dried (MgSO 4 ), and concentrated to give the crude free pyrrolidine (270 mg, 92%), which was clean enough to use without further purification. LCMS-ESI+: calculated for C 3 3

H

3 6

F

3

N

7 0 3 : 635.28; observed [M+1]+: 636.17. 15 (4,4,4-Trifluoro-1-{2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yI}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl) carbamic acid methyl ester: To a solution of crude [4,4,4-Trifluoro-1-(2-{5-[4'-(2-pyrrolidin 2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-I H-imidazol-2-yl}-pyrrolidine-l -carbonyl)-butyl] 20 carbamic acid methyl ester (125 mg, 0.20 mmol) in dimethylformamide (0.6 mL) was added a solution of 2-methoxycarbonylamino-3-methyl-butyric acid (38 mg, 0.22 mmol) and HATU (82 mg, 0.22 mmol) in dimethylformamide (0.6 mL). Diisopropylethylamine (70 P L, 0.40 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The solution was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H 2 0 + 25 0.1% HCO 2 H) to yield (4,4,4-trifluoro-1 -{2-[5-(4'-{2-[I-(2-methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-I H-imidazol-2-yl]-pyrrolidine-I carbonyl}-butyl)-carbamic acid methyl ester (73 mg, 47%). LCMS-ESI: calculated for

C

40

H

47

F

3

N

8 0 6 : 792.85; observed [M+1]*: 794.33. 'lH-NMR: 400 MHz, (CD 3 0D) 8: 7.82-7.70 (m, 4H), 7.68-7.63 (m, 4H), 7.32-7.31 (m, 2H), 5.20-5.16 (m, 2H), 4.56-4.51 (m, I H), 4.26-4.22 30 (m, I H), 4.04-3.96 (m, I H), 3.91-3.84 (m, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.51-3.46 (m, I H), 2.38-1.96 (m, 12H), 1.90-1.78 (m, I H), 1.01-0.89 (m, 6H) ppm. 837 Example HV 0 H NH H

F

3 C No NF U j H HATU, DIPEA, DMF, RT [4,4,4-Trifluoro-1-(2-{5-[4'-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl] 1 H-imidazol-2-yl-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester NH H 0- 0N ,-N CF 3

F

3 C N N H HN-. UZ 0 (4,4,4-Trifluoro-1-(2-[5-(4'{2-[1-(5,5,5-trfluoro-2-methoxycarbonylamino pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl)-biphenyl-4-yl)-1H imidazol-2-yl]-pyrrolidine-1-carbonyl)-butyl)-carbamic acid methyl ester (4,4,4-Trifluoro-1-{2-[5-(4'-12-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl) 5 pyrrolidin-2-yll-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1 carbonyl}-butyl)-carbamic acid methyl ester: To a solution of crude [4,4,4-Trifluoro-l-(2-{5 [4'-(2-pyrrolidin-2-yl-3H-imidazol-4-yi)-biphenyl-4-yl]-1 H-imidazol-2-yl}-pyrrolidine-l carbonyl)-butyl]-carbamic acid methyl ester (115 mg, 0.18 mmol) in dimethylformamide (0.5 mL) was added a solution of 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid (44 mg, 10 0.19 mmol) and HATU (72 mg, 0.19 mmol) in dimethylformamide (0.5 mL). Diisopropylethylamine (65 4L, 0.37 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The solution was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H 2 0 + 0.1% HCO 2 H) to yield (4,4,4-Trifluoro-1 -{2-[5 (4'- {2- [1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3 H- -imidazol-4 15 yl}-biphenyl-4-yl)- 1 H-imidazol-2-yl]-pyrrolidine- 1 -carbonyl}-butyl)-carbamic acid methyl ester (35 mg, 23%). LCMS-ESl*: calculated for C 4 0H44F 6

N

8

O

6 : 846.82; observed [M+1 ]+: 847.34. 'H-NMR: 400 MHz, (CD 3 0D) 8: 7.81-7.72 (m, 4H), 7.67-7.64 (m, 4H), 7.38-7.32 (m, 2H), 5.20-5.16 (m, 2H), 4.55-4.51 (m, 2H), 3.91-3.86 (m, 4H), 3.67 (s, 6H), 2.38-2.20 (m, 8H), 2.18 1.79 (m, 8H) ppm. 20 N O 'O N -' O'CF 2-Isopropyl-3,6-dimethoxy-5-[2-(2,2,2 trfluoro-ethoxy)-ethyl]-2,5-dihydro-pyrazine 838 2-Isopropyl-3,6-d imethoxy-5-[2-(2,2,2-trifluoro-ethoxy)-ethyl] -2,5-d ihydro-pyrazine: This compound was made in 65% yield by the same procedure as 2-Isopropyl-3,6-dimethoxy-5 (3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine, substituting 1 -Iodo-3,3,3-trifluoropropane with 2 (2-Bromoethoxy)-I,1,l-trifluoroethane. 'H-NMR: 400 MHz, (CDCl 3 ) 6: 4.11-4.05 (m, I H), 5 3.95 (t, J = 3.5 Hz, I H), 3.86-3.75 (m, 3 H), 3.74-3.66 (m, 7H), 2.30-2.18 (m, 2H), 1.92-1.82 (m, I H), 1.03 (d, J = 6.9 Hz, 3H), 0.70 (d, J = 6.8 Hz, 3H) ppm. Or H 0 O CF 3 2-Methoxycarbonylamino-4 (2,2,2-trifiuoro-ethoxy)-butyric acid methyl ester 2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyric acid methyl ester: This 10 compound was made by the same procedure as 5,5,5-Trifluoro-2-methoxycarbonylamino pentanoic acid methyl ester, using 2-Isopropyl-3,6-dimethoxy-5-[2-(2,2,2-trifluoro-ethoxy) ethyl]-2,5-dihydropyrazine as the starting material. 1 H-NMR: 400 MHz, (CDCl 3 ) 6: 5.51-5.43 (br, I H), 4.51-4.43 (m, I H), 3.83-3.63 (m, I OH), 2.22-2.13 (m, I H), 2.13-2.03 (m, I H) ppm. 15 NH H 0 NO-O 0 N N

CF

3 <- H 2-{5-[4'-(2-{1-[2-Methoxycarbonylamino-4-(2,2,2-trifluoro ethoxy)-butyryl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-biphenyl-4 yl]-lH-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester 2-{5-14'-(2-{1-[2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyryll-pyrrolidin-2 yI)-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yI}-pyrrolidine-1-carboxylic acid tert 20 butyl ester: This compound was made in 74% yield by the same procedure as 2-[5-(4'-{2-[1 (5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrol idin-2-yl]-3 H-imidazol-4-yl} biphenyl-4-yl)-l H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid Iert-butyl ester, using 2 Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyric acid methyl ester as the starting material. LCMS-ESl*: calculated for C 39

H

46

F

3

N

7 0 6 : 765.35; observed [M+1]+: 766.12. 25 839 ~-0 o- N N oN N C<\ H \-CF 3 _' [1 -(2-{5-[4'-(2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1 H imidazol-2-yl}-pyrrolidine-1 -carbonyl)-3-(2,2,2-trifluoro-ethoxy) propyl]-carbamic acid methyl ester [1-(2-{5-[4'-(2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-y]-1H-imidazol-2-yl} pyrrolidine-1-carbonyl)-3-(2,2,2-trifluoroethoxy)-propyl]-carbamic acid methyl ester: This 5 compound was made by the same procedure as [4,4,4-Trifluoro-I-(2-{5-[4'-(2-pyrrolidin-2-yl 3 H-imidazol-4-yl)-biphenyl-4-yl]- I H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-butyl]-carbamic acid methyl ester, using 2-{5-[4'-(2-{ -[2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy) butyryl]-pyrrolidin-2-yI}-3 H-imidazol-4-yl)-biphenyl-4-yl]-I H-imidazol-2-yl}-pyrrolidine-l carboxylic acid tert-butyl ester as the starting material. LCMS-ESI*: calculated for 10 C 34

H

38

F

3

N

7 0 4 : 665.29; observed [M+1]+: 666.20. Example HW D F FHH D0 0 H D D O D D D& D~ N-~ + N N - - NH 2 D Na 2

CO

3 , NaOH H' H L-Valine, d8 2-Methoxycarbonylamino 3-methyl-butyric acid, d8 2-(2-Aza-bicyclo[2.2.1]hept-3-yl)-6{7-[5-(5-aza spiro[2.4]hept-6-yl)-1H-pyrrol-2-y]-9,9-difluoro-9H-fluoren 2 -yl}-1 H-benzoimidazole

D

0 NF F H- 7 ) DO DIPDM D ON N N D D DP ,HOBt D N (1 -{3-[6-(9,9-Difluoro-7-{2-[5-(2 methoxycarbonylamino-3-methyl-butyryl, d8)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2 yl)-1 H-benzoimidazol-2-yl]-2-aza bicyclo[2.2. 1 ]heptane-2-carbony}-2-methyl-propyl) carbamic acid methyl ester,d8 15 To a solution of L-valine, d8 (Cambridge Isotope Laboratories, 0.4949 g) in IN sodium hydroxide (3.95 mL) was added sodium carbonate (0.419 g). The solution was cooled to 0*C and methyl chloroformate (0.289 mL) was added dropwise over 30 minutes and reaction mixture 840 was stirred for 3 h at 0*C. Reaction mixture was washed with ethyl ether (3 x 15 mL) and aqueous layer was acidified to pH =1 with concentrated HCL. Aqueous layer was extracted dichloromethane (3 x 15 mL) and organic layers were dried (MgSO 4 ) and concentrated to give 2-Methoxycarbonylamino-3-methyl-butyric acid, d8 as a white solid (0.5681 g). 5 LCMS-ESI~: calc'd for C 7 HsD 8

NO

4 : 184.2 (M+H*); Found: 184.0 (M+H*). A solution of hydroxybenzotriazole (0.242 g), 1-(3-dimethylaminepropyl)-3-ethylcarbodiimide HCI (0.328 g) and 2-Methoxycarbonylamino-3-methyl-butyric acid, d8 (0.315g) in DMF (5.0 mL) was stirred at rt for I hr. Reaction mixture was cooled to 0 0 C and a solution of 2-(2-Aza 10 bicyclo[2.2.1 ]hept-3-yl)-6-{7-[5-(5-aza-spiro[2.4]hept-6-yl)-I H-pyrrol-2-yl]-9,9-difluoro-9H fluoren-2-yl}-1H-benzoimidazole in DMF (2.0 mL) was added, followed by dropwise addition of diisopropylethylamine over 15 min. Reaction mixture was warmed to rt overnight, diluted with ethyl acetate and washed with brine, brine/saturated sodium bicarbonate solution (1:1) and aqueous layers back-extracted with ethyl acetate. The combined organic layer was dried 15 (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 0 to 5% methanol/ethyl acetate), then and purified by preparative reverse phase HPLC (Gemini, 25 to 100% ACN/H 2 0 + 0.1% TFA). The product-containing fractions were pooled and treated with saturated sodium bicarbonate solution at 0 *C for I h. Product was extracted with ethyl acetate (2x), combined organic layer was dried (MgSO 4 ), concentrated and lyophilized from ACN/H 2 0 20 to give (I -{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl, d8)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-I H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester,d8 as a white powder (0.3947) ' H-NMR: 300 MHz, (DMSO-d 6 ) 8: 12.13 (s, I H), 11.77 (s, I H), 8.1 - 7.1 (m, 12H), 7.23 (s, 25 1 H), 7.14 (s, I H), 5.2-5.1 (m, I H), 4.60 (d, J=4.5 Hz, I H, 4.48 (s, I H), 3.8-3.6 (m, 2H), 3.48 (s, 6H), 2.60 (s, I H), 2.40-2.01 (m, I OH), 0.64-0.52 (m, 4 H). LCMS-ESI: calc'd for C 4 9

H

3 8

DI

6

F

2

N

8 0 6 : 906.1 (M+H*); Found: 905.6 (M+H*). 841 Example HX F F H H N '' 1. HCI, dioxane Bn0 0 /\c /\ \ Bn" N2. ECOI, HOBt, N rN - -DIEPA, DMF HO .--- 3-(6-{7-[5-(5-Benzyloxycarbonyl-5-HO.N.O. aza-spiroL2.4]hept-6-y)-1 H-pyrrol- 0 H 2-yl]-9,9-difluoro-gH-fluoren-2-y}- 2-Methoxycarbonylamino 1 H-benzoimidazol-2-yI)-2-aza- 3-methyl-butyric acid bicyclo[2 .2. 1 ]heptane-2-carboxylic 3. Pd/C, H 2 , acid tedt-butyl ester wet IPA F F H H1. Pd/C, H 2 , wet iPA 2. ECDI, HOBt, H i ~ /\ /\ N DIEPA, DMF H 0 0 0 HO N 0.1 {1 -[3-(6-{7-[5-(5-Aza-spiro[2.4]hept-6-y)-1 H- 0 H pyrrol-2-yI]-9,9-difluoro-9H-fluoren-2-y}-1 H- 0 H benzoimidazol-2-yi)-2-aza- 2-Methoxycarbonylamino bicyclo[2.2. 1 ]heptane-2-carbonyl]-2-methyl- 3-methyI-butyrnc acid propyl}-carbamic acid methyl ester " ' 0 ECDI, HOBt 0 N\ / \ / - T.O~ No DIEPA, DMF N N H-

-

H (1 -{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl butyryl)-5-aza-spiro[2.4]hept-6-y]-3H-imidazol-4-y}-9H-fluoren-2 yl)-l H-benzoimidazol-2-yI]-2-aza-bicyclo[2.2. 1 ]heptane-2-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester 0H HO C1 O 0HO HO CN 0 0Na2CO3 NaOH H' f

NH

2 23 oN 0-Valine 2-Methoxycarbaonylamino 3-methyl-butyric acid 842 To a solution of 3-(6-(7-[5-(5-Benzyloxycarbonyl-5-aza-spiro[2.4]hept-6-yl)- I H-pyrrol-2-yl] 9,9-difluoro-9H-fluoren-2-yl}-I H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2 carboxylic acid tert-butyl ester (1.0 g), in CH 2 C1 2 (10 mL) at 0 *C was added 4 N HCI in 5 dioxane (2.0 mL). Reaction mixture was stirred at 0 *C for 5 minutes, then warmed to rt. After stirring for 1.5 h, reaction mixture was concentrated and dried overnight under vacuum to give an off-white powder (0.8826 g). Powder was suspended in ethyl acetate and saturated sodium bicarbonate solution and stirred for I h. Aqueous layer was extracted with ethyl acetate (2x), dried (MgSO 4 ), and concentrated. A portion of this residue was used in the next step. 10 A solution of hydroxybenzotriazole (40 mg), 1-(3-dimethylaminepropyl)-3-ethylcarbodiimide HCI (57 mg) and 2-Methoxycarbonylamino-3-methyl-butyric acid (54 mg) in DMF (0.5 mL) and CH 2 Cl 2 (0.5 mL) was stirred at 0*C for I hr. This solution was added to a solution the above amine (150 mg) in DMF (0.5 mL) and CH 2

C

2 (0.5 mL) at -20*C and stirred at this temperature overnight. Reaction mixture was diluted with ethyl acetate and washed with brine, 15 brine/saturated sodium bicarbonate solution (1:1) and aqueous layers back-extracted with ethyl acetate. The combined organic layer was dried (MgSO 4 ), concentrated and purified by flash column chromatography (silica gel, 0 to 5% methanol/ethyl acetate) to 6-[5-(9,9-Difluoro-7-{2 [2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2. I ]hept-3-yl]-3H benzoimidazol-5-yl}-9H-fluoren-2-yl)-I H-pyrrol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic 20 acid benzyl ester as a yellow foam (127 mg). LCMS-ESI+: calc'd for CsoH 49

F

2

N

7 0 5 : 865.96 (M+H*); Found: 866.3 (M+H*). A mixture of 6-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2. I ]hept-3-yl]-3 H-benzoimidazol-5-yl}-9H-fluoren-2-yl)- I H-pyrrol-2-yl]-5-aza 25 spiro[2.4]heptane-5-carboxylic acid benzyl ester (127 mg) and 10% palladium on carbon, wet (29 mg) in ethanol (4 mL) was stirred under an hydrogen atmosphere for 18 h. Added more and 10% palladium on carbon, wet (50 mg) and continued reaction for 30 h. Reaction mixture was filtered through a pad of CELITE, concentrated and purified by flash column chromatography (silica gel, 5 to 20% methanol/dichloromethane) to give { -[3-(6-{7-[5-(5-Aza-spiro[2.4]hept-6 30 yl)-l H-pyrrol-2-yl]-9,9-difluoro-9H-fluoren-2-yl}-I H-benzoimidazol-2-yl)-2-aza bicyclo[2.2.l]heptane-2-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester as a pale yellow film (21 mg). LCMS-ESl*: calc'd for C 4 2

H

4 3

F

2

N

7 0 3 : 732.8 (M+H*); Found: 732.4 (M+H*). 843 A solution of hydroxybenzotriazole (5.4 mg), 1-(3-dimethylaminepropyl)-3-ethylcarbodiimide HCI (7.7 mg) and 2-Methoxycarbonylamino-3-methyl-butyric acid (7.0 mg) in DMF (0.2 mL) and CH 2 Cl 2 (0.2 mL) was stirred at 0 0 C for 1 hr. This solution was added to a solution {1 -[3-(6 {7-[5-(5-Aza-spiro[2.4]hept-6-yl)-I H-pyrrol-2-yl]-9,9-difluoro-9H-fluoren-2-y}-I H 5 benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane-2-carbonyl]-2-methyl-propyl }-carbamic acid methyl ester (21 mg) in DMF (0.4 mL) and CH 2

CI

2 (0.4 mL) at -25*C and stirred at this temperature overnight. Reaction mixture was diluted with ethyl acetate and washed with brine, brine/saturated sodium bicarbonate solution (1:1) and aqueous layers back-extracted with ethyl acetate. The combined organic layer was dried (MgSO 4 ), concentrated and purified by 10 preparative reverse phase HPLC (Gemini, 25 to 100% ACN/H 2 0 + 0.1% TFA). The product containing fractions were pooled, diluted with ethyl acetate and treated with saturated sodium bicarbonate solution at for I h. Product was extracted with ethyl acetate (2x), combined organic layer was dried (MgSO 4 ), concentrated and lyophilized from ACN/H 2 0 to (-{3-[6-(9,9 Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H 15 imidazol-4-yl}-9H-fluoren-2-yl)-I H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as a white powder (11.8 mg) 'H-NMR: 300 MHz, (DMSO-d 6 ) 8: 12.18 (s, I H), 12.05 (s 0.5H ), 11.48 (s, 0.5H), 8.1 - 7.1 (m, 10H), 5.75 (d, J=4.5 Hz, 0.5H), 5.190 (d, J=4.5 Hz, 0.5H), 4.63 (d, J=4.8 Hz, I H), 4.54 (s, I H), 4.12-4.0 (m, 2H), 3.8-3.2 (m , 9H), 2.65 (s, I H), 2.40-2.01 (m, 27H). 20 LCMS-ESl*: calc'd for C 4 9

H

54

F

2

N

8 0 6 : 890.0 (M+H*); Found: 889.4 (M+H*). To a solution of d-valine, (5.0 g) in IN sodium hydroxide (42.7 mL) was added sodium carbonate (4.53 g). The solution was cooled to 0*C and methyl chloroformate (0.289 mL) was added dropwise over 2 h and reaction mixture was stirred for 2 h at 0 0 C. White reaction mixture 25 was diluted with enough H 2 0 to form a colorless solution and washed with ethyl ether (3 x 30 mL). Aqueous layer was acidified to pH =2 with concentrated HCI to give a white precipitate that collected by filtration, washed with H 2 0 and dried under high vacuum to give 2 Methoxycarbonylamino-3-methyl-butyric acid as a crystalline white solid (4.668 g). LCMS ESr~: calc'd for C 7

H

13

NO

4 : 176.2 (M+H+); Found: 175.9 (M+H*). 30 844 Example HY -0 $.NH o N o

WCF

3 - H HN 0 [1-(2-{5-[4'-(2-{1-[2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy) butyryfl-pyrrolidin-2-yl}-3H-imidazol-4-yl)-biphenyl-4-y]-1 H-imidazol 2-yI}-pyrrolidine-1-carbonyl)-2-methyl-propy]-carbamic acid methyl ester 5 [1-(2-{5-[4'-(2-{1-[2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyryl]-pyrrolidin 2-yl}-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester: This compound was made in 45% yield by the same procedure as (4,4,4-Trifluoro-l -{2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-biphenyl-4-yl)-I H-imidazol-2-yl]-pyrrolidine-1 10 carbonyl}-butyl)-carbamic acid methyl ester, using [I -(2-{5-[4'-(2-Pyrrolidin-2-yl-3H-imidazol 4-yl)-biphenyl-4-yl]-l H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-3-(2,2,2-trifluoroethoxy) propyl]-carbamic acid methyl ester as the starting material. LCMS-ES*: calculated for

C

41

H

49

F

3

N

8 0 7 : 822.87; observed [M+l]]: 823.45. 'H-NMR: 400 MHz, (CD 3 0D)6: 7.82-7.72 (m, 4H), 7.69-7.65 (m, 4H), 7.38-7.32 (m, 2H), 5.22-5.16 (m, 2H), 4.65-4.61 (m, I H), 4.26-4.21 15 (m, I H), 4.04-3.84 (m, 6H), 3.72-3.48 (m, 8H), 2.39-1.98 (m, I OH), 1.88-1.78 (m, i H), 1.01 0.89 (m, 6H) ppm. Example HZ HH NH

F

3 C N N N 0

CF

3 H HN [1 -(2-{5-[4'-(2-{1-[2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy) butyryl)-pyrrolidin-2-yI}-3H-imidazo-4-y)-bipheny-4-y]-1 H-imidazol-2-yl} 20 pyrrolidine-1-carbonyl)-3-(2.2,2-trifluoro-ethoxy)-propyll-carbamic acid methyl ester [1-(2-{5-[4'-(2-{1-[2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyryl]-pyrrolidin 2-yl}-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl)-3-(2,2,2 trifluoro-ethoxy)-propyll-carbamic acid methyl ester: This compound was made in 27% 25 yield by the same procedure as (4,4,4-Trifluoro-1-{2-[5-(4'-{2-[1-(5,5,5-trifluoro-2 methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3 H-i midazol-4-yl}I -biphenyl-4-yl)- I H imidazol-2-yI]-pyrrolidine-I -carbonyl}-butyl)-carbamic acid methyl ester, using [1 -(2-{5-[4'-(2 845 Pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]- 1 H-imidazol-2-yl}-pyrrolidine- I -carbonyl)-3 (2,2,2-trifluoroethoxy)-propyll-carbamic acid methyl ester as the starting material. LCMS-ESI*: calculated for C 4 2

H

4 8

F

6

N

8 0 8 : 906.87; observed [M+11: 907.45. 'H-NMR: 400 MHz, (CD 3 0D) 8: 7.73-7.65 (m, 4H), 7.62-7.59 (m, 4H), 7.38-7.35 (m, 2H), 5.14-5.10 (m, 2H), 4.55-4.51 (m, 5 2H), 3.86-3.77 (m, 8H), 3.63-3.43 (m, 10H), 2.34-2.24 (m, 2H), 2.22-1.87 (m, 8H), 1.86-1.68 (m, 2H) ppm. Example IA Br S n-BuLi, THF, -78 *C; S O O N \Sn N N Si S n-Bu 3 SnC, -78 "C s Benzo[1,2-b:4,5-bldithiophene 2,6-bis(tri-n-butylstannyl) benzo[1,2-b:4,5-bJdithiophene 2-[4-Bromo.1 -(2-tnmettyilanyl pyrrolidine-1-carboxylic acid tert-butyl ester Pd(PP 3

)

4 0_' S N N conc. HCI toluene, 1N0 N O OO EtoH, 60 0 C HO H H 0 y OH SI N0 H j \ I H N N S 4 HCI O H HATU, DIPEA, DMF, RT 2-[5-(6-{2-[pyrrolidin-2-yl]-3H-imidazol-4-yl} benzo[1,2-b:4,5-bldithiophene-2-yl)-1H-imidazol-2-yl] pyrrolidine tetrahydrochloride ~-0 NH H O O O N N H HN 0 (1-{2-[5-(6-{2-(1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y] 3H-imidazol-4-yl}-benzo[1,2-b:4,5-bldithiophene-2-y)-1 H-imidazol-2-yl] pyrrolidine- 1 -carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 10 2,6-Bis(tri-n-butylstannyl)-benzo[1,2-b:4,5-b']dithiophene: To a stirred solution of benzo[1,2-b:4,5-b']dithiophene (820 mg, 4.3 mmol) in THF (100 mL) under argon at -78* C was added a solution of n-butyllithium (2.5 M, 3.44 mL, 8.6 mmol). The solution was stirred at -78* 15 C for 30 minutes and then warmed to -20* C for 30 minutes. Tri-n-butyltin chloride (2.34 mL, 8.6 mmol) was added and the reaction mixture was stirred at -20' C for 30 minutes and then allowed to warm to room temperature. After 16 hours, hexane was added and the reaction was 846 successively washed with water and brine, dried (MgSO 4 ), concentrated and purified by flash chromatography (100% hexanes). 2,6-bis(tri-n-butylstannyl)-benzo[ 1,2-b:4,5-b']dithiophene (1.4 g, 42%) was isolated along with product contaminated with the monostannylated benzodithiophene. ' H-NMR: 400 MHz, (CDCl 3 ) 8: 8.27 (s, 2H), 7.38 (s, 2H), 1.65-1.57 (m, 5 12H), 1.41-1.32 (m, 12H), 1.26-1.11 (m, 12H), 0.91 (t, J = 7.3 Hz, 18H) ppm. Fully protected 2-[5-(6-{2-[pyrrolidin-2-yl]-3H-imidazol-4-yl}-benzo[1,2-b:4,5 b']dithiophene-2-yl)- IH-imidazol-2-yl]-pyrrolidine: Pd(PPh 3

)

4 (61 mg, 0.053 mmol) was added to a degassed solution of 2,6-bis(tri-n-butylstannyl)-benzo[1,2-b:4,5-b']dithiophene (202 10 mg, 0.26 mmol) and 2-[4-Bromo- I -(2-trimethylsi lanyl-ethoxymethyl)- I H-imidazol-2-yl] pyrrolidine-l-carboxylic acid tert-butyl ester (260 mg, 0.58 mmol) in toluene (4 mL). The reaction was refluxed for 24 hours, then cooled to room temperature and filtered through CELITE and a palladium scavenging column (Stratospheres m PL-Guanidine MP SPE+, Part #: PL3514-CM89). The solids were rinsed twice with toluene. The filtrate was concentrated and 15 the crude product purified by flash chromatography to yield the desired, fully protected product (100 mg,41%). LCMS-ESlI: calculated for C 4 6

H

6 8

N

6 0 6

S

2 Si 2 : 920.42; observed [M+l ]+: 921.45. (1-{2-15-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl] 20 3H-imidazol-4-yl}-benzoll,2-b:4,5-b']dithiophene-2-yl)-IH-imidazol-2-yll pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: A solution of fully protected 2-[5-(6-{2-[pyrrolidin-2-yl]-3H-imidazol-4-yl}-benzo[1,2-b:4,5-b']dithiophene-2-yl) I H-imidazol-2-yl]-pyrrolidine (100 mg, 0. 11 mmol), ethanol (4 mL) and concentrated HCI (I mL) was heated to 600 C for 16 hours. The reaction was concentrated and the crude material 25 dissolved in DCM (10 mL). This solution was concentrated to yield crude 2-[5-(6-{2 [pyrrolidin-2-yl]-3H-imidazol-4-yl}-benzo[l,2-b:4,5-b']dithiophene-2-yl)-I H-imidazol-2-yl] pyrrolidine tetrahydrochloride. To this material was added a solution of 2 methoxycarbonylamino-3-methylbutyric acid (38 mg, 0.22 mmol) and HATU (83 mg, 0.22 mmol) in DMF (1.5 mL). To the resulting solution was added diisopropylethylamine (190 PL, 30 1.1 mmol). After stirring for 2 hours at room temperature, the reaction was concentrated and purified twice by preparative reverse phase HPLC (Gemini, 10 to 45% ACN/H 2 0 + 0.1%

HCO

2 H). The product fractions were passed through a freebasing column

(STRATOSPHERES"

m

PL-HCO

3 MP SPE, Part #: PL3540-C603) and lyophilized to give (1-{2 [5-(6-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl} 35 benzo[1,2-b:4,5-b']dithiophene-2-yl)-IH-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl 847 propyl)-carbamic acid methyl ester (29 mg, 34%). LCMS-ESI': calculated for C 38

H

46

N

8 0 6

S

2 : 774.95; observed [M+l ]+: 775.96. 'H-NMR: 400 MHz, (CD 3 0D) 8: 8.16-8.11 (m, 2H), 7.49 7.47 (m, 2H), 7.38-7.29 (m, 2H), 5.18-5.15 (m, 2H), 4.24 (d, J = 7.4 Hz, 2H), 4.04-3.96 (m, 2H), 3.91-3.86 (m, 2H), 3.66 (br s, 6H), 2.38-2.17 (m, 6H), 2.11-1.98 (m, 4H), 1.00-0.89 (m, 12H) 5 ppm. Example IB F F H H NB' 1. HCI, dioxane 00Bo BnY ~ \ / N N 2. ECDI, HOBt, DIEPA, DMF HHO O - r 3-(6-{7-[5-(5-Benzyloxycarbonyl-5- NO aza-spiro[2.4]hept-6-yl)-1 H-pyrrol- H' 2-yl]-9,9-difluoro-9H-fluoren-2-yl}-

O

1 H-benzoimidazol-2-yl)-2-aza- 2-Methoxycarbonylamino bicyclo[2.2. 1 ]heptane-2-carboxylic 3-methyl-butyric acid acid tert-butyl ester FN N 1. Pd/C, H 2 , wet iPA 0 0 N1'N Bn' O \ \N 2. ECDI, HOBt, N N - - - 0 DIEPA, DMF H HN O - H~' HO ON 6-[5-(9,9-Difluoro-7-{2-[2-(2- H'N O methoxycarbonylamino-3-methyl-butyryl)-2- O aza-bicyclo[2.2. 1 ]hept-3-yl]-3H benzoimidazol-5-yl}-9H-fluoren-2-yl)-1 H- 2-Methoxycarbonylamino pyrrol-2-yl]-5-aza-spiro[2.4]heptane-5- 3-methyl-butyric acid carboxylic acid benzyl ester 0 HF F H 1H O---N' N ECDI, HOBt N N N DIEPA, DMF N N HN H H (1 -{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2 yl)-1 H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2. 1 ]heptane-2-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester 848 (1 -{3-[6-(9,9-Difluoro-7- {2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)- I H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.l]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester was prepared in a similar manner as Example B to give title compound as a white powder (88.9 mg). 5 'H-NMR: 300 MHz, (DMSO-d 6 ) 6: 12.56 (d, J=13.5Hz, 0.5H ), 12.04 (d, J=17.1Hz, 0.5H), 11.84 (s, 1 H), 8.1 - 7.1 (m, 12H), 5.3-5.1 (m, 1 H), 4.8-4.5 (m, I H), 4.1-3.7 (m, 4H), 3.6-3.2 (m, 20H), 2.8-1.1 (m, 12H), 0.9-0.4 (m , 16H). LCMS-ESI*: calc'd for C 4 9

H

54

F

2

N

8 0 6 : 890.0 (M+H*); Found: 889.4 (M+H*). 10 Example IC O H 0 0 H 0 H O1. Ny0, 1/ 1,1,3,3-tetramethylguanidine 1 Y N O LiOH o O O O THF. -78 0 C to RT MeOH, RT Tetrahydro- N-Methoxycarbonyl-2-methyl- Methoxycarbonylamino pyran-4-one (dimethylphosphono) glycinate (tetrahydro-pyran-4-ylidene) acetic acid methyl ester H 0 -0

H

0 -NH O OH 0 Nk 0 N H I HATU, DIPEA, O + H I r DMF, RT Methoxycarbonylamino- (2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl) (tetrahydro-pyran-4-ylidene)- phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine acetic acid 1 -carbonyl]-propyl)-carbamic acid methyl ester tihydrochloride -0 NH NN NN N. H

-

\ I HN0 0 HN 0-. (1 -[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-ylidene) acetyl]-pyrrolidin-2-yl)-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1 H-imidazol 2-yl)-pyrrolidine-1-carbonylJ-2-methyl-propyl)-carbamic acid methyl ester 15 Methoxycarbonylamino-(tetrahydropy ran-4-ylidene)-acetic acid methyl ester: A solution of N-methoxycarbonyl-2-methyl-(dimethylphosphono) glycinate (1.45 g, 5.68 mmol) in tetrahydrofuran (22 mL) was cooled to -78' C. 1,1,3,3-Tetramethylguanidine (0.680 mL, 5.42 nmol) was added and the resulting solution was stirred at -78' C for 30 minutes. Tetrahydropyran-4-one (0.500 mL, 5.42 mmol) was added and the reaction was stirred at -78' C 20 for 1 hour. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. In the morning, the reaction was diluted with ethyl acetate. The organics 849 were washed with IN aqueous HCI and brine, dried (MgSO 4 ) and concentrated. The crude residue was purified by flash chromatography to yield methoxycarbonylamino-(tetrahydropyran 4-ylidene)-acetic acid methyl ester. ' H-NMR: 400 MHz, (CDC 3 ) 5: 5.94 (br s, I H), 3.80-3.74 (in, 7H), 3.71 (s, 3H), 2.95-2.91 (m, 2H), 2.45-2.41 (in, 2H) ppm. 5 {1-[2-(5-{6-[4-(2-{1-12-Methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyll pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1 H-imidazol-2-yl) pyrrolidine-1-carbonyll-2-methyl-propyl}-carbamic acid methyl ester: To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester (141 mg, 0.62 10 mmol) in methanol (1.8 mL) was added an aqueous LiOH solution (I M, 1.8 mL, 1.8 mmol). The resulting solution was stirred at room temperature for 16 hours and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCL. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO 4 ), and concentrated to give 15 methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid. To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid (23 mg, 0.11 immol) in dimethylformamide (0.6 mL) was added HATU (41 mg, 0. 11 mmol). After stirring for 5 minutes, a solution of (2-methyl-I-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl] naphthalen-2-yl} - H-imidazol-2-yl)-pyrrolidine-l -carbonyl]-propyl}-carbamic acid methyl ester 20 trihydrochloride (50 mg, 0.068 mmol) in dimethylformamide (0.6 mL) was added to the reaction, followed immediately by diisopropylethylamine (85 iL, 0.49 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO 3 solution, water and brine, dried (MgSO 4 ), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H 2 0 + 25 0.1% HCO 2 H) to yield {I -[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4 ylidene)-acetyl]-pyrrolidin-2-yl}-3 H-imidazol-4-yl)-phenyl]-naphthalen-2-yl }-I H-imidazol-2 yl)-pyrrolidine- I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (28 mg, 50%). LCMS-ESIl: calculated for C 46

H

52

N

8 0 7 : 828.95; observed [M+I]*: 830.32. 'H-NMR: 400 MHz,

(CD

3 0D) 5: 8.24-8.07 (m, 3H), 7.96-7.76 (m, 7H), 7.45-7.34 (m, 2H), 5.28-5.18 (m, 2H), 4.27 30 4.23 (m, I H), 4.05-3.98 (m, I H), 3.94-3.86 (m, I H), 3.84-3.41 (m, 12H), 2.48-1.98 (m, 13 H), 1.02-0.90 (m, 6H) ppm. 850 Example ID H N <>O , NaHC0 3 , ~N \ BI-1 3 SMe 2 . ci EtOAc, RT THF, RT (Z)-Ethyl 2-chloro-2- 5-Oxa-6-aza-spiro[3.4]oct-6- 5-Oxa-6-aza-spiro[3.4]octane (hydraxyimino)acetate ene-7-carboxylic acid ethyl ester 7-Carboxyic acid ethyl ester Y 0 0 0 NH Br .O NH ) .'Y Br-j \ HATU, DIPEA, DMF, 60 0 C 0 --\ EtOH-, 45 0 C 0 OH DIPEA, ACN, RT 6-(2-Methoxcycarbonylamino-3- 6-(2-Methoxycarbonylamino-3 methyl-butyryl)-5-oxa-6-aza- methyl-butyryl)-5-oxa-6-aza spiro[3.4]octane-7-carboxylic acid ethyl ester spiro[3.4]actane-7-carbxylic acid 0 NH 0 -INH 4 B B 'iih ly00

NH

4 OAc, o 0NABr toluene, 110 0 C N. Pd(dpp)C12, KOAc, 0 H~J Br dioxane, 85 OC 6-(2-Metlioxycarbonylamino-3-methyl-butyryl)- (1-{7-[5-(4-Bromo-phenyl)-1H-imidazol-2-y] 5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid 2- 5-oxa-6-aza-spira[3.4loctane-6-carbnyl)-2 (4-bromo-phenyl)-2-axo-ethyl ester methyl-propyl)-carbamic acdd methyl ester N .

0

N

0 0- N H 0 NH N .. r0 N 'Y N-- Pd(PPh 3

)

4 , K 2 C0 3 ,+N __J/(\_ _ _ _ Hi 7 ' H / Br [2-Methyl-1-(7-{5-[4-(4,4,5,5-tetramethyl- (1 -{7-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl] [1 ,3,2]dioxaborolan-2-yl)-phenyq-1 H-imnidazol-2-yl)- 5-oxa-6-aza-spiro[3.4]octane-6-carbony}.2 5-oxa-6-aza-spirol3.4]octane-6-carbonyl)- methyl-propyl)-carbamic acid methyl ester propyl]-carbamic acid methyl ester -0 (1 -{7-[5-(4-{2-[6-(2-Methoxycarbonylamino-3-methyl-butyryl).5-oxa-6-aza-spiro[.4]oct 7-yll-3H-imidazol-4-yl}-biphenyl-4-yl)-lH-imidazol-2-yl]-5-oxaaza-spiro[3.4]octane-6-carony}-2-methyl-propyl)-carbamic acid methyl ester 5 851 5-Oxa-6-aza-spiro[3.4]oct-6-ene-7-carboxylic acid ethyl ester: To a solution of methylenecyclobutane (2 mL, 21.6 mmol) in ethyl acetate (125 mL) was added (Z)-ethyl 2 chloro-2-(hydroxyimino)acetate (6.55 g, 43.2 mmol) and solid sodium bicarbonate (16.3 g, 194 mmol). The reaction mixture was sealed and stirred at room temperature for 6 hours. More (Z) 5 ethyl 2-chloro-2-(hydroxyimino)acetate (4 g, 26.4 mmol) and sodium bicarbonate (8 g, 95.2 mmol) were added and the reaction was stirred at room temperature for an additional 12 hours. The reaction was diluted with ethyl acetate and washed successively with water and brine, dried (MgSO 4 ) and concentrated to yield crude 5-oxa-6-aza-spiro[3.4]oct-6-ene-7-carboxylic acid ethyl ester, contaminated with (Z)-Ethyl 2-chloro-2-(hydroxyimino)acetate and related 10 compounds. 5-Oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester: To a solution of crude 5-oxa-6 aza-spiro[3.4]oct-6-ene-7-carboxylic acid ethyl ester (7.5 g, <40.9 mmol) in tetrahydrofuran (270 mL) at 0' C was slowly added a solution of borane-dimethyl sulfide complex (10 M in 15 THF, 16.4 mL, 164 mmol). The reaction was allowed to warm to room temperature overnight then recooled to 0' C, and quenched by the careful addition of water. The mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO 4 ), and concentrated to yield a large amount of white solids. These solids were thoroughly triturated three times with dichloromethane (150 mL). The combined dichloromethane washings were concentrated and 20 the resulting oil was purified by flash chromatography to yield 5-oxa-6-aza-spiro[3.4]octane-7 carboxylic acid ethyl ester (1.08 g, 29% over 2 steps). 1 H-NMR: 400 MHz, (CDCl 3 ) 6: 8.01-7.95 (br, I H), 4.39-4.28 (m, 2H), 4.18-4.10 (m, I H), 2.80-2.75 (m, I H), 2.62-2.49 (m, 2H), 2.37-2.29 (m, I H), 2.25-2.17 (m, I H), 2.13-1.95 (m, 1 H), 1.88-1.79 (m, I H), 1.68-1.56 (m, I H), 1.34 (t, J = 7.1 Hz, 3H) ppm. 25 6-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester: To a solution of 2-methoxycarbonylamino-3-methyl-butyric acid (1.1 1 g, 6.33 mmol) and HATU (2.41 g, 6.34 mmol) in dimethylformamide (13 mL) was added a solution of 5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester (980 mg, 5.3 mmol) in 30 dimethylformamide (13mL). To the resulting reaction mixture was added diisopropylethylamine (1.85 mL, 10.6 mmol) and the reaction was heated to 600 C for 16 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO 4 ) and concentrated. The resulting residue was purified by flash chromatography to give 6-(2 methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl 35 ester (1.31 g, 72%). LCMS-ESI t : calculated for C 16

H

26

N

2 0 6 : 342.18; observed [M+I]+: 342.90. 852 6-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4|octane-7-carboxylic acid: To a solution of 6-(2-methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza spiro[3.4]octane-7-carboxylic acid ethyl ester (1.31 g, 3.83 mmol) in ethanol (10 mL) was added 5 a solution of lithium hydroxide (IM in water, 7.6 mL, 7.6 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was partially concentrated and the resulting aqueous solution was washed with ethyl acetate. The ethyl acetate layer was discarded and the aqueous layer was acidified using concentrated HCL. The acidic aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO 4 ) 10 and concentrated to yield crude 6-(2-methoxycarbonylam ino-3-methyl-butyryl)-5-oxa-6-aza spiro[3.4]octane-7-carboxylic acid, which was used without further purification. 6-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid 2-(4-bromophenyl)-2-oxo-ethyl ester: To a solution of 6-(2-methoxycarbonylamino-3 15 methyl-butyryl)-5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid (-3.83 mmol) and 2,4' dibromoacetophenone (1.1 g, 3.96 mmol) in acetonitrile (19 mL) was added diisopropylethylamine (1.32 mL, 7.59 mmol). The reaction was stirred at room temperature for 16 hours and was then diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO 4 ) and concentrated. The resulting crude residue was purified by flash 20 chromatography, cleanly separating the two diastereomers of 6-(2-methoxycarbonylamino-3 methyl-butyryl)-5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid 2-(4-bromophenyl)-2-oxo-ethyl ester (330 mg of the (R) diastereomer, 360 mg of the (S) diastereomer, 35% total yield over 2 steps). ' H-NMR for the desired (S) diastereomer: 400 MHz, (CDC 3 ) 6: 7.74-7.71 (m, 2H), 7.62-7.60 (m, 2H), 5.47 (d, J = 16.4 Hz, I H), 5.40-5.35 (m, 1 H), 5.20 (d, J = 16.4 Hz, 1 H), 4.92 25 (dd, J = 7.1 Hz, J 2 = 9.0 Hz, I H), 4.74-4.70 (m, I H), 3.65 (s, 3H), 2.84 (dd, J' = 9.0 Hz, J 2 = 12.6 Hz, I H), 2.60 (dd, J' = 7.0 Hz, J 2 = 12.6 Hz, I H), 2.52-2.12 (m, 5H), 2.07-1.86 (m, 2H), 1.75-1.65 (m, I H), 1.01 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 7.1 Hz, 3H) ppm. (1-{7-15-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6-carbonyl}-2 30 methyl-propyl)-carbamic acid methyl ester: To a solution of 6-(2-methoxycarbonylamino-3 methyl-butyryl)-5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid 2-(4-bromophenyl)-2-oxo-ethyl ester (150 mg, 0.29 mmol) in toluene (3 mL) was added ammonium acetate (230 mg, 3.0 mmol). The reaction mixture was vigorously refluxed for 3 hours, cooled to room temperature and diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO 4 ), and 35 concentrated. The crude residue was purified by flash chromatography to yield (1-{7-[5-(4 853 bromophenyl)- I H-imidazol-2-yli-5-oxa-6-aza-spiro[3.4]octane-6-carbonyl)-2-methyl-propyl) carbamic acid methyl ester (95 mg, 66%). LCMS-ESI: calculated for C 22

H

2 7 BrN 4 0 4 : 490.12/492.12; observed [M+l ]*: 490.99/492.99. 'H-NMR: 400 MHz, (CDC 3 ) 5: 7.60-7.55 (m, 2H), 7.50-7.46 (m, 2H), 7.26 (s, I H), 5.38-5.29 (m ,2H), 4.76-4.70 (br, I H), 3.70 (s, 3H), 3.36 5 3.29 (m, I H), 2.84 (dd, J' = 8.2 Hz, J 2 = 12.5 Hz, I H), 2.51-2.32 (m, 3H), 2.13-2.03 (m, 2H), 2.00-1.89 (m, I H), 1.83-1.71 (m, 1 H), 0.97 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), ppm. [2-Methyl-1-(7-{5-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2 yl}-5-oxa-6-azaspiro[3.4]octane-6-carbonyl)-propyl]-carbamic acid methyl ester: A 10 degassed mixture of (1 -{7-[5-(4-bromophenyl)-l H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane 6-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (85 mg, 0.17 mmol), bis(pinacolato)diboron (66 mg, 0.26 mmol), potassium acetate (51 mg, 0.52 mmol) and dichloro[1,l'-bis(diphenylphosphino)ferrocene]palladium(lI) (13 mg, 0.0 18 mmol) in 1,4 dioxane (1.7 mL) was heated to 850 C for 75 minutes. After cooling to room temperature, the 15 reaction was filtered through a palladium scavenging column (STRATOSPHERESTM PL Guanidine MP SPE+, Part #: PL3514-CM89) and the solids were rinsed with ethyl acetate. The filtrate was washed with water and brine, dried (MgSO 4 ), and concentrated. The crude residue was purified by flash chromatography to yield [2-methyl-1-(7-{5-[4-(4,4,5,5 tetramethyl[ I,3,2]dioxaborolan-2-yl)-phenyl]- I H-imidazol-2-yl}-5-oxa-6-azaspiro[3.4]octane-6 20 carbonyl)-propyl]-carbamic acid methyl ester (81 mg, 87%). LCMS-ESI*: calculated for

C

2 8

H

3 9

BN

4 0 6 : 538.30; observed [M+1]+: 539.12. (1 -{7- [ 5

-(

4

'-{

2 -6-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4] oct 7-yl]-3H-imidazol-4-yl}-biphenyl-4-y)-1H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6 25 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: To a solution of [2-methyl-l-(7-{5 [4-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-phenyl]-I H-imidazol-2-yl}-5-oxa-6 azaspiro[3.4]octane-6-carbonyl)-propyl]-carbamic acid methyl ester (81 mg, 0.15 mmol), (1-{7 [5-(4-bromophenyl)- I H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6-carbony }-2-methyl propyl)-carbamic acid methyl ester (60 mg, 0.12 mmol) and 30 tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) in 1,2-dimethoxyethane (2.0 mL) was added a solution of potassium carbonate (2M in water, 0.250 mL, 0.50 mmol). The resulting mixture was degassed forl 5 minutes with a stream of argon and then heated to 850 C for 3 hours. After cooling to room temperature, the reaction was filtered through a palladium scavenging column (STRATOSPHERESTm PL-Guanidine MP SPE+, Part #: PL3514-CM89) 35 and the solids were rinsed with methanol. The filtrate was concentrated and purified by 854 preparative reverse phase HPLC (Gemini, 15 to 51% ACN/H 2 0 + 0.1% HCO 2 H) to yield (1-{7 [5-(4'-{2-[6-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4]oct-7-yl]-3H imidazol-4-yl}-biphenyl-4-yl)- I H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester (26 mg, 26%). LCMS-ESI: calculated for 5 C 4 4

H

54

N

8 0 8 : 822.41; observed [M+1]+: 823.43. 'H-NMR: 400 M Hz, (CD 3 0D) 6: 7.78-7.75 (m, 4H), 7.68-7.65 (m, 4H), 7.38 (s, 2H), 6.94-6.89 (br, 2H), 5.47-5.42 (m, 2H), 4.74-4.68 (br, 2H), 3.66 (s, 6H), 3.00-2.94 (m, 2H), 2.78-2.71 (m, 2H), 2.61-2.53 (m, 2H), 2.49-2.40 (m, 2H), 2.38 2.30 (m, 2H), 2.22-2.09 (m, 4H), 2.00-1.90 (m, 2H), 1.84-1.75 (m, 2H), 0.98 (d, J = 6.8 Hz, 6H), 0.88 (d, J = 6.7 Hz, 6H) ppm. 10 Example IE O NH O 'NH 0 N +, o NPd(PPh 3

)

4 , K 2 C0 3 B,_ Br.. DME. 85 0 C H ~B'-j H Br [2-Methyl-1-(7-{5-[4-(4,4,5,5-tetramethyl- (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl] [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2-yl}- pyrrolidine-1 -carbonyI)-2-methyl-propy) 5-oxa-6-aza-spiro[3.4]octane-6-carbonyl)- carbamic acid methyl ester propyl]-carbamic acid methyl ester NH H 0> 0~. N -,-N N H HN NHo0 (1 -{7-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryi)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1 H-imidazol-2 yl]-5-oxa-6-aza-spiro[3.4]octane-6-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 15 (1-{7-[5-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl)-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester: To a solution of [2-methyl-l-(7-{5-[4-(4,4,5,5 tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]- IH-imidazol-2-yl}-5-oxa-6-azaspiro[3.4]octane-6 20 carbonyl)-propyl]-carbamic acid methyl ester (81 mg, 0.15 mmol), (1-{2-[5-(4-bromophenyl) I H-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (81 mg, 0.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) in 1,2 dimethoxyethane (3.0 mL) was added a solution of potassium carbonate (2M in water, 0.300 mL, 0.60 mmol). The resulting mixture was degassed forl5 minutes with a stream of argon and 855 then heated to 85* C for 3 hours. After cooling to room temperature, the reaction was filtered through a palladium scavenging column (STRATOSPHERES

T

m PL-Guanidine MP SPE+, Part #: PL3514-CM89) and the solids were rinsed with methanol. The filtrate was concentrated and purified by flash chromatography (0%-5% methanol/dichloromethane). The resulting residue 5 was repurified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H 2 0 + 0.1%

HCO

2 H) to yield (1-{7-[5-(4'-{2-[I-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3 H-imidazol-4-yl}-biphenyl-4-yl)-I H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (35 mg, 30%). LCMS-ESI*: calculated for C 4 2

H

52

N

8 0 7 : 780.40; observed [M+I]*: 781.29. 'H-NMR: 400 MHz, (CD 3 0D) 6: 7.82-7.72 10 (m, 4H), 7.69-7.65 (m, 4H), 7.38 (s, I H), 7.32 (s, I H), 6.99-6.90 (m, 2H), 5.47-5.42 (m, I H), 5.20-5.16 (m, I H), 4.75-4.68 (m, I H), 4.226-4.21 (m, I H), 4.03-3.96 (m, I H), 3.91-3.85 (m, 1 H), 3.71-3.48 (m, 7H), 3.00-2.94 (m, I H), 2.78-2.71 (m, I H), 2.61-1.90 (m, 10H), 1.83-1.73 (m, I H), 1.00-0.86 (m, 12H) ppm. 15 Example IF (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl) acetic acid (3) OOH4M HCl Dioxane H2N OH O Cl 0 N AOH O 7DCM Na 2

CO

3 / H 2 0 [ 1 2 3 20 To (S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl) acetic acid 1 (1.5 g, 5.8 mmol) in dichloromethane (5 mL) was added 4M HCI in dioxane (5 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After concentrated in vacuo to afford 2 To (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl) acetic acid 2 (780 mg; 5 mmol) in water (25 ml) 25 was added sodium carbonate (1.06g; 10 mmol), and the resultant mixture was cooled to 0.deg. C. and then methyl chloroformate (0.53 ml; 5.5 mmol) was added dropwise over 5 minutes. The reaction was allowed to stir for 18 hours while allowing the bath to thaw to ambient temperature. The reaction mixture was then partitioned between I N HCI and ethyl acetate. The organic layer was removed and the aqueous layer was further extracted with 2 additional portions of ethyl 30 acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3 a colorless residue. MS (ESI) m/z: 218 [M + H]*. 856

H

0

H

0 H 0 0 N OH 1-O N OH O N OH O OH O 0 0 S S 4 5 6 7 H H O N O O - OH OH 0 0 50 8 N 9 10 Compounds 4-10 were prepared according to the method employed to prepare ((S)-2 5 (methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl) acetic acid (3) (S)-2-((S)-2-(5-(4-(6-(2-((S)- I -((S)-2-(methoxycarbonylamino) 3-methylbutanoyl)pyrrolidin-2-y)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol 10 2-yl)pyrrolidin- 1-yl)-2-oxo-1 -(tetrahydro-2H-pyran-4-yI)ethylcarbam ic acid methyl ester: ~-0 -~0 0 YN\H H NH ' O/N 1 .) 4 N H C -d Mo x a G N 0 (* ( S)-2-bm xc *r - To compound 11 (50 mg, 0.068mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane 15 (0.8 mL) and the reaction mixture was cooled to 0 0 C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. To these HCI salts in DMF (0.8 mL) was added compound 3(20 mg, 0.09 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and hydroxybenzotriazole hydrate (HOBt), (13 mg, 0.09 mmol). The mixture was cooled down in an 20 ice bath to 0*C and N-methylmorpholine (NMM)(20iL, 0.18 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting 857 mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (36 mg, 65%). ' H-NMR: 400 MHz, (CD 3 0D) 6 8.03 (s, I H), 7.99 (s, I H), 7.79 - 7.66 (m, I OH), 7.33 (s, I H), 7.24 (s, I H), 7.05-6.9l (m, I H), 5.22 -5.09(m, I H), 4.23-4.15 (m, I H), 3.98 - 3.78 (m, 4H), 3.57 5 (s, 6H), 3.38 - 3.31 (m, 8H), 2.65 (m, I H), 2.30 - 2.09 (m, 5H), 2.02 - 1.95 (m, 2H), 1.56 1.29 (m, 5H), 0.92 - 0.82 (m, 6H). MS (ESI) m/z 832 [M + H]f. Example IG 10 (S)-1-(2,3-dihydro-1H-inden-2-yl)-2-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2 (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen 2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxoethylcarbamic acid methyl ester O0 --O HO N M D CH 1.) 4NHCIoxane N 0 ((S)-2-(mthoxyce noo I)-3-dbi 2no-)pyrr diken2 yl)- 1 H-midazo45- ~aphtake-2-yl)phenyli)H-~miazoI-2 yl~yrr~iIn-O12-oxoethy4catmic add rmOW,~ este 15 To compound 11 (50 mg, 0.068mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0 0 C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. To these HCI salts (32 mg) in DMF (0.7 mL) was added compound 10 (16 mg, 0.063 mmol), N 20 (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (12 mg, 0.063 mmol) and hydroxybenzotriazole hydrate (HOBt), (9 mg, 0.063 mmol). The mixture was cooled down in an ice bath to 0 0 C and N-methylmorpholine (NMM)(20 1 L, 0.12 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as 25 white solid (23 mg, 62 %). MS (ESI) m/z 864 [M + H]+. 858 Example IH (R)-2-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2 5 yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamic acid methyl ester -o -0 H-NHHIH NHC0 H 11 ~~NMM.DMF.0 HC N~ o To compound 111(50 mg, 0.068mmo) in dichloromethane (0.8 mL) was added 4M H-C in dioxane (0.8 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After 10 concentrated in vacuo to afford HCI salts. To these H CI salts (33 mg) in DMF (0.8 mL) was added compound 4 (15 mg, 0.068 mmol), N (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (13 mg, 0.068 mmol) and hydroxybenzotriazole hydrate (HOBt), (II mg, 0.068 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(4p.L, 0.l3mmoI) was added from a 15 syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. H PLC to afford title compound as white solid (25 mg, 67%). MS (ES I) m/z 832 [M + H]*f. 20 Example II (2S)-1-((2S)-2-(5-(6-(4-(2-((2S)-1-(2-(1,1-d ioxo-hexahydro-thiopyran-4-yl)-2 (methoxycarbonylamino)acetyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)naphthalen-2 yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1 -oxobutan-2-ylcarbamic acid methyl ester To opon 11 (50,J mg I6m ) inHCS-dloromehan (08m) a ddd4 Ii HN&4 25 rxbnztizl hyrt )~) I g .6 ml)i-. The ~4~miued was1 ced ow i 859 To compound 11 (50 mg, 0.068mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. To these HCI salts (33 mg) in DMF (0.8 mL) was added compound 5 (18 mg, 0.068 mmol), N 5 (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (13 mg, 0.068 mmol) and hydroxybenzotriazole hydrate (HOBt), (11 mg, 0.068 mmol). The mixture was cooled down in an ice bath to 0 0 C and N-methylmorpholine (NMM)(14pL, 0.13mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title 10 compound as white solid (16 mg, 40%). MS (ESI) m/z 880 [M + H]*. Example IJ (S)-1 -((S)-2-(5-(6-(4-(2-((S)- 1 -(2-(methoxycarbonylamino)-2-(thiophen-3 15 yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yI)-2 methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester -0 -O 0 0>N , ~ N N1.)4NHCI-dkoxane N~ S > y~~~N - Bo2.) EC1. HOBT N N ON NMM DMFC N 0 (S) 1-((S) 2 ( " 2- (S met - -xcaay amino)-2 (thlopenylat rckn-2-y HnI daz4-5 yiy)p~nnapas2-)-HImdazo-2-yI).2-MylprTddlrn OY4)3ettI- -oxobJtan-2-yIcatbnmIc acW rm"~ este To compound 11 (50 mg, 0.068mmol) in dichloromethane (0.8 mL) was added 4M HCI in 20 dioxane (0.8 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. To these HCI salts (33 mg) in DMF (0.8 mL) was added compound 6 (15 mg, 0.068 mmol), N (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (13 mg, 0.068 mmol) and hydroxybenzotriazole hydrate (HOBt), (1 mg, 0.068 mmol). The mixture was cooled down in 25 an ice bath to 0 0 C and N-methylmorpholine (NMM)(14p L, 0.l3mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (22 mg, 60%). MS (ESI) m/z 830 [M + H]*. 30 860 Example IK (S)-1 -((S)-2-(5-(6-(4-(2-((S)-1 -((R)-2-(methoxycarbonylamino)-3-(1 -methyl-1 H-indol-3 yl)propanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2 yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester 5 '0 -o H 'NN N I N N\ ONMM DMF0 *CN 11 H0 (1-mth-1HInd4.3-y)ppanoy1)pyrdkn-2-i)-Hlrdazo-5 y)O-phenaUi-2-yIIH4mdaz-2-y)pyro~idin-)-3 methY1-1-oxcbtn-2y1Carb acW rdmtiy estnu To compound 11 (50 mg, 0.068mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. 10 To these HCI salts (20 mg) in DMF (0.5 mL) was added compound 9 (11 mg, 0.039 mmol), N (3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (8 mg, 0.039 mmol) and hydroxybenzotriazole hydrate (HOBt), (6 mg, 0.039 mmol). The mixture was cooled down in an ice bath to 0 0 C and N-methylmorpholine (NMM)(8.3[tL, 0.075mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting 15 mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (10 mg, 42%). MS (ESI) m/z 891 [M + H]*. Example IL 20 (S)-2-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)naphthalen-2-y)-1 H-imidazol-2 yl)pyrrolid in-I -yl)-2-oxo- 1 -(tetrahyd ro-2H-pyran-4-yl)ethylcarbamic acid methyl ester -0 N H T NH (JNi 12 N N ~ ~ C J( /\ o-~ NMM, DMF, 0 * N 0 medrthbannynv)fdi.2-y)-1Hmidzo45 (Spey1tO dn2y)-2-(S H&( ( S 2- x nog1-)-2 25 oxol(athydro2H-m4)et~1cabamc gc fw meU~lsW To compound 12 (50 mg, 0.068mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0 0 C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. 861 To these HCl salts (43 mg) in DMF (0.8 mL) was added compound 3 (20 mg, 0.09 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and hydroxybenzotriazole hydrate (HOBt), (13 mg, 0.09 mmol). The mixture was cooled down in an ice bath to 0 0 C and N-methylmorpholine (NMM)(20 1 iL, 0.1 8mmol) was added from a syringe to 5 the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (32 mg, 465%). MS (ESI) m/z 832 [M + H]f. 10 Example IM (S)-2-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4 yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2 yl)pyrrolidin-1 -yl)-2-oxo-1-(tetrahyd ro-2H-pyran-4-yl)ethylcarbamic acid methyl ester 15 HN 0-.. To compound 13 (50 mg, 0.074mmol) in dichloromethane (0.9 mL) was added 4M HCI in dioxane (0.9 mL) and the reaction mixture was cooled to 0 0 C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. 20 To these HCI salts in DMF (0.8 mL) was added compound 3(41 mg, 0.19 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) and hydroxybenzotriazole hydrate (HOBt), (26 mg, 0.19 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(25p L, 0.22 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting 25 mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (32 mg, 50%). MS (ESI) m/z 874 [M + H]*. 862 Example IN (S)-2-((S)-6-(5-(6-(4-(2-((1 R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2 azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yI) 5 5-azaspiro[2.4]heptan-5-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamic acid methyl ester HH -o H Do" NN'/\ O Tocopn 14 (5 m1.) 4NHCI-dioxanoe 0 n . m cocn eN in vu tEDCo aHOfT Nd HCN 14 iNn.m NMM dMFe0 c- 3 NO dimehylainoropy)-N'ethlcarodiiidehydrchloide( mg, .09 mm()--(-to) aanUw~ yl)pherny1)naphhaln-2-y1iHmidazo-2-yt-5-aznair(24hpunn-B hydoxyenztrazoe hdrte HO~), 3mg,0.0 mol). -Tefhe o2Hpmxtueicre ai was cooe dotwnna To compound 14 (50 mg, 0.64mmol) in dichloromethane (0.8 mL) was added 4M HCI in 10 dioxane (0.8 mL) and the reaction mixture was cooled to neC and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. To these HCI salts in DMF (0.8 mL) was added compound 3(20 mg, 0.09 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and hydroxybenzotriazole hydrate (1-1O1t), (13 mg, 0.09 mmol). The mixture was cooled down in an 15 ice bath to 0 0 C and N-methylmorpholine (NMM)(l 8 L, 0. 16 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (30 mg, 54%). MS (ESI) m/z 884 [M + H]*. 20 Example 10 (2S,3R)-3-methoxy-1-((S)-6-(5-(6-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yI)-1H-imidazol-5-yl)phenyl)naphthalen-2 25 yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-1-oxobutan-2-ylcarbamic acid methyl ester -8 H ~- -i1~'~-- )4NHCI~dlxans //\-' N H N IT ?\ 14 0N-~f NMM.DMF,0-C/\N.N 0.- (med ox acoboymwnoy-meth4butanoyi)-2-azablcydo(2.2.llheptan-3 y1)-1H-imidaoh-e~ny1)rMJaei-2)-Hiao-2-AY&)6 azaspro(24]epta-5-yi)-1 -oxatxutn-2-ylcafrbrki adid me"~y OSat 863 To compound 14 (50 mg, 0.064mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0 0 C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. To these HCI salts in DMF (0.8 mL) was added compound 8(17 mg, 0.09 mmol), N-(3 5 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and hydroxybenzotriazole hydrate (HOBt), (13 mg, 0.09 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(l8pL, 0.16 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as 10 white solid (30 mg, 54%). MS (ESI) m/z 858 [M + H]+. Example IP 15 (S)-1-((S)-6-(5-(6-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H pyran-4-yl)acetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2 yI)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester -0 H17 - H P NMM, DMF, 0 *CN 20 0 5-yhn)naphtUwaln-2-IH-imdazol-2,4)5zaspIro2.4]hpa-I.3 20 ff~IIO~~aW2yabm acid rmtiy aste To compound 15 (50 mg, 0.064mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. 25 To these HCI salts in DMF (0.8 mL) was added compound 3(20 mg, 0.09 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and hydroxybenzotriazole hydrate (HO3t), (13 mg, 0.09 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(20.L, 0.16 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting 30 mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (25 mg, 45%). 864 MS (ESI) m/z 884 [M + H]f. Example IQ 5 (S)-2-((S)-6-(5-(6-(4-(2-((1 R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H pyran-4-yl)acetyl)-2-azabicyclo[2.2.11 heptan-3-yl)-1 H-imidazol-5-yl)phenyl)naphthalen-2 yl)-1 H-imidazol-2-yl)-5-azaspiro[2.4] heptan-5-yI)-2-oxo-1 -(tetrahydro-2H-pyran-4 yl)ethylcarbamic acid methyl ester 10 He0 T c n 16 1()4NHC-dioxane (-0 . H H - - 2.). EDC1, HOBTN\ / dioxane (0.8 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. 15 To these HCI salts in DMF (0.8 mL) was added compound 3(41 mg, 0.19 mmol), N-(3 dimethylaminopropyl)-N' -ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) and hydroxybenzotriazole hydrate (HIOBt), (26 mg, 0.19 mmol). The mixture was cooled down in an ice bath to 0C and N-methylmorpholine (NMM)(25p L, 0.22 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting 20 mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (28 mg, 44%). MS (ESI) m/z 926 [M + H]*. Example IR 25 (2S,3R)-3-methoxy-1-((S)-6-(5-(6-(4-(2-((1R,3S,4S)-2-((2S,3R)-3-methoxy-2 (methoxycarbonylamino)butanoyl)-2-azabicyclo[2.2.1]heptan-3-yI)-1H-imidazol-5 yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4] heptan-5-yl)-1-oxobutan-2 ylcarbamic acid methyl ester 30 865 -0 H BOO H\/ ~~ 1.)4NHC1-di...n 0/N* 0~ H .E 0 N (N H - - N 2.).ED,HOOT /\ N 0 O~ isNMM, DMF, 0 -CN t H O' (2S3R-3-nmetxy-i-(S-&<5-(6-(4-(2-<(1R.3S.4S)-2-((2S.3R)-3 mthoxy-2 (ymeaox i onamno)buano)- bc o2.2.i1heptan 1-l I -mklz 5y )ph na ~h lem--o H Wmdazol-2-yt5 azasprc2.4hepan-1-i~-oxobun-2-y4cwbamf* ecW mfefitl ser To compound 16 (50 mg, 0.069mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0 0 C and then stirred for 2 hours. After 5 concentrated in vacuo to afford HCl salts. To these HCI salts in DMF (0.8 mL) was added compound 8(38 mg, 0.2 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (38 mg, 0.2 mmol) and hydroxybenzotriazole hydrate (HOBt), (27 mg, 0.2 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM) (55pL, 0.5 mmol) was added from a syringe to 10 the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (29 mg, 40%). MS (ESI) m/z 874 [M + H)*. 15 Example IS (S)-1-((S)-6-(5-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)pyrrolidin-2-yl)-I H-imidazol-4-yl)-9H-fluoren-2-yl)-1 H-imidazol-2-yl)-5 azaspiro[2.4]heptan-5-yI)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester 0- 0 ONH ONHN N F F NF F Br PdCI 2 (dppf) 2 N Pd(O )2.PPh N - - r KOAc/ 1,4-Dioxane N - 1M NAHCO,/ DME 17 18 H 1.) 4NHCI-dioxane H NO FF 2.). EOCI, HOT -NFF N Boc 2MM C HMM OMF, 0 C YH N' - - NH B-HO: N' -1 N N0"H HN 0 20 0 21 0 (S)-1-((S)-6-(5-(99-difluro-7-(2-((S)-l-((S)-2 (methoxycrbonyramino)-7thy butanol)pyrroidin 2-y9-1 -lmldazo l-4y 9H-fluoren-2-OY1)H~midazo-2 y5)-5 aspr[2.4]heptan-5-yl)-a-rnfthy -1-oxobutar-2 20 yicarbamic acd methyl ester 866 Compound 17 (1.2 g, 2 mmol), bis(pinacolato)diboron (Ig, 4 mmol), potassium acetate (510 mg, 5.2 mmol), and Pd(dppf)C1 2 (82 mg, 0.1 mmol) were all weighed out in a glass pressure vessel and anhydrous 1,4-Dioxane (10 mL) was added. The mixture was bubbled with nitrogen gas for 5 about 5 min. The vessel was then capped and sealed and heated in an oil bath at 90*C overnight with continuous stirring. The reaction vessel was cooled down to room temperature and all volatiles were removed under reduced pressure and the resulting oil was subjected to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 0 - 50 % with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent 10 was removed under reduced pressure to provide (18) (968 mg, 75 %). To compound 18 (950 mg, 1.47 mmol), compound 19 (488 mg, 1.54 mmol, .), Pd(OAc)2 (23mg, 0.1 mmol) and PPh3 (42mg, 0.16 mmol). DME (16 mL) was added and followed by 6 mL I M NaHCO3 aqueous solution. The reaction was purged with Argon and heated to 90 C for 3 hours under Ar. The reaction was cooled to room temperature and concentrated down. EtOAc 15 was added and washed with sat. NaHC03 aqueous (2X) and sat. NaCl aqueous (lX). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40 - 100 % with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent was removed under reduced pressure to provide product 20 (1g, 90 %). MS (ESI) m/z 757 [M + 20 H]*. To compound 20 (50 mg, 0.066mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0 0 C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. To these HCI salts in DMF (0.8 mL) was added compound 21(16 mg, 0.09 mmol), N-(3 25 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and hydroxybenzotriazole hydrate (HOBt), (13 mg, 0.09 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(20pL, 0.18 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as 30 white solid (33 mg, 62 %). MS (ESI) m/z 814 [M + H]*. 867 Example IT (S)-1-((S)-6-(5-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H pyran-4-yl)acetyl)pyrrolid in-2-yl)-1 H-imidazol-4-yl)-9H-fluoren-2-yl)- 1 H-imidazol-2-yl)-5 5 azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester 0o - 0,0 NHH NF F 1.)Ba 4NHCI-dioxare NOB vC. H /F F/~ I -H H N BNH N NH 20 HN 0 (S 1 ((S)-6-(r 9.9-diflur--(2- (S)- -(( 2-(m hxyabny mino)-2 (tetrahydr-2H-pyrn-4-y)aeyI)pyrrldir-2-y)-1H-lmidazol-4-y9H fluorer-2-y1-Hmdazo-2-)--aaspro[24]hept -- O)3-mthyoxobutart-2-ylcarbsmic acdd methyl ester To compound 20 (50 mg, 0.066mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After 10 concentrated in vacuo to afford HCI salts. To these HCI salts in DMF (0.8 mL) was added compound 3(20 mg, 0.09 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and hydroxybenzotriazole hydrate (HOBt), (13 mg, 0.09 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(20pL, 0.18 mmol) was added from a syringe 15 to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (30 mg, 54 %). MS (ESI) m/z 856 [M + H]*. 868 Example IU (S)-1 -((S)-6-(5-(9,9-difluoro-7-(2-((S)- 1 -((S)-2-(methoxycarbonylam ino)-4 (methylthio)butanoyl)pyrrolidin-2-yI)-1H-imidazol-4-yI)-9H-fluoren-2-yl)-1H-imidazol-2 5 yl)-5-azaspiro[2.4]heptan-5-yI)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester OO- Oo H NH 0 F F _ 1. 4NHCI-dioxn 0 F MMDH 2.). EDGI. HOBT /H , N H NMM, DMF. 0 -C N N 20 HN 0 4-(methyita)butnoi)pyroidin-2-y)-1H4Mrddzo-4-0i)-gH-fluorer-2 y)-1H-imidazoI-2-yl)-5-azaspiro{2.4 hepten-5-y m3-methy-1-oxobutan 2-ytcarbamic adid methl ester To compound 20 (50 mg, 0.066mmol) in dichloromethane (0.8 mL) was added 4M HCI in dioxane (0.8 mL) and the reaction mixture was cooled to 0*C and then stirred for 2 hours. After 10 concentrated in vacuo to afford HCI salts. To these HCI salts in DMF (0.8 mL) was added compound 7(19 mg, 0.09 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol) and hydroxybenzotriazole hydrate (-1OBt), (13 mg, 0.09 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(20p L, 0.18 mmol) was added from a syringe 15 to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (30 mg, 55 %). MS (ESI) m/z 846 [M + H]*. 869 Example IV (S)-1-((S)-6-(5-(9,9-difluoro-7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3 methylbutanoyl)pyrrolidin-2-yl)-IH-imidazol-5-yl)phenyl)-9H-fluoren-2-yI)-1H-imidazol 5 2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester

O

NH ~ ~ B B r - .I N 1M NAHC -N 24 NHH /2. FC T HHN N OHNOPd(OAc).PPh, N - / N' Br 1 MNAHCO, 24 ME 22 1.) 4M HCI In ) dioxaneMfCM 2.) EDCI. HOBT -O F F NMM, DMF. N "I-, ~HN f .110 (S)-l-((S) - (9.9-dMuoro-7-(4-(2((S-((S2 (miethxyaronyfamno)mbaotylay)pyrrolidn-2-yl)- H imidazot.-yl)pheny9H-fluoen-2-y)-1 H~midazai-2-yt) sp [2.4]heptan 5-yi)-mothy1- -oxobutan-2-ycarbamic acid methyl ester To compound 22 (320 mg, 0.53 mmol), compound 23 (282mg, 0.64 mmol, .), Pd(OAc)2 (8.4mg, 0.04 mmol) and PPh3 (16mg, 0.06 mmol). DME (5.5 mL) was added and followed by 2.2 mL I M NaHCO3 aqueous solution. The reaction was purged with Argon and heated to 900 10 C for 3 hours under Ar. The reaction was cooled to room temperature and concentrated down. EtOAc was added and washed with sat. NaHCO3 aqueous (2X) and sat. NaCl aqueous (I X). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40 - 100 % with an ISCO column (12 g silica gel). The fractions containing product were combined and the 15 solvent was removed under reduced pressure to provide product 24 (266 mg, 60 %). MS (ESI) m/z 833 [M + H]+. To compound 24 (120 mg, 0.15mmol) in dichloromethane (1.5 mL) was added 4M HCI in dioxane (1.5 mL) and the reaction mixture was cooled to 0 0 C and then stirred for 2 hours. After concentrated in vacuo to afford HCI salts. 20 To these HCI salts in DMF (1.5 mL) was added compound 21(35 mg, 0.2 mmol), N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (38 mg, 0.2 mmol) and hydroxybenzotriazole hydrate (HOBt), (27 mg, 0.2 mmol). The mixture was cooled down in an ice bath to 0*C and N-methylmorpholine (NMM)(50pL, 0.45 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting 870 mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (65 mg, 56 %). MS (ESI) m/z 890 [M + H]*. Example IW NH PdCl 2 (dppf) w* 0 q O O N \\ 0 KOAc N Br +B-O'N 1,4-dioxane - H 85 *C (1 -{6-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-5-aza spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 0 N'H O O O N ON \ \P H N Br - H [2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl- (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5 [1,3,2]dioxaborolan-2-yl)-phenyl]-1 H-imidazol-2-yl)-5-aza- aza-spiro[2.4]heptane-5-carbony)-2-methyl-propyl) spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester carbamic acid methyl ester PdCl 2 (dppf) 0 Pd(PPh 3

)

4 KOAc O NH

K

3 P0 4 0H 1,4-dioxane N N - ' \' 0, 85 OC H - HN -f 0 0 [1 -(6-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyry)-5 aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl] 1 H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2 5 methyl-propyl]-carbamic acid methyl ester [1-(6-{5-16-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3H-imidazol-4-yI}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane 5-carbonyl)-2-methyl-propyll -carbamic acid methyl ester: 10 (1 -{6-[5-(4-Bromo-phenyl)-l H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl propyl)-carbamic acid methyl ester (0.10g, 0.24mmol), bis(pinacolato)diboron (0.073g, 0.29mmol), Palladium dichloride(dppf) (0.0 18g, 0.024mmol), and potassium acetate (0.071g, 0.72mmol) were suspended in 1,4-dioxane (1.2mL) and degassed with argon for 30 minutes. The suspension was heated at 850 C for 2 hours. The mixture was cooled, (1-{6-[5-(6-Bromo 15 naphthalen-2-yl)- I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl) carbamic acid methyl ester (0.1 82g, 0.346mmol) and aqueous potassium phosphate (2M, 0.84mL, 0.84mmol) was added. The mixture was returned to heat for 16 hours at which time, 871 Palladium(tetrakis)triphenylphosphine (0.014g, 0.012mmol) was added. The reaction was heated for an additional 4 hours. Upon completion, the crude reaction mixture was concentrated in vacuo and filtered through a Pd scavenging cartridge (Polymer Labs, PL-Guanidine MP SPE). The resulting slurry was diluted in DMF and purified by reverse phase HPLC (15-40% 5 acetonitrile: water; 0.1% formic acid modifier), and lyophilized giving [1 -(6-{5-[6-(4-{2-[5-(2 Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3 H-imidazol-4-yl} phenyl)-naphthalen-2-yl]-l H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl propyl]-carbamic acid methyl ester (0.0 4 8g, 24%) as a white solid. 'H NMR (400 MHz, CDCl 3 ) 6 8.33 - 7.34 (m, 12H), 5.65 - 5.20 (m, 3H), 4.30 (s, 2H), 4.03 10 3.87 (m, I H), 3.74 (d, 9H), 3.53 (s, 1 H), 2.97 (s, I H), 2.34 - 1.88 (m, 5H), 1.26 (s, I H), 1.10 (m, 3H), 0.91 (m, 12H), 0.71 (s, 6H). LCMS-ESI+: calc'd for C 4 8

H

56

N

8 0 6 : 840.43 (M*); Found: 841.9 (M+H*). Example IX

N

0 0 S0NH H O J+ B r ' O N H O-HN- 0 0 [2-Methyl-1 -(2-{5-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1 H- .. (1-{2-[5-.(4-Bromo-phenyl)-1H1-l imidazol-2-yl}-pyrrolidine-1 -carbonyl)-propyl]- imidazol-2-yl]-4-methylene-pyrroidine-1 carbamic acid methyl ester carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 0 Pd(PPh 3

)

4 0< NH

K

3

PO

4 0 DME N -N - N N 900 *C H 0 HN O 0 [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) 4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl)-phenyl) naphthalen-2-yl]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyll carbamic acid methyl ester I5 (1-{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare (1- {2-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-pyrrolidine- 1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester using 4-Methylene-pyrrolidine-1,2 20 dicarboxylic acid 1-tert-butyl ester. LCMS-ESI*: calc'd for C 2 1

H

25 BrN 4 0 3 : 460.11 (M*); Found: 463.61 (M+H*). 872 [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylene pyrrolidin 2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1 5 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare [1-(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl butyryl)-2-aza-bicyclo[2.2. I]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using [2-Methyl-I -(2-{5-[6-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-naphthalen-2 10 yl]-I H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-propyl]-carbamic acid methyl ester (0.177g, 0.324mmol) and (1-{2-[5-(4-Bromo-phenyl)-1 H-imidazol-2-yl]-4-methylene-pyrrolidine-1 carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.100g, 0.216mmol). Potassium phosphate (aqueous, 0.32mL, 0.648mmol) was substituted for potassium carbonate and the reaction was performed under an argon atmosphere. The crude reaction was purified by reverse 15 phase HPLC (10-45% acetonitrile: water; 0.1% formic acid modifier), and lyophilized giving [1 (2-{5-[6-(4-{2-[I-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylene pyrrolidin-2-yl] 3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-2 methyl-propyl]-carbamic acid methyl ester (0.009g, 5%) as a white solid. 'H NMR (400 MHz, CDCl 3 ) 8 8.12 - 7.96 (m, I H), 7.93 - 7.79 (m, 5H), 7.77 - 7.67 (m, 5H), 20 6.32 (s, I H), 5.73 - 5.54 (m, I H), 5.50 - 5.22 (m, 6H), 4.49 - 4.28 (m, 3H), 3.96 - 3.82 (m, 2H), 3.72 (s, 9H), 3.06 - 2.86 (m, 2H), 2.50 - 2.34 (m, I H), 2.31 - 2.21 (m, I H), 2.18 - 2.09 (m, 2H), 2.05 - 1.95 (m, 3H), 1.90 (s, 4H), 1.26 (s, 3H), 1.13 - 1.04 (m, 3H). LCMS-ESI+: calc'd for C 4 5

H

52

N

8 0 6 : 800.4 (M+); Found: 801.90 (M+H*). 25 873 Example IY OAH O- N'HH + Br [2-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl- 6-[5-(4-Bromo-phenyl)-1H-imidazol [1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1 H- 2-yl]-5-aza-spiro[2.4]heptane-5 imidazol-2-yl}-2-aza-bicyclo[2.2. 1 ]heptane-2- carboxylic acid tert-butyl ester carbonyl)-propyl]-carbamic acid methyl ester Pd(PPh 3

)

4 O" N' H

K

2 C03 O OME N NN 6-{5-[4-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2 aza-bicydo[2.2. 1 ]hept-3-yl]-3H-imidazol-4-yl)-naphthalen 2-yl)-phenyl]-1 H-imidazol-2-yl}-5-aza-spiro[2.4]heptane 5-carboxylic acid tert-butyl ester 5 6-(5-[4-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3 yl]-3H-imidazol-4-yl)-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl)-5-aza-spiro[2.4]heptane 5-carboxylic acid tert-butyl ester: This compound was prepared using the procedure used to prepare [1 -(6-{ 5-[6-(4-{ 2

-[

2

-(

2 -Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.1 ]hept-3-yl]-3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-5-aza 10 spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example EZ) using [2-Methyl-I-(3-{5-[6-(4,4,5,5-tetramethyl-[I,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-I

H

imidazol-2-yl} -2-aza-bicyclo[2.2.1 ]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester (2.25mmol), 6-[5-(4-Bromo-phenyl)-l H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (2.39mmol), and potassium carbonate (2M, 4.3mL, 8.55mmol). The 15 reaction was performed under an argon atmosphere. The crude reaction was diluted in ethyl acetate, washed with water and purified by normal phase silica chromatography (50-100% Hexanes:EthylAcetate+ 1 0%Methanol). 6-{5-[4-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl butyryl)-2-aza-bicyclo[2.2.1]hept-3-yi]-3 H-imidazol-4-yI)-naphthalen-2-yl)-phenyl]-

IH

imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.05g, 60%) was 20 obtained as a tan solid. LCMS-ESI: calc'd for C 4 6

H

53

N

7 0 5 : 783.41 (M*); Found: 784.35 (M+H*). 874 Example IZ 1) HCI, dioxane H MeOH \N NI_ __ HN 0 2) HATU, NMM, CH 2

CI

2 0- 0 3-{5-[6-(4-{2-[-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6- 10 OH yl]-3H-imidazol-4-yI)-phenyl)-naphthaen-2-y]-1 H-imidazol-2-yl}-2-aza- o bicydo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 2-Methoxycarbonylamino 0-O 3-methyl-butyric acid SN'H /\ 0 0 0 [1 -(3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl) naphthalen-2-yl]-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 [1-(3-{5-16-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3H-imidazol-4-yI}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl)-2-aza bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyll-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2 10 Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3H-imidazol-4 yl}-naphthalen-2-yl)-phenyl]-l H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl propyl]-carbamic acid methyl ester using 2-Methoxycarbonylamino-3-methyl-butyric acid to provide [1 -(3-{5-[6-(4- { 2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yI}-phenyl)-naphthalen-2-yI]- IH-imidazol-2-yl}-2-aza 15 bicyclo[2.2.I]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.070g, 65%) as a white powder. 1 H-NMR: 400 MHz, (DMSO-d 6 ) 8: 11.75 (s, I H), 11.72 (s, I H), 8.24 (s, I H), 8.15 (d, I H), 7.93-7.74 (m, 8H), 7.63 (s, I H), 7.54 (s, I H), 7.30 (d, I H), 7.16 (d, I H), 5.22 (t, I H), 4.52-4.50 (m, 2H), 4.16 (t, I H), 4.00 (t, I H), 3.81 (d, I H), 3.75 (d, I H), 3.72 (s, 3H), 3.31 (s, 3H), 2.55 (m, 20 1 H), 2.32-1.41 (m, IOH), 1.01-0.57 (m, 16H). LCMS-ESI*: calc'd for C 48

H

56

N

8 0 6 : 840.43 (M*); Found: 841.99 (M+H*). 875 Example JA O O Mel, NaH O H OH OH O O OH THF, 0 "C to RT O TO 2-tert-Butoxycarbonylamino- 2-tert-Butoxycarbonylamino 3-hydroxy-3-methyl-butyric acid 3-methoxy-3-methyl-butyrc acid 1) HCI, dioxane H O .11 O N A OH 2) 0 O C11 NaOH (aq) 3-Methoxy-2-methoxycarbonylamino THF 3-methyl-butyric acid 0 OC to RT 2-tert-Butoxycarbonylamino-3-methoxy-3-methyl-butyric acid: 5 2-tert-Butoxycarbonylamino-3-hydroxy-3-methyl-butyric acid (1.0g, 4.29mmol) was dissolved in THF (I4mL) and cooled to 00 C in an external ice/brine bath. Mel (2.13mL, 34.3mmol) was added at 0* C. Solid NaH (60% dispersion in mineral oil, 0.514g, 12.87mmol) was added slowly at 00 C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction 10 mixture was diluted in ethyl acetate and water was added slowly with stirring. The quenched mixture was concentrated in vacuo and partitioned between diethyl ether and water. The ether layer was extracted with sodium bicarbonate twice. The combined bicarbonate layers were acidified with aqueous citric acid to pH 3 and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water, sodium thiosulfate, water, dried with 15 sodium sulfate and concentrated to yield 2-iert-Butoxycarbonylamino-3-methoxy-3-methyl butyric acid (0.99g, 94%) as an oil. 'H NMR (400 MHz, CDCl 3 ) 8 3.76 - 3.66 (m, 3H), 3.29 (s, I H), 1.50 (s, 3H), 1.45 (s, 9H), 1.33 (s, 3 H). 20 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid: 2-tert-Butoxycarbonylamino-3-methoxy-3-methyl-butyric acid was dissolved in dioxane (40m L) and HCI (4N in dioxane, 5.4mL, 21.6mmol) was added at room temperature. The resulting solution was stirred at room temperature for 18 hours and the concentrated to dryness. The solid was dissolved in THF (I4mL) and cooled to 00 C in an external ice/brine bath. Aqueous sodium 25 hydroxide (6.25M, 1.9mL, I 1.76mmol) and methyl chloroformate (0.5mL, 5.88mmol) were 876 added at 0* C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction mixture was adjusted to pH 1 with IN HCI and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated to give 5 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid (0.653g, 65%) as an off-white solid. H NMR (400 MHz, acetone) 5 3.76 (s, 3H), 3.60 (s, 3H), 3.22 (s, 3H), 3.18 (s, 3H), 1.37 - 1.31 (m, I H). 10 Example JB 1) HC, dioxane MeOH N\/ N O 2) HATU, NMM, CH 2 Cl 2 H N O HO 110 N -- OH 3{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)5-aza- 0 'O spiro[2.4]hept-6-y]-3H-imidazol-4-y}-phenyl)-naphthalen-2-y-1lH-imidazol-2 yI)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 3-Methoxy-2-methoxycarbonylamino 3-methyl-butyric acid

N

0 O~N NO N [2-Methoxy-1 -(3-(5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-y]-1 H-imidazol 2-yl}-2-aza-bicyclo[2.2. 1 ]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester [2-Methoxy-1-(3-{5-16-(4-{2-5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4jhept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yi]-iH-imidazol-2-yl}-2-aza 15 bicyclo[2.2.llheptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2 Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3H-imidazol-4 yl}-naphthalen-2-yl)-phenyl]-l H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl propyl]-carbamic acid methyl ester (example from JJC) using 3-Methoxy-2 20 methoxycarbonylamino-3-methyl-butyric acid (0.020g, 0.096mmol) to provide [2-Methoxy-1 (3-{5-[6-(4-f{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H 877 imidazol-4-yI}-phenyl)-naphthalen-2-yl]- I H-imidazol-2-yl }-2-aza-bicyclo[2.2.1 ]heptane-2 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.0 19g, 35%) as a white solid. 'H NMR (400 MHz, CDC1 3 ) 8 8.37 -7.88 (m, 4H), 7.84 - 7.35 (m, 8H), 5.81 - 5.33 (m, 2H), 4.88 - 4.57 (m, 2H), 4.34 (s, I H), 3.91 - 3.54 (m, 9H), 3.46 - 3.16 (m, 4H), 3.09 - 2.82 (m, I H), 5 2.24 (dd, 2H), 1.93 (m, 6H), 1.61 (s, I H), 1.47 - 1.17 (m, 7H), 1.11 (d, I H), 1.02 - 0.83 (m, 7H), 0.72 (s, 3H). LCMS-ESI*: calc'd for C 4 9

H

58

N

8 0 7 : 870.44 (M*); Found: 871.90 (M+H*). Example JC OCl 0

H

2 N OI O N OH NaOH (aq) OH o THF, 0 OC to RT N N 2-Amino-4-cyano-butyric acid 4-Cyano-2-methoxycarbonylamino 10 butyric acid 4-Cyano-2-methoxycarbonylamino-butyric acid: This compound was prepared using the procedure used to prepare 3-Methoxy-2 methoxycarbonylamino-3-methyl-butyric acid using 2-Amino-4-cyano-butyric acid. 15 LCMS-ESI*: calc'd for C 7

H

1 oN 2 0 4 : 186.06 (M*); Found: 187.09 (M+H*). Example JD 1) HCl, dioxane MeOH O ON HH N N N ? H 0, '2) HATU, NMM, CH 2 Cl 2 HN-O H O Os NO N OH 6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza- = bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester N O 4-Cyano-2-methoxycarbonylamino O< NH butyric acid N N Jill N N H O 0 [3-Cyano-1 -(6-{5-[6-(4-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2. 1] hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H imidazol-2-yI}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester 878 [3-Cyano-1-(6-{5-[6-(4-{2-2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.1 ] hept-3-yll-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yi}-5 aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester: This compound was 5 prepared using the procedure used to prepare [I-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2 methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2 yl)-phenyl]-IH-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example from JJC) using 4-Cyano-2-methoxycarbonylamino-butyric acid to provide [3-Cyano- 1-(6-{5-[6-(4-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza 10 bicyclo[2.2.l]hept-3-yl]-3 H-imidazol-4-yI}-phenyl)-naphthalen-2-yl]- IH-imidazol-2-yl)-5-aza spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (0.01 5g, 28%) as a white solid. 'H NMR (400 MHz, CDCl 3 ) 5 8.34 - 8.10 (m, I H), 8.05 - 7.84 (m, I H), 7.80 - 7.62 (m, 8H), 7.53 (d, 2H), 5.47 - 5.22 (m, I H), 4.92 - 4.61 (m, I H), 4.49 (d, 2H), 4.25 (s, 2H), 4.10 (d, 2H), 15 3.79 (s, 2H), 3.70 - 3.42 (m, 6H), 3.32 - 3.23 (m, 2H), 3.00 - 2.85 (m, I H), 2.59 - 2.06 (m, 4H), 2.02 - 1.79 (m, 3H), 1.75 - 1.60 (m, 2H), 1.50 - 1.38 (m, 1 H), 1. 18 (s, 3H), 1.06 - 0.77 (m, 6H), 0.72 - 0.50 (m, 3H). LCMS-ES+: calc'd for C 48

H

53

N

9 0 6 : 851.41 (M*); Found: 852.90 (M+H*). 20 Example JE 1) HCI, dioxane 0 NH MeOH 0r H H -NN 2) HATU, NMM, CH 2

CI

2 0,0O N - H 0~N -~~1 NH - - "'4,J 'o 3-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza- O spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl} 2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 3-Methoxy-2-methoxycarbonylamino 3-methyl-butyric acid O NH 0 O - F 0 [2-Methoxy-1-(3-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl-1 H-imidazol-2 yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 879 [2-Methoxy- 1 -(3-{5-[4-(6-{2-[5-(2-methoxyca rbonylamino-3-methyl-butyryl)-5-aza spiro[2.41 hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl}-2-aza bicyclo[2.2.lheptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare [1 -(6-{5-[4-(6-{2-[2-(2 5 Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2. I ]hept-3-yl]-3H-imidazol-4 yl}-naphthalen-2-yl)-phenyl]- I H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl propyl]-carbamic acid methyl ester (example from JJC) using 3-Methoxy-2 methoxycarbonylamino-3-methyl-butyric acid (0.020g, 0.096mmol) to provide [2-Methoxy- 1 (3-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H 10 imidazol-4-yl} -naphthalen-2-yi)-phenyl]- I H-imidazol-2-yI}-2-aza-bicyclo[2.2. I ]heptane-2 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.016g, 29%) as a white solid. ' H NMR (400 MHz, CDCl 3 ) 8 8.37 - 7.88 (m, 4H), 7.84 - 7.35 (m, 8H), 5.81 - 5.33 (m, 2H), 4.88 - 4.57 (m, 2H), 4.34 (s, I H), 3.91 - 3.54 (m, 9H), 3.46 - 3.16 (m, 4H), 3.09 - 2.82 (m, I H), 2.24 (dd, 2H), 1.93 (m, 6H), 1.61 (s, I H), 1.47 - 1.17 (m, 7H), 1.11 (d, I H), 1.02 - 0.83 (m, 7H), 15 0.72 (s, 3H). LCMS-ESl*: calc'd for C 4 9

H

58

N

8 0 7 : 870.44 (M*); Found: 871.47 (M+H*). Example JF 1) HCI, dioxane 0 NH MeOH Ir0 N f________ N -N N-- N A 2) HATU, NMM, CH 2

CI

2 C, / 0 0 H OH 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H- O imidazol-4-yI}-naphthalen-2-yl)-pheny]-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester 0 S-Cyclohexyl-methoxycarbonylamino acetic acid O N0 C H Id_ HNO 0 (1-(2-{5-[6-(4-{2-[1-(2-Cyclohexyl-2-methoxycarbonylamino-acetyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenyl)-naphthalen-2-y}-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl) 20 2-methyl-propyl]-carbamic acid methyl ester 880 i-(2-{5-[6-(4-{2-[1-(2-Cyclohexyl-2-methoxycarbonylamino-acetyl)-pyrrolidin-2-yll-3H imidazol-4-yl)-phenyl)-naphthalen-2-yli-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyl]-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare [1 -(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino 5 acetyl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3 H-imidazol-4-yI}-naphthalen-2-yl)-phenyl]-1 H imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example from JJC) using S-Cyclohexyl-methoxycarbonylamino-acetic acid (0.022g, 0.1 02mmol) to provide [1 -(2-{5-[6-(4-{2-[l-(2-Cyclohexyl-2-methoxycarbonylamino-acetyl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-pyrrolidine- I 10 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.036g, 28%) as a white solid. 'H NMR (400 MHz, CDC 3 ) 6 7.90 - 7.62 (m, 10H), 7.30 (s, I H), 7.25 (s, I H), 5.60 (d, I H), 5.53 (d, 1 H), 5.41 (d, 1 H), 5.31 (dd, I H), 4.38 (t, I H), 4.25 (t, 1 H), 4.03 - 3.74 (m, 5H), 3.72 3.65 (m, 6H), 2.97 - 2.65 (m, 2H), 2.39 (m, I H), 2.13 (m, 6H), 1.96 - 1.63 (m, 6H), 1.36 - 0.99 (m, 6H), 0.93 (dd, 6H). 15 LCMS-ESI*: calc'd for C 4 7

H

56

N

8 0 6 : 828.43 (M*); Found: 829.70 (M+H*). Example JG 'O 1) HCI, dioxane 0< NH MeOH 0~ H H -N 2) HATU, NMM CH 2 Cl 2 O N OH 2-{5-[4-(6-{2-[1-(2-Methoxycarbonyamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol- 0 4-yI}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester R-Cyclohexyl-methoxycarbonylamino acetic acid O O NH N -NN 0H HN -f 0 0 [1 -(2-{5-[6-(4-{2-1-(2-Cyclohexyl-2-methoxycarbonylamino-acetyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl) 2-methyl-propyl]-carbamic acid methyl ester 20 [1-(2-{5-[6-(4-{2-[1-(2-Cyclohexyl-2-methoxycarbonylamino-acetyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2 methyl-propyll-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare [1 -(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino 881 acetyl)-2-aza-bicyclo[2.2. I ]hept-3-yl]-3 H-imidazol-4-yI}-naphthalen-2-yl)-phenyl]- I H imidazol-2-yI}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example from JJC) using R-Cyclohexyl-methoxycarbonylamino-acetic acid (0.041g, 0.191mmol) to provide [1-(2-{5-[6-(4-{2-[1-(2-Cyclohexyl-2-methoxycarbonylamino-acetyl) 5 pyrrolidin-2-yl]-3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yI]-I H-imidazol-2-yl}-pyrrolidine-1 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.047g, 59%) as a white solid. 'H NMR (400 MHz, CDC1 3 ) 8 7.90 - 7.62 (m, 10 H), 7.30 (s, I H), 7.25 (s, I H), 5.60 (d, I H), 5.53 (d, I H), 5.41 (d, I H), 5.31 (dd, 1 H), 4.38 (t, I H), 4.25 (t, I H), 4.03 - 3.74 (m, 5H), 3.72 3.65 (m, 6H), 2.97 - 2.65 (m, 2H), 2.39 (m, I H), 2.13 (m, 6H), 1.96 - 1.63 (m, 6H), 1.36 - 0.99 10 (m, 6H), 0.93 (dd, 6H). LCMS-ESI+: calc'd for C 4 7

H

56

N

8 0 6 : 828.43 (M*); Found: 829.70 (M+H*). Example JH 0 OH 0H

H

2 N OH NaOH (aq) O11 N ",:AOH THF, 0 OC to RT s F F S-Amino-(4-fluoro-phenyl)- S-(4-Fluoro-phenyl) acetic acid methoxycarbonylamino-acetic acid 15 S-(4-Fluoro-phenyl)-methoxycarbonylamino-acetic acid: This compound was prepared using the procedure used to prepare 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid using S-Amino-(4-fluoro-phenyl)-acetic acid to give S-(4-Fluoro-phenyl)-methoxycarbonylamino acetic acid (0.560g, 82%). 20 LCMS-ESI*: calc'd for CIOHIOFN0 4 : 227.06 (M*); Found: 227.84 (M+H*). 882 Example JI O 1) HCI, dioxane MeOH 0 N / H 2) HATU, NMM CH 2 Cl 2 - N HN -N N H O 0 N y OH 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol 4-yl}-naphthalen-2-yl)-pheny]-1 H-imidazol-2-yl}-pyrrolidine-1 -carboxylic acid terf-butyl ester F S-(4-Fluoro-phenyl) O methoxycarbonylamino-acetic acid O NH F H O 0.

{1-[2-(5-{6-[4-(2-{1-[2-(4-Fluoro-phenyt)-2-methoxycarbonylamino-acety]-pyrrolidin-2-yl}-3H imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-y)-pyrrolidine-1-carbonyl] 2-methyl-propyl}-carbamic acid methyl ester {1-12-(5-{6-[4-(2-{1-12-(4-Fluoro-phenyl)-2-methoxycarbonylamino-acetyll-pyrrolidin-2 5 yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl] 2-methyl-propyl}-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare [1 -(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino acetyl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3 H-imidazol-4-yI}-naphthalen-2-yl)-phenyl]- I H imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl 10 ester (example from JJC) using S-(4-Fluoro-phenyl)-methoxycarbonylamino-acetic acid (0.023g, 0.100mmol) to provide { 1-[2-(5-{6-[4-(2-{1-[2-(4-Fluoro-phenyl)-2 methoxycarbonylamino-acetyl]-pyrrolidin-2-y} -3 H-imidazol-4-y1)-phenyl]-naphthalen-2-yl} I H-imidazol-2-yi)-pyrrolidine- 1 -carbonyl]-2-methyl-propyl} -carbamic acid methyl ester (0.01 5g, 27%) as a white solid. 15 'H NMR (400 MHz, CDCl 3 ) 8 8.01 - 7.71 (m, 8H), 7.55 - 6.93 (m, 8H), 6.06 (d, I H), 5.43 (dd, I H), 5.30 (m, 3H), 4.34 (t, 1 H), 3.85 - 3.77 (m, 2H), 3.74 - 3.47 (d, 6H), 3.25 - 2.92 (m, 4H), 2.36 (s, I H), 2.23 - 1.98 (m, 7H), 1.05 (t, I H), 0.88 (t, 6H). LCMS-ESI*: calc'd for C 4 7

H

4 9

FN

8 0 6 : 840.38 (M*); Found: 841.42 (M+H*). 20 883 Example JJ 0 O CI O H O H2N OH NaOH (aq) 1O N OH 0~~ THF, 0 0 C to RT F F R-Amino-(4-fluoro-phenyl)- R-(4-Fluoro-phenyl) acetic acid methoxycarbonylamino-acetic acid R-(4-Fluoro-phenyl)-methoxycarbonylamino-acetic acid: This compound was prepared 5 using the procedure used to prepare 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid using R-Amino-(4-fluoro-phenyl)-acetic acid to give R-(4-Fluoro-phenyl) methoxycarbonylamino-acetic acid (0.575g, 84%) LCMS-ESl*: calc'd for CIOHIOFN0 4 : 227.06 (M*); Found: 227.84 (M+H*). 10 Example JK 1) HCI, dioxane O- NH MeOH H 2) HATU, NMM, CH 2 Cl2 NN N H y - OH 0~~ 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-y]-3H-imidazol 4-yl}-naphthalen-2-yl)-pheny]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester F R-(4-Fluoro-phenyl) NO methoxycarbonylamino-acetic acid O NH F H O N N N N 0 HN f 0 0 {1-[2-(5-{6-[4-(2-{1-[2-(4-Fluoro-phenyl)-2-methoxycarbonylamino-acety]-pyrrolidin-2-y}-3H imidazol-4-yl)-phenyt)-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl] 2-methyl-propyl}-carbamic acid methyl ester {1-[2-(5-{6-[4-(2-{1-12-(4-Fluoro-phenyl)-2-methoxycarbonylamino-acetyl]-pyrrolidin-2 yl)-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl] 15 2-methyl-propyl)-carbamic acid methyl ester: This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino acetyl)-2-aza-bicyclo[2.2. I ]hept-3-yi]-3 H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]- I H 884 imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example from JJC) using R-(4-Fluoro-phenyl)-methoxycarbonylamino-acetic acid (0.023g, 0.100mmol) to provide { I-[2-(5-{6-[4-(2-{ I-[2-(4-Fluoro-phenyl)-2 methoxycarbonylamino-acetyl]-pyrrolidin-2-y}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl} 5 1 H-imidazol-2-yl)-pyrrolidine-I -carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.008g, 14%) as a white solid. 'H NMR (400 MHz, CDCl 3 ) 5 8.01 - 7.71 (m, 8H), 7.55 - 6.93 (m, 8H), 6.06 (d, I H), 5.43 (dd, I H), 5.30 (m, 3H), 4.34 (t, I H), 3.85 - 3.77 (m, 2H), 3.74 - 3.47 (d, 6H), 3.25 - 2.92 (m, 4H), 2.36 (s, I H), 2.23 - 1.98 (m, 7H), 1.05 (t, I H), 0.88 (t, 6H). 10 LCMS-ES 4 : calc'd for C 4 7

H

4 9

FN

8 0 6 : 840.38 (M*); Found: 841.27 (M+H*). Example JL FFF H H N 1. Pd/C, H 2 , wet iPA H N 2. ECDI, HOBt, N N O N 0 DIEPA, DMF H' I HO {1-[3-(6-{7-[5-(5-Aza-spiro[2.4]hept-6-yl)-1 H-pyrrol- O O 2-yl]-9,9-difluoro-9H-fluoren-2-yl}-1 H- H'N benzoimidazol-2-yl)-2-aza-bicyclo[2.2. 1 ]heptane-2- O carbonyl]-2-methyl-propyl}-carbamic acid methyl ester 2-Methoxycarbonylamino 3-methyl-butyric acid ECDI, HOBt 0N DIEPA, DMF N N H'N O f ONI (1 -{3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2 yl)-l H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1 ]heptane-2-carbonyl} 2-methyl-propyl)-carbamic acid methyl ester 15 (1- {3-[6-(9,9-Difluoro-7- {2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl} -9H-fluoren-2-yl)- I H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.1]heptane-2-carbonyl} -2-methyl-propyl)-carbamic acid methyl ester was prepared in a similar manner as Example C to give title compound as a white powder (68 mg). 885 H-NMR: 300 MIHz, (DMSO-d 6 ) 6: 12.56 (d, J=13.5Hz, 0.5H), 12.05 (dd, I H), 11 .84 (s, 0.5 H), 8.1 - 7.1 (m, 12H), 5.71 (d, 0.51H), 5.27 (s, 0.51H), 5.19 (d, 0.5H), 4.70 (s, 0.5H), 4.64 (s, 0.5H), 4.49 (s, 0.5H), 4.2-3.9(m, 2H), 3.6-3.2 (m, 20H), 2.8-1.1 (m, 12H), 0.9-0.4 (m , 16H). LCMS-ESI*: calc'd for C 4 9

H

54

F

2

N

8 0 6 : 890.0 (M+H*); Found: 889.4 (M+H*). 5 Example JM CN CN LiOH HOOC+ Br HATU, DIEA NeO~ N - NH 2 DMF Bc Boc 4-Cyano-pyrrolidine-1,2- 4-Cyano-pyrrolidine- 2-Amino-1-(4 dicarboxylic acid 1-tedt- 1,2-dicarboxylic acid bromo-phenyl) butyl ester 2-methyl ester 1-tert-butyl ester ethanone ON ,CN 0NH 4 Ac BrI Br oc Bo N+ 2-[2-(4-Bromo-pheny)-2-oxo- 2-[5-(4-Bromo-pheny)-1 H ethylcarbamoyl]-4-cyano-pyrrolidine- imidazol-2-yl]-4-cyano-pyrrolidine 1-carboxylic acid tert-butyl ester 1-carboxylic acid fert-butyl ester N - N N - HN-I N I /-N / \~ o N /Oc Pd(PPh 3

)

4 , K 2 0 3 Boc Bo B- ; ' DM EIH 2 0,90 0 C N NCf 2-(5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan- 2-[5-(4-{6-(2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H 2-yl)-naphthalen-2-yl]-1 H-imidazol-2-yl}- imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1 H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester 4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester H N N o " Boc HCHO LAH BN N N NaB(OAc) 3 H H

H

2 N_ 4-Aminomethyl-2-[5-(4-{6-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl) 3H-imidazol-4-yl]-naphthalen-2-y}-phenyl)-1H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester H 1 TFA N N ______ Boc N Boc 2 HATU DIEA H HO 2-[5-(4-{6-[2-(1 -tert-Butoxycarbonyl-pyrrolidin-2-yl)- H 0 N- 3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1 H imidazol-2-yl]-4-dimethylaminomethyl-pyrrolidine-1 - 2-Methoxycarbonylamino-3 carboxylic acid tert-butyl ester methyl-butyric acid 0 H N N N N N [1-(4-Dimethylaminomethyl-2-{5-[4-(6-{2 NJ ,N [1 -(2-methoxycarbonylamino-butyryl) /- H H pyrrolidin-2-yl]-3H-imidazol-4-yl}

-

0 naphthalen-2-yl)-phenyl]-1 H-imidazol-2 yl}-pyrrolidine-1-carbonyl)-2-methyl N~ propyl]-carbamic acid methyl ester 886 LiOH.H 2 0 (167 mg, 3.98 mmol) was added to 4-cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert butyl ester 2-methyl ester (674 mg, 2.65 mmol) in methanol (5 mL) solution. The reaction was 5 stirred at room temperature overnight. The reaction mixture was concentrated down. The crude is used in next step reaction. 2-Amino-1 -(4-bromo-phenyl)-ethanone HCI salt (664 mg, 2.65 mmol) was dissolved in DMF (10 mL) and to this solution was added 4-Cyano-pyrrolidine-1,2-dicarboxylic acid I-tert-butyl 10 ester crude from the previous step, diisopropyl ethylamine (0.93 mL, 5.3 mmol), followed by HATU (I g, 2.65 mmol). Reaction mixture was stirred at 0 0 C for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[2-(4-Bromo-phenyl)-2-oxo 15 ethylcarbamoyl]-4-cyano-pyrrolidine-l -carboxylic acid tert-butyl ester (1.05 g, yield 9 1%). LCMS-ESI-: calc'd for C 19 gH 22 BrN 3 0 4 : 435.08; Found: 458.0 (M+Na'). A mixture of 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-I -carboxylic acid tert-butyl ester (1.05 g, 2.4 mmol) and ammonia acetate (3.7 g, 20 eq.) in Xylene (2 mL) 20 was heated in microwave at I 10 0 C for 2 hours. The mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(4 Bromo-phenyl)-l H-imidazol-2-yl]-4-cyano-pyrrolidine-I -carboxylic acid tert-butyl ester (356 mg, containing 15% starting material, yield 35%). LCMS-ESI~: calc'd for C 19

H

21 BrN 4 0 2 : 417.30; Found: 418.9 (M+H*). 25 The mixture of 2-[5-(4-Bromo-phenyl)- I H-imidazol-2-yl]-4-cyano-pyrrolidine- I -carboxylic acid tert-butyl ester (356 mg, 0.85 mmol), 2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2 yl)-naphthalen-2-yl]- I H-imidazol-2-yl}I -pyrrolidine- I -carboxylic acid tert-butyl ester (501 mg, 1.02 mmol), tetrakis(triphenylphosphine)palladium(99 mg, 0.08 mmol) and potassium acetate 30 (425 mg, 3.07 mmol) in 7 mL 1,2-dimethoxyethane and 2 mL water was heated to 90 0 C for 2 hour. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[5-(4-{6-[2 (I -tert-Butoxycarbonyl-pyrrol idin-2-yl)-3 H-imidazol-4-yl]-naphthalen-2-yl) -phenyl)- I H 887 imidazol-2-yli]-4-cyano-pyrrolidine-I-carboxylic acid tert-butyl ester (200 mg, yield 33%) and the amide product. LCMS-ESI~: calc'd for C 4 1

H

4 5

N

7 0 4 : 699.84; Found: 700.2 (M+H*). LAH (45 mg, 6 eq.) was added to the solution of mixture of 2-[5-(4-{6-[2-(1-tert 5 Butoxycarbonyl-pyrrolidin-2-yl)-3 H-imidazol-4-yl]-naphthalen-2-y}-phenyl)-I H-imidazol-2 yl]-4-cyano-pyrrolidine- I-carboxylic acid tert-butyl ester (146 mg, 0.066 mmol) in 3 ml THF at 0 UC. The reaction was quenched after 30 minutes using water, 10%NaOH aqueous solution and water in 3 steps. The reaction mixture was filtered. The filtrate was concentrated down and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). 10 Product lyophilized to give 4-Aminomethyl-2-[5-(4-{6-[2-(I-tert-butoxycarbony-pyrrolidin-2 yl)-3 H-imidazol-4-yl]-naphthalen-2-yl } -phenyl)- I H-imidazol-2-yl]-pyrrolidine-l -carboxylic acid tert-butyl ester TFA salt (150 mg, yield 95%). LCMS-ESI-: calc'd for C 4 1 1H 4 9

N

7 0 4 : 703.87; Found: 704.2 (M+H*). 15 Sodium triacetyl boron hydride (54mg, 3 eq.) was added to the mixture of 4-Aminomethyl-2-[5 (4-{6-[2-(1 -tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yI]-naphthalen-2-y}-phenyl) I H-imidazol-2-yl]-pyrrolidine- I -carboxylic acid tert-butyl ester (60 mg, 0.085 mmol) and 0.1 mL formaldehyde (37% in water) in 3 ml THF, followed by I drop of acetic acid. The reaction was stirred at room temperature for 30 minutes. The reaction was complete by monitoring using 20 LC-MS. The reaction mixture was filtered. The filtrate was concentrated down and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product lyophilized to give 2-[5-(4-{6-[2-(I-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl] naphthalen-2-yl}-phenyl)- I H-imidazol-2-yl]-4-dimethylaminomethyl-pyrrolidine- I -carboxylic acid tert-butyl ester TFA salt (41.7 mg, yield 67%). LCMS-ESr~: calc'd for C 4 3

H

5 3

N

7 0 4 : 25 731.93; Found: 732.3 (M+H*). Trifluoroacetic acid (0.5 mL)was added to 2-[5-(4-{6-[2-(l-tert-Butoxycarbonyl-pyrrolidin-2 yl)-3 H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-I H-imidazol-2-yl]-4-dimethylaminomethyl pyrrolidine-l -carboxylic acid tert-butyl ester (41.7 mg, 0.057 mmol) in I ml DCM and the 30 reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (1.5 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (20 mg, 0.124 mmol), diisopropyl ethylamine (60 p1), followed by HATU (43 mg). Reaction mixture was stirred at 0 0 C for 60 minutes. The reaction mixture was dissolved in ethyl acetate and washed 35 with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated 888 and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product lyophilized to give [I -(4-Dimethylaminomethyl-2-{5-[4-(6-{2-[1-(2 methoxycarbonylamino-butyryl)-pyrrol idin-2-yl]-3H-imidazol-4-yl }-naphthalen-2-y)-phenyl] 1 H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester the bis 5 TFA salt (Example A) (13.1 mg). H-NMR: 300 MHz, (CD 3 0D-d 4 ) 8: 8.28 (d, 2H), 8.02 (m, 2H), 7.83-7.92 (m, 8H), 5.38 (m, 2H), 4.58(m, I H), 4.22(m, 2H), 4.18(m, 2H), 3.92 (m, 2H), 3.62 (s, 6H),3.42(m,2H), 3.02(s, 6H), 3.00(m,l H), 2.81(m,1 H), 2.62 (m, I H), 2.40-2.00 (m, 5 H), 0.95-1.05 (m, 12 H). LCMS-ESI*: calc'd for C 4 7

H

59

N

9 0 6 : 846.03; Found: 848.4 (M+H*). 10 Example JN H - N N Boc Boc MsCI, DIEA N N H

H

2 N-' 4-Aminomethyl-2-[5-(4-{6-[2-(1-tert butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl] naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester H N N 1. TFA N\ N\- / \ Boc Boc N N / 2. HATU DIEA N N 00 0 H HO N- 2-[5(4{6-[2-(1 -tert-Butoxycarbonyl- H O pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen- 0 2-yl}-phenyl)-1H-imidazol-2-yl]-4- 2-Methoxycarbonylamino-3 (methanesulfonylamino-methyl)-pyrrolidine- methyl-butyric acid 1-carboxylic acid tert-butyl ester 0 H ' -~ NN N 0 N O O N N N O H 0 \SO / N H [1-(4-(Methanesulfonylamino-methyl)-2-{5-[4-(6-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol 4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester MsCl (7.6 mg, I eq.) was added to the mixture of 4-Aminomethyl-2-[5-(4-{6-[2-(l-tert 15 butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-y]-naphthalen-2-yl} -phenyl)- I H-imidazol-2 889 yl]-pyrrolidine-l-carboxylic acid tert-butyl ester (69 mg, 0.098 mmol) and DIEA( 51 Ll, 3eq) in I ml MeCN. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated down and purified by preparative reverse phase HPLC (Gemini, 5 to 100%

ACN/H

2 0 + 0.1% TFA). Product lyophilized to give 2-[5-(4-{6-[2-(1-tert-Butoxycarbonyl 5 pyrrolidin-2-yl)-3 H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-l H-imidazol-2-yi]-4 (methanesulfonylamino-methyl)-pyrrolidine-I-carboxylic acid tert-butyl ester TFA salt (29 mg, yield 38%). LCMS-ESr: calc'd for C 4 2

H

5

N

7 0 6 S: 781.96; Found: 782.2 (M+H*). Trifluoroacetic acid (0.5 mL)was added to 2-[5-(4-{6-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2 10 yl)-3 H-im idazol-4-yl]-naphthalen-2-yl} -phenyl)- I H-imidazol-2-yl]-4-(methanesulfonylamino methyl)-pyrrolidine-I-carboxylic acid tert-butyl ester (29 mg, 0.037 mmol) in I ml DCM and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (0.5 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (13 mg, 2 eq.), 15 diisopropyl ethylamine (39 pl, 6 eq.), followed by HATU (28 mg, 2 eq.). Reaction mixture was stirred at 0 0 C for 60 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product lyophilized to give [I -(4-(Methanesulfonylamino-methyl)-2-{5-[4-(6-{2-[1-(2 20 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3 H-im idazol-4-yl} -naphthalen-2-yl) phenyl]-I H-imidazol-2-yl}-pyrrolidine-I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester the bis-TFA salt (Example B) (12.9 mg). H-NMR: 300 MH z, (CD 3 0D-d 4 ) 5: 8.28 (d, 2H), 8.08 (m, 2H), 7.95 (m, 4H), 7.82(m, 4H), 5.28 (m, 2H), 4.38(m, I H), 4.22(m, 2H), 4.12(m, 2H), 3.92 (m, 2H), 3.62 (s, 6H),3.61(m,2H), 25 3.02(s, 3H), 2.72(m,2H), 2.60 (m, 1 H), 2.40-1.98 (m, 5H), 0.95-1.05 (m, 12 H). LCMS-ESI*: calc'd for C 4 6

H

57

N

9 0 8 S: 896.07; Found: 896.3 (M+H*). 890 Example JO H - N N Boc // Boc AcCl, DIEA N, -N 3 H

H

2 N_~ 4-Aminomethyl-2-[5-(4-{6-[2-(1-tert butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl] naphthalen-2-yl}-phenyl)-1 H-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester H N N 1. TFA N\ \ - / \ Boc Boc / 2. HATU, DIEA N -N O H H 4-(Acetylamino-methyl)-2-[5-(4-{6-[2-(1-tert- HO butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]- O H naphthalen-2-yl)-phenyl)-1H-imidazol-2-yl]- 2-Methoxycarbonylamino-3 pyrrolidine-1-carboxylic acid tert-butyl ester methyl-butyric acid 0 H H N N N / ~N 0j~ N N O H 0

N

H [1-(4-(Acetylamino-methyl)-2-{5-[4-(6-{2-[1-(2 methoxycarbonylamino-3-methy-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl propyl]-carbamic acid methyl ester 5 AcCl (5 pil, I eq.) was added to the mixture of 4-Aminomethyl-2-[5-(4-{6-[2-(l-tert butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-y]-naphthalen-2-yl}-phenyl)- I H-imidazol-2 yl]-pyrrolidine-l -carboxylic acid tert-butyl ester (50 mg, 0.071 mmol) and DIEA( 37 pl, 3eq) in I ml DCM and I mL MeCN mixture. The reaction was stirred at room temperature for I hour. 10 LC-MS shows desired and Bis-acetyl product. The reaction mixture was concentrated down and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/-1 2 0 + 0.1% TFA). Product lyophilized to give 4-(Acetylamino-methyl)-2-[5-(4-{6-[2-(I -tert-butoxycarbonyl pyrrolidin-2-yI)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-I H-imidazol-2-yi]-pyrrolidine-l carboxylic acid terl-butyl ester TFA salt (13 mg, yield 25%). LCMS-ESI~: calc'd for 15 C 43

H

5

IN

7 0 5 : 745.91; Found: 746.2 (M+H+). 891 Trifluoroacetic acid (0.5 mL)was added to 4-(Acetylamino-methyl)-2-[5-(4-{6-[2-(I-tert butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)- I H-imidazol-2 yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (13 mg, 0.017 mmol) in I ml DCM and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was 5 concentrated and dried overnight under vacuum. The residue was dissolved in DMF (0.5 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (6 mg, 2 eq.), diisopropyl ethylamine (18 il, 6 eq.), followed by HATU (13 mg, 2 eq.). Reaction mixture was stirred at 0 0 C for 60 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated 10 and purified by preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H 2 0 + 0.1% TFA). Product lyophilized to give [I -(4-(Acetylamino-methyl)-2-{5-[4-(6-{2-[1-(2 methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl) phenyl]- I H-imidazol-2-yl} -pyrrolidine- I -carbonyl)-2-methyl-propyl]-carbamic acid methyl ester the bis-TFA salt (Example C) (6.6 mg). 1 5 ' H-NMR: 300 MHz, (CD 3 0D-d 4 ) : 8.28 (d, 2H), 8.08 (m, 2H), 7.95 (m, 4H), 7.82(m, 4H), 5.28 (m, 2H), 4.38(m, I H), 4.22(m, 2H), 4.17(m, 2H), 3.92 (m, 2H), 3.62 (s, 6H), 3.59(m,I H), 3.42(m, 2H), 2.64(m,2H), 2.24 (m, 3H), 2.10 (m, 2H), 1.99 (s, 3H), 0.95-1.05 (m, 12 H). LCMS-ESI*: calc'd for C 4 7

H

57

N

9 0 7 : 859.44; Found: 860.4 (M+H*). 20 Example JP 0IOH Ebz C/ Br NH 4 OAc Br<- + / DMF/CH 3 CN N o - xylene/140 C 5-Aza-spiro[2.4]heptane-5,6 2-Bromo-1-(7-bromo- 5-Aza-spiro[2.4]heptane-5.6- dicarboxylic acid 5-benzyl ester dibenzofuran-3-yl)-ethanone dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-dibenzofuran-3-yl)-2-cxo-ethyl] ester H H~ imd-[-yl]-5-aodizan-i[.]hptne dioxaborolan-2-yl)-1 H-benzoimidazo-2-yl] imidazot-4-yI}-dibenzofuran-3-yl}-1 H-benzoimidazo-2-yl)-2-aza 5-carboxylic acid benzyl ester 2 b tbtie rbcco221hpae2-carboxylic acid tert-buty ester H N a. BrIH+c N -N /Y b BOOH/ ATUiPr 2 NEt/DMF O ON O H0 (1-{6-(5-(7-(2-[2-(2-Meth oxycarn 3-(rio 73m(thy-butyryl) -2-aza-bcyclo[2.2. 1]hept-3-yt}-3H-benzoimidazo-5-yl dibenzofuran-3-y)-1 H-imidazot-2-yt}-5-aza-spiro [2.4]heptane-5-carbonyl-2-methypropy)-crbeamic acid methyl ester 892 5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-d ibenzofu ran 3-yl)-2-oxo-ethyll ester: To the solution of (s) 5-aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5 5 benzyl ester (138 mg, 0.5 mmol) and triethylamine (65 pl, 0.47 mmol) in acetonitrile (3 ml) was added slowly a solution of 2-bromo-l-(7-bromo-dibenzofuran-3-yl)-ethanone (143 mg, 0.39 mmol) in DMF (4 ml). The mixture was stirred for 12 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with 1.0 N NaOH solution, water and brine, and was dried with sodium sulfate. Concentration gave 5-Aza-spiro[2.4]heptane-5,6 10 dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-dibenzofuran-3-yl)-2-oxo-ethyl] ester (210 mg) 6-[5-(7-Bromo-dibenzofuran-3-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.41heptane-5-carboxylic acid benzyl ester: The mixture of 5-aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-[2-(7-bromo-dibenzofuran-3-yl)-2-oxo-ethyl] ester (210 mg, 0.39 mmol) and ammonium 15 acetate (330 mg, 4.3 mmol) in xylene (3 ml) was heated at 140 C for 80 minutes under microwave. The mixture was quenched with water, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 6-[5-(7-bromo-dibenzofuran-3-yl) I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (150 mg). m/z: 542.1 20 (M+l), 540.1 (M-1). 3-(6-{7-[2-(5-Benzyloxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl] dibenzofuran-3-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: To the solution of 6-[5-(7-bromo-dibenzofuran-3-yl)- I H-imidazol-2-yl]-5-aza 25 spiro[2.4]heptane-5-carboxylic acid benzyl ester (150 mg, 0.28 mmol) and 3-[6-(4,4,5,5 Tetramethyl-[ 1,3,2]dioxaborolan-2-yl)- I H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2. I ]heptane-2 carboxylic acid tert-butyl ester (160 mg, 0.36 mmol) in DME (2.25 ml) and water (0.75 ml) was added potassium carbonate (78 mg, 0.56 mmol), followed by Pd(PPh 3

)

4 (15 mg) and PdCl 2 (dppf)CH 2 Cl 2 (15 mg). The mixture was heated at 90 C for 16 hours. The mixture was 30 diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-(6-{7 [2-(5-benzyloxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3 H-imidazol-4-yl]-dibenzofuran-3-yl}-1 H benzoimidazol-2-yl)-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (190 mg). m/z: 775.2 (M+1), 773.3 (M-1), 338.2 (M+2)/2. 35 893 (1 -{6-[5-(7-{2-12-(2-Methoxycarbonylamino-3-methyl-butyryl) -2-aza-bicyclo[2.2.1] hept-3-yli]-3H-benzoimidazol-5-yli-d ibenzofu ran-3-yl)- 1 H-imidazol-2 yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester: To the solution of 3-(6-{7-[2-(5-benzyloxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl] 5 dibenzofuran-3-yl} -1 H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert butyl ester (185 mg, 0.24 mmol) in DCM (3.6 ml) was added slowly 33% HBr/HOAc (1 ml). The mixture was stirred for two hours, and the solvent and reagent were removed under reduced pressure to give a brown solid. The solid was suspended in DCM/Et 2 0 (2.5 ml/25 ml) and was stirred. The solid was collected through filtration. To the solution of above solid (0.24 mmol) 10 and MeOCO-Val-OH (84 mg, 0.48 mmol) in DMF (7.0 ml) was added HATU (192 mg, 0.50 mmol), followed by diisopropylethylamine (0.42 ml, 2.4 mmol). The mixture was stirred for ten hours and was evaporated and then diluted with EtOAc. The organic phase was washed with I N NaOH solution, water, and brine, and was dried with sodium sulfate. Concentration and purification by HPLC (0.1 %TFA/CH 3 CN/0. I %TFA/H 2 0) gave (1 -{6-[5-(7-{2-[2-(2 15 methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2. 1 ]hept-3-yl]-3H-benzoimidazol-5 yl}-dibenzofuran-3-yl)-I H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl propyl)-carbamic acid methyl ester (151 mg). m/z: 855.3 (M+1), 853.2 (M-I), 428.4 (M+2)/2. 'H NMR (CD 3 0D, 300 MHz) 8 8.25-7.70 (10 H, in), 5.4 (1 H, m), 4.95-4.7 (1 H, m), 4.38 (1 H, in), 4.16 (1 H, m), 3.95 (1 H, m), 3.83 (1 H, m), 3.69 (3 H, s), 3.67 (3 H, s), 3.5-3.2 (1 H, m), 20 2.98 (1 H, m), 2.5 -1.7 (10 H, m), 1.2-0.8 (16 H, m). 894 Example JQ Br BrO 0 Sr BBr 3 HO S Tf 2 0 2-(4-Bromo-phenyl)-6- DCM 2-(4-Bromo-phenyl)- pyridine Trifluoro-methanesulfonic acid 2 methoxy-benzo[b]thiophene benzo[b]thiophen-6-oI (brom phenels) benza[bjthiaphen-6-y ester OEt HO O 0 -N'' O Sn(Bu) 3 O Boc o= S Boc 1. Pd(PPh 3

)

4 DIPEA Boc--N O O PdCl 2 (PPh 3

)

2 DMF o LiCI Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-[2 DMF (2-{4-[2-(1-Boc-pyrrolidine-2-carbonyloxy)-acetyl] 2. NBS/H 2 0 phenyl)-benzolb]thiophen-6-yl)-2-oxo-ethyl] ester HN 40A c N BN oc

NH

4 0AC N~< xyleneH MW 2-[5-(2-{4-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-y] phenyl}-benzo[b]thiophen-6-y)-1 H-imidazol-2-yl] pyrrolidine-1 -carboxylic acid tert-butyl ester OH O HH N _ _ _ _J NH HCI HATU oNH MeOH DIPEAN DMF H [1-(2-{5-[2-(4-{2-1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin 2-yl]-3H-imidazol-4-yl)-phenyl)-benzo[bthiophen-6-y]-1 H-imidazo-2-yl} pyrrolidine-1 -carbonyl)-2-methyl-propyll-carbamic acid methyl ester 5 2-(4-Bromo-phenyl)-6-methoxy-benzo[blthiophene was reported in the literature (Journal of Medicinal Chemistry, 2007, 50, 2682-2692). 2-(4-Bromo-phenyl)-benzojbjthiophen-6-ol. To a stirred solution of 2-(4-bromo-phenyl)-6 methoxy-benzo[b]thiophene (80 mg, 0.25 mmol) was added BBr 3 (0.5 mL of I M in DCM, 0.5 10 mmol) at 0* C. The mixture was stirred for 3 hours at ambient temperature. DCM was removed under vacuum, and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was treated with hexane to give the product (67 mg, 88%). m/z 303.0, 305.0 (M-H)-. 15 895 Trifluoro-methanesulfonic acid 2-(4-bromo-phenyl)-benzo[bjthiophen-6-yI ester. Tf2O was added slowly to a mixture of 2-(4-bromo-phenyl)-benzo[b]thiophen-6-ol (200 mg, 0.66 mol) in pyridine (3 mL) at 00 C with stirring. The mixture was stirred at ambient temperature for 16 hours before quenched with NaHCO 3 solution. The mixture was extracted with ethyl acetate (50 5 mL). The organic layer was washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was used for next step reaction without further purification. Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-[2-(2-(4-[2-(1-Boc-pyrrolidine-2 10 carbonyloxy)-acetyll-phenyl}-benzolblthiophen-6-yl)-2-oxo-ethyl] ester. Pd(Ph 3

)

4 (43 mg, 0.037 mmol), PdCl 2 (Ph 3

)

2 (26 mg, 0.037 mmol) and LiCl (78 mg, 1.8 mmol) were added to a mixture trifluoro-methanesulfonic acid 2-(4-bromo-phenyl)-benzo[b]thiophen-6-yl ester (200 mg, 0.46 mmol) and tributyl( -ethoxyvinyl)tin (0.37 mL, 1.1 mmol) in 8 mL DMF. The reaction mixture was flushed with nitrogen, heated at 800 C for 16 hours, then cooled to ambient 15 temperature. Water (3 mL) and NBS (180 mg, 1.0 mmol) were added and the mixture was stirred at room temperature for 40 min, then diluted with ethyl acetate (300 mL). The ethyl acetate layer was washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was suspended in acetonitrile (30 mL). To it was added a solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (792 mg, 3.7 mmol) and DIPEA (0.56 mL, 20 3.2 mmol) in 5 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO 3 solution and water, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (90 mg, 27% over two steps). m/z 743.2 (M+Na)*. 25 2-[5-(2-{4-12-(I-Boc-pyrrolidin-2-yl)-3H-imidazol-4-y]-phenyl-benzoibthiophen-6-yl) 1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester. A mixture of pyrrolidine 1,2-dicarboxylic acid 1-tert-butyl ester 2-[2-(2-{4-[2-(1-Boc-pyrrolidine-2-carbonyloxy) acetyl]-phenyl}-benzo[b]thiophen-6-yl)-2-oxo-ethyl] ester (90 mg, 0.12 mmol) and ammonium 30 acetate (192 mg, 2.5 mmol) in xylene (10 mL) was heated in a sealed tube at 140* C for 1.5 hours under microwave condition. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (60 mg, 70%). m/z 681.2 (M+H)+. 35 896 [1-(2-{5-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yI -3H imidazol-4-yl}-phenyl)-benzoibithiophen-6-yl]-1 H-imidazol-2-yI-pyrrolidine-1-carbonyl) 2-methyl-propyl]-carbamic acid methyl ester. To a solution of 2-[5-(2-{4-[2-(l-Boc pyrrolidin-2-yI)-3 H-imidazol-4-yl]-phenyl}-benzo[b]thiophen-6-yl)- I H-imidazol-2-yl] 5 pyrrolidine- I -carboxylic acid tert-butyl ester (60 mg, 0.09 mmol) in methanol (3 mL) was added 4N HCI in 1,4-dioxane (0.4 mL, excess). The mixture was stirred for 2 hours at 50' C and concentated under reduced pressure. The residue was dissolved in wather and freezing-dired overnight. The obtained white solid was dissoved in DMF (3 mL), to the solution was added 2 methoxycarbonylamino-3-methyl-butyric acid (34 mg, 0.19 mmol), HATU (84 mg, 0.22 mmol) 10 and NN-diisopropylethylamine (0.12 mL, 0.70 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with I N NaOH solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a TFA salt (45 mg, 64%). 'H-NMR (300 MHz, CD 3 0D) 6 8.26 (s, I H), 8.00 15 7.70 (m, 9H), 5.30-5.20 (m, 2H), 4.23 (d, 2H), 4.18-4. 10 (m, 2H), 3.95-3.80 (m, 2H), 3.75-3.60 (m, 6H), 2.65-2.50 (m, 2H), 2.35-2.00 (m, 8H), 1.00-0.80 (m, 12H); m/z 795.3 (M+H)*. Example JR Br - Br Et2Zn Br - ',Br 2,7-oibromo-9- TFA 2',7-dibromospirocyclopropanc methylene-9H-fluorene CH 2 12 1,9'-fluorene 0CM19-lorn )~SnBU HOOC'Nj Cbz >N.b 3 Cbz N 0 0 - NH Br - -- . Ij Br 1 P HOO- Br NH 4 0Ac NBr I+C,(PPh 3 ) DIPEA, DMF xylene PdCl2(PPh)2 D5-Cbz-5-aza-spiro[2.4]heptanc-6-carboxylic 6-[5-(7-Bromospirocyclopropane- 1,9' 2. NBSIH 2 O acid 2-(7-bromospirocyclopropanc- 1,9'- fluoren-2-yl)- I H-imidazol-2-yIj-5-Cbzl-5 fluoren-2-yI)-2-oxo-ethyl ester aza-spiro[2.4]heptane N, PdCl 2 (PPha) 2 2M K 2

CO

3 2-(2-Boc-2-aza-bicyclo[2.2. I ]hept-3-yl)-64 7-[2-(5-Cbz-5 DME aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-y] spirocyclopropanc- I,9'-fluoren-2-yIl}-I H-benzoimidazole 0 HO 0O ,C -NH -I NH H~r HO~N EON/ /\ / /\ N CM P0 EC N acetonitrile HN 0 (1{-6(-2[5(-ehxcrbnEmn--ety-uyy)5aza-spiro[2.4]hept-6-)31imd ol-yl} 3H-iidazol-yspir cloropane- 1,9-fluren-2-yi)-1 H-benzoimdazol-2-1-aza 897 2,7-Dibromo-9-methylene-9H-fluorene was reported in the literature (Tetrahedron, 2006, 62, 3355-3361). 5 2',7'-Dibromospirocyclopropane-1,9'-fluorene. To a stirred solution of diethylzinc (9.0 mL of 1.0 M in hexane, 9.0 mmol) in DCM (10 mL) was added trifluoroacetic acid (0.69 mL, 9.0 mmol) in DCM (10 mL) slowly at 0' C. The mixture was stirred for 20 min at 0' C before the addition of diiodomethane (0.72 mL, 9.0 mmol). The mixture was stirred for another 20 min at 0* C, then a solution of 2,7-dibromo-9-methylene-9H-fluorene (750 mg, 2.2 mmol) in DCM (5 10 mL) was added. The mixture was stirred at ambient temperature for 5 days, then quenched slowly with NH 4 CI solution. The mixture was extracted with ethyl acetate, washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was dissolved in a mixed solvent of THF/water/acetone (18 mL with ration 12/4/4), NMO (264 mg, 2.2 mmol) and OS04 was added. The mixture was stirred for 16 hs at ambient temperature, 15 quenched with I M Na 2

S

2

O

3 , then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (480 mg, 61%). 5-Cbz-5-aza-spiro[2.4]heptane-6-carboxylic acid 2-(7-bromospirocyclopropane-1,9' 20 fluoren-2-yl)-2-oxo-ethyl ester. Pd(Ph 3

)

4 (67 mg, 0.058 mmol) and PdCl 2 (Ph 3

)

2 (41 mg, 0.058 mmol) were added to a mixture 2',7'-dibromospirocyclopropane-1,9'-fluorene (670 mg, 1.93 mmol) and tributyl(l-ethoxyvinyl)tin (0.66 mL, 1.93 mmol) in 20 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 800 C for 16 hours, then cooled to ambient temperature. Water (7 mL) and NBS (344 mg, 1.93 mmol) were added and the mixture was 25 stirred at room temperature for 40 min, then diluted with ethyl acetate (300 mL). The ethyl acetate layer was washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was suspended in acetonitrile (30 mL). To it was added a solution of pyrrolidine- 1,2-dicarboxylic acid I -benzyl ester (780 mg, 2.8 mmol) and DIPEA (0.44 mL, 2.5 mmol) in 5 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, 30 diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO 3 solution and water, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (825 mg, 73% over two steps). m/z 585.9, 587.9 (M+H)*. 898 6-[5-(7-Bromospirocyclopropane-1,9'-fluoren-2-yI)-1 H-imidazol-2-yJ-5-Cbzl-5-aza spiro[2.41heptane. A mixture of 5-Cbz-5-aza-spiro[2.4]heptane-6-carboxylic acid 2-(7 bromospirocyclopropane-l,9'-fluoren-2-yl)-2-oxo-ethyl ester (825 mg, 1.4 mmol) and ammonium acetate (1.5 g, 19.5 mmol) in xylene (15 mL) was heated in a sealed tube at 140* C 5 for 1.5 hours under microwave condition. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (100 mL), washed with NaHC0 3 solution, water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (140 mg, 18%). m/z 566.1, 568.1 (M+H)*. 10 2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-yl)-6-{7-[2-(5-Cbz-5-aza-spiro[2.4]hept-6-yl)-3H imidazol-4-ylI]-spirocyclopropane-1,9'-fluoren-2-yl}-IH-benzoimidazole. Pd(Ph 3

)

4 (14 mg, 0.012 mmol) and PdCl 2 (Ph 3

)

2 (9 mg, 0.012 mmol) were added to a mixture 6-[5-(7 bromospirocyclopropane- 1,9'-fluoren-2-yi)- I H-imidazol-2-yl]-5-Cbzl-5-aza-spiro[2.4]heptane 15 (140 mg, 0.25 mmol), 3-[6-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)- I H-benzoimidazol-2 yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (120 mg, 0.27 mmol), 2M

K

2

CO

3 (0.5 mL, 1.0 mmol) in 1,2-dimethoxyethane (5 mL). The reaction mixture was flushed with nitrogen, heated at 80* C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO 3 solution, 20 water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (80 mg, 40%). m/z 799.3 (M+H)*. (1-{3-[ 6 -(7-{2-5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl] 25 3H-imidazol-4-yl}-spirocyclopropane-1,9'-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza bicyclo[2.2.llheptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. To a solution of 2-(2-Boc-2-aza-bicyclo[2.2. I ]hept-3-yI)-6-{7-[2-(5-Cbz-5-aza-spiro[2.4]hept-6-yl) 3H-imidazol-4-yl]-spirocyclopropane-l,9'-fluoren-2-yl}-1 H-benzoimidazole (80 mg, 0.1 mmol) in DCM (3 mL) was added HBr (0.8 mL 5.7M in AcOH, excess). The mixture was stirred for 2 30 hours at ambient temperature and concentated under reduced pressure. The residue was treated with with ether/DCM to give an off-white solid. The obtained product was dissoved in DMF (3 mL), to the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (39 mg, 0.22 mmol), HATU (95 mg, 0.25 mmol) and NN-diisopropylethylamine (0.14 mL, 0.80 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in 35 vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with I N NaOH solution, 899 water and brine, dried over Na 2

SO

4 , filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a TFA salt (55 mg, 62%). m/z 879.4 (M+H)*. 5 Example JS O o H N /B4Bj ~ 40 - S NyBo Br S OBr0 o N Br PdCl 2 dppf, KOAc N B Pd(PPh) 4 , 1 M NaHCO 3 DMSO, 80 C. 18 h, 60% - DME, 90*C, 18 h, 26% Bo N 1. 4 N HCI/dioxane, r.t., 2 h H N Boc 2. (S)-Moc-Val-OH, IATU, NMM H N DMF, r.t., 18 h. 2% 0 O07. 0 N\ N N H NH, 0 2,7-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10H-phenothiazine: 2,7-Dibromo- OH phenothiazine (590 mg, 1.65 mmol, WuXi AppTec) in DMSO (16 mL) was treated with 10 bis(pinacolato)diboron (1.68 g, 6.60 mmol), KOAc (1.30 g, 13.2 mmol), and PdCl 2 dppf (135 mg, 0.165 mmol). The reaction mixture was stirred at 80 *C for 18 h and the mixture was cooled and filtered through a CELITE pad. The mixture was diluted with EtOAc (100 mL) and washed with H 2 0 (2 x 50 mL) and saturated NaCl solution (I x 50 mL). The solution was dried over MgSO 4 and treated to a 80 g SiO 2 COMBIFLASH column (0-25% EtOAc-hexanes gradient) to 15 afford 2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-I1H-phenothiazine (450 mg, 60%): HPLC (RP: 6-98% MeCN-H 2 0 gradient [non-polar], 0.05% TFA modifier) IR = 6.821 min (-80% purity @ 254 nM). (2S,2'S)-tert-Butyl 2,2'-(5,5'-(1 OH-phenothiazine-2,7-diyl)bis(1 H-imidazole-5,2 20 diyl))dipyrrolidine-1-carboxylate: 2,7-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10H phenothiazine (450 mg, 1.00 mmol) in DME (10 mL) was treated with (S)-ter-butyl 2-(5 bromo-l H-imidazol-2-yl)pyrrolidine-I-carboxylate (662 mg, 2.09 mmol), I M NaHC0 3 (5 mL, 5.00 mmol), and Pd(PPh 3

)

4 (69 mg, 0.06 mmol). The reaction mixture was stirred at 90 'C for 900 18 h and the mixture was cooled and filtered through a CELITE pad. The mixture was diluted with EtOAc (100 mL) and washed with H 2 0 (2 x 50 mL) and saturated NaCl solution (I x 50 mL). The solution was dried over MgSO 4 and treated to a 40 g SiO 2 COMBIFLASH column (0 100% EtOAc-hexanes gradient, followed by a 0-100% 20/o-MeOH/EtOAc-hexanes gradient) 5 to afford (2S,2'S)-tert-butyl 2,2'-(5,5'-(0 H-phenothiazine-2,7-diyl)bis(I H-imidazole-5,2 diyl))dipyrrolidine-1 -carboxylate (175 mg, 26%): MS (ESI) m/z 670 [M + H]*. Dimethyl (2S,2'S)-1,1'-(( 2 S,2'S)-2,2'-(5,5'-(1OH-phenothiazine-2,7-diyl)bis(1H-imidazole 5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate: (2S,2'S) 10 tert-butyl 2,2'-(5,5'-( OH-phenothiazine-2,7-diyl)bis(I H-imidazole-5,2-diyl))dipyrrolidine- I carboxylate (175 mg, 0.26 mmol) was treated with 4 N HCI (5 mL) and stirred for 2 h. The reaction mixture was concentrated and the mixture was suspended in DMF (5.5 mL) and treated with (S)-Moc-Val-OH (96 mg, 0.55 mmol), HATU (219 mg, 0.57 mmol), and 4 methylmorpholine (143 pL, 1.31 mmol; or until basic). The stirred for 18 h then diluted with 15 EtOAc (100 mL) and washed with saturated NaHCO 3 solution (2 x 50 mL), H 2 0 (2 x 50 mL), and saturated NaCl solution (I x 50 mL). The solution was dried over MgSO 4 and treated to a 40 g SiO 2 COMBIFLASH column (0-100% EtOAc-hexanes gradient, followed by a 0-100% 20 0 /o-MeOH/EtOAc-hexanes gradient) and RP HPLC (6-98% MeCN-H 2 0 gradient, 0.1% TFA modifier). Finally, the material was subjected to a 20 x 20 preparative TLC (10% MeOH 20 EtOAc) to afford dimethyl (2S,2'S)-I, I'-((2S,2'S)-2,2'-(5,5'-( OH-phenothiazine-2,7-diyl)bis(I

H

imidazole-5,2-diyl))bis(pyrrolidine-2, I -diyl))bis(3-methyl- I -oxobutane-2, I -diyl)dicarbamate (3.6 mg, 2%): MS (ESI) m/z 784 [M + H]*. 901 Example JT Pd(PPh 3

)

4 H NaHC0 3 DME, H 2 0 Bc- N B'O + / \ \ O 80 C fJLN Hr H N ______ 3-(5-{4-(4,4,5,5-Tetramethyl-[1,3,2)dioxabomlan-2-yl)- (1-(8-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-ylF5 pheny}-1H-imidazol-2-yl}-2-aza-bicydo[2.2. 1heptane-2- aza-spiro[2.4jheptane-5arbony)2methyl-propyl) carboxylic acid tert-buty ester Carbamnic ad methyl ester O0 H 1) HCI, Dioxanes N 0N H 2) HATU, NMM, DMF NN N

-

ocH O 0 -(6--{6-(4-{-{2-(2-Methoxycarbonylamino- yl- 2-aza-io2.]hept- 3- 2-Methoxycaroyamino i midazol-4-yl)-naphth alen2-yl)-pheny l }-1 H-imi dazol2-yt)2-aza-bicydo[22.1 ]heptane.2- popionic ad carbon xylic acd tert-buty ester -0H H H H H 0 [-(6-{56(4-{2-2-(2-Met 2xoxycarynonyca aiino-pnpionyy az2-aza-)icy-bo[2i2hept-3-yy 2 t 3H-imidazol-4-y l }-phenyp)-naphthaen ]--H-yiHm-midazo-52-y- s[5-aza-spro2-4]heptane 5-cartbonyt)-2-methy-popylj-carbamic acid methyl ester [1 -(6- (5-16-(4- f2- 1 2 -(2-Methoxycarbonylamino-propionyl)-2-aza-biyclo[2.2. 1hept-3-ylj 5 3H-imidazol-4-yI)-phenyl)-naphthalen-2-yJ-I H-imidazol-2-yl}-5-aza-spiro[2.4j heptane-5 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: A solution of (1-{6-[5-(6-bromo naphthalen-2-yl)- IH-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl) carbamic acid methyl ester (1.00 g, 1.9 mmol), 3-{5-[4-(4,4,5,5-tetramethyl [I ,3,2]dioxaborolan-2-yl)-phenyl]-I H-imidazol-2-yl}-2-aza-bicyclo[2.2. I ]heptane-2-carboxylic 10 acid tert-butyl ester (1.31 g, 2.8 mmol) and aq NaHCO 3 (7.6 mL of a I M solution, 7.6 mmol) in DME (20 mL) was degassed with N 2 gas for 20 minutes. To the degassed solution was added Pd(PPh 3

)

4 (1 10 mg, 0.095 mmol) and then the reaction was heated to 80* C overnight. After cooling to room temperature, the solvent was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate. The organic phase was washed with H 2 0 and then brine 15 then dried over sodium sulfate. After filtration the solvent was removed from the filtrate under reduced pressure. The crude material was purified by silica gel chromatography (70-100% EtOAc/Hexanes) to afford 3-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-I H-imidazol-2-yl}-2-aza bicyclo[2.2. I ]heptane-2-carboxylic acid tert-butyl ester (835 mg, 1.07 mmol, 56% yield). 20 LCMS-ESI: calc'd for C 46

H

54

N

7 0 5 : 784.4 (M+H*); Found: 784.8 (M+H*). 902 [1 -(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-propionyl)-2-aza-bicyclo[2.2.1 hept-3-yl] 3H-imidazol-4-yl)-phenyl)-naphthalen-2-y]-1 H-imidazol-2-yl}-5-aza-spiro[2.41 heptane-5 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: To 3-{5-[4-(6-{2-[5-(2 methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl} 5 naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yI}-2-aza-bicyclo[2.2.1 ]heptane-2-carboxylic acid tert butyl ester (46 mg, 0.059 mmol) in dioxanes (2 mL) and MeOH (0.5 mL) was added 4N HCI in dioxanes (160 pL). The suspension was stirred for 2 h then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (I mL) was added N-methylmorpholine (19.5 pL, 0.18 mmol), 2-methoxycarbonylamino-propionic acid (13 mg, 0.089 mmol) and HATU (25 10 mg, 0.065 mmol). After stirring for overnight the reaction was quenched with formic acid then purified by reverse phase preparative HPLC (5-45% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product (26 mg, 0.032 mmol, 54% yield). LCMS-ESI*: calc'd for C 46

H

53

N

8 0 6 : 813.4 (M+H*); Found: 813.4 (M+H*). Example JU O H 1) HCI, Dioxanes N 0 H H 2) HATU, NMM, DMF 0 Noc H O 3

-(

5 -[4-( 6

-{

2 -[5-(2-Methoxycarbonyamino-3methy-butyry)5azaspiro[24]hept-6yl]-3H- 4-Methoxy-2 imidazol-4-yl}-naphthalen-2-yl)-phenyl-1 H-imidazol-2-yl}-2-aza-bicyclo[2.2. 1]heptane-2- methoxycarbonylamino carboxylic acid tert-butyl ester butyric acid O H N O H N [1-( 6 -{5-[6-C4-{2-[2-(4-Methoxy-2-methoxycabonylamino.butyl)-2-aza bicyclo[2.2.1]hept-3-y]-3H-imidazol-4-yl-phenyl)-naphthalen-2-yI]-.1 H-imidazol-2-yl)-5 15 aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]carbamic acid methyl ester [1 -(6-{(5-[16-(4- {2-[2-(4-Methoxy-2-methoxyca rbonylamino-butyryl)-2-aza bicyclo[2.2.1]jhept-3-yI]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-5 aza-spiro[ 2

.

4 ]heptane-5-carbonyl)-2-methylpropyl]-carbamic acid methyl ester: To 3-{ 5 20 [4-(6- {2-[5-(2-methoxycarbonylam ino-3-methyl-butyryl)-5-aza-spiro[2 .4]hept-6-yl]-3 H imidazol-4-y } -naphthalen-2-yl)-phenyl]- I H-imidazol-2-yl }-2-aza-bicyclo[2.2. I]heptane-2 carboxylic acid tert-butyl ester (46 mg, 0.059 mmol) in dioxanes (2 mL) and MeOH (0.5 mL) was added 4N HCI in dioxanes (160 piL). The suspension was stirred for 2 h then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (1 mL) was added N 903 methylmorpholine (19.5 iL, 0.18 mmol), 4-methoxy-2-methoxycarbonylamino-butyric acid (17 mg, 0.089 mmol) and HATU (25 mg, 0.065 mmol). After stirring for overnight the reaction was quenched with formic acid then purified by reverse phase preparative HPLC (5-45% MeCN

H

2 0; 0.1% formic acid modifier) to afford the title product (40 mg, 0.047 mmol, 79% yield). 5 LCMS-ESI*: calc'd for C 4 8

H

5 7

N

8 0 7 : 857.4 (M+H*); Found: 857.4 (M+H*). Example JV 1) HCI, Dioxanes N H H 2) HATU, NMM, DMF Boc, N N0. N N H 00~ N, N- OH H - 0 6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.1 ]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2- 2-Methoxycarbonylamino yI}-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester butync acid -0 H 0 IH [1-(3-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1 ]heptane-2 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 10 [1-(3-{5-14-(6-12-[5-(2-Methoxycarbonylamino-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H imidazol-4-yI}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2 carbonyl)-2-methyl-propyll-carbamic acid methyl ester: To 6-{5-[6-(4-{2-[2-(2 methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1 ]hept-3-yl]-3H-imidazol-4-yl} 15 phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylic acid tert butyl ester (50 mg, 0.064 mmol) in dioxanes (2 mL) and MeOH (0.5 mL) was added 4N HC in dioxanes (160 pL). The suspension was stirred for 2 h then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (1 mL) was added N-methylmorpholine (21 pL, 0.19 mmol), 2-methoxycarbonylamino-butyric acid (16 mg, 0.096 mmol) and HATU (27 mg, 20 0.070 mmol). After stirring for overnight the reaction was quenched with formic acid then purified by reverse phase preparative HPLC (5-45% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product (30 mg, 0.036 mmol, 57% yield). LCMS-ESI+: calc'd for C 4 7

H

5 5

N

8 0 6 : 827.4 (M+H*); Found: 827.4 (M+H*). 904 Example JW -0 H 1) HCI, Dioxanes N 0 H H 2) HATU, NMM, DMF 0 N N N Boc 70 OH O O 3-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H- 2-Methoxycarbonylamino imidazol-4-yl)-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2- butyric acid carboxylic acid tert-butyl ester -- H [1 -(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-butyryl)-2-aza-bicyclo[2.2.1]hept 3-yl]-3H-imidazol-4-yI}-phenyt)-naphthalen-2-y]-1 H-imidazol-2-yl}-5-aza spiro[2.4lheptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 [1 -(6-{5-[6-(4-{t2-[2-(2-Methoxycarbonylamino-butyryl)-2-aza-bicyclo[2.2.1]ihept-3-yl] -3H imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: To 3- {5-[4-(6-{2-[5-(2 methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-y]-3H-imidazol-4-.y} 10 naphthalen-2-yl)-phenyl]-1I H-imidazol-2-yl }-2-aza-bicyclo[2.2. I]heptane-2-carboxylic acid tert butyl ester (60 mg, 0.077 mmol) in dioxanes (2 mL) and MeOH (0.5 mL) was added 4N H CI in dioxanes (160 siL). The suspension was stirred for 2 h then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (1 mL) was added N-methylmorpholine (34 p L, 0.31 mmol), 2-methoxycarbonylamino-butyric acid (19 mg, 0.11l mmol) and H AT U (35 mg, 15 0.09 mmol). After stirring for overnight the reaction was quenched with formic acid then purified by reverse phase preparative HPLC (5-45% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product (51l mg, 0.062 mmol, 80% yield). LCMS-ES1*: calc'd for C 47 Hs 5 Ns0 6 : 827.4 (M+H*1); Found: 827.4 (M+H*). 20 905 Example JX 0 H 1) HCI, Dioxanes N o - H 2) HATU, NMM, DMF 0 ~ N \ -~ 1 N N/ . oBoH HN 11 N -J OH 0 3-{5-[4-(6-2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H- 2-Methoxycarbonylamino-3,3 imidazol-4-yl)-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl-2-aza-bicyclo[22.1]heptane-2- dimethyl-butyric acid carboxylic acid teit-butyl ester -0 H 0 N - H NNN N -N N 0 H [1 -(3-(5-[4-(6-(2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3H-imidazol-4-yl)-naphthalen-2-yl)-phenyl-1 H-imidazol-2-yl)-2-aza bicyclo[2.2.1]heptane-2-carbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl ester 5 [1-( 3 -{5-1 4

-(

6

-{

2 -[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6 yl]-3H-imidazol-4-yli-naphthalen-2-yl)-phenyll-1 H-imidazol-2-yi)-2-aza bicyclo[2.2.1lheptane-2-carbonyl)-2,2-dimethyl-propyl]-carbamic acid methyl ester: To 3 {5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H imidazol-4-yI}-naphthalen-2-yl)-phenyl]- IH-imidazol-2-yl}-2-aza-bicyclo[2.2. I]heptane-2 10 carboxylic acid tert-butyl ester (60 mg, 0.077 mmol) in dioxanes (2 mL) and MeOH (0.5 mL) was added 4N HCI in dioxanes (160 p L). The suspension was stirred overnight then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (1 mL) was added N-methylmorpholine (25 p L, 0.23 mmol), 2-methoxycarbonylamino-3,3-dimethyl-butyric acid (22 mg, 0.12 mmol) and HATU (35 mg, 0.092 mmol). After stirring for overnight the 15 reaction was quenched with formic acid then purified by reverse phase preparative HPLC (5 45% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product (42 mg, 0.049 mmol, 57% yield). LCMS-ESl*: calc'd for C 49

H

59 NS0 6 : 855.5 (M+H*); Found: 855.5 (M+H*). 906 Example JY -O H 1) HCI, Dioxanes N o H P2) HATU, NMM, DMF N NN- \ \ Y NcOO H O H 0~ 3-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-buty)-5-aza-spiro[2.4]hept-6-yl]-3H- Methoxycarbonylamino imidazol-4-yl)-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2- phenyl-acetic acid carboxylic acid tert-butyl ester 0 H / -N- H H y/ N N \/ 'N H' 0 [1 -(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-2-phenyl-acetyl)-2-aza bicyclo[2.2. 1 ]hept-3-yl]-3H-imidazol-4-yql-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yI}-5 aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 [1 -(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylam ino-2-phenyl-acetyl)-2-aza-bicyclo[2.2. 11 hept-3 yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane 5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: To 3-(5-[4-(6-{2-[5-(2 methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl} 10 naphthalen-2-yl)-phenyl]- IH-imidazol-2-yl}-2-aza-bicyclo[2.2.I]heptane-2-carboxylic acid tert butyl ester (60 mg, 0.077 mmol) in dioxanes (2 mL) and MeOH (0.5 mL) was added 4N HCI in dioxanes (160 iL). The suspension was stirred for 6 h then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (I mL) was added N-methylmorpholine (25 stL, 0.23 mmol), methoxycarbonylamino-phenyl-acetic acid (22 mg, 0.12 mmol) and HATU (35 mg, 15 0.092 mmol). After stirring for overnight the reaction was quenched with formic acid then purified by reverse phase preparative HPLC (5-45% MeCN-H 2 0; 0.1% formic acid modifier) to afford the different diastereomers of the title product (Diastereomer 1: 24 mg, 0.027 mmol, 36% yield; Diastereomer 2: 17 mg, 0.019 mmol, 22% yield). LCMS-ESI*: calc'd for CsI Hs 5

N

8 0 6 : 875.4 (M+H*); Found: 875.5 (M+H*). 20 907 Example JZ 1) HCI, Dioxanes

O

N~ ~ N 6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2 yl)-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester Methoxycarbonylamino phenyl-acetic acid 00 O N//- N N H NH N [1 -(3-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-2-phenyl-acetyl)-5-aza-spiro[2.4]hept-6 yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H-imidazol-2-yl)-2-aza bicyclo[2.2.1 ]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 [1-(3-{5-[4-(6-{ 2

-[

5

-(

2 -Methoxycarbonylamino-2-phenyl-acetyl)-5-aza-spiro[2.41hept-6-yl] 3H-imidazol-4-yI}-naphthalen-2-yI)-phenyl]-I H-imidazol-2-yl}-2-aza bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: To 6-{5 [6-(4-{ 2

-[

2

-(

2 -Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyc lo[2.2.1 ]hept-3-yl]-3H 10 imidazol-4-yI}-phenyl)-naphthalen-2-yl]-I H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5 carboxylic acid tert-butyl ester (60 mg, 0.077 mmol) in dioxanes (2 mL) and MeOH (0.5 mL) was added 4N HCI in dioxanes (160 RL). The suspension was stirred for 6 h then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (I mL) was added N methylmorpholine (25 pL, 0.23 mmol), methoxycarbonylamino-phenyl-acetic acid (22 mg, 0.12 15 mmol) and HATU (35 mg, 0.092 mmol). After stirring for overnight the reaction was quenched with formic acid then purified by reverse phase preparative HPLC (5-45% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title product as a diastereometric mixture (30 mg, 0.035 mmol, 39% yield). LCMS-ESI*: calc'd for Csi H 55

N

8 0 6 : 875.4 (M+H*); Found: 875.6 (M+H*). 20 908 Example KA O0 H 1) HCI, Dioxanes O N O H 2) HATU, NMM, DMF oVr- Y 0/ - / ~ j Boc Oi OH <,- ; k 0 OH 2 -{5-[ 4 -(6-(2-[1-(2-Methoxycarbonylamino-3-methykbutyryl) pyrrolidin-2-yl-3H-imidazol-4-yl}-naphthalen-2-yi)-phenyl]-1

H

imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester Hydroxy-phenyl-acetic acid O H N N 0 H [1 -(2-{5-[6-(4-{2-[1 -(2-Hydroxy-2-phenyl-acetyl)-pyrrolidin2-yl]-3H imidazol-4-yl}-phenyl)-naphthalen-2-y]-1 H-imidazol-2-yl}-pyrrolidine-1 carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 [1-(2-{(5-[6-(4- {2-[ 1-(2-Hyd roxy-2-phenyl-acetyl)-pyrrolidin-2-yl]j-3H-im idazol-4-yl} phenyl)-naphthalen-2-yll-1 H-imidazol-2-yl}-pyrrolidine-1 -carbonyl)-2-methyl-propyl] carbamic acid methyl ester: To 2- {5-[4-(6- {2-{lI-(2-Methoxycarbonylam ino-3-methyl butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-.y } -naphthalen-2-yl)-phenyl]- I H-imidazol-2-yl} 10 pyrrolidine-I-carboxylic acid tert-butyl ester (40 mg, 0.055 mmol) in MeOH (I mL) was added 4N HCI in dioxanes (160 p L). The reaction was stirred overnight then concentrated to afford the H-Il salt of the crude amine. To the crude amine in DMIF (1 mL) was added N methylmorpholine (100 p L), hydroxy-phenyl-acetic acid (21 mg, 0.083 mmol) and H ATU (35 mg, 0.092 mmol). After stirring overnight the reaction was quenched with formic acid then 15 purified by reverse phase preparative HPLC (10-40% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title compound (32 mg, 0.042 mmol, 76% yield). LCMS-ESI*: calc'd for

C

4 5

H

4 sN 7 0 5 : 766.4 (M4+H*); Found: 766.4 (M+H*). 909 Example KB -0 H 1) HCI, Dioxanes N 0 H 2) EEDQ, DMF ~\ - N N ~\ N N /O 0 - ' - \/ \~Boc OI O OH 2-5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1 H imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester Methoxy-phenyl-acetic acid -O H N0 N\H I \/~ - N N : k0 /o [1 -(2-{5-[6-(4-{2-[1-(2-Methoxy-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-pyrrolidine 1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 5 [1-(2-15-16-(4-{2-[1-(2-Methoxy-2-phenyl-acetyl)-pyrrolidin-2-ylI-3H-imidazol-4-yl} phenyl)-naphthalen-2-yl]-1 H-imidazol-2-yl}-pyrrolidine-I-carbonyl)-2-methyl-propyl] carbamic acid methyl ester: To 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl butyryl)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]- I H-imidazol-2-yl} pyrrolidine-1-carboxylic acid lert-butyl ester (40 mg, 0.055 mmol) in MeOH (1 mL) was added 10 4N HCI in dioxanes (160 pL). The reaction was stirred overnight then concentrated to afford the HCI salt of the crude amine. To the crude amine in CH 2 Cl 2 and DMF (1 ml of 4:1 solution) was added (R)-methoxy-phenyl-acetic acid (13.7 mg, 0.083 mmol) and 2-ethoxy-1-ethoxycarbonyl 1,2-dihydroquinoline (17 mg, 0.069 mmol). After stirring overnight the reaction was concentrated then purified by reverse phase preparative HPLC (10-40% MeCN-H 2 0; 0.1% 15 formic acid modifier) to afford the title compound (13.1 mg, 0.017 mmol, 31% yield). LCMS ESI+: calc'd for C 46

H

50

N

7 0 5 : 780.4 (M+H+); Found: 780.4 (M+H*). 910 Example KC HO0 Tf 2 O, pyridine, O HO- OH/~ CH 2

CI

2 TfO - O~ 6H-Dibenzo[c,h]chromene-2,8-diol Trifluoro-methanesulfonic acid 8-trifluoromethanesulfonyloxy 6H-dibenzo[c,h]chromen-2-yl ester Bis(pinacolato)diboron PdCl 2 dppf, Et 3 N, N N 1,4-Dioxanes Br N1 Boc 2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1- - - 0 carboxylic acid tert-butyl ester _ B ,0/ _ O BC Pd(OAc) 2 , O NaHCO 3 , 2,8-Bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan DME, H 2 0 2-yl)-6H-dibenzo[c,h]chromene 80 *C 1) HCI, Dioxanes 0 H 2) HATU, NMM, DMF Boc B \Boc O (1 -2-[5-(2-{2-[1 -(carboxylic acid tert-butyl ester)-pyrrolidin-2- 0 yll-3H-imidazol-4-yl}-6H-dibenzo[c,h]chromen-8-yl)-1 H- 2-Methoxycarbonylamino-3 imidazol-2-yl]-pyrrolidine--1-carboxylic acid tert-butyl ester methyl-butyric acid -0 H N- 0 H 0z N\ N N H

O

(1 -{2-[5-(2-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-6H-dibenzo[c,h]chromen-8-y)-1 H-imidazol-2-yl] pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester 5 Trifluoro-methanesulfonic acid 8-trifluoromethanesulfonyloxy-6H-dibenzo c,hlchromen-2 yl ester: To a suspension of 6H-Dibenzo[c,h]chromene-2,8-diol (3.46 g, 13.1 mmol) in CH 2

CI

2 at 0 -c was added pyridine (2.65 mL, 32.8 mmol) followed by triflic anhydride (4.85 mL, 28.8 mmol). The reaction was allowed to warm to room temperature then poured into H 2 0, The organic phase was collected then washed with IN HCI and Brine. After concentration, the crude 10 material was recrystallized from CH 2

CI

2 /Hexanes to afford the title compound (4.07 g, 7.70 mmol, 59% yield). 'IH NMR (CDCIb, 400 MHz): 8 8.35 (d, I H), 7.88 (d, I H), 7.79 (d, I H), 7.71 (d, I H), 7.57 (d, I H), 7.40 (dd, I H), 7.34 (dd, I H), 7.18 (s, I H), 5.34 (s, 2H). 2,8-Bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-6H-dibenzo[c,hjchromene: A 15 solution of Trifluoro-methanesulfonic acid 8-trifluoromethanesulfonyloxy-6H dibenzo[c,h]chromen-2-yl ester (1.00 g, 1.9 mmol), bis(pinacolato)diboron (1.44 g, 5.7 mmol) 911 and triethylamine (1.32 mL, 9.5 mmol) in 1,4-Dioxanes (20 mL) was degassed with Argron gas for 20 minutes. To the degassed solution was added PdCl 2 dppf (139 mg, 0.19 mmol) and then the reaction was heated to 90' C overnight. Reaction stalled at approximately 60% conversion so additional PdCl 2 dppf (139 mg, 0.19 mmol) and bis(pinacolato)diboron (0.500 g, 1.97 mmol) 5 was added and reaction stirred for 3 h. After cooling to room temperature, the crude material was preabsorbed onto silica then purified by silica gel chromatography (25-50%

CH

2

CI

2 /Hexanes) to afford the title compound [1.106 g, >100 % yield due to some bis(pinacolato)diboron impurity]. LCMS-ESl*: calc'd for C 2 9

H

35

B

2 0 5 : 485.3 (M+H+); Found: 485.3 (M+H*). 'H NMR (CDC 3 , 400 MHz): 6 8.28 (s, I H), 8.21 (d, I H), 7.84-7.8 1 (m, 3H), 10 7.72 (d, I H), 7.64 (s, I H), 7.55 (d, I H), 5.31 (s, 2H), 1.38 (s, 12H), 1.35 (s, 12H). (1-{2-15-(2-{2-[1-(carboxylic acid tert-butyl ester)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-6H dibenzo[c,hlchromen-8-yl)-1H-imidazol-2-yl]-pyrrolidine--1-carboxylic acid tert-butyl ester: A solution of 2,8-bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-6H 15 dibenzo[c,h]chromene (500 mg, 1.03 mmol), 2-(5-bromo- I H-imidazol-2-yl)-pyrrolidine- I carboxylic acid tert-butyl ester (979 mg, 3.09 mmol) and NaHCO 3 (3.8 ml of IN solution, 3.8 mmol) in DME (10 mL) and DMF (3 mL) was degassed with Argron gas for 20 minutes. To the degassed solution was added Pd(OAc) 2 (22 mg, 0.098 mmol) and PPh 3 (52 mg, 0.19 mmol) and then the reaction was heated to 900 C overnight. After cooling to room temperature, the reaction 20 was poured into H 2 0 then extracted with EtOAc. The organic phase was then washed with Brine. Purification of the crude material by silica gel chromatography (50-100% EtOAc/Hexanes) afforded the title compound [250 mg, 0.35 mmol, 35% yield). LCMS-ESI*: calc'd for C 4 1

H

47

N

6 0 5 : 703.4 (M+H*); Found: 703.2 (M+H*). 25 (1-{ 2

-[

5

-(

2

-{

2 -[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H imidazol-4-yl}-6H-dibenzo[c,hjchromen-8-yl)- 1H-imidazol-2-yl]-pyrrolidine-1 -carbonyl}-2 methyl-propyl)-carbamic acid methyl ester: To (1-{2-[5-(2-{2-[l-(carboxylic acid tert-butyl ester)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-6H-dibenzo[c,h]chromen-8-yl)- I H-imidazol-2-yl] pyrrolidine--l-carboxylic acid tert-butyl ester (70 mg, 0.10 mmol) in MeOH (0.5 mL) was 30 added 4N HCI in dioxanes (1 mL). The reaction was stirred overnight then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (1 mL) was added N methylmorpholine (44 pL, 0.40 mmol), HATU (46 mg, 0.12 mmol) and 2 methoxycarbonylamino-3-methyl-butyric acid (26 mg, 0.15 mmol). After stirring for 3h the reaction was quenched with formic acid then purified by reverse phase preparative HPLC (10 912 40% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title compound (27 mg, 0.033 mmol, 33% yield). LCMS-ESI*: calc'd for C 4 5

H

53

N

8 0 7 : 817.4 (M+H*); Found: 817.4 (M+H*). Example KD 5 1) HCI, Dioxanes 0 H 2) HATU, NMM, DMF -o N N N N 0 Bo\/ N Boc ON OH 0 (1-{2-[5-(2-{2-[1-(carboxylic acid tert-butyl ester)-pyrrolidin-2 yl]-3H-imidazol-4-yl}-6H-dibenzo[c,h]chromen-8-yl)-1

H

imidazol-2-yl]-pyrrolidine--1 -carboxylic acid tert-butyI ester Methoxycarbonylamino phenyl-acetic acid -- O H 0 O NN ~- N N N HPC\ \ H O (2-{2-[5-(2-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl] 3H-imidazol-4-yl}-6H-dibenzo[c,h]chromen-8-yl)-1H-imidazol-2-yl] pyrrolidin-1-yl}-2-oxo-1-phenyl-ethyl)-carbamic acid methyl ester (2-{2-[5-(2-{2- [1-( 2 -Methoxycarbonylamino-2-pheny-acetyl)-pyrrolidin-2-yl]-3H-imidazol 4-yli-6H-dibenzo[c,h]chromen-8-yl)-1 H-imidazol-2-yi]-pyrrolidin-1 -yl}-2-oxo-1 -phenyl 10 ethyl)-carbamic acid methyl ester: To (I-{ 2 -[5-(2-{2-[1-(carboxylic acid tert-butyl ester) pyrrolidin-2-yl]-3H-imidazol-4-yl}-6H-dibenzo[c,h]chromen-8-yl)- IH-imidazol-2-yl] pyrrolidine--I-carboxylic acid tert-butyl ester (60 mg, 0.85 mmol) in MeOH (0.5 mL) was added 4N HCI in dioxanes (0.5 mL). The reaction was stirred for 4h then concentrated to afford the HCI salt of the crude amine. To the crude amine in CH 2 Cl 2 (1 mL) was added K 3

PO

4 (90 15 mg, 0.42 mmol), HATU (80 mg, 0.21 mmol) and methoxycarbonylamino-phenyl-acetic acid (45 mg, 0.21 mmol). After stirring for 3h the reaction was filtered then concentrated. Purification by reverse phase preparative HPLC (10-40% MeCN-H 2 0; 0.1% formic acid modifier) afforded the title compound (34 mg, 0.038 mmol, 45% yield). LCMS-ESI: calc'd for C 51

H

4 9

N

8 0 7 : 885.4 (M+H*); Found: 885.9 (M+H*). 20 913 Example KE 1) HCI, Dioxanes O H 2) HATU, NMM, DMF 8 I N\/,' N N H HO o HN Boc , O (1 -{2-[5-(2-{2-[1 -(carboxylic acid terf-butyl ester)-pyrrolidin-2 yI]-3H-imidazol-4-yl}-6H-dibenzo[c,h]chromen-8-y)-1H- Q imidazol-2-yl]-pyrrolidine--1-carboxylic acid tert-butyl ester Methoxycarbonylamino-(tetrahydro pyran-4-yl)-acetic acid 0 - 0 H H 0 N N / \ U\~ [2-(2-{S-[2-(2-{1-[-ehxcroya io2(erhdr-ya -- l-ctl-yrldn 2-y}-3H-imidazol-4-y)-6H-dibenzo[c,h]chromen8-yl]-1 H-imidazol-2-y}-pyrroiidin-1 -yl) 2-oxo-1-(tetrahydro-pyran-4-yI)-ethyl]-carbamic acid methyl ester 5 [2-(2-{5-[2-(2-{1 -[ 2 -Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin 2 -yI}-3H-imidazol-4-yl)-6H-dibenzo[c,hchromen-8-yl]-1l H-imidazol-2-yl}-pyrrolidin-1-yl) 2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester: To (1-{2-[5-(2-{2-[I (carboxylic acid tert-butyl ester)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-6H-dibenzo[c,h]chromen 8 -yl)-l H-imidazol-2-yl]-pyrrolidine--I-carboxylic acid tert-butyl ester (20 mg, 0.028 mmol) in 10 MeOH (0.5 mL) was added 4N HCI in dioxanes (0.5 mL). The reaction was stirred for 4h then concentrated to afford the HCI salt of the crude amine. To the crude amine in DMF (1 mL) was added N-methylmorpholine (15 pL, 0.14 mmol), HATU (33 mg, 0.085 mmol) and methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (19 mg, 0.085 mmol). After stirring overnight the reaction was quenched with formic acid then purified by reverse phase preparative 15 HPLC (10-40% MeCN-H 2 0; 0.1% formic acid modifier) to afford the title compound (15 mg, 0.017 mmol, 59% yield). LCMS-ESI*: calc'd for C 49

H

5 7

N

8 0 9 : 901.4 (M+H*); Found: 901.4 (M+H*). 20 914 Example KF HON HO BOC 0 0 Br Br 2 Br Br I Br d

NH

4 OAc 6-Bromo-344ihydro- 2.6-Dibromo-3.4-dihydro- Pyrrolidine-1, 2-dicarboxylic acd 2 2H-naphthalen-1 -0fl6 2H-naphthalen.1 -one (6-bromo-1-oxo-1,2,3,4-tetrahydro naphthalen-2-y) ester 1-tert-butyl ester HO H OB-B O OBr P Br oNOb Br NyN0 _______ \/\N m HCI HATU HN~.f KOAc, Pd(dPPt)C1 2 2-(7-Bromo-4,5-dihydro-1H-naphtho-{2- 2-(2-Mhyr o--mthyl [1,24imdazl-2yl)pyrrolidin--- 12-]-Br4,5-dihydro- H-naphtho ,2-djzl7y} c1 ,2-ddarb o ynaliphthae-2-)e-H -imidazo l-2-y l)-py rroidin e- -carb onyl }-2 2-methyl-propyl-carbamic acid methyl ester 00 -NH0 0 \- 0 N \/ QNHQ Br \I - N N ~H H 0 \ KP04 UHN 0 (1 -{2-[5-(6-{2-11-(2-Methoxycarbonylamino-3-methyl-butyryl) pyrrolidin-2-yI]-4,5-dihydro- IH-naphtho[1 .2-d~imidazal-7-y} naphthalen-2-yl).1 H-imidazol-2-yI]-pyrrolidine-1 -carbonyl} 2-methyl-propyl)-carbamic acid methyl ester 5 2-6-Dibromo-3,4-dihydro-2H-naphthalen-I -one: 6-Bromo-3,4-dihydro-2H-naphthalen-1 one (2.0 g) was dissolved in ether (80 mL), and Br 2 (455 pl) was added at 0*C over 30 min. After diluting with ether (80 mL), the reaction mixture was washed with 10% Na 2

SO

3 , sat. NaHCO 3 and brine. After the solvent was removed, the crude material was used for the next step without further purification. 10 Pyrrolidine-1,2-dicarboxylic acid 2-(6-bromo-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) ester 1-tert-butyl ester : The crude 2-6-dibromo-3,4-dihydro-2H-naphthalen- -one and pyrrolidine- 1,2-dicarboxylic acid I -tert-butyl ester (3.15 g)were dissolved in MeCN (80 mL), and DIEA (2.55 mL) was added. The mixture was stirred at 65*C for overnight and diluted with 15 ethyl acetate. The mixture was washed with I N HCL. NaHCO 3 and brine. After the solvent was removed, the resulting material was subjected to silica gel chromatography using effluent of 10 40 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide pyrrolidine-1,2-dicarboxylic acid 2-(6-bromo-l oxo- 1,2,3,4-tetrahydro-naphthalen-2-yl) ester I -tert-butyl ester (1.54 g, 40 % over 2 steps). 20 915 2-(7-Bromo-4,5-dihydro-1H-naphtho[1,2-diimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester: Pyrrolidine-1,2-dicarboxylic acid 2-(6-bromo- I-oxo-1,2,3,4-tetrahydro naphthalen-2-yl) ester I -tert-butyl ester (1.54 g) and ammonium acetate (2.71 g) were suspended in toluene (35 mL). The reaction mixture was stirred at I I0 C for overnight and evaporated 5 under reduced pressure and resulting residue was taken up in ethyl acetate (100 mL). The organic phase was washed with saturated sodium bicarbonate (1 x 150 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 60 -90 % ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-(7 10 bromo-4,5-dihydro-I H-naphtho[ I,2-d]imidazol-2-yl)-pyrrolidine-I -carboxylic acid tert-butyl ester (1.05 g, 71 %) as a pale brown solid. MS (ESI) m/z 418.1 [M + H]*.

(

1 -(2-15-(6-{2-[1-( 2 -Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5 dihydro-1H-naphtho[1,2-djimidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine 15 1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to [l-( 6 -{5-[ 6

-(

4

-{

2 -[1-(2-Methoxycarbonylamino-3-methyl butyryl)-4-(2-methoxy-ethoxy)-pyrrolidin-2-yl]-3 H-imidazol-4-yl}-phenyl)-naphthalen-2-yl] I H-imidazol-2-yl}-5-aza-spiro[ 2 .4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: MS (ESI) m/z 815.5 [M + H]*. 20 BIOLOGICAL ASSAYS Effect of serum proteins on replicon potency Replicon assays are conducted in normal cell culture medium (DMEM + 10%FBS) supplemented with physiologic concentrations of human serum albumin (40 mg/mL) or a-acid 25 glycoprotein (1 mg/mL). EC 5 os in the presence of human serum proteins are compared to the

EC

50 in normal medium to determine the fold shift in potency. Enyzmatic Selectivity: The inhibition of mammalian proteases including Porcine Pancreatic Elastase, Human Leukocyte Elastase, Protease 3, and Cathepsin D are measured at Km for the respective substrates for each enzyme. IC 50 for each enzyme is compared to the IC 50 obtained 30 with NS3 l b protease to calculate selectivity. Representative compounds of the invention have shown activity. MT-4 Cell Cytotoxicity: MT4 cells are treated with serial dilutions of compounds for a five day period. Cell viability is measured at the end of the treatment period using the Promega CellTiter-Glo assay and non-linear regression is performed to calculate CC 5 o. 916 Compound Concentration Associated with Cells at ECso: Huh-luc cultures are incubated with compound at concentrations equal to EC 50 . At multiple time points (0 - 72 hours), cells are washed 2X with cold medium and extracted with 85% acetonitrile; a sample of the media at each time-point will also be extracted. Cell and media extracts are analyzed by LC/MSIMS to 5 determine the Molar concentration of compounds in each fraction. Representative compounds of the invention have shown activity. Solubility and Stability: Solubility is determined by taking an aliquot of 10 mM DMSO stock solution and preparing the compound at a final concentration of 100 pM in the test media solutions (PBS, pH 7.4 and 0.1 N HCI, pH 1.5) with a total DMSO concentration of 1%. The 10 test media solutions are incubated at room temperature with shaking for I hr. The solutions will then be centrifuged and the recovered supernatants are assayed on the HPLC/UV. Solubility will be calculated by comparing the amount of compound detected in the defined test solution compared to the amount detected in DMSO at the same concentration. Stability of compounds after an 1 hour incubation with PBS at 37"C will also be determined. 15 Stability in Cryopreserved Human, Dog, and Rat Hepatocytes: Each compound is incubated for up to 1 hour in hepatocyte suspensions (100 pl, 80,000 Cells per well) at 37'C. Cryopreserved hepatocytes are reconstituted in the serum-free incubation medium. The suspension is transferred into 96-well plates (50 pL/well). The compounds are diluted to 2 PM in incubation medium and then are added to hepatocyte suspensions to start the incubation. Samples are taken 20 at 0, 10, 30 and 60 minutes after the start of incubation and reaction will be quenched with a mixture consisting of 0.3% formic acid in 90% acetonitrile/l0% water. The concentration of the compound in each sample is analyzed using LC/MS/MS. The disappearance half-life of the compound in hepatocyte suspension is determined by fitting the concentration-time data with a monophasic exponential equation. The data will also be scaled up to represent intrinsic hepatic 25 clearance and/or total hepatic clearance. Stability in Hepatic S9 Fraction from Human, Dog, and Rat: Each compound is incubated for up to 1 hour in S9 suspension (500 pl, 3 mg protein/mL) at 37'C (n = 3). The compounds are added to the S9 suspension to start the incubation. Samples are taken at 0, 10, 30, and 60 minutes after the start of incubation. The concentration of the compound in each sample is 30 analyzed using LC/MS/MS. The disappearance half-life of the compound in S9 suspension is determined by fitting the concentration-time data with a monophasic exponential equation. Caco-2 Permeability: Compounds are assayed via a contract service (Absorption Systems, Exton, PA). Compounds are provided to the contractor in a blinded manner. Both forward (A to-B) and reverse (B-to-A) permeability will be measured. Caco-2 monolayers are grown to 917 confluence on collagen-coated, microporous, polycarbonate membranes in 12-well Costar TRANSWELL@ plates. The compounds are dosed on the apical side for forward permeability (A-to-B), and are dosed on the basolateral side for reverse permeability (B-to-A). The cells are incubated at 37*C with 5% CO 2 in a humidified incubator. At the beginning of incubation and 5 at 1 hr and 2 hr after incubation, a 200-pL aliquot is taken from the receiver chamber and replaced with fresh assay buffer. The concentration of the compound in each sample is determined with LC/MS/MS. The apparent permeability, Papp, is calculated. Plasma Protein Binding: Plasma protein binding is measured by equilibrium dialysis. Each compound is spiked into 10 blank plasma at a final concentration of 2 pM. The spiked plasma and phosphate buffer is placed into opposite sides of the assembled dialysis cells, which will then be rotated slowly in a 37*C water bath. At the end of the incubation, the concentration of the compound in plasma and phosphate buffer is determined. The percent unbound is calculated using the following equation: 15 % Unbound= 100 C 1 ( C YC,+C Where Cf and Cb are free and bound concentrations determined as the post-dialysis buffer and plasma concentrations, respectively. CYP450 Profiling: Each compound is incubated with each of 5 recombinant human CYP450 enzymes, including 20 CYP IA2, CYP2C9, CYP3A4, CYP2D6 and CYP2C19 in the presence and absence of NADPH. Serial'samples will be taken from the incubation mixture at the beginning of the incubation and at 5, 15, 30, 45 and 60 minutes after the start of the incubation. The concentration of the compound in the incubation mixture is determined by LC/MS/MS. The percentage of the compound remaining after incubation at each time point is calculated by comparing with the 25 sampling at the start of incubation. Stability in Rat, Dog, Monkey and Human Plasma: Compounds will be incubated for up to 2 hours in plasma (rat, dog, monkey, or human) at 37"C. Compounds are added to the plasma at final concentrations of I and 10 pg/mL. Aliquots are taken at 0, 5, 15, 30, 60, and 120 minutes after adding the compound. Concentration of 30 compounds and major metabolites at each timepoint are measured by LC/MS/MS. Evaluation of cell-based anti-HCV activity: Antiviral potency (EC 5 o) was determined using a Renilla luciferase (RLuc)-based HCV replicon reporter assay. To perform the assay, HCV lb RLuc cells (harboring a dicistronic 918 genotype l b Con I replicon that encodes a RLuc reporter), or HCV Ia RLuc cells (harboring a dicistronic genotype Ia H77 replicon that encodes a RLuc reporter), were dispensed into 384 well plates. Compounds were re-suspended in DMSO at a concentration of 10 mM and serially diluted in DMSO using an automated pipeting instrument. Serially diluted compounds were 5 mixed with cell culture media and added to the seeded cells. DMSO was used as a negative (solvent) control, and the protease inhibitor ITMN- 191 was included at a concentration > 100 x

EC

5 o as a positive control. 72 hours later, cells were lysed and Renilla luciferase activity quantified as recommended by the manufacturer (Promega-Madison, WI). Non-linear regression was performed to calculate EC 50 values. 10 Typically the compounds of the invention can inhibit multiple genotypes of HCV. For example, compounds of the present invention are active against multiple HCV genotypes selected from I a, I b, 2a, 2b, 3a, 4a, and 5a. Biological data (antiviral potency [EC 5 o] was determined using a Renilla luciferase (RLuc)-based HCV replicon reporter assay - HCV l b RLuc) for representative compounds of 15 the invention is provided in the following table. These compounds can be prepared using procedures similar to those described above. Activity Representative Compound of the Invention (nM) 0 H H 0N N\N0 H 0 O N0-024 0 -O H, ~O H N 37.7670 H N H H919 0 O HN O0 0.0852 O N i H ONH H H O O . 0 N 0 0 82 H H .23 NH 92 0 NHIIINH -N 3812 H, N H 0N0 H 920 H H0.0050

HN

000 H HN /11'' ljj 1.40 10 0\ \H N/\ N~> 00.07 N H H 0 N/ O=s=O ?NHN N \ / N \ 0.0383 0 K 0 N 0 OHN O N HN NN OI -?0N N 0 H 0~ H 0 H 91N 0.037 91 0 o IN ......... H Y;-T0 N' IN %0.1238 0 o II HH N c IN NN ...... 0.0664 0~ 0~N~ 0-.

IN ON N / J iJ 0.0535 O<NH H N, 0 0\.~( N\ N\N m -I ~ 04 N 0 N H >21.259 /NH IN 0 922 N HN O -NH HN- N NH 0 N N 0 HN\ 0 0.0385 ~-0 0NS 0 N O NH HNN --- N 0.0989 NH O N N O HN0 98 ~-0 S Z 0 0 O N H t9), NH 26.7302 H N 0 N ~ ~ 7 Ft0.0032 0 0 N' H 0 N NH 0 00 >NH 0H NN 0.7293 N NN 0 11.1 196 N H 923 N'~ 0 0 \/ '' '~~ 00.0074 H 00 o NHH 0

-

-

N N \ N 0' 0.0074 H 0 0 0 0 NNH N( I N 00.0174 0 0 0 0 N - s N.~<N0.0074 H Fj 00 0 A, N924 0 NH 0 N N 0.0539 O HN-< 0 H H 0N N0.0126 ONH N -N 0 0/\~ O0 H 00 N N 0.1985 00 0 N H

-

N~ Z~ / O 0.0327 O N NH 0 H 0_ N N N 0.1389 H H NoO . -00 O N\N NO N O 0.093 H H 0 NH NH O~~o- / N N' 0.013 H 0 '~' / / -0 H925 H =-O H H-N 0.H249 ~j~j~N H H H H0- H, N' .HH \ / N 4.8013 N:) N 0 0N H HN 0 /\ /\ NW0.0580 N O- H H N H 0~ H N -N NO 0 0 - 0 35.4673 NH N -, N.H HH N N~ N 0~t~4 0 0.1468 HH \/ / N - 0.1468 926 1110 926 I-i - - N N \ ....... ......... 0.1559 0 0 N H H 7 N "N 1.3319 0 H Nj1I-A N\ N H A\. 0.0067 -Q - H NN H~N ~ \ o~ a 0513 H 0N 0 N H 0, - H 0 0 .01 (~H 0 927 H HH 0 N - N 0-,.%%006 N .... H NI, 0I. 8 0 0~ N, \/ NN 00 IN 0.051 -l NNH0 Hl N N 0 0 ~JH N NN N 0.51 O~s=N 00 O H 00 , 928 H H N 0.0030 SN H NO 0 NH H W{ 0.0474 (JH HN H~ NH H HN H\N .04 N H H O O0 o H H N H, O4 N-.,A , N N-H0.2395 0 90 0 N \N N Q 0.0142 'H N H' N y o 0 929 I H N 3.4144 N H H N 0 0+ \/-f 0.0115 0 N 0 0 NON- N oj- >44.400 N~~~ 0 ' 0 HH N0N >44.400 N 2&N V/ 0 H N N N' N1 0 H NN\ xH~ 1/ \ 0.0184 0 00 NHHN4O0 >44.400 930 -0 $ H N, ~0 \1 4 0 N\ N N / 4\ ~ 0.0103 HH NHH -I - l , H N - ON~ 0.0865 H -. 00 NH ~jN' N\ N V 0.0075 00

ON

-

// / N HH H 0 - N93 N 0 -NHH 0 0 ~ N N / f\ 1, ,>.. 0.0 137 K>H 0 N I7N'\/=='N 0 0.0300 U H /H 0 o 00 -- ANN N % \ 0.0300 H~ 0N N N N H - oJH 0 - N N H 0) NH N /\ N: N-. 001 932 )X- 0 N - H 1.1 ~ / N ~ K 0.0158 H y 0 /- N/ 0.0106 N.2L 'N 0" -s H Hy 0 0_ 0.0261 N H HH 0 H I.H H N- N - - ~ 0.6074 HH /I 0 0 H -0N- 0 0.021 H HH / N 0 - N3 N OIN,H% IN 0.0239 00. O N HH N 1.5060 C H HN N 0 F O NH 0 N" N- H C N NN 0 F 0H 0 N\H, N N - . N 0 /\0 0.004 [N - O 934N 'NI 0.49 N HH 0 H 0S N H, \I 0.934 N N. 1. 0.0058 N N HN 00 0 N \/-\ 0.1270 \3 H 0IN.. 0 0 H H -, -l 4.7270 N ~ ....... \ NN 0 H- N -Af H~ H H' 0- 935 N, 0- N N K 'N - - ~ N 0.3841 H 0 - F F HH 0 - I N N \ 0.0091 .... ......... % 0 U a- HH' 0 H 0H H IN N H HN - ) ........Y '0 .20 12 0-, 0 .K N \N -NW 0.0403 HNI 0 0 -- N H 0 - % >0.0 187 NI N 0y0 0 ~0 l N ~H NyNN ~ 0.0224 0 936 O NH OW O r 1 0.00 2 7 N O N- N0 H \N HH /o N N NNO N O 0.0102 N-A H N/ /H H H H O OH O NNJ 0.0088 HH H H HN H N 0.0060 H 0 /,,-oi \ /\ 1 N /.23 HH H0 0 N N0.0198 H 0 937 HH - /\' N < ) 0.0074 H N

-

N (~H 0- .... HN NW >44.400 F F N (h 0 H' N 0 0 00 H IN lj_ /N N 0.2042 4N N~ / - 0-~ H HN N 0i~ N 044 H , H 0-.. 938 N H H k \ III N 0.0530 N H N 0 NN N ' ' / 'H N 0 104876 NN HH H H-. 0.0052 NHs NN<7 0~ N - '/'/N0.037 0. 0 00 "OA, N'939 HF FH 00 NN H N 0,, 0071 iH-' 00 00 HH N H O'Q N 0.0N082 N N\~ 0.01719 0 N0 N 94 I\ H 0 N0H 'yH N0.02 N N ' 0o 0 N 0.2231 N 0 / \ 007 0 /

N

0 N H N N _< - N0.0779 H0H >NH N H 0 Kr N N o 0.0045 00 0 N 941 H ol N s N N 0.0037 N H H N O N HH 0 IHH NHO 0 0 % O N N H N O0 ONH H' OO >W rN H H, ON OO N K 0.0195 HHNNO0 C E %H H N 0 ll 0 / N N / \('N 0.0068 IH~ 0 00 - F H Hk . N N N N 0.00298 0 0 H F F942 }-NH 00 ~HNH

NN-

/ H H N/ N 0 N / 00 -NH 0 \0 HHI 0 0 N 0.0056 K)H 0 0 00 0 - N43 - / 1.17 NH H o NS -N N ~ Y 0.0185 IH~ N N N 0 o N' J, ' N

-

H N NN

-

N j( H H -0 H' N0 0 >No N 0.011 HN 0.034 944 -0 H H H - - / \~,~< 0.073 -0 H N 0 HH %

-

N H IH NN 0 HN N NN N NN HI 0 -- NK 0.073 DN , 0 0 0.1 HS' N /1/ 0 N H H N 945 0H H N - o N N .- V ._N 0 j N N / \/N \\ 0.0 14 N NI 0.0 149H 0 N'H N. ly 0....... 0.0149 H H' N 0 oN N~ ~~Kr0 N ~ 0.0059 N ~ f/ H H N o 0 0 N % 0 - NNHFN-H N 0 NN 946 o N F F N N N 0.0036 0 0 , , HH H o F F N N /\/\/\N 0.0045 H 0 0 H ,N NN H~ o N>9'i " -'N 0.0067 N N / Hy r, H 0 0 ,. .H H H o F F 0 N N N N 0.0218 __N 0., & H' 0 HH H o N F F 4/N V 0 N N \ N \ /0/\ 0.0064 H SH Hy~ 0 N4 o 0~ ED IQ~N - N 0.2561 HN O 0 N o N, || IN 0.0405 H N N ON 0 o H H 000 0- / /0.0097 1/i IN oHH H 0 N 0.007 oN NH -0\ O H H NN NI' Ny 0.006 'N N, 0'' (~JH H 0 948 0H ~NH FF O\O 0.004 SO0 00 HH H N O NHN OHO H Ozrs N N O 0 HN A -0.~ 0 H 00 N H H ,N O YHt> 0 NO N NS - - N0N00 NN H 0 94 Additional Representative Compounds of the Invention Activity (nM) 0- 0.0073 NH N 0HN O NH N 0 0 N 4 0.0041 NHHN 0U\ /\ - / N NH N .52 O>- NHN O O.09 0 H1.7224 N~- 0, N S H N N N N NO H50 N 0 0.1 1-0 N' 0.525 NN NI N -N- N 'H N H'N Y01 0 0.0093 0 o NH N ~ HN 0 \NN H 0 950 O O- 0.0125 NH FL F N N H O NO 0.0614.~' NH_ HNO N N Os 0- 0.0614 iNH N NHO HN 0 ON, 0.0204 N H NC. F F N N N' - NH 0 HN 0 0.0208 0, OO F F H H /\l, N N HN 951 0 0.0169 O N'H N -H'N/O O NN N 0 0 O 0.0155 O N'H H'H O N \ / N N -(\-/\ .,L_ O I N N Ow HO 0 0 0.1249 N N N O 0 - f ON H 0 H 0.1196 d- N N N o ~ N\ - N 04~ 00 N~' H,0 0 H H ) 0.1383 H N N O N N H N ~~0 952 O 0.0165 IH'N O N- I NO N 0 0.0156 H HO - i>- N N H H' - \ / NN 0 O N 0.0119 -0 H G S0.0176 O N'H N N O H

NN

O N, 0 0 Ab 0.0127 ON'H H'N O NO 0 0 9D 0.953 0.0136 0 H >-NO> H N N~ 0 0.0402 0~~ \ 0 H N~:i~/ HA- N N o 0.0092 o N'H N H'% - H

N

N O O 0 0.0192 HHO 0.01 81 0 H N-H , N / \ -0 H /\ N 09H4 0.1324 0 0~ 'i /\ HH N N I/ /0 0.00863 0 H 0 -' 0 n H H N -N - - N H N " 0 0.0086 -0 H N N / \ N: N - \I H - - NH 0 0.0017 -0 H N 0H H> N N- I N - - \N 0 0.0215 -0 H N 0H 0 o ~NN H N 0 0 0 0.025 0.009 -0 H ~NN N N N N--AN- N\/ H 0 H 0

N

0 0.0048 H H u N..

N

N N N N

-.

N 0 H' y 0 0.0159 o GR) N - 0 H N 0H07 00 H H 0 N **..rON

-

NN KNN .N 0 H H N N- E 0.0155 0 H H N- N N NN N 0 I NH ' -N. N 956 0.0146 -0 H O .0 H N ~ N' N\ SN N H O 0.014 -0 H J N NO N'H0.0084 kN 0 H -/ N H NI NN H 0 0 0 0.0534 0N HHH O< N9 5 H N H H 0~ 00 I95 0.0201 -0 H O N OH -NN H O 0.0071 O H HO NN NN

HO--

0.0261 O0 H H

O

N N - N N OH'H 011 H N 0 0.0114 O N'H J'YN H H F 0 N LL- - N N ~1N' / - ' HN O N.

O/

95 0 0.0978 0.0147 0 G O H H H H'N-O ON NN HH 0 0.0097 O O HHN 0.0145 O H N 0 H N- O H 0.0394 O H O 0.14 H HN 0.004 O H N N H O0 9 5 9 N IH0 0.0374 -~0 H $-NN IN N 0 o H /959 0.04 NH H F N NO F-H N 0.0635 ~-0 F F

Q

4 NH H bN F F NO 0 F F H HN 0 O_ 0.0083 NH H 0 0 N N N N 1 0055 O H H NO N'0 0.0555 N H H H H O 0.1282 0 0 H O N O F. ON H HN 0 0 0.5458 NOA N' H O/ O H N

--

NN O O0 N N N H N N HHH 0 960 F (ED 0.0147 0 'H H F H H'N(O~ O 0.0273 N Hi NN F 00 N NO F H HN-i Fy 0.0244 NH H ,:,C0 N \\ F - H HN O F o O~N " 0.1049 O - H N 0.1103 O NH H o { 0 \ N, N N N O O H HN FO 0 0 0.01 H N N O N 0 o NH 0.961 0.0054 NH H 0 0 N% N "N IN N - / k O H HN O &O N 0.0052 H o N' e_ N\ H 0 .N F '( N N -N N \F 0 O 0.015 o N' HH 0 N N N N -- \/ H HN O F o 90.0129 0 NN / ' N- N N -J H H' N oll Oa IF 0.0092 /QXNQ N -- H N N -N N H - ~ 0 a-. 0 962 0.0193 O H 0 0.0116 o N' HNO 0 H cK)~~ NN--/< \N H '0 00 0.016 oj".-,y'IH Hy

H

4 N .H H /0 0.01366 -0 H 0 NN ONN N O 96 3 , H HI 0-. 96 0.0081 O NO 02 H SNN NO N0 NN HH 0\ 0.0272 O0 0.0228 N H H H HN . H 0.0074 0 NHH N N N S H H N 0 0.0087 NNH I N N. / H - \/ 0.014 ~0 HR d'NH 0' N N - \/ H N - lN 964N 0.0686 O H H H N~~~ N0-- N H 0.0161 0 0 N O Ns N H H 0.0044 -0NH0 0 H N - N N O H H H O H 0 39.7293 O N ON 0 H NO <N/NN (HI 0.1709 O H HN N N N 0 H /\9 H0 H N N 0 H965 0.1062 0 H H 1 0 N \ / Q.S N N S N / 0 4~ OD H H1~ 0.214 N- N / 0 0.0212 ~~0 -- ,N H HII N N N' / / \1 H H - - N 0 HN

N

0 0.0112 N I HP N- N N 0 'NH'N-f 'Hl 96635 I'll 00.0972 0/ NO H IN' N 0

H

0 0 C R 0.0729 0, N k - NN N N Cz HH 0.

s~N N N NS H H 0-. 96772 0 0.7879 0 HN N N N N H' N \/ \ O 0.0197 O H IH

-

00 0.0181 0 H H O N N - /

N

H H00 0.858 -O H HHO N 0 N01 - - N 0 H 0 / H 0 0.0189 NH 0 968 0 0.0229 H,N Ok.. F 0.017 O Hr NO O N' N O O H 0 F 0.0171 O N\NHN -0 H F -N N H / 0/\ -NN //~ H O H 0 GO 0.0113 00 /O O H N1 N N N0 N H 0 /\ \I I H- -\N 0 0 G 0.0142 N H N-N \ \ /\ N SHN--f /0 969 0.0097 -0~ H G N 0 H N N'-- N N H Ni <~ 0 j H 0.0163 -0 H N 0 H N N - - N N H N' o 0.0417 -0 H G >-N 0 0 H /~-\ N N - N N k~/ o H H 0.0906 -0 H N 0 H H #~ N N - N N IH o - A-- N N S HH - -- 0 Abs0.0157 -0NHH I/- N N\ N I 970 Hl H 0.026 H O NN O N H Os. 0.0282 O H N ' N N H 0 NN H O 0.07 H 0.0195 O HH NH N N H H 0.0103 0 O 00

-

H N O NH N IN H N0N \ 0 971 0 0.043 ONH 24.0657 0 NH O- H 0.04 14 N H O O N N HHN 0 0.0262 IHH N N H \ \/ 0 0.0275 O H O OO _ N\ /\H H N0 N N H O-- 972H d- N 1 0972 O H 0.0083 /1-~ O HH

NN-

N N HNN O O 0.0794 N H H - NN 0 N H - N N~~ N0 / H 0 0 0.0059 0o) N' H H N'0 N N N (,-N S N 0 H' N 0rON 0 0.0765 O N I97 N N H HN 0 N'~ HYS\'. N I I HN 0 H Diastereomer 2 0.0309 -a0 H N NIN- N 00 I97 0.0083 O HO N-, N\N N N \/ uI~~. 0 O 0.0117

-

H N O < N "A N N H

O

0 0.0073

V/O

0 0.009 O N'H N N - - 0 a--. <ON 0 0 0 AbD 0.0097 0 NN 0H N\ 0 H ~ ~~~ - N ' N. 0 0 All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference 5 to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. 974

Claims (26)

1. A composition comprising: (1) a compound of formula: H H -N O H 0 (2) a NS5B polymerase inhibitor; and (3) a NS3 protease inhibitor.

2. The composition of claim 1, wherein the NS3 protease inhibitor is boceprevir.

3. The composition of claim 1, wherein the NS3 protease inhibitor is telaprevir.

4. The composition of claim 1, wherein the NS3 protease inhibitor is TMC435350.

5. The composition of claim 1, wherein the NS3 protease inhibitor is BI-1335.

6. The composition of claim 1, wherein the NS3 protease inhibitor is BI-1230.

7. The composition of claim 1, wherein the NS3 protease inhibitor is MK-7009.

8. The composition of claim 1, wherein the NS3 protease inhibitor is VBY-376.

9. The composition of claim 1, wherein the NS3 protease inhibitor is ITMN-191.

10. A method of treating hepatitis C in a human patient in need thereof comprising administering to said human: (1) a compound of formula: 0 0 N F F 0 H O N SH HN O 0 (2) a NS5B polymerase inhibitor; and (3) a NS3 protease inhibitor.

11. The method of claim 10, wherein the NS3 protease inhibitor is boceprevir.

12. The method of claim 10, wherein the NS3 protease inhibitor is telaprevir.

13. The method of claim 10, wherein the NS3 protease inhibitor is TMC435350.

14. The method of claim 10, wherein the NS3 protease inhibitor is BI-1335.

15. The method of claim 10, wherein the NS3 protease inhibitor is BI-1230.

16. The method of claim 10, wherein the NS3 protease inhibitor is MK-7009.

17. The method of claim 10, wherein the NS3 protease inhibitor is VBY-376.

18. The method of claim 10, wherein the NS3 protease inhibitor is ITMN- 191.

19. The method of any one of claims 10 to 18, wherein the human is treated for 12 weeks or less.

20. The method of any one of claims 10 to 18, wherein the human is treated for 8 weeks or less.

21. The method of any one of claims 10 to 18, wherein the human is treated for 6 weeks or less.

22. The method of any one of claims 10 to 18, wherein the human is treated for 4 weeks or less.

23. The method of any one of claims 10 to 18, wherein the human is treated for 2 weeks or less.

24. The method of any one of claims 10 to 23, wherein the compound of formula: 0 H 'HH HN O 0 N FF -o ; 00 and the NS5B polymerase inhibitor are administered together with the NS3 inhibitor.

25. The method of any one of claims 10 to 23, wherein the compound of formula: 0 o N F; 0: H 0 and the NS5B polymerase inhibitor are administered separately from the NS3 inhibitor.

26. Use of (1) a compound of formula: 0 H H- O NN o N ; 0 (2) a NS5B polymerase inhibitor; and (3) a NS3 protease inhibitor in the preparation of a medicament for treating hepatitis C in a human patient.