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NZ612899B2 - Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (amd) - Google Patents
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NZ612899B2 - Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (amd) - Google Patents

Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (amd) Download PDF

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NZ612899B2
NZ612899B2 NZ612899A NZ61289912A NZ612899B2 NZ 612899 B2 NZ612899 B2 NZ 612899B2 NZ 612899 A NZ612899 A NZ 612899A NZ 61289912 A NZ61289912 A NZ 61289912A NZ 612899 B2 NZ612899 B2 NZ 612899B2
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New Zealand
Prior art keywords
amide
carbamoyl
indolyl
acid
pyrrolidine
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NZ612899A
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NZ612899A (en
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Eva Altmann
Ulrich Hommel
Edwige Liliane Jeanne Lorthiois
Juergen Klaus Maibaum
Nils Ostermann
Jean Quancard
Stefan Andreas Randl
Oliver Simic
Veronique Starkrogel
Anna Vulpetti
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Novartis Ag
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Priority claimed from PCT/EP2012/050005 external-priority patent/WO2012093101A1/en
Publication of NZ612899A publication Critical patent/NZ612899A/en
Publication of NZ612899B2 publication Critical patent/NZ612899B2/en

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Abstract

Provided are indole derivative compounds of the general formula (I), where the variables are as defined in the specification. Examples of the compounds include (2R,3S,4S)-1-[2-(3-Acetyl-indol-1-yl)-acetyl]-3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluorobenzylamide, (2S,5R)-5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol-3-yl)-amide] 2-(3-chloro-2-fluoro-benzylamide) and 2-({[(2S,4R)-1-(1-Carbamoyl-1H-indol-3-ylcarbamoyl)-4-fluoro-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid. A particularly preferred compound is 1-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazole-3-carboxamide. The compounds modulate Factor D of the complement system. The compounds may be useful in the treatment of ophthalmic, autoimmune, respiratory and cardiovascular diseases. The compounds may be particularly useful in the treatment of age-related macular degeneration (AMD). rolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol-3-yl)-amide] 2-(3-chloro-2-fluoro-benzylamide) and 2-({[(2S,4R)-1-(1-Carbamoyl-1H-indol-3-ylcarbamoyl)-4-fluoro-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid. A particularly preferred compound is 1-(2-((1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazole-3-carboxamide. The compounds modulate Factor D of the complement system. The compounds may be useful in the treatment of ophthalmic, autoimmune, respiratory and cardiovascular diseases. The compounds may be particularly useful in the treatment of age-related macular degeneration (AMD).

Description

INDOLE COMPOUNDS OR ANALOGUES THEREOF USEFUL FOR THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION (AMD) FIELD OF THE INVENTION The invention relates to the inhibition of the complement alternative pathway and particularly to inhibition of Factor D, in patients ing from conditions and diseases ated with complement ative pathway activation such as age-related macular degeneration, diabetic retinopathy and d ophthalmic diseases.
BACKGROUND OF THE INVENTION The complement system is a crucial component of the innate immunity system and comprises a group of ns that are normally present in an inactive state. These proteins are organized in three activation ys: the classical, the lectin, and the alternative pathways (V. M . Holers, In Clinical Immunology: Principles and Practice, ed. R.R. Rich, Mosby Press; 1996, 363-391). Molecules from rganisms, antibodies or cellular components can activate these ys resulting in the formation of protease complexes known as the vertase and the C5-convertase. The classical pathway is a calcium/magnesiumdependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by the binding of C- reactive protein complexed to ligand and by many pathogens including gram-negative bacteria.
The alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g., cell wall polysaccharides of yeast and ia, and certain biopolymer materials).
Factor D may be a suitable target for the inhibition of this amplification of the complement pathways because its plasma concentration in humans is very low (about 1.8 mg/mL), and it has been shown to be the limiting enzyme for activation of the alternative complement pathway (P.H. Lesavre and H.J. Muller-Eberhard. J . Exp. Med., 1978; 148: 1498- 1510; J.E. Volanakis et al., New Eng. J . Med., 1985; 312:395-401).
Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of l vision associated with abnormalities of s membrane, the choroid, the neural retina and/or the retinal pigment epithelium. In the center of the retina is the macula lutea, which is about 1/3 to ½ cm in diameter. The macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density and because of the high ratio of ganlion cells to eceptor cells. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all ced to the side r than resting above the photoreceptor cells), thereby allowing light a more direct path to the cones. Under the retina is the choroid, a part of the uveal tract, and the retinal pigmented epithelium (RPE), which is between the neural retina and the choroid. The choroidal blood vessels provide nutrition to the retina and its visual cells.
Age-related macular ration (AMD), the most prevalent form of macular degeneration, is associated with progressive loss of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity. Two principal clinical manifestations of AMD have been bed as the dry, or atrophic, form and the cular, or exudative, form. The dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces. About 10-20% of these AMD patients progress to the second form of AMD, known as neovascular AMD (also ed to as wet AMD).
Neovascular AMD is terized by the abnormal growth of blood s under the macula and vascular leakage, resulting in displacement of the retina, hemorrhage and scarring. This results in a deterioration of sight over a period of weeks to years. cular AMD cases originate from intermediate or advanced dry AMD. The neovascular form accounts for 85% of legal blindness due to AMD. In neovascular AMD, as the abnormal blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina.
The new blood vessels in neovascular AMD are usually derived from the choroid and are referred to as choroidal neovascularizaton (CNV). The pathogenesis of new dal vessels is poorly understood, but such factors as inflammation, ischemia, and local production of angiogenic s are thought to be important. A published study suggests that CNV is caused by complement tion in a mouse laser model (Bora P.S., J . Immunol. 2005;174; 491-497).
Human genetic evidence implicates the involvement of the complement system, particularly the alternative pathway, in the pathogenesis of Age-related Macular Degeneration (AMD). Significant associations have been found between AMD and polymorphisms in complement factor H (CFH) (Edwards AO, et al. Complement factor H polymorphism and age- related r degeneration. Science. 2005 Apr 15;308(5720):421-4; Hageman GS, et a l Acommon haplotype in the complement tory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A . 2005 May 17;102(20):7227-32; Haines JL, et al. Complement factor H variant increases the risk of agerelated macular degeneration. Science. 2005 Apr 15;308(5720):419-21; Klein RJ, et al ment factor H polymorphism in age-related macular degeneration. Science. 2005 Apr ;308(5720):385-9; Lau LI, et al. Association of the Y402H rphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Invest lmol Vis Sci. 2006 Aug;47(8):3242-6; Simonelli F, et al. rphism >H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population. Br J Ophthalmol. 2006 Sep;90(9): ; and Zareparsi S, et a l Strong association of the Y402H variant in ment factor H at 1q32with susceptibility to lated macular degeneration. Am J Hum Genet. 2005 Jul;77(1):149-53. ) , complement factor B (CFB) and complement C2 (Gold B, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006 Apr;38(4):458-62 and Jakobsdottir J , et al. C2 and CFB genes inage-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One. 2008 May 21;3(5):e2199), and most recently in complement C3 iet DD, et al Complement component C3 and risk of age-related macular degeneration. Ophthalmology. 2009 Mar;1 474-480.e2; Mailer JB, et a l Variation in complement factor 3 is associated with risk of age-related macular degeneration.
Nat Genet. 2007 Oct;39(10): 1200-1 and Park KH, et al Complement component 3 (C3) haplotypes and risk of advanced lated macular degeneration. Invest Ophthalmol Vis Sci. 2009 (7):3386-93. Epub 2009 Feb 21.). Taken together, the genetic variations in the alternative pathway components CFH, CFB, and C3 can predict clinical outcome in nearly 80% of cases. tly there is no proven medical therapy for dry AMD and many patients with neovascular AMD become legally blind despite current therapy with anti-VEGF agents such as Lucentis. Thus, it would be desirable to provide therapeutic agents for the ent or prevention of complement mediated diseases and particularly for the treatment of AMD.
SUMMARY OF THE INVENTION The present invention provides compounds that modulate, and preferably inhibit, activation the ative complement pathway. In certain embodiments, the present invention provides compounds that modulate, and preferably inhibit, Factor D activity and/or Factor D mediated complement pathway activation. Such Factor D modulators are preferably high affinity Factor D tors that inhibit the catalytic activity of complement Factor D, such as e Factor D and particularly human Factor D.
The nds of the present invention inhibit or suppress the amplification of the complement system caused by C3 activation irrespective of the initial mechanism of activation (including for e activation of the classical, lectin or ficolin pathways).
Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
Within certain aspects, Factor D tors provided herein are compounds of Formula I and salts thereof: Within certain other aspects, Factor D tors provided herein are compounds of Formula VII and salts thereof: (VII), In another ment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the definition of formula (I) or subformulae thereof and one or more pharmaceutically acceptable carriers.
In another ment, the invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to the definition of formula (I) or subformulae thereof and one or more eutically active.
The invention r provides methods of treating or preventing complement mediated diseases, the method comprising the steps of fying a patient in need of complement modulation therapy and administering a compound of Formula (I) or a subformulae thereof.
Complement mediated es include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), Respiratory diseases, cardiovascular diseases.
Other aspects of the invention are discussed infra.
DETAILED DESCRIPTION OF THE INVENTION As noted above, the present invention provides compounds that modulate Factor D activation and/or Factor D-mediated signal transduction of the complement system. Such compounds may be used in vitro or in vivo to te (preferably inhibit) Factor D activity in a variety of contexts.
In a first embodiment, the invention provides compounds of Formula I and pharmaceutically acceptable salts thereof, which modulate the alternative y of the complement system. Compounds of Formula I are represented by the structure: or a ceutically acceptable salt thereof, wherein Z is C and L is a nt residue selected from the group consisting of-N(H)- and - 1)-, or Z is N and L is CH ; R is hydrogen, y, or amino; Z2 is C(R2) or N ; Z3 is C or N , Z4 is C(R4) or N ; Z5 is C(R5) or N , or an e thereof; Z6 is C(R6) or N , or an N-oxide thereof; Z7 is C(R7) or N , or an N-oxide thereof; Z8 is C or N ; Z9 is C or N ; wherein one of Z Z3, Z8 and Z9 is N and three of Z Z3, Z8 and Z9 are C ; wherein 0 , 1, or 2 or 3 of Z2, Z4, Z5, Z6 and Z7 are N ; R2 is hydrogen or -C alkyl; R3 is ed from the group consisting of hydrogen, C C alkyl, hydroxyC C alkyl, C C alkoxyC C alkyl, haloC C alkyl, amino or methylamino; R4 is selected from the group consisting of hydrogen, halogen, and CrC alkyl; R5 and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxy, NR8R9, cyano, C0 H , CONR 0R1 1 S0 C C alkyl, and S0 NH , SO NR 0R1 1 , C 2 2 6 2 2 2 C alkoxycarbonyl, -C(NR 0)NR8R9, C C alkyl, haloC C alkyl, C -C l, C C , 6 6 6 2 6 6 haloCrC alkoxy, C -C alkenyloxy, wherein each alkyl, alkenyl, alkoxy and alkenyloxy is 6 2 6 unsubstituted or substituted with up to 4 substitutents independently selected from halogen, hydroxy, ole, C C alkoxy, C C haloalkoxy, C0 H , C C alkoxycarbonyl, C(O)NR 0 R1 1 , 4 4 2 6 NR8R9, optionally substituted phenyl, heterocycle having 4 to 7 ring atoms and 1, 2 , or 3 ring heteroatoms selected from N , O or S , heteroaryl having 5 or 6 ring atoms and 1 or 2 ring heteroatoms selected from N , O or S , and wherein optional phenyl substituents are selected from halogen, hydroxy, C C alkyl, C C alkoxy and C0 H ; R5 and R6, taken in combination with the atoms to which they are attached, form a cycle having 4 to 7 ring atoms and 0 , 1 or 2 additional ring N , O or S atoms; R7 is selected from the group consisting of en, halogen, C C alkyl, C C alkoxy, 6 6 haloC-C alkyl, C alkoxy C C alkoxycarbonyl, C0 H and C(O)NR 0R1 1 ; 6 6 6 2 R8 and R9 are independently selected from the group consisting of hydrogen, and C C alkyl, haloC C alkyl, C C alkoxyCi-C alkyl, yC C alkyl, or NR8R9, taken in 6 6 6 6 6 combination, form a heterocycle having 4 to 7 ring atoms and 0 or 1 additional ring N , O or S atoms, which heterocycle is substituted with 0 , 1 , or 2 substituents independently selected from the group consisting of C C alkyl, n, hydroxy, C C alkoxy; R 0 and R , are each independently selected from the group consisting of hydrogen and CrC alkyl, haloCrC alkyl, Ci-C 6alkoxyCrC alkyl, or hydroxyCrC alkyl; 6 6 6 6 X1 is CR 4 R15 or sulfur; X2 is CR 6 R17 , oxygen sulfur, N(H) or N(C C alkyl), wherein at least one of X1 and X2 is carbon; or X1 and X2, in combination, forms an olefin of the formula -C(R 6)=C(H)- or - C(R 6)=C(C C alkyl)-, wherein the C(R16) is attached to X3; X3 is (CR 8R 9) or N(H) wherein m is 0,1 or 2 , wherein X3 is CR 8R19 or (CR 8 R 9) m 2 when either X1 or X2 is sulfur or X2 is oxygen; or X2 and X3, taken in ation, are -N=C(H)- or -N=C(C C alkyl)- in which the C(H) or C(C C alkyl) is attached to X1; R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, amino and C C alkyl; R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, -C alkyl, haloC C alkyl, C -C alkenyl, C -C alkynyl, C C , haloC C alkoxy, NR8R9, N(H)C(0)C 6 2 6 2 6 6 6 C alkyl, N(H)C(0)OC C alkyl and OC(O)NR 0R1 1 each of alkyl, alkoxy, alkenyl, and l 6 6 substituents may be substituted with 0 , 1 , or 2 groups independently selected at each occurrence from the group ting of halogen, hydroxy, CrC alkyl, CrC alkoxy, and 6 6 NR8R9; R 6 is hydrogen, halogen, hydroxy, azide, cyano, COOH, CrC alkoxycarbonyl, C C alkyl, C C alkoxy, C C haloalkyl, C C haloalkoxy, NR8R9, N(H)C(0)C C alkyl, hydroxyd- 6 6 6 6 6 C alkyl, Ci-CealkoxyCi-Cealkyl, or C C alkyl substituted with NR8R9, N(H)C(0)H or 6 6 N(H)C(0)(C C alkyl); R 7 is hydrogen, halogen, hydroxy, cyano, CrC alkyl, CrC alkoxy, hydroxyCrC alkyl, 6 6 6 Ci-C 6alkoxyCrC alkyl, haloCrC alkyl, or CrC koxy; 6 6 6 R 8 is selected from the group consisting of hydrogen, phenyl and CrC alkyl, which alkyl group is unsubstituted or substituted with y, amino, azide, and NHC(0)CrC alkyl; R 9 and R20 are each independently selected from hydrogen and CrC alkyl; or CR 6 R17 , taken in combination forms a spirocyclic 3 to 6 membered carbocycle which is substituted with 0 , 1, or 2 substituents independently selected from the group ting of halogen and methyl; or R 6 and R 7 , taken in combination, form an exocyclic methylidene (=CH ) ; R 5 and R 6 taken in combination form an epoxide ring or a 3 to 6 membered yclic ring system which carbocyclic ring is substituted with 0 , 1, or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, yC C alkyl, Ci-C alkoxyCrC alkyl, C C alkoxycarbonyl, C0 H , and C C alkyl substituted with NR8R9; or 6 2 R 6 and R 8 or R 7 and R 9 , taken in combination, form a fused 3 membered carbocyclic ring system which is substituted with 0 , 1, or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxyC C alkyl, Ci-C alkoxyCrC alkyl, C C carbonyl, C0 H , and C C alkyl substituted with NR8R9; or R 4 and R20 taken in combination form a fused 3 carbocyclic ring system; R 4 and R 9 taken in combination form a form 1 to 3 carbon alkylene linker; R 7 and R20 taken in ation form 1 to 3 carbon alkylene linker; G is a divalent residue selected from C(0)-N(H), CH -N(H)-S(0) - CH -N(H)-C(0), 2 2 2 CH -N(H)-C(0)-0, CH N(H), CH -N(H)-C(0)-N(H), CH -N(H)-C(0)-N(Me), CH N(H)-S(0) - 2 2 2 2 2 2 N(H)-, and CH N(H)-S(0) -N(Me)-, wherein the right most e is attached to -(CR 2 R22) ; 2 2 q q is 0 , 1, 2 , 3 or 4 ; R is independently ed at each occurrence from the group consisting of hydrogen, hydroxy, halogen, C C alkyl, haloC C alkyl, , C0 H , C C alkoxy carbonyl, 6 6 2 6 C(0)NH , hydroxyC C alkyl, d-Cealkoxyd-Cealkyl, C C alkyl substituted with NR8R9, 2 6 6 imidazoylC C alkyl heterocycleC C alkyl, where the cycle is selected from azetidinyl, 6 6 pyrrolidinyl, piperidinyl, morpholinyl, 1-oxaaza-spiro[3.3]heptane, 2-oxaazaspiro [3.3]heptane, piperazinyl, 1,6-diaza-spiro[3.3]heptane, and 2,6-diaza-spiro[3.3]heptane each of which is optionally substituted by 1 or 2 substituent selected from fluoro, hydroxy, C C alkyl or C C alkoxy; R22 is independently selected at each occurrence from hydrogen or CrC alkyl; or when q is 1, 2 , 3 or 4 , R2 and a R22 tuent, taken in combination with the carbon atoms to which they are ed, form a 3 to 6 membered carbocycle or 4 to 6 ed heterocyle having a ring oxygen or en; or when q is 2 , 3 or 4 , two R2 or R22 residues, located on adjacent carbon atoms, form, together with the carbon atoms to which they are attached, a 3 to 6 membered carbocycle; and Z is CrC alkyl, CrC haloalkyl, phenyl, phenoxy, naphthyl, naphthyloxy, C - 6 6 3 Cycycloalkyl, indanyl, a 5 , 6 , 9 or 10 membered saturated or partially unsaturated, monocyclic or bicyclic heterocycle having 1 , 2 , or 3 ring heteroatoms selected from N , O , or S , or a 5 or 6 membered heteroaryl or heteroaryloxy, which heteroaryl has 1 or 2 ring heteroatoms selected from N , O or S provided that the ring does not have 2 O or S atoms, each residue is unsubstituted or substituted with 1, 2 , 3 , or 4 substituents which are independently selected from the group consisting of substituted or unsubstituted C C alkyl, C C haloalkyl, halogen, 6 6 CN, hydroxy, C0 H , tetrazolyl, C(0)R 25, S(0) R26, tuted or unsubstituted C C alkoxy, 2 2 6 haloC C alkoxy, phenoxy, NR2 R24, CH NR2 R24, 5 or 6 membered heteroaryl and 6 2 unsubstituted or substituted phenyl, which substituted phenyl has 1 or 2 substituents independently selected from the group consisting of cyano, halo, CrC alkyl or CrC haloalkyl, 6 6 OH, COOH, COR25, S(0) R26, amino, and CH NH , and which substituted alkyl or alkoxy has a 2 2 2 substituent selected from hydroxy, C C alkoxy, cyano, C0 H , tetrazole or NR2 R24; R23 is hydrogen or CrC alkyl; R24 is hydrogen, CrC alkyl, hydroxyCrC alkyl, Ci-C 6alkoxyCrC alkyl, aminoCr 6 6 6 C alkyl, mono- and di-CrC 6 6alkylaminoCrC6alkyl; or NR2 R24, taken in combination form a 4 , 5 or 6 membered heterocycle having 0 or 1 additional ring atoms selected from the group consisting of N , O or S , and which is substituted with 0 , 1 or 2 substituents independently ed from fluoro, hydroxy, C C alkyl or C C alkoxy; R25 is ndently ed at each occurrence from the group consisting of C C alkoxy and NR2 R24; and R is ed from the group consisting of amino, hydroxy, CrC alkyl, and, mono- and di-CrC alkylamino.
In certain aspects, the compounds of formula (I) preferably have the stereochemistry of compounds represented by formula (la): (la), In one aspect, compounds of a (I) include those compounds represented by formula (II): Z2 is CH or N ; X1 is CHR or S ; X2 is CR 6 R17 or S , wherein at least one of X1 and X2 is not sulfur; X3 is CR 8 R19 or N(H); R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, -C alkyl, haloC Cealkyl, CrC alkoxy, haloC C alkoxy, NR8R9, N(H)C(0)C C alkyl, N(H)C(0)OC C alkyl and 6 6 4 4 OC(O)NR 0 R1 1 , each alkyl and alkoxy may be substituted with 0 , 1, or 2 groups independently ed at each occurrence from the group consisting of hydroxy, CrC alkyl, C C alkoxy, 6 6 and NR8R9; R 6 is hydrogen, halogen, y, amino, cyano, C C alkyl, C C alkoxy, C C haloalkyl, C C haloalkoxy, heterocycleC -C alkyl, NR8R9, N(H)C(0)C C alkyl, hydroxyC C alkyl, C 4 0 4 4 4 C alkoxyC C alkyl or C C alkyl substituted with NR8R9; 4 4 4 R 7 is hydrogen, halogen, hydroxy, C C alkyl, hydroxyC C alkyl or CrC alkoxyC C alkyl; R 8 is selected from the group consisting of hydrogen, phenyl and CrC alkyl, which alkyl group is unsubstituted or substituted with hydroxy, amino, NHC(0)CrC alkyl, amide or mono- or di- CrC alkyl-amide; R 9 is hydrogen; or CR 6 R17 , taken in combination, forms a spirocyclic 3 to 6 membered ycle; or R 5 and R 6 , taken in ation, form a cyclopropyl ring which is substituted with 0 , 1 , or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxy methyl, yethyl, methoxymethyl, ; or R 7 and R 9 taken in combination form a cyclopropyl ring.
In another embodiment, the invention provides compounds of Formula (VII): or a pharmaceutically acceptable salt thereof, wherein L is a divalent residue selected from the group consisting of-N(H)- and -C(H)(R 1)-, R1 is hydrogen, hydroxy, or amino; Z1 is C or N ; Z2 is C(H) or N ; Z3 is C or N , Z5 is C(R5) , N or an N oxide thereof; Z6 is C(R6) , N or an N oxide thereof; z7 is C(R7) , N or an N oxide thereof; z8 is C or N wherein one of Z and Z3 is N and the other is C ; wherein 0 , 1, 2 or 3 of Z2, Z5, Z6, Z7 and Z8 are N ; R3 is selected from the group consisting of en, C C alkyl, hydroxyC C alkyl, C C alkoxyC C alkyl, haloC C alkyl, amino or methylamino; R5 and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxy, NR8R9, cyano, C0 H , CONR 0R1 1 S0 C C alkyl, and SO NR 0R1 1 , Ci- 2 2 6 2 Cealkoxycarbonyl, C(NR8)NR8R9, C C alkyl, haloC C alkyl, C -C alkenyl, C C alkoxy, 6 6 2 6 6 haloCrC , C -C loxy, wherein each alkyl, alkenyl, alkoxy and loxy is 6 2 6 unsubstituted or substituted with up to 4 substitutents independently selected from halogen, hydroxy, tetrazole, C C alkoxy, C C koxy, C0 H , C C alkoxycarbonyl, C(O)NR 0 R1 1 , 4 4 2 6 NR8R9 optionally substituted phenyl, heterocycle having 4 to 7 ring atoms and 1 , 2 , or 3 ring heteroatoms ed from N , O or S , heteroaryl having 5 or 6 ring atoms and 1 or 2 ring heteroatoms selected from N , O or S , and wherein optional phenyl substituents are selected from halogen, hydroxy, C C alkyl, C C alkoxy and C0 H ; R5 and R6, taken in combination with the atoms to which they are attached, form a cycle having 4 to 7 ring atoms and 0 or 1 additional ring N , O or S atoms; R7 is selected from the group consisting of hydrogen, halogen, C C alkyl, -C , 6 6 haloC-C alkyl, haloC-C alkoxy C C alkoxycarbonyl, C0 H and C(O)NR 0R ;R8 and R9 are 6 6 6 2 independently selected from the group consisting of hydrogen, and CrC alkyl, C alkyl, 6 6 Ci-C 6alkoxyCrC alkyl, hydroxyCrC alkyl, or NR8R9, taken in combination, form a heterocycle 6 6 having 4 to 7 ring atoms and 0 or 1 additional ring N , O or S atoms, which heterocycle is substituted with 0 , 1, or 2 substituents independently selected from the group consisting of C C alkyl, halogen, hydroxy, C C alkoxy; R8 and R9 are independently selected from the group consisting of hydrogen, and C C alkyl, haloC C alkyl, Ci-C alkoxyCi-C alkyl, hydroxyC C alkyl, or NR8R9, taken in 6 6 6 6 6 combination, form a heterocycle having 4 to 7 ring atoms and 0 or 1 additional ring N , O or S atoms, which heterocycle is tuted with 0 , 1 , or 2 substituents independently selected from the group consisting of C C alkyl, halogen, hydroxy, C C alkoxy; R 0 and R , are each independently selected from the group consisting of hydrogen and CrC alkyl, haloCrC alkyl, Ci-C 6alkoxyCrC alkyl, or hydroxyCrC alkyl; 6 6 6 6 R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, amino and C C alkyl; R 5 is selected from the group consisting of hydrogen, hydroxy, halogen, -C alkyl, haloC C alkyl, C -C alkenyl, C -C alkynyl, C C alkoxy, haloC C alkoxy, NR8R9, N(H)C(0)C 6 2 6 2 6 6 6 C alkyl, N(H)C(0)OC C alkyl and OC(O)NR 0R1 1 each of alkyl, alkoxy, l, and alkynyl 6 6 substituents may be substituted with 0 , 1 , or 2)groups independently selected at each occurrence from the group consisting of halogen, hydroxy, CrC alkyl, CrC , and 6 6 NR 0 R1 1 ; R 6 is hydrogen, halogen, hydroxy, azide, cyano, COOH, CrC alkoxycarbonyl, C C alkyl, C C alkoxy, C C kyl, C C haloalkoxy, NR8R9, N(H)C(0)C C alkyl, hydroxyd- 6 6 6 6 6 C alkyl, Ci-C alkoxyCi-C alkyl, or C C alkyl substituted with NR8R9, 0)H or 6 6 6 6 0)(C C alkyl); R 7 is hydrogen, halogen, hydroxy, CrC alkyl, C C alkoxy, hydroxyCrC alkyl, Ci- 6 6 CealkoxyCi-Cealkyl, or CrC haloalkoxy; R 8 is ed from the group consisting of hydrogen, phenyl and CrC alkyl, which alkyl group is unsubstituted or tuted with hydroxy, amino, azide, and NHC(0)CrC alkyl; R 9 and R20 are each independently ed from hydrogen and CrC alkyl; or CR 6 R17 , taken in combination, form a spirocyclic 3 to 6 membered carbocycle which is substituted with 0 , 1 , or 2 substituents independently selected from the group consisting of halogen and methyl; or R 6 and R 7 , taken in combination, form an exocyclic methylidene (=CH ) ; R 5 and R 6 or R 4 and R 7 taken in combination form an epoxide ring or a 3 to 6 membered carbocyclic ring system which carbocyclic ring is substituted with 0 , 1 , or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxyCrC alkyl, Ci-C alkoxyCrC alkyl, C C alkoxycarbonyl, C0 H , and C C alkyl 4 6 4 2 tuted with NR8R9; or R 7 and R 9 or R 6 and R 8 , taken in combination, form a fused 3 membered carbocyclic ring system which is substituted with 0 , 1, or 2 substituents independently selected from the group consisting of n, methyl, ethyl, hydroxyC C alkyl, C C carbonyl, C0 H , and C C alkyl substituted with NH8R9; or R 4 and R20 taken in ation form a fused 3 carbocyclic ring system; R 4 and R 9 , taken in combination, form a 1 to 3 carbon alkylene linker; or R 7 and R20, taken in combination, form a 1 to 3 carbon alkylene linker; G is a divalent residue selected from C(0)-N(H), CH -N(H)-S(0) - CH -N(H)-C(0), 2 2 2 CH -N(H)-C(0)-0, CH N(H), CH -N(H)-C(0)-N(H), CH -N(H)-C(0)-N(Me), CH N(H)-S(0) - 2 2 2 2 2 2 N(H)-, and CH N(H)-S(0) -N(Me)-, wherein the right most residue is attached to -(CR 2 R22) ; 2 2 q q is 0 , 1, 2 , 3 or 4 ; R2 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, halogen, C C alkyl, haloC C alkyl, phenyl, C0 H , C C alkoxy yl, 6 6 2 6 C(0)NH , hydroxyC C alkyl, d-Cealkoxyd-Cealkyl, C C alkyl substituted with NR8R9, 2 6 6 imidazoylC C alkyl heterocycleC C alkyl, where the heterocycle is ed from inyl, 6 6 pyrrolidinyl, piperidinyl, morpholinyl, 1-oxaaza-spiro[3.3]heptane, 2-oxaazaspiro [3.3]heptane, zinyl, 1,6-diaza-spiro[3.3]heptane, and 2,6-diaza-spiro[3.3]heptane each of which is optionally sustituted by 1 or 2 substituent selected from fluoro, hydroxy, C C alkyl or C C alkoxy; R22 is ndently selected at each occurrence from hydrogen or CrC alkyl; or when q is 1, 2 , 3 or 4 , R2 and a R22 substituent, taken in combination with the carbon atoms to which they are attached, form a 3 to 6 ed ycle or 4 to 6 ed heterocyle having a ring oxygen or nitrogen; or when q is 2 , 3 or 4 , two R2 or R22 residues, located on adjacent carbon atoms, form, together with the carbon atoms to which they are attached, a 3 to 6 membered carbocycle; and Z is CrC alkyl, CrC haloalkyl, phenyl, phenoxy, naphthyl, naphthyloxy, C - 6 6 3 Cycycloalkyl, indanyl, a 5 , 6 , 9 or 10 membered saturated or partially unsaturated, clic or bicyclic heterocycle having 1 , 2 , or 3 ring heteroatoms selected from N , O , or S , or a 5 or 6 membered heteroaryl or heteroaryloxy, which aryl has 1 or 2 ring heteroatoms selected from N , O or S provided that the ring does not have 2 O or S atoms, each residue is tituted or substituted with 1, 2 , 3 , or 4 substituents which are independently ed from the group consisting of substituted or unsubstituted C C alkyl, C C kyl, halogen, 6 6 CN, hydroxy, C0 H , tetrazolyl, C(0)R 25, S(0) R26, substituted or tituted C C alkoxy, 2 2 6 haloC C alkoxy, phenoxy, NR2 R24, CH NR2 R24, 5 or 6 membered heteroaryl and 6 2 unsubstituted or substituted phenyl, which substituted phenyl has 1 or 2 substituents independently selected from the group consisting of cyano, halo, CrC alkyl or CrC haloalkyl, 6 6 OH, COOH, COR25, S(0) R26, amino, and CH NH , and which substituted alkyl or alkoxy has a 2 2 2 substituent selected from hydroxy, C C alkoxy, cyano, C0 H , tetrazole or NR2 R24; R23 is hydrogen or CrC alkyl; R24 is hydrogen, CrC alkyl, yCrC alkyl, C -C6alkoxyCrC alkyl, aminod- 6 6 6 C alkyl, mono- and di-CrC 6 6alkylaminoCrC6alkyl; or NR2 R24, taken in combination form a 4 , 5 or 6 membered heterocycle having 0 or 1 onal ring heteroatoms selected from the group consisting of N , O or S , and which is substituted with 0 , 1 or 2 substituents independently ed from fluoro, hydroxy, C C alkyl or C C alkoxy; R25 is independently selected at each occurrence from the group consisting of C C alkoxy and NR2 R24; and R26 is selected from the group consisting of amino, hydroxy, C C alkyl, and, mono- and di-CrC alkylamino.
In another aspect, compounds of formula (I) or (II) are provided in which X1 is CHR 5 ; and R 5 is hydrogen, fluoro, hydroxy, amino, C C alkyl, C C alkoxy, OCH CH OMe, or C - 6 2 2 2 C alkoxy substituted with NR8R9; X2 is CR 6 R17 ; R 6 is hydrogen, halogen, hydroxy, C C alkyl, C C alkoxy, C C haloalkyl, C C haloalkoxy, NR8R9, hydroxyC C alkyl, CrC alkoxyC C alkyl, C C alkyl substituted with NR8R9 or C -C alkoxy substituted with NR8R9; 2 4 R 7 is hydrogen, halogen, hydroxy or C C alkyl; or R 5 and R 6 taken in combination form a cyclopropyl ring; or R 7 and R 9 taken in ation form a cyclopropyl ring.
In yet r aspect, compounds of formula (I) or (II) are provided in which X1 is S ; and X2 and X3 are CH ; or X1 is CHR 5 , wherein R 5 is hydrogen, fluoro, methyl, hydroxy, methoxy, , methoxyethoxy or amino; X3 is CH ; and X2 is CR 6 R17 , wherein R 6 is fluoro, amino, hydroxymethyl, methoxymethyl, aminomethyl or methyl and R 7 is hydrogen or fluoro; or X1 is CHR 15, X2 is CR 6R17, and X3 is CHR19 , wherein R 7 and R 9 , taken in combination form a ropyl ring, and R 6 is hydrogen, hydroxymethyl, or methoxymethyl, and R 5 is hydrogen; or X1 is CHR 15, X2 is CR 6R17, and X3 is CHR19 , wherein R 5 and R 6 , taken in combination form a cyclopropyl ring, R 7 and R 9 are hydrogen; or X1 and X2 are CH , and X3 is N(H).
Other compounds of a (I) or (II) provided herein include those compounds in which the heteroc clic ring of the formula: Is selected from the roup consisting of: In certain embodiments, the heterocyclic ring of the compounds of formula (I) and formula (II) of the formula: Is a 4-fluoro pyrrolidine, e.g., a heterocyle of the formula: In certain aspects, compounds of formula (I) or (II) include compounds in which the heteroc clic ring of the formula: is selected from the roup consisting of: In certain aspects, nds of a (VII) include compounds in which the heterocyclic ring of the formula: is selected from the roup ting of: Other compounds of formula (I) provided herein include those compounds in which the formula: is selected from the group consisting of: Certain other compounds of formula (I) provided herein include those compounds in m of the formula: is ed from the group consisting of: n75“ N/ N \ / R5 N / / N \ / R6 “7% / N | \N N\ / Other nds of formula (II) or formula (VII) provided herein include those compounds in which the bicyclic ring system of formula (II) or formula (VII) is selected from the group consisting of: Certain preferred compounds of formula (I), (la), (II), (VII) or any subformula thereof provided herein include those compounds in which L is -N(H)- or -CH - Certain other preferred compounds of formula (I), (la), (II), (VII) or any subformula thereof provided herein include those compounds in which G is N(H)-.
Still other preferred compounds of a (I), (la), (II) or (VII) or any subformula thereof provided herein include those compounds in which q is 0 or 1; R2 is ed from the group consisting of hydrogen, CrC alkyl, hydroxyCrC alkyl, 6 6 Ci-C alkoxyCi-C alkyl and C C alkyl substituted with NR8R9; e e 6 R22 is hydrogen; or CR2 R22, taken in combination, form a cyclopropyl ring; Z is phenyl, l, oxazolyl, olyl, thiazolyl, pyrazolyl, thienyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of: halogen, hydroxy, C C alkyl, C C alkoxy, haloC C alkyl, haloC C alkoxy, NR2 R24, C0 H , 4 4 4 4 2 C(0)NR 2 R24, C0 (C C alkyl), tetrazole, piperidinyl, piperazinyl, morpholino, and alkyl substituted with C C alkoxy or NR2 R24.
In still other preferred compounds of a (I), (la), (II), or (VII), or any subformulae thereof provided herein, q is 2 ; R2 is selected, at each occurrence, from the group consisting of hydrogen, -C alkyl, hydroxyC C alkyl, Ci-CealkoxyCi-Cealkyl and C C alkyl substituted with NR8R9; 6 6 R22 is hydrogen; or CR R CR taken in ation, forms a cis or trans cyclopropane ring; Z is phenyl, l, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, thienyl, each of which is unsubstituted or substituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of: halogen, hydroxy, C C alkyl, C C alkoxy, haloC C alkyl, haloC C alkoxy, NR2 R24, C0 H , 4 4 4 4 2 C(0)NR 2 R24, C0 (C C alkyl), tetrazole, piperidinyl, piperazinyl, morpholino, and alkyl substituted with C C alkoxy or NR2 R24.
Still other preferred compounds of formula (I), (la), (II) or (VII) or any subformula thereof provided herein include those compounds in which q is 0 or 1; R2 is selected from the group consisting of hydrogen, CrC alkyl, hydroxyCrC alkyl, 6 6 Ci-C 6alkoxyCrC alkyl, aminoC alkyl, and mono- and di-CrC alkylaminoCrC alkyl; 6 6 6 R22 is hydrogen; or CR2 R22, taken in combination, form a cyclopropyl ring; and Z is phenyl which is unsubstituted or substituted with 1, 2 , or 3 substituents, each of which is ndently selected from the group consisting of halogen, hydroxy, C C alkyl, C C , haloC C alkyl, haloC C alkoxy, C0 H , C(0)NH , C0 (C C alkyl), amino, and 4 4 4 2 2 2 4 mono- and di-C C alkylamino, wherein each N-alkyl residue is tuted with 0 or 1 residues selected from the group consisting of hydroxy, C C , amino, or mono- or di-C C alkylamino.
Still other preferred compounds of formula (I), (la), (II) or (VII) or any subformula thereof ed herein include those nds in which q is 0 , 1 or 2 ; R2 is hydrogen; R22 is hydrogen, methyl, or ethyl, which methyl and ethyl are unsubstituted or substituted with hydroxy, methoxy, amino, or mono- or di-methyl amino; or CR2 R22, taken in combination, form a cyclopropane ring; when q is 2 , CR2 R22CR2 R22, taken in combination form a cis- or trans- cyclopropane ring; Z is phenyl which is unsubstituted or substituted with 1 , 2 , or 3 es selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, y, trifluoromethoxy, amino, mono- and di-C C alkylamino, tetrazole or C0 H ; or 2 2 Z is pyridyl or thienyl, each of which is unsubstituted or substituted with 1 or 2 substitutents selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
In another aspect, the ion provides compounds of formula (I) or formula (II) in which the compounds are represented by formulae (III), (IV) or (V): 26/ \ LL / (III) (IV) Z2 is CH or N ; Z5 is CR5 or N ; Z6 is CR6 or N ; Z7 is CH or N , wherein 0 , 1 or 2 of Z5, Z6 and Z7 is N ; R3 is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH20Me, or mono-, di- and tri-fluoromethyl, NHMe; R5 is hydrogen, halogen, C C alkyl, C C alkoxy, C -C alkenyl, C -C alkenyloxy, 2 2 hydroxy, C0 H , tetrazole , C C alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents ed from the group consisting of hydroxy, tetrazole, C C alkoxy, C0 H , C C alkoxycarbonyl, optionally tuted phenyl, pyridyl and pyrimidinyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents ndently ed from halogen, hydroxy, methyl, methoxy and C0 H ; R6 is hydrogen, n, C C alkyl, C C alkoxy, C -C alkenyl, C -C alkenyloxy, 2 2 y, C0 H , C C alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents selected from the group consisting of hydroxy, NR 0R1 1 , tetrazole, cyano, olyl, C C alkoxy, C0 H , C C alkoxycarbonyl, optionally substituted phenyl, pyrrolyl, morpholino, dino, piperazino, and pyridyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, hydroxy, methyl, methoxy, mono- and dimethyl amino, and C0 H ; L is CH or NH ; R 5 is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH 2CH2OMe, OCH2CH 2N(CI-l3)2, amino or OCH 2CH2pyrrolyl; R 6 is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl, or aminomethyl; R 7 is hydrogen, fluoro or methyl; R 9 is hydrogen or R 9 and R 7 , taken in combination, form a cyclopropyl ring; or R and R 6 , taken in combination, form a cyclopropyl ring; G is -C(0)N(H)-; and q is O, 1, or 2 ; R2 is hydrogen, methyl, or ethyl, which methyl and ethyl are unsubstituted or substituted with hydroxy, methoxy, amino, mono- or hyl amino, morpholinomethyl, optionally substituted azetidinomethyl, which ino ring is substituted with 0 or 1 fluoro or methoxy; or R22 is hydrogen; CR2 R22, taken in combination, form a ropane ring; or when q is 2 , CR2 R22CR2 R22, taken in combination form a cis- or trans- cyclopropane ring; Z is phenyl, pyridyl, or thienyl , each of which is unsubstituted or substituted with 1 , 2 , or 3 residues independently selected at each occurrence from the group consisting of n, methyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy, C0 2H , tetrazole, and NR2 R24.
Certain compounds of Formula (III) ed by the invention include compounds ented by formula (Ilia): (Ilia) wherein R3 is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH20Me, or mono-, di- and tri-fluoromethyl, NHMe; R5 is hydrogen, n, C C alkyl, C C alkoxy, C2-C alkenyl, C2-C alkenyloxy, hydroxy, C0 2H , tetrazole , C C alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents selected from the group consisting of hydroxy, tetrazole, C C alkoxy, C0 2H , C C alkoxycarbonyl, optionally substituted phenyl, pyridyl and pyrimidinyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, hydroxy, methyl, methoxy and C0 2H ; R6 is hydrogen, halogen, C C alkyl, C C alkoxy, C2-C alkenyl, C2-C alkenyloxy, hydroxy, C0 2H , C C alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional tuents selected from the group consisting of hydroxy, NR 0R1 1 , tetrazole, cyano, olyl, C C , C0 2H , C C alkoxycarbonyl, optionally substituted , pyrrolyl, morpholino, dino, piperazino, and pyridyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, hydroxy, methyl, methoxy, monoand dimethyl amino, and C0 2H ; R7 is hydrogen or methyl; R 5 is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH 2CH2OMe, OCH 2CH2N(CH 3)2, amino or OCH 2CH2pyrrolyl; R 6 is en, fluoro, methyl, amino, ymethyl, methoxymethyl, or aminomethyl; R 7 is en, fluoro or methyl; R 9 is hydrogen or R 9 and R 7 , taken in combination, form a cyclopropyl ring; or R and R 6 , taken in combination, form a cyclopropyl ring; G is -C(0)N(H)-; and q is 0 or 1 ; Z is pyridyl, pyrazinyl, or thienyl , each of which is unsubstituted or substituted with 1, 2 , or 3 residues independently selected at each ence from the group consisting of halogen, methyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy, C0 2H , tetrazole, and NR2 R24.
In r embodiment, compounds of the first embodiment include those compounds represented by one of the formulae (1Mb) or (IVb): wherein Z2 is CH or N ; Z5 is CR5 or N ; Z6 is CR6 or N ; Z7 is CH, C(CH ) or N , wherein 0 or 1 or 2 of Z5, Z6 and Z7 is N ; R3 is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH20Me, or mono-, di- and tri-fluoromethyl, NHMe; R5 is hydrogen, halogen, C C alkyl, C C alkoxy, C -C l, C -C alkenyloxy, 4 2 2 hydroxy, C0 H , tetrazole , C C alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents selected from the group consisting of hydroxy, cyano, tetrazole, C C alkoxy, C0 H , C C alkoxycarbonyl, tetrahydrofuranyl, optionally substituted phenyl, pyridyl and dinyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, hydroxy, methyl, methoxy and C0 H ; R6 is hydrogen, n, C C alkyl, C C alkoxy, C -C alkenyl, C -C alkenyloxy, 2 2 hydroxy, C0 H , C C alkoxycarbonyl, cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and with 0 or 1 additional substituents selected from the group consisting of hydroxy, NR 0R1 1 , tetrazole, cyano, imidazolyl, C C alkoxy, C0 H , C C alkoxycarbonyl, ally substituted phenyl, pyrrolyl, lino, piperidino, zino, and pyridyl, and wherein the phenyl is unsubstituted or substituted with 1 or 2 substituents independently ed from halogen, hydroxy, methyl, methoxy, mono- and dimethyl amino, and C0 H ; L is CH or NH ; R 5 is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH CH OMe, 2 2 OCH CH N(CH ) , amino or OCH CH pyrrolyl; 2 2 3 2 2 2 R 6 is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl, or aminomethyl; R 7 is en, fluoro or methyl; R 9 is hydrogen or R 9 and R 7 , taken in combination, form a cyclopropyl ring; or R and R 6 , taken in combination, form a cyclopropyl ring; G is (H)-; and q is 0 or 1 ; R2 is hydrogen, methyl, or ethyl, which methyl and ethyl are unsubstituted or substituted with hydroxy, methoxy, cyano, amino, mono- or di-methyl amino, morpholinomethyl, optionally substituted azetidinomethyl, which azetidino ring is subsituted with 0 or 1 fluoro or methoxy; or R22 is hydrogen; CR2 R22, taken in combination, form a ropane ring; Z is phenyl, pyridyl, pyrazinyl or thienyl , each of which is unsubstituted or substituted with 1, 2 , or 3 residues independently selected at each occurrence from the group consisting of halogen, methyl, cyclopropyl, methoxy, y, trifluoromethyl, trifluoromethoxy, SF C0 H , tetrazole, and NR2 R24, unsubstituted or substituted phenyl and unsubstituted or tuted nyl, which substituted phenyl and pyridinyl has 1 or 2 substituents independently selected from the group consisting of n and methyl.
Certain compounds, or salts thereof, provided by formula (I) or formula (II) include those compounds which are represented by formula (VI): wherein q is 0 , 1 or 2 ; R2 is hydrogen; R22 is hydrogen, methyl, or ethyl, which methyl and ethyl are tituted or substituted with hydroxy, methoxy, amino, or mono- or di-methyl amino; or CR2 R22, taken in combination, form a cyclopropane ring; when q is 2 , CR2 R22CR2 R22, taken in combination form a cis- or trans- cyclopropane ring; Z is phenyl which is unsubstituted or substituted with 1 , 2 , or 3 residues ed from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, NR2 R24, tetrazole or C0 H ; or Z is pyridyl or thienyl, each of which is unsubstituted or substituted with 1 or 2 substitutents selected from the group ting of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
In certain aspects, the compound of formula (I) is represented by the structure of formula (VI): In another embodiment, individual compounds according to the invention are those listed in the Examples section below. In n aspects the compound is selected from the group consisting of: (2S,4R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzylamide 1-[(1-carbamoyl-1 H- 3-yl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(pyridinylmethyl)-amide]; )Fluoro-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide}; )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(pyridinylmethyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[3-chlorofluoro(4-methyl-piperazinyl)-benzylamide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chloro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-hydroxy-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[3-chlorofluoro(4-methyl-piperazinylmethyl)-benzylamide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-[(5-chloro-thiophenylmethyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorodiethylamino-methylfluoro-benzyl-amide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[((S)hydroxyphenyl-ethyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-(2,3-difluoro-benzylamide); (2S,3S){[(2S,4R)(1-Carbamoyl-1 H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}methyl-pentanoic acid tert-butyl ester; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 lyl)-amide] hlorofluoro(4-methoxy-piperidinyl)-benzylamide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chloro{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}fluoro- benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoromorpholinylmethyl-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 lyl)-amide] 2-(3-chlorofluoromorpholinyl-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] hlorofluoro(4-methoxy-piperidinylmethyl)-benzylamide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{3-chlorofluoro[(2-methoxy-ethyl)-methyl-amino]- benzylamide}; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{3-chloro[(2-dimethylamino-ethylamino)-methyl]fluoro-benzylamide}; 2-({[(2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidinecarbonyl]- amino}-methyl)-benzoic acid; 2-({[(2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidinecarbonyl]- amino}-methyl)-benzoic acid; (2S,3S){[(2S,4R)(1-Carbamoyl-1 H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}methyl-pentanoic acid; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-phenylamide; (2S,4S)Amino-pyrrolidine-1 arboxylic acid 2-benzylamide 1-[(1-carbamoyl-1 H- indolyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chloro-benzylamide) as a formate salt; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(3-methyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(3-trifluoromethyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(3-fluoro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(3-cyano-benzylamide); (2S,4S)Amino-pyrrolidine-1 arboxylic acid 2-(3-bromo-benzylamide) 1-[(1- carbamoyl-1 H-indolyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 lyl)-amide] 2-(3-hydroxy-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(3-methoxy-benzyIamide) ; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] rifluoromethoxy-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] henoxy-benzylamide); )Amino-pyrrolidine-1 ,2-dicarboxylic acid 2-[(biphenylylmethyl)-amide] 1-[(1- carbamoyl-1H-indolyl)-amide] as a formate salt; (2S,4S)Amino-pyrrolidine-1 arboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(3-pyrrolyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-[3-(5-chloro-thiophenyl)-benzylamide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-[(5'-chloro-[2,2']bithiophenylylmethyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(4-methyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1 [(1-carbamoyl-1 H-indolyl)-amide] 2-(4-chloro-benzylamide); )Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(4-trifluoromethyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(4-trifluoromethoxy-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(4-hydroxy-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(2-hydroxy-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(2-fluoro-benzylamide); (2S,4S)Amino-pyrrolidine-1 arboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(2-chloro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 2 biphenylylmethyl)-amide] 1-[(1- carbamoyl-1H-indolyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(2,3-difluoro-benzylamide); )Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(5-chIoromethoxy-benzyIamide); (2S,4S)Amino-pyrrolidine-1 arboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(3-chIoromethoxy-benzyIamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(5-chlorofluoro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(3-chloromethyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 arboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(5-chloromethyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid bamoyl-1 H-indolyl)-amide] hloromethyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(3,5-dichloro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 lyl)-amide] 2-(3,4-dichloro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid ;i-carbamoyl-1 H-indolyl)-amide] 2-(3-chloro-2,6-difluoro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -[(naphthalenylmethyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -[(naphthalenylmethyl)-amide]; (2S,4S)Amino-pyrrolidine-1 arboxylic acid -[(1-carbamoyl-1 lyl)-amide] -[(5-methyl-thiazolylmethyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid arbamoyl-1 H-indolyl)-amide] -[(5-chloro-thiophenylmethyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -[(4-methyl-pyridinylmethyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid arbamoyl-1 H-indolyl)-amide] -{[(S)(3-chloro-phenyl)-ethyl]-amide} as a formate salt (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -{[(R)(3-chloro-phenyl)-ethyl]-amide} as a formate salt (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -{[1-(3,5-dichloro-phenyl)hydroxy-ethyl]-amide}; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -{[1-(3-chloro-phenyl)hydroxy-propyl]-amide}; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -[(1-phenyl-cyclopropyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 2 benzhydryl-amide 1-[(1-carbamoyl- H-indolyl)-amide] as a formate salt; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] hexylmethyl-amide; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -[((1R,2S)hydroxy-cyclohexylmethyl)-amide]; (2S,4S)Amino-pyrrolidine-1 arboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -[((1S,2S)hydroxy-cyclohexylmethyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -cyclohexylamide; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid arbamoyl-1 H-indolyl)-amide] -[(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinylyl)-amide]; (2S,4S)Amino-pyrrolidine-1 arboxylic acid -[(1-carbamoyl-1 H-indolyl)-amide] -[(6-chloro-indanyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid -[(1-carbamoyl-1 lyl)-amide] -[(6-chloro-chromanyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(phenethyl-amide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(2-hydroxyphenyl-ethyl)-amide]; )Amino-pyrrolidine-1 ,2-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-[((1 R,2S)phenyl-cyclopropyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[((R)phenyl-propyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[((S)phenyl-propyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid carbamoyl-1 lyl)-amide] 2-{[2-(3-chloro-phenyl)-ethyl]-amide}; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 Hindolyl)-amide] 2-{[2-(2-chloro-phenyl)-ethyl]-amide}; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 Hindolyl)-amide] 2-{[2-(2-fluoro-phenyl)-ethyl]-amide}; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 yl)-amide] 2-{[2-(3-fluoro-phenyl)-ethyl]-amide}; (2S,4S)Amino-pyrrolidine-1 arboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{[2-(3-chlorofluoro-phenyl)-ethyl]-amide}; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(2-phenoxy-ethyl)-amide]; (2S,3S){[(2S,4S)Amino(1-carbamoyl-1 H-indolylcarbarnoyl)-pyrrolidine carbonyl]-amino}methyl-pentanoic acid methyl ester; (S){[(2S,4S)Amino(1-carbamoyl-1H-indolylcarbamoyl)-pyrrolidinecarbonyl]- amino}-pentanoic acid methyl ester; (R){[(2S,4S)Amino(1-carbamoyl-1H-indolylcarbamoyl)-pyrrolidinecarbonyl]- amino}methyl-butyric acid methyl ester; (S){[(2S,4S)Amino(1-carbamoyl-1H-indolylcarbamoyl)-pyrrolidinecarbonyl]- amino}methyl-pentanoic acid methyl ester; (S){[(2S,4S)Amino(1-carbamoyl-1H-indolylcarbamoyl)-pyrrolidinecarbonyl]- amino}tert-butoxy-propionic acid methyl ester; (S){[(2S,4S)Amino(1-carbamoyl-1H-indolylcarbamoyl)-pyrrolidinecarbonyl]- amino}phenyl-propionic acid methyl ester; (S)-{[(2S,4S)Amino(1-carbamoyl-1 H-indolylcarbamoyl)-pyrrolidinecarbonyl]- amino}-phenyl-acetic acid methyl ester; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[((1S,2S)carbamoylmethyl-butyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-ethyl-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[((1S,2S)hydroxymethylmethyl-butyl)-amide]; (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-isopropyl-phenyl)-amide]; (2S,4S)Amino-pyrrolidine-1,2-dicarboxylic acid 2-biphenylylamide carbamoyl- 1H-indolyl)-amide]; 3-{[(2S,4R)(Benzenesulfonylamino-methyl)fluoro-pyrrolidinecarbonyl]-amino}- indolecarboxylic acid amide; 3-({(2S,4R)Fluoro[(3-fluoro-benzenesulfonylamino)-methyl]-pyrrolidinecarbonyl}- amino)-indolecarboxylic acid amide; 3-({(2S,4R)Fluoro[(3-chloro-benzenesulfonylamino)-methyl]-pyrrolidinecarbonyl}- amino)-indolecarboxylic acid amide; S,4R)Fluoro[(3-bromo-benzenesulfonylamino)-methyl]-pyrrolidinecarbonyl}- amino)-indolecarboxylic acid amide; 3-({(2S,4R)Fluoro[(3-trifluoromethoxy-benzenesulfonylamino)-methyl]-pyrrolidine carbonyl}-amino)-indolecarboxylic acid amide; S,4R)[(3-Chlorofluoro-benzenesulfonylamino)-methyl]fluoro-pyrrolidine carbonyl}-amino)-indolecarboxylic acid amide; 3-({(2S,4R)[(5-Chloro-thiophenesulfonylamino)-methyl]fluoro-pyrrolidine carbonyl}-amino)-indolecarboxylic acid amide; 3-({(S)[(3-Chloro-benzenesulfonylamino)-methyl]-pyrrolidinecarbonyl}-amino)- indole- 1-carboxylic acid amide; 3-{[(2S,4R)Fluoro(phenylacetylamino-methyl)-pyrrolidinecarbonyl]-amino}-indole- 1-carboxylic acid amide; [(2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidinylmethyl]- ic acid phenyl ester; [(1 R,3S,5R)(1-Carbamoyl-1H-indolylcarbamoyl)aza-bicyclo[3.1.0]hex ylmethyl]-carbamic acid 3-chlorofluoro-phenyl ester; 3-({(2S,4R)[(3-Chlorofluoro-benzylamino)-methyl]fluoro-pyrrolidinecarbonyl}- amino)-indolecarboxylic acid amide; 3-({(S)[(3-Trifluoromethoxy-phenylamino)-methyl]-pyrrolidinecarbonyl}-amino)- indole- 1-carboxylic acid amide; 1-{2-Oxo[(S)(3-trifluoromethoxy-phenylcarbamo 3-carboxylic acid amide; (S)[2-(1 -Acetyl- 1H-indolyl)-acetyl]-pyrrolidinecarboxylic acid (3-trifluoromethoxyphenyl )-amide; (2S,4R)[2-(1-Acetyl-1H-indolyl)amino-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizinyl)-amide] 2-[(3- oromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizinyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-indolizinyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (S)-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (2S,4S)Cyano-pyrrolidine-1 ,2 dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,3R)Methyl-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (1-Carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- o[3.1 .0]hexanecarbonyl]-amino}-1 H-indolyl)-acetic acid tert-butyl ester; (2S,4S)Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Azabicyclo[3.1 ane-2,3-dicarboxylic acid 2-[(1-acetyl-1H-indolyl)- amide] )(3-chlorofluoro-phenyl)-2hydroxy-ethyl]-amide}; ,5R)Azabicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-(3-chlorofluorobenzylamide ) methylcarbamoyl-1 H-indolyl)-amide]; (2S,4R)Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,4R)Fluoromethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-{[1-carbamoyl(2- methoxy-ethoxy)-1 H-indolyl]-amide} 2-(3-chlorofluoro-benzylamide); (1-Carbamoyl{[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexanecarbonyl]-amino}-1H-indolyloxy)-acetic acid methyl ester; (1S,3S,5S)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(3-trifluoromethoxy-phenyl)-amide]; (1S,2S,5R)Aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-[(1 -carbamoyl- 1H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); 2-Aza-bicyclo[2.1 .1]hexane-1 ,2-dicarboxylic acid 2-[(1-carbamoyl-1H-indolyl)-amide] hlorofluoro-benzylamide); (2S,4S)Methyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] trifluoromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-(3-bromofluoro-benzylamide) 1- [(1-carbamoyl-1 H-indolyl)-amide]; (2S,5R)(Acetylamino-methyl)-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (R)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (1S,2S,5R)Aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-[(1 -carbamoyl- 1H-indol yl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(2-fluoro- 3-trifluoromethoxy-phenyl)-amide]; 3-Chloro{[(2S,4R)(1-carbamoyl-1 H-indolylcarbamoyl)fluoro-pyrrolidine yl]-amino}-benzoic acid methyl ester; 3-({[(2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidinecarbonyl]- amino}-methyl)chlorofluoro-benzoic acid; (S)-2,5-Dihydro-pyrrole-1 ,2-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (1R,2S,5S)Oxaaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H- indolyl)-amide] hlorofluoro-benzylamide); (2S,4S)Trifluoromethyl-pyrrolidine-1 arboxylic acid 1-[(1-carbamoyl-1 H-indol ide] 2-(3-chlorofluoro-benzylamide); ( 1R,3S,5R)Aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 3-[(3-bromo-phenyl)-amide] 2-[(1-carbamoyl-1H-indolyl)-amide]; (1S,5R)Aza-bicyclo[3.1 .0]hexane-1 ,2-dicarboxylic acid 2-[(1-carbamoyl-1H-indolyl)- amide] 1-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(3-bromo-phenyl)-amide] 1-[(1- carbamoyl-1 H-indolyl)-amide] ; (R)-2,2-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-[(1-carbamoyl-1 H-indolyl)-amide] 4-[(3-trifluoromethoxy-phenyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-[(4'-cyanobiphenylyl )-amide]; 3-Bromo{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-benzoic acid methyl ester; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[3-chloro(2-dimethylamino-ethylcarba-moyl)fluoro-benzylamide]; ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(5-chloro-thiophenylmethyl)-amide]; 2-Bromo{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-benzoic acid methyl ester; (2S,4R)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(6-ethyl-pyridinyl)-amide]; 3-Bromo{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-benzoic acid; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-[(4-tert-butyl-thiazolyl)-amide] 1-[(1-carbamoyl- 1H-indolyl)-amide]; iazolidine-3,4-dicarboxylic acid 3-[(1-carbamoyl-1H-indolyl)-amide] 4-[(3- trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- methoxy-ethoxy)-1 H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 lyl)-amide] 2-[(6-ethyl-pyridinyl)-amide]; (2S,4S)Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(5-bromomethyl-pyridinyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 l yl)-amide] 3-(3-chlorofluoro-benzylamide); (1R,2S,5S)Aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indol yl)-amide] 2-(3-chloro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-[(5-bromomethyl-pyridinyl)- amide] 1-[(1-carbamoyl-1 H-indolyl)-amide]; (S)-Thiazolidine-2,3-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-(2,3- difluoro-benzylamide); (S)-Pyrrolidine-1,2-dicarboxylic acid carbamoyl-1H-indolyl)-amide] 2-(3-chloro fluoro-benzylamide); ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(5-bromo-pyridinyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(3-fluoro-pyridinyl)-amide]; (1R,3S,5R)Azabicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-(2-fluoro-benzylamide); (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chloro- benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(2-fluorotrifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(3-chlorofluoro-phenyl)-amide] ; )Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-(3-chloro-benzylamide) ; (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chloro- 2-fluoro-benzylamide); (2S,5R)Azidomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (S)Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-[(1-carbamoyl-1H-indolyl)-amide] hloro-benzylamide); (2S,4R)Fluorohydroxymethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Methyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-(3-chloro-benzylamide) ; (1R,3S,5S)Methoxymethylaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1- oyl-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(3-fluoro-pyridinyl)-amide]; )Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] hlorofluoro-benzylamide); (S)-Piperidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (2S,4S)Cyano-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(2-fluorotrifluoromethoxy-phenyl)-amide]; (2R,3S,4R)Dimethylaminofluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl- olyl)-amide] 2-(3-chlorofluoro-benzylamide); (2R,3R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (S)Methyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2- [(3-trifluoromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] chloro-pyridinyl)-amide] ; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(5-bromo-pyridinyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol ide] 3-(2,3-difluoro-benzylamide); (2S,4R)Hydroxyhydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl- 1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (1S,2S,5R)Oxaaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); 3-Bromo{[(S)(1-carbamoyl-1 lylcarbamoyl)-thiazolidinecarbonyl]-amino}- c acid methyl ester; (S)-Pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-[(2-methyl- -phenyl-2H-pyrazolyl)-amide]; (3S,5S)(1-Carbamoyl-1H-indolylcarbamoyl)(3-chlorofluoro-benzylcarbamoyl)- pyrrolidinecarboxylic acid methyl ester; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 5-(3- chlorofluoro-benzylamide); (2S,4S)Hydroxyhydroxymethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl- 1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-{[(S)(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide}; (2S,3S,4S)Fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Fluoromethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol yl)-amide] hlorofluoro-benzylamide); (2S,3S,4S)Acetylaminofluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (1S,2S,5R)Azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indol yl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide}; )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Fluoromorpholinylmethyl-pyrrolidine-1 ,2-dicarboxylic acid (1- carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (1R,2S,5S)Aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid carbamoyl-1 H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); (2R,3S,4R)Acetylaminofluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -carbamoyl- 1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (1R,2S,5S)Azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indol yl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide}; (2S,3R)Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide); ,5R)Methoxymethylaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1- carbamoyl-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(5-fluoro-pyridinylmethyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoylmethoxy- olyl)-amide] 3-(3-chlorofluoro-benzylamide); (1R,3S,5R)Azabicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-{[(S)(3-bromo-phenyl)- 2-hydroxy-ethyl]-amide} 2-[(1-carbamoyl-1 H-indolyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(2-fluorotrifluoromethyl-phenyl)-amide]; 3-{[(S)(1-Carbamoyl-1H-indolylcarbamoyl)-pyrrolidinecarbonyl]-amino}-benzoic acid methyl ester; (S)-Piperidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chloro -benzylamide); (2S,4S)(Acetylamino-methyl)fluoro-pyrrolidine-1 ,2-dicarboxylic acid carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(2-fluorotrifluoromethyl-benzylamide); (1R,3S,5R)Azabicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-{[(R)(3-chlorofluoro-phenyl)hydroxy-propyl]-amide}; (2S,4S)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 lyl)-amide] trifluoromethoxy-phenyl)-amide]; (S)-Thiazolidine-2,3-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-(2,3- difluoromethoxy-benzylamide); (1R,3S,5R)-2Azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)amide] 3-[(pyridinylmethyl)-amide]; (2S,3S)Methyl-pyrrolidine-1 arboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid carbamoyl-1 H-indol yl)-amide] 3-[(5-chloro-pyridinylmethyl)-amide]; (2S,4R)Fluoromethyl-pyrrolidine-1 ,2-dicarboxylic acid carbamoyl-1 H-indol yl)-amide] 2-{[(R)(3-chlorofluoro-phenyl)hydroxy-propyl]-amide}; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-fluoro-pyridinylmethyl)-amide]; (1R,2S,5S)Aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indol yl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)methoxy-ethyl]-amide}; (2S,4R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-fluorotrifluoromethyl-pyridinylmethyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3- sulfamoyl-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid carbamoyl-1 H-indol yl)-amide] difluoromethoxy-phenyl)-amide]; (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indolyl)-amide] 2-(2,3- difluoromethoxy-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-{[(S)(3-chlorofluoro-phenyl)methoxy-ethyl]-amide}; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(5-chloro-pyridinylmethyl)-amide]; rrolidine-1,2-dicarboxylic acid carbamoyl-1H-indolyl)-amide] 2-[(6-ethylpyridinyl )-amide]; (2S,4R)Fluoromethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol yl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide}; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoromethylcarbamoyl-benzylamide); (2S,4S)Fluorofluoromethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); 5R)Aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol yl)-amide] 3-[(3-fluoro-pyridinylmethyl)-amide]; (2S,4S)Fluoromorpholinylmethyl-pyrrolidine-1,2-dicarboxylic acid (1- carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); 3-({[(2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidinecarbonyl]- amino}-methyl)chlorofluoro-benzoic acid methyl ester; (1S,2S,5R)Aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-[(1 -carbamoyl- 1H-indol yl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)methoxy-ethyl]-amide}; {[(2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidinecarbonyl]- amino}-(3-chloro-phenyl)-acetic acid; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid carbamoyl-1 H-indol ide] 3-[(5-chloro-pyridinyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)dimethylamino-ethyl]-amide}; (2S,4S)Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] hlorofluoro(morpholinecarbonyl)-benzylamide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] methoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorodiethylaminofluoro-benzylamide); (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indolyl)-amide] 2-{[(S)(3- chlorofluoro-phenyl)hydroxy-ethyl]-amide}; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(3-chloro-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[3-chlorofluoro(3-methoxy-azetidinecarbonyl)-benzylamide]; )Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 lyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; )Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)- amide] 2-(3-chloro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-benzylamide 2-[(1- carbamoyl-1 H-indolyl)-amide]; (2S,3R)Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(5-chloro-thiophenylmethyl)-amide]; (2S,4S)Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-(2-fluorotrifluoromethyl-benzylamide); (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indolyl)-amide] 2-(2,3- difluoromethoxy-benzylamide); iazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(2-chlorothiazolylmethyl )-amide]; (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoylfluoro-1H-indolyl)-amide] 2- (3-chlorofluoro-benzylamide); ( 1R,3S,5S)Hydroxymethylaza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 3-(3- chlorofluoro-benzylamide) 2-[(1-methylcarbamoyl-1H-indolyl)-amide]; (S)Methylene-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(5-allyloxycarbamoyl- olyl)-amide] 3-(3-chlorofluoro-benzylamide); S)-Pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoylmethyl-1 H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-{[(S)(3-chlorofluorophenyl )methoxy-ethyl]-amide} 2-[(1-methylcarbamoyl-1 H-indolyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; 3-Bromo{[(1 R,3S,5R)(1-carbamoyl-1H-indolylcarbamoyl)aza- bicyclo[3.1 .0]hexanecarbonyl]-amino}-benzoic acid methyl ester; (2S,5R)Phenyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(2-fluorotrifluoromethoxy-phenyl)-amide]; (1R,3S,5S)Hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(1- acetyl-1H-indolyl)-amide] hlorofluoro-benzylamide); (1-Carbamoyl{[(1R,3S,5R)(3-trifluoromethoxy-phenylcarbamoyl)azabicyclo [3.1.0]hexanecarbonyl]-amino}-1 H-indolyloxy)-acetic acid methyl ester; )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorodimethylcarbamoylfluoro-benzylamide); 2-Bromo{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-benzoic acid; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-[(5-tert-butylmethyl-2H-pyrazolyl)-amide] 1- [(1-carbamoyl-1 H-indolyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(6-allyloxycarbamoyl-1H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-acetyl-1 H-indolyl)- amide] 3-{[(S)(3-chlorofluoro-phenyl)dimethylamino-ethyl]-amide}; rrolidine-1,2-dicarboxylic acid 1-[(1-methylcarbamoyl-1H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (2S,3R)Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(2-chloro-thiazolylmethyl)-amide]; ( 1R,3S,5S)Methoxymethylaza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 3-(3- chlorofluoro-benzylamide) 2-[(1-methylcarbamoyl-1H-indolyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(3-isopropyl-phenyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(6-bromocarbamoyl-1 lyl)-amide] 2- [(3-trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Azabicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-{[(S)(3-chlorofluorophenyl droxy-ethyl]-amide}2-[(1-methylcarbamoyl-1 H-indolyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoylethyl-1 H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-{[(S)(3-chlorofluorophenyl )dimethylamino-ethyl]-amide} 2-[(1-methylcarbamoyl-1H-indolyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyltrifluoromethyl-1 H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoylchloro-1H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoylmethoxy-1 H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); iazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 lyl)-amide] 2-[(5-chlorothiophenylmethyl )-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoylfluoro- olyl)-amide] 3-(3-chlorofluoro-benzylamide); ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(2-chloro-thiazolylmethyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{[(S)(3-chloro-phenyl)-2,2,2-trifluoro-ethyl]-amide}; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoylfluoro- 1H-indolyl)-amide] 3-[(3-trifluoromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid carbamoylmethoxy-1 H-indol yl)-amide] 2-[(2-fluorotrifluoromethoxy-phenyl)-amide]; (S)-Azetidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoylmethoxy- 1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); (S)-4,4-Difluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2- (3-chlorofluoro-benzylamide); -Dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-{[1-carbamoyl(2-methoxy-ethoxy)- 1H-indolyl]-amide} 2-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-fluoromethyl-pyridinylmethyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(5-trifluoromethyl-pyridinylmethyl)-amide]; (1-Carbamoyl{[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo ]hexanecarbonyl]-amino}-1H-indolyl)-acetic acid ethyl ester; (1S,5R)Aza-bicyclo[3.1 .0]hexane-1 ,2-dicarboxylic acid 2-[(1-carbamoyl-1H-indolyl)- amide] 1-[(3-trifluoromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1 arboxylic acid 1-[(1-carbamoyldifluoromethoxy-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] methoxy-pyridinyl)-amide]; (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(5-chloropyridinyl )-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(6-allyloxycarbamoyl- 1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); (2S,4S)Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(6-benzyloxycarbamoyl-1H-indolyl)-amide]2- [(3-trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-{[(S)(3-chlorofluoro-phenyl)dimethylarnino-ethyl]-arnide}; (1-Carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexanecarbonyl]-amino}-1 H-indolyl)-acetic acid ethyl ester; (2S,4R)Methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(2-tert-butyl-pyridinyl)-amide] 1- [(1-carbamoyl-1 H-indolyl)-amide]; (1-Carbamoyl{[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoromethylpyrrolidinecarbonyl ]-amino}-1H-indolyloxy)-acetic acid methyl ester; (2S,4R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{[(R)(3-chloro-phenyl)-2,2,2-trifluoro-ethyl]-amide}; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-{[(S)(3-chloro-phenyl)hydroxy-ethyl]-amide}; (S)-Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indolyl)-amide] 2-[(5-bromopyridinyl )-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[3-chlorofluoro(4-methyl-piperazinecarbonyl)-benzylamide]; )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-fluoro-pyridinyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2-[(3- carbamoyl-phenyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3- methanesulfonyl-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(6-chloro-chromanyl)-amide] (mixture of 2 diastereoisomers); )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 lyl)-amide] 2-[(3-fluoro-pyridinyl)-amide]; (2S,4S)Dimethylaminomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid (1- carbamoyl-1H-indolyl)-amide] hlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{3-chloro[(2-dimethylamino-ethyl)-methyl-amino]fluoro-benzylamide}; ( 1R,3S,5R)Aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 3-[(3-tert-butyl-phenyl)- amide] 2-[(1-carbamoyl-1 H-indolyl)-amide]; (2S,4S)Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid carbamoyl-1 H-indolyl)- amide] hlorofluoro-benzylamide); (S)-4,4-Difluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2- [(3-trifluoromethoxy-phenyl)-amide]; 3-Bromo{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}fluoro-benzoic acid ethyl ester ; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1 H-indol yl)-amide] 3-[(3-trifluoromethoxy-phenyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(5-allyloxycarbamoyl-1H-indolyl)-amide] 2- [(3-trifluoromethoxy-phenyl)-amide]; (2S,5R)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,5S)Methyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,5R)Ethyl-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H-indolyl)-amide] 2- [(3-trifluoromthoxy-phenyl)-amide]; 3-Chloro{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-benzoic acid; 3-Bromo{[(1 R,3S,5R)(1-carbamoyl-1H-indolylcarbamoyl)aza- bicyclo[3. 1.0]hexanecarbonyl]-amino}-benzoic acid; 3-Bromo{[(S)(1-carbamoyl-1 H-indolylcarbamoyl)-thiazolidinecarbonyl]-amino}- benzoic acid; 3-Bromo{[(1 R,3S,5R)(1-carbamoylmethoxy-1 lylcarbamoyl)aza- bicyclo[3. 1.0]hexanecarbonyl]-amino}-benzoic acid; 3-Bromo{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}fluoro-benzoic acid; ( 5R)Aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 3-{[3-bromo(1 H-tetrazol- -yl)-phenyl]-amide} 2-[(1-carbamoyl-1H-indolyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-{[3-bromo(1-tert-butyl- 1H-tetrazolyl)-phenyl]-amide} 2-[(1-carbamoyl-1 H-indolyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[3-chlorofluoro(1H-tetrazolyl)-benzylamide]; (2S,4R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-[5-( 1-tert-butyl- azolyl) chlorofluoro-benzylamide] 1-[(1-carbamoyl-1 H-indolyl)-amide]; (2R,3S)Fluoro-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 lyl)-amide] 2-(3-chloro-benzylamide); (2R,3R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chloro-benzylamide); (2S,5R)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,5R)Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2- (3-chlorofluoro-benzylamide); (2S,4R)Hydroxymethyl-pyrrolidine-1 ,2-dicarboxylic acid carbamoyl-1 H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); (3S,5S)(1-Carbamoyl-1H-indolylcarbamoyl)(3-chloro-2,6-difluorobenzylcarbamoyl )-pyrrolidinecarboxylic acid methyl ester; (3S,5S)(1-Carbamoyl-1H-indolylcarbamoyl)(3-chloro-2,6-difluorobenzylcarbamoyl )-pyrrolidinecarboxylic acid; (2S,4S)Hydroxymethyl-pyrrolidine-1 ,2-dicarboxylic acid 2-(3-bromofluorobenzylamide ) 1-[(1-carbamoyl-1H-indolyl)-amide]; (2S,4S)Fluorohydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (1S,3S,5R)Hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(1- carbamoyl-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); (1R,3S,5S)Hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(1- carbamoyl-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); (2S,4S)Difluoromethyl-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide); (2S,5R)Hydroxymethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol yl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 5-(3- chloro-benzylamide); (S)-4,5-Dihydro-pyrazole-1 ,5-dicarboxylic acid carbamoyl-1H-indolyl)-amide] 5- (3-chlorofluoro-benzylamide); (R)-4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 5- (3-chlorofluoro-benzylamide); (2S,3R)Hydroxy-pyrrolidine-1 arboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-{[(R)(3-chlorofluoro-phenyl)-ethyl]-amide}; (2S,3R)Hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-{[(S)(3-chlorofluoro-phenyl)-ethyl]-amide}; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-{[1-(2-hydroxy-acetyl)-1 H-indolyl]-amide} 2-[(3- trifluoromethoxy-phenyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid acetylcyano-1 H-indolyl)-amide] 2-[(3- oromethoxy-phenyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyldifluoromethoxy-1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoylhydroxy-1H-indolyl)-amide] 2- [(3-trifluoromethoxy-phenyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoylhydroxy-1H-indolyl)-amide] 2- [(3-trifluoromethoxy-phenyl)-amide]; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid carbamoylhydroxy- 1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoylhydroxy- 1H-indolyl)-amide] 3-(2-fluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl cyanomethoxy-1 H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); (1-Carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexanecarbonyl]-amino}-1H-indolyloxy)-acetic acid; (1-Carbamoyl{[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoromethylpyrrolidinecarbonyl ]-amino}-1 H-indolyloxy)-acetic acid; (1-Carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexanecarbonyl]-amino}-1H-indolyloxy)-acetic acid; (1-Carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- bicyclo[3. 1.0]hexanecarbonyl]-amino}-1 H-indolyl)-acetic acid; bamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- bicyclo[3. 1.0]hexanecarbonyl]-amino}-1 H-indolyl)-acetic acid; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- hydroxy-ethoxy)-1 H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide); (S)-Thiazolidine-2,3-dicarboxylic acid 3-{[1-carbamoyl(2-hydroxy-ethoxy)-1 H-indol yl]-amide} 2-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- hydroxy-ethoxy)-1 lyl]-amide} 3-[(3-trifluoromethoxy-phenyl)-amide]; (1S,2S,5R)Aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-{[1-carbamoyl(2- hydroxy-ethoxy)-1 H-indolyl]-amide} hlorofluoro-benzylamide); (2S,4R)Fluoromethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-{[1-carbamoyl(2- hydroxy-ethoxy)-1 H-indolyl]-amide} 2-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- hydroxy-ethyl)-1 H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid carbamoyl(2- hydroxy-ethyl)-1 H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide); ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- hydroxymethyl-propoxy)-1 H-indolyl]-amide} hlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- dimethylamino-ethoxy)-1 H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- pyrrolidinyl-ethoxy)-1 H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide); (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- imidazolyl-ethoxy)-1H-indolyl]-amide} hlorofluoro-benzylamide); bamoyl{[(1 R,3S,5R)(2-fluoro-benzylcarbamoyl)aza-bicyclo[3.1.0]hexane- 2-carbonyl]-amino}-1 H-indolyloxy)-acetic acid tert-butyl ester; (1-Carbamoyl{[(1 R,3S,5R)(2-fluoro-benzylcarbamoyl)aza-bicyclo[3.1.0]hexane- 2-carbonyl]-amino}-1 H-indolyloxy)-acetic acid; ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoylhydroxy- 1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoylhydroxy-1 H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); (1-Carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexanecarbonyl]-amino}-1 lyloxy)-acetic acid methyl ester; (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl(2- hydroxy-ethoxy)-1 H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,3S,4R)Aminomethoxy-pyrrolidine-1 ,2-dicarboxylicacid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(6-benzyloxycarbamoyl- 1H-indol- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (S)-Piperazine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chlorobenzylamide (S)-Pyrrolidine-1,2-dicarboxylic acid -aminomethyl-biphenylyl)-amide] 1-[(1- carbamoyl-1H-indolyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-[(4'-aminomethyl-2'-fluoro-biphenylyl)-amide] 1- [(1-carbamoyl-1 H-indolyl)-amide]; (2S,5R)Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,4R)Aminomethyl-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,4S)Aminomethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide]; (2S,4R)Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Dimethylaminomethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Aminomethylhydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4R)Aminomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Fluoroformylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl- 1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); )Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1 H- indolyl)-amide] 2-(3-chloro-2,6-difluoro-benzylamide); )Aminomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -acetyl- 1H-indol yl)-amide] hlorofluoro-benzylamide); (2S,4S)Aminomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-{[(S)(3-bromophenyl )fluoro-ethyl]-amide} 1-[(1-carbamoyl-1 H-indolyl)-amide]; (2S,4S)Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] trifluoromethoxy-phenyl)-amide]; (2S,3S,4S)Aminofluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-acetyl-1 H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide); (2S,3R,4S)Aminohydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); )Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 lyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,3R)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1 H-indolyl)-amide] 2-(3- chlorofluoro-benzylamide); )Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)-2,2,2-trifluoro-ethyl]-amide}; (2S,3S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,3S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chloro-benzylamide); (2S,3R)Acetylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide); (2S,3R)(2-Methoxy-ethylamino)-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -carbamoyl- 1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Fluoromethylaminomethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl- 1H-indolyl)-amide] hlorofluoro-benzylamide); (2S,4S)Methylamino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)(2-Methoxy-ethylamino)-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -carbamoyl- 1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,4S)Dimethylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide); (S)-4,4-Dimethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,3S,4R)Aminohydroxy-pyrrolidine-1 ,2-dicarboxylic acid carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); (2R,3S,4R)Aminofluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol- 3-yl)-amide] 2-(3-chlorofluoro-benzylamide); (2S,3S,4S)Aminofluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol- 3-yl)-amide] 2-(3-chlorofluorobenzylamide); (S)(3-Chlorofluoro-benzylcarbamoyl)-pyrazolidinyl]oxo-ethyl}-indole ylic acid amide; 3-{2-[(R)(3-Chlorofluoro-benzylcarbamoyl)-pyrazolidinyl]oxo-ethyl}-indole carboxylic acid amide; lidine-1 ,5-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 5-(3-chlorobenzylamide (3S,5S)(1-Carbamoyl-1H-indolylcarbamoyl)(2-fluorotrifluoromethoxyphenylcarbamoyl )-pyrrolidinecarboxylic acid methyl ester; (2S,4S)Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol yl)-amide] hloro-2,6-difluoro-benzylamide); (2S,4R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-[(3-bromocarbamoyl-phenyl)- amide] 1-[(1-carbamoyl-1 H-indolyl)-amide]; (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[3-chlorofluoro(2-methoxy-ethylcarbamoyl)-benzylamide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[(3- isopropyl-isoxazolyl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid carbamoyl-1H-indolyl)-amide] 2-[(3-phenylisoxazolyl )-amide]; 3-{2-[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl]oxo-ethyl}-indole carboxylic acid amide; 3-{2-[(2S,4R)Fluoro(2-fluorotrifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl] oxo-ethyl}-indolecarboxylic acid amide; 3-(2-{(1S,2S,5R)[(S)(3-Chlorofluoro-phenyl)hydroxy-ethylcarbamoyl] azabicyclo[3.1.0]hexyl}oxo-ethyl)-indolecarboxylic acid amide; 3-{2-[(2S,3R)(3-Chlorofluoro-benzylcarbamoyl)hydroxy-pyrrolidinyl]oxoethyl }-indolecarboxylic acid amide; (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)dimethylaminomethylfluoropyrrolidinyl ]oxo-ethyl}-indolecarboxylic acid amide; 3-{2-[(1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 yl] oxo-ethyl}-indolecarboxylic acid amide; 3-(2-{(2S,4R)[(R)(3-Chlorofluoro-phenyl)hydroxy-propylcarbamoyl]fluoro methyl-pyrrolidinyl}oxo-ethyl)-indolecarboxylic acid amide; 3-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- indole- 1-carboxylic acid amide; 3-(2-{(1R,3S,5R)[(S)(3-Chlorofluoro-phenyl)hydroxy-ethyl carbamoyl]azabicyclo [3.1.0]hexyl}oxo-ethyl)-indolecarboxylic acid amide; 3-{2-[(S)(3-Chlorofluoro-benzylcarbamoyl)-thiazolidinyl]oxo-ethyl}-indole carboxylic acid amide; 3-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluorohydroxymethyl-pyrrolidin- 1-yl]oxo-ethyl}-indole- 1-carboxylic acid amide; 3-{2-[(1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hexyl] oxo-ethyl}methoxy-indolecarboxylic acid amide; 3-{2-[(1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hexyl] oxo-ethyl}(2-hydroxy-ethoxy)-indole-1 -carboxylic acid amide; 3-{2-[(1 S)(3-Chlorofluoro-benzylcarbamoyl)methoxymethylaza- bicyclo[3.1.0]hexyl]oxo-ethyl}-indole-1 -carboxylic acid amide; ydroxy-ethoxy){2-oxo[(1 R,3S,5R)(3-trifluoromethoxy-phenylcarbamoyl) aza-bicyclo[3.1.0]hexyl]-ethyl}-indolecarboxylic acid amide; 3-(2-{(1R,3S,5R)[(5-Chloro-thiophenylmethyl)-carbamoyl]aza-bicyclo[3.1 .0]hex- 2-yl}oxo-ethyl)-indole-1 -carboxylic acid amide; 3-(2-{(1R,3S,5R)[(R)(3-Chlorofluoro-phenyl)hydroxy-propylcarbamoyl] azabicyclo[3.1.0]hexyl}oxo-ethyl)-indolecarboxylic acid amide; 3-(2-{(1R,3S,5R)[(S)(3-Chlorofluoro-phenyl)dimethylamino-ethylcarbamoyl] cyclo[3.1.0]hexyl}oxo-ethyl)-indolecarboxylic acid amide; 3-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoromethyl-pyrrolidinyl] oxo-ethyl}(2-hydroxy-ethoxy)-indole-1 -carboxylic acid amide; 3-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- -fluoro-indolecarboxylic acid amide; 3-{2-[(1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hexyl] oxo-ethyl}methyl-indolecarboxylic acid amide; 3-{2-[(S)(3-Chlorofluoro-benzylcarbamoyl)-thiazolidinyl]oxo-ethyl}(2- hydroxy-ethoxy)-indolecarboxylic acid amide; 3-(2-{(1R,2S,5S)[(S)(3-Chlorofluoro-phenyl)hydroxy-ethylcarbamoyl] azabicyclo[3.1.0]hexyl}oxo-ethyl)-indolecarboxylic acid amide; 3-(2-{(1R,3S,5R)[(S)(3-Chlorofluoro-phenyl)methoxy-ethylcarbamoyl]azabicyclo ]hexyl}oxo-ethyl)-indolecarboxylic acid amide; (1 S,2S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo[3. 1.0]hexyl] oxo-ethyl}(2-hydroxy-ethoxy)-indolecarboxylic acid amide; 3-{2-[(2S,3S,4S)Amino(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]- 2-oxo-ethyl}-indolecarboxylic acid amide; 3-{2-[(1 R,3S,5S)(3-Chlorofluoro-benzylcarbamoyl)hydroxymethylaza- bicyclo[3.1.0]hexyl]oxo-ethyl}-indolecarboxylic acid amide; 3-{2-[(2S,4S)Amino(3-chlorofluoro-benzylcarbamoyl)-pyrrolidinyl]oxoethyl }-indolecarboxylic acid amide; 3-{2-[5-(3-Chloro-benzylcarbamoyl)-pyrazolidinyl]oxo-ethyl}-indolecarboxylic acid amide; 3-{2-[(2S,4S)Aminomethyl(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin yl]oxo-ethyl}-indolecarboxylic acid amide; 3-{2-[(2S,4S)Aminomethyl(3-chloro-2,6-difluoro-benzylcarbamoyl)fluoropyrrolidinyl ]oxo-ethyl}-indolecarboxylic acid amide; 3-{2-[(1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hexyl] oxo-ethyl}(2-dimethylamino-ethoxy)-indolecarboxylic acid amide; (1-Carbamoyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3. 1.0]hexyl]oxo-ethyl}-1 H-indolyl)-acetic acid; (1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hexyl] oxo-ethyl}(2-hydroxy-ethyl)-indolecarboxylic acid amide; 1-{2-[(1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hexyl] oxo-ethyl}-1 H-indolecarboxylic acid amid; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 1H-indolecarboxylic acid amide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- oxy-1 H-indolecarboxylic acid amide; (S)[2-(3-Acetyl-indolyl)-acetyl]-piperidinecarboxylic acid 3-chlorofluorobenzylamide 6-Bromo{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] oxo-ethyl}fluoro-1 H-indolecarboxylic acid amide; 3-[({(1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1 .0]hexanecarbonyl}- amino)-methyl]chlorofluoro-benzoic acid methyl ester; 1-{2-[(2S,4R)(3-Bromofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 1H-indolecarboxylic acid amide; (2S,4R)[2-(3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetyl]fluoromethyl-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid 3-chlorofluoro-benzylamide; ,5R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid (5-chloro-thiophenylmethyl)-amide; (2S,3S,4S)[2-(3-Acetylmethoxy-indolyl)-acetyl]fluoromethoxy-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; 1-{2-[(2S,4R)(3-Chlorofluoro-phenylcarbamoyl)fluoro-pyrrolidinyl]oxo- -1 H-indolecarboxylic acid amide; (2S,3S,4S)[2-(3-Acetylmethoxy-indolyl)-acetyl]fluoromethoxy-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; -Chloro{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] oxo-ethyl}-1 H-indolecarboxylic acid amide ; 7-Chloro{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] oxo-ethyl}-1 lecarboxylic acid amide ; (1R,3S,5S)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]methoxymethylaza- bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide; 6-Chloro{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] oxo-ethyl}-1 H-indolecarboxylic acid amide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- ,6-difluoro-1 H-indolecarboxylic acid amide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 6-trifluoromethoxy-1 H-indolecarboxylic acid amide; (1R,3S,5R)[2-(3-Acetylmethoxy-pyrrolo[2,3-b]pyridinyl)-acetyl]aza- bicyclo[3.1 anecarboxylic acid 3-chlorofluoro-benzylamide; ,5R){2-[3-(2,2,2-Trifluoro-acetyl)-indolyl]-acetyl}aza-bicyclo[3.1.0]hexane- 3-carboxylic acid 3-chlorofluoro-benzylamide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoromethyl-pyrrolidinyl] oxo-ethyl}-1 H-indolecarboxylic acid amide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- -methoxy-1 H-indolecarboxylic acid amide; (2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chloro cyanofluoro-benzylamide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 6-methoxy-1 H-indolecarboxylic acid amide; (2S,4R)[2-(3-Acetylmethoxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (S)[2-(3-Acetylmethoxy-indolyl)-acetyl]-piperidinecarboxylic acid 3-chloro -benzylamide; (2S,4R)[2-(3-Acetyl-pyrrolo[3,2-c]pyridinyl)-acetyl]fluoromethyl-pyrrolidine carboxylic acid rofluoro-benzylamide; -Benzyloxy{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]- 2-oxo-ethyl}-1 H-indolecarboxylic acid amide; (1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid [(R)(3-chlorofluoro-phenyl)hydroxy-propyl]-amide; ,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxy-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (1R,2S,5S)[2-(3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chloro fluoro-benzylamide; (2S,4R)[2-(3-Acetylbenzyloxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetyltrifluoromethoxy-indolyl)-acetyl]fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoromethyl-pyrrolidinecarboxylic acid rofluoro-benzylamide; (1R,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[2.2.1]heptanecarboxylic acid 3-chlorofluoro-benzylamide; (S)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]-thiazolidinecarboxylic acid 3- chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid (2-fluoro trifluoromethoxy-phenyl)-amide; (1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid [3-bromo(2H-tetrazolyl)-phenyl]-amide; )[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-bromo fluoro-benzylamide; 1-{2-[(2S,4R)Fluoro(2-fluorotrifluoromethyl-phenylcarbamoyl)-pyrrolidinyl] hyl}-1 lecarboxylic acid amide; (2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid [(S)(3- chlorofluoro-phenyl)hydroxy-ethyl]-amide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 1H-indolecarboxylic acid methylamide ; (2S,3S,4S)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]fluoromethoxypyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chloro fluoro(1H-tetrazolyl)-benzylamide; (1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid [(S)(3-chlorofluoro-phenyl)dimethylamino-ethyl]-amide; 3-[({(2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarbonyl}-amino)- methyl]chlorofluoro-benzoic acid methyl ester; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[3,2-c]pyridinyl)-acetyl]aza-bicyclo[3.1.0]hexane- 3-carboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid 3-chlorofluoro(1 H-tetrazolyl)-benzylamide; 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hex- 2-yl]oxo-ethyl}-1 H-indolecarboxylic acid methyl ester; (1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid 3-chlorocyanofluoro-benzylamide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 6-difluoromethoxy-1 H-indolecarboxylic acid amide; 6-Benzyloxy{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]- 2-oxo-ethyl}-1 H-indolecarboxylic acid amide ; (2S,4R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]fluoromethyl-pyrrolidine ylic acid 3-chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetylchloro-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3- chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetylcyano-pyrrolo[2,3-b]pyridinyl)-acetyl]aza- bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid [(S)(3-chlorofluoro-phenyl)methoxy-ethyl]-amide; (2S,4R)[2-(3-Acetylbenzyloxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; ,5R)[2-(3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetyl]aza-bicyclo[3.1.0]hexane- 3-carboxylic acid [(S)(3-chlorofluoro-phenyl)methoxy-ethyl]-amide; (1R,3S,5R)[2-(3-Acetylbenzyloxy-indolyl)-acetyl]aza-bicyclo[3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide; (1R,2S,5S)[2-(3-Acetyl-pyrrolo[3,2-c]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide; (1R,2S,5S)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo[3.1.0]hexane- 2-carboxylic acid rofluoro-benzylamide; (2S,4R)[2-(3-Acetyltrifluoromethoxy-indolyl)-acetyl]fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 - 2-yl]oxo-ethyl}-1 lecarboxylic acid methyl ester; 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluorobenzylcarbamoyl)aza-bicyclo[3.1.0]hex- 2-yl]oxo-ethyl}-1 H-indolecarboxylic acid methyl ester; 3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] hyl}-1 H-indolecarboxylic acid methyl ester; (2S,4R)Fluoro{2-[3-(2-hydroxy-acetyl)-indolyl]-acetyl}methyl-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (1S,2S,5R)[2-(3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide; (3-Acetyl{2-[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexyl]oxo-ethyl}-1 H-indolyl)-acetic acid methyl ester; (2S,4R)Fluoro{2-[3-(2,2,2-trifluoro-acetyl)-indolyl]-acetyl}-pyrrolidinecarboxylic acid 3-bromofluoro-benzylamide; (2S,4R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; 3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoromethylpyrrolidinyl ]oxo-ethyl}-1 H-indolecarboxylic acid methyl ester; (3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] oxo-ethyl}-1 H-indolyl)-acetic acid methyl ester; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetyl]aza-bicyclo[3.1.0]hexane- 3-carboxylic acid rofluorobenzylamide; (2S,4R)Fluoro{2-[3-(2-hydroxy-acetyl)-indolyl]-acetyl}-pyrrolidinecarboxylic acid [(S)(3-bromo-phenyl)fluoro-ethyl]-amide; (2S,4R)[2-(3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[3,2-b]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid rofluoro-benzylamide; (2S,4R)Fluoromethyl{2-[3-(2,2,2-trifluoro-acetyl)-indolyl]-acetyl}-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (2R,3S,4R)[2-(3-Acetyl-indolyl)-acetyl]dimethylaminofluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R){2-[3-(2-Hydroxy-acetyl)-indolyl]-acetyl}aza-bicyclo[3.1 .0]hexane carboxylic acid rofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid [(R)(3-chlorofluoro-phenyl)hydroxy-propyl]-amide; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid (3-trifluoromethoxy-phenyl)-amide; (S)[2-(3-Formyl-indolyl)-acetyl]-pyrrolidinecarboxylic acid (3-trifluoromethoxyphenyl )-amide; (2S,4R)Fluoro[2-(3-formylmethoxy-indolyl)-acetyl]-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)Fluoro{2-[3-(2,2,2-trifluoro-acetyl)-indolyl]-acetyl}-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide; (2S,4R)Fluoro{2-[3-(2-hydroxy-acetyl)-indolyl]-acetyl}-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)Fluoro{2-[3-(2-hydroxy-acetyl)-indolyl]-acetyl}-pyrrolidinecarboxylic acid ofluoro-benzylamide; (2S,4R)Fluoro{2-[3-(2-methoxy-acetyl)-indolyl]-acetyl}-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluorohydroxymethyl-pyrrolidin- 1-yl]oxo-ethyl}-1 H-indolecarboxylic acid amide; 1-{2-[(S)(3-Chlorofluoro-benzylcarbamoyl)-thiazolidinyl]oxo-ethyl}-1 H-indole- 3-carboxylic acid amide ; (1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid [(S)(3-chlorofluoro-phenyl)methoxy-ethyl]-amide; (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoroethoxy-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxy-pyrrolidinecarboxylic acid [(R)(3-chlorofluoro-phenyl)-ethyl]-amide; (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxy-pyrrolidinecarboxylic acid [(S)(3-chlorofluoro-phenyl)-ethyl]-amide; (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxy-pyrrolidinecarboxylic acid [1-(3-chloro-phenyl)-cyclopropyl]-amide; (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxy-pyrrolidinecarboxylic acid chloro-phenyl)-cyclopropyl]-amide; 1-{2-[(2S,3S,4S)Amino(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]- 2-oxo-ethyl}-1 H-indolecarboxylic acid amide; (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]aminofluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (2R,3S,4R)[2-(3-Acetyl-indolyl)-acetyl]aminofluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- -hydroxy-1 H-indolecarboxylic acid amide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 6-hydroxy-1 H-indolecarboxylic acid amide; (2S,4R)[2-(3-Acetylhydroxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; )[2-(3-Acetylhydroxy-indolyl)-acetyl]fluoromethyl-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetylhydroxy-indolyl)-acetyl]aza-bicyclo[3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetylhydroxy-indolyl)-acetyl]fluoromethyl-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetylhydroxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(3-Acetylhydroxy-indolyl)-acetyl]aza-bicyclo[3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- tetrazolylmethoxy)-1 H-indolecarboxylic acid amide; (2S,4R){2-[3-Acetyl(1H-tetrazolylmethoxy)-indolyl]-acetyl}fluoro-yrrolidine- 2-carboxylic acid 3-chlorofluoro-benzylamide; (2S,4R)[2-(3-Acetylmethoxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (2S,4R){2-[3-Acetyl(pyridinylmethoxy)-indolyl]-acetyl}fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (2S,4R){2-[3-Acetyl(pyrimidinylmethoxy)-indolyl]-acetyl}fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 6-(2-methoxy-ethoxy)-1 H-indolecarboxylic acid amide; (3-Carbamoyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin yl]oxo-ethyl}-1 lyloxy)-acetic acid methyl ester; (3-Carbamoyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin yl]oxo-ethyl}-1 H-indolyloxy)-acetic acid; 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo-ethyl}- 6-(2-hydroxy-ethoxy)-1H-indolecarboxylic acid amide; (3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] oxo-ethyl}-1 H-indolyl)-acetic acid; (3-Acetyl{2-[(1 R)(3-chlorofluoro-benzylcarbamoyl)aza- bicyclo[3. 1.0]hexyl]oxo-ethyl}-1 lyl)-acetic acid; 3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] oxo-ethyl}-1 H-indolecarboxylic acid; 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hex- 2-yl]oxo-ethyl}-1 H-indolecarboxylic acid; 3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoromethylpyrrolidinyl ]oxo-ethyl}-1 lecarboxylic acid; (2S,3S,4S)Fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide); 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hex- 2-yl]oxo-ethyl}-1 H-indolecarboxylic acid; 4-(3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]- 2-oxo-ethyl}-1 H-indolyloxymethyl)-benzoic acid; 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hex- 2-yl]oxo-ethyl}-1 H-indolecarboxylic acid; (2S,4R)[2-(3-Acetylhydroxymethyl-indolyl)-acetyl]fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; 3-[({(2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarbonyl}-amino)- methyl]chlorofluoro-benzoic acid; 3-[({(1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1 .0]hexanecarbonyl}- amino)-methyl]chlorofluoro-benzoic acid; (2S,4S)[2-(3-Acetyl-indolyl)-acetyl]aminomethylfluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; (2S,4S)[2-(3-Acetyl-indolyl)-acetyl]methylamino-pyrrolidinecarboxylic acid 3- chlorofluoro-benzylamide; (2S,4S)[2-(3-Acetyl-indolyl)-acetyl](2-methoxy-ethylamino)-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5S)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]hydroxymethylaza- bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5S)[2-(3-Acetyl-indolyl)-acetyl]hydroxymethylaza- bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide; (1S,2S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid [(S)(3-chlorofluoro-phenyl)-2hydroxy-ethyl]-amide; (1R,3S,5R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo[3.1 .0]hexane- 3-carboxylic acid [(S)(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide; (2S,4R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]fluoromethyl-pyrrolidine carboxylic acid -(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide; (1R,3S,5R){2-[3-Acetyl(N,N-dimethyl-carbamimidoyl)-indolyl]-acetyl}aza- bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R){2-[3-Acetyl(N,N-dimethyl-carbamimidoyl)-indolyl]-acetyl}aza- bicyclo[3.1 anecarboxylic acid 3-chlorofluoro-benzylamide; ){2-[3-Acetyl(1H-tetrazolyl)-indolyl]-acetyl}fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R){2-[3-Acetyl(1H-tetrazolyl)-indolyl]-acetyl}aza- bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide; (2S,3S,4S)[2-(3-Acetyl-d3-indolyl)-acetyl]fluoromethoxy-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxy-d3-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide; (1R,3S,5R)[2-(1-Acetyl-imidazo[1 yridinyl)-acetyl]aza-bicyclo[3.1 ane- 3-carboxylic acid 3-chlorofluoro-benzylamide; and {(1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexylmethyl}- carbamic acid 3-chlorofluoro-phenyl ester.
In r embodiment, pharmaceutical compositions are provided which comprise one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a mulae thereof.
In another embodiment, combinations, in particular pharmaceutical combinations, are ed which comprise a therapeutically effective amount of the compound of any one of ae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof.
In another embodiment, s of modulating complement alternative pathway activity in a subject are provided which methods comprise administering to the subject a therapeutically effective amount of the compound of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof.
In yet other embodiments, methods of ng a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, are provided, which methods comprise administering to the subject a therapeutically effective amount of the compound of any one of formulae (I), (la), (II), (III), (IV), (V) , (VI), (VII), or a subformulae thereof.
In another embodiment, methods of treating age related macular degeneration in a subject are provided which methods comprise administering to the subject a therapeutically effective amount of the nd of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof.
In another aspect, the invention provides for the use of compounds of any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), or a subformulae thereof for use in the preparation of a medicament and more particularly for use in the manufacture of a medicament for the ent of a disorder or e in a t mediated by complement activation or activation of the ment alternative pathway. In n other aspects, the invention provides for the use of a compound according to any one of formulae (I), (la), (II), (III), (IV), (V), (VI) , (VII), or a subformulae thereof in the treatment of age-related macular degeneration.
In another embodiment, compounds which are synthetic intermediates in the preparation of nds according to any one of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII) , or a subformulae f are provided. In particular, compounds provided herein as synthetic intermediates include the nds of the formulae: carboxamide In one embodiment, the invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to the definition of formula (I), (la), (II), (VII) or subformulae thereof or any one of the specifically disclosed compounds of the invention and one or more therapeutically active agents (preferably selected from those listed .
For purposes of interpreting this specification, the following tions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.
As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 20 carbon atoms. Unless otherwise provided, alkyl refers to hydrocarbon moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, /so-propyl, l, sec-butyl, tyl, -butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl and the like.
As used , the term ene" refers to divalent alkyl group as defined herein above having 1 to 20 carbon atoms. It comprises 1 to 20 carbon atoms, Unless otherwise ed, alkylene refers to moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, /so-propylene, n-butylene, tylene, iso- butylene, -butylene, ylene, isopentylene, neopentylene, n-hexylene, 3- methylhexylene, 2,2- dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n- nonylene, n-decylene and the like.
As used herein, the term "haloalkyl" refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein. The kyl can be loalkyi, dihaloalkyi or polyhaloalkyi including perhaloalkyl. A monohaloalkyi can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalky and polyhaloalkyi groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhaloalkyi contains up to 12, or 10, or 8 , or 6 , or 4 , or 3 , or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, roethyl and dichloropropyl. A perhaloalkyl refers to an alkyl having all en atoms replaced with halo atoms.
The term "aryl" refers to an ic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms.
Furthermore, the term "aryl" as used herein, refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together.
Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted by 1-4 tuents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(0), aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl- S-, nitro, cyano, carboxy, alkyl-O-C(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl, and heterocyclyl.
As used herein, the term "alkoxy" refers to alkyl-O-, wherein alkyl is defined herein above. entative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, te/f-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Typically, alkoxy groups have about 1-7, more preferably about 1-4 carbons.
As used herein, the term "heterocyclyl" or "heterocyclo" refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or ered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered ic or 10-, 11-, 12-, 13-, 14- or 15- membered tricyclic ring system and contains at least one atom selected from O, S and N , where the N and S can also optionally be oxidized to various oxidation states. The cyclic group can be attached at a atom or a carbon atom. The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran (THF), ofuran, 1 , 4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, olidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.
The term "heterocyclyl" further refers to heterocyclic groups as defined herein substituted with 1 to 5 tuents independently selected from the groups consisting of the following: (a) alkyl; (b) hydroxy (or protected y); (c) halo; (d) oxo, i.e., =0; (e) amino, alkylamino or dialkylamino; (f) alkoxy; (g) cycloalkyi; (h) carboxyl; (i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge; (j) alkyl-O-C(O)-; (k) mercapto; (I) nitro; (m) cyano; (n) sulfamoyl or amido; (o) aryl; (p) C(0); (q) aryl-C(0); (r) aryl-S-; (s) y; (t) alkyl-S-; (u) formyl, i.e., HC(O)-; (v) carbamoyl; (w) lkyl-; and (x) aryl substituted with alkyl, cycloalkyi, alkoxy, hydroxy, amino, alkyl-C(0)-NH-, alkylamino, dialkylamino or halogen.
As used herein, the term "cycloalkyi" refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms. Unless otherwise provided, cycloalkyi refers to cyclic hydrocarbon groups having between 3 and 9 ring carbon atoms or between 3 and 7 ring carbon atoms, each of which can be optionally substituted by one, or two, or three, or more substituents independently selected from the group consisting of alkyl, halo, oxo, hydroxy, , alkyl-C(O)-, acylamino, carbamoyl, alkyl-NH-, (alkyl) N-, thiol, alkyl- -, nitro, cyano, y, alkyl-O-C(O)-, sulfonyl, sulfonamido, sulfamoyl, and heterocyclyl.
Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups e bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6- dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1 .1]heptyl, bicyclo[2.2.2]octyl and the like.
Exemplary tricyclic hydrocarbon groups include tyl and the like.
As used , the term "aryloxy" refers to both an yl and an 0-O-heteroaryl group, wherein aryl and heteroaryl are defined herein.
As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring , having 1 to 8 heteroatoms selected from N , O or S .
Typically, the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle or an 8-10 memberred bicycle) or a 5-7 membered ring system. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5- isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1 ,2, 3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4- pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.
The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. iting examples e 1-, 2-, 3-, 5-, 6-, 7-, or 8- indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7- indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6- , 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3- , 4-, 5-, or 6-naphthyridinyl, 2-, 3- , 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or olinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or zaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10- phenanthridinyl, 1- , 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9- perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2- , 3-, 4-, 6-, 7-, 8-, or 9- phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10- phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- oqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 - , or 11-7H-pyrazino[2,3-c]carbazolyl,2-, 3-, 5-, 6- , or 7-2H- furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5- 1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d] thiazolyl, 3-, 5-, or 8-pyrazino[2,3- d]pyridazinyl, 2-, 3-, 5-, or 6- imidazo[2,1-b] lyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1 ,2- b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- idazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9- apinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1 ,2- b][2]benzazapinyl. Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
A heteroaryl group may be substituted with 1 to 5 tuents independently selected from the groups consisting of the following: (a) alkyl; (b) y (or protected hydroxy); (c) halo; (d) oxo, i.e., =0; (e) amino, alkylamino or dialkylamino; (f) alkoxy; (g) cycloalkyl; (h) carboxyl; (i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge; (j) alkyl-O-C(O)-; (k) mercapto; (I) nitro; (m) cyano; (n) sulfamoyl or sulfonamido; (o) aryl; (p) alkyl-C(0); (q) aryl-C(0); (r) aryl-S-; (s) aryloxy; (t) alkyl-S-; (u) formyl, i.e., HC(O)-; (v) carbamoyl; (w) aryl-alkyl-; and (x) aryl substituted with alkyl, cycloalkyl, alkoxy, y, amino, alkyl-C(0)-NH-, alkylamino, dialkylamino or halogen.
As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo, and iodo.
As used herein, the term "optionally substituted" unless otherwise ied refers to a group that is unsubstituted or is substituted by one or more, typically 1, 2 , 3 or 4 , suitable non- hydrogen substituents, each of which is independently ed from the group ting of: (a) alkyl; (b) hydroxy (or protected hydroxy); (c) halo; (d) oxo, i.e., =0; (e) amino, alkylamino or dialkylamino; (f) alkoxy; (g) cycloalkyl; (h) carboxyl; (i) heterocyclooxy, n heterocyclooxy denotes a heterocyclic group bonded through an oxygen ; (j) alkyl-O-C(O)-; (k) mercapto; (I) nitro; (m) cyano; (n) sulfamoyl or sulfonamido; (o) aryl; (p) alkyl-C(0); (q) aryl-C(0); (r) aryl-S-; (s) aryloxy; (t) alkyl-S-; (u) formyl, i.e., HC(O)-; (v) carbamoyl; (w) aryl-alkyl-; and (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(0)-NH-, alkylamino, dialkylamino or halogen.
As used herein, the term rs" refers to different compounds that have the same molecular formula but differ in arrangement and uration of the atoms. Also as used herein, the term "an optical " or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. The asterisk (*) indicated in the name of a compound designate a racemic mixture.
"Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not -images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) ing on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute chemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or configuration. All tautomeric forms are also intended to be included.
As used , the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the nds of this ion and, which typically are not biologically or otherwise undesirable. In many cases, the nds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups r thereto.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g. , acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, isulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, e, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, oate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen ate, polygalacturonate, nate, stearate, succinate, alicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, c acid, tartaric acid, citric acid, benzoic acid, mandelic acid, esulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for e, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include um, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, hine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
The pharmaceutically acceptable salts of the present ion can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
Generally, such salts can be prepared by ng free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, onate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic t, or in a e of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where cable. Lists of additional suitable salts can be found, e.g., in gton's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Any formula given herein is also intended to ent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H , H , C, C, 4C , N , 8F P, 2P, S, 36 | 125| respectively. The invention es various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as H , C, and 4C , are present. Such isotopically labelled nds are useful in metabolic studies (with 4C), reaction kinetic studies (with, for e 2H or H), detection or imaging techniques, such as positron on aphy (PET) or single-photon on computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of ts. In particular, an 8F or labeled compound may be particularly desirable for PET or SPECT s. ically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily ble isotopically labeled reagent for a otopically labeled reagent.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for e increased in vivo ife or reduced dosage requirements or an ement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The tration of such a heavier isotope, specifically deuterium, may be defined by the ic enrichment factor. The term pic enrichment " as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% ium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
In certain embodiments, selective deuteration of compounds of Formula (I) include deuteration of R3, when R3 is alkanoyl, e.g., C(0)CD . In other embodiments, certain substitutents on the pyrrole ring are selectively deuterated. For example, when any of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , or R20 are methoxy or ethoxy, the alkyl residue is preferably deuterated, e.g., OCD or OC D . In certain other compounds, when two substituents of the pyrrole ring are 3 2 5 ed to form a cyclopropyl ring, the unsubstituted methylene carbon is selectively ated. Certain preferred deuterated compounds are provided in Examples 619 and 620 infra.
Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate icallylabeled reagents in place of the non-labeled reagent usly employed.
The compounds of the present invention may inherently or by design form solvates with solvents (including water). Therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term te" refers to a lar x of a compound of the present invention (including salts thereof) with one or more solvent molecules. Such solvent les are those commonly used in the pharmaceutical art, which are known to be innocuous to a recipient, e.g., water, ethanol, dimethylsulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 0 , d -acetone, d -DMSO. 2 6 6 Compounds of the invention, i.e. nds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co- crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in on compounds of a (I) with the stal former under crystallization ions and isolating co-crystals thereby formed.
Suitable co-crystal formers include those described in WO 78163. Hence the invention further provides co-crystals comprising a compound of formula (I).
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, vatives (e.g., antibacterial agents, ngal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, s, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for e, Remington's Pharmaceutical es, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except r as any tional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
The term "a therapeutically effective amount" of a nd of the present invention refers to an amount of the compound of the present invention that will elicit the biological or l response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder, or a disease or biological process (e.g., tissue regeneration and reproduction) (i) ed by Factor D, or (ii) associated with Factor D activity, or (iii) characterized by activity l or abnormal) of the complement alternative pathway; or (2) reducing or inhibiting the activity of Factor D ; or (3) reducing or ting the expression of Factor D ; or (4) reducing or inhibiting activation of the complement system and particularly reducing or ting generation of C3a, iC3b, C5a or the ne attack complex generated by activation of the complement alternative pathway. In another non- limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a noncellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of Factor D and/or the complement ative pathway; or at least partially reducing or ting the expression of Factor D and/or the complement alternative pathway.
The meaning of the term "a therapeutically effective amount" as illustrated in the above embodiment for Factor D and/or the complement alternative pathway.
As used herein, the term "subject" refers to an animal. Typically the animal is a mammal . A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, s, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom , or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term "treat", ing" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e. , slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical ter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or ment" refers to modulating the e or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical ter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, a subject is "in need of a treatment if such subject would t biologically, medically or in quality of life from such treatment.
As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the ar and plural unless ise indicated herein or clearly contradicted by the t.
All methods described herein can be performed in any suitable order unless ise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the ion and does not pose a limitation on the scope of the invention otherwise claimed.
Any asymmetric atom (e.g. , carbon or the like) of the compound(s) of the present ion can be present in c or enantiomerically enriched, for example the (R)-, (S)- or (R, S)- uration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % omeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- ( )- form.
Accordingly, as used herein a compound of the t invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
Any ing racemates of final ts or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the reomeric salts f, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their l antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, oyl ic acid, diacetyl ic acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphorsulfonic acid.
Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives f.
When both a basic group and an acid group are present in the same molecule, the compounds of the present ion may also form internal salts, e.g., zwitterionic molecules.
The t invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention. A pro-drug is an active or inactive compound that is modified chemically through in vivo physiological , such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject. The suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art. Prodrugs can be conceptually d into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal try, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001). Generally, bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or zed delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage n the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the ort moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., n rs or other moieties, such as cyclodextrins. Carrier prodrugs can, for example, be used to improve one or more of the following ties: increased lipophilicity, increased duration of pharmacological effects, sed site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For e, lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic ls).
Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein. Suitable prodrugs are often pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower l esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the o-(amino, mono- or di-lower alkylamino, y, lower alkoxycarbonyl)-lower alkyl esters, the er alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the yloxymethyl ester and the like conventionally used in the art. In addition, amines have been masked as rbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and dehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)).
Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
Within the scope of this text, only a y removable group that is not a constituent of the particular desired end product of the compounds of the present ion is designated a "protecting group", unless the context indicates otherwise. The tion of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J . F. W . McOmie, ctive Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G . M . Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The es"; Volume 3 (editors: E . Gross and J . Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H . Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: ccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g. by tic cleavage).
Salts of compounds of the present ion having at least one salt-forming group may be prepared in a manner known to those skilled in the art. For example, salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable c carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, ates or hydrogen ates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric s or only a small excess of the orming agent ably being used. Acid addition salts of compounds of the present invention are ed in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by ent with ion exchangers.
Salts can be ted into the free compounds in accordance with methods known to those skilled in the art. Metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent. es of isomers obtainable according to the invention can be separated in a manner known to those skilled in the art into the individual isomers; diastereoisomers can be separated, for example, by ioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming ts and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over lly active column materials.
Intermediates and final products can be worked up and/or ed according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
The following applies in general to all processes mentioned herein before and hereinafter.
All the above-mentioned process steps can be carried out under reaction conditions that are known to those skilled in the art, including those mentioned specifically, in the e or, customarily, in the presence of solvents or ts, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or ce of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a ature range of from about -100 °C to about 190 °C, ing, for e, from approximately -80 °C to approximately 150 °C, for example at from -80 to -60 °C, at room temperature, at from -20 to 40 °C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.
At all stages of the reactions, mixtures of isomers that are formed can be separated into the individual isomers, for e diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps".
The solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for e, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic arbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2- propanol, nitriles, such as itrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or yl ide, bases, such as heterocyclic nitrogen bases, for example pyridine or A/-methylpyrrolidinone, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methycyclohexane, or mixtures of those ts, for example s solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in g up, for example by chromatography or partitioning.
The compounds, ing their salts, may also be obtained in the form of hydrates, or their crystals may, for e, include the solvent used for crystallization. Different crystalline forms may be present.
The invention relates also to those forms of the process in which a compound able as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for e in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ry skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
Typically, the compounds of a (I) can be prepared according to the Schemes provided infra.
A compound of the formula IV or V can, for example, be ed from a corresponding N-protected aminoacid as described below: By reacting an ected aminoacid I n PG is a protecting group or a reactive derivative thereof with an amino compound, under sation conditions to obtain a compound of the formula II. Removing the protecting group and reacting the compound of the formula III with an isocyanate to obtain a compound of the formula IV or with an acid or a reactive derivative thereof under condensation conditions to obtain a compound of the formula The invention r includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure materials.
Compounds of the invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.
In r aspect, the present invention provides a pharmaceutical composition comprising a nd of the present invention and a pharmaceutically acceptable carrier.
The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and ophthalmic administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions, emulsions, each of which may be suitable for ophthalmic stration). The pharmaceutical compositions can be subjected to conventional ceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
Typically, the pharmaceutical itions are s or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum te, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and ners.
Tablets may be either film coated or c coated ing to methods known in the art. le compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily sions, dispersible powders or granules, emulsion, hard or soft es, or syrups or elixirs.
Compositions intended for oral use are prepared according to any method known in the art for the cture of pharmaceutical compositions and such compositions can contain one or more agents ed from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide ceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic ceutically acceptable excipients which are suitable for the manufacture of tablets.
These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, e, calcium phosphate or sodium phosphate; ating and disintegrating agents, for e, corn starch, or alginic acid; g agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and tion in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft n capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or sions, and suppositories are ageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable nces.
Said compositions are prepared according to conventional , ating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
Suitable compositions for transdermal application include an ive amount of a compound of the ion with a suitable carrier. Carriers suitable for transdermal delivery include able pharmacologically acceptable ts to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a g member, a oir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous ons, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for ophthalmic application, e.g., for the treatment of eye diseases e.g., for therapeutic or prophylactic use in treating age related macular degeneration and other complement mediated ophthalmic disorders. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with olipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or ser, with or without the use of a suitable propellant.
Dosage forms for the topical or transdermal administration of a compound of this ion include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any vatives, buffers, or propellants that may be desirable.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, ose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a nd of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these nces. Sprays can additionally n customary lants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a nd of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
The t invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the nds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
Anhydrous ceutical compositions and dosage forms of the ion can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical ition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are ed using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, ically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the t invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not d to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
Prophylactic and Therapeutic Uses The compounds of formula I in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. Factor D modulating properties, complement y modulating ties and modulation of the ment alternative pathway properties, e.g. as indicated in in vitro and in vivo tests as ed in the next sections and are therefore indicated for therapy.
The present invention provides methods of treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of the compounds of a (I) of the invention. In certain aspects, methods are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, methods of treating or preventing compelment mediated diseases are provided in which the complement activation is induced by dy-antigen interactions, by a component of an autoimmune disease, or by ischemic damage.
In a specific embodiment, the present invention es a method of treating or preventing age-related macular ration (AMD) by administering to a subject in need thereof an effective amount of the compound of Formula (I) of the invention. In certain embodiments, patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for stration with a compound of the invention. The methods of treating or ting AMD include, but are not limited to, methods of treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, mation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization ding CNV), retinal detachment, photoreceptor degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, l damage in response to light exposure, damage of the Bruch's membrane, and/ or loss of RPE function.
The compound of Formula (I) of the invention can be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic y, to slow and/or prevent progression of geographic atrophy, to treat or t macular edema from AMD or other conditions (such as ic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve vision lost due to isting early or advanced AMD. It can also be used in combination with anti-VEGF therapies for the ent of neovascular AMD patients or for the prevention of neovascular AMD. The present invention further provides methods of treating a complement related disease or disorder by administering to a t in need thereof an effective amount of the compound(s) of the invention, wherein said disease or disorder is selected from uveitis, adult macuar degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ic optic athy, post operative inflammation, and retinal vein occlusion.
In some embodiments, the t invention provides methods of treating a complement d disease or disorder by administering to a subject in need thereof an effective amount of the compounds of the invention. Examples of known complement related diseases or disorders include: neurological disorders, multiple sis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, ers of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's e, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, schemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious e or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE) , SLE tis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue ration and neural regeneration. In addition, other known complement related disease are lung e and disorders such as a, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and ts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, en dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze) , asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, sture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complexassociated inflammation, uveitis (including Behcet's disease and other sub-types of uveitis), ospholipid syndrome.
In a specific ment, the present invention provides methods of treating a complement d disease or disorder by administering to a subject in need thereof an effective amount of the compounds of the invention, wherein said disease or disorder is asthma, arthritis (e.g., rheumatoid arthritis) , autoimmune heart disease, multiple sclerosis, inflammatory bowel e, ia-reperfusion injuries, Barraquer-Simons Syndrome, hemodialysis, systemic lupus, lupus erythematosus, psoriasis, multiple sclerosis, transplantation, diseases of the central nervous system such as mer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome (aH US), glomerulonephritis (including membrane erative ulonephritis) , blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis bullosa), ocular cicatrical pemphigoid or MPGN II.
In a specific embodiment, the present invention provides methods of treating glomerulonephritis by administering to a subject in need thereof an effective amount of a composition comprising a compound of the present invention. Symptoms of glomerulonephritis include, but not limited to, proteinuria; reduced glomerular filtration rate (GFR); serum electrolyte changes including azotemia (uremia, excessive blood urea en- BUN) and salt retention, leading to water retention resulting in hypertension and edema; ria and al urinary sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and lipiduria. In a specific embodiment, the present invention provides methods of treating paroxysmal nocturnal hemoglobinuria (PN H) by administering to a subject in need thereof an effective amount of a composition comprising an compound of the present invention with or without concomitent administration of a complement C5 inhibitor or C5 convertase inhibitor such as Soliris.
In a specific embodiment, the present invention provides methods of reducing the dysfunction of the immune and/or hemostatic systems associated with extracorporeal circulation by stering to a t in need thereof an effective amount of a composition comprising an compound of the present ion. The nds of the present ion can be used in any procedure which involves circulating the patient's blood from a blood vessel of the t, through a conduit, and back to a blood vessel of the patient, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion. Such procedures include, but are not d to, all forms of ECC, as well as procedures involving the introduction of an artificial or n organ, tissue, or vessel into the blood t of a patient.
More particularly, such procedures include, but are not limited to, transplantation procedures including kidney, liver, lung or heart transplant ures and islet cell transplant procedures.
In other embodiments, the nds of the ion are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.
In another embodiment, the compounds of the invention may be used in blood s, diagnostic kits and other equipment used in the collection and sampling of blood.
The use of the compounds of the invention in such stic kits may inhibit the ex vivo activation of the complement pathway associated with blood sampling.
The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ient(s) for a subject of about 50-70 kg, or about 1- 500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, ian or narian of ordinary skill can readily determine the ive amount of each of the active ients necessary to prevent, treat or inhibit the progress of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of ons, e.g., aqueous solutions, and in vivo either enterally, erally, advantageously intravenously, e.g., as a suspension or in s solution. The dosage in vitro may range between about 10 3 molar and 10 9 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
The activity of a compound according to the present invention can be assessed by the ing in vitro & in vivo methods.
The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The compound of the present invention may be administered tely, by the same or ent route of administration, or together in the same pharmaceutical composition as the other agents.
In one embodiment, the invention es a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by alternative complement pathway. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
In one embodiment, the ion provides a pharmaceutical ition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
In one embodiment, the invention provides a kit comprising two or more te pharmaceutical compositions, at least one of which contains a compound of a (I). In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil . An example of such a kit is a blister pack, as lly used for the ing of tablets, capsules and the like.
The kit of the ion may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the ation t to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the ian themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
Accordingly, the ion provides the use of a compound of formula (I) for treating a disease or condition mediated by the complement alternative pathway, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the complement alternative pathway, wherein the medicament is administered with a compound of formula (I).
The invention also provides a compound of a (I) for use in a method of treating a disease or condition mediated by the complement alternative y, wherein the compound of formula (I) is prepared for administration with r therapeutic agent. The invention also provides another eutic agent for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, n the other therapeutic agent is ed for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a e or condition mediated by the complement alternative pathway and/or Factor D, wherein the compound of formula (I) is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein the other therapeutic agent is administered with a compound of formula (I).
The invention also es the use of a compound of formula (I) for treating a disease or condition mediated by the complement alternative pathway and/or Factor D, wherein the patient has previously (e.g. within 24 hours) been treated with another eutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the complement alternative pathway and/or Factor D wherein the patient has previously (e.g. within 24 hours) been treated with a nd of formula (I).
The pharmaceutical compositions can be administered alone or in combination with other molecules known to have a beneficial effect on retinal attachment or damaged retinal tissue, including molecules capable of tissue repair and regeneration and/or inhibiting inflammation. Examples of useful , ors include anti-VEGF agents (such as an antibody or FAB against VEGF, e.g. , Lucentis or Avastin), basic fibroblast growth factor , ciliary neurotrophic factor (CNTF), axokine (a mutein of CNTF) , leukemia inhibitory factor (LI F), neutrotrophin 3 (NT-3), neurotrophin-4 (NT-4) , nerve growth factor (NGF) , insulin-like growth factor II, prostaglandin E2, 30 kD survival factor, taurine, and vitamin A . Other useful ors include symptom-alleviating cofactors, including antiseptics, antibiotics, antiviral and ngal agents and analgesics and anestheticsSuitable agents for combination treatment with the compounds of the invention include agents known in the art that are able to modulate the activities of complement components.
A combination y regimen may be additive, or it may e synergistic results (e.g., reductions in complement pathway activity more than expected for the combined use of the two agents). In some embodiments, the present invention provide a ation y for preventing and/or treating AMD or another complement d ocular e as described above with a compound of the invention and an anti-angiogenic, such as anti-VEGF agent (including Lucentis and Avastin) or photodynamic therapy (such as verteporfin).
In some embodiments, the present invention provide a combination therapy for preventing and/or treating autoimmune e as described above with a compound of the invention and a B-Cell or T-Cell modulating agent (for e cyclosporine or analogs thereof, rapamycin, RAD001 or s thereof, and the like). In particular, for multiple sclerosis therapy may e the combination of a compound of the invention and a second MS agent selected from fingolimod, cladribine, tysarbi, laquinimod, rebif, avonex and the like.
In one embodiment, the invention provides a method of modulating activity of the complement alternative pathway in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound ing to the definition of formula (I). The invention further provides methods of modulating the activity of the complement alternative pathway in a subject by modulating the activity of Factor D, wherein the method comprises administering to the subject a eutically effective amount of the compound according to the definition of Formula (I).
In one embodiment, the invention provides a nd according to the definition of formula (I), (la), (VII) or any subformulae thereof, for use as a medicament.
In one embodiment, the invention provides the use of a compound according to the definition of formula (I), (la), (VII) or any subformulae thereof, for the treatment of a disorder or disease in a subject mediated by complement activation. In particular, the invention provides the use of a compound according to the definition of formula (I), (la), (VII) or any subformulae thereof, for the treatment of a disorder or disease mediated by tion of the complement alternative pathway.
In one embodiment, the ion provides the use of a compound according to the definition of formula (I), (la), in the cture of a medicament for the ent of a disorder or disease in a subject characterized by activation of the complement system. More particularly in the manufacture of a medicament for the treatment of a disease or disorder in a subject characterized by over activiation of the complement ative pathway.
In one embodiment, the invention provides the use of a compound according to the definition of formula (I), (la), or subformulae thereof for the treatment of a disorder or disease in a subject characterized by activation of the complement system. More particularly, the invention provides uses of the compounds provided herein in the treatment of a disease or disorder characterized by over activiation of the complement alternative pathway or the C3 amplification loop of the alternative pathway. In certain embodiments, the use is in the treatment of a disease or disorder is selected from retinal diseases (such as age-related macular degeneration).
The present ion provides use of the compounds of the invention for treating a disease or disorder associated with sed complement activity by administering to a subject in need thereof an effective amount of the compounds of a (I) of the invention.
In certain aspects, uses are provided for the treatment of diseases ated with increased activity of the C3 amplification loop of the complement pathway. In certain ments, uses of treating or ting compelment mediated diseases are provided in which the complement activation is d by antibody-antigen interactions, by a component of an autoimmune disease, or by ischemic .
In a specific embodiment, the present ion provides use of the compounds of the invention for treating or preventing age-related macular degeneration (AMD). In n embodiments, patients who are tly omatic but are at risk of ping a symptomatic macular degeneration related disorder are suitable for administration with a compound of the invention. The use in ng or preventing AMD include, but are not limited to, uses in treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor degeneration, RPE degeneration, l degeneration, chorioretinal degeneration, cone ration, retinal dysfunction, retinal damage in response to light exposure, damage of the Bruch's membrane, and/ or loss of RPE The compound of Formula (I) of the invention can be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic y, to slow and/or prevent progression of phic y, to treat or t macular edema from AMD or other conditions (such as ic retinopathy, uveitis, or post surgical or non-surgical trauma), to t or reduce the loss of vision from AMD, and to improve vision lost due to isting early or ed AMD. It can also be used in combination with anti-VEGF therapies for the treatment of cular AMD patients or for the prevention of neovascular AMD. The present invention further provides methods of treating a complement d e or disorder by administering to a subject in need thereof an effective amount of the compound(s) of the invention, wherein said e or disorder is selected from uveitis, adult macuar degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post operative inflammation, and retinal vein occlusion.
In some embodiments, the present invention provides uses for treating a complement related disease or disorder. Examples of known complement related diseases or disorders include: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or rable complement activation, hemodialysis complications, hyperacute aft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's e, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial tion, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, erative nephritis, liver fibrosis, hemolytic anemia, enia gravis, tissue regeneration and neural regeneration. In addition, other known complement d disease are lung disease and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary sms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), ary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze) , asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complexassociated mation, uveitis (including Behcet's disease and other sub-types of uveitis), antiphospholipid syndrome.
In a specific ment, the present invention es use of the compounds of the invention for treating a complement related disease or disorder, wherein said disease or disorder is asthma, arthritis (e.g., rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel e, ischemia-reperfusion injuries, Barraquer-Simons Syndrome, hemodialysis, systemic lupus, lupus erythematosus, psoriasis, multiple sis, transplantation, diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions, atypicaly hemolytic uremic syndrome (aH US), glomerulonephritis (including ne erative glomerulonephritis) , blistering cutaneous diseases (including bullous pemphigoid, pemphigus, and epidermolysis a), ocular cicatrical pemphigoid or MPGN II.
In a specific embodiment, the t invention provides use of the compounds of the invention for treating glomerulonephritis. Symptoms of glomerulonephritis include, but not limited to, proteinuria; d glomerular filtration rate (GFR); serum electrolyte changes including azotemia a, excessive blood urea nitrogen-BU N) and salt retention, leading to water retention resulting in hypertension and edema; hematuria and abnormal urinary sediments including red cell casts; hypoalbuminemia; hyperlipidemia; and ria. In a specific embodiment, the present invention provides methods of treating paroxysmal nocturnal hemoglobinuria (PN H) by administering to a subject in need thereof an ive amount of a composition comprising an compound of the present ion with or without concomitent administration of a complement C5 inhibitor or C5 convertase inhibitor such as Soliris.
In a ic embodiment, the t invention provides use of the compounds of the invention for reducing the dysfunction of the immune and/or hemostatic systems associated with extracorporeal circulation. The nds of the present invention can be used in any procedure which involves circulating the t's blood from a blood vessel of the patient, through a conduit, and back to a blood vessel of the patient, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, yte activation, or et-leukocyte adhesion. Such procedures include, but are not limited to, all forms of ECC, as well as procedures involving the introduction of an artificial or foreign organ, tissue, or vessel into the blood circuit of a patient.
More particularly, such ures e, but are not limited to, transplantation procedures including kidney, liver, lung or heart lant procedures and islet cell transplant procedures.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centrigrade (°C). If not ned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is med by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be ed by organic synthesis methods known to one of ry skill in the art as shown in the following examples.
Inter Alia the following in vitro tests may be used Human complement factor D assay: Method 1 Recombinant human factor D (expressed in E. coli and purified using standard methods) at 10 nM concentration is incubated with test compound at various concentrations for 1 hour at room ature in 0.1 M Hepes , pH 7.5, containing 1 mM MgCI , 1 M NaCI and 0.05 % CHAPS. A synthetic substrate Z-Lys-thiobenzyl and 2,4-dinitrobenzenesulfonyl-fluoresceine are added to final concentrations of 200 mM and 25 mM, respectively. The increase in fluorescence is recorded at excitation of 485 nm and emission at 535 nm in a microplate spectrofluorimeter. IC values are ated from tage of tion of complement factor D-activity as a function of test nd concentration.
Human complement factor D assay: Method 2 Recombinant human factor D (expressed in E. coli and purified using standard methods) at a nM concentration is incubated with test compound at various concentrations for 1 hour at room temperature in 0.1 M PBS pH 7.4 containing 7.5 mM MgCI and 0.075% (w/v) CHAPS.
Cobra venom factor and human complement factor B substrate complex is added to a final concentration of 200 nM. After 1 hour incubation at room temperature, the enzyme reaction was stopped by addition of 0.1 M sodium carbonate buffer pH 9.0 containing 0.15 M NaCI and 40 mM EDTA. The t of the reaction, Ba, was quantified by means of an enzyme-linked- immunosorbent assay. IC50 values are calculated from percentage of inhibition of factor D- activity as a function of test compound concentration.
The following Examples, while representing preferred embodiments of the invention, serve to illustrate the invention without limiting its scope.
Abbreviations: abs. Absolute Ac acetyl EtOAc ethyl acetate AcOH acetic acid aq aqueous cc concentrated c-hexane cyclohexane CSA Camphor sulfonic acid DIPEA isopropylethylamine DBU azabicyclo[5.4.0]undecene DCC icyclohexylcarbodiimide DIBALH diisobutylaluminium hydride DMF dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride Ether diethylether Et^N triethylamine Et20 diethylether EtOH ethanol Flow flow rate h hour(s) HMPA hexamethylphosphoroamide HOBt 1-hydroxybenzotriazole HBTU 2-(1H-benzotriazolyl)-1 -tetramethyluronium tetrafluoroborate HPLC High Performance Liquid Chromatography iPrOH isopropanol L liter(s) KHMDS potassium hexamethyldisilazane LC-MS Liquid tography/Mass Spectrometry LDA lithium diisopropylamine Me methyl Mel methyl iodide MeOH methanol MesCI Mesyl Chloride min (s) ml_ milliliter MS Mass Spectrometry NBS N-Bromo succinimide NMM 4-methylmorpholine NMR Nuclear Magnetic Resonance Pd/C palladium on charcoal Ph phenyl PyBOP (benzotriazol-l-yloxy)-tripyrrolidinophosphonium- Hexafluorophosphate SEM-CI 2-(Trimethylsilyl)ethoxymethyl de RT room temperature TBAF tetra-butylammonium fluoride TBDMS-CI tert-butyldimethylsilyl chloride TBDMS tert-butyldimethylsilyl TBME tert-Butylmethylether TEA triethylamine TMEDA tetramethylethylenediamine TEMPO 2,2,6,6,-tetramethylpiperidinyloxy free radical TFA trifluoroacetic acid THF tetrahydrofurane T P Propylphosphonic anhydride RP e phase Prep Preparative TLC Thin Layer tography t retention time Trademarks Celite = Celite (The Celite Corporation) = filtering aid based on aceous earth NH Isolute (= Isolute® NH , Isolute® is registered for Argonaut Techno 2 2 logies, Inc.) = ion exchange with amino groups based on silica gel Nucleosil = sil® , trademark of Machery & Nagel, Duren, FRG for HPLC materials PTFE membrane = Chromafil 0-45/1 5MS Polytetrafluoroethylene Machereynagel) PL Thiol Cartridge = Stratosphere ® SPE, PL-Thiol MP SPE+, 500mg per 6 ml_ tube, 1.5 mmol (nominal) Temperatures are measured in degrees Celsius. Unless otherwise indicated, the ons take place at RT.
Phase tor : Biotage - Isolute Phase separator (Part Nr: 120F for 70 ml_ and Part Nr: 120J for 150 ml_) TLC conditions: R values for TLC are measured on 5 x 10 cm TLC plates, silica gel f F254, Merck, Darmstadt, Germany.
HPLC ions: HPLC were performed using an Agilent 1100 or 1200 series instrument. Mass spectra and LC/MS were determined using an Agilent 1100 series instrument. a : Waters Symmetry C18, 3.5um, 2.1x50mm, 20-95% CH CN/H 0/3.5 min, 95% CH CN/2 3 2 3 min, CH CN and H 0 containing 0.1% TFA, flow: 0.6 mL/min 3 2 b : Agilent Eclipse XDB-C18; 1,8um; 4.6x50mm 20-100% CH CN/H 0/6min, 3 2 100%CH CN/1 .5min, CH CN and H 0 containing 0.1% of TFA, flow : 1 mL/min 3 3 2 c . t e XDB-C18, 1.8um, 4.6x50mm, 5-100% CH CN/H 0/6 min, 100% CH CN/1 .5 3 2 3 min, CH CN and H 0 containing 0.1% TFA, flow: 1 mL/min 3 2 d . Waters XBridge C18, 2.5um, 3x30mm, 10-95% CH CN/H 0/1 .7 min/flow: 1.4 mL/min, 95% 3 2 CH CN/flow: 0.7 min/1 .6 mL/min, CH CN containing 0.05% TFA, H 0 containing 0.05% TFA 3 3 2 and 5% CH CN e . Waters XBridge C18, 2.5um, 3x30mm, 1% CH CN/H O/0.5 min/flow: 1.4 mL/min, 1-95% 3 2 CH CN/H 0/1.7 min/flow: 1.4 mL/min, 95% CH CN/flow: 0.7 min/1.6 mL/min, CH CN 3 2 3 3 containing 0.05% TFA, H 0 containing 0.05% TFA and 5% CH CN 2 3 f . Waters Sunfire C18, 2.5um, 3x30mm, 10-98% in 2.5 min, CH CN and H 0 containing 0.1% 3 2 TFA, flow: 1.4 mL/min g . Waters Sunfire C18, 2.5um, 3x30mm, 0-10% in 0.5 min, 10-98% in 2.5 min, CH CN and H 0 containing 0.1% TFA, flow: 1.4 mL/min h . Waters e C18, 2.5um, 3x30mm, 10-98% in 4.5 min, CH CN and H 0 containing 0.1% 3 2 TFA, flow: 1.4 mL/min i . Waters Sunfire C18, 5um, 21x50mm, 20-95% CH CN/H 0/3.5 min, 95% CH CN/2 min, 3 2 3 CH CN and H 0 containing 0.1% HCOOH, flow: 0.6 mL/min 3 2 j . Waters Atlantis; 2.1x30mm, 20-95% CH CN/H 0/2.5 min, 95% CH CN/H O/0.05 min, 20 3 2 3 2 % CH CN/H O/0.45 min CH CN and H 0 containing 0.1% of HCOOH, flow: 0.6 mL/min 3 2 3 2 k . Agilent Eclipse XDB-C18; 1,8um; mm 5-100% CH CN/H 0/3 min, 100% CH CN/0.75 3 2 3 min, CH CN and H 0 containing 0.1% of TFA, flow : 0.6 mL/min 3 2 I . Agilent Eclipse XDB-C18; 1,8um; 2.1x30mm 20-100% CH CN/H 0/3min, 100%CH CN/0.75 3 2 3 min, CH CN and H 0 containing 0.1% of TFA, flow : 0.6 mL/min 3 2 UPLC conditions: m . UPLC/MS: Waters Acquity; UPLC column: Waters Acquility HSS T3; 1,8um; 2.1x50mm 10- 95% CH CN/H 0/1 .5 min, H 0 ning 0.05% HCOOH and CH CN containing 0.04% 3 2 2 3 HCOOH + 3.75 mM NH OAc, flow 1.2 mL/min The asterisk (*) ted in the name of a compound designate a racemic mixture.
Part A : Synthesis of substituted ic or romatic building blocks: Scheme A 1: general protocol for the preparation of various isocyanate ng blocks 3-isocvanato-indolecarboxylic acid amide A. 1H-lndolecarboxylic acid benzyl ester To a solution of 1H-indolecarboxylic acid (5 g , 3 1 mmol) in DMF (70 mL) under nitrogen atmosphere at 0°C was added cesium carbonate ( 1 1 g , 3 1 mmol) and benzyl bromide (4.05 mL, 34.1 mmol). The reaction mixture was stirred at RT for 48 h and poured into water. EtOAc was added and the layers were separated, the aqueous one being back extracted three times with EtOAc. The combined organic layers were washed with water, dried over Na S0 , filtered and concentrated. The residue was taken up in Et 0 and the resulting precipitate was filtered- off to give the title compound. TLC, R (c-hexane/EtOAc 1:1) = 0.55; MS (LC-MS): 252.1 [M+H]+, 274.0 [M+Na]+, 525.1 ]+, 250.1 [M-H]-; t (HPLC conditions a) 3.77 min.
B. 1-Carbamoyl-1H-indolecarboxylic acid benzyl ester To a solution of 1H-indolecarboxylic acid benzyl ester (3.5 g , 13.9 mmol) in THF (70 mL) at °C, was added NaH (60 % in l oil, 557 mg, 13.9 mmol). The mixture was stirred at 5°C for 30 min before slow dropwise addition of chlorosulfonyl isocyanate (2.42 mL, 27.9 mmol) maintaining the temperature between 5°C and 10°C. The pale yellow solution was further stirred at RT for 3.5 h . Acetic acid (22.5 mL) was added (exothermic), and the ing solution was stirred at RT for 1.5 h before addition of ice cubes and water (100 mL). The white thick suspension was d at RT for 30 min and the precipitate was filtered-off, taken up in MeOH and ed-off again to afford the desired compound. 1H-NMR (400 MHz, DMSO): d (ppm) 8.64 (s, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.90 (m, 2H), 7.50 (d, 2H), 7.42 (t, 2H), 7.36- 7.30 (m, 3H), 5.38 (s, 2H).
C. 1-carbamoyl-1H-indolecarboxylic acid 1-Carbamoyl-1H-indolecarboxylic acid benzyl ester ( 1 .33 g , 4.52 mmol) was dissolved in a mixture of DMF/THF 1:1 (28 mL), Pd/C (10 % , 250 mg) was added and the solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere overnight and the catalyst was removed through a pad of Celite and washed with THF. The solvents were concentrated under high vacuum to give a yellowish solid which was taken up in Et 0 and filtered-off to afford the title compound. 1H-NMR (400 MHz, DMSO): d (ppm) 12.6 (m, 1H), 8.54 (bs, 1H), 8.28 (d, 1H), 8.05 (d, 1H), 7.85 (m, 2H), 7.34-7.27 (m, 2H).
D. 3-isocyanato-indolecarboxylic acid amide To a suspension of 1-carbamoyl-1 H-indolecarboxylic acid ( 1 .31 g , 6.42 mmol) in toluene (30 mL, CH2CI2 can also be used d of toluene) under nitrogen was added Et N (893 m I, 6.42 mmol). After 15 min DPPA (1.54 mL, 6.42 mmol) was added and the reaction mixture was further stirred at RT ght. Toluene was concentrated, the e was taken up in CH C I 2 2 and the precipitate was filtered-off to give the acyl azide intermediate (565 mg). Toluene (20 mL) was added and the suspension refluxed for 1.5 h under nitrogen atmosphere until no more acyl azide could be detected by TLC. Toluene was concentrated under vacuum and the desired isocyanate was ly used in the next step without further purification. 1H-NMR (400 MHz, CDCI3): d (ppm) 8.18 (d, 1H), 7.61 (d, 1H), 7.44 (t, 1H), 7.35 (t, 1H), 7.23 (s, 1H), 5.39 (bs, 2H). 3-lsocvanatomethoxy-indolecarboxylic acid amide was prepared from 6-methoxy-indolecarboxylic acid using the protocol described for the ation of 3-isocyanato-indolecarboxylic acid amide scheme A1. 1-(3-lsocyanato-indol-1 -yl)-ethanone A. 1-Acetyl-1H-indolecarboxylic acid benzyl ester To a on of olecarboxylic acid benzyl ester (600 mg, 2.39 mmol) in THF (10 mL) at 0°C under nitrogen was added NaH (60 % in mineral oil, 191 mg, 4.78 mmol). The mixture was stirred for 20 min at 0°C, acetyl chloride (339 m I, 4.78 mmol) was added and the resulting suspension was stirred at RT for 48 h . The solvent was concentrated and the residue poured in water and extracted twice with CH C I . The Combined organic layers were dried over 2 2 Na S0 , filtered and trated. The crude residue was purified by flash column 2 4 chromatography on silica gel (c-hexane to c-hexane/EtOAc 75:25) to give the desired product as a white solid. TLC, R (c-hexane/EtOAc 3:1) = 0.38; MS (LC-MS): 294.1 [M+H]+, 316.0 [M+Na]+; t (HPLC conditions a): 4.69 min.
B. 1-Acetyl-1H-indolecarboxylic acid 1-Acetyl-1H-indolecarboxylic acid benzyl ester (300 mg, 1.02 mmol) was dissolved in MeOH (10 mL), Pd/C 10 % (60 mg) was added and the solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere 2 h and the catalyst was removed h a pad of Celite and washed with MeOH. The solvent was concentrated under vacuum to give a mixture of 1-acetyl-1 H- indolecarboxylic acid and 1-acetyl-2,3-dihydro-1H-indolecarboxylic acid benzyl ester in a ~ 7:3 ratio as measured by NMR. The desired compound was not purified at this stage but was used directly in the next step. 1-Acetyl-1H-indolecarboxylic acid: TLC, R (CH C I /MeOH 9:1) = 0.31 ; MS (LC-MS): 204.1 [M+H]+, 202.1 [M-H]-; t (HPLC conditions a): 2 2 R 3.14 min. 1-Acetyl-2,3-dihydro-1H-indolecarboxylic acid benzyl ester: MS (LC-MS): 206.1 [M+H]+, 228.1 [M+Na]+, 433.0 [2M+Na]+, 204.1 [M-H]-; t (HPLC conditions a): 1.93 min.
C. socyanato-indol-1 -yl)-ethanone To a suspension of of 1-acetyl-1 H-indolecarboxylic acid (containing ca 30 % of 1-acetyl-2,3- dihydro-1H-indolecarboxylic acid benzyl ester, 194 mg) in toluene (5 mL) was added Et N (130 m I, 0.935 mmol) and the resulting on was d at RT under nitrogen for 15 min.
DDPA (225 m I, 0.935 mmol) was added and the reaction mixture was further stirred at RT overnight. Toluene was trated under vacuum and the residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give the desired acyl azide intermediate as a white powder (96 mg; t HPLC conditions a : 3.86 min). Toluene (3 ml_) was added and the mixture was refluxed for 1.5 h until completion of the reaction. e was concentrated under vacuum to give the d isocyanate. TLC, R (c-hexane/EtOAc 1:2) = 0.58; t (HPLC conditions a): 3.92 min. 1H-NMR (400 MHz, CDCI ) : d (ppm): 8.44 (m, 1H), R 3 7.56 (d, 1H), 7.44 (t, 1H), 7.36 (t, 1H), 7.23 (d, 1H), 2.60 (s, 3H).
Scheme A2: reparation of 3-lsocvanato-indolecarboxylic acid methylamide A. lndole-1,3-dicarboxylic acid 3-benzyl ester 1-(4-nitro-phenyl) ester To a solution of 1H-indolecarboxylic acid benzyl ester (100 mg, 0.398 mmol) in dry THF (2 mL) at 0°C under nitrogen was added NaH (60 % in l oil, 32 mg, 0.796 mmol). The resulting solution was d at 0°C for 10 min, and added dropwise to a stirred solution of 4- nitrophenyl chloroformate (160 mg, 0.796 mmol) in dry THF (2 mL) cooled at 0°C. The resulting solution was stirred at RT under nitrogen for 48 h . The mixture was poured into water and extracted twice with CH C I . The combined organic layers were dried over Na S0 , filtered 2 2 2 4 and concentrated. The crude residue was successively purified by flash column tography on silica gel (c-hexane to c-hexane/EtOAc 7:3) and by preparative HPLC (Waters e C18-ODB, 5 m , 19x50 mm, 20% CH CN/H 0 2.5 min, 20-100% 3 2 CH CN/H 0 in 10 min, CH CN/H 0 containing 0.1 % HCOOH flow: 20 mL/min) to give after 3 2 3 2 tion of the pure fractions the desired compound. TLC, R (c-hexane/EtOAc 1:1) = 0.8; MS ): 439.0 [M+Na]+; t (HPLC conditions a): 4.58 min.
B. 1-Methylcarbamoyl-1H-indolecarboxylic acid benzyl ester To a solution of indole-1 ,3-dicarboxylic acid 3-benzyl ester 1-(4-nitro-phenyl) ester (45 mg, 0.108 mmol) in dry THF ( 1 mL) was added methylamine (2 M in THF, 270 m I, 0.54 mmol) and the reaction was stirred at RT for 15 min. The mixture was concentrated and the residue was taken up in Et 0 and filtered to give the desired compound. TLC, R (c-hexane/EtOAc 1:1) = 2 f 0.52; MS (LC/MS): 309.1 [M+H]+, 331.1 [M+Na]+, 639.2 [2M+Na]+, 353.2 [M+HCOO]-; t (HPLC conditions a): 3.86 min.
C. 1-Methylcarbamoyl-1H-indolecarboxylic acid To 1-Methylcarbamoyl-1 H-indolecarboxylic acid benzyl ester ( 115 mg, 0.373 mmol) dissolved in a mixture of MeOH/CH C I 1-1 (4 mL), Pd/C 10 % (20 mg) was added and the 2 2 solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The on mixture was further stirred under hydrogen atmosphere for 1 h . The mixture was placed under a en atmosphere and the st was removed h a pad of Celite and washed with MeOH. Solvents were concentrated under vacuum to give the desired compound.
MS (LC/MS): 219.1 [M+H]+; t (HPLC conditions a): 2.54 min.
D. 3-lsocyanato-indolecarboxylic acid amide A solution of 1-methylcarbamoyl-1H-indolecarboxylic acid (80 mg, 0.367 mmol) and Et N (51 m I, 0.367 mmol) in a mixture of e/THF 1/1 (4 mL) was stirred at RT under nitrogen for 30 min. DPPA (90 % , 88 m I, 0.367 mmol) was added and the reaction mixture was further stirred at RT under nitrogen overnight. Solvents were concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1-1) to give the acyl azide intermediate as white cristals (83 mg, t (HPLC ions a): 3.40 min).
The acyl azide intermediate was refluxed in toluene (2 mL) for 1 h to give after concentration of the solvent the desired isocyanate. The compound was used ly in the next step without r purification.
Scheme A3: preparation of 6-ethylisocvanato-indolecarboxylic acid amide A. 6-Vinyl-1 H-indolecarbaldehyde 6-bromoindolecarboxaldehyde (5 g , 22.3 mmol), potassium vinyltrifluoroborate (4.48 g , 33.5 mmol), PdCI (396 mg, 2.23 mmol), PPh (1.75 mg, 6.7 mmol) and Cs C0 (2.18 mg, 66.9 2 3 2 3 mmol) were combined in a 500 mL flask placed under a nitrogen atmosphere. THF (135 mL) and H 0 (15 mL) were added and the yellow solution was heated at 85°C for 2 days. The reaction was allowed to cool to RT, water was added and the mixture was extracted twice with CH C I . The combined organic layers were dried over Na S0 , filtered and concentrated. The 2 2 2 4 crude residue was purified by flash column chromatography on silica gel (c-hexane to c- hexane/EtOAc 1:1) to give the title compound. TLC, R (c-hexane/EtOAc 1:1) = 0.4; MS (LC/MS) : 172.0 [M+H]+ 170.1 [M-H]-; t (HPLC conditions a): 2.95 min.
B. 6-Ethyl-1 H-indolecarbaldehyde 6-Vinyl-1 lecarbaldehyde ( 1 .5 g , 8.76 mmol) was dissolved in THF (45 mL), Pd/C 10% (300 mg) was added and the solution was degassed 3 times replacing air by nitrogen and finally en by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere 4 h and the catalyst was removed through a pad of Celite and washed with THF.
The solvent was concentrated under and the crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give the d compound.
TLC, R (c-hexane/EtOAc 1:1) = 0.40; MS (LC/MS): 174.1 [M+H]+, 196.1 [M+Na]+, 172.1 [M- H]-; t (HPLC ions a): 3.05 min.
C. 6-Ethylformyl-indolecarboxylic acid amide To a on of NaH (60 % in mineral oil, 259 mg, 6.47 mmol) in THF (10 mL) cooled to 5°C under nitrogen a solution of 6-ethyl-1 H-indolecarbaldehyde ( 1 .12 g , 6.47 mmol) in THF (20 mL) was slowly added and the mixture was stired at 5°C for 30 min. While maintaining the internal temperature between 5°C and 10°C, chlorosulfonyl isocyanate ( 1 .12 mL, 12.9 mmol) was added dropwise and the solution was further stirred at RT overnight. Acetic acid (15 mL) was added (slightly exothermic) and the solution was stirred at RT for 1.5 h . Ice cubes and water (25 mL) were added, and the solution was r stirred at RT for 30 min. Water was added and the mixture was extracted with EtOAc. The aqueous layer was back-extracted twice with EtOAc. The combined organic layers were dried (Na S0 ) , filtered and concentrated. The 2 4 crude residue was ed by flash column chromatography on silica gel (c-hexane to EtOAc) to give the desired compound. LC/MS: 290.0 [M+H]+, 312.0 [M+Na]+; t (HPLC conditions a): 3.02 min.
D. amoylethyl-1H-indolecarboxylic acid 6-Ethylformyl-indolecarboxylic acid amide (720 mg, 3.33 mmol) was dissolved in a mixture of THF (60 mL) and t-butanol (18 mL). 2-methylbutene (2 M solution in THF, 66.6 mL, 133 mmol) was added, followed by a water (16 mL) solution of NaCI0 (80 % , 3.76 g , 33.3 mmol) and NaH P0 (3.20 g , 26.6 mmol). The resulting solution was stirred at RT for 4 h and 2 4 THF was trated. EtOAc was added and the layers separated. The aqueous layer was acidified by addition of HCI 1N and extracted twice with EtOAc. The ed organic extracts were dried (Na S0 ) , filtered and concentrated. The crude e was purified by flash column chromatography on silica gel (eluent: c-hexane to EtOAc to CH C I /MeOH 8:2) to give 2 2 the desired compound. t (HPLC conditions a): 2.17 min. 1H-NMR (400 MHz, CDCI ) : d (ppm): R 3 12.9 (m, 1H), 8.81 (s, 1H), 8.66 (bs, 1H), 8.23 (d, 1H), ) , 8.09 (m, 2H), 7.70 (dd, 1H).
E. 6-Ethylisocyanato-indolecarboxylic acid amide To a solution of 1-carbamoylethyl-1H-indolecarboxylic acid (330 mg, 1.42 mmol) in toluene (8 mL) was added triethylamine (0.198 mL, 1.42 mmol) and the resulting suspension was stirred at RT under nitrogen for 15 min. DPPA (0.34 mL, 1.42 mmol) was added and the reaction mixture was further stirred at RT for 3 h . TLC indicated completion of the on. The mixture was concentrated, CH2C I2 was added and the sion was filtered to give the acyl azide intermediate. Toluene (4 mL) was added and the reaction mixture was refluxed for 3 h .
The crude compound was directly used in the next step.
Scheme A4: general protocol described for the preparation of 5-allyloxyisocyanatoindolecarboxylic acid amide A. 5-Allyloxy-1H-indole To a suspension of 5-hydroxyindole (1.23 g , 9.24 mmol) and cesium carbonate (3.01 g , 9.24 mmol) in DMF (40 mL) under nitrogen atmosphere at 0°C was added allylbromide (879 m I, .16 mmol). The reaction e was stirred at RT for 2 h and poured into water and extracted with EtOAc (x3). The combined organic layers were washed twice with water, dried over Na2S0 4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 9:1) to give the desired compound.
TLC, Rf (c-hexane/EtOAc 1:1) = 0.76; tR tions a): 3.46 min.
B. 5-Allyloxy-1 H-indolecarbaldehyde To a solution of oxalyl chloride (1.22 mL, 14.1 mmol) in dry CH2C I2 (20 mL) was added at 0°C under nitrogen a solution of dry DMF ( 1 .3 mL) in dry CH2C I2 (20 mL). The mixture was stirred at 0°C for 30 min and a solution of 5-allyloxy-1H-indole (1.25 g , 7.22 mmol) in CH2C I2 (10 mL) was added. The resulting solution was allowed to reach RT and stirred for 4 h . The solvent was trated and the residue dissolved in THF (35 mL) and 20% aqueous ammonium acetate (48 mL) and heated at reflux for 30 min, cooled, treated with an aqueous saturated solution of NaHC0 3, and ted twice with EtOAc. The combined organic layers were dried over Na2S0 , filtered and concentrated. The crude solid was taken up in CH2C I2 and filtered-off to give the d compound. TLC, Rf (c-hexane/EtOAc 1:2) = 0.56; MS (LC/MS): 202.0 [M+H]+, 224.1 [M+Na]+, 200.1 [M-H]-, 159.1 [M-H-allyl]-; tR (HPLC conditions a): 2.89 min.
C. 5-Allyloxyformyl-indolecarboxylic acid amide To a suspension of NaH (60 % in mineral oil, 352 mg, 8.79 mmol) in THF (12 mL) under nitrogen atmosphere at 5°C was added a solution of loxy-1 H-indolecarbaldehyde (1.18 g , 5.86 mmol) in THF (28 mL) and the ing mixture was stirred at 5°C for 30 min before slow addition of chlorosulfonyl isocyanate ( 11.02 mL, 11.7 mmol) while maintaining the temperature between 5°C and 10°C. The solution was r stirred at RT for 4 h , acetic acid ( 1 1 mL) was added and the solution was stirred at RT for 1 h . Ice cubes and water (100 mL) were added and the mixture was stirred at RT for 30 min. The solution was extracted twice with EtOAc and the combined organic extracts were dried over Na S0 , ed and 2 4 concentrated. The crude residue was ed by flash column chromatography on silica gel (100% c-hexane to 100% EtOAc) to give the title compound. TLC, R (c-hexane/EtOAc 1:2) = 0.36; MS (LC/MS): 245.1 [M+H]+, 267.0 [M+Na]+, 200.1 [M-CONH ]-; t (HPLC conditions a): 2 R 2.95 min.
D. 5-Allyloxycarbamoyl-1H-indolecarboxylic acid -Allyloxyformyl-indolecarboxylic acid amide (530 mg, 2.17 mmol) was dissolved in a mixture of THF (38 mL) and t-butanol (12 mL). 2-methylbutene 2 M solution in THF (40 mL, 80 mmol) was added, followed by a water (9.5 mL) solution of NaCI0 (80 % , 2.45 g , 21.7 mmol) and NaH P0 (2.08 g , 17.4 mmol). The resulting solution was stirred at RT for 1 h , until consumption of the starting material. HCI 1N (3 mL) was added, and the organic solvents were concentrated. The remaining aqueous layer was filtered and the resulting itate was washed with water and Et 0 to give the desired compound. TLC, R ane/EtOAc 1:2) = 2 f 0.08; LC/MS: 261.1 [M+H]+, 259.0 [M-H]-, 216.1 [M-CONH ]-, 519.1 -; t (HPLC 2 R ions a): 2.8 min.
E. 5-Allyloxyisocyanato-indolecarboxylic acid amide To a suspension of 5-allyloxycarbamoyl-1H-indolecarboxylic acid (500 mg, 1.92 mmol) in THF (10 mL) was added Et N (267 m I, 1.92 mmol) and the resulting solution was stirred at RT under nitrogen for 15 min. DDPA (462 m I, 1.92 mmol) was added and the on was further stirred at RT under nitrogen for 1 h . TLC indicated consumption of the starting material. THF was concentrated and the residue was taken up in CH C I and filtered-off to give the crude acyl 2 2 azide intermediate (TLC, R (c-hexane/EtOAc 1:2) = 0.65; t (HPLC conditions a): 3.50 min). f R The acyl azide intermediate was suspended in toluene (7 mL) and refluxed under nitrogen for 2 h until completion of the reaction. The crude isocyanate was used as was in the next step. 6-Allyloxyisocvanato-indolecarboxylic acid amide was prepared from 6-hydroxy-indole using the protocol described for the preparation of 5- allyloxyisocyanato-indolecarboxylic acid amide in Scheme A4. ylisocvanato-indolecarboxylic acid amide was prepared from 6-methyl-1 H-indolecarbaldehyde using the ol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. 6-Bromoisocvanato-indolecarboxylic acid amide was prepared from 6-bromo-1H-indolecarbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. 6-Chloroisocvanato-indolecarboxylic acid amide was prepared from 6-chloroindole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. 6-Trifluoromethylisocvanato-indolecarboxylic acid amide was ed from 6-trifluoromethylindole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide except that the acyl azide intermediate was prepared in 1,2 dimethoxyethane instead of toluene.
-Fluoroisocvanato-indolecarboxylic acid amide was prepared from 5-fluoro-1H-indolecarbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. 6-Fluoroisocvanato-indolecarboxylic acid amide was prepared from 6-fluoro-1H-indolecarbaldehyde [27957] using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxyisocyanatoindolecarboxylic acid amide. 3-lsocvanatomethoxy-indolecarboxylic acid amide was prepared from 5-methoxy-1H-indolecarbaldehyde using the protocol bed for steps C, D and E in scheme A4 for the preparation of 5-allyloxyisocyanato-indole carboxylic acid amide. 6-Benzyloxyisocvanato-indolecarboxylic acid amide was ed from 6-benzyloxyindole using the protocol described for steps B-E in scheme A4 for the ation of 5-allyloxyisocyanato-indolecarboxylic acid amide. 6-Difluoromethoxyisocvanato-indolecarboxylic acid amide was prepared from 6-difluoromethoxy-1H-indole 72] using the protocol described for steps B-E in Scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. 6-Difluoromethoxyisocyanato-1H-indole To a suspension of 1-carbamoyldifluoromethoxy-1H-indolecarboxylic acid (180 mg, 0.66 mmol) in THF (6 ml_) was added Et^N ( 1 11 m I, 0.8 mmol) and the resulting solution was stirred at RT under nitrogen for 10 min. DDPA (220 m I, 0.8 mmol) was added and the reaction was further stirred at RT under nitrogen for 3 h . TLC indicated consumption of the starting material.
The reaction mixture was concentrated and the crude residue was ed by flash column chromatography on silica gel (c-hexane/EtOAc 4:1 to 1:1) to give 6-difluoromethoxy-1 H-indole- 3-carbonyl azide (MS: 251 [M-H]-; tR (HPLC conditions k): 3.57 min) and 1-carbamoyl difluoromethoxy-1H-indolecarbonyl azide (MS: 251 H 2]-; 268 [M-N2]+; tR (HPLC conditions k): 3.46 min). uoromethoxy-1 H-indolecarbonyl azide intermediate was suspended in toluene (6 ml_) and refluxed under nitrogen for 3 h until completion of the reaction. The crude isocyanate was used as was in the next step. 1-Carbamoyldifluoromethoxy-1H-indolecarboxylic acid was prepared from 6-difluoromethoxy-1H-indole [2002072] using the protocol described for steps B-D in Scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. 3-lsocyanato(2-methoxy-ethoxy)-indole-1 -carboxylic acid amide was prepared from 5-(2-methoxy-ethoxy)-1H-indole using the protocol described for steps B-E in scheme A4 for the preparation of loxyisocyanato-indolecarboxylic acid amide. ethoxy-ethoxy)-1 H-indole -hydroxyindole (5 g , 15 mmol) was dissolved in acetone (75 ml_), cesium carbonate (5.38 g , 16.5 mmol) and 2-bromoethyl methyl ether ( 1 .55 ml_, 16.5 mmol) were added and the reaction mixture was stirred at reflux under nitrogen overnight. Acetone was concentrated. The residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and concentrated. The crude e was purified by flash column 2 4 chromatography on silica gel (c-hexane to ne/EtOAc 7/3) to give the desired material.
TLC, R (c-hexane/EtOAc 1:1) = 0.6; MS (LC-MS): 192.1 [M+H]+, 214.0 [M+Na]+, 405.1 [2M+Na]+; tR (HPLC conditions f): 1.56 min. (1-Carbamoylisocyanato-1H-indolyloxy)-acetic acid methyl ester was prepared from (1H-indolyloxy)-acetic acid methyl ester using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. (1H-lndolyloxy)-acetic acid methyl ester A solution of oxyindole (5.07 g , 38.1 mmol) and cesium carbonate (12.4 g , 38.1 mmol) in acetone (150 ml_) was cooled to 0°C and methyl bromoacetate (3.96 ml_, 4 1.9 mmol) was added. The reaction e was then stirred at RT under nitrogen for 2 h . The reaction mixture was concentrated. The residue was diluted with water and extracted twice with CH C I . 2 2 The combined organic layers were dried over Na S0 , filtered and concentrated. The resulting solid was taken up in Et 0 and filtered-off to the d material. TLC, R (c-hexane/EtOAc 2 f 1:1) = 0.55; MS (LC-MS): 206.1 [M+H]+, 433.0 [2M+Na]+; t (HPLC conditions ) : 1.64 min. (1-Carbamoylisocvanato-1H-indolyloxy)-acetic acid methyl ester was prepared from dolyloxy)-acetic acid methyl ester using the ol described for the preparation of (1-carbamoylisocyanato-1 H-indolyloxy)-acetic acid methyl ester. (1-Carbamoylisocyanato-1H-indolyl)-acetic acid ethyl ester was prepared from ( 1 H-indolyl)-acetic acid ethyl ester using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. (1H-lndolyl)-acetic acid ethyl ester To a solution of 6-ethoxycarbonylmethyl-indolecarboxylic acid methyl ester (965 mg, 3.25 mmol) in EtOH (10 mL) was added dimethylamine (-5.6 M in EtOH, 24.4 mL, 48.8 mmol) and the solution was stirred at RT overnight. EtOH was concentrated and the crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 85:15) to give the desired material. MS (UPLC): 204.2 [M+H]+, 221.2 [M+NH4]+, 248.2 O]-; t (HPLC conditions f): 1.87 min. xycarbonylmethyl-indolecarboxylic acid methyl ester A mixture of 6-bromo-indolecarboxylic acid methyl ester (1.12 g , 4.43 mmol), ethyl cetate (1.23 mL, 9.74 mmol), palladium acetate (20 mg, 0.089 mmol), 2-di-tertbutylphosphino-2'-methylbiphenyl (55 mg, 0.177 mmol) and K P0 (2.58 g , 12.2 mmol) in 3 4 toluene (6 mL) was heated at 100°C under nitrogen overnight. The reaction was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and concentrated. The crude material was ed by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 93:7) to give the desired material. TLC, R (c- hexane/EtOAc 4:1) = 0.3; MS (UPLC): 262.2 [M+H]+, 279.2 [M+NH ]+, 284.2 +, 523.3 [M+Na]+, 545.3 [2M+Na]+; t (HPLC conditions f): 2.1 1 min. 6-Bromo-indolecarboxylic acid methyl ester To a solution of 6-bromoindole ( 1 .46 g , 7.44 mmol) in DMF (35 mL) under en atmosphere, was added NaH (60 % in mineral oil, 327 mg, 8.19 mmol), followed by methyl chloroformate (652 m , 8.19 mmol) and the resulting on was sitrred at RT overnight. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed again with water, dried over Na S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c- hexane/EtOAc 88:12) to give the desired material. TLC, R ) = 0.75; MS (UPLC): 254.2/255.2 [M+H]+; t (HPLC conditions ) : 2.32 min. (1-Carbamoylisocyanato-1H-indolyl)-acetic acid ethyl ester was prepared from oindole as described for the synthesis of (1-carbamoyl isocyanato-1 H-indolyl)-acetic acid ethyl ester. (1-Carbamoylisocyanato-1H-indolyl)-acetic acid utyl ester was prepared from (1H-indolyl)-acetic acid tert-butyl ester using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide. (1H-lndolyl)-acetic acid tert-butyl ester To a solution of 6-bromoindole (2 g , 10.2 mmol) in THF (20 mL) under nitrogen atmosphere was added KH (30 % in mineral oil de-greased with pentane, 1.5 g , 11.22 mmol) and the mixture was stirred at RT for 30 min before addition of [P(t-Bu) PdBr] (40 mg, 0.051 mmol) 3 2 diluted in THF (20 mL). The resulting mixture was added to a solution of 2-tert-butoxy oxoethylzinc chloride (0.5 M in Et 0 , 22.4 mL, 11.2 mmol) stirred under nitrogen atmosphere and the e was further stirred at RT for 24 h . The reaction e was diluted with EtOAc, and washed with a saturated aqueous solution of NaHC0 , then with water. The organic layer was dried over Na S0 , filtered and concentrated. The crude residue was purified 2 4 by flash column chromatography on silica gel (c-hexane to ne/EtOAc 94:6 to c- hexane/EtOAc 8:2) to give the desired material. TLC, R (c-hexane/EtOAc 4:1) = 0.3; MS (UPLC): 232.2 [M+H]+, 176.1 [MH-tBu]+, 249.2 [M+NH ]+, 463.4 [2M+H]+, 273.3 O]-. 3-lsocyanato-1H-indolecarbonitrile To a on of 1-carbamoylcyano-1H-indolecarboxylic acid (210 mg, 0.916 mmol) in toluene (6 mL) was added Et N (128 m I, 0.916 mmol) and the resulting yellow suspension was stirred at RT under nitrogen 15 min before addition of DDPA (220 m I, 0.916 mmol). The reaction e was further stirred at RT overnight. The crude reaction mixture was concentrated and ed by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1) to give 6-cyano-1H-indolecarbonyl azide (TLC, R (EtOAc) = 1); t (HPLC conditions a): 3.29 f R min; 1H-NMR (400 MHz, DMSO): d (ppm): 12.7 (bs, 1H), 8.45 (s, 1H), 8.20 (d, 1H), 8.04 (bs, 1H), 7.62 (dd, 1H). Toluene (4 ml_) was added and the reaction mixture was refluxed for 3 h to generate the corresponding isocynate, which was used without purification in the next step. 1-Carbamoylcyano-1H-indolecarboxylic acid was ed from 6-cyano-indole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide.
Scheme A5: ation of 2-benzyloxy(3-isocyanato-indolyl)-ethanone A. enzyloxy-acetyl)-1H-indolecarbaldehyde To a solution of indolecarboxaldehyde (2 g , 13.8 mmol) in THF (70 ml_) at 5°C, was added NaH (60 % in l oil, 551 mg, 13.8 mmol) under en atmosphere. The mixture was stirred at 5°C for 30 min before dropwise addition of benzyloxyacetyl chloride (2.6 ml_, 16.53 mmol) over 20 min maintaining the internal temperature between 5°C and 10°C. The resulting dark solution was further stirred at RT for 1 h . As the reaction was not completed benzyloxyacetyl de ( 1 ml_, 6.44 mmol, 0.5 eq) and NaH (60 % in mineral oil, 551 mg, 13.8 mmol) were added and the mixture was further d at RT for 3 days. The reaction mixture was concentrated, and the residue taken up in CH C I and washed with water. The organic 2 2 layer was dried over Na S0 , filtered, and concentrated. The crude material was purified by 2 4 flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4-1) corresponding to the desired compound. TLC, R (c-hexane/EtOAc 1:1) = 0.61 ; MS (LC/MS): 294.1 [M+H]+, 316.1 [M+Na]+; t (HPLC conditions a): 3.87 min.
B. 1-(2-Benzyloxy-acetyl)-1H-indolecarboxylic acid To a solution of 1-(2-benzyloxy-acetyl)-1 H-indolecarbaldehyde (1.53 g , 5.22 mmol) in a mixture of THF (80 mL) and t-butanol (24 mL). A 2 M 2-methylbutene solution in THF (104 mL, 209 mmol) was added, followed by a water (20 mL) solution of NaCI0 (80 % , 5.9 g , 52.2 mmol) and NaH P0 (5 g , 41.7 mmol). The resulting yellow solution was stirred at RT for 2 h .
The solvents were concentrated and the aqueous layer was filtered and the resulting precipitate was washed with Et 0 to give the desired nd. LC/MS: 310.1 , 332.0 [M+Na]+, 308.0 [M-H]-, 617.0 [2M-H]-; t (HPLC conditions a): 3.62 min.
C. 2-Benzyloxy(3-isocyanato-indolyl)-ethanone A solution of 1-(2-benzyloxy-acetyl)-1 H-indolecarboxylic acid (200 mg, 0.647 mmol) and Et N (90 m I, 0.647 mmol) in toluene (3 mL) was stirred at RT under nitrogen for 15 min. DDPA (90 % , 155 m I, 0.647 mmol) was added and the reaction mixture was further stirred at RT for 3 h . Toluene was trated to give the acyl azide intermediate (TLC-R (c-hexane/EtOAc 1:1) = 0.73; t (HPLC conditions a) = 4.26 min). The crude azide was refluxed in toluene (3 mL) for 1 h and e was concentrated to give the desired nate which was used in the next step without further purification.
Scheme A6: ation of 1-isocvanato-indolizinecarboxylic acid benzyl ester A. 1-Benzyloxycarbonylmethyl-pyridinium bromide To a on of benzyl bromoacetate (10 g , 43.7 mmol) in e (200 mL) was added a solution of pyridine (3.51 mL, 43.7 mmol) in acetone (20 mL) and the resulting mixture was stirred at 60°C under nitrogen over the week-end. Then allowed to cool to RT and concentrated to give the desired material. MS (LC/MS): 228.1 [MH]+.
B. lndolizine-1,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester To a suspension of 1-benzyloxycarbonylmethyl-pyridinium bromide (1.50 g , 9.74 mmol) and -butyl propiolate ( 1 .34 mL, 9.74 mmol) in DMF (80 mL) was added a solution of triethylamine (4.1 mL, 29.2 mmol) in DMF (10 mL). The mixture was vigourously stirred 4 h at 60°C under air atmosphere. The solution was allowed to cool to RT, poured into water and extracted with EtOAc (2x). The combined organic extracts were dried over Na S0 , filtered and 2 4 concentrated. The crude residue was purified by flash column tography on silica gel (c- hexane to c-hexane/EtOAc 8:2) to give the desired material. TLC, R (c-hexane/EtOAc 8:2) = 0.6; MS (LC/MS): 725.3 [2M+Na]+; t (HPLC conditions a): 4.84 min.
C. lndolizine-1,3-dicarboxylic acid 3-benzyl ester A solution of indolizine-1 ,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester (400 mg, 1.14 mmol) and TFA (872 m I, 11.4 mmol) in CH C I (10 mL) was stirred at RT overnight. The 2 2 reaction mixture was concentrated and the crude solid was taken-up in a mixture of MeOH and CH C I , the precipitate was filtered-off and washed with a minimum of MeOH to give the 2 2 d compound as a white powder. The filtrate was concentrated and purified by flash column chromatography on silica gel (CH C I to CH C I /MeOH 95:5) to give again the desired 2 2 2 2 compound. TLC, R (CH C I /MeOH 9:1) = 0.6; MS (LC/MS): 296.0 [M+H]+ 294.1 [M-H]-; t f 2 2 R (HPLC conditions a): 3.64 min.
D. 1-lsocyanato-indolizinecarboxylic acid benzyl ester was prepared from indolizine-1,3-dicarboxylic acid 3-benzyl ester using the protocol described in step E scheme A4 for the preparation of 5-allyloxyisocyanato-indolecarboxylic acid amide.
Scheme A7: tion of 3-isocvanato-indolizinecarboxylic acid benzyl ester lndolizine-1,3-dicarboxylic acid 3-allyl ester 1-benzyl ester The title compound was prepared using the protocol described in steps A and B for the preparation of 1-isocyanato-indolizinecarboxylic acid benzyl ester scheme A6 using cetic acid allyl ester in step A and nic acid benzyl ester in step B. TLC, R (c- hexane/EtOAc 1:1)= 0.8; MS (LC/MS): 336.1 [M+H]+, 358.1 [M+Na]+, 693.2 [2M+Na]+; t (HPLC conditions a): 4.55 min.
A. lndolizine-1,3-dicarboxylic acid 1-benzyl ester To a solution of zine-1 ,3-dicarboxylic acid 3-allyl ester yl ester (300 mg, 0.895 mmol) in THF (6 mL) were added Pd(PPh ) (34.5 mg, 0.09 mmol) and line (260 mg, 8.95 mmol). The reaction mixture was stirred at RT under nitrogen atmosphere for 30 min. The reaction mixture was diluted in EtOAC, extracted twice with HCI 1N and the combined organic extracts were washed with brine, dried over Na S0 , filtered and concentrated to give the desired compound which was used without further purification in the next step TLC, R (CH C I /MeOH 9:1)= 0.4: MS (LC/MS): 294.0 [M-H]-; t (HPLC conditions a): 3.62 min. 2 2 R B. 3-lsocyanato-indolizinecarboxylic acid benzyl ester The title compound was prepared from indolizine-1 ,3-dicarboxylic acid 1-benzyl ester using the protocol described in step E scheme A4 for the ation of 5-allyloxyisocyanato-indole carboxylic acid amide.
Scheme A8: reparation of (1-carbamoyl-1H-indolyl)-acetic acid A. (1-Carbamoyl-1H-indolyl)-acetic acid ethyl ester To a solution of (1H-indolyl)-acetic acid ethyl ester (2.5 g , 12.30 mmol) in THF (58 mL) at 0°C was added sodium hydride (60% in l oil, 0.354 g , 14.8 mmol) portionwise under argon. The dark brown solution was stirred at 0°C for 45 min before dropwise addition of chlorosulfonylisocyanate (2.14 mL, 24.6 mmol). The reaction mixture was allowed to warm to RT overnight under stirring. Acetic acid (3 mL) was then added to the mixture which was stirred at RT for 20 min. Ice was added to mixture which was stirred for 60 min then diluted with water and extracted with EtOAc (3x). The ed organic extracts were washed with brine, dried (Phase separator) and concentrated in vacuo. The residual oil was purified via flash column chromatography on silica gel (EtOAc/cyclohexane 1:3 to 2:3) to give the desired material. TLC, R (EtOAc/cyclohexane 1:1) = 0.35; MS: 247 [M+H]+, 493 [2M+H]+; t (HPLC f R conditions b) 3.51 min.
B. (1-Carbamoyl-1H-indolyl)-acetic acid To a suspension of (1-carbamoyl-1H-indolyl)-acetic acid ethyl ester in methanol (61 mL) and water (6.1 mL) was added an 1N s solution of NaOH (12.2 mL, 12.2 mmol) and the resulting yellow solution was stirred at RT for 4 h . The reaction mixture was concentrated under reduced pressure and the e was ded in HCI 1N. The aqueous mixture was extracted with EtOAC (3x), the combined organic extracts were dried (phase tor) and trated in vacuo. The crude product was used directly in the next step without any further purification. MS: 219 [M+H]+, 437 [2M+H]+; t (HPLC conditions b) 2.16 min. ( 1-Carbamoylmethyl-1 H-indolyl)-acetic acid was prepared in a r manner as described in Scheme A8 Step B for (1-carbamoyl-1H- indolyl)-acetic acid starting from (1-carbamoylmethyl-1H-indolyl)-acetic acid ethyl ester. The crude product (brownish solid) obtained after tive work-up was used directly in the next step without purification. MS: 233 [M+H]+; t (HPLC conditions b) 3.26 min. bamoylmethyl-1H-indolyl)-acetic acid ethyl ester The title compound was prepared in a similar manner as bed in Scheme A8 Step A starting from (2-methyl-1H-indolyl)-acetic acid ethyl ester [219099] (1.20 g , 5.52 mmol), NaH (60 % in l oil, 331 mg, 8.28 mmol) and chlorosulfonylisocyanate (0.959 ml_, 11.1 mmol). Purification by flash column chromatography on silica gel (EtOAc/c-hexane 1:4 to 1:1) afforded a yellowish solid. TLC, R (EtOAc/c-hexane 1:1) = 0.31; MS: 261 [M+H]+; t (HPLC f R conditions b) 3.54 min. ( 1-Carbamoylfluoro-1 H-indolyl)-acetic acid was prepared in a r manner as described in Scheme A8 Step B for (1-carbamoyl-1H- indolyl)-acetic acid starting from (1-carbamoylfluoro-1 H-indolyl)-acetic acid ethyl ester.
The crude product (yellowish solid) obtained after extractive work-up was used directly in the next step without purification. MS: 236.9 [M+H]+; t (HPLC conditions b) 2.4 min. (1-Carbamoylfluoro-1H-indolyl)-acetic acid ethyl ester The title compound was prepared in a similar manner as described in Scheme A8 Step A starting from (5-fluoro-1H-indolyl)-acetic acid methyl ester [4972584] (150 mg, 0.724 mmol), NaH (60 % in mineral oil, 37.4 mg, 0.869 mmol) and sulfonylisocyanate (0.126 mL, 1.45 mmol). Purification by flash column chromatography on silica gel (EtOAc/c-hexane gradient 1:3 to 2:3) afforded the title compound. TLC, R (EtOAc/c-hexane 1:1) = 0.16; MS: 261 [M+H]+, 501 [2M+H]+; t (HPLC conditions b) 3.2 min. ( 1-Carbamoylmethoxy-1 H-indolyl)-acetic acid was prepared from 5-methoxyindolylacetic acid methyl ester according to the ol described scheme A8 for the preparation of (1-carbamoyl-1 H-indolyl)-acetic acid. Rf, TLC (EtOAC) = 0.2; MS (LC/MS): 248.9 [M+H]+, 271.0 [M+Na]+, 247.1 [M-H]-, 495.1 [2M-H]-, 204.1 [M-CONH ]-; t (HPLC conditions f): 1.54 min. 2 R -methoxyindolylacetic acid methyl ester To a sion of 5-methoxyindolylacetic acid (500 mg, 2.44 mmol) in CH C I (7 mL) were 2 2 added DCC (553 mg, 2.68 mmol), DMAP (30 mg, 0.244 mmol) and methanol (99 m , 2.44 mmol). The resulting white suspension was stirred at RT under nitrogen for 2.5 h . The mixture was filtered and the filtrate concentrated to give a brown oil which was purified by flash column chromatography on silica gel (c-hexane to c-hexane/ EtOAc 8-2) to afford the desired material as a brown oil. TLC, Rf ) = 0.82; MS (LC-MS): 220.0 [M+H]+, 242.1 [M+Na]+, 461.0 ]+, 218.1 [M-H]-; t (HPLC conditions f) 3.2 min.
Scheme A9: i -carbamoyl(2-hvdroxy-ethoxy)-1H-indolyl1-acetic acid A. roxy-1H-indolyl)-oxo-acetic acid methyl ester To a solution of oxalyl chloride (3.18 mL, 37.6 mmol) in dry ether (50 mL) was added 5- hydroxyindole (2.5 g , 18.8 mmol) in small portions over 15 min at - 5°C under en, and the resulting mixture was stirred at RT for 30 min. The suspension was filtered and the residue was washed with Et 0 . Dry MeOH (60 mL) was carefully added, and the ing mixture was stirred at RT for 1 h . The suspension was filtered and successively washed with MeOH and Et 0 to afford the desired material. TLC, R (EtOAc) = 0.75; MS (LC-MS): 220.0 [M+H]+, 242.1 2 f [M+Na]+, 461 .0 [2M+Na]+, 218.1 [M-H]-; t (HPLC conditions ) : 1.02 min.
B. (5-Hydroxy-1H-indolyl)-acetic acid methyl ester To a suspension of roxy-1H-indolyl)-oxo-acetic acid methyl ester ( 1 g , 4.56 mmol) in e (14 mL) was added Pd/C 10% (400 mg) and a solution of NaH P0 .H 0 (4.84 g , 45.6 2 2 2 mmol) in water (2.35 mL). The reaction mixture was stirred and heated to reflux for 1.5 h . After completion the reaction mixture was cooled to RT, and the catalyst removed by filtration through a pad of Celite and washed with MeOH. Solvents were concentrated, and the residue was dissolved in CH C I and washed with water. The organic layer was dried over Na S0 , 2 2 2 4 filtered and concentrated to give the desired material. TLC, R (EtOAc) = 0.85; MS (LC-MS): 206.1 [M+H]+. 1H-NMR (400 MHz, DMSO): d (ppm): 10.64 (bs, 1H), 8.64 (s, 1H), 7.14 (m, 2H), 6.78 (d, 1H), 6.60 (dd, 1H), 3.65 (s, 3H), 3.58 (s, 2H).
C. [5-(2-Acetoxy-ethoxy)-1H-indolyl]-acetic acid methyl ester To a solution of (5-hydroxy-1H-indolyl)-acetic acid methyl ester (670 mg, 3.26 mmol) in acetone (15 mL) was added cesium carbonate (1.17 g , 3.59 mmol) and oethyl acetate (395 m , 3.59 mmol). The sion was refluxed ght under nitrogen. Acetone was concentrated and the residue was dissolved in water and extracted twice with EtOAc. The combined c layers were dried over Na S0 , filtered and concentrated. The crude residue 2 4 was ed by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 6:4) to give the desired material. TLC, R (c-hexane/EtOAc 1:1) = 0.45; MS (LC-MS): 292.1 [M+H]+, 314.0 [M+Na]+, 290.0 [M-H]-; t (HPLC conditions ) : 1.70 min.
D. 5-(2-Acetoxy-ethoxy)carbamoyl-1H-indolyl]-acetic acid methyl ester A suspension of NaH (60 % in mineral oil, 43 mg, 1.06 mmol) in THF (2.5 mL) under nitrogen here was cooled to 5°C and a solution of [5-(2-acetoxy-ethoxy)-1 H-indolyl]-acetic acid methyl ester (249 mg, 0.71 mmol) in THF (2.5 mL) was added. The mixture was stirred min before slow addition of chlorosulfonyl isocyanate (123 m , 1.42 mmol) at 5°C. The resulting solution was then d overnight allowing the temperature to slowly reach RT.
Acetic acid ( 1 .3 mL) was added, and the solution was stirred at RT for 1h, before addition of ice and water (16 mL). The mixture was further stirred at RT for 30 min and was extracted twice with EtOAc. The combined organic layers were washed with water, dried over Na S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (100% c-hexane to 100% EtOAc) to afford the desired material. TLC, R (EtOAc) = 0.7; MS (LC-MS): 335.0 [M+H]+, 357.1 +, 333.1 [M-H]-, 290.0 [M-CONH ]-, 379.0 [M+HCOO]-; t R (HPLC conditions f): 1.63 min.
E. [1-Carbamoyl(2-hydroxy-ethoxy)-1H-indolyl]-acetic acid -(2-Acetoxy-ethoxy)carbamoyl-1 H-indolyl]-acetic acid methyl ester (54 mg, 0.153 mmol) was dissolved in MeOH ( 1 .3 mL) and H20 (130 m ) . NaOH 1N (307 m , 0.307 mmol) was added and the mixture was stirred at RT for 1h. The reaction e was concentrated, the crude poured into HCI 1N and extracted twice with CH C I . A precipitate formed in the aqueous 2 2 layer and was filtered-off to give the desired material. TLC, R (EtOAc) = 0.15; MS (LC/MS): 279.1 [M+H]+, 301 .0 [M+Na]+, 277.0 [M-H]-, 233.9 [M-CONH ]-; 1H-NMR (400 MHz, DMSO): d (ppm): 12.4 (bs, 1H), 8.13 (d, 1H), 7.73 (s, 1H), 7.43 (bs, 2H), 7.05 (d, 1H), 6.89 (dd, 1H), 4.0 (t, 2H), 3.74 (t, 2H), 3.64 (d, 2H). (6-tert-Butoxycarbonylmethylcarbamoyl-1H-indolyl)-acetic acid was prepared from (1H-indolyl)-acetic acid tert-butyl ester ibed for the preparation of bamoylisocyanato-1H-indolyl)-acetic acid tert-butyl ester) according to the protocol described scheme A9 steps A , B, D, E for the preparation of [1-carbamoyl(2-hydroxyethoxy )-1H-indolyl]-acetic acid. MS (LC/MS): 350.2/352.2 [M+NH4]+, 687.2/689.2 [2M+Na]+, 277.0/279.0 [MH-tBu]+, 288.0/290.0 [M-CONH ]-, 376.9/378.8 [M+HCOO]-, 662.8/664.7 [2M-H]-; t (HPLC ions f): 1.79 min. 1-Carboxymethyl-1H-indolecarboxylic acid ethyl ester 1-tert-Butoxycarbonylmethyl-1H-indolecarboxylic acid ethyl ester (700 mg, 2.31 mmol) was ved in CH C I (12 ml_), TFA (2.65 ml_, 34.6 mmol) was added and the solution was 2 2 stirred at RT over week end. CH C I and water were added, the layers were separated and the 2 2 aqueous one re-extracted with CH C I (2x). The combined organic layers were dried with 2 2 Na S0 , filtered and concentrated to give the desired compound. TLC, R (EtOAc) = 0.62; MS 2 4 f (LC/MS): 248.1 , 246.0 [M-H]- ; t (HPLC conditions a): 3.03 min. 1-tert-Butoxycarbonylmethyl-1H-indolecarboxylic acid ethyl ester To a suspension of 1H-indolecarboxylic acid ethyl ester (800 mg, 4.23 mmol) and potassium carbonate (1.34 g , 9.72 mmol) in CH CN (21 mL) under nitrogen was added -butyl bromoacetate (875 m , 5.92 mmol) and the reaction mixture was heated at reflux overnight.
The reaction mixture was allowed to cool to RT, EtOAc and water were added and the layers were separated, the aqueous one being re-extracted with EtOAc. The organic layers were washed with brine, dried (Na S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography ane to c-hexane/EtOAc 1:1) to afford the desired compound. TLC, R (EtOAc) = 0.77; MS (LC/MS) : 304.1 [M+H]+, 302.0 ; t (HPLC f R conditions a): 4.01 min.
Scheme A10: preparation of (3-carbamoylmethoxy-indolyl)-acetic acid A. 1-tert-Butoxycarbonylmethylmethoxy-1H-indolecarboxylic acid To an ice-cooled suspension of 6-methoxy-1 H-indolecarboxylic acid ( 1 g , 5.23 mmol) in DMF (35 mL) was added NaH (60% suspension in oil; 0.523 g , 13.1 mmol) in one portion, and the e was stirred at 0°C for 30 min. Tert-butylbromoacetate (0.85 mL, 5.75 mmol) was then added dropwise, and stirring was continues at RT overnight. The reaction mixture was neutralized by addition of saturated NH4CI, and the solution was then ed to pH=2-3 by addition of 0.1 N HCI. The aqueous layer was repeatedly extracted with CH2C I2, the combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The residue was ved in a small volume of methanol, followed by on of water until a solid precipitated. The precipiate was filtered off, washed with water and dried in vacuo to afford the title compound as a white solid. MS (LC/MS): 306 [M+H]+, 328 [M+Na]+; tR (HPLC conditions c): 4.67 min.
B. (3-Carbamoylmethoxy-indolyl)-acetic acid tert-butyl ester To a mixture of -butoxycarbonylmethylmethoxy-1 H-indolecarboxylic acid (500 mg, 1.28 mmol) in DMF (6 mL) were added successively NH4C I (137 mg, 2.55 mmol), HBTU (1.21 g , 3.19 mmol) and DIPEA (0.90 mL, 5.1 1 mmol), and ng was continued at RT for 16 h .
Additional aliquots of NH4C I (2 equiv) and DIPEA (4 equiv) were added to the reaction mixture.
After stirring for 16 h , water was added and the aqueous layer was extracted repeatedly with EtOAc. The combined organics were washed with saturated aqueous NaHC0 3 solution and brine, dried (phase separator) and concentrated in vacuo. Purification by preparative HPLC (Macherey Nagel, VP250/40, C18 nucleosil 100-10, eluent: 20-100% CH3CN/H 2O/20 min, 100% CH3CN/2 min, CH3CN and H20 containing 0.1% TFA, flow: 40 mL/min) and lization of the purified fractions afforded the title compound as a beige solid. MS: 305 [M+H]+, 609 +; tR (HPLC conditions c): 4.26 min.
C. (3-Carbamoylmethoxy-indolyl)-acetic acid To a solution of (3-carbamoylmethoxy-indolyl)-acetic acid tert-butyl ester (300 mg, 0.99 mmol) in CH2C I2 (9 mL) was added TFA (4.5 mL) at RT, and stirring was continued for 2 h . ol was then added to the reaction e, and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated under reduced pressure to afford the title compound as a grey solid: MS: 249 [M+H]+, 497 [2M+H]+; tR (HPLC conditions c): 2.86 min.
The material thus obtained was used in the next reaction step without further purification. cheme A 11: preparation of (3-carbamoylchloro-indolyl)-acetic acid A. (5-Chloroformyl-indolyl)-acetic acid tert-butyl ester To a suspension of 5-chloro-1H-indolecarbaldehyde [8270] (500 mg, 2.78 mmol) and K C0 (885 mg, 6.40 mmol) in (14 ml_) was added tert-butyl 2-bromoacetate (0.576 ml_, 3.90 2 3 mmol) dropwise at RT. The resulting e was then heated to reflux for 18 h . After g to RT, the e was diluted with EtOAc and water. The organic layer was separated, subsequently washed with water (1x) and brine (1x), dried (Phase separator) and concentrated in vacuo to give the crude title compound. MS (LC/MS): 294 [M+H]+; t (HPLC conditions b): .45 min. The product was used in the next reaction step without further purification.
B. 1-tert-Butoxycarbonylmethylchloro-1 H-indolecarboxylic acid To a solution of (5-chloroformyl-indolyl)-acetic acid tert-butyl ester (902 mg, 2.92 mmol) in THF (12 ml_) and tert-butanol (4.80 ml_) were added successively 2-methylbutene (9.27 ml_, 88.0 mmol), a solution of NaCI0 (2.64 g , 29.2 mmol) and sodium dihydrogen phosphate (2.80 g , 23.3 mmol) in water (4.80 ml_), followed by stirring at RT for 18 h . The on mixture was acidified with 0.1 N HCI (pH 2 to 3) and extracted with EtOAc (3x). The combined organics were dried (Phase separator) and concentrated in vacuo. The residue was triturated with diethyl ether, the solid was filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a white solid. MS (LC/MS): 310 [M+H]+; t (HPLC conditions b): 5.16 min.
C. (3-Carbamoylchloro-indolyl)-acetic acid tert-butyl ester To a mixture of 1-tert-butoxycarbonylmethylchloro-1H-indolecarboxylic acid (400 mg, 1.29 mmol) in CH C I (6 mL) were added successively NH C I (138 mg, 2.58 mmol), HBTU 2 2 4 ( 1 .22 g , 3.23 mmol) and DIPEA (0.902 mL, 5.17 mmol). Stirring was continued at RT for 16 h .
Additional aliquots of NH C I (2 equiv) and DIPEA (4 equiv) were added to the reaction mixture.
After stirring for 4 h , the reaction mixture was d with CH C I and the on was washed 2 2 with water (2x), 0.1N aqeous HCI (2x), ted aqueous NaHC0 (2x) and brine, dried (Phase tor) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 2:1 to 1:0) to give the title compound as a white solid. TLC R /c-hexane 2:1) = 0.20; MS (LC/MS): 309 [M+H]+, 617 [2M+H]+; t (HPLC conditions b): 4.75 min.
D. (3-Carbamoylchloro-indolyl)-acetic acid To a solution of (3-carbamoylchloro-indolyl)-acetic acid tert-butyl ester (455 mg, 0.973 mmol) in CH C I (6.0 ml_) was added TFA (3.0 ml_) at RT and stirring was continued for 2 h . 2 2 ol was then added to the reaction mixture and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure. The residue was dissolved in 1N aqueous NaOH and washed with CH C I (3x). The water phase 2 2 was acidified to pH 2 by adding 6N aqueous HCI to form a white suspension. The itate was filtered off, washed with water and dried in vacuo to afford the crude title compound as a white solid. MS (LC/MS): 253 [M+H]+, 505 [2M+H]+; t (HPLC conditions b): 3.99 min. The product was used in the next reaction step without further cation.
-Carbamo lchloro-indolyl)-acetic acid was prepared from ro-1H-indolecarbaldehyde [10087] using r protocols as described in Scheme A 11 for the preparation of (3-carbamoylchloro-indolyl)-acetic acid.
White solid. MS (LC/MS): 253 [M+H]+, 505 [2M+H]+; t (HPLC conditions b): 3.32 min. (6-Benzyloxycarbamoyl-indol-1 -yl)-acetic acid was prepared from 6-benzyloxy-1 H-indolecarbaldehyde [928556] using similar protocols as described in Scheme A 11 for the preparation of (3-carbamoylchloro-indolyl)-acetic acid. White solid. MS (LC/MS): 325 [M+H]+, 649 [2M+H]+; t (HPLC conditions b): 4.06 min. (5-Benzyloxycarbamoyl-indol-1 -yl)-acetic acid was prepared from 5-benzyloxy-1H-indolecarbaldehyde [69536] using similar protocols as described in Scheme A 11 for the preparation of (3-carbamoylchloro-indolyl)-acetic acid. White solid. MS (LC/MS): 325 [M+H]+, 649 [2M+H]+; tR (HPLC conditions b): 4.04 min. (3-Carbamoylmethoxy-indol-1 -yl)-acetic acid was prepared from oxy-1H-indolecarbaldehyde [1090212] in a similar manner as described in Scheme A 11 for the preparation of bamoylchloro-indolyl)-acetic acid.
White solid. MS (LC/MS): 249 , 497 [2M+H]+; tR (HPLC conditions c): 3.05 min. (3-carbamoyl-5,6-difluoro-indolyl)-acetic acid was prepared from 5,6-difluoro-1H-indolecarbaldehyde in a similar manner as described in Scheme A 11 for the preparation of bamoylchloro-indolyl)-acetic acid. The title compound was obtained as a white solid: MS (LC/MS): 255.0 [M+H]+, 509.0 [2M+H]+; tR (HPLC conditions k): 2.58 min. ,6-Difluoro-1H-indolecarbaldehyde To an ice-cooled solution of oxalyl chloride ( 1 .21 mL, 13.8 mmol) in CH2C I2 (40 mL) was added a solution of DMF (2.02 mL) in CH2C I2 (40.0 mL). The reaction was stirred for 30 min, then 5,6- difluoro-1H-indole [1696745] (2.00 g , 13.1 mmol) was added in one portion. The reaction mixture was allowed to warm to RT overnight. Volatiles were evaporated, and the residue was taken up in THF (20 mL) and 20% aqueous ammonium acetate solution (20 mL). The resulting mixture was heated to reflux for 30 min. After cooling, the mixture was treated with ted aqueous NaHC0 3 on and extracted three times with EtOAc. The combined organic layers were dried (phase separator) and evaporated in vacuo to afford the title compound as a beige solid: MS (LC/MS): 182.0 ; tR (HPLC ions c): 3.94 min. The material thus obtained was used in the next step without further purification. (3-Carbamoyltrifluoromethoxy-indol-1 -yl)-acetic acid was prepared from 6-trifluoromethoxy-1 H-indole [4674518] in a similar manner as described for the preparation of bamoyl-5,6-difluoro-indolyl)-acetic acid. White solid.
MS (LC/MS): 303.0 [M+H]+, 605.0 [2M+H]+; t (HPLC conditions k): 2.75 min. (6-Bromocarbamoylfluoro-indolyl)-acetic acid was prepared from 6-bromofluoro-1 H-indole [2598607] in a similar manner as described for the preparation of (3-carbamoyl-5,6-difluoro-indolyl)-acetic acid. White solid. MS ): 315.0 [M+H]+, 631 .0 [2M+H]+; t (HPLC conditions k): 2.79 min. (3-Carbamoyldifluoromethoxy-indol-1 -yl)-acetic acid was prepared from 6-difluoromethoxy-1 H-indole [2002072] in a similar manner as bed for the preparation of (3-carbamoyl-5,6-difluoro-indolyl)-acetic acid. White solid.
MS (LC/MS): 285 [M+H]+, 569 [2M+H]+; t (HPLC conditions k): 2.64 min.
-Meth lcarbamo l-indolvD-acetic acid was prepared from olecarbaldehyde using r protocols as described in Scheme A 11 for the preparation of (3-carbamoylchloro-indolyl)-acetic acid (using methylamine hydrochloride in step C). MS (LC/MS): 233 [M+H]+; 465 [M+H]+; 231 [M-H]-; 463 [M+H]-; t (HPLC conditions b): 1.8 min.
Scheme A12 : Pre aration of (3-Carbamoylmethoxy-indolyl)-acetic acid A. (5-Benzyloxycarbamoyl-indolyl)-acetic acid tert-butyl ester The title compound was prepared from 5-benzyloxy-1H-indolecarbaldehyde [69536] in a similar manner as described in Scheme A 11 for steps A to C .
B. (3-Carbamoylhydroxy-indolyl)-acetic acid utyl ester (5-Benzyloxycarbamoyl-indolyl)-acetic acid tert-butyl ester (250 mg, 0.657 mmol) was suspended in THF (13 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10 % (25 mg) was added to the solution which was again ed, placed under a hydrogen atmosphere and stirred at RT overnight. The catalyst was removed through a 0.45 microns filter and concentrated in vacuo. The crude material was purified by preparative HPLC (SunFire C18-ODB, 5 m , 30x100 mm, eluent: 5-100% CH CN/H O/20 min, 100% CH CN/2 3 2 3 min, CH CN and H 0 containing 0.1% TFA, flow: 40 mL/min) to give after lyophilization of the 3 2 purified ons the desired compound as a white solid. MS: 291 , 313 [M+Na]+, 581 [2M+H]+, 603 [2M+Na]+; t (HPLC conditions c): 3.75 min.
C. (3-Carbamoylmethoxy-indolyl)-acetic acid tert-butyl ester To a solution of (3-carbamoylhydroxy-indolyl)-acetic acid tert-butyl ester (50 mg, 0.172 mmol) in DMSO ( 1 .7 mL) was added Cs C0 (336 mg, 1.03 mmol). The mixture was stirred at 2 3 RT for 5 min, followed by addition of methyl iodide (0.048 mL, 0.774 mmol), and stirring was continued at RT for 3 days. The reaction mixture was ioned between water and CH C I , 2 2 the layers were separated and the aqueous phase was extracted twice with CH C I . The 2 2 combined organics were washed twice with brine, dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow solid: MS (LC/MS): 305 [M+H]+, 327 [M+Na]+, 609 [2M+H]+; t (HPLC conditions c): 4.31 min. The material thus obtained was used in the next on step without further purification.
D. bamoylmethoxy-indolyl)-acetic acid To a solution of (3-carbamoylmethoxy-indolyl)-acetic acid tert-butyl ester (45.0 mg, 0.1 18 mmol) in CH C I (2.0 mL) was added TFA ( 1 .0 mL) at RT, and stirring was continued for 3 h . 2 2 Methanol was then added to the reaction mixture and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure to afford the title compound as a beige solid: MS (LC/MS): 249 [M+H]+, 277 [M+Na]+; t (HPLC conditions c): 2.93 min. The material thus obtained was used in the next reaction step without further purification.
Scheme A13 : Preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid A. 1-(5-Trifluoromethoxy-1H-indolyl)-ethanone To a solution of 5-(trifluoromethoxy)-1 H-indole [2625935 ] (1.00 g , 4.97 mmol) in CH C I 2 2 (20 ml_), cooled to 0°C, was added dropwise diethylaluminum chloride (1M solution in hexane; 7.46 ml_, 7.46 mmol), and stirring was continued for 30 min. A solution of acetyl chloride (0.532 ml_, 7.46 mmol) in CH C I (20 ml_) was subsequently added, and the reaction mixture was 2 2 stirred at 0°C for 1 h . A 5% aqueous citric acid on (100 ml_) was then added at 0°C, and the mixture was stirred for 15 min at RT. The e (two phases) was filtered, and the precipitate was dried at 50°C in vacuo for 1 h to afford the title compound. Beige solid. MS : 244.0 [M+H]+; t (HPLC conditions c): 4.60 min. The material thus obtained was used directly in the next step without r purification B. (3-Acetyltrifluoromethoxy-indolyl)-acetic acid tert-butyl ester To a solution of 1-(5-trifluoromethoxy-1H-indolyl)-ethanone (0.50 g , 2.06 mmol) in CH CN (10 ml_) was added K C0 (0.313 g , 2.26 mmol) and tert-butyl 2-bromoacetate (0.334 ml_, 2.26 2 3 mmol). The on mixture was stirred at 90°C overnight. The reaction mixture was filtered, and the te was diluted with CH C I . The cs were washed with 1M s HCI 2 2 solution (5 ml_) and saturated aqueous NaHC0 solution (5 ml_). The organic layer was dried (phase separator) and evaporated in vacuo to afford the title compound as a yellowish oil: MS: 358.0 [M+H]+; t (HPLC conditions c): 5.66 min. The material thus obtained was used directly in the next step without further purification.
C. (3-Acetyltrifluoromethoxy-indolyl)-acetic acid To a solution of (3-acetyltrifluoromethoxy-indolyl)-acetic acid tert-butyl ester (680 mg, 1.90 mmol) in CH C I (10 mL) was added TFA (1.47 mL, 19.0 mmol), and stirring was 2 2 continued at RT overnight. The reaction mixture was then d with CH C I and MeOH, and 2 2 volatiles were evaporated under reduced pressure. The residue was taken up in MeOH and then ated again. The crude material was taken up in 1M aqueous NaOH solution (5 ml_), and the water layer was washed with CH C I and subsequently acidified to pH=1 by 2 2 on of a 6M HCI solution. The precipitate was ed and dried at 50°C in vacuo for 1 h to afford the title compound as a off-white solid: MS: 302.0 [M+H]+; t (HPLC conditions c): 4.40 min. The material thus obtained was used directly in the next step without further cation. (3-Acetyltrifluoromethoxy-indolyl)-acetic acid was prepared from 6-trifluoromethoxy-1 H-indole [4674518] in a similar manner as described in Scheme A13 for the preparation of (3-ccetyltrifluoromethoxy-indolyl)-acetic acid. MS: 302.0 [M+H]+; t (HPLC conditions c): 4.39 min. (3-Acetylmethoxy-indolyl)-acetic acid was prepared from ethoxy-1H-indolyl)-ethanone [995322] in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyltrifluoromethoxyindolyl )-acetic acid. Brown solid. MS: 248 [M+H]+, 517 [2M+Na]+; t (HPLC conditions k): 2.30 min. (3-Acetylchloro-indol-1 -yl)-acetic acid was prepared from 6-chloro-1H-indole in a similar manner as bed in Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid. Brown solid. MS: 252 [M+H]+, 274 [M+Na]+; t (HPLC conditions k): 2.89 min. (3-Acetylcyano-indolyl)-acetic acid was prepared from olecarbonitrile in a similar manner as described in Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid. MS: 243 [M+H]+; t (HPLC conditions k): 2.72 min. (3-Acetylcyano-indolyl)-acetic acid was prepared from 1H-indolecarbonitrile in a similar manner as described in Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid. MS (LC/MS): 241 .2 [M-H]-; 243.2 [M+H]+; t (HPLC conditions a): 2.62 min. (3-Acetylbenzyloxy-indolyl)-acetic acid was prepared from 5-benzyloxy-1 H-indole in a similar manner as bed in Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid. MS: 324 [M+H]+, 346 [M+Na]+; t (HPLC conditions k): 3.34 min. (3-Acetylbenzyloxy-indolyl)-acetic acid was prepared from 6-benzyloxy-1 H-indole in a similar manner as described in Scheme A13 for the preparation of tyltrifluoromethoxy-indolyl)-acetic acid. MS: 324 [M+H]+, 647 +; t (HPLC conditions k): 3.38 min. 3-Acetylcarboxymethyl-1H-indolecarboxylic acid methyl ester was prepared from 1H-indolecarboxylic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid. MS: 276 [M+H]+; t (HPLC conditions k): 2.84 min. 3-Acetylcarboxymethyl-1H-indolecarboxylic acid methyl ester was prepared from 1H-indolecarboxylic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid. MS: 276 [M+H]+; t (HPLC conditions k): 2.89 min. 3-Acetylcarboxymethyl-1H-indolecarboxylic acid methyl ester was prepared from 3-acetyl-1 H-indolecarboxylic acid methyl ester [1068961] in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl trifluoromethoxy-indolyl)-acetic acid. Colored solid. MS: 276 ; t (HPLC conditions k): 2.80 min. (3-Acetylmethoxycarbonylmethyl-indol-1 -yl)-acetic acid was prepared from (3-acetyl-1H-indolyl)-acetic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid. Brown solid. MS: 290 ; t (HPLC conditions k): 2.83 min. (3-Acetyl-1H-indolyl)-acetic acid methyl ester To a stirred solution of (3-acetyl-1H-indolyl)-acetic acid [396892 ] (500 mg, 2.85 mmol) in MeOH (14 mL), cooled to at 0°C, was added thylsilyl)diazomethane (2M on in Et 0 ; 6.00 mL, 12.0 mmol). After stirring at RT for 30 min, the on mixture was concentrated in vacuo to afford the title compound as a yellow wax. MS: 190 [M+H]+; t (HPLC conditions k): 3.20 min. The material thus obtained was used directly in the next step without further purification. (3-Acetyl-pyrrolor2,3-blpyridin-1 -yl)-acetic acid was ed in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid from 1-(1 H-pyrrolo[2,3- b]pyridinyl)-ethanone [833938]. MS (UPLC/MS): 219.2 [M+H]+, 217.2 [M-H]-, 263.3 [M+HCOO]-, 435.3 [2M-H]-; t (HPLC conditions ) : 1.16 min. 1H-NMR (400 MHz, DMSO): d (ppm): 8.55 (bs, 1H), 8.49 (dd, 1H), 8.36 (dd, 1H), 7.31 (dd, 1H), 5.12 (s, 2H), 2.48 (s,3H).
-Acet olor3,2-b p ridinvD-acetic acid was prepared in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid from 1-(1 H-pyrrolo[3,2- dinyl)-ethanone red according to J. Org. Chem. 2002, 67, 6226). MS (UPLC/MS): 219.2 [M+H]+, 217.3 [M-H]-, 435.3 [2M-H]-; t (HPLC conditions ) : 1.16 min. 1H- NMR (400 MHz, DMSO): d (ppm): 8.79 (bs, 1H), 8.64 (m, 2H), 7.64 (m, 1H), 5.33 (s, 2H), 2.67 (s,3H). r3-(2,2,2-Trifluoro-acetyl)-indol-1 -yll-acetic acid was prepared from 2,2,2-trifluoro(1H-indolyl)-ethanone in a similar manner as described in Scheme A13 (step B and C) for the preparation of (3-acetyltrifluoromethoxy-indolyl)- acetic acid. White solid. MS: 272.0 ; t (HPLC conditions c): 4.59 min. r3-(2-Hydroxy-acetyl)-indol-1 -yll-acetic acid was prepared from 2-hydroxy(1H-indolyl)-ethanone [24003] in a similar manner as described in Scheme A13 (step B and C) for the preparation of (3-acetyltrifluoromethoxyindolyl )-acetic acid. Colored solid. MS: 234.0 , 489.0 [2M+Na]+; t (HPLC conditions c): 3.1 1 min. r3-(2-Methoxy-acetyl)-indolvn-acetic acid was prepared from 1H-indole in a similar manner as described in Scheme A13 (in step A , 2- methoxyacetyl chloride was used instead of acetyl chloride) for the preparation of tyl trifluoromethoxy-indolyl)-acetic acid. Brown solid. MS: 248.0 ; t (HPLC ions c): 3.42 min. 3-Acetylcarboxymethyl-1H-pyrrolor2,3-blpyridinecarboxylic acid methyl ester was ed from methyl 3-acetyl-1 H-pyrrolo[2,3-b]pyridinecarboxylate using a similar protocol as described in Scheme A13, Steps C and D : MS (LC/MS): 277 [M+H]+; t (HPLC conditions k): 2.68 min.
Methyl 3-acetyl-1 olor2,3-blpyridinecarboxylate was prepared from methyl 1H-pyrrolo[2,3-b]pyridinecarboxylate using a similar protocol as described in Scheme A17, Step A : MS (LC/MS): 219 [M+H]+; t (HPLC conditions k): 2.58 min.
Methyl 1H-pyrrolor2,3-blpyridinecarboxylate To a stirred solution of 1H-pyrrolo[2,3-b]pyridinecarboxylic acid [8987465] (500 mg, 3.08 mmol) in MeOH was added a 2M solution of trimethylsilyldiazomethane in Et 0 at 0°C, and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo to give the title compound. MS (LC/MS): 177 [M+H]+, 375 [2M+H]+; t (HPLC conditions k): 2.71 Scheme A14: preparation of (3-acetyltriisopropylsilanyloxymethyl-indolyl)-acetic acid A. sopropylsilanyltriisopropylsilanyloxymethyl-1H-indole To a solution of ( 1 lyl)-methanol ( 1 .00 g , 6.79 mmol) in THF (60 ml_), cooled to 0°C, was added sodium e (60% in mineral oil; 1.36 g , 34.0 mmol) portionwise. After stirring for 5 min, triisopropylsilyl chloride (2.88 ml_, 13.6 mmol) was added, and the resulting solution was stirred at RT for 2 h . The reaction was quenched by addition of a saturated aqueous NaHC0 3 solution at 0°C. The aqueous layer was repeatedly extracted with EtOAc, and the combined organics were washed with H20 (1x) and brine (1x), dried (phase separator) and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane to c-hexane/EtOAc 9:1) afforded the title compound as a white solid. TLC, Rf (c-hexane/EtOAc 9:1) = 0.72. 1H-NMR (400 MHz, fe): d ppm 7.61 (s, 1H), 7.49 (d, 1H), 7.32 (d, 1H), 6.93 (d, 1H), 6.57 (d, 1H), 4.92 (s, 2H), 1.60 - 1.85 (m, 3H), 1.01 - 1.12 (m, 39H).
B. 5-Triisopropylsilanyloxymethyl-1 H-indole To a suspension of sopropylsilanyltriisopropylsilanyloxymethyl-1 H-indole (2.80 g , 6.09 mmol) in EtOH (30 ml_) / THF (10 mL) / water (10 ml_) was added K2C0 3 (4.21 g , 30.4 mmol), and the reaction mixture was heated at 85°C for 16 h . The reaction was quenched with 1N HCI at 0°C. The aqueous layer was extracted with CH2C I2 (2x) and the combined organic layers were washed with brine, dried (phase separator) and concentrated under reduced pressure.
The oily residue was purified by flash column tography on silica gel (eluent gradient: c- hexane to c-hexane/EtOAc 9:1) to afford the title compound as a yellow oil. TLC, Rf (c- hexane/EtOAc 9:1) = 0.29. tR (HPLC conditions k): 5.02 min. MS (LC/MS): 304 [M+H]+.
C. 1-(5-Triisopropylsilanyloxymethyl-1H-indolyl)-ethanone The title nd was prepared from 5-triisopropylsilanyloxymethyl-1 H-indole in a r manner as described in step A of Scheme A13 for the preparation of (3-acetyl trifluoromethoxy-indolyl)-acetic acid. Brown solid. MS: 346 [M+H]+; t (HPLC conditions c): 6.86 min.
D. (3-Acetyltriisopropylsilanyloxymethyl-indolyl)-acetic acid methyl ester The title compound was prepared from 1-(5-triisopropylsilanyloxymethyl-1H-indolyl)- ethanone in a similar manner as described in step B of Scheme A13 for the ation of (3- acetyltrifluoromethoxy-indolyl)-acetic acid. MS: 418 [M+H]+; t (HPLC conditions k): 4.75 min.
E. (3-Acetyltriisopropylsilanyloxymethyl-indol-1 cetic acid To a solution of (3-acetyltriisopropylsilanyloxymethyl-indolyl)-acetic acid methyl ester (109 mg, 0.138 mmol) in THF (5 ml_) and water (0.5 ml_) was added 1N NaOH (0.69 ml_, 0.69 mmol), and stirring was continued at RT for 16 h . The reaction mixture was partitioned between EtOAc and saturated aqueous NaHC0 . The aqueous layer was extracted with EtOAC (2x), the combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow wax. MS (LC/MS): 404 [M+H]+; t (HPLC conditions k): 4.35 min.
Scheme A15: Preparation of (3-acetyl-pyrrolor2,3-clpyridinyl)-acetic acid trifluoroacetate A. (3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetic acid tert-butyl ester To a suspension of NaH (60 % in mineral oil, 90 mg, 2.25 mmol) in DMF (4.2 mL) cooled at 0°C was added a solution of 1-(1H-pyrrolo[2,3-c]pyridinyl)-ethanone (prepared according to J. Org. Chem. 2002, 67, 6226) (300 mg, 1.87 mmol) in DMF (4.2 mL) and the resulting suspension was stirred at 0°C under nitrogen atmosphere for 30 min before slow on of tert-butyl bromoacetate (277 m , 1.87 mmol). The reaction mixture was allowed to reach RT and further stirred at RT for 1.5 h . After completion of the reaction, the mixture was purified first by catch-release on SiliaPrep Tosic Acid-(2x10 g) (Varian) (eluent: MeOH (50 mL) by 2 M a in MeOH (50 mL)) to give a e of regioisomers: (3-acetyl-pyrrolo[2,3-c]pyridin- 1-yl)-acetic acid utyl ester and (3-acetyl-pyrrolo[2,3-c]pyridinyl)-acetic acid tert-butyl ester followed by flash column chromatography on silica gel (CH C I to CH C I /MeOH 85-15) 2 2 2 2 to give (3-acetyl-pyrrolo[2,3-c]pyridinyl)-acetic acid tert-butyl ester as a yellow powder. TLC, R (CH C I / MeOH 9-1) = 0.50; MS (UPLC/MS): 275.3 [M+H]+, 319.2 [M+HCOO]-; t (HPLC f 2 2 R conditions ) : 1.28 min; 1H-NMR (400 MHz, DMSO-d ) : d (ppm): 8.88 (s, 1H), 8.50 (s, 1H), 8.33 (d, 1H), 8.06 (d, 1H), 5.27 (s, 2H), 2.48 (s,3H), 1.45 (s, 9H).
B. (3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetic acid oroacetate A solution of (3-acetyl-pyrrolo[2,3-c]pyridinyl)-acetic acid tert-butyl ester (230 mg, 0.8 mmol) and TFA (0.915 mL, 11.95 mmol) in CH C I (3.1 mL) was stirred at RT overnight. The reaction 2 2 mixture was concentrated and the e was dried under high vacuum. The ing solid was taken-up in Et 0 and filtered to give the desired compound (TFA salt) as beige powder which was used in the next step t purification. MS (UPLC/MS): 219.2 [M+H]+, 217.2 [M- H]-; 1H-NMR (400 MHz, DMSO): d (ppm): 9.50 (s, 1H), 9.03 (s, 1H), 8.54 (d, 1H), 8.51 (d, 1H), .40 (s, 2H), 2.57 (s,3H). (3-Acetyl-pyrrolor3,2-clpyridinyl)-acetic acid trifluoroacetate was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3- c]pyridinyl)-acetic acid in Scheme A15 from 1-(1H-pyrrolo[3,2-c]pyridinyl)-ethanone (prepared according to J. Org. Chem. 2002, 67, 6226). MS (UPLC/MS): 219.1 , 217.2 [M-H]-, 435.3 [2M-H]-; 1H-NMR (400 MHz, DMSO): d (ppm): 9.54 (s, 1H), 8.89 (s, 1H), 8.66 (d, 1H), 8.30 (d, 1H), 5.38 (s, 2H), 2.58 (s, 3H). (3-Acetylmethoxy-pyrrolor2,3-blpyridin-1 cetic acid was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3- c]pyridinyl)-acetic acid in Scheme A15 from 1-(6-methoxy-1H-pyrrolo[2,3-b]pyridinyl)- ethanone. MS (UPLC/MS): 249.2 [M+H]+, 497.3 [2M+H]+, 519.3 [2M+Na]+, 247.1 [M-H]-, 293.2 [M+HCOO]-, 495.3 [2M+HCOO]-; t (HPLC conditions ) : 1.55 min. 1H-NMR (400 MHz, DMSO): d (ppm): 12.3 (bs, 1H), 8.33 (d, 1H), 8.21 (s, 1H), 6.70 (d, 1H), 3.89 (s, 3H), 3.32 (s, 2H), 2.43 (s,3H). 1-(6-methoxy-1 H-pyrrolo[2,3-b]pyridinyl)-ethanone To a suspension of AICI (1.37 g , 10.3 mmol) in CH C I (40 ml_) was added 6-methoxy 3 2 2 azaindole (315 mg, 2.07 mmol) and the mixture was d at RT for 30 min under nitrogen.
Acetyl chloride (736 m I_ , 10.3 mmol) was added dropwise and the resulting mixture d at RT overnight. MeOH (8 ml_) was added cautiously to quench the reaction and the solvents were removed under . The residue was purified by flash column chromatography on silica gel (CH C I to CH C I /MeOH 93-7) and by preparative HPLC (Waters e C18-ODB, 2 2 2 2 mhi , 30x100 mm, 5% to 100% CH CN in H 0 in 25 min, CH CN and H 0 containing 0.1% 3 2 3 2 TFA, flow: 40 mL/min) to give after lization (aqueous saturated NaHC0 ) and extraction (CH C I ) of the purified fractions the desired compound TLC, R (CH C I /MeOH 9:1) = 0.55; MS 2 2 f 2 2 (UPLC/MS): 191 .2 [M+H]+, 189.1 [M-H]-, 379.2 [2M-H]-; t (HPLC conditions ) : 1.45 min. 1H- NMR (400 MHz, DMSO): d (ppm): 8.35 (d, 1H), 8.29 (s, 1H), 6.75 (d, 1H), 5.04 (s, 2H), 3.89 (s, 3H), 2.44 (s, 3H). (3-Acetylmethoxy-pyrrolor2,3-blpyridinyl)-acetic acid trifluoroacetate was prepared using r procedures as described for the sis of (3-acetylmethoxypyrrolo [2,3-b]pyridinyl)-acetic acid in Scheme A15 from 1H-pyrrolo[2,3-b]pyridine carbonitrile. TLC, R (CH C I /MeOH 4:1) = 0.50; MS (UPLC/MS): 191 .2 [M+H]+, 189.1 [M-H]-; f 2 2 t (HPLC conditions f): 1.23 min. (3-Acetylcvano-pyrrolor2,3-blpyridinyl)-acetic acid was prepared using similar procedures as described for the synthesis of (3-acetylmethoxypyrrolo [2,3-b]pyridinyl)-acetic acid in Scheme A15 from 1H-pyrrolo[2,3-b]pyridine carbonitrile. MS (UPLC/MS): 244.1 [M+H]+, 242.1 [M-H]-; t (HPLC conditions ) : 1.42 min. (3-Acetylmethyl-pyrrolor2,3-clpyridin-1 -yl)-acetic acid trifluoroacetate was prepared using similar procedures as described for the synthesis of tyl-pyrrolo[2,3- c]pyridinyl)-acetic acid in Scheme A15 from 1-(5-methyl-1 H-pyrrolo[2,3-c]pyridi nyl)-ethanone (prepared according to J. Org. Chem. 2002, 67, 6226). MS (UPLC/MS): 233.2 [M+H]+, 231 .2 [M-H]-. (5-Acetyl-pyrrolor2,3-clpyridazinyl)-acetic acid was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3- c]pyridinyl)-acetic acid in Scheme A15 from 1-(7H-pyrrolo[2,3-c]pyridazinyl) one (prepared according to J. Org. Chem. 2002, 67, 6226). MS (UPLC/MS): 220.1 [M+H]+, 178.0 [MH-CH CO]+, 218.1 [M-H]-, 437.2 [2M-H]-. (3-Propionyl-pyrrolor2,3-clpyridin-1 -yl)-acetic acid trifluoroacetate was prepared using similar procedures as bed for the sis of tylmethoxypyrrolo [2,3-b]pyridinyl)-acetic acid in Scheme A15 from 1-(1 H-pyrrolo[2,3-c]pyridinyl)- propanone. 1H-NMR (400 MHz, DMSO-d ) : d (ppm): 9.56 (s, 1H), 9.09 (s, 1H), 8.58 (m, 2H), 5.42 (s, 2H), 3.0 (q, 2H), 1.15 (t, 3H). 1-(1H-Pyrrolo[2,3-c]pyridinyl)-propanone 6-Azaindole (500 mg, 4.23 mmol) was added to a suspension of AICI (2.82 g , 21.16 mmol) in CH C I (100 mL) under argon atmosphere. The mixture was stirred at RT for 30 min and 2 2 propionyl chloride (1.84 mL, 21.16 mmol) was added dropwise. The reaction mixture was stirred for 2.5 h and quenched by cautious addition of MeOH (20 mL). The solvents were d under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (CH C I to CH C I / MeOH 87:13). TLC, R (CH C I /MeOH 9:1) = 2 2 2 2 f 2 2 0.35; MS (UPLC/MS): 175.2 [M+H]+, 173.1 [M-H]-, 347.3 [2M-H]-, 219.1 [M+HCOO]-; t (HPLC conditions ) 0.42 min.
Scheme A16: Preparation of (5-Acetyl-pyrrolor2,3-dlpyrimidinyl)-acetic acid trifluoroacetate A. 5-Bromo-7H-pyrrolo[2,3-d]pyrimidine A solution of bromine (0.086 mL, 1.68 mmol) in DMF (5.5 mL) was added to a solution of 7H- pyrrolo[2,3-d]pyrimidine (200 mg, 1.68 mmol) in DMF (5.5 mL). The reaction mixture was stirred at RT for 4 h and poured into a mixture of ice and water ning Na2S20 3. A saturated aqueous solution of NaHC0 3 was added (until basic pH), the layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2S0 4) , filtered and concentrated. The al thus obtained was used without further purification in the next step. TLC, Rf (CH2C I2/MeOH 9:1) = 0.45; MS (UPLC/MS): 198.1/200.1 [M+H]+, 196.1/198.1 [M-H]-.
B. (5-Bromo-pyrrolo[2,3-d]pyrimidinyl)-acetic acid tert-butyl ester To suspension of NaH (60 % in mineral oil, 34 mg, 0.85 mmol) in DMF (1.5 mL) at 0°C under nitrogen here was added a solution of 5-bromo-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.71 mmol) in DMF ( 1 .5 mL). The reaction mixture was stirred at 0°C for 30 min and tert-butyl bromoacetate (104 m , 0.71 mmol) was slowly added. The mixture was further stirred at RT for min, then poured into water and extracted with EtOAc (x3). The combined organic ts were washed with water, dried (Na2S0 ) , ed and concentrated. MS (UPLC/MS): 312.3/314.2 [M+H]+.
C. (5-Acetyl-pyrrolo[2,3-d]pyrimidinyl)-acetic acid tert-butyl ester A solution of (5-bromo-pyrrolo[2,3-d]pyrimidinyl)-acetic acid tert-butyl ester (220 mg, 0.71 mmol), tri-butyl(1-ethoxyvinyl)tin (285 m , 0.85 mmol) and tetrakis(triphenylphosphine) palladium (16.28 mg, 14.1 mhioI) in toluene (7 mL) was heated at 110°C for 72 h under argon atmosphere. The mixture was allowed to cool to RT, poured into water and extracted with EtOAc (x2). The combined organic layers were dried (Na2S0 ) , filtered and concentrated. The crude residue was purified by flash column tography on silica gel (CH2C I2 to CH2C I2/ MeOH 94:6). TLC, Rf (CH2C I2/ MeOH 9:1) = 0.54; MS (UPLC/MS): 276.3 [M+H]+, 320.4 [M+HCOO]-; tR (HPLC conditions f): 1.40 min.
D. (5-Acetyl-pyrrolo[2,3-d]pyrimidinyl)-acetic acid A solution of tyl-pyrrolo[2,3-d]pyrimidinyl)-acetic acid tert-butyl ester (146 mg, 0.53 mmol) and TFA (0.814 mL, 10.62 mmol) in CH2C I2 (2.5 mL) was stirred at RT for 24 h .
Solvents were removed under reduced pressure and the material thus obtained was used without further purification in the next step. 1H-NMR (400 MHz, DMSO): d (ppm): 9.45 (s, 1H), 9.0 (s, 1H), 8.68 (s, 1H), 7.66-7.56 (m, 2H), 5.16 (s, 2H), 2.53 (s, 3H). 3-Acetylcarboxymethyl-1H-indazolecarboxylic acid benzyl ester was prepared using similar protocols as described in Scheme A16 Step C and D from 3- bromotert-butoxycarbonylmethyl-1 H-indazolecarboxylic acid benzyl ester. MS (UPLC/MS): 553.4 , 351.4 , 703.6 [2M-H]-; t (HPLC ions f): 2.10 min. 3-Bromotert-butoxycarbonylmethyl-1H-indazolecarboxylic acid benzyl ester was prepared using similar protocol as described in Scheme A20 Step C from 3-bromo-1 H- indazolecarboxylic acid benzyl ester. MS (UPLC/MS): 445.4/447.3 [M+H]+; t (UPLC conditions m): 1.45 min. 3-Bromo-1H-indazolecarboxylic acid benzyl ester A solution of 3-bromo-indazole-1,6-dicarboxylic acid 6-benzyl ester 1-tert-butyl ester (2.05 g , 4.75 mmol) and TFA (3.66 mL, 47.5 mmol) in CH C I (30 mL) was stirred at RT for 16 h . A 2 2 saturated aqueous solution of NaHC0 was added, the layers were separated and the s layer was ted with CH C I (x3). The combined organic extracts were dried 2 2 (Na S0 ) , filtered and concentrated and the material thus obtained was used without further 2 4 purification in the next step. MS (UPLC/MS): 331.2/333.2 [M+H]+, 329.3/331 .2 [M-H]-; t (UPLC conditions m): 1.18 min. 3-Bromo-indazole-1,6-dicarboxylic acid 6-benzyl ester 1-tert-butyl ester A solution containing o-indazole-1,6-dicarboxylic acid 1-tert-butyl ester ( 1 .80 g , 5.28 mmol), benzylbromide (0.753 mL, 6.33 mmol), Cs C0 (1.89 g , 5.80 mmol) and sodium iodide 2 3 (0.095 g , 0.633 mmol) in DMF (30 mL) was stirred 16 h at RT. The mixture was diluted with water and extracted with EtOAc (x3). The combined organic extracts were dried (Na S0 ) , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:4). MS (UPLC/MS): 431 .2/433.2 [M+H]+; t (UPLC conditions f): 2.77 min. 3-Bromo-indazole-1,6-dicarboxylic acid 1-tert-butyl ester A solution ning 3-bromo-1H-indazolecarboxylic acid (1.40 g , 5.81 mmol), triethylamine (0.89 ml, 6.39 mmol), DMAP (0.071 g , 0.58 mmol) and (Boc) 0 ( 1 .90 g , 8.71 mmol) in CH C I 2 2 2 (60 mL) was stirred 16 h at 25°C. Volatils were removed under reduced pressure, water and Et 0 were added. The aqueous layer was acidified by on of KHS0 (10% in water) and 2 4 extracted with EtOAc (x3). The combined c extracts were dried (Na S0 ) , filtered and concentrated in vacuo. The material thus obtained was used without further purification in the next step. MS (UPLC/MS): 441.2/443.2 [M+H]+. 3-Bromo-1 H-indazolecarboxylic acid Bromine (0.385 mL, 7.48 mmol) was added dropwise to a solution of 1H-indazolecarboxylic acid ( 1 g , 5.98 mmol) in acetic acid (30 mL) and the reaction mixture was d for 16 h at °C in the dark. The on was quenched by addition of a saturated s solution of Na S0 (12 mL) and brine (25 mL) and extracted with EtOAc (x3). The ed organic 2 3 extracts were washed with brine, dried (Na S0 ) , filtered and concentrated. The material thus obtained was used without further purification in the next step. MS (UPLC/MS): 239.1/241 .1 [M-H]-, 481.3/483.3 [2M-H]-; t (UPLC ions f): 1.59 min. (3-Acetylamino-pyrrolor2,3-blpyridinyl)-acetic acid A. 1-(6-Chloro-1 H-pyrrolo[2,3-b]pyridinyl)-ethanone 6-Chloroazaindole ( 1 g , 6.55 mmol) was added to a suspension of AICI (4.37 g , 32.8 mmol) in CH C I (150 mL) under nitrogen atmosphere. The mixture was stirred at RT for 30 min, and 2 2 acetyl chloride (2.34 mL, 32.8 mmol) was added dropwise. The resulting mixture was further stirred at RT for 2 h . After completion, MeOH (40 mL) was added cautiously and volatils were removed under reduced pressure. The residue was diluted in CH C I and neutralized by 2 2 addition of a saturated aqueous solution of NaHC0 . The layers were separated and the organic extratcs were dried (Na S0 ) , ed and concentrated. The crude residue was purified twice by flash column chromatography on silica gel (CH C I to CH C I / MeOH 95-5). 2 2 2 2 TLC, R (CH C I /MeOH 9:1) = 0.5; MS (UPLC/MS): 195.1/197.1 [M+H]+, 193.1/195.1 [M-H]-; t f 2 2 R (HPLC ions f): 1.54 min.
B. 1-[6-(4-Methoxy-benzylamino)-1H-pyrrolo[2,3-b]pyridinyl]-ethanone The reaction was performed ing to the protocol described in Org. Lett., 2010, 72(20), 4438-4441. A vial containing 1-(6-chloro-1H-pyrrolo[2,3-b]pyridinyl)-ethanone (100 mg, 0.49 mmol), BrettPhos (2.62 mg, 4.88 mhioI) and BrettPhos precatalyst (3.9 mg, 4.88 mhioI) and a magnetic stir bar was sealed with a teflon screw-cap, evacuated and backfilled with argon. A ballon of argon was placed on top of the vial, to allow a pressure e and LiHMDS ( 1 M in THF, 1172 m I_ , 1.17 mmol) was added, followed by 4-methoxybenzylamine (76 m I_ , 0.59 mmol).
The reaction e was d and heated at 65°C for 22 h , then allowed to cool to RT, quenched by the addition of 1 M HCI ( 1 ml_) diluted with EtOAc and poured into a saturated aqueous solution of NaHC0 . After extracting twice with EtOAc, the combined organic layers were washed with brine, dried (Na S0 ) , filtered and concentrated. The crude was purified by 2 4 flash column chromatography on silica gel ane to EtOAc). TLC, R (EtOAc) = 0.75; MS (UPLC/MS): 296.2 [M+H]+, 591 .3 [2M+H]+, 613.2 [2M+Na]+; t (HPLC conditions ) : 1.5 min.
C. [3-Acetyl(4-methoxy-benzylamino)-pyrrolo[2,3-b]pyridinyl]-acetic acid tert-butyl ester Tert-butyl bromoacetate (27 m I_ , 0.18 mmol) was added to a suspension of 1-[6-(4-methoxybenzylamino )-1H-pyrrolo[2,3-b]pyridinyl]-ethanone (0.17 mmol) and potassium carbonate (27.5 mg, 0.20 mmol) in CH CN (0.33 ml_) and THF (0.33 ml_). The reaction mixture was stirred at RT for 7 h . Potassium carbonate (27.5 mg, 0.20 mmol) and utyl bromoacetate (27 m I_ , 0.18 mmol) were added again and stirring was continued overnight, this operation was repeated the next day. The suspension was filtered, the filtrate concentrated under d pressure and the crude residue was purified by flash column tography on silica gel (CH C I to CH C I /MeOH 98:2). TLC, R (CH C I /MeOH 9:1) = 0.9; MS (UPLC/MS): 410.2 2 2 2 2 f 2 2 [M+H]+, 819.4 +, 841.3 [2M+Na]+, 454.1 [M+HCOO]-; t (HPLC conditions ) : 2.30 min.
D. (3-Acetylamino-pyrrolo[2,3-b]pyridinyl)-acetic acid trifluoroacetate A solution of [3-acetyl(4-methoxy-benzylamino)-pyrrolo[2,3-b]pyridinyl]-acetic acid tert- butyl ester (51 mg, 0.125 mmol) and TFA (191 m , 2.49 mmol) in CH C I (0.6 mL) was stirred 2 2 at RT for 24 h . Volatils were removed under reduced pressure and the brown solid thus obtained was used without further purification in the next step. MS (UPLC/MS): 234.1 [M+H]+, 232.1 [M-H]-. 1H-NMR (400 MHz, DMSO): d (ppm): 8.08 (d, 1H), 8.02 (s, 1H), 6.83 (m, 2H), 6.44 (d, 1H), 4.90 (s, 2H), 2.38 (s, 3H).
Scheme A18: Preparation of (3-acetylmethoxy-indolyl)-acetic acid A. (3-Acetylhydroxy-indolyl)-acetic acid tert-butyl ester To a solution of (3-acetylbenzyloxy-indolyl)-acetic acid tert-butyl ester (MS: 380.0 [M+H]+; tR (HPLC conditions c): 5.72 min; prepared from 5-benzyloxy-1 H-indole [12154] in a similar manner as described in Scheme A13 (step A and B)) (3.3 g , 8.70 mmol) in CH2C I2/MeOH (80 ml_) was added Pd/C (0.093 g , 0.870 mmol). The reaction mixture was stirred at RT for 5 h under H2 atmosphere. The reaction mixture was filtered over a pad of Celite and washed with CH2C I2 and MeOH. Volatiles were evaporated, and the crude mixture was purified by flash chromatography on silica gel (gradient c-hexane/EtOAc 2:1 to 100% EtOAc). TLC, Rf (c-hexane/EtOAc 1:1) = 0.35; MS: 312.0 [M+Na]+; tR (HPLC conditions c): 4.27 min.
B. (3-Acetylmethoxy-indolyl)-acetic acid tert-butyl ester To a solution of tylhydroxy-indolyl)-acetic acid tert-butyl ester (500 mg, 1.73 mmol) in CH3CN (15 ml_) was added K2C0 3 (358 mg, 2.59 mmol) and thane (0.162 ml_, 2.59 mmol). The reaction mixture was stirred at 50°C overnight. Additional K2C0 3 (716 mg, 5.18 mmol) and iodomethane (0.324 ml_, 5.18 mmol) were added and heating was continued for an additional 2 days. Volatiles were evaporated, the on mixture was taken up in water and extracted twice with AcOEt. The combined organic phases were dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 304.0 [M+H]+, 629.0 [2M+Na]+; tR (HPLC conditions c): 4.92 min.
C. (3-Acetylmethoxy-indolyl)-acetic acid To (3-acetylmethoxy-indolyl)-acetic acid tert-butyl ester (520 mg, 1.71 mmol) in CH2C I2 (15 mL) was added TFA (1.32 mL, 17.1 mmol). The reaction mixture was stirred at RT overnight. les were evaporated, then the crude material was taken up in 5 mL of 1M aqueous NaOH solution and washed with CH2C I2 which was discarded. The water phase was acidified to pH=1 by adding a 6M aqueous HCI solution, and then was ted twice with AcOEt. The ed organic phases were dried (Phase tor) and evaporated to give the title nd. MS (LC/MS): 248.1 [M+H]+, 246.1[M-H]-; tR (HPLC conditions c): 3.47 min.
Scheme A19 : Preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid A. lmidazo[1,5-a]pyridinyl-acetic acid methyl ester A suspension of imidazo[1,5-a]pyridinylacetic acid (Ellanovalabs, 2 g , 11.35 mmol) and camphorsulfonic acid (2.9 g , 12.49 mmol) in MeOH (120 mL) was refluxed for 4 h . Then allowed to cool to RT and concentrated under reduced pressure. The crude residue was diluted in CH C I and the organic layer was washed with a saturated aqueous solution of 2 2 NaHC0 . The cs were dried (Na S0 ) , filtered and trated. The material thus 3 2 4 ed was used in the next step without further purification: TLC, R (CH C I /MeOH 9:1) = f 2 2 0.55; MS (UPLC/MS): 191.1 [M+H]+; t (HPLC conditions ) : 0.4 min.
B. tyl-imidazo[1,5-a]pyridinyl)-acetic acid methyl ester A solution of imidazo[1,5-a]pyridinyl-acetic acid methyl ester (1.38 g , 7.26 mmol) in CH C I 2 2 (50 mL) was added to a suspension of AICI (2.9 g , 21.77 mmol) in CH C I ( 115 mL) and the 3 2 2 mixture was stirred at RT for 30 min under en here. Acetyl chloride ( 1 .55 mL, 2 1.77 mmol) was subsequently added dropwise and the mixture was further stirred overnight.
AICI ( 1 .94 g , 14.51 mmol) and 15 min later acetyl chloride ( 1 .04 mL, 14.51 mmol) were added and stirring was continued overnight to complete the reaction. The reaction mixture was cooled with at 0°C and carefully quenched by us addition of MeOH (35 mL). Solvents were evaporated under d pressure and the crude residue was purified by flash column chromatography on silica gel (eluent: CH C I to CH C I /MeOH 94:6). TLC, R (CH C I /MeOH 2 2 2 2 f 2 2 9:1) = 0.60; MS (UPLC/MS): 233.1 [M+H]+, 255.1 +, 487.1 [2M+Na]+; t (HPLC conditions ) 1.27 min.
C. Lithium (1-acetyl-imidazo[1,5-a]pyridinyl)-acetate To a solution of (1-acetyl-imidazo[1,5-a]pyridinyl)-acetic acid methyl ester (1.12 g , 4.82 mmol) in THF (15 mL) and water (7.5 mL) was added LiOH.H 0 (202 mg, 4.82 mmol). The reaction was stirred at RT for 5.5 h until completion of the reaction. The mixture was concentrated under reduced pressure and the material thus obtained was used in the next step without further purification: MS (UPLC/MS): 219.2 [M+H]+, 241 .2 [M+Na]+, 217.2 [M-H]-; t (HPLC conditions f): 1 03 min.
Scheme A20: Preparation of (3-Acetylmethyl-pyrazolor3,4-clpyridinyl)-acetic acid trifluoroacetate A. 3-Bromomethyl-1 H-pyrazolo[3,4-c]pyridine -Methyl-1H-pyrazolo[3,4-c]pyridine (2 g , 15.02 mmol) and bromine (0.774 ml_, 15.02 mmol) in water (71 .5 ml_) were stirred at RT for 1 h . The reaction mixture was neutralized with NaOH (20% in water), the precipitate was filtered, washed with water and dried under high vacuum.
Yellow powder, MS (UPLC/MS): 212/214 [M+H]+, 210/212 [M-H]-; t (HPLC conditions f): 0.74 min.
B. 1-(5-Methyl-1H-pyrazolo[3,4-c]pyridinyl)-ethanone A solution of 3-bromomethyl-1H-pyrazolo[3,4-c]pyridine (2.13 g , 10.04 mmol), tri-butyl(1- ethoxyvinyl)tin (6.78 ml_, 20.09 mmol) and PdCI (PPh ) (0.705 mg, 1 mmol) in DMF (12.6 ml_) 2 3 2 was heated at 80°C overnight under argon atmosphere. Then trated under reduced pressure and diluted with EtOAc. HCI (2N) was added, the layers were separated and the aqueous layer was ed by addition of NaHC0 (1N in water) and extracted with EtOAc (3x). The combined organic extracts were dried (Na S0 ) , filtered and concentrated. The 2 4 yellow oil thus obtained was used t further purification in the next step. TLC, Rf (c- / EtOAC 1:1) = 0.05; MS (UPLC/MS): 176 [M+H]+, 174 [M-H]-.
C. (3-Acetylmethyl-pyrazolo[3,4-c]pyridinyl)-acetic acid tert-butyl ester To a solution of 1-(5-methyl-1H-pyrazolo[3,4-c]pyridinyl)-ethanone ( 1 g , 5.71 mmol) in CH CN (30 ml_) were added potassium carbonate ( 1 .81 g , 13.13 mmol) and utyl bromoacetate (0.927 ml_, 6.28 mmol). The reaction mixture was stirred at reflux for 1 h , then poured into water and extracted with EtOAc (x3). The ed organic extracts were dried (Na S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 3:2). TLC, Rf (c-hexane/ EtOAC 1:1) = 0.25; MS (UPLC/MS): 290 [M+H]+; t (HPLC conditions ) : 1.50 min.
D. (3-Acetylmethyl-pyrazolo[3,4-c]pyridinyl)-acetic acid A solution of (3-acetylmethyl-pyrazolo[3,4-c]pyridinyl)-acetic acid tert-butyl ester (126 mg, 0.37 mmol) and TFA (0.171 mL, 2.22 mmol) in CH C I (5 mL) was stirred at RT for 24 h . 2 2 Solvents were removed under d pressure, Et 0 was added and the itate was filtered, washed with Et 0 and dried under high vacuum. The material thus obtained was used without r purification in the next step. MS (UPLC/MS): 234 [M+H]+, 232 [M-H]-, 465 [2M- H]-; t (HPLC conditions ) : 0.53 min. (3-Acetyl-pyrazolor4,3-clpyridinyl)-acetic acid trifluoroacetate was prepared using similar procedures as described for the synthesis of (3-acetylmethylpyrazolo ]pyridinyl)-acetic acid in Scheme A20 from 1-(1 H-pyrazolo[4,3-c]pyridinyl)- ethanone (Sphinx Scientific laboratory LLC, catalog number: PPY-CS0001). 1H-NMR (400 MHz, DMSO): d (ppm): 9.57 (s, 1H), 8.52 (m, 1H), 8.08 (m, 1H), 5.56 (s, 2H), 2.69 (s, 3H). (3-Acetyl-pyrazolor3,4-clpyridinyl)-acetic acid trifluoroacetate was prepared using similar ures as described for the synthesis of (3-acetylmethylpyrazolo [3,4-c]pyridinyl)-acetic acid in Scheme A20 from 1-(1 zolo[3,4-c]pyridinyl)- ethanone (Sphinx Scientific laboratory LLC, catalog number: PPYCS01). MS (UPLC/MS): 220 ; t (HPLC conditions I): 0.69 min. (3-Acetyl-pyrazolor3,4-blpyridin-1 -yl)-acetic acid trifluoroacetate was prepared using similar procedures as described for the sis of (3-acetylmethylpyrazolo [3,4-c]pyridinyl)-acetic acid in Scheme A20 from 1-(1H-pyrazolo[3,4-b]pyridinyl)- ethanone (Sphinx Scientific laboratory LLC, 14], PYP0043). MS (UPLC/MS): 220 [M+H]+, 218.2 [M-H]-; t (HPLC conditions k): 2.51 min.
Scheme A21 : ation of 2-(3-acetyl(methoxycarbonyl)-1H-indazolyl)acetic acid A. Methyl 3-bromo-1 -(2-tert-butoxyoxoethyl)-1 H-indazolecarboxylate The title compound was prepared from methyl 3-bromo-1 H-indazolecarboxylate [192945- 56-5] in a similar manner as described in step B of Scheme A13 for the preparation of (3- acetyltrifluoromethoxy-indolyl)-acetic acid. MS: 392 [M+Na]+, 313 [M-tBu]+; t (HPLC conditions k): 4.08 min.
B. Methyl 3-acetyl-1 -(2-tert-butoxyoxoethyl)-1 H-indazolecarboxylate A solution of methyl 3-bromo(2-tert-butoxyoxoethyl)-1 H-indazolecarboxylate (1.00 g , 2.71 mmol), n-butyl vinylether ( 1 .75 ml_, 13.5 mmol), palladium acetate (61 mg, 0.27 mmol), triphenylphosphine (142 mg, 0.54 mmol) and triethylamine (0.45 ml_, 3.25 mmol) in dry CH CN (10 ml_) was heated at 100°C under microwave irradiation for 7 h . Then, the mixture was further heated at 120°C for 5 h under microwave irradiation . The solvent was evaporated, and the e was then d with 4N HCI/dioxane with stirring at RT for 16 h . Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 m , 30x100 mm, flow: 40 mL/min, eluent: 5-100% CH CN/H O/20 min, 100% CH CN/2 min, 3 2 3 CH CN and H 0 containing 0.1% TFA) to give after lyophilization of the pure fractions the title 3 2 compound. MS ): 333 [M+H]+, 355 [M+Na]; t (HPLC conditions k): 3.83 min.
C. 2-(3-Acetyl(methoxycarbonyl)-1H-indazolyl)acetic acid The title compound was prepared from methyl 3-acetyl(2-tert-butoxyoxoethyl)-1H- indazolecarboxylate in a similar manner as described in step C of Scheme A13 for the preparation of (3-acetyltrifluoromethoxy-indolyl)-acetic acid. MS: 277 [M+H]+; t (HPLC conditions k): 2.95 min.
Scheme A22: Preparation of 2-(3-(2-vvdroxyacetyl)-1H-indazolyl)acetic acid A. Tert-butyl 2-(3-acetyl-1H-indazolyl)acetate The title compound was prepared from indazolyl)ethanone [44980] in a similar manner as described in step B of Scheme A13 for the ation of (3-acetyl trifluoromethoxy-indolyl)-acetic acid. MS: 275 [M+H]+; t (HPLC conditions k): 3.78 min.
B. 2-(3-Acetyl-1H-indazolyl)acetic acid The title compound was prepared from tert-butyl 2-(3-acetyl-1H-indazolyl)acetate in a similar manner as bed in step C of Scheme A13 for the ation of (3-acetyl trifluoromethoxy-indolyl)-acetic acid. MS: 219 [M+H]+; t (HPLC ions k): 2.78 min.
C. 2-(3-(2-Hydroxyacetyl)-1H-indazolyl)acetic acid The title compound was prepared in a similar manner as described by N.Yoshikawa et al., J.
Org. Chem., 2002, 67, 565: A mixture of 2-(3-acetyl-1H-indazolyl)acetic acid (100 mg, 0.46 mmol), TFA (0.71 mL, 0.92 mmol) and bis-(trifluoroacetoxy)-iodobenzene (394 mg, 0.92 mmol) in CH CN (4 mL) and water (0.6 mL) was heated to reflux (90°C) for 16 h . ts were evaporated and the crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, flow: 40 mL/min, : 5-100% CH CN/H O/20 min, 100% 3 2 CH CN/2 min, CH CN and H 0 containing 0.1% TFA) to give after lyophilization of the purified 3 3 2 fractions the title compound. MS (LC-MS): 233 ; t (HPLC conditions k): 2.41 min.
Scheme A23: Preparation of cetyl-5,6-dimethoxy-1H-indazolyl)acetic acid TBAF, THF A. 5,6-Dimethoxy((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole The title compound was prepared in a similar manner as bed by G . Luo et al., J. Org.
Chem. 2006, 71, 5392-5395: To a solution of 5,6-dimethoxyindazole [77467] (356 mg, 2.00 mmol) in THF (20 mL) was added dicyclohexylmethylamine (0.51 mL, 2.40 mmol) ed by SEM-CI (0.43 mL, 2.40 mmol). The mixture was stirred at RT for 24 h , followed by dilution with EtOAc and quench with 1N aqueous NaOH solution. The layers were separated and the organic layer was washed with water and brine, then dried (Phase separator) and ated.
The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 4:1 to 1:1) to separate from the regioisomer 5,6-dimethoxy((2-(trimethylsilyl)ethoxy)methyl)-1 H- indazole and to provide the title compound. TLC, R (c-hexane/EtOAc 1:1) = 0.37; MS (LC/MS): 309 [M+H; t (HPLC conditions k): 3.70 min.
B. 1-(5,6-Dimethoxy((2-(trimethylsilyl)ethoxy)methyl)-2H-indazolyl)ethanone The title compound was prepared in a similar manner as described by G . Luo et al., J. Org.
Chem. 2006, 71, 5392-5395: To a solution of 5,6-dimethoxy((2-(trimethylsilyl) )methyl)-2H-indazole (200 mg, 0.65 mmol) in THF (5 mL) at -78°C was added dropwise a 2.5 M solution of n-BuLi in hexanes (0.29 mL, 0.71 mmol). The reaction mixture was stirred at -78°C for 20 min. Acetyl chloride (0.07 mL, 0.97 mmol) was then added dropwise, and the mixture was stirred at RT for 16 h . Saturated aqueous NH C I solution was added to the reaction mixture, followed by stirring for 30 min. The aqueous phase was extracted twice with EtOAc and the combined organics were washed with brine, dried (Phase tor) and evaporated to give the crude title compound which was used directly in the next step without further purification.
C. 1-(5,6-Dimethoxy-1 H-indazolyl)ethanone The title compound was prepared in a similar manner as described by G . Luo et al. , J. Org.
Chem. 2006, 7 1, 5392-5395: To a solution of 1-(5,6-dimethoxy((2-(trimethylsilyl) ethoxy)methyl)-2H-indazolyl)ethanone (200 mg, 0.57 mmol) in THF (6 ml_) was added a 1M solution in THF of TBAF (2.85 ml_, 2.85 mmol) , and the mixture was heated to reflux for 16 h .
The reaction mixture was then diluted with EtOAc and successively washed with water and brine, then dried (Phase separator) and evaporated. The crude product was purified by preparative HPLC (Waters Sunfire, C 18-ODB, 5 m h , 30x1 00 mm, flow: 40 mL/min, eluent: 5- 100% CH /2O min, 100% CH CN/2 min, CH CN and H 0 containing 0 .1% TFA) to give 3 3 3 2 after lyophilization of the ed fractions the title compound. MS (LC-MS): 221 [M+H]+; t (HPLC conditions k) : 2.61 min.
D. utyl 2-(3-acetyl-5,6-dimethoxy-1 zol-1 -yl)acetate The title compound was prepared from 1-(5,6-dimethoxy-1 H-indazolyl)ethanone in a similar manner as described in step B of Scheme A 13 for the ation of (3-acetyl trifluoromethoxy-indol-1 -yl)-acetic acid. MS: 335 ; t (HPLC conditions k): 3.58 min.
E. 2-(3-Acetyl-5,6-dimethoxy-1 H-indazol-1 -yl)acetic acid The title compound was prepared from tert-butyl 2-(3-acetyl-5,6-dimethoxy-1 H-indazol-1 - yl)acetate in a similar manner as described in step C of Scheme A 13 for the ation of (3- acetyltrifluoromethoxy-indol-1 -yl)-acetic acid. MS: 279 [M+H]+; t (HPLC conditions k) : 2.73 min.
Scheme A24: Preparation of 2-(3-acetyl(pyrimidinylmethoxy)-1 H-indazol-1 -yl)acetic acid A. 5-(Benzyloxy)-N-methoxy-N-methyl-1 H-indazolecarboxamide The title compound was prepared in a r manner as described by F. Crestey et al., Tetrahedron 2007, 63, 419-428: To 5-(benzyloxy)-1 H-indazolecarboxylic acid [1779411] (3.50 g , 13.1 mmol) in THF (70 mL) was added N,O-dimethylhydroxylamine (1.40 g , 14.4 mmol). The mixture was cooled to 0°C before the addition of pyridine (2.30 mL, 28.7 mmol).
The on was stirred at 0°C for 1.5 h , and then at RT for 1 h . ne (2.10 mL, 26.1 mmol) and EDCI (5.00 g , 26.1 mmol) were added and the mixture was d at RT overnight. Water was added to the reaction mixture followed by extraction (x3) with CH2C I2. The combined organics were washed with saturated aqueous NaHC0 3 solution, then dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 312.0 [M+H]+, 334.0 +, 645.1 [2M+Na]+, 310.0 ; tR (HPLC conditions c): 4.44 min.
B. Tert-butyl 5-(benzyloxy)(methoxy(methyl)carbamoyl)-1 H-indazole-1 -carboxylate The title compound was prepared in a similar manner as described by F. Crestey et al., Tetrahedron 2007, 63, 419-428: To a solution of 5-(benzyloxy)-N-methoxy-N-methyl-1H- lecarboxamide (3.40 g , 10.9 mmol) in CH2C I2 (70 mL) was added DMAP (0.13 g , 1.09 mmol), TEA (1.67 mL, 12.0 mmol) and Boc-anhydride (3.80 mL, 16.4 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h and allowed to return to RT overnight. The reaction mixture was diluted with CH2C I2 and washed with 50 mL of 0.1 M aqueous HCI solution and water. The organic phase was dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 434.0 [M+Na]+, 845.0 [2M+Na]+; tR (HPLC conditions c): 5.79 min.
C. Tert-butyl 3-acetyl(benzyloxy)-1 H-indazole-1 -carboxylate and 1-(5-(benzyloxy)-1H- indazolyl)ethanone The title compound was ed in a similar manner as described by F. Crestey et ai, Tetrahedron 2007, 63, 419-428: To tert-butyl 5-(benzyloxy)(methoxy(methyl)carbamoyl)-1 H- indazolecarboxylate (4.70 g , 11.4 mmol) in THF (60 mL), cooled to -78°C, was added a 3 M on of MeMgBr (22.9 mL, 68.5 mmol) in Et20 . The reaction mixture was stirred at -78°C for 1 h . A saturated aqueous NH4C I solution was added to the reaction mixture and temperature was allowed to raise to RT. The mixture was extracted twice with CH2C I2, the combined organics were dried (Phase separator) and evaporated to give the title mixture which was used without purification in the next step.
D. 1-(5-(Benzyloxy)-1H-indazolyl)ethanone To the mixture of tert-butyl 3-acetyl(benzyloxy)-1H-indazolecarboxylate and 1-(5- (benzyloxy)-1 H-indazolyl)ethanone (3.80 g , 10.4 mmol) in CH2C I2 (50 mL) was added TFA (7.99 mL, 104 mmol). The reaction mixture was stirred at RT ght. The reaction mixture was diluted with CH2C I2 and washed with 100 mL of 2N s NaOH solution. The basic phase was extracted twice with CH2C I2, then the combined organic phases were dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 267.0 [M+H]+, 289.0 [M+Na]+, 265.1 [M-H]-; tR (HPLC ions c): 4.71 min.
E. Methyl 2-(3-acetyl(benzyloxy)-1H-indazolyl)acetate To 1-(5-(benzyloxy)-1 H-indazolyl)ethanone (3.50 g , 13.1 mmol) in CH3CN (100 mL) was added K2C0 3 (4.54 g , 32.9 mmol) and methyl 2-bromoacetate (1.33 mL, 14.5 mmol). The reaction mixture was stirred at 90°C for 90 min. The reaction mixture was filtered and the solid was washed with CH3CN. Volatiles were evaporated and then the crude mixture was purified by flash column tography on silica gel (gradient: c-hexane/EtOAc 1:1 to 1:3). TLC, Rf (c-hexane/EtOAc 1:3) = 0.64; MS (LC/MS): 339.0 [M+H]+, 361.0 [M+Na]+; tR (HPLC conditions c): 5.09 min.
F. Methyl 2-(3-acetylhydroxy-1H-indazolyl)acetate To methyl 2-(3-acetyl(benzyloxy)-1H-indazolyl)acetate (3.70 g , 10.9 mmol) in THF (80 mL) was added Pd/C (10%, 400 mg). The reaction mixture was stirred at 50°C overnight under a H2 atmosphere. The reaction mixture was filtered over a pad of Celite and washed with CH2C I2, then volatiles were ated to give the title compound. MS (LC/MS): 248.9 [M+H]+, 271.0 [M+Na]+; tR (HPLC conditions c): 3.36 min.
G. Methyl 2-(3-acetyl(pyrimidinylmethoxy)-1H-indazolyl)acetate To methyl 2-(3-acetylhydroxy-1 H-indazolyl)acetate (1.80 g , 7.25 mmol) in CH3CN (75 mL) was added 2-(chloromethyl)pyrimidine hydrochloride salt (1.32 g , 7.98 mmol) and Cs2C0 3 (5.91 g , 18.13 mmol). The reaction mixture was stirred at 70°C for 2 h . The reaction mixture was filtered and washed with CH3CN. Solvent was evaporated and the crude mixture was purified by flash column chromatography on silica gel (gradient: c-hexane/EtOAc 1:1 to 1:3).
TLC, Rf (c-hexane/EtOAc 1:3) = 0.35; MS (LC/MS): 340.9 [M+H]+, 363.0 [M+Na]+; tR (HPLC conditions c): 3.64 min.
H. cetyl(pyrimidinylmethoxy)-1H-indazolyl)acetic acid To methyl 2-(3-acetyl(pyrimidinylmethoxy)-1 H-indazolyl)acetate (1.93 g , 5.67 mmol) in THF (15 mL) and water (15 mL) was added LiOH.H20 (0.25 g , 5.95 mmol). The reaction mixture was stirred at RT for 1.5 h . Volatiles were evaporated and the residue was freeze-dried overnight to give the title nd. MS (LC/MS): 327.0 [M+H]+, 325.1 [M+H]+; tR (HPLC conditions c): 3.24 min. (3-Acetylbenzyloxy-indazol-1 cetic acid To a solution of (3-acetylbenzyloxy-indazolyl)-acetic acid methyl ester (prepared as described in Scheme A24, 1.50 g , 4.43 mmol) in MeOH (40 mL) was added a 10% aqueous solution of NaOH (5.32 mL, 13.30 mmol) and the resulting mixture was d at RT for 16 h .
The e was concentrated, diluted in water and acidified to pH = 2 with 6N HCI. The mixture was then extracted with EtOAc and the organic layer was dried (Na2S0 4) , ed and concentrated. The product was used in the next step without further purification. MS (UPLC- MS): 325 [M+H]+; tR (UPLC conditions m): 0.90 min. cheme A25: Pre aration of (3-carbamoyl-indazolyl)-acetic acid A. Tert-butyl 2-(3-carbamoyl-1H-indazolyl)acetate To a suspension of 1H-indazolecarboxamide [900049] (2.00 g , 12.4 mmol) and potassium carbonate (4.12 g , 29.8 mmol) in CH3CN (60 mL) was added tert-butyl bromoacetate (2.20 mL, 14.9 mmol) dropwise at RT, and the resulting mixture was heated to reflux for 16 h . The mixture was then cooled to RT and filtered, the solid was washed with CH3CN and the filtrate was concentrated under vacuum. The residual oil was used directly in the next reaction step without further purification. MS (LC/MS): 276.0 [M+H]+; t (HPLC conditions k): 3.22 min.
B. (3-Carbamoyl-indazolyl)-acetic acid To a solution of tert-butyl 2-(3-carbamoyl-1H-indazolyl)acetate (3.42 g , 12.4 mmol) in CH C I (20 mL) was added TFA (10 mL, 130 mmol) and the resulting mixture was stirred at RT 2 2 for 16 h . The reaction mixture was concentrated in vacuo, the residual solid was suspended in methanol and concentrated again in vacuo to give the title compound. MS (LC/MS): 220 [M+H]+; t (HPLC conditions k): 1.79 min.
Scheme A26: ation of 2-(3-carbamoyl-1H-pyrazolor3,4-clpyridinyl)acetic acid A. 3-lodo-1 H-pyrazolo[3,4-c]pyridine To a solution of 1H-pyrazolo[3,4-c]pyridine [2716 ] (4.00 g , 33.6 mmol) in DMF (50 mL) were added iodine (12.8 g , 50.4 mmol) and potassium hydroxide (4.70 g , 84.0 mmol). The reaction mixture was stirred at RT for 16 h . The mixture was diluted with 10% sodium lfate and water, then extracted (3x) with EtOAc. The combined organic ts were washed with brine, then dried (Phase tor) and concentrated under . MS (LC/MS): 246.0 [M+H]+; t (HPLC ions k): 0.48 min.
B. Tert-butyl 2-(3-iodo-1H-pyrazolo[3,4-c]pyridinyl)acetate To a suspension of 3-iodo-1 H-pyrazolo[3,4-c]pyridine (6.24 g , 22.9 mmol) and potassium carbonate (7.29 g , 52.7 mmol) in acetonitrile (50 mL) was added utyl bromoacetate (4.06 mL, 27.5 mmol) dropwise at RT and the resulting mixture was heated to reflux for 2 h . The mixture was cooled to RT and filtered, the solid was washed with CH CN and the te was concentrated under vacuum. The residual oil was purified by flash column chromatography on silica gel (gradient EtOAc/c-hexane 1:4, then 1:2, then 1:1). MS (LC/MS): 360.0 [M+H]+; t (HPLC conditions k): 2.93 min.
C. Tert-butyl 2-(3-cyano-1H-pyrazolo[3,4-c]pyridinyl)acetate A mixture of tert-butyl 2-(3-iodo-1H-pyrazolo[3,4-c]pyridinyl)acetate (3.76 g , 10.5 mmol), Zn(CN) (1.35 g , 11.5 mmol), Pd(dppf)CI (855 mg, 1.05 mmol), Pd (dba) (959 mg, 1.05 2 2 2 3 mmol), water (4 mL) and DMF (30 mL) was stirred at 100°C for 16 h under argon. The reaction mixture was diluted with EtOAc and then was successively washed with water, sat. aq.
NaHC0 3 (2x) and brine, dried (Phase separator) and concentrated under vacuum. The residual oil was purified by flash column tography on silica gel (EtOAc/c-hexane 1:1 then 100% . MS (LC/MS): 259.0 [M+H]+; tR (HPLC conditions k): 3.10 min. Further elution of the column with CH2C I2/MeOH 8:2 and subsequent purification by preparative HPLC (Macherey- Nagel Nucleosil 100-10 C18, 5 m h , 40x250 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H 2O/20 min, 100% CH3CN/2 min, CH3CN and H20 containing 0.1% TFA) afforded tertbutyl 2-(3-carbamoyl-1 zolo[3,4-c]pyridinyl)acetate as a side-product. MS (LC/MS): 277.0 [M+H]+; tR (HPLC conditions k): 2.39 min.
D. 2-(3-Carbamoyl-1H-pyrazolo[3,4-c]pyridinyl)acetic acid A solution of tert-butyl 2-(3-cyano-1 H-pyrazolo[3,4-c]pyridinyl)acetate (663 mg, 2.40 mmol) in TFA (6 mL) was subjected to microwave irradiation at 140°C for 90 min. The reaction mixture was concentrated in vacuo, the residual solid was suspended in MeOH and volatiles were removed again in vacuo. MS: 221 .0 ; tR (HPLC conditions k): 0.23 min.
From tert-butyl 2-(3-carbamoyl-1 H-pyrazolo[3,4-c]pyridinyl)acetate: To a solution of tert-butyl 2-(3-carbamoyl-1 zolo[3,4-c]pyridinyl)acetate (663 mg, 2.40 mmol) in CH2C I2 (20 mL) was added TFA (10 mL, 130 mmol), and the ing mixture was stirred at RT for 6 h . The reaction mixture was concentrated in vacuo, the residual solid was suspended in methanol and volatiles were d again in vacuo to give the title compound. bamoylethyl-pyrazolor3,4-clpyridinyl)-acetic acid was prepared from 5-ethyl-1H-pyrazolo[3,4-c]pyridine by using the same procedures as for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridinyl)acetic acid (Scheme A26). MS (LC-MS): 249 [M+H]+, tR (HPLC conditions k): 0.49 min.
-Ethyl-1H-pyrazolo[3,4-c]pyridine Triethylaluminum (21 .7 mL, 40.4 mmol, 25 wt% solution in toluene) was added to a usly stirred solution of 5-bromo-1 H-pyrazolo[3,4-c]pyridine [9296176] (4.00 g , 20.2 mmol) and Pd(PPh 3)4 ( 1 .17 g , 1.01 mmol) in THF (100 mL) under argon. The reaction mixture was stirred at 65°C for 60 h . The mixture was cooled to RT and poured into sat. aq. NH CI. The resulting suspension was filtered, the solid was washed with water and discarded. The filtrate and combined washings were extracted with EtOAc (3x). The combined organic extracts were washed with brine, then dried (Phase separator) and concentrated under reduced pressure.
The residual oil was purified by flash column chromatography on silica gel (EtOAc/c-hexane 50:50, then 75:25, then 100:0). TLC, R (c-hexane/EtOAc 1:3) = 0.22; MS (LC-MS): 148 [M+H]+, t (HPLC conditions k): 0.71 min. (3-Carbamoylmethyl-pyrazolor3,4-clpyridin-1 -yl)-acetic acid was ed using the same procedure as for the preparation of 2-(3-carbamoyl-1H- pyrazolo[3,4-c]pyridinyl)acetic acid starting from 7-methyl-1H-pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 235 [M+H]+, t (HPLC conditions k): 0.6 min. 7-Methyl-1H-pyrazolo[3,4-c]pyridine Trimethylaluminum (23.9 mL, 47.8 mmol, 2M sol. in toluene) was added to a vigorously stirred solution of 7-chloro-1 H-pyrazolo[3,4-c]pyridine (3.67 g , 23.9 mmol) and Pd(PPh ) ( 1 .38 g , 1.19 mmol) in THF (109 mL) under argon. The reaction mixture was stirred at 65°C for 16 h . The mixture was cooled to RT and poured into sat. aq. NH CI. The resulting sion was filtered, the solid washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3x). The combined organic extracts were washed with brine then dried (Phase separator) and concentrated under reduced pressure to give 7-methyl-1H- pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 134 [M+H]+, t (HPLC conditions k): 0.25 min. 7-Chloro-1H-pyrazolo[3,4-c]pyridine A solution of 2-chloromethylpyridinamine 79] (3.0 g , 21.0 mmol) in acetic acid (300 mL) was treated with a solution of sodium nitrite ( 1 .45 g , 2 1.0 mmol) in water (2.5 mL).
The reaction mixture was d at rt for 15 min then d to stand at ambient temperature for 24 h . An additional solution of sodium nitrite (500 mg, 7.25 mmol) in water ( 1 mL) was added to the mixture which was allowed to stand at rt for 3 h . Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHC0 . The ble solid was filtered off (dried under vacuum; batch 1) and the organic filtrate was washed with water and brine, then dried (Phase separator) and concentrated under vacuum (batch 2). The two s were combined to give ro-1H- pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 153 [M+H]+, t (HPLC conditions k): 0.9 min. (3-Carbamoyl-5,7-dimethyl-pyrazolor3,4-clpyridinyl)-acetic acid was prepared from 5,7-dimethyl-1H-pyrazolo[3,4-c]pyridine by using the same procedures as described for the preparation of 2-(3-carbamoyl-1 H-pyrazolo[3,4-c]pyridinyl)acetic acid (Scheme A26). MS (LC-MS): 249 [M+H]+, t (HPLC conditions c): 0.9 min. ,7-Dimethyl-1H-pyrazolo[3,4-c]pyridine To a vigorously stirred solution of 7-bromomethyl-1 H-pyrazolo[3,4-c]pyridine (3.65 g , 14.6 mmol) and Pd(PPh ) (845 mg, 0.73 mmol) in THF (65 ml_) was added trimethylaluminum (14.6 ml_, 29.3 mmol; 2 M sol. in toluene) under argon. The reaction mixture was stirred at 65°C for 60 h , and then was cooled to RT and poured into a sat. aq. NH C I solution. The resulting sion was ed, the solid was washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3x). The ed cs were washed with brine, then dried (Phase tor) and concentrated under reduced pressure to give 5,7-dimethyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 148 [M+H]+, t (HPLC conditions k): 0.50 min. 7-Bromomethyl-1H-pyrazolo[3,4-c]pyridine A on of 2-bromo-4,6-dimethylpyridinamine [1048293] (4.00 g , 19.9 mmol) in acetic acid (300 mL) was treated with a solution of sodium nitrite (1.37 g , 19.9 mmol) in water (2.5 mL). The reaction mixture was stirred at RT for 15 min and was then allowed to stand at t temperature for 24 h . An additional solution of sodium nitrite (500 mg, 7.25 mmol) in water ( 1 mL) was added to the mixture which was allowed to stand at RT for 16 h . Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHC0 . The precipitate was filtered off, washed and discarded.
The combined filtrates were washed with water and brine, then dried (Phase separator) and concentrated under vacuum to give 7-bromomethyl-1 H-pyrazolo[3,4-c]pyridine as a solid.
MS (LC-MS): 212 [M+H]+, t (HPLC conditions k): 2.49 min. (3-Carbamoylcvclopropyl-1H-pyrazolor3,4-clpyridinyl)acetic acid was prepared by using the same procedure as described for the ation of 2-(3- carbamoyl-1H-pyrazolo[3,4-c]pyridinyl)acetic acid and by starting from 5-cyclopropyl-1H- pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 261 [M+H]+, tR (HPLC conditions c): 1.84 min. opropyl-1H-pyrazolo[3,4-c]pyridine A solution of 6-cyclopropylmethylpyridinamine (130 mg, 0.88 mmol) in AcOH (10 mL) was treated with a solution of sodium nitrite (61 mg, 0.88 mmol) in water (0.5 mL). The reaction mixture was stirred at RT for 15 min and then was allowed to stand at RT for 24 h . AcOH was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHC0 3. The organic on was washed with water and brine, then dried (Phase separator) and concentrated under. MS (LC-MS): 160 [M+H]+, tR (HPLC conditions c): 2.07 min. 6-Cyclopropylmethylpyridinamine To a solution of 2-cyclopropylmethylnitropyridine (201 mg, 0.96 mmol) in MeOH (5 mL) were added 3N aqueous HCI (9.6 mL, 28.8 mmol) and Zn powder (376 mg, 5.75 mmol). The mixture was stirred 18 h at RT. The solution was neutralized with a sat. aq. NaHC0 3 solution and extracted with CH2C I2 (3x). The combined organics were dried (Phase tor) and concentrated under reduced pressure. MS (LC-MS): 149 , tR (HPLC conditions c): 2.22 min. 2-Cyclopropylmethylnitropyridine Potassium cyclopropyltrifluoroborate (857 mg, 5.79 mmol), 2-chloromethylnitropyridine (500 mg, 2.90 mmol), Pd(OAc) 2 (26 mg, 0.12 mmol), Cs2C0 3 (2.83 g , 8.69 mmol), and n-butyldi-adamantylphosphine (62 mg, 0.17 mmol) were charged into a capped vial. The vial was purged with argon and then sealed with a septum cap. Toluene/H 20 10:1 ( 1 1 mL) was added by syringe and the e was heated at 100°C for 16 h . More potassium cyclopropyltrifluoroborate (857 mg, 5.79 mmol) was added to the e which was further heated at 100°C for 72 h . The e was d with CH2C I2 and filtered through a pad of Celite. The filtrate was dried (Phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, flow: 40 mL/min, : 5-100% CH3CN/H 2O/30 min, 100% CH3CN/3 min, CH3CN and H20 containing 0.1% TFA). MS (LC-MS): 179 [M+H]+, tR (HPLC conditions c): 4.26 min. (3-Carbamoyl(trifluoromethyl)-1 H-pyrazolor3,4-clpyridin-1 -vPacetic acid was prepared by using the same procedure as described for the preparation of 2-(3- carbamoyl-1H-pyrazolo[3,4-c]pyridinyl)acetic acid and by starting from 5-trifluoromethyl-1 H- pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 289 [M+H]+, t (HPLC conditions c): 2.93 min. luoromethyl-1H-pyrazolo[3,4-c]pyridine A solution of 4-methyl(trifluoromethyl)pyridinamine [9443178] (1.00 g , 5.68 mmol) in acetic acid (75 mL) was treated with a solution of sodium e (392 mg, 5.68 mmol) in water ( 1 mL). The reaction mixture was stirred at RT for 15 min and then was allowed to stand at ambient temperature for 48 h . Acetic acid was evaporated under reduced pressure and the residual aqueous on was partitioned between EtOAc and sat. aq. NaHC0 . The organic solution was washed with water and brine, then dried (Phase separator) and concentrated under vacuum. MS (LC-MS): 188 [M+H]+, t (HPLC conditions k): 2.49 min. (3-Carbamoylmethoxy-pyrazolor3,4-clpyridinyl)-acetic acid was prepared from 5-methoxy-1H-pyrazolo[3,4-c]pyridine 0] by using the same procedures as described for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin tic acid (Scheme A26). MS (LC-MS): 251 [M+H]+, t (HPLC conditions k): 0.62 min.
Scheme A27: Preparation of (3-carbamoylmethyl-pyrazolor3,4-clpyridinyl)-acetic acid A. 3-lodomethyl-1 H-pyrazolo[3,4-c]pyridine To a solution of 5-methyl-1H-pyrazolo[3,4-c]pyridine [760069 ] ( 1 .00 g , 7.51 mmol) in DMF (15 mL) were added iodine (2.86 g , 11.3 mmol) and potassium hydroxide (1.05 g , 18.8 mmol).
The reaction e was stirred at RT for 60 h . The mixture was diluted with 10% sodium thiosulfate and water, the resulting suspension was filtered. The solid was washed with water and then dried under vacuum. MS (LC/MS): 260.0 ; t (HPLC conditions k): 0.28 min.
B. Tert-butyl 2-(3-iodomethyl-1H-pyrazolo[3,4-c]pyridinyl)acetate To a suspension of 3-iodomethyl-1H-pyrazolo[3,4-c]pyridine ( 1 .00 g , 3.86 mmol), and potassium carbonate ( 1 .28 g , 9.26 mmol) in acetonitrile (40 ml_) was added tert-butyl cetate (0.685 ml_, 4.63 mmol) dropwise at RT and the resulting mixture was heated to reflux for 16 h . The mixture was cooled to RT and filtered, the solid was washed with acetonitrile and the filtrate was concentrated under vacuum. The residual oil was used directly in the next step without further purification. MS (LC/MS): 374.0 [M+H]+; t (HPLC conditions k): 2.96 min.
C. Tert-butyl 2-(3-cyanomethyl-1 H-pyrazolo[3,4-c]pyridin-1 etate A mixture of tert-butyl 2-(3-iodomethyl-1H-pyrazolo[3,4-c]pyridinyl)acetate (1.00 g , 2.55 mmol), Zn(CN) (329 mg, 2.55 mmol), Pd(dppf)CI (208 mg, 0.25 mmol), Pd (dba) (233 mg, 2 2 2 3 0.25 mmol), water (2.7 ml_) and DMF (20 ml_) was subjected to microwave irradiation at 120°C for 30 min under argon. The on mixture was filtered through a pad of Celite and the filtrate was diluted with water and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic ts were washed with brine, then dried (Phase separator) and concentrated under vacuum. The residual oil was purified by flash tography on silica gel /c-hexane 1:2 then 1:1). MS (LC/MS): 273.0 [M+H]+; t (HPLC conditions k): 3.04 min.
D. bamoylmethyl-pyrazolo[3,4-c]pyridinyl)-acetic acid A solution of tert-butyl 2-(3-cyanomethyl-1 H-pyrazolo[3,4-c]pyridinyl)acetate (250 mg, 0.92 mmol) in TFA (4 mL) was subjected to microwave irradiation at 140°C for 90 min. The reaction mixture was concentrated in vacuo, the residual solid was suspended in methanol and concentrated again in vacuo. MS: 235.0 [M+H]+; t (HPLC conditions k): 0.24 min. (3-Carbamoyl-pyrazolor3,4-blpyridin-1 -yl)-acetic acid was prepared from azolo[3,4-b]pyridine [2718] by using the same procedures as described for the preparation of (3-carbamoylmethyl-pyrazolo[3,4-c]pyridinyl)-acetic acid (Scheme A27). MS (LC-MS): 221 [M+H]+, t (HPLC conditions k): 0.87 min. (3-Carbamoyl-pyrazolor4,3-clpyridin-1 -yl)-acetic acid was prepared from 1H-pyrazolo[4,3-c]pyridine [2713] by using the same procedures as for the preparation of (3-carbamoylmethyl-pyrazolo[3,4-c]pyridinyl)-acetic acid (Scheme A27). MS (LC-MS): 221 , t (HPLC conditions k): 0.19 min. (3-Carbamoylmethyl-pyrazolor4,3-clpyridin-1 -yl)-acetic acid was prepared from yl-1H-pyrazolo[4,3-c]pyridine by using the same procedures as for the preparation of bamoylmethyl-pyrazolo[3,4-c]pyridinyl)-acetic acid (Scheme A27). MS (LC-MS): 235 [M+H]+, t (HPLC conditions k): 0.29 min. 6-Methyl-1H-pyrazolo[4,3-c]pyridine A on of 4-chloromethyl-1 H-pyrazolo[4,3-c]pyridine [ 1 1598282] (750 mg, 4.48 mmol) in a mixture of ethanol (25 mL) and THF (10 mL) was hydrogenated over 10% Pd/C (75 mg, 0.07 mmol) at RT for 24 h . The reaction mixture was filtered, the st was washed with ethanol and the filtrate was concentrated under vacuum. MS ): 134 [M+H]+, t (HPLC conditions k): 0.23 min.
Scheme A28: Preparation of 2-(3-carbamoyl-1H-pyrazolor3,4-clpyridazinyl)acetic acid A. Methyl 2-(3-iodo-1H-pyrazolo[3,4-c]pyridazinyl)acetate To a solution of 1H-pyrazolo[3,4-c]pyridazine [2710] (450 mg, 3.75 mmol) in DMF (10 mL) was added iodine (951 mg, 3.75 mmol) and KOH (525 mg, 9.37 mmol). The mixture was stirred at RT for 16 h until completion of the reaction. Methyl 2-bromoacetate (0.380 mL, 4.12 mmol) was then added to the reaction mixture and stirring was continued at RT for 2 h . The mixture was diluted with EtOAc and washed with water (10 mL), the organic phase was dried (Na S0 ) and evaporated under vacuum. The crude mixture was purified by flash column 2 4 chromatography on silica gel (c-Hex/EtOAc 66 :33) to afford the title compound as a brown solid. TLC, Rf (c-Hex/EtOAc 1:1) = 0.40; MS (LC/MS): 318.9 [M+H]+; tR (HPLC conditions c): 3.35 min.
B. 2-(3-Carbamoyl-1H-pyrazolo[3,4-c]pyridazinyl)acetic acid To a solution of methyl 2-(3-iodo-1H-pyrazolo[3,4-c]pyridazinyl)acetate (675 mg, 2.12 mmol) in DMF (7.5 ml_) and water (1.5 ml_) was added Zn(CN) 2 (274 mg, 2.33 mmol), Pd2dba3 (194 mg, 0.21 mmol) and PdCI2(dppf) CH2C I2 adduct (173 mg, 0.21 mmol). The reaction mixture was stirred at 100°C for 16 h . The resulting suspension was filtered and the filtrate was ated under vacuum. The residue was suspended in CH3CN/MeOH 1:1 , the solid was filtered off and the filtrate was purified by preparative HPLC (Macherey Nagel, VP250/40, C18 Nucleosil 100-10, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H20 containing 0.1% TFA) to give the title compound after lyophilisation. MS ): 222.1 [M+H]+; tR (HPLC conditions c): 1.34 min.
Part B : Synthesis of various 5-membered heterocvcles : Scheme B 1: ation of (2S.5R) and (2S,5S)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in a (7:1) ratio following a similar procedure as described in J. Org.
Chem. 2003, 60, 7219.
A. (S)Acetoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester yl ester To a on of (S)oxo-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester red according to J. Org. Chem. 2003, 60, 7219) (1.9 g , 7.8 mmol) in THF (25 mL), cooled to -78°C, was slowly added DibalH ( 1 M in toluene; 11.0 mL, 11.0 mmol) under an argon atmosphere, followed by stirring of the solution at -78°C for 1 h . The reaction was quenched by addition of a saturated s solution of NH4C I (30 mL). The e was allowed to warm up to RT, and a 10% aqueous Na2C0 3 solution (20 mL) and CH2C I2 (70 mL) were subsequently added. The layers were separated and the aqueous phase was extracted with CH2C I2 (2x50 mL). The combined organics were dried (Na2S0 ) and concentrated in vacuo. The residue was dissolved in CH2C I2 (25 mL), acetic ide (2.21 mL, 23.4 mmol), NEt3 (3.26 mL, 23.4 mmol) and 4-dimethylaminopyridine (0.2 g , 1.6 mmol) were subsequently added and the reaction mixture was stirred at RT overnight. The organics were washed with a saturated aqueous NaHC0 3 solution (10 mL) and 1M aqueous HCI, dried (Phase separator) and trated in vacuo. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc nt 3:1 to 1:1) to give the title compound. TLC, Rf (c-hexane/EtOAc 1:1) = 0.5; MS: 310.0 [M+Na]+, 597.3 [2M+Na]+.
B. (2S,5R)- and (2S,5S)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2- methyl ester To a suspension of copper bromide-dimethylsulfide complex (1.09 g , 5.32 mmol) in Et20 (30 ml_), cooled to -40°C, was added methyl lithium ( 1 .6M in Et20 ; 3.32 ml_, 5.32 mmol) se under an argon here. The solution was stirred for 45 min, then cooled to -78°C, and boron trifluoride etherate was added dropwise (0.67 ml_, 5.32 mmol). After 15 min, a solution of (S)acetoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.51 g , 1.77 mmol) in Et20 (5 ml_) was added se. The reaction mixture was stirred for 15 min and was, after warming up to RT over 1 h , quenched by addition of a 1:1 (v/v) mixture of an aqueous saturated NH4C I solution and a 25% aqueous NH OH on (10 ml_). After stirring for 30 min, the two layers were separated and the aqueous phase was extracted with Et20 (2x50 ml_). The combined organics were dried (Na2S0 ) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (c- hexane/EtOAc 8:2) to give the title nd as a (trans:cis) mixture of diastereoisomers in a 7:1 ratio. TLC, Rf (c-hexane/EtOAc 3:1) = 0.42; MS: 266.0 [M+Na]+, 509.2 [2M+Na]+.
C. (2S,5R)- and (2S,5S)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester To a on of (2S.5R)- and (2S,5S)methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.33 g , 1.35 mmol; trans:cis ratio 7:1) in MeOH (2 ml_) was added 1N NaOH (2 ml_) and the reaction mixture was stirred at RT overnight. An additional t of 1N NaOH (2 ml_) was added and the mixture was heated at 50°C for 5 h . Volatiles were removed under d pressure, and the aqueous phase was acidified to pH 1 by addition of 6N HCI, followed by extraction with CH2C I2 (2x25 ml_). The combined organics were dried (Phase separator) and concentrated to afford the title compound a (trans:cis) mixture of reoisomers in a 7:1 ratio. TLC, Rf (CH2C I2/MeOH (10% AcOH) 9:1) = 0.41; MS (LC/MS): 227.9 [M-H]-. (2S,5S)Ethyl-pyrrolidine-1,2-diarboxylic acid 1-tert-butyl ester A. (2S,5R)Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a stirred suspension of copper bromide-dimethylsulfide complex (2.15 g , 10.4 mmol) in dry Et20 (40 mL), cooled to -40°C, was added dropwise ethyl magnesium chloride (2M in Et20 ; .22 mL, 10.4 mmol; Aldrich 300330) under an argon atmosphere. After stirring for 45 min, the mixture was cooled to -78°C, followed by dropwise addition of boron trifluoride etherate ( 1 .32 mL, 10.4 mmol) and stirring for 15 min. Then, a solution of acetoxy-pyrrolidine-1 ,2- dicarboxylic acid 1-tert-butyl ester 2-methyl ester ( 1 .00 g , 3.48 mmol, prepared as described in Scheme B1) in dry Et20 (10 mL) was added dropwise to result in a black sion. The reaction mixture was stirred for 15 min and uently was allowed to warm up to RT over a period of 1 h . The reaction was quenched by addition of a ( 1 :1)-mixture of a saturated aqueous NH4C I solution and a concentrated s NH3 solution (10 mL), followed by stirring for 30 min. The organic layer was separated, and the aqueous phase was extracted with Et20 (2x50 mL). The combined organics were dried (Na2S0 4) and evaporated under reduced pressure.
The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:8) to afford the title nd (contained less than 10% of the minor (2S,5S)-diastereoisomer according to 1H-NMR). TLC Rf (EtOAc/c-hexane 1:3) = 0.48.
B. )Ethyl-pyrrolidine-1,2-diarboxylic acid 1-tert-butyl ester To a solution of (2S,5R)ethyl-pyrrolidine-1,2-dicarboxylic acid -butyl ester 2-methyl ester ining <10 % of the minor (2S,5R)-diastereomer) (340 mg, 1.32 mmol) in MeOH (15 mL) was added a 2N aqueous NaOH solution (1.32 mL, 2.64 mmol), followed by stirring the reaction e at 50°C overnight. An additional aliquot of NaOH (2 equiv) was added and stirring was continued at 50°C for 6 h . Volatiles were removed under reduced pressure and the residue was taken up in water. The aqueous layer was acidified (pH 1) by adding 6N aqueous HCI, followed by extraction with CH2C I2 (2x20 mL). The combined organics were dried (Phase separator) and evaporated in vacuo to afford the title compound ined less than 10% of the minor (2S,5S)-diastereoisomer). TLC, Rf (CH2C I2/MeOH (2% AcOH): 9:1) = 0.40.
Scheme B2: ation of (2S.4R) and (2S,4S)(3-Trifluoromethoxyphenylcarbamoyl )methyl-pyrrolidinecarboxylic acid tert-butyl ester H OCF3 A. (S)(3-Trifluoromethoxy-phenylcarbamoyl)methylene-pyrrolidinecarboxylic acid tert-butyl ester To a suspension of N-Bocmethylene-L-proline ( 1 g , 4.4 mmol) in CH2C I2 (40 mL) was added 3-(trifluoromethoxy)aniline (0.71 mL, 5.28 mmol), HBTU ( 1 .14 g , 6.6 mmol) and diisopropylethylamine (1.51 mL, 8.8 mmol). The reaction mixture was stirred at RT for 2 days.
The mixture was successively washed with 30 mL of a saturated aqueous NaHC0 3 solution and an HCI 1M solution. The organic layers were dried (phase separator) and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane/EtOAc: 65/35) to give the title compound. TLC, R (c-hexane/EtOAc: 1:1) = 0.55; MS (LC/MS): 287.0 [M-Boc]+, 385.0 [M-H]-.
B. (2S,4R) and (2S,4S)(3-Trifluoromethoxy-phenylcarbamoyl)methyl-pyrrolidine carboxylic acid tert-butyl ester To a solution of (S)(3-trifluoromethoxy-phenylcarbamoyl)methylene-pyrrolidine carboxylic acid tert-butyl ester (0.5 g , 1.29 mmol) in EtOAc (15 ml_) was added Pd/C (10 %) and the reaction mixture was placed under en atmosphere overnight. The reaction mixture was filtered on a pad of Celite, the catalyst residue was washed with EtOAc and the solvent was concentrated. The crude material was purified by preparative HPLC (waters SunFire C18-ODB, 5 m , 30x100 mm, : 20-100% CH CN/H O/20 min, 100% CH CN/2 3 2 3 min, CH CN and H 0 containing 0.1% TFA, flow: 40 mL/min, loading 150 mg per run) to give 3 2 after lyophilization of the purified ons the desired compounds: (2S,4S)(3- trifluoromethoxy-phenylcarbamoyl)methyl-pyrrolidinecarboxylic acid utyl ester: t (HPLC conditions b): 5.34 min; LC/MS: 387.0 [M-H]-; (2S,4R)(3-trifluoromethoxyphenylcarbamoyl )methyl-pyrrolidinecarboxylic acid tert-butyl ester: t (HPLC conditions b): 5.53 min ; MS (LC/MS): 387.0 [M-H]-. (2S,3R)Methyl-pyrrolidine-1,2-dicarboxylic acid -butyl ester A. (2S,3R)Methyl((S)phenyl-ethyl)-pyrrolidinecarboxylic acid benzyl ester was prepared following the ure described in Tet. Lett. 1997, 38 (1), 89-92 starting from [but- 3-enyl-((S)phenyl-ethyl)-amino]-acetic acid benzyl ester.
B. (2S,3R)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2S,3R)Methyl((S)phenyl-ethyl)-pyrrolidinecarboxylic acid benzyl ester (245 mg, 0.758 mmol) and Boc 0 (165 mg, 0.758 mmol) were ved in MeOH (3.5 mL). Air was removed from the flask and replaced with en three times. Pd/C 10 % (76 mg) was added and the solution was again degassed and placed under a hydrogen atmosphere. The mixture was d at RT for 1.5 h , filtered through a pad of Celite and the solvent was concentrated in vacuo. The residue was dissolved in EtOAc and an s saturated solution of NaHC0 was added. The layers were separated and the aqueous one acidified with HCI 1 N (pH = 1) and extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered 2 4 and concentrated to give the desired compound which was used without further purification in the next step. 1H-NMR (400 MHz, DMSO): d (ppm): 12.5 (bs, 1H), 4.02 (d, 1H), 3.47 (q, 1H), 3.19 (m, 1H), 2.4 (m, 1H), 1.92 (m, 1H), 1.54 (m, 1H), 1.40 and 1.35 (2s, 9H), 0.96 (d, 3H). (3S,5S)(3-Chlorofluoro-benzylcarbamoyl)-pyrrolidine-1 ,3-dicarboxylic acid - butyl ester 3-methyl ester A. )Cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester A solution of N-boc-ciscyano-L-proline methyl ester (800 mg, 3.15 mmol) in MeOH (27 mL) was cooled to 0°C and LiOH.H 0 (792 mg, 18.9 mmol) was added. The colorless solution was allowed to reach RT and stirred for 4 h . LiOH.H 0 (792 mg, 18.9 mmol) was added and the reaction r stirred at for 1 hour to complete the reaction. MeOH was concentrated and the e diluted in CH C I and treated with aqueous 1M HCI adjusting the pH to 1. The layers 2 2 were separated and the aqueous one re-extracted with CH C I (x2). The combined organic 2 2 extracts were dried (Na S0 ) , filtered and trated to give the desired compound which 2 4 was used in the next step without further purification. MS (LC/MS) : 263.0 [M+Na]+, 503.2 [2M+Na]+, 239.1 [M-H]-.
B. (2S,4S)(3-Chlorof luoro-benzylcarbamoyl)cyano-pyrrolidine-1 -carboxylic acid tert-butyl ester To a mixture of (2S,4S)cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (700 mg, 2.91 mmol), 3-chlorofluorobenzylamine (558 mg, 3.50 mmol), HBTU (1.66 g , 4.37 mmol) in DMF (15 mL) was added DIPEA (1.5 mL, 8.74 mmol) and the resultion mixture was stirred at RT under nitrogen for 48 h . The mixture was poured in water and extracted with EtOAc (2x).
The combined organic extracts were washed with water (1x), dried (Na S0 ) , filtered and trated. The crude material was purified by flash column chromatography (c-hexane to chexane /EtOAc 1:1) to give the desired compound. TLC, R (c-hexane/EtOAc 1:1) = 0.40; MS: 404.0 [M+Na]+, 380.0 [M-H]-, t (HPLC conditions a): 3.45 min.
C. (3S,5S)(3-Chlorofluoro-benzylcarbamoyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert- butyl ester 3-methyl ester Chlorotrimethylsilane (5.66 mL, 44.8 mmol) was added se to dry MeOH (7.6 mL) at 0°C followed by a solution of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)cyano-pyrrolidine carboxylic acid tert-butyl ester (900 mg, 2.36 mmol) in dry CH C I (6.7 mL) and the ing 2 2 mixture was stirred at RT for 5 h . The mixture was cooled to 0°C, quenched with a saturated aqueous solution of NaHC0 and extracted with CH C I (x3). To the organic extracts was 3 2 2 added di-tert-butyl dicarbonate (514 mg, 2.36 mmol) at RT and the resulting solution was d overnight. The reaction mixture was concentrated in vacuo and the crude material purified by flash column tography (c-hexane to c-hexane/EtOAc 1:1) to give the expected compound. t (HPLC conditions a): 3.50 min. (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)hvdroxymethyl-pyrrolidinecarboxylic acid tert-butyl ester To a solution (3S,5S)(3-chlorofluoro-benzylcarbamoyl)-pyrrolidine-1,3-dicarboxylic acid 1- tert-butyl ester 3-methyl ester (550 mg, 1.33 mmol) in THF (6 mL) was added lithium borohydride (2 M in THF, 1.46 mL, 2.92 mmol) at RT and the mixture was further d for 2 h under N atmosphere. After completion brine and CH C I were added, the layers were 2 2 2 ted and the aqueous one re-extracted with CH C I . The combined organic layers were 2 2 dried (MgS0 ) , filtered and concentrated. The crude was purified by flash column chromatography on silica gel (eluent: EtOAc) to give the desired al. MS (LC/MS) : 409.1 [M+Na]+, 287.0 [MH-Boc]+, 385.1 [M-H]-; t (HPLC conditions ) : 1.82 min. )(3-Chlorofluoro-benzylcarbamoyl)methoxy-pyrrolidinecarboxylic acid tert-butyl ester A. (2S,3R)Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a solution of (2S,3R)hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester [186132- 96-7] (500 mg, 2.16 mmol; Chem-lmpex International, Inc.) in acetone (10 mL) were added successively Ag 0 (1.65 g , 7.14 mmol) and Mel (0.473 mL, 7.57 mmol), followed by stirring at RT overnight. The reaction mixture was filtered, the filtrate was evaporated and the residue was taken up again in acetone (10 mL). To this on was added Ag 0 (1.65 g , 7.14 mmol) and Mel (0.473 mL, 7.57 mmol) and the reaction mixture was stirred for 60 h . Solids were then removed by filtration, the filtrate was trated under reduced pressure and the residue was purified by flash column chromatography on silica gel (EtOAC/c-hexane gradient 1:2 to 1:1) to afford the title compound as a colorless oil. MS (LC/MS): 282 [M+Na]+; 160 [M-BOC]+; t (HPLC conditions b): 3.37 min.
B. (2S,3R)Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester To a solution of (2S,3R)methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester yl ester (150 mg, 0.578 mmol) in THF (4 mL) and water (2.0 mL) was added LiOH (69.3 mg, 2.89 mmol) and the reaction mixture was stirred at RT for 40 h . Another aliquot of LiOH was added (69.3 mg, 2.89 mmol). Stirring was continued at RT for 60 h and subsequently at 50°C for 16 h to complete the reaction. Water was added and volatiles were removed under reduced pressure. The aqueous phase was adjusted to pH 2 to 3 by addition of 1N aqueous HCI, followed by extraction with EtOAC (3x). The combined organics were dried (Phase separator) and concentrated in vacuo to give the title compound as a white solid. MS ): 262 [M+Na]+, 190 [MH-tBu]+, 146 [MH-Boc]+, tR (HPLC conditions b): 3.51 min.
C. (2S,3R)(3-Chlorofluoro-benzylcarbamoyl)methoxy-pyrrolidinecarboxylic acid tert-butyl ester The e of )methoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester (60.0 mg, 0.245 mmol), (3-chlorofluorophenyl)methanamine (0.034 mL, 0.269 mmol), HBTU (139 mg, 0.367 mmol) and DIPEA (0.085 mL, 0.489 mmol) in CH2C I2 (5 mL) was d for 20 h at RT.
The n mixture was then diluted with CH2C I2, and the organics were washed subsequently with 0.1 N aqueous HCI (3x), aqueous NaHC0 3 on (2x) and brine. The organic layers were dried (Phase separator), concentrated in vacuo and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 m h , 30x100 mm; flow: 40 mL/min; eluent: 5- 100% CH3CN/H20 for 20 min, 100% CH3CN for 2 min, CH3CN and H20 containing 0.1% TFA) to afford the title compound as a white solid. MS ): 387 [M+H]+, 331 [MH-tBu]+, 287 [MH-Boc]+; tR (HPLC conditions b): 4.26 min. )(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine-1 -carboxylic acid tert- butyl ester A. (2S,3R)Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a solution of )hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester [186132- 96-7] (500 mg, 2.162 mmol; Chem-lmpex International, Inc.) in MeOH (9.0 mL), cooled to 0°C, was added with stirring a solution of Cs2C0 3 (704 mg, 2.162 mmol) in water (6.0 mL). The mixture was concentrated by rotary evaporation and the residue was suspended in DMF (17.0 mL). The suspension was cooled to 0°C, followed by additon of benzylbromide (0.514 mL, 4.32 mmol) and stirring overnight at RT. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHC0 3 (2x) and water (2x), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:3) to give the title compound as an oil. MS (LC/MS): 322 [M+H]+, 665 [2M+Na]+; tR (HPLC ions b): 4.12 min.
B. (2R,3S)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester -butyl ester The title compound was prepared in a similar manner as described by J . A . Hodges et al., J.
Amer. Chem. Soc. 2005, 2 7, 15923-15932: To a solution of (2S,3R)hydroxy-pyrrolidine- 1,2-dicarboxylic acid yl ester 1-tert-butyl ester (490 mg, 1.53 mmol) in CH2C I2 (30 ml_), cooled to -78°C, was added dropwise DAST (1.01 ml_, 7.62 mmol). The reaction mixture was stirred at -78°C for 5 h , and then was allowed to warm to RT and stirred overnight. After cooling to 0°C, the reaction was quenched with MeOH, followed by on of aqueous NaHC0 3 solution. Volatiles were removed under reduced re and the residue was taken up in EtOAc. The organics were washed with aqueous NaHC0 3 (3x), water and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel /c-hexane 1:9) to give the title compound (89% purity by HPLC/215 nm). MS (LC/MS): 346 [M+Na]+, 268 [MH-tBu]+, 224 [MH-Boc]+; tR (HPLC conditions b): 5.31 min.
C. (2R,3S)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester A solution of (2R,3S)fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (252 mg, 0.778 mmol; 72% purity by HPLC/215 nm) in MeOH (20 mL) was hydrogenated at RT ( 1 atm) over Pd/C 10% (35 mg, 10% w/w) for 24 h . The reaction mixture was filtered through a 0.45 microns filter and concentrated under d pressure to give the crude title compound (70% purity by HPLC/215 nm) as a white solid. This al was used in the next reaction step without further cation. MS (LC/MS): 232 [M-H]+; tR (HPLC conditions b): 2.78 min.
D. (2R,3S)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2R,3S)fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester (120 mg, 0.514 mmol) in CH2C I2 (5 mL) were added successively 3-chlorofluorobenzylamine (0.065 mL, 0.514 mmol), HBTU (293 mg, 0.772 mmol) and DIPEA (0.18 mL, 1.03 mmol), and stirring was continued at RT for 20 h . The reaction mixture was then d with CH2C I2, and the organics were washed with 0.1N aqeous HCI (2x), aqueous NaHC0 3 (2x) and brine (1x), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 1:4 to 1:3) to afford the title compound as a white foam. TLC R (EtOAc/c-hexane 1:1) = 0.62; MS (LC/MS): 397 [M+Na]+, 319 [MH- tBu]+, 275 [MH-Boc]+; t (HPLC conditions b): 4.72 min. )(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester A. )Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a solution of (2S,3S)hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [187039- 57-2] (500 mg, 2.16 mmol) in MeOH (9.0 mL), cooled to 0°C, was added with stirring a solution of Cs C0 (704 mg, 2.162 mmol) in water (6.0 mL). The mixture was concentrated by rotary 2 3 evaporation and the e was suspended in DMF (17.0 mL). The suspension was cooled to 0°C, followed by n of benzylbromide (0.514 mL, 4.32 mmol) and stirring overnight at RT.
The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHC0 (2x) and water (2x), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:3) to give the title compound as a white solid. MS (LC/MS): 665 [2M+Na]+, 266 [MH-tBu]+, 222 [MH-Boc]+; t (HPLC conditions b): 4.18 min.
B. (2R,3R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester The title nd was prepared in a r manner as described by L . Demange et al., Tetrahedron Letters 2001 , 42, 651-653: To a solution of (2S,3R)hydroxy-pyrrolidine-1 ,2- oxylic acid 2-benzyl ester 1-tert-butyl ester (360 mg, 1.12 mmol) in CH C I (30 mL), 2 2 cooled to -78°C, was added dropwise DAST (0.740 mL, 5.60 mmol). The reaction mixture was stirred at -78°C for 5 h , and then was allowed to warm to RT and stirred overnight. After cooling to 0°C, the reaction was quenched with MeOH, followed by addition of aqueous NaHC0 solution. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. The cs were washed with aqueous NaHC0 (3x), water and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:9) to give the title compound (99% purity by HPLC/215 nm). TLC R /c-hexane 1:4) = 0.2; MS (LC/MS): 346 [M+Na]+, 268 [MH- tBu]+, 224 [MH-Boc]+; t (HPLC conditions b): 5.01 min.
C. )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester A on of (2R,3R)fluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (70.0 mg, 0.216 mmol) in MeOH (10 mL) was hydrogenated at RT ( 1 atm) over Pd/C 10% (35 mg, 50% w/w) for 48 h . The reaction mixture was filtered through a 0.45 microns filter and concentrated under reduced pressure to give the crude title nd (>95% purity by 1H- NMR) as a white solid. MS (LC/MS): 232 [M-H]+; tR (HPLC conditions b): 2.26 min. This material was used in the next reaction step without further purification.
D. (2R,3R)(3-Chlorofluoro-benzylcarbamoyl)f luoro-pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of (2R,3R)fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (45.0 mg, 0.193 mmol) in CH2C I2 (5 mL) were added successively rofluorobenzylamine (0.024 mL, 0.193 mmol), HBTU ( 1 10 mg, 0.289 mmol) and DIPEA (0.067 mL, 0.386 mmol), and stirring was continued at RT for 20 h . The rection mixture was then diluted with CH2C I2, and the organics were washed with 0.1N aqueous HCI (2x), aqueous NaHC0 3 (2x) and brine (1x), dried (Phase separator) and concentrated in vacuo. The residue was ed by flash column chromatography on silica gel (eluent: EtOAc/c-hexane nt 1:4 to 1:3) to afford the title nd. TLC Rf (EtOAc/c-hexane 1:1) = 0.31; MS (LC/MS): 397 [M+Na]+, 319 [MH-tBu]+, 275 [MH-Boc]+; tR (HPLC conditions b): 4.37 min.
Procedure 1 for the ation of (2S,3R)Azido-pyrrolidinecarboxylic acid 3- A. (2S,3R)Azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester To a solution of (2S,3R)azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [3613677] (210 mg, 0.777 mmol; Sunshine Ltd) in THF (6 mL) was added a solution of LiOH (55.8 mg, 2.33 mmol) in water (3 mL), followed by stirring at RT for 20 h . The reaction mixture was concentrated under reduced pressure and the residual aqueous phase was washed with EtOAc (3x). The water phase was adjusted to pH 2 to 3 by adding 1N aqueous HCI, followed by extraction with EtOAc (3x). The combined organics were dried (Phase separator) and concentrated in vacuo to give the crude title compound as a colorless oil. The crude product was used in the next on step without further purification. MS (LC/MS): 279 [M+Na]+, 200 [MH-tBu]+, 157 [MH-Boc]+; tR (HPLC conditions b): 2.77 min.
B. )Azido(3-chlorofluoro-benzylcarbamoyl)-pyrrolidine-1 -carboxylic acid tert-butylester To (2S,3R)azido-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester (170 mg, 0.663 mmol) in CH C I (12 ml_) were added successively 3-chlorofluorobenzylamine (0.092 mL, 0.730 2 2 mmol), HBTU (377 mg, 0.995 mmol) DIPEA (0.232 mL, 1.33 mmol) and stirring was continued at RT for 20 h . The reaction mixture was diluted with CH C I and the organics were washed 2 2 with 1N aqueous HCI (2x), aqueous 1N NaOH 1N (2x) and brine, dried (Phase separator) and concentrated in vacuo. The crude product was purified in two steps: first by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 m h , 40x250 mm; flow: 20 mL/min; eluent: 20-100% CH CN/H 0 for 20 min, 100% CH CN for 2 min, CH CN and H 0 containing 0.1% TFA) and 3 2 3 3 2 subsequently by flash column chromatography on silica (EtOAc/c-hexane gradient 1:3 to 1:1) to afford the title compound as a colorless wax. TLC R (EtOAc/c-hexane 1:1) = 0.41 ; MS ): 420 [M+Na]+, 342 [MH-tBu]+, 298 [MH-Boc]+; t (HPLC conditions b): 4.66 min.
C. (2S,3R)Azido-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide trifluoroacetate To a on of (2S,3R)azido(3-chlorofluoro-benzylcarbamoyl)-pyrrolidinecarboxylic acid tert-butylester (87 mg, 0.22 mmol) in CH C I (6 mL) was added TFA at RT, and stirring 2 2 was continued overnight at RT. Methanol was added to the reaction mixture and les were removed under reduced pressure. The e was taken up in MeOH and concentrated in vacuo to afford the crude title compound as a colorless wax. The product was used in the next reaction step without r purification. MS (LC/MS): 298 [M+H]+; t (HPLC conditions b): 2.71 min. (2S,3S)Azido-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide was prepared in a similar manner as described in procedure 1 for (2S,3R)azido-pyrrolidine- oxylic acid 3-chlorofluoro-benzylamide trifluoroacetate from (2S,3S)azidopyrrolidine-1 ,2-dicarboxylic acid -butyl ester 2-methyl ester [3613679]. MS ): 298 [M+H]+; t (HPLC conditions b): 2.68 min.
Alternative procedure 2 for the preparation of (2S,3R)Azido-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide trifluoroacetate A. (2S,3S)(3-Chlorofluoro-benzylcarbamoyl)hydroxy-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,3S)hydroxy-pyrrolidine-1 arboxylic acid 1-tert-butyl ester (800 mg, 3.46 mmol; prepared according to J. Amer. Chem. Soc. 2005, 2 7, 15923-15932) in CH2C I2 (35 mL) were added successively 3-chlorofluorobenzylamine (0.435 mL, 3.46 mmol), HBTU ( 1 .97 g , 5.19 mmol), DIPEA (1.21 mL, 6.92 mmol). After stirring at RT for 18 h , the reaction mixture was diluted with CH2C I2 and the organics were washed with water (2x), 0.1N aqueous HCI (2x), aqueous NaHC0 3 on (2x) and brine, dried (phase separator) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel /c-hexane 1:2 to 4:1 then EtOAc) to afford the title compound as a colorless wax. TLC Rf (EtOAc/c-hexane 1:1) = 0.32; MS (LC/MS): 373 [M+H]+, 395 [M+Na]+, 767[2M+Na]+; tR (HPLC conditions C): 4.42 min.
B. (2S,3S)(3-Chlorofluoro-benzylcarbamoyl)methanesulfonyloxy-pyrrolidine carboxylic acid tert-butyl ester To an ice-cooled solution of (2S,3S)(3-chlorofluoro-benzylcarbamoyl)hydroxypyrrolidinecarboxylic acid utyl ester (0.98 g , 2.64 mmol) in dry pyridine (13 mL) was added methanesulfonyl chloride (0.31 mL, 3.96 mmol). The reaction was stirred at 0°C for 2 h and then at RT for 72 h . The volatiles were evaporated in vacuo and the residue was ioned between water and EtOAc. The aqueous layer was repeatedly extracted with EtOAc, the combined organics were washed with 0.1 N HCI and brine, dried (phase separator) and concentrated in vacuo to afford the title compound. Brown oil. MS (LC-MS): 451 [M+H]+, 395 [MH-tBu]+, 351 c]+; tR (HPLC conditions c): 5.08 min. The material thus obtained was used without any purification.
C. (2S,3R)Azido(3-chlorofluoro-benzylcarbamoyl)-pyrrolidine-1 xylic acid tert-butyl ester A mixture of (2S,3S)(3-chlorofluoro-benzylcarbamoyl)methanesulfonyloxy-pyrrolidine- 1-carboxylic acid tert-butyl ester (1.60 g , 2.35 mmol) and NaN (0.370 g , 5.67 mmol) in dry DMF (12 ml_) was stirred at 110°C for 60 h . The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3x), the combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:4 to 1:2) to afford the title compound as a colorless foam. MS (LC-MS): 398 [M+H]+, 342 u]+, 298 [MH-Boc]+; t (HPLC conditions c): 5.15 min.
D. (2S,3R)Azido-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide trifluoroacetate To a solution of (2S,3R)azido(3-chlorofluoro-benzylcarbamoyl)-pyrrolidinecarboxylic acid tert-butyl ester (560 mg, 1.41 mmol) in CH C I (8 ml_) was added TFA (4 ml_), and the 2 2 solution was stirred at RT for 2 h . Methanol was added then added, and les were removed under reduced pressure. The residue was taken up in methanol and concentrated in vacuo to afford the crude title compound as a yellow resin. MS (LC/MS): 298.0 [M+H]+; t (HPLC ions c): 3.59 min. The product was used directly in the next step without further purification.
Scheme B3: preparation of -(2S,5R)Azidomethyl-pyrrolidinecarboxylic acid (3- trifluoromethoxy-phenvD-amide (2R,5S)Benzyl-pyrrolidine-2,5-dicarboxylic acid monoethyl ester The title compound was prepared according to the procedure described in Gazzetta a Italians, 1996, 126, 543-554 from (2R,5S)benzyl-pyrrolidine-2,5-dicarboxylic acid diethyl ester prepared from benzylamine and diethyl meso-dibromoadipate according to the procedure described in J. Med. Chem. 2006, 49, 11 , 076.
A. (2R,5S)Benzyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarboxylic acid ethyl ester To a suspension of (2R,5S)benzyl-pyrrolidine-2,5-dicarboxylic acid monoethyl ester (2 g , 7.21 mmol) in DMF (25 ml_) was added 3-(trifluoromethoxy)aniline ( 1 .53 ml_, 8.65 mmol), HBTU (4.19 g , 10.8 mmol) and diisopropylethylamine (3.78 ml_, 21.6 mmol). The reaction mixture was stirred at RT overnight. EtOAc and 1N HCI were added, the layers were separated and the aqueous one was back-extracted with EtOAc (x3). The combined organic extracts were washed with an aqueous solution containing 5% of NaHC0 3, dried over Na2S0 4, filtered and trated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 80:20) to give the title compound. MS (LC/MS): 437.2 [M+H]+; tR (HPLC conditions b) 5.50 min.
B. (2S,5R)Benzylhydroxymethyl-pyrrolidinecarboxylic acid (3-trifluoromethoxyphenyl To a solution of (2R,5S)benzyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine ylic acid ethyl ester (2.5 g , 5.73 mmol) in a mixture of THF (40 ml_) and EtOH (20 ml_) was added LiCI (486 mg, 11.5 mmol) followed by NaBH (451 mg, 11.5 mmol) and the mixture was stirred at RT overnight. The crude on mixture was concentrated, EtOAc and 1N HCI were added, the layers were separated and the aqueous one back-extracted with EtOAc. The combined organic ts were washed with brine, dried over Na2S0 , filtered and concentrated. The crude residue was used t further purification in the next step. MS (LC/MS): 395 [M+H]+; tR (HPLC conditions b): 3.66 min.
C. (2S,5R)Hydroxymethyl-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)- amide To a solution of (2S,5R)benzylhydroxymethyl-pyrrolidinecarboxylic acid (3- trifluoromethoxy-phenyl)-amide (500 mg, 1.27 mmol) in THF (5 mL) containing 5 drops of MeOH was added Pd/C (10%, 27 mg). The solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was r stirred under hydrogen here ght. The catalyst was removed through a pad of Celite and washed with THF. Solvents were concentrated and the resulting material was used without cation in the next step. MS (LC/MS): 305 [M+H]+; tR (HPLC conditions b): 2.89 min.
D. (2S,5R)Hydroxymethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine carboxylic acid tert-butyl ester A mixture of (2S,5R)hydroxymethyl-pyrrolidinecarboxylic acid (3-trifluoromethoxyphenyl )-amide (422 mg, 1.27 mmol), (Boc)20 (420 mg, 1.91 mmol) and NaHC0 3 (161 mg, 1.91 mmol) in water/dioxane (2.5/2.5 mL) was stirred for 48 h . CH2C I2 and HCI 0.1 N were added, the layers were separated and the aqueous one re-extracted with CH2CI2. The crude organic extracts were washed with brine, dried over Na2S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 1:1) to give the desired compound. MS (LC-MS): 403 [M-H]-; t (HPLC conditions b) 4.76 min.
E. (2R,5S)Methanesulfonyloxymethyl(3-trifluoromethoxy-phenylcarbamoyl)- pyrrolidinecarboxylic acid tert-butyl ester To a on of (2S,5R)hydroxymethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine- 1-carboxylic acid tert-butyl ester (390 mg, 0.97 mmol) in CH C I (3.5 mL) was added at 0°C 2 2 under nitrogen atmosphere Et N (296 m I, 2.12 mmol) and mesylchloride (167 m I, 2.12 mmol) and the mixture was further d at RT for 3 h . CH C I and HCI 0.1 N were added, the layers 2 2 were separated and the aqueous one re-extracted with CH C I . The crude organic extracts 2 2 were washed with brine dried over Na S0 , filtered and concentrated. The crude material was 2 4 used without purification in the next step. MS (LC-MS): 383 c]+; t (HPLC conditions b) .1 min.
F. (2R,5S)Azidomethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine carboxylic acid tert-butyl ester To a solution of (2R,5S)methanesulfonyloxymethyl(3-trifluoromethoxy-phenylcarba moyl)- pyrrolidinecarboxylic acid utyl ester (465 mg, 0.97 mmol) in DMF (3 mL) was added a solution of sodium azide (313 mg, 4.82 mmol) in water (0.5 mL) and the e was stirred at 80°C under nitrogen atmosphere overnight. EtOAc and a saturated aqueous solution of NaHC0 were added, the layers were separated and the aqueous one back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 1:1) to give the desired nd. MS (LC-MS): 330 c]+; t (HPLC ions b) 5.75 min.
G. (2S,5R)Azidomethyl-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)- amide (2R,5S)Azidomethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarboxylic acid tert-butyl ester (100 mg, 0.233 mmol) was dissolved in CH C I (0.2 mL), TFA (0.18 mL, 2.33 2 2 mmol) was added and the solution was stirred at RT 3 h . The solution was concentrated under high vacuum to give the desired TFA salt. MS (LC/MS): 328 [M-H]-; t (HPLC conditions b): 3.45 min. (2S,5R)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinecarboxylic acid 3 trifluoromethoxy-phenvD-amide A. (2S,5R)Benzyl(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide A mixture containing (2S,5R)benzylhydroxymethyl-pyrrolidinecarboxylic acid (3- trifluoromethoxy-phenyl)-amide (300 mg, 0.76 mmol)(prepared as described in Scheme B3), TBDMSCI (129 mg, 0.84 mmol) and imidazole (57 mg, 0.84 mmol) in DMF (3 mL) was stirred at RT overnight. The mixture was concentrated and the residue taken-up in CH C I , 1 N 2 2 aqueous HCI was added, the layers were separated and the aqueous one back-extracted with CH C I . The organic extracts were washed whith brine, dried over Na S0 , filtered and 2 2 2 4 trated. The crude residue was purified by flash column chromatography on silica gel (c- hexane/EtOAc gradient 100:0 to 1:1) to give the title compound. MS ): 509.2 [M+H]+; t (HPLC conditions b): 5.99 min.
B. (2S,5R)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinecarboxylic acid (3- trifluoromethoxy-phenyl)-amide To a solution of (2S,5R)benzyl(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine carboxylic acid (3-trifluoromethoxy-phenyl)-amide (97 mg, 0.19 mmol) in THF ( 1 mL) was added Pd/C (10%, 20 mg). The solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The on e was further stirred under hydrogen atmosphere overnight. The st was d h a pad of Celite and washed with THF. Solvent was concentrated and the crude residue was purified by preparative HPLC (Waters SunFire C18-ODB 5 m , 19x50, 5-100% CH CN/H 0 in 17 min, 100% CH CN for 3 3 2 3 min, CH CN and H 0 containing 0.1% TFA, flow: 20 mL/min) to give the desired compound. 3 2 MS (LC/MS): 419 [M+H]+; t (HPLC conditions b): 5.28 min.
Scheme B4: preparation of (2S,5R)(acetylamino-methyl)-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide *° H OCF , Pd/C 10% ° H OCF o O A. (2R,5S)Hydroxymethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine carboxylic acid benzyl ester To a solution of )hydroxymethyl-pyrrolidinecarboxylic acid (3-trifluoromethoxyphenyl )-amide (797 mg, 2.62 mmol)(prepared as described in Scheme B3) in CH C I (10 mL) 2 2 was added under nitrogen atmosphere Et N (440 m I, 3.14 mmol) and benzylchloroformate (406 m I, 2.88 mmol) and the mixture was further stirred at RT overnight. CH C I and HCI 0.1 N were 2 2 added, the layers were separated and the aqueous one re-extracted with CH C I . The crude 2 2 organic extracts were washed with brine dried over Na S0 , ed and concentrated. The 2 4 crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 1:1) to give the title compound. MS (LC-MS): 439 [M+H]+; t (HPLC ions b) 4.88 min.
B. (2R,5S)Methanesulfonyloxymethyl(3-trifluoromethoxy-phenylcarbamoyl)- pyrrolidinecarboxylic acid benzyl ester To a solution of (2R,5S)hydroxymethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine- 1-carboxylic acid benzyl ester (500 mg, 1.14 mmol) in CH C I (5 mL) was added at 0°C under 2 2 nitrogen atmosphere Et N (350 m I, 2.5 mmol) and mesylchloride (197 m I, 2.5 mmol) and the mixture was r stirred at RT for 3 h . CH C I and HCI 0.1 N were added, the layers were 2 2 separated and the aqueous one re-extracted with CH C I . The crude organic extracts were 2 2 washed with brine dried over Na S0 , filtered and concentrated. The crude material was used without further cation in the next step. MS (LC-MS): 517 [MH-Boc]+; t (HPLC ions b) 5.15 min.
C. (2R,5S)Azidomethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine carboxylic acid benzyl ester To a solution of (2R,5S)methanesulfonyloxymethyl(3-trifluoromethoxy-phenylcarbamoyl)- pyrrolidinecarboxylic acid benzyl ester (589 mg, 1.14 mmol) in DMF (4.5 mL) was added a on of sodium azide (371 mg, 5.7 mmol) in water (0.5 mL) and the mixture was stirred at 80°C under nitrogen atmosphere overnight. EtOAc and a water were added, the layers were separated and the aqueous one back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 6:5) to give the desired compound. MS (LC-MS): 464 c]+; t (HPLC conditions b) 5.73 min.
D. (2R,5S)Aminomethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine carboxylic acid benzyl ester A mixture of )azidomethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine ylic acid benzyl ester (460 mg, 0.99 mmol) and triphenylphosphine (312 mg, 1.19 mmol) in THF (4 ml_) was stirred at RT overnight. After completion of the reaction, THF was removed and the crude reaction mixture was purified by preparative HPLC (Waters SunFire B 5 m , 19x50, 5-100% CH CN/H 0 in 17 min, 100% CH CN for 3 min, CH CN and H 0 3 2 3 3 2 containing 0.1% TFA, flow: 20 mL/min) to give the title compound. MS: 438 [M+H]+; t (HPLC conditions b): 3.8 min.
E. (2R,5S)(Acetylamino-methyl)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine- oxylic acid benzyl ester To a solution of (2R,5S)aminomethyl(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine carboxylic acid benzyl ester (200 mg), and Et N (77 m I_ , 0.55 mmol) in CH C I (3 ml_) was 3 2 2 added under nitrogen atmosphere at 0°C acetyl chloride (39 m I_ , 0.55 mmol) and the mixture was stirred at 0°C for 1 h . CH C I and 1 N aqueous HCI were added, the layers were 2 2 separated and the aqueous one xtracted with CH C I . The combined organic extracts 2 2 were washed whith brine, dried over Na S0 , filtered and concentrated. The crude residue was 2 4 purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 0:100) to give the title compound. MS (LC/MS): 480.1 [M+H]+; t (HPLC conditions b): 4.69 min.
F. (2S,5R)(Acetylamino-methyl)-pyrrolidinecarboxylic acid (3-trifluoromethoxyphenyl )-amide To a solution of (2R,5S)(acetylamino-methyl)(3-trifluoromethoxy-phenylcarbamoyl)- pyrrolidinecarboxylic acid benzyl ester (48 mg, 0.1 mmol) in THF (0.3 mL) was added Pd/C (10%, 2.1 mg). The solution was degassed 3 times replacing air by nitrogen and finally en by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for h . The catalyst was removed through a pad of Celite and washed with THF. Solvents were concentrated and the resulting residue was used t further purification in the next step.
MS (LC/MS): 346 [M+H]+; t (HPLC conditions b): 2.94 min.
Scheme B5: preparation of 3,4-dihvdro-2H-pyrazolecarboxylic acid 3-chlorofluorobenzylamide A. N-(3-Chlorofluoro-benzyl)-acrylamide To a solution of 2-fluorochlorobenzylamine ( 1 g , 6.27 mmol) and TEA ( 1 .05 ml_, 7.52 mmol) in THF (20.9 ml_) was added acryloyl chloride (0.61 ml_, 7.52 mmol) se and the reaction mixture was stirred at 23°C for 2 h . The reaction mixture was diluted in EtOAc, HCI 1N was added and the layers separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were dried, filtered and concentrated to dryness. The crude residue was purified by flash column chromatography on silica gel (xyclohexane/EtOAc gardient 100:0 to 1:1) to give the desired material. TLC, R (c-hexane/EtOAc 5:5) = 0.41; MS (LC/MS): 214.0 ; t (HPLC conditions b) : 3.35 min.
B. 4-Dihydro-2H-pyrazolecarboxylic acid 3-chlorofluoro-benzylamide To a solution of N-(3-chlorofluoro-benzyl)-acrylamide ( 1 .25 g , 5.85 mmol) in 1/1 mixture of toluene (58.5 ml_)/hexane (58.5 ml_) was added trimethylsilyldiazomethane (5.85 ml_, 11.7 mmol, 2M in ). The reaction was stirred at 23°C for 20 h until tion. Solvents were removed in vacuo then CH C I (58.5 ml_) was added followed by TFA (0.49 ml_, 6.44 mmol) 2 2 and the reaction mixture was further stirred at 23°C for 1 h . The reaction mixture was quenched with NaHC0 5% aqueous solution and extracted with CH C I . The combined 3 2 2 organic layers were dried, ed and ated to dryness. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc nt 100:0 to 0:100) followed by preparative HPLC (Waters SunFire C180DB, 5 m h , 30x100, eluent: 20% CH CN/80% H 0 to 100% CH CN in 20 min, CH CN and H 0 containing 0.1% of TFA, flow 40 3 2 3 3 2 mL/min) to give the desired material after lyophilization of the purified fractions. TLC, R ) = 0.23; MS (LC-MS): 256.0 [M+H]+; t (HPLC conditions b) : 2.53 min.
C. (S)(3-Chlorofluoro-benzylcarbamoyl)-pyrazolidinecarboxylic acid tert-butyl ester and (R)(3-Chlorofluoro-benzylcarbamoyl)-pyrazolidinecarboxylic acid tert- butyl ester To a solution of pyrazolidinecarboxylic acid 3-chlorofluoro-benzylamide (600 mg, 2.35 mmol) in acetic acid glacial (10.4 mL) was added NaCNBH (369 mg, 5.87 mmol) and the reaction mixture was stirred at 23°C for 2 h . The reaction mixture was diluted with EtOAc and quenched with a saturated aqueous K2C0 3 solution. The layers were separated and the aqueous one extracted again with EtOAc. The combined organic layers were dried, ed and evaporated to dryness to give the desired material which was used in the next step without purification. The residue was dissolved in THF (9.4 mL), Boc20 (0.817 mL, 3.52 mmol), TEA (0.654 mL, 4.69 mmol) and DMAP (28.7 mg, 0.235 mmol) were added and the reaction mixture was stirred at 23°C for 2 h . The crude was concentrated and purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 0:100) to give the desired c material. TLC, Rf (EtOAc) = 0.4; MS (LC/MS): 380 [M+Na]+, 258 [MH-Boc]+; tR (HPLC conditions b): 4.22 min.
The racemic mixture was purified by chiral preparative HPLC (Chiralpak A D 00SC-JF004, 5 x 50 cm, heptane/isopropanol 90/10, flow 35 mL/min, detection 210 nM) to give peak 1 (tR: 6 1.43 min) and peak 2 (tR: 99.77 min). Peak 1 : (R )(3-chlorofluoro-benzylcarbamoyl)- pyrazolidinecarboxylic acid tert-butyl ester, MS : 258.0 oc], 379.9 [MNa+]; tR (HPLC, Chiralpak AD, 250mmx4.6mm, heptane/isopropanol 91/10, flow 1 mL/min, detection 220 nM): 14.1 min. Peak 2 : (S -chlorofluoro-benzylcarbamoyl)-pyrazolidinecarboxylic acid tert-butyl ester, MS : 258.0 [MH+-boc] [MH+], 379.9 [MNa+]; tR (HPLC, Chiralpak AD, 250mmx4.6mm, heptane/isopropanol 91/10, flow 1 mL/min, ion 220 nM): 22.37 min. The absolute stereochemistry has been ed tentatively based on the test results for the final compounds Example 432 and Example 433 in the biological assay.
Scheme B6: preparation of S)rMethyl-(2,2,2-trichloro-ethoxycarbonyl)-amino1- pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester A. (2S,4S)(2,2,2-Trichloro-ethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1- tert-butyl ester 2-methyl ester To a solution of (2S,4S)-1 -tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (4.6 g , 10.7 mmol) in CH2C I2 (100 mL) were added 2,2,2-trichloroethyl carbonochloridate ( 1 .73 mL, 12.88 mmol) and DIPEA (2.81 mL, 16.1 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water. The desired compound was extracted with EtOAc (2 x 100 mL), the organic phases were , washed with 1N HCI then brine, dried over Na2S0 4, filtered and concentrated. The crude e was purified by flash column chromatography on silica gel (c- hexane to c-hexane/EtOAc 1:1). MS (UPLC): 421 [M+H]+, 419 [M-H]-; tR (HPLC conditions ) : 1.1 1 min.
B. (2S,4S)[Methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2- dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a solution of (2S,4S)(2,2,2-trichloro-ethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (420 mg, 1 mmol) and methyl iodide (0.18 mL, 3 mmol) in DMF (10 mL) cooled at 0°C under argon was added sodium hydride (44 mg, 1.1 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water. The d compound was extracted with EtOAc (2 x 25 mL), the organic phases were joined, washed with 1N HCI then brine, dried over Na S0 , filtered and concentrated. The crude residue was purified by 2 4 flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). MS (UPLC): 436 [M+H]+, 434 [M-H]-; t (HPLC conditions ) : 2.35 min.
C. (2S,4S)[Methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2- dicarboxylic acid 1-tert-butyl ester To a solution of ((2S,4S)[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2- dicarboxylic acid 1-tert-butyl ester yl ester (360 mg, 0.83 mmol) in MeOH (20 mL) was added aq. 1N NaOH (1.66 mL, 1.66 mmol). The reaction was stirred at RT for 16 h then was concentrated. The residue was acidified with aq 2N HCI to pH 3 , extracted with EtOAc (2 x 25 mL). The organic phases were joined, dried over Na S0 , filtered and trated. The crude residue was used without further purification in the next step. MS (UPLC): 421 [M+H]+, 419 [M- H]- ; t (HPLC ions ) : 1.00 min.
Scheme B7: preparation of (2S,4R)(3-Bromocarboxy-phenylcarbamoyl)fluoropyrrolidinecarboxylic acid utyl ester A. (2S,4R)(3-Bromomethoxycarbonyl-phenylcarbamoyl)fluoro-pyrrolidine ylic acid tert-butyl ester To a mixture of N-Boc-transfluoro-L-proline (500 mg, 2.14 mmol), methyl 3-amino bromobenzoate (592 mg, 2.57 mmol) and HBTU ( 1 .22 g , 3.22 mmol) in DMF (6 mL) was added DIPEA (734 m I, 4.29 mmol) and the resulting solution was stirred at RT under en overnight. The mixture was poured into water and extracted three times with EtOAc. The combined organic layers were washed twice with water, dried over Na S0 , filtered and concentrated. The crude e was purified by flash column chromatography on silica gel (c- hexane 100% to c-hexane/EtOAc 70:30) to give the desired material. TLC, R (c-hexane/EtOAc 1:2) = 0.8; MS (LC/MS): 467.0/469.0 [M+Na]+, 345.1/347.0 [MH-Boc]+, 443.1/445.1 [M-H]-; tR (HPLC conditions a): 3.77 min.
B. (2S,4R)(3-Bromocarboxy-phenylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,4R)(3-bromomethoxycarbonyl-phenylcarbamoyl)fluoro-pyrrolidine- 1-carboxylic acid tert-butyl ester (480 mg, 1.08 mmol) in MeOH (10 ml_), cooled to 0°C was added LiOH.H 0 (271 mg, 6.47 mmol) and the resulting solution was d to reach RT and stirred for 5 h . MeOH was trated and the e was d in CH C I , HCI 1 M was 2 2 added (pH = 1) and the layers were separated. The aqueous layer was back extracted twice with CH C I and the combined organic layers were dried over Na S0 , filtered and 2 2 2 4 concentrated to give the desired material which was used without further purification in the next step. MS ): 453.0/455.0 [M+Na]+, 375.1/377.1 [MH-tBu]+, 331 .1/333.1 [MH-Boc]+, 429.0/431 .0 [M-H]-; t (HPLC conditions a): 3.27 min. (2S,4R)(3-Bromocarboxy-phenylcarbamoyl)fluoro-pyrrolidinecarboxylic acid A. )(3-Bromomethoxycarbonyl-phenylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester A mixture of (2S,4R)fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester (355 mg, 1.52 mmol), and 4-aminobromo-benzoic acid methyl ester (prepared as bed in Part C) (350 mg, 1.52 mmol), HBTU (865 mg, 2.282 mmol) and DIPEA (0.531 ml_, 3.04 mmol) in CH C I (15 2 2 ml_) was stirred at RT for 60 h . Additional aliquots of (2S,4R)fluoro-pyrrolidine-1,2- dicarboxylic acid 1-tert-butyl ester (180 mg), HBTU (580 mg) and DIPEA (0.265 ml_) were added to the mixture, and stirring was continued at RT for 20 h and subsequently at 40°C for 24 h . The reaction mixture was diluted with CH C I and the organic layer was washed with 2 2 water, 1N aqueous HCI (3x), aqueous NaHC0 solution (2x) and brine, dried (Phase separator) and concentrated in vacuo. The e was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane nt 1:3 to 1:2) to afford the title compound as a white foam. TLC R (EtOAc/c-hexane 1:2) = 0.24; MS (LC/MS): 468 [M+Na]+, 388/390 [MH-tBu]+, 345/347 [MH-Boc]+; t (HPLC conditions b): 4.36 min.
B. (2S,4R)(3-Bromocarboxy-phenylcarbamoyl)fluoro-pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of (2S,4R)(3-bromomethoxycarbonyl-phenylcarbamoyl)fluoro-pyrrolidine- 1-carboxylic acid tert-butyl ester (400 mg, 0.898 mmol) in MeOH (9 ml_) was added a 2N aqueous NaOH solution ( 1 .78 ml_, 3.59 mmol). The on mixture was stirred at RT for 20 h and then evaporated under reduced pressure. The residue was taken up in water and the aqueous phase was acidified (pH 2 to 3) by adding 0.1N aqueous HCI. The resulting suspension was extracted with EtOAc (4x) and the combined organics were concentrated under reduced pressure to afford the crude title compound as a pale yellow solid. This product was used in the next on step without further purification. MS (LC/MS): 454 [M+Na]+, 374 [MH-tBu]+, 330 [MH-Boc]+; tR (HPLC conditions b): 3.41 min. )frcarboxy-(3-chloro-phenyl)-methvn-carbamoylV4-fluoro-pyrrolidine carboxylic acid tert-butyl ester (2S,4R){[(3-Chloro-phenyl)-methoxycarbonyl-methyl]-carbamoyl}fluoro-pyrrolidine- oxylic acid tert-butyl ester To a mixture of N-Boc-transfluoro-L-proline (200 mg, 0.86 mmol), amino-(3-chloro-phenyl)- acetic acid methyl ester (233 mg, 0.94 mmol) and HBTU (488 mg, 1.29 mmol) in DMF (2.5 ml_) was added DIPEA (294 m I, 1.72 mmol) and the mixture was stirred at RT under nitrogen overnight. Then poured into water and extracted twice with EtOAc. The combined organic layers were washed again with water, dried over Na2S0 4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (CH2C I2 to CH2C H 9:1) to give the desired material. TLC, Rf (CH2C I2/MeOH 4:1) = 0.3; MS (LC/MS) : 437.0 [M+Na]+, 315.1 [MH-Boc]+, 413.0 [M-H]-; tR (HPLC conditions a): 3.59 min. (2S,4R){[carboxy-(3-chloro-phenyl)-methyl]-carbamoyl}fluoro-pyrrolidine ylic acid utyl ester To a solution of (2S,4R){[(3-chloro-phenyl)-methoxycarbonyl-methyl]-carbamoyl}fluoropyrrolidinecarboxylic acid tert-butyl ester (diastereomeric mixture, 365 mg, 0.88 mmol) in MeOH (8 mL) was added LiOH.H20 (222 mg, 5.28 mmol) at 0°C. The solution was slowly d to reach RT and d for 1 h . MeOH was concentrated and the residue was diluted in CH2C I2 and acidified by addition of HCI 1N. The layers were separated and the aqueous one extracted twice with CH2C I2. The combined organic layers were dried over Na2S0 , fitered and concentrated to give the desired material. TLC, Rf ( EtOAc) = 0.1; MS (LC-MS): 301.0/303.0 [MH-Boc]+; tR (HPLC conditions a): 3.20 min. 3-Chlorofluorofr((2S,4R)fluoro-pyrrolidinecarbonyl)-amino1-methylVbenzoic acid (2S,4R)(3-Chlorofluoromethoxycarbonyl-benzylcarbamoyl)fluoro-pyrrolidine- 1-carboxylic acid tert-butyl ester To a mixture of N-boc-transfluoro-L-proline (143 mg, 0.61 mmol), 3-aminomethylchloro fluoro-benzoic acid methyl ester (prepared as described in Part C, 275 mg, 0.61 mmol) and HATU (0.35 g , 0.92 mmol) in DMF (4 mL) was added DIPEA (430 m I, 2.45 mmol) and the resulting solution was stirred ght at ambient temperature. The reaction mixture was splitted in two batches and the crude product was purified without aqueous workup by RP- preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, 5-100% CH CN/H O/20 min, 3 2 100% C H3C N/2 min, CH CN and H 0 containing 0.1% TFA, flow: 40 ml/min) to give the title 3 2 compound. MS (LC-MS): 333.0 [M-100]+; t (HPLC conditions c): 5.05 min. (2S,4R)(5-Carboxychlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine ylic acid tert-butyl ester To a mixture of (2S,4R)(3-chlorofluoromethoxycarbonyl-benzylcarbamoyl)fluoropyrrolidinecarboxylic acid tert-butyl ester (140 mg, 0.3 mmol) in THF/MeOH/H 0 2:1:1 (4 mL) was added LiOH (7 mg, 0.3 mmol). The reaction e was stirred for 4 h at ambient temperature and the solvent was removed in vacuo to give the title compound which was used without further purification. MS (LC/MS): 319.0 [M-100]+. t (HPLC conditions c): 4.40 min. 3-Chlorofluoro{[((2S,4R)fluoro-pyrrolidinecarbonyl)-amino]-methyl}-benzoic acid To a mixture of (2S,4R)(5-carboxychlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine- 1-carboxylic acid tert-butyl ester (146 mg, 0.3 mmol) in CH C I (4 mL) was added TFA ( 1 mL). 2 2 The reaction mixture was stirred for 1 h at ambient ature and the t was removed in vacuo to give the title compound which was used t further purification. t (HPLC conditions c): 3.1 1 min.
Scheme B8: preparation of ,5R)aza-bicyclor3.1.01hexanecarboxylic acid G3- bromo(1H-tetrazolyl)-phenvn-amide and (1R,3S,5R)aza-bicyclor3.1.01hexane carboxylic acid r3-bromo(1-tert-butyl-1H-tetrazolyl)-phenyl1-amide A. (1R,3S,5R)[3-Bromo(1H-tetrazolyl)-phenylcarbamoyl]aza-bicyclo[3.1.0] hexanecarboxylic acid tert-butyl ester To a solution of ( 1 R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid -butyl ester (250 mg, 1.1 mmol) in CH C I (6 ml_) was added 3-bromo(1H-tetrazolyl)-phenylamine 2 2 dihydrochloride (prepared as described in Part C, 365 mg, 1.32 mmol), HBTU (626 mg, 1.65 mmol) and DIPEA (0.576 ml, 3.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with CH C I and sively washed with 1M aqueous HCI 2 2 solution (30 ml_) and a saturated aqueous NaHC0 solution. The organic phase was dried (phase separator) and evaporated under vacuum. The crude mixture was purified by preparative HPLC (C18 Nucleosil 100-10, flow: 40 ml/min, eluent: 5-100% CH CN/H O/20 min, 3 2 100% CH CN/2 min, CH CN and H 0 containing 0.1% TFA). After combination of the purified 3 3 2 fractions, CH CN was removed under vacuum and lyophilization gave the desired compound.
MS (LC/MS): 447.1 [M-H]-; t (HPLC conditions k): 4.62 min.
B. (1R,3S,5R)Aza-bicyclo[3.1.0]hexanecarboxylic acid [3-bromo(1H-tetrazolyl)- phenyl]-amide and (1R,3S,5R)Aza-bicyclo[3.1.0]hexanecarboxylic acid [3-bromo ( 1-tert-butyl-1 H-tetrazolyl)-phenyl]-amide To a solution of ( 1 R,3S,5R)[3-bromo(1H-tetrazolyl)-phenylcarbamoyl]aza- bicyclo[3.1 .0] hexanecarboxylic acid utyl ester (200 mg, 0.445 mmol) in CH C I (2 ml_) 2 2 was added TFA (0.686 ml, 8.9 mmol). The reaction e was stirred at RT for 4 h . After completion the on mixture was diluted with CH C I and MeOH and the volatiles were 2 2 removed under vacuum. MeOH was added and the reaction e concentrated again under vacuum. This operation was repeated twice to afford a mixture in a 2/3 ratio of (1R,3S,5R) cyclo[3.1.0]hexanecarboxylic acid [3-bromo(1 azolyl)-phenyl]-amide: MS (LC/MS): 349.2 [M+H]+; t (HPLC conditions k): 3.06 min and ( 1 R,3S,5R)aza- bicyclo[3.1.0]hexanecarboxylic acid [3-bromo(1-tert-butyl-1H-tetrazolyl)-phenyl]-amide: MS (LC/MS): 405.3 [M+H]+; t (HPLC conditions k): 4.46 min. (2S,4R)Fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro(2H-tetrazolyl)- benzylamide and )Fluoro-pyrrolidinecarboxylic acid 5-(1 -tert-butyl-1 H- tetrazolyl)chlorofluoro-benzylamide To a solution of a 1:2 mixture of (2S,4R)[5-(1-tert-butyl-1 H-tetrazolyl)chlorofluorobenzylcarbamoyl ]fluoro-pyrrolidinecarboxylic acid tert-butyl ester and (2S,4R)[3- chlorofluoro(2H-tetrazolyl)-benzylcarbamoyl]fluoro-pyrrolidinecarboxylic acid tert- butyl ester (86 mg, 0.19 mmol) in CH C I (3 ml_) was added TFA ( 1 ml_) and the reaction 2 2 mixture was stirred for 2 h at ambient temperature. The solvent was removed in vacuo to give the title compounds which were used without separation in the next step. (2S,4R)Fluoropyrrolidinecarboxylic acid 3-chlorofluoro(2H-tetrazolyl)-benzylamide: MS (LC-MS): 343.0 [M]+; t (HPLC conditions c): 2.47 min and (2S,4R)fluoro-pyrrolidinecarboxylic acid -(1-tert-butyl-1 azolyl)chlorofluoro-benzylamide : MS ): 399.0 [M]+; t (HPLC conditions c): 3.16 min. (2S,4R)[3-Chlorofluoro(2H-tetrazolyl)-benzylcarbamoyl]fluoro-pyrrolidine carboxylic acid tert-butyl ester and (2S,4R)[5-(1-tert-Butyl-1H-tetrazolyl)chloro fluoro-benzylcarbamoyl]fluoro-pyrrolidinecarboxylic acid tert-butyl ester To a e of N-boc-transfluoro-L-proline (107 mg, 0.46 mmol) and HATU (260 mg, 0.69 mmol) in DMF (2 mL) was added a 1:2 mixture of 5-( 1-tert-butyl- 1H-tetrazolyl)chloro fluoro-benzylamine and 3-chlorofluoro(2H-tetrazolyl)-benzylamine ration described in Part C, 220 mg, 0.46 mmol) and DIPEA (319 m I, 1.8 mmol) and the resulting solution was stirred overnight at ambient temperature. The reaction mixture was purified without s workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, 5-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 containing 0.1% TFA, 3 2 3 3 2 flow: 40 ml/min) to give the title compounds (2S,4R)[3-chlorofluoro(2H-tetrazolyl)- benzylcarbamoyl]fluoro-pyrrolidine-1 -carboxylic acid tert-butyl ester: MS (LC-MS): 343.0 [M- 100]+; t (HPLC conditions c): 3.27 min and (2S,4R)[5-(1-tert-butyl-1 azolyl) fluoro-benzylcarbamoyl]fluoro-pyrrolidinecarboxylic acid tert-butyl ester: MS (LC- MS): 499.0 [M]+; t (HPLC conditions c): 4.02 min.
Scheme B9: preparation of (1R,3S,5R)-3 -r(S)(3-Chlorofluoro-phenyl)methoxy- ethylcarbamovnaza-bicvclor3.1.01hexanecarboxylic acid tert-butyl ester A. (1R,3S,5R)[(S)(3-Chlorofluoro-phenyl)hydroxy-ethylcarbamoyl]azabicyclo [3.1.0]hexanecarboxylic acid tert-butyl ester To a mixture of (1R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (750 mg, 3.30 mmol), (2S)amino(3-chlorofluorophenyl)ethanol (746 mg, 3.30 mmol) and HBTU ( 1 .75 g , 4.62 mmol) in CH C I (30 mL) was added under nitrogen DIPEA (2.31 mL, 2 2 13.20 mmol). The reaction mixture was stirred at RT overnight. CH C I and water were added, 2 2 the layers were separated and the aquoues one back-extracted with CH C I (x3). The 2 2 combined organic extracts were dried (Na S0 ) , filtered and concentrated. The crude material 2 4 was purified by flash column tography on silca gel (c-hexane/EtOAc 1:1 to EtOAc) to give the desired compound as a colorless oil. MS (UPLC/MS): 399.3/401.3 [M+H]+, 443.4/445.3 [M+HCOO]-; t (HPLC conditions a): 3.28 min.
B. (1R,3S,5R)[(S)(3-Chlorofluoro-phenyl)methoxy-ethylcarbamoyl]azabicyclo [3.1.0]hexanecarboxylic acid tert-butyl ester To a sion of NaH (60 % in mineral oil, 25.7 mg, 0.64 mmol) in THF (3 mL) cooled at 0°C under Argon was added ( 1 R,3S,5R)[(S)(3-chlorofluoro-phenyl)hydroxy- ethylcarbamoyl]aza-bicyclo[3.1 .0]hexanecarboxylic acid tert-butyl ester (270 mg, 0.64 mmol). The reaction mixture was stirred at 0°C for 30 min and iodomethane (0.06 mL, 0.97 mmol) was added. After 1 h the on mixture was poured into ted NaHC0 aqueous on. CH C I was added, the layers were separated and the aqueous one back-extracted 2 2 with CH C I (x3). The ed organic extracts were dried (Na S0 ) , ed and 2 2 2 concentrated. The crude material was purified by flash column chromatography on silica gel (c- hexane to c-hexane/EtOAc 20:80) the desired compound as a colorless oil. TLC, R (EtOAc) = 0.65; MS (UPLC/MS): 413.4/415.4 [M+H]+, 457.4/459.4 [M+HCOO]-; t (HPLC conditions a): 3.67 min. (1R,3S,5R)[(R)(3-Chlorofluoro-phenyl)methoxy-propylcarbamoyl]azaanecarboxylic acid tert-butyl ester was prepared according to Scheme B9 (Step B) from ( 1 R,3S,5R)[(R)(3-chlorofluoro- phenyl)hydroxy-propylcarbamoyl]aza-bicyclo[3.1 .0]hexanecarboxylic acid tert-butyl ester. TLC, R (EtOAc) = 0.82; MS (UPLC/MS): 427.4/429.4 [M+H]+, 471 .4 O]-; t f R (HPLC conditions a): 3.71 min. (1R,3S,5R)-3 -r(R)(3-Chlorofluoro-phenyl)hvdroxy-propylcarbamovnaza- bicyclor3.1.01hexanecarboxylic acid tert-butyl ester was ed ing to Scheme B9 (Step A) using (3R)amino(3-chloro fluorophenyl)propanol. TLC, R (EtOAc) = 0.55; MS (UPLC/MS): 413.4/415.4 [M+H]+, 457.5 [M+HCOO]-; t (HPLC conditions a): 3,33 min. (2S,4R)[(S)(3-Chlorofluoro-phenyl)methoxy-ethylcarbamoyl]fluoro methyl-pyrrolidinecarboxylic acid tert-butyl ester was prepared according to Scheme B9 (Step B) from (2S,4R)[(S)(3-chlorofluorophenyl )hydroxy-ethylcarbamoyl]fluoromethyl-pyrrolidinecarboxylic acid utyl ester. TLC, R (EtOAc) = 0.90; MS (UPLC-MS): 433.4/435.4 [M+H]+, 477.4 [M+HCOO]-; t f R (HPLC conditions a): 3.73 min. (2S^R)-2 -r(S)(3-Chlorofluoro-phenyl)hvdroxy-ethylcarbamovnfluoromethyl- pyrrolidinecarboxylic acid tert-butyl ester was prepared according to Scheme B9 (Step A) from (2S,4R)fluoromethyl-pyrrolidine- 1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described Scheme B18). TLC, R (EtOAc) = 0.8; MS (UPLC-MS): 419.3 [M+H]+, 463.2 [M+HCOO]-; t (HPLC conditions A): 3.35 min. (2S,4R)[(R)(3-Chlorofluoro-phenyl)hydroxy-propylcarbamoyl]fluoro methyl-pyrrolidinecarboxylic acid tert-butyl ester was ed according to Scheme B9 (Step A) from (2S,4R)fluoromethyl-pyrrolidine- 1,2-dicarboxylic acid 1-tert-butyl ester red as described Scheme B18) and (R)amino- hlorofluoro-phenyl)-propanol. TLC, R (EtOAc) = 0.55; MS (UPLC/MS): 433.3 [M+H]+, 477.3 [M+HCOO]-; t (HPLC conditions a): 3.26 min. (1S,2S,5R)[(S)(3-Chlorofluoro-phenyl)methoxy-ethylcarbamoyl]azabicyclo [3.1.0]hexanecarboxylic acid tert-butyl ester was prepared according to Scheme B9 (Step B) from (1S,2S,5R)[(S)(3-chlorofluorophenyl )hydroxy-ethylcarbamoyl]aza-bicyclo[3. 1.0]hexanecarboxylic acid tert-butyl ester. TLC, R (EtOAc): 0.65; MS (UPLC/MS): 413.4/415,4 [M+H]+, 457.4/459,4 O]-; t (HPLC conditions a): 3.67 min. (1S,2S,5R)-2 -r(S)(3-Chlorofluoro-phenyl)hvdroxy-ethylcarbamovnaza- bicyclor3.1.01hexanecarboxylic acid tert-butyl ester was ed according to Scheme B9 (Step A) from (1S,2S,5R)aza-bicyclo[3.1.0]hexane- 2,3-dicarboxylic acid 3-tert-butyl ester (Enamine, EN12629). TLC, R (EtOAc) = 0.65; MS (UPLC/MS): 399.3/401 ,3 [M+H]+, 443.4/445,4 [M+HCOO]-; t (HPLC conditions a): 3.28 min. (1R,2S,5S)[(S)(3-Chlorofluoro-phenyl)methoxy-ethylcarbamoyl]azaxa ne ca rboxy lic acid tert-butyl ester was prepared according to Scheme B9 (Step B) from ( 1 R,2S,5S)[(S)(3-chlorofluoro- phenyl)hydroxy-ethylcarbamoyl]aza-bicyclo[3. 1.0]hexanecarboxylic acid utyl ester. TLC, R (EtOAc): 0.45; MS MS): 413.3/415.3 [M+H]+, 457.3 [M+HCOO]-; t f R (HPLC conditions a): 3.64 min. (1R,2S,5S)-2 -r(S)(3-Chlorofluoro-phenyl)hvdroxy-ethylcarbamovnaza- bicvclor3.1.01hexanecarboxylic acid utyl ester was prepared according to Scheme B9 (Step A) from racemic (1R*,2S*,5S*)aza- bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 3-tert-butyl ester. Diastereoisomers were separated by chiral HPLC (Chiralpak ADOOCM-EL001, 5x50cm, mobile phase: ane/ IPA 75/25, Flow: 50ml/min, detection: 220 nm) to give (1S,2R,5R)[(S)(3-chlorofluoro-phenyl) hydroxy-ethylcarbamoyl]aza-bicyclo[3.1 .0]hexanecarboxylic acid tert-butyl ester: t (HPLC, Chiralpak ) 046x25cm, n-Heptan/IPA 80:20, flow: 1ml/min): 7.25 min; TLC, R (EtOAc) = 0.58; MS (UPLC/MS): 399.4 [M+H]+, 443.3 [M+HCOO]- and (1R,2S,5S)[(S)(3- chlorofluoro-phenyl)hydroxy-ethylcarbamoyl]aza-bicyclo[3.1.0]hexanecarboxylic acid tert-butyl ester: t (HPLC, Chiralpak (20mm) 046x25cm, n-Heptan/IPA 80:20, flow: 1ml/min): 8.37min; TLC, R ) = 0.58; MS (UPLC/MS): 399.3 [M+H]+, 443.3 [M+HCOO]-.
The absolute stereochemistry of the diastereoisomers was assigned based on the test results for the final compound Example 212 in the biological assay.
S*.5S*)aza-bicvclor3.1.01hexane-2.3-dicarboxylic acid 3-tert-butyl ester To a solution of racemic ( 1 R*,2S*,5S*)aza-bicyclo[3.1.0]hexanecarboxylic acid (10 g , 79 mmol)(ABCR [2225519]) in a e of THF (84 ml_) and water (42 ml_) was added a solution of NaOH (4.18 g , 105 mmol) in water (42 ml_, 10% w/v) and a on of Boc20 (27.4 ml_, 118 mmol) in THF (84 ml_) and water (42 ml_). The resulting biphasic mixture was stirred at RT overnight. The mixture was concentrated under vacuum and the resulting s layer was extracted EtOAc (x5), then acidified to pH 2-3 by addition of HCI 1N , satured with NaCI and extracted with CHCI3/EtOH 2:1 (x3). The combined organic layers were dried (Na2S0 4) , filtered and concentrated to give the desired material which was used without further purification in the next step. MS (UPLC/MS): 226.2 [M-H]-; 1H-NMR (400 MHz, DMSO): d (ppm) 12,4 (m, 1H), 4,19 (m, 1H), 3,46 (m, 1H), 3,38 (m, 1H), 1,88 (m, 1H), 1,64 (m, 1H), 1.35 ( 1 , 9H), 0,65 (m, 1H), 0,54 (m, 1H).
Scheme B10: preparation of (2S,4S)(9H-fluorenylmethoxycarbonylamino)(R- carbamoyl) pyrrolidinecarboxylic acid A. (2S,4S)(9H-fluorenylmethoxycarbonylamino)-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a suspension of (2S,4S)-Fmocaminoboc-pyrrolidinecarboxylic acid (7.7 g , 17.1 mmol) in CH2C I2 (50 ml_) were added DCC (4.2 g , 20.5 mmol), DMAP (0.2 g , 1.7 mmol) and benzyl alcohol (1.7 ml_, 17.08 mmol). The resulting white suspension was stirred at RT overnight under nitrogen. TLC indicated completion of the reaction. The e was filtered, and the filtrate was trated to give the crude residue which was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4:1) to afford the title compound.
TLC, Rf (c-hexane/EtOAc 3:1) = 0.25; MS (LC/MS): 565.3 [M+Na]+, 443.2 [MH-Boc]+; tR (HPLC conditions a): 4.5 min; 1H-NMR (400 MHz, DMSO): d (ppm) 7.91 (d, 2H,), 7.70 (d, 2H), 7.53 (d, 1H), 7.45-7.32 (m, 9H), 5.23-5.06 (m, 2H), 4.35-4.22 (m, 4H), 4.05 (q, 1H), 3.72-3.65 (m, 1H), 3.1 1-3.06 (m, 1H), 1.86-1 .81 (m, 1H), 1.41 (s, 4H), 1.28 (s, 5H).
B. (2S,4S)(9H-fluorenylmethoxycarbonylamino)-pyrrolidinecarboxylic acid benzyl ester To a solution of (2S,4S)(9H-fluorenylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (7.3 g , 13.49 mmol) in CH C I (45 ml_) was added TFA 2 2 (5.1 ml_, 67.5 mmol). The solution was stirred at RT overnight. The solvent was concentrated and the residue co-evaporated three times with CH C I to remove the excess of TFA. The 2 2 crude residue was taken-up in diethylether and the resulting precipitate filtered-off to give the title compound as a white powder. MS ): 443.2 [MH]+; t (HPLC conditions a): 3.3 min; 1H-NMR (400 MHz, DMSO): d (ppm) 9.84 (s, 1H), 9.14 (s, 1H), 7.90 (d, 2H), 7.68 (d, 2H), 7.62 (d, 1H), 7.45-7.33 (m, 9H), 5.28-5.21 (m, 2H), 4.59-4.54 (m, 1H), 4.41 (d, 2H), 4.26-4.16 (m, 2H), 3.46-3.41 (m, 1H), 3.16-3.1 1 (m, 1H), 2.64-2.58 (m, 1H).
C. )(1-Carbamoyl-1H-indolylcarbamoyl)(9H-fluorenylmethoxy carbonylamino)-pyrrolidinecarboxylic acid benzyl ester To a solution of (2S,4S)(9H-fluorenylmethoxycarbonylamino)-pyrrolidinecarboxylic acid benzyl ester (3.03 g , 5.45 mmol) and Et N ( 1 .1 ml_, 8.2 mmol) in dry THF (60 ml_) was added a solution of 3-isocyanato-indolecarboxylic acid amide (1.1 g , 5.4 mmol, prepared as described in Scheme A1) in dry THF (60 ml_). The resulting solution was stirred at RT under en for 20 min. The mixture was poured into water and ted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and concentrated under high 2 4 vacuum (the ature of the water bath of the rotary evaporator was kept to RT) to give the title compound. R (c-hexane/EtOAc 1:3) = 0.39 ; MS (LCMS): 644.2 [M+H]+, 666.2 [M+Na]+; t (HPLC conditions a): 4.0 min.
D. (2S,4S)(1-Carbamoyl-1H-indolylcarbamoyl)(9H-fluorenylmethoxy carbonylamino)(R-carbamoyl)pyrrolidinecarboxylic acid (2S,4S)(9H-Fluorenylmethoxycarbonylamino)(R-carbamoyl)pyrrolidinecarboxylic acid benzyl ester (2.83 g , 4.4 mmol) was dissolved in a mixture of MeOH/THF (1:1) (60 ml_).
Air was d from the flask and replaced with nitrogen three times. Then Pd/C 10 % (425 mg) was added to the solution which was once again degassed and refilled with nitrogen three times. The mixture was placed under a hydrogen atmosphere, and stirred at RT for 2 h . The catalyst was removed through a pad of Celite and washed with THF. The filtrate was concentrated, the residue was taken up in diethylether and the resulting precipitate filtered-off to give the title compound. MS (LC/MS): 554.2 [M+H]+, 552.1 [M-H]-; t (HPLC conditions a): 3.5 min. (2S,4R)-1 -(1 -Carbamoyl-1 H-indolylcarbamoyl)fluoro-pyrrolidinecarboxylic acid A. (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a suspension of N-Boc-transfluoro-L-proline (4.5 g , 19.29 mmol) in CH C I (68 ml_) were 2 2 added DCC (4.78 g , 23.15 mmol), DMAP (0.236 g , 1.93 mmol) and benzyl alcohol (2 ml_, 19.29 mmol). The resulting white suspension was stirred at RT for 48 h and filtered. The filtrate was concentrated to give a ess oil which was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4-1) to give the desired compound. TLC, R (c- hexane/EtOAc 3:1) = 0.3; MS: 346.0 [M+Na]+; t (HPLC conditions a): 3.85 min.
B. (2S,4R)Fluoro-pyrrolidinecarboxylic acid benzyl ester (2S,4R)Fluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (3.16 g , 9.76 mmol) was dissolved in CH C I (50 ml_), TFA (7.47 ml_, 98 mmol) was added and the solution 2 2 was stirred at RT 16 h . The solution was concentrated under high vacuum to give the desired TFA salt as a brown oil which was used without further purification in the next step. MS (LC/MS): 224.1 [M+H]+.
C. (2S,4R)-1 -(1 -Carbamoyl-1 lylcarbamoyl)f luoro-pyrrolidinecarboxylic acid benzyl ester To a solution of (2S,4R)fluoro-pyrrolidinecarboxylic acid benzyl ester TFA salt (4.45 g , 13.2 mmol), 3-isocyanato-indolecarboxylic acid amide (2.65 g , 13.2 mmol) (prepared as described in Scheme A1) and THF (66 mL) was added triethylamine (5.51 mL, 39.6 mmol).
The resulting on was stirred at RT under nitrogen for 1 h until completion of the reaction.
The mixture was poured in water and extracted with EtOAc. The organic layer was washed with an aqueous saturated solution of NaHC0 , dried over Na S0 , filtered and concentrated. 3 2 4 The crude material was purified by flash column tography on silica gel (c- /EtOAc 9:1 to pure EtOAc) to give the desired nd. TLC, R (CH C I /MeOH 9:1) f 2 2 = 0.40; MS: 425.2 [M+H]+; t (HPLC conditions a): 3.6 min.
D . (2S,4R)-1 -(1 -Carbamoyl-1 H-indolylcarbamoyl)f luoro-pyrrolidinecarboxylic acid To a solution of (2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carboxylic acid benzyl ester (2.5 g , 5.89 mmol) in THF (40 ml_) was added Pd/C 10% (500 mg). Air was removed from the flask under high vacuum and replaced with nitrogen, this operation was repeated three times and finally nitrogen was removed and replaced with hydrogen. The mixture was stirred under a hydrogen atmosphere for 16 h . Hydrogen was removed under vacuum and replaced with nitrogen and the st was d by filtration over a pad of Celite and washed with THF. Solvents were concentrated to give the title product. MS (LC/MS): 335.0 , 691 .2 [2M+Na]+, 333.1 [M-H]-; t (HPLC conditions a): 2.22 min. f1-(1-Acetyl-1H-indolyl)-2 -r(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro- pyrrolidinyl1oxo-ethylVcarbamic acid tert-butyl ester To a solution of (2S,4R)fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide.
TFA salt (600 mg, 1.54 mmol), N-Boc(indoleyl)-DL-glycine (538 mg, 1.85 mmol) and HBTU (878 mg, 2.32 mmol) in DMF (5.14 ml_) was added DIPEA (809 m I_ , 4.63 mmol) and the reaction mixture was stirred at 23°C for 24h. The e was diluted with EtOAc and successively washed with HCI 1N and aqueous NaHC0 5%. The organic layer was dried (Na S0 ) , filtered and condentrated. The crude e was purified by flash column 2 4 chromatography on silica gel (Cyclohexane/EtOAc gradient 100:0 to 1:1) to give two fractions P 1 and P2 containing each one diastereosiomer. P 1 : TLC, R (c-hexane/EtOAc 1:1) = 0.25; MS (LC/MS): 545.2 [M-H]-; t (HPLC conditions b): 4.89 min. P2: TLC, R (c-hexane/EtOAc 1:1) = R f 0.15; MS (LC/MS): 545.2 [M-H]-; t (HPLC conditions b) : 4.96 min. (2S,4R)fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared as a TFA salt according to Scheme D5 (steps A and B) from 3-chlorofluoro-benzylamine and (2S,4R)fluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-tert- butyl ester. MS ): 274.9 [M+H]+; t (HPLC conditions b) : 2.23 min.
Scheme B11 : ation of S,4R)Aminomethylfluoro-pyrrolidinecarbonyl)- aminol-indolecarboxylic acid amide A. (2S,4R)Fluorohydroxymethyl-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,4R)fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3 g , 12.9 mmol) in dry THF (130 mL) under en at - 10°C was added dropwise over 45 min a solution of borane dimethyl sulfide complex (2N in THF, 14.1 mL, 28.3 mmol) and the resulting solution was allowed to warm to RT, and stirred overnight under nitrogen. The reaction was quenched by careful addition of ol (30 mL). The mixture was co-evaporated with methanol (2x140 mL), then CH2C I2 and a ted aqueous solution of NaHC0 3 were added.
The layers were separated and the aqueous one ted with CH2C I2 (x2), dried over Na2S0 4, filtered and concentrated to give the desired material. TLC, Rf ) = 0.70; 1HNMR (400 MHz, DMSO): d (ppm) 5.23 (d, 1H), 4.78 (bs, 1H), 3.85 (m, 1H), 3.71 (m, 1H), 3.55 (m, 1H), 3.48 (m, 1H), 3.7-3.3 (m, 1H), 2.17 (m, 2H), 1.42 (s, 9H).
B. (2S,4R)Fluoromethanesulfonyloxymethyl-pyrrolidinecarboxylic acid tert- butyl ester (2S,4R)Fluorohydroxymethyl-pyrrolidinecarboxylic acid tert-butyl ester (2.87 g , 13.1 mmol) was dissolved in 45 mL of CH2C I2. The mixture was cooled down to 0°C, and methanesulfonyl chloride (2.55 mL, 32.8 mmol) and triethylamine (4.56 mL, 32.8 mmol) were added. The mixture was allowed to warm to RT and stirred for 1.5 h . The mixture was ed with a saturated aqueous solution of NaHC0 3, extracted twice with CH2C I2, dried over Na2S0 and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAC 3:7) to afford the desired material.
TLC, Rf (c-hexane/EtOAc 1:1) = 0.4; MS: 320.0 [M+Na]+, 198.1 [MH-Boc]+, 617.2 [2M+Na]+.
C. (2S,4R)Azidomethylfluoro-pyrrolidinecarboxylic acid utyl ester A mixture of (2S,4R)fluoromethanesulfonyloxymethyl-pyrrolidinecarboxylic acid tyl ester (3.3 g , 11.1 mmol) and NaN3 (721 mg, 11.1 mmol) in DMF (50 mL) was stirred at 75°C under nitrogen overnight. The mixture was diluted with water and extracted with EtOAc (x3). The combined organic extracts were washed with water (x3), dried over Na2S0 , and concentrated. The crude residue was purified by flash column chromatography on silica gel (c- hexane/EtOAc 100/0 to 0/100) to give the desired al. 1H-NMR (400 MHz, DMSO): d (ppm) 5.25 (d, 1H), 4.03 (m, 1H), 3.92-3.70 (m, 2H), 3.5-3.25 (m, 2H), 2.27 (m, 1H), 2.2-1.8 (m, 1H), 1.43 (s, 9H).
D. (2S,4R)Azidomethylfluoro-pyrrolidine To a solution of (2S,4R)azidomethylfluoro-pyrrolidinecarboxylic acid tert-butyl ester (600 mg, 2.45 mmol) in CH2C I2 (2.5 mL) was added TFA (1.88 mL, 24.6 mmol) and the solution was stirred at RT for 2 h . CH2C I2 was concentrated and the crude was dried under high vacuum to give the desired material which was used without r cation in the next step.
E. 3-[((2S,4R)Azidomethylfluoro-pyrrolidinecarbonyl)-amino]-indole carboxylic acid amide To a solution of (2S,4R)azidomethylfluoro-pyrrolidine (2.46 mmol) and Et3N (1.7 mL, 12.3 mmol) in THF (8 mL) was added a solution of 3-isocyanato-indolecarboxylic acid amide (543 mg, 2.70 mmol) in THF (4 mL) and the resulting solution was stirred at RT under nitrogen for 20 min. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2S0 4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to ne/EtOAc 1:4 to 100 % EtOAc) to give the d material. TLC, Rf (EtOAc) = 0.7; MS (LC-MS): 346.1 [M+H]+, 368.0 [M+Na]+, 344.0 ; tR (HPLC conditions ) : 1.61 min.
F. 3-[((2S,4R)Aminomethylf luoro-pyrrolidine-1 -carbonyl)-amino]-indole-1 - carboxylic acid amide S,4R)Azidomethylfluoro-pyrrolidinecarbonyl)-amino]-indolecarboxylic acid amide (500 mg, 2.84 mmol) was suspended in THF (5 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10 % (100 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere, and stirred at RT for 1.5 h . The catalyst was removed through a pad of Celite and washed with THF and MeOH to give the desired material which was used in the next step without further purification. MS (LC-MS): 320.2 [M+H]+, 639.2 [2M+H]+, 661 .3 [2M+Na]+, 318.1 [M-H]-; tR (HPLC conditions ) : 0 + 1.02 + 1.61 min.
Scheme B12: preparation of (2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro hydroxymethyl-pyrrolidine-l -carboxylic acid tert-butyl ester A. (S)(3-Chlorofluoro-benzylcarbamoyl)methylene-pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of N-Bocmethylene-L-proline (5.3 g , 22.6 mmol) in CH C I (25 ml_) was added 2 2 a solution of 3-chlorofluorobenzylamine (3.61 g , 22.6 mmol) in CH C I (25 mL) followed by 2 2 HBTU (10.3 g , 27.1 mmol) and DIPEA (5.81 mL, 33.9 mmol) and the resulting solution was stirred at RT under nitrogen for 2 h . The mixture was poured into HCI 1N and extracted twice with CH C I . The combined organic layers were neutralized with an aqueous saturated solution 2 2 of NaHC0 , dried (Na S0 ) , filtered and concentrated. The crude e was purified by flash 3 2 4 column chromatography on silica gel (c-hexane to c-hexane/EtOAc 85:15 to c-hexane/EtOAc 50:50) to give the desired material. TLC, R (EtOAc) = 0.75; MS (LC-MS): 391.0/393.1 [M+Na]+, 313.0/315.0 [MH-tBu]+, 413.0/415.0 [M+HCOO]-; t (HPLC conditions f): 2.12 min.
B. (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)hydroxyhydroxymethyl- pyrrolidine-1 -carboxylic acid tert-butyl ester and (2S,4R)(3-Chlorofluorobenzylcarbamoyl )hydroxyhydroxymethyl-pyrrolidine-1 -carboxylic acid tert-butyl ester A flask was charged with t-butanol (13 mL), water (13 mL), and AD-mix-a (3.8 g). The mixture was stirred at RT until both phases were clear, and then cooled to 0°C. (S)(3-Chloro fluoro-benzylcarbamoyl)methylene-pyrrolidine-1 -carboxylic acid utyl ester ( 1 g , 2.71 mmol) was added at once, and the heterogeneous slurry was stirred vigorously from 0°C to RT overnight. The reaction was quenched at 0°C by addition of sodium sulfite (4 g) and then warmed to RT and d for 45 min. The on mixture was extracted with CH C I (x 3). 2 2 The combined organic layers were dried (Na S0 ) , filtered and concentrated to give a e of diastereosiomers in a 2:1 ratio. The crude e was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1-1 to 100% EtOAc, and then from CH C I to 2 2 CH C I /MeOH 8:2) to give (2S,4S)(3-chlorofluoro-benzylcarbamoyl)hydroxy 2 2 hydroxymethyl-pyrrolidinecarboxylic acid tert-butyl ester (major isomer): TLC, R (EtOAc) = 0.3; MS ): 405.1 [M+H]+, 425.0/427.1 [M+Na]+, 827.2/829.2 [2M+Na]+, 347.0/349.0 [MH-tBu]+, 401.0/403.0 [M-H]-, 447.1/449.0 [M+HCOO]-; t (HPLC conditions ) : 1.71 min and (2S,4R)(3-chlorofluoro-benzylcarbamoyl)hydroxyhydroxymethylpyrrolidinecarboxylic acid tert-butyl ester (minor isomer): TLC, Rf (EtOAc) = 0.2; MS (LC- MS): 425.0/427.1 [M+Na]+, 827.2/829.2 [2M+Na]+, 347.0/349.0 [MH-tBu]+, 447.1/449.0 [M+HCOO]-; tR (HPLC ions f): 1.66 min.
C. (2S,4S)(tert-Butyl-dimethyl-silanyloxymethyl)(3-chlorofluoro-benzyl carbamoyl)hydroxy-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)hydroxyhydroxymethylpyrrolidinecarboxylic acid tert-butyl ester (200 mg, 0.5 mmol) in DMF (2 ml_) was added tertbutyldimetylsilyl chloride (75 mg, 0.5 mmol), ylamine (69 m I_ , 0.5 mmol) and DMAP (6 mg, 0.05 mmol). The mixture was stirred at RT under nitrogen overnight. Tert-butyldimetylsilyl chloride (75 mg, 0.5 mmol), and triethylamine (69 m I_ , 0.5 mmol) were again added and the mixture further stirred at RT for 2.5 h . The mixture was poured into an aqueous saturated NaHC0 3 solution, and extracted with EtOAc (x 3). The combined c layers were washed with water, dried (Na2S0 4) , filtered and concentrated. The crude mixture was purified by flash column chromatography on silica gel (eluent: EtOAc) to afford the desired material. TLC, Rf (c- hexane/EtOAc 1:1) = 0.50; MS (LC-MS): 518.2/520.2 [M+H]+, 540.2/542.2 +, 462.0/464.0 [MH-tBu]+, 516.0/518.2 [M-H]-; tR (HPLC conditions ) : 2.72 min.
D. (2S,4R)(tert-Butyl-dimethyl-silanyloxymethyl)(3-chlorofluoro-benzyl carbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,4S)(tert-butyl-dimethyl-silanyloxymethyl)(3-chlorofluoro-benzyl carbamoyl)hydroxy-pyrrolidinecarboxylic acid tert-butyl ester (200 mg, 0.35 mmol) in CH2C I2 (10 mL) under N2 atmosphere at -78°C was added DAST (92 m , 0.7 mmol). The reaction e was then d to reach RT and further stirred for 1.5 h then poured into an aqueous saturated solution of NaHC0 3 and extracted twice with CH2C I2. The combined organic layers were dried (Na2S0 ) , filtered and concentrated to give the desired material which was used t further purification in the next step. TLC, Rf (c-hexane/EtOAc 1:1) = 0.75; MS (LC/MS): 541 .1 [M+Na]+, 463.1/465.1 [MH-tBu]+, 419.0/421.1 c]+; tR (HPLC conditions f): 2.81 min.
E. (2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluorohydroxymethylpyrrolidinecarboxylic acid tert-butyl ester A solution of (2S,4S)(tert-butyl-dimethyl-silanyloxymethyl)(3-chlorofluoro-benzyl carbamoyl)hydroxy-pyrrolidinecarboxylic acid tert-butyl ester (180 mg, 0.34 mmol) in THF ( 1 .5 mL) and TBAF (680 m , 0.680 mmol, 1M solution in THF) was stirred at RT under en for 30 min. After completion of the reaction, the mixture was poured in water and extracted twice with EtOAc. The combined organic layers were washed with water, dried over Na2S0 4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 1:1 to EtOAc) to give the desired material. TLC, Rf (EtOAc) = 0.45; MS (LC-MS): 427.0 [M+Na]+, 349.0 [MH-tBu]+, 305.0 [MH-Boc]+, 403.1/405.1 , 449.2/451 . 1 O]-; tR (HPLC conditions f): 1.91 min. (2S,4S)(3-chlorofluoro-benzylcarbamoyl)fluorofluoromethyl-pyrrolidine carboxylic acid tert-butyl ester To a solution of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)fluorohydroxymethylpyrrolidinecarboxylic acid tert-butyl ester (80 mg, 0.19 mmol)(prepared using the same protocol as described in Scheme B12 for )(3-chlorofluoro-benzylcarbamoyl) fluorohydroxymethyl-pyrrolidinecarboxylic acid tert-butyl ester) in CH2C I2 (5 mL) at -78°C under nitrogen was added DAST (50 m I_ , 0.375 mmol) and the solution was allowed to reach RT and stirred for 2 h . The reaction mixture was poured into an s ted solution of NaHC0 3 and extracted twice with CH2C I2. The combined organic layers were dried (Na2S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel ane/EtOAc nt 2:1 to 1:3) to give the desired material. TLC, Rf (EtOAc) = 0.72; MS (LC-MS): 429.1/431.0 [M+Na]+, 351 .0/353.0 [MH-tBu]-, 453.1 O]-; tR (HPLC conditions f): 2.14 min.
Scheme B13: preparation of (2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro methyl-pyrrolidine-1 -carboxylic acid tert-butyl ester A. (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)hydroxymethanesulfonyloxy methyl-pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)hydroxyhydroxymethylpyrrolidinecarboxylic acid tert-butyl ester (3.53 g , 8.76 mmol)(prepared as described Scheme B12) and Et3N ( 1 .46 mL, 10.5 mmol) in CH2C I2 (90 mL) at 0°C under nitrogen, was added methanesulfonyl chloride (819 m , 10.52 mmol) dropwise. The resulting solution was stirred at 0°C for 1.5 h and quenched with a saturated aqueous solution of NaHC0 3, extracted twice with CH2C I2, dried (Na2S0 ) , filtered and concentrated. The crude material was purified by flash column tography on silica gel (c-hexane to c-hexane/EtOAc 4:6) to give the desired material. TLC, R (EtOAc) = 0.7, MS (UPLC/MS): 481 .3/483.3 [M+H]+, 381 .2/383.2 [MH-Boc]+, 425.2/427.2 [MH-tBu]+, 479.3/481 .3 [M-H]-, 525.3/527.3 [M+HCOO]-; t (HPLC conditions ) 2.04 min.
B. (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)hydroxymethyl-pyrrolidine carboxylic acid tert-butyl ester (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)hydroxymethanesulfonyloxy methylpyrrolidinecarboxylic acid tert-butyl ester ( 1 g , 2.08 mmol) was dissolved in THF (21 ml_) under en atmosphere before addition of lithium triethylborohydride ( 1 M in THF, 20.8 ml_, .8 mmol). The solution was stirred at RT for 15 min, then poured into cold water and extracted with EtOAc (x 2). The combined organic layers were dried (Na S0 ) , filtered and 2 4 concentrated. The crude material was purified by flash column chromatography on slica gel (c- hexane/EtOAc 1:1) to give the desired material. TLC, R (EtOAc) = 0.7; MS (UPLC/MS): 387.3/389.3 [M+H]+, 409.3/41 1.3 [M+Na]+, 331.2/333.2 [MH-tBu]+, 287.2/289.2 [MH-Boc]+, 795.5/797.6 [2M+Na]+, 385.3/387.2 [M-H]-, 431 .3/433.3 [M+HCOO]-.
C. (2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoromethyl-pyrrolidine carboxylic acid utyl ester To a solution of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)hydroxymethyl-pyrrolidine- 1-carboxylic acid tert-butyl ester (865 mg, 2.1 mmol) in CH C I (60 mL) under nitrogen at -78°C 2 2 was added DAST (550 m , 4.16 mmol) and the solution was slowly allowed to reach RT and stirred for 1 h . The reaction e was poured into cold aqueous ted NaHC0 solution and extracted with CH C I (x 2). The combined organic layers were dried (Na S0 ) , filtered and 2 2 2 concentrated to give the desired material which was used in the next step without further purification. TLC, R (EtOAc) = 0.75; MS (UPLC/MS): 389.3/391 .3 [M+H]+, 4 11.3/413.2 [M+Na]+, 333.2/335. [MH-tBu]+, 289.2/291.2 [MH-Boc]+, 387.2/389.4 , 4337435.2 [M+HCOO]-; t (HPLC ions f): 2.2 min.
Scheme B14: preparation of (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)fluoro morpholinylmethylpyrrolidine-1 -carboxylic acid utyl ester A. )(3-Chlorofluoro-benzylcarbamoyl)hydroxymorpholin yl-pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)hydroxy methanesulfonyloxy methyl-pyrrolidinecarboxylic acid tert-butyl ester (200 mg, 0.416 mmol)(prepared as described Scheme B13) in DMF (10 ml_) was added morpholine (181 ml_, 2.079 mmol) and the solution was stirred for 16 h at 80°C. The reaction e was diluted with EtOAc, washed with a saturated aqueous solution of NaHC0 3 (3 times). The organic layers were dried (Na2S0 4) , filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (CH2C I2/MeOH 8:2) to give the desired material. MS (LC/MS): 472.1/474.1 [M+H]+, 472.1 ; tR (HPLC conditions ) : 1.58 min; 19F NMR (100 MHz, DMSO- ) d (ppm): -120.
B. (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)fluoromorpholinylmethyl idinecarboxylic acid tert-butyl ester To a solution of (2S,4R)(3-chlorofluoro-benzylcarbamoyl)hydroxymorpholin ylmethyl-pyrrolidinecarboxylic acid tert-butyl ester (85 mg, 0.18 mmol) in CH2C I2 (10 ml_) under N2 atmosphere at - 78°C was added DAST (47 m I_ , 0.359 mmol). The reaction mixture was then allowed to reach RT and further stirred for 1.5 h then poured into an aqueous saturated solution of NaHC0 3 and extracted twice with CH2C I2. The combined organic layers were dried (Na2S0 ) , filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (CH2C I2/MeOH 8:2) to give the d al. MS ): 474.1/476.2 [M+H]+, 472.1 [M-H]-; tR (HPLC conditions ) : 1.59 min. (2S^R)(3-Chlorofluoro-benzylcarbamoyl)fluoromorpholinylmethylrrolidinecarbox lic acid tert-butyl ester was obtained using the same protocols as described in Scheme B14 for the preparation of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)fluoromorpholinylmethylpyrrolidine carboxylic acid tert-butyl ester starting from starting from )(3-chlorofluoro-benzyl carbamoyl)hydroxymethanesulfonyloxymethyl-pyrrolidinecarboxylic acid tert-butyl ester (prepared from (2S,4R)(3-chlorofluoro-benzylcarbamoyl)hydroxy ymethyl-pyrrolidinecarboxylic acid tert-butyl ester as described scheme B13). MS (LC/MS): 474.1/476.2 [M+H]+, 472.1 [M-H]-; tR (HPLC conditions ) : 1.62 min.
Scheme B15: (2S^S)(3-Chlorofluoro-benzylcarbamoyl)dimethylaminomethyl fluoro-pyrrolidinecarboxylic acid tert-butyl ester A. (2S,4S)azidomethyl(3-chlorofluoro-benzylcarbamoyl)hydroxy-pyrrolidine carboxylic acid tert-butyl ester To a solution of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)hydroxy methanesulfonyloxy methyl-pyrrolidine-1 -carboxylic acid tert-butyl ester (580 mg, 1.21 mmol) (prepared as described Scheme B13) in DMF (20 ml_) was added sodium azide (392 ml_, 6.03 mmol) and the solution was d for 16 h at 80°C. The reaction mixture was diluted with EtOAc, washed with a saturated aqueous solution of NaHC0 3 (3 times). The organic layers were dried (Na2S0 4) , filtered and concentrated. The crude material was purified by flash column tography on silica gel (c-hexane/EtOAc 1:1) to give the d material. MS ): 430.1/432.1 [M+H]+, 374.1 [MH-tBu]+, 332 [MH-Boc]+; tR (HPLC conditions ) : 2.22 B. (2S,4R)azidomethyl(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine- 1-carboxylic acid tert-butyl ester To a solution of (2S,4S)azidomethyl(3-chlorofluoro-benzylcarbamoyl)hydroxypyrrolidinecarboxylic acid tert-butyl ester (430 mg, 1.0 mmol) in CH2C I2 (25 ml_) under N2 atmosphere at -78°C was added DAST (266 m I_ , 2.01 mmol). The reaction mixture was allowed to warm up to RT and further d for 1.5 h . The reaction e was poured into an aqueous saturated solution of NaHC0 3 and extracted twice with CH2C I2. The combined c layers were dried (Na2S0 ) , filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) to give the desired material. MS (LC/MS): 474.1/476.2 [M+H]+, 472.1 [M-H]-; tR (HPLC conditions ) : 2.23 min, 19F NMR (100 MHz, DMSO- ) d (ppm): -120, -150.
C. (2S,4S)aminomethyl(3-chlorofluoro-benzylcarbamoyl)fluoro- idine-1 -carboxylic acid tert-butyl ester To a solution of (2S,4R)azidomethyl(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinecarboxylic acid tert-butyl ester (380 mg, 0.884 mmol) in THF (25 mL) under N2 atmosphere at RT was added 1M PMe3 in THF ( 1 ,06 mL, 1.06 mmol). The reaction mixture was stirred for 16 h then quenched with water and extracted twice with EtOAc. The combined organic layers were dried (Na2S0 4) , filtered and concentrated. The crude al was purified by flash column tography on silica gel (CH2C I2/MeOH 8:2) to give the desired material.
MS (LC/MS): 404/406 [M+H]+, 402 [M-H]-; tR (HPLC conditions ) : 1.57 min, 19F NMR (100 MHz, DMSO-d 6) d (ppm): -120, -154.
D. (2S,4S)(3-chlorofluoro-benzylcarbamoyl)dimethylaminomethylfluoropyrrolidinecarboxylic acid utyl ester To a solution of (2S,4S)aminomethyl(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinecarboxylic acid tert-butyl ester (245 mg, 0.607 mmol) in MeOH (2 ml_) were added formaldehyde (836 m I_ , 6.07 mmol), sodium orohydride (126 mg, 2.0 mmol) and acetic acid (69.5 m I_ , 1.21 mmol). The reaction mixture was stirred for 16 h at RT then concentrated. The crude material was purified by flash column chromatography on silica gel (CH2C I2/MeOH 8:2) to give the desired material. MS (LC/MS): 432.1/434.1 [M+H]+, 430.1 [M- H]-; tR (HPLC conditions ) : 1.62 min, 19F NMR (100 MHz, DMSO- ) d (ppm): -121 , -149. (2S,4R)Azidomethyl(3-chlorofluoro-benzylcarbamoyl)hvdroxy-pyrrolidine carboxylic acid tert-butyl ester was ed using the same protocols as described in Scheme B15 step A for the preparation of (2S,4R)azidomethyl(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester starting from (2S,4R)(3-chlorofluoro-benzylcarbamoyl) ymethanesulfonyloxy methyl-pyrrolidine-1 -carboxylic acid tert-butyl ester (prepared from (2S,4R)(3-chlorofluoro-benzylcarbamoyl)hydroxyhydroxymethyl-pyrrolidine carboxylic acid tert-butyl ester as described scheme B13). MS (UPLC/MS): 450/452 [M+Na]+, 472/474 [M+HCOO]-; tR (HPLC conditions ) : 2.08 min. (2S,4S)Azidomethyl(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester was obtained using the same protocols as described in Scheme B15 step A and B for the preparation of (2S,4R)azidomethyl(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinecarboxylic acid tert-butyl ester ng from (2S,4R)(3-chlorofluorobenzylcarbamoyl )hydroxymethanesulfonyloxy methyl-pyrrolidinecarboxylic acid tert- butyl ester (prepared from (2S,4R)(3-chlorofluoro-benzylcarbamoyl)hydroxy hydroxymethyl-pyrrolidinecarboxylic acid tert-butyl ester as described scheme B13). MS (LC/MS): 474.1/476.2 [M+H]+, 472.1 [M-H]-; t (HPLC ions f): 2.180 min, 19F NMR (100 MHz, DMSO-d ) d (ppm): -120 , -150. (2S,4S)(Acetylamino-methyl)(3-chlorofluoro-benzylcarbamoyl)fluororrolidinecarbox lic acid tert-butyl ester To a solution of (2S,4S)aminomethyl(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinecarboxylic acid tert-butyl ester (179 mg, 0.51 mmol) in MeOH (5 ml) was added acetic anhydride (0.52 mL, 5.1 mmol). The reaction mixture was stirred at RT for 16 hours then quenched with 6N NaOH. After extraction with CH C I (3 x 30 mL), the organic phases were 2 2 joined and dried on Na2S04, filtered and concentrated. Purification by flash column chromatography on silica gel ane/EtOAc 1:1). ] . MS (UPLC/MS): 395 [M+H]+; t (HPLC conditions ) 2.02 min.
Scheme B16: preparation of (2S,4R)Azidomethyl-2 -r(S)(3-bromo-phenyl)fluoro- ethylcarbamovnfluoro-pyrrolidinecarboxylic acid tert-butyl ester A. (S)Methylene-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To (S)(tert-butoxycarbonyl)methylenepyrrolidinecarboxylic acid (4 g , 17.60 mmol) ved in DMF (100 mL) at 0°C were added benzyl bromide (2.51 mL, 2 1.12 mmol) and cesium carbonate (6.31 g , 19.36 mmol). The solution was stirred 16 h at RT then was concentrated. Purification by flash column tography on silica gel (c-hexane/EtOAc 1:1).
MS (UPLC/MS): 218 [MH-tBu]+, t (HPLC conditions f): 2.44 min.
B. (2S,4S)Hydroxyhydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S,4S)Hydroxyhydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester A solution of AD-mix-alpha (30 g , 21.43 mmol) in tBuOH (120 mL) and Water (120 mL) was d until both phases were clear and then cooled to 0°C. (S)Methylene-pyrrolidine-1,2- dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (6.48 g , 20.42 mmol) was added and the reaction mixture was stirred at RT for 16 h . The reaction mixture was quenched at 0°C by on of sodium e (14.5 g) and then allowed to reach RT and stirred for 1 h . After extraction with CH C I (3 x 100 mL), the organic phases were joined, dried with Na S0 , 2 2 2 4 filtered and concentrated. cation by flash column chromatography on silica gel (c- hexane/EtOAc 1:1) gave the desired compounds as an unseparable mixture. MS (UPLC/MS): 352 [M+H]+, t (HPLC conditions f): 1.50 min.
C. (2S,4R)(tert-Butyl-dimethyl-silanyloxymethyl)hydroxy-pyrrolidine-1,2- dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S,4S)(tert-Butyl-dimethylsilanyloxymethyl )hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a solution of (2S,4S)hydroxyhydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S,4S)hydroxyhydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (5.46 g , 15.54 mmol) in DMF (80 mL) were added tert- butyl dimethylchlorosilane (2.45 g , 16.32 mmol), triethylamine (2.16 mL, 15.54 mmol) and DMAP (0.19 g , 1.55 mmol). The solution was stirred for 16 h at RT then was washed with sat NaHC0 (2 x 100 mL). The organic layer was dried with Na S0 , filtered and concentrated. 3 2 Purification by flash column chromatography on silica gel (c-hexane/EtOAc 9:1) gave )- t-butyl-dimethyl-silanyloxymethyl)hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester -butyl ester: MS (UPLC/MS): 466 [M+H]+ ]+, 510 [M+HCOO]-; t (HPLC conditions f): 2.83 min and (2S,4S)(tert-butyl-dimethyl-silanyloxymethyl)hydroxy-pyrrolidine-1,2- dicarboxylic acid 2-benzyl ester 1-tert-butyl ester: MS (UPLC/MS): 466 [M+H]+ , 510 [M+HCOO]-; t (HPLC ions f): 2.95 min.
D. (2S,4R)(tert-Butyl-dimethyl-silanyloxymethyl)fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a solution of (2S,4S)(tert-butyl-dimethyl-silanyloxymethyl)hydroxy-pyrrolidine-1 ,2- dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (5.20 g , 11.17 mmol) in CH C I (100 mL) at - 2 2 78°C was added DAST (2.21 mL, 16.75 mmol). The solution was stirred for 16 hours at RT then was washed with sat NaHC0 (2 x 100 mL). The organic layer was dried with Na S0 , 3 2 4 ed and trated. cation by flash column chromatography on silica gel (c- hexane/EtOAc 9:1). MS (UPLC/MS): 468 [M+H]+ , 512 [M+HCOO]-; t (HPLC conditions ) : 3.00 min.
E. (2S,4R)Fluorohydroxymethyl-pyrrolidine-1,2-dicarboxylic acid yl ester 1- tert-butyl ester To a on of (2S,4R)(tert-butyl-dimethyl-silanyloxymethyl)fluoro-pyrrolidine-1 ,2- dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (4.10 g , 8.77 mmol) in THF (80 mL) at RT was added 1M TBAF in THF (17.53 mL, 17.53 mmol). The on was stirred at RT for 30 min then poured into water and extracted with EtOAc. The organic layer was dried with Na S0 , filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 3:2). MS (UPLC/MS): 354 [M+H]+, 398 [M+HCOO]-; t (HPLC conditions f): 2.07 min.
F. (2S,4R)Azidomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert- butyl ester To a solution of (2S,4R)fluorohydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester -butyl ester ( 1 .76 g , 4.98 mmol) in CH C I (30 mL) and few drops of NEί was 2 2 stirred at RT for 10 min then methanesulfonyl chloride (0.39 mL, 5.03 mmol) was added. The on was stirred at RT for 30 min then poured into water and extracted with EtOAc. The organic layer was dried with Na S0 , filtered and concentrated. The residue (2.25 g , 4.21 mmol) was dissolved in DMF (50 mL) and sodium azide ( 1 .69 g , 26.1 mmol) was added. The solution was stirred for 16 hours at 80°C then was cooled to RT, poured into water and extracted with EtOAc. The organic layer was dried with Na S0 , filtered and concentrated.
Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 379 [M+H]+; t (HPLC conditions ) : 2.44 min.
G. (2S,4R)Azidomethyl[(S)(3-bromo-phenyl)fluoro-ethylcarbamoyl]fluoropyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,4R)azidomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (500 mg, 1.32 mmol) in methanol (20 mL), 1M sodium hydroxide (2.64 mL, 2.64 mmol) was added. The solution was stirred for 2 hours at RT then was diluted with water, the methanol was removed under reduced pressure. The aqueous layer was washed with Et 0 (2 x 100 mL). The aqueous layer was acidified until pH 3 with 2N HCI and extracted with EtOAc (2 x 100 mL), dried with Na S0 , filtered and concentrated. To the residue (100 mg, 0.34 mmol), (S)(3-bromo-phenyl)fluoro-ethylamine (described in Part C) (83 mg, 0.38 mmol) and HBTU (197 mg, 0.52 mmol) in DMF (5 mL) was added DIPEA (0.12 mL, 0.69 mmol). The reaction mixture was stirred for 16 h at RT then poured into water and extracted with EtOAc. The organic layer was dried with Na S0 , filtered and concentrated. Purification by 2 4 flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 488 [M+H]+, 532 [M+HCOO]-; t (HPLC conditions f): 2.32 min.
Scheme B17: preparation of )Fluorofrmethyl-(2,2,2-trichloroethoxycarbonyl )-amino1-methylVpyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert- butyl ester A. )Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert- butyl ester A on of (2S,4R)azidomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1- utyl ester (prepared as bed in Scheme B16) ( 1 g , 2.64 mmol), trimethylphosphine in THF (3.17 mL, 3.17 mmol) and water (0.10 mL, 5.29 mmol) in THF (40 mL) was stirred for 16 h at RT. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na S0 , filtered and concentrated. Purification by flash column chromatography on silica gel (CH C I /MeOH 9:1). MS (UPLC/MS): 353 [M+H]+, 4 11 2 2 [M+HCOO]-; t (HPLC conditions f): 1.62 min.
B. (2S,4S)(3-Chlorofluoro-benzylcarbamoyl)fluoro{[methyl-(2,2,2-trichloroethoxycarbonyl )-amino]-methyl}-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,4S)aminomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (100 mg, 0.28 mmol) in CH C I (10 mL) was added Troc-CI (0.05 mL, 2 2 0.34 mmol). The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na S0 , filtered, concentrated and purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1).
To a solution of (2S,4S)Fluoro[(2,2,2-trichloro-ethoxycarbonylamino)-methyl]-pyrrolidine- 1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (50 mg, 0.09 mmol) and methyl iodide (0.02 ml_, 0.28 mmol) in DMF (5 ml_) at 0°C was added sodium hydride (2.50 mg, 0.10 mmol) in ns. The reaction mixture was stirred 90 min at 0°C and 16 h at RT. The reaction e was quenched with water, extracted with EtOAc, washed with brine, dried over Na S0 , filtered and concentrated. Purification by flash column chromatography on silica gel 2 4 (c-hexane/EtOAc 1:1). MS (UPLC/MS): 541/543 [M+H]+, 586/587 [M+HCOO]- ; t (HPLC conditions ) 2.66 min.
C. (2S,4S)Fluoro{[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-methyl}- pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a solution of (2S,4S)(3-chlorofluoro-benzylcarbamoyl)fluoro{[methyl-(2,2,2- trichloro-ethoxycarbonyl)-amino]-methyl}-pyrrolidinecarboxylic acid tert-butyl ester ( 1 10 mg, 0.20 mmol) in methanol (5 ml_), 1M sodium hydroxide 0.40 ml_, 0.40 mmol) was added. The solution was stirred for 2 h at RT then was diluted with water, the methanol was removed under reduced pressure. The aqueous layer was washed with Et 0 (2 x 25 ml_). The s layer was acidified until pH 3 with 2N HCI and extracted with EtOAc (2 x 25 ml_), dried with Na S0 , ed and concentrated. To the residue (80 mg, 0.17 mmol), (3-chloro fluorophenyl)methanamine (33.9 mg, 0.21 mmol) and HBTU (101 mg, 0.26 mmol) dissolved in DMF (5 ml_) was added DIPEA (0.06 ml_, 0.35 mmol). The reaction mixture was stirred for 16 h at RT. The on mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na S0 , filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 592/594 [M+H]+, 636/638 O]-; t (HPLC conditions f): 2.49 min.
Scheme B18: preparation of (R)Fluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1- tert-but l ester A. (2S,4R)Fluoro(4-fluoro-phenoxythiocarbonyloxymethyl)-pyrrolidine-1,2- dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a on of (2S,4R)fluorohydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (synthesis described in Scheme B16) (300 mg, 0.85 mmol) in CH C I 2 2 (10 mL) was added 4-fluorophenylthiono chloro formate (0.18 mL, 1.27 mmol) and DMAP (31 1 mg, 2.55 mmol). The reaction mixture was stirred at RT for 2 days then was diluted with CH C I (40 ml_), washed with aq 0.5 HCI (50 ml_), water (50 ml_) and brine, dried over Na S0 , 2 2 2 4 filtered and concentrated. cation by flash column chromatography on silica gel (c- hexane/EtOAc 3:1) gave the desired compound. MS (UPLC/MS): 508 [M+H]+; t (HPLC conditions ) 2.73 min.
B. (2S,4R)Fluoromethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a solution of (2S,4R)fluoro(4-fluoro-phenoxythiocarbonyloxymethyl)-pyrrolidine-1 ,2- dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (290 mg, 0.57 mmol) in dioxane (5 ml_) were added VAZO (69 mg, 0.28 mmol) and rimethylsilyl) silane (0.24 ml_, 0.77 mmol). The reaction mixture was refluxed for 30 min then was stirred for 16 h at RT and concentrated.
Purification by flash column chromatography on silica gel (c-hexane/EtOAc 4:1). MS (UPLC/MS): 338 [M+H]+; t (HPLC conditions ) : 2.38 min.
C. (2S,4R)Fluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester A solution containing (2S,4R)fluoromethyl-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (700 mg, 2.075 mmol) and Pd/C 10% (221 mg, 2.075 mmol) in THF (6 mL) was placed under a nitrogen atmosphere and d for 5 h . The catalyst was removed through a pad of celite and washed with MeOH. Solvents were removed under vacuum to give the desired al as a colorless oil which was used without further purification in the next step. MS (UPLC/MS): 246,2 [M-H]-, 292,2 O-]-, 493,4 -.
Scheme B19: preparation of (2R,3R,4R)Azidofluoro-pyrrolidinecarboxylic acid 3- chlorofluoro-benzylamide and (2S,3S,4S)azidofluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide A. (S)-2,5-Dihydro-pyrrole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To a solution of (S)(tert-butoxycarbonyl)-2,5-dihydro-1 H-pyrrolecarboxylic acid (10 g , 46.9 mmol) in DMF (249 ml_) cooled at 0°C were added cesium carbonate (16.8 g , 5 1 .6 mmol) then benzyl bromide (6.69 ml_, 56.3 mmol ) and the mixture was allowed to warm up to RT overnight. The reaction mixture was quenched with water (500 ml_) and extracted with ethyl acetate (3 x 200 ml_). The organic layers were ed and washed with brine, dried (Na S0 ) , filtered and concentrated. The crude residue was ed by flash column 2 4 chromatography on silica gel (c-hexane to ne/EtOAc 4:1) to give the desired material.
TLC, R (c-hexane/EtOAc 4:1) = 0.25; MS (UPLC): 326 [M+Na]+, 204 [MH-Boc]+; t (HPLC f R conditions ) 2.35 min.
B. (1R,2S,5S)Oxaaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3- tert-butyl ester and (1S,2S,5R)oxaaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2- benzyl ester 3-tert-butyl ester To a solution of (S)-2,5-dihydro-pyrrole-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (6.14 g , 20.2 mmol) were added 3-chloroperbenzoic acid (6.99 g , 40.5 mmol) and 4,4' thiobis(6-tert-butyl-m cresol) (0.726 g , 2.02 mmol). The mixture was refluxed under nitrogen atmosphere overnight then an additional batch of 3-chloroperbenzoic acid (6.99 g , 40.5 mmol) and 4,4' thiobis(6-tert-butyl-m cresol) (0.726 g , 2.02 mmol) was added. Refluxing was continued for 24 h . The reaction mixture was diluted with CH C I , washed with sodium 2 2 metabisulphite aqueous (5%), saturated aqueous NaHC0 , brine, dried over Na S0 , filtered 3 2 and trated. The diastereomeric epoxides in a ratio of 65/35 (determined by NMR on the crude mixture) were separated by flash column chromatography (c-hexane to c-hexane/EtOAc 4:1) to give ( 1 R,2S,5S)oxaaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester -butyl ester: TLC, R ane/EtOAc 4:1) = 0.20; MS ): 220 c]+, 342 [M+Na]+; t (HPLC conditions f): 2.14 min and (1S,2S,5R)oxaaza-bicyclo[3.1.0]hexane- 2,3-dicarboxylic acid yl ester 3-tert-butyl ester: TLC, R ane/EtOAc 4:1) = 0.15 ; MS (LC/MS): 220 [MH-Boc]+, 342 [M+Na]+; t (HPLC conditions ) : 2.03 min .
C. (1R,2S,5S)Oxaaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-tert-butyl ester A solution ( 1 S)oxaaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3- tert-butyl ester (2.62 g , 8.21 mmol) in ethyl acetate (32 mL) was hydrogenated under H with palladium hydroxide on carbon ( 1 .15 g , 8.21 mmol) for 1 night. The reaction mixture was filtered over a glass fiber filter, quenched with Na C0 saturated aqueous solution and was 2 3 extracted twice with EtOAc. The aqueous layer was acidified with HCI 1N to pH = 2 and extracted 4 times with ethyl acetate, washed with brine, dried over Na S0 , filtered and concentrated to give the desired al which was used in the next step without further purification. MS (UPLC): 230 [M+H]+, 228 [M-H]-.
D. (1R,2S,5S)(3-Chlorofluoro-benzylcarbamoyl)oxaaza-bicyclo[3.1.0]hexane- 3-carboxylic acid tert-butyl ester To a mixture of (1R,2S,5S)oxaaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-tert-butyl ester ( 1 .55 g , 6.79 mmol), (3-chlorofluoro) benzylamine (1.63 g , 10.19 mmol) and HBTU (3.86 g , 10.2 mmol) in CH C I (17 ml_) was added diisopropylethylamine (1.78 ml_, 10.19 2 2 mmol). The ing solution was stirred overnight at RT under nitrogen then poured into an aqueous saturated NaHC0 solution and extracted with CH C I (x3). The organic layers were 3 2 2 combined, washed with brine, dried over Na S0 , filtered and concentrated. The crude residue 2 4 was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1).
TLC, R (EtOAc) = 0.65; MS (UPLC): 371 , 271 [MH-Boc]+; t (HPLC conditions ) : 2.04 f R min.
E. ,4R)Azido(3-chlorofluoro-benzylcarbamoyl)hydroxy-pyrrolidine carboxylic acid tert-butyl ester and (2S,3S,4S)Azido(3-chlorofluorobenzylcarbamoyl )hydroxy-pyrrolidinecarboxylic acid tert-butyl ester A solution of (1R,2S,5S)(3-chlorofluoro-benzylcarbamoyl)oxaaza-bicyclo [3.1.0]hexanecarboxylic acid tert-butyl ester (2.3 g , 5.95 mmol), sodium azide (2.32 g , 35.7 mmol) and NH C I (0.637 g , 11.9 mmol) in DMF (23 ml_) with H 0 (3.22 ml_, 179 mmol) was 4 2 heated at 100°C for 1 h . The reaction e was poured into ice, extracted with CH C I , 2 2 washed with water and brine, dried over Na S0 , filtered and concentrated. The crude residue was ed by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give a mixture of unseparable regioisomers (2S,3R,4R)azido(3-chlorofluorobenzylcarbamoyl )hydroxy-pyrrolidine-1 -carboxylic acid tert-butyl ester and ,4S) azido(3-chlorofluoro-benzylcarbamoyl)hydroxy-pyrrolidine-1 -carboxylic acid tert-butyl ester in a ratio 3:2 ute stereochemistry was assigned by NMR). TLC, R (c- hexane/EtOAc 1:1) = 0.3; MS (UPLC): 414 [M+H]+, 315 [MH-Boc]+, 412 [M-H]-; t (HPLC conditions ) 2.06 min.
F. (2R,3R,4R)Azido(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester and (2S,3S,4S)Azido(3-chlorofluorobenzylcarbamoyl uoro-pyrrolidine-1 -carboxylic acid tert-butyl ester To a solution of (2S,3R,4R)azido(3-chlorofluoro-benzylcarbamoyl)hydroxypyrrolidinecarboxylic acid tert-butyl ester and (2S,3S,4S)azido(3-chlorofluorobenzylcarbamoyl )hydroxy-pyrrolidinecarboxylic acid tert-butyl ester (ratio 3/2, 1.14 g , 2.75 mmol) in CH C I (55 mL) was added DAST ( 1 .456 mL, 11.02 mmol) at -78°C and the 2 2 reaction mixture was stirred overnight at RT. The reaction mixture was carefully quenched with a saturated aqueous solution of NaHC0 , extracted with CH C I , dried over Na S0 , filtered 3 2 2 2 4 and concentrated. The crude residue was purified by flash column chromatography on silica gel ane to c-hexane/EtOAc 9:1) to give a mixture of the two regioisomers, which were separated by preparative HPLC (Sunfire prep C18-ODB, 5 m h , 30X100 mm, 30% CH CN/H 0 3 2 1.5 min, % CH CN/H 0 in 58.5 min, CH CN/H 0 containing 0.1 % TFA flow: 20 3 2 3 2 mL/min) to give after lyophilization of the purified fractions: (2R,3R,4R)azido(3-chloro fluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester; TLC, R (c- hexane/EtOAc 4:1) = 0.23; MS (LC/MS): 416 [M+H]+, 316 [MH-Boc]+; 414 [M-H]- , t (HPLC conditions h): 3.1 1 min and (2S,3S,4S)azido(3-chlorofluoro-benzyl carbamoyl) fluoro-pyrrolidinecarboxylic acid tert-butyl ester; R (c-hexane/EtOAc 4:1) = 0.13; MS (LC/MS): 416[M+H]+, 316 c]+; 414 ; t (HPLC conditions h): 3.02 min.
Scheme B20: preparation of (2R,3S,4R)(3-Chlorofluoro-benzylcarbamoyl) dimethylaminofluoro-pyrrolidinecarboxylic acid tert-butyl ester A. (2R,3S,4R)Amino(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester A solution of ,4R)azido(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester (described in Scheme B19) (485 mg, 1.16 mmol), trimethylphosphine in THF (2.33 mL, 2.33 mmol) and water (0.04 mL, 2.33 mmol) in THF (20 mL) was stirred for 16 h at RT. The reaction mixture was quenched with water and extracted twice with EtOAc. The organic phase was washed with brine , dried over Na S0 , filtered and trated. Purification by flash column chromatography on silica gel (CH C I /MeOH 95:5). 2 2 MS (UPLC/MS): 390/392 [M+H]+, 434/436 [M+HCOO]-; t (HPLC conditions ) : 1.64 min.
B. (2R,3S,4R)(3-Chlorofluoro-benzylcarbamoyl)dimethylaminofluoro- pyrrolidine-1 -carboxylic acid tert-butyl ester To a on of (2R,3S,4R)amino(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinecarboxylic acid tert-butyl ester (190 mg, 0.48 mmol) in MeOH (2 mL) was added formaldehyde (134 m I, 4.87 mmol). The on mixture was stirred 30 min at RT before addition of sodium cyanoborohydride (101 mg, 1.60 mmol) and acetic acid (56 m I, 0.97 mmol).
After stirring for 30 min, the solution was concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) gave the desired compound. MS (UPLC/MS): 418/420 , 462/464 [M+HCOO]- ; tR (HPLC conditions f): 1.61 min.
Scheme B21 : preparation of r(3R,4S,5S)tert-Butylcarbamoyl(3-chlorofluoro- benzylcarbamoyl)methoxy-pyrrolidin-3 -vn-carbamic acid orenylmethyl ester A. (2S,3R,4R)Azidobenzylcarbamoylhydroxy-pyrrolidinecarboxylic acid tertbutyl ester and (2S,3S,4S)azidobenzylcarbamoylhydroxy-pyrrolidine carboxylic acid tert-butyl ester A solution of (1R,2S,5S)oxaaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester (described in Scheme B19) (5.43 g , 11.90 mmol), sodium azide (4.64 g , 7 1.4 mmol) and NH4C I ( 1 .27 g , 23.80 mmol) in DMF (74 ml_) with H20 (6.43 ml_, 357 mmol) was heated at 100°C for 1 h . The reaction mixture was poured into ice, extracted with CH2C I2 (3 x 250 ml_), washed with water and brine, dried over Na2S0 , filtered and concentrated.
Purification by flash column chromatography on silica gel ane/EtOAc 1:1) gave the desired compounds as an unseparable mixture. MS (UPLC/MS): 307 [MH-tBu]+, 407 [M+HCOO]- ; tR (HPLC conditions f): 1.04 min.
B. (2S,3R,4R)Azidomethoxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tertbutyl ester A solution of (2S,3R,4R)azidobenzylcarbamoylhydroxy-pyrrolidinecarboxylic acid tert-butyl ester and (2S,3S,4S)azidobenzylcarbamoylhydroxy-pyrrolidinecarboxylic acid tert-butyl ester (517 mg, 1.42 mmol) in CH2C I2 (10 mL), silver oxide (1.32 g , 5.71 mmol) and methyl iodide (0.35 mL, 5.71 mmol) was heated in a sealed tube for 1 week at 40°C in the dark. The reaction e was filtered over celite pad and concentrated. cation by flash column chromatography on silica gel (c-hexane/EtOAc 4:1) gave only (2S,3R,4R)azido methoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester. MS (UPLC/MS): 321 [MH-tBu]+, 421 [M+HCOO]- ; tR (HPLC conditions ) : 2.40 min.
C. (2S,3S,4R)(3-Chlorofluoro-benzylcarbamoyl)(9H-fluorenylmethoxy ylamino)methoxy-pyrrolidinecarboxylic acid tert-butyl ester A solution of (2S,3R,4R)azidomethoxy-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1- tert-butyl ester (440 mg, 1.16 mmol) in methanol (3 mL) was hydrogenated with palladium on carbon 10% (124 mg, 1.16 mmol) overnight. The reaction mixture was filtered over a glass fiber filter, washed with methanol and evaporated in vacuo. The residue was dissolved in THF (2 mL) and a 10% aqueous Na C0 (3.09 mL, 1.1 1 mmol) solution was added. The on 2 3 mixture was cooled at 0°C then FmocOSu dissolved in THF (7 mL) was added and stirred for 2 h at RT. The reaction mixture was concentrated in vacuo to leave a residue which was dissolved in EtOAc (10 mL) and treated with saturated aq. NH C I on. The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were collected, dried over MgS0 , filtered and concentrated. The residue was dissolved in DMF (3 mL) then 3-chlorofluoro benzylamine (267 mg, 1.67 mmol) and HBTU (526 mg, 1.38 mmol), DIPEA (292 m I, 1.67 mmol) were added. The resulting orange solution was stirred overnight at RT. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 3:2) afforded the title compound.
MS (UPLC/MS): 624/626 , 668/670 [M+HCOO]-; t (HPLC conditions ) : 2.65 min.
Scheme B22: preparation of (2R,3S,4R)(3-chlorofluoro-benzylcarbamoyl)(9H- fluorenylmethoxycarbonylamino)fluoro-pyrrolidinecarboxylic acid tert-butyl ester and (2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)(9H-fluoren ylmethoxycarbonylamino)fluoro-pyrrolidinecarboxylic acid tert-butyl ester A. (2R,3R,4R)Azidofluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester - butyl ester and (2S,3S,4S)azidofluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester A solution of (2S,3R,4R)azidohydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1- tert-butyl ester and (2S,3S,4S)azidohydroxy-pyrrol 1 arboxylic acid 2-benzyl ester -butyl ester (described in Scheme B21) (3.95 g , 10 mmol) in CH C I (100 mL) was 2 2 cooled under Argon at -78°C then DAST (6.62 mL) was added. The reaction mixture was stirred for 16 h at RT, lly quenched with sat. aq. NaHC0 (100 mL) and stirred for 30 min at 0°C, extracted twice with CH C I , dried over Na S0 , filtered and concentrated. Purification 2 2 2 by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 365 [M+H]+; t (HPLC conditions f): 2.40 min.
B. (2R,3S,4R)(3-Chlorofluoro-benzylcarbamoyl)(9H-fluorenylmethoxy carbonylamino)fluoro-pyrrolidinecarboxylic acid tert-butyl ester and (2S,3S,4S) orofluoro-benzylcarbamoyl)(9H-fluorenylmethoxycarbonylamino)fluoropyrrolidinecarboxylic acid tert-butyl ester A solution of (2R,3R,4R)azidofluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1- tert-butyl ester and (2S,3S,4S)azidofluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (2.78 g , 7.63 mmol) in methanol (25 mL) was hydrogenated with palladium on carbon 10% (812 mg, 0.76 mmol) overnight. The reaction mixture was filtered over a glass fiber filter, washed with methanol and concentrated. 200 mg (0.084 mmol) of the residue was dissolved in THF (2 mL) and a 10% aqueous Na C0 ( 1 mL, 1 mmol) solution was added. The 2 3 reaction mixture was cooled at 0°C then u (284 mg, 0.084 mmol) dissolved in THF (7 mL) was added and stirred for 2 h at RT. The reaction mixture was trated in vacuo to give a residue which was dissolved in EtOAc (10 mL) and treated with saturated aq NH C I solution. The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were collected, dried over MgS0 , filtered and concentrated. The residue was dissolved in DMF (3 mL) then 3-chloro-2 fluoro benzylamine (192 mg, 1.2 mmol) and HBTU (456 mg, 1.2 mmol), DIPEA (210 m I, 1.2 mmol) were added. The resulting solution was d overnight at RT.
Purification by flash column tography on silica gel (c-hexane/EtOAc 4:1). MS MS): 612/614 [M+H]+, 656/658 [M+HCOO]-; t (HPLC conditions f): 0.75/0.76 min.
Scheme B23: preparation of (2R,3S,4R)Acetylamino(3-chlorofluorobenzylcarbamoyl uoro-pyrrolidinecarboxylic acid tert-butyl ester and (2S.3S.4S)- 3-acetylamino(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic A. (2S,3S,4S)Aminofluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert- butyl ester and (2R,3S,4R)aminofluoro-pyrrolidine-1,2-dicarboxylic acid yl ester 1-tert-butyl ester A mixture of (2R,3R,4R)azidobenzylcarbamoylfluoro-pyrrolidinecarboxylic acid tert- butyl ester and (2S,3S,4S)azidobenzylcarbamoylfluoro-pyrrolidinecarboxylic acid tert-butyl ester (3.52 g , 8.98 mmol) ibed in Scheme B22), trimethylphosphine in THF (17.97 ml_, 17.97 mmol) and water (0.32 ml_, 17.97 mmol) in THF (100 ml_) was stirred for 16 h at RT. The reaction mixture was quenched with water and extracted twice with EtOAc. The organic phases were joined, washed with brine, dried over Na S0 , filtered and concentrated. 2 4 Purification by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) gave (2S,3S,4S)aminofluoro-pyrrolidine-1,2-dicarboxylic acid yl ester 1-tert-butyl ester: MS (UPLC/MS): 339 [M+H]+ ; t (HPLC conditions ) : 1.59 min and (2R,3S,4R)amino fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester: MS (UPLC/MS): 339 [M+H]+ ; t (HPLC conditions f): 1.62 min.
B. (2R,3S,4R)Acetylaminofluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1- tert-butyl ester To a solution of (2S,3S,4S)aminofluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1- tert-butyl ester (762 mg, 2.25 mmol) in methanol (20 mL) was added acetic anhydride (3.19 mL, 33.8 mmol) under argon. The reaction mixture was stirred for 16 h at RT. After concentration, the residue was purified by flash column chromatography on silica gel (c- hexane/EtOAc 3:1). MS (UPLC/MS): 381 [M+H]+, 281 [MH-Boc]- ; t (HPLC conditions ) : 2.00 min.
C. ,4R)Acetylaminofluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester A solution of (2R,3S,4R)acetylaminofluoro-pyrrolidine-1 arboxylic acid 2-benzyl ester 1-tert-butyl ester (315 mg, 0.82 mmol) in methanol (2 mL) was hydrogenated with palladium on carbon 10% (88 mg, 0.82 mmol) overnight. The on mixture was filtered over glass fiber and was concentrated. The residue was used as was for the next step.
D. (2R,3S,4R)Acetylamino(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrroli dinecarboxylic acid tert-butyl ester To a e of (2R,3S,4R)acetylaminofluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester (245 mg, 0.84 mmol), (3-chlorofluoro) amine (202 mg, 1.26 mmol) and HBTU (480 mg, 1.26 mmol) in DMF (7.5 mL) was added DIPEA (0.22 mL, 1.26 mmol). The resulting solution was stirred overnight at RT. The reaction mixture was poured into aq. sat. NaHC0 and was extracted with CH C I (3 X 20 mL). The organic phases were joined, washed with 2 2 brine, dried over Na S0 , filtered and concentrated. Purification by flash column 2 4 chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC/MS): 376 [MH-tBu]+, 476 [M+HCOO]-; t (HPLC conditions f): 1.93 min. (2S,3S,4S)Acetylamino(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid utyl ester The title compound was prepared in a similar manner as described above from (2R,3S,4R) 3-fluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester. MS (UPLC/MS): 432 [M+H]+, 476 [M+HCOO]-; t (HPLC conditions ) : 1.96 min.
Scheme B24: preparation of ,4S)Fluoromethoxy-pyrrolidinecarboxylic A. (2S,3S,4S)fluorohydroxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester To a on of (1S,2S,5R)oxaaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid dibenzyl ester (prepared as described Scheme B19, 4 g , .3 mmol) in THF (3 mL) was added 3HF.Et N (18.5 mL, 113 mmol). The reaction mixture was microwaved at 130°C (6x40 min) then was poured into a saturated solution of Na C0 and stirred for 30 min. The mixture was 2 3 extracted with EtOAc (2 x 100 mL), the organic phases were joined, washed with brine, dried over Na S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel ane/EtOAc 7:3) to give a mixture containing (2S,3S,4S) fluorohydroxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester as the major isomer. MS : 374 [M+H]+; t (HPLC conditions ) : 2.13 min.
B. (2S,3S,4S)Fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl To a solution of (2S,3S,4S)fluorohydroxy-pyrrolidine-1 ,2-dicarboxylic acid dibenzyl ester (531 mg, 1.42 mmol) cooled with an ice-bath and under argon was added NaH (60 % in mineral oil, 62 mg, 1.52 mmol). The reaction mixture was stirred for 30 min then Mel (0.26 mL, 4.27 mmol) was added. The reaction mixture was stirred for 30 min then was quenched with water. After extraction with EtOAc (2 x 25 mL), the organic phases were joined, washed with brine, dried over Na S0 , filtered and trated. The crude residue was purified by flash 2 4 column chromatography on silica gel (c-hexane to ne/EtOAc 7:3). MS (UPLC): 388 [M+H]+ ; t (HPLC conditions ) : 2.36 min.
C. ,4S)Fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester To a solution of (2S,3S,4S)fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester (430 mg, 1.1 1 mmol) in MeOH (25 mL) was added Pd/C 10% (100 mg). The reaction was placed under hydrogen atmosphere and was stirred for 2 h then was filtered over glass-fiber, rinsed with MeOH (25 mL) and water (25 mL). After concentration, the residue was lyophilized overnight. The powder obtained was dissolved in THF/Water 1/1 (20 mL) then aq. 1N NaOH (0.755 mL) and Boc ide (412 mg , 2.22 mmol) were added and the reaction e was stirred at RT ght. After concentration, the crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 + 0.5% AcOH). MS (UPLC): 264 [M+H]+; t (HPLC conditions f): 0.65 min.
D. (2S,3S,4S)(3-Chlorofluoro-benzylcarbamoyl)fluoromethoxy-pyrrolidine carboxylic acid tert-butyl ester To a on of (2S,3S,4S)fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (500 mg, 1.90 mmol) in DMF (20 mL) were added 3-chlorofluoro-benzylamine (330 mg, 2.1 mmol), HBTU ( 1 .4 g , 3.8 mmol) and DIPEA ( 1 .32 mL, 7.6 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water (50 mL). After extraction with ETOAc (3 x mL), the organic phases were joined, washed with brine, dried over Na S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c- hexane to c-hexane/EtOAc 1:1) to give (2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl) methoxy-pyrrolidinecarboxylic acid tert-butyl ester: R , TLC (c-hexane/EtOAc 1:1) = 0.37; MS (UPLC): 405.1/407.2 [M+H]+, 349.1/351.1 [MH-tBu]+, 449.2/451 .2 [M+HCOO]-; t (HPLC conditions ) : 2.12 min. 1H NMR (400 MHz, DMSO-d ) d (ppm): 8.59 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.20 (m, 1H), 5.20 (br.d, 1H), 4.47 - 4.26 (m, 3H), 4.19 (ddd, 1H), 3.81- 3.65 (m, 1H), 3.54 - 3.40 (m, 1H), 3.36 (s, 3H), 1.42 and 1.27 (2 s , 9H).
E. (2S,3S,4S)Fluoromethoxy-pyrrolidinecarboxylic acid rofluorobenzylamide trifluoroacetate TFA (0.86 ml_, 11.12 mmol) was added to a solution of (2S,3S,4S)(3-chlorofluorobenzylcarbamoyl uoromethoxy-pyrrolidinecarboxylic acid tert-butyl ester (450 mg, 1.12 mmol) in CH C I (20 ml_). The reaction e was stirred overnight then was 2 2 concentrated. The residue was triturated with Et 0 (10 ml_) to give a itate which was filtered off, washed with Et 0 (10 ml_) then dried under high vacuum. The absolute stereochemistry was confirmed by X-ray. t (HPLC conditions ) 0.40 min; MS (UPLC): 349 [M+HCOO]-, 305 [M+H]+.
Scheme B25: Alternative for the preparation of ,4S)(3-chlorofluorobenzylcarbamoyl )fluoromethoxy-pyrrolidinecarboxylic acid tert-butyl ester A. (2S,3S,4S)Hydroxymethoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester and (2S,3R,4R)hydroxymethoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester To a solution of (1R,2S,5S)Oxaaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid dibenzyl ester (prepared as described Scheme B19, 30 g , 85 mmol) in MeOH (150 ml_) was added Amberlyst 15 (30 g). The reaction mixture was heated ght at 65°C, then allowed to cool to RT and filtered. Amberlyst 15 residue was washed with MeOH. The combined filtrates were combined and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane 100% to EtOAc 100%) to give a mixture of the 2 regioisomers as a yellow oil. R , TLC (c-hexane/EtOAc 1:1) = 0.5; MS (UPLC): 386.2 [M+H]+, 430.2 [M+HCOO]-; t (HPLC conditions a): 1.93 min.
B. (2S,3S,4S)Fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid yl ester and (2R,3R,4R)fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester A solution of (2S,3S,4S)hydroxymethoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester and (2S,3R,4R)hydroxymethoxy-pyrrolidine-1 ,2-dicarboxylic acid dibenzyl ester (17.8 g , 46.2 mmol) in CH C I (250 mL) was cooled under Argon at -78°C then DAST (12.2 mL, 92 2 2 mmol) was added dropwise. The reaction mixture was allowed to reach RT and further stirred for 16 h . The reaction mixture was d with CH C I and carefully quenched with sat. aq. 2 2 NaHC0 . The layers were separated, the aqueous layer extracted twice with CH C I , the 3 2 2 combined organic layers were dried over Na S0 , filtered and trated. Purification by 2 4 flash column chromatography on silica gel (c-hexane/EtOAc 100:0 to 0:100) gave a mixture of the 2 regioisomers as a yellow solid. MS (UPLC/MS): 388.3 [M+H]+, 405.3 [M+NH ]+; t 4 R (HPLC conditions f): 2.34 min.
C. (2S,3S,4S)Fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)Fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester were obtained as a mixture using the protocol described in Scheme B24 step C. R , TLC (EtOAc) = 0.1.
D. (2S,3S,4S)(3-Chlorofluoro-benzylcarbamoyl)fluoromethoxy-pyrrolidine ylic acid tert-butyl ester and (2R,3R,4R)(3-Chlorofluoro-benzylcarbamoyl) fluoromethoxy-pyrrolidinecarboxylic acid tert-butyl ester.
To a solution of (2S,3S,4S)fluoromethoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester ( 1 .55 g , 5.89 mmol) in CH C I (50 mL) were added 3-chlorofluoro-benzylamine ( 1 ,03 g , 6.48 2 2 mmol), propylphosphonic anhydride (50% in EtOAc, 5.20 mL, 8.83 mmol) and DIPEA (3.08 mL, 17.7 mmol). The reaction mixture was stirred at RT for 2 h and trated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 7:3) to give (2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)fluoromethoxy-pyrrolidine carboxylic acid tert-butyl ester: R , TLC (c-hexane/EtOAc 1:1) = 0.35; MS (UPLC): 405.1/407.2 [M+H]+, 351.1 [MH-tBu]+, 449.2/451 .2 [M+HCOO]-; t (HPLC conditions ) : 2.12 min and (2R,3R,4R)(3-chlorofluoro-benzylcarbamoyl)fluoromethoxy-pyrrolidinecarboxylic acid tert-butyl ester: R , TLC (c-hexane/EtOAc 1:1) = 0.5; MS (UPLC): 405.1/407.2 [M+H]+, 351 .1 [MH-tBu]+, 449.2/451 .2 [M+HCOO]-; t (HPLC conditions ) : 2.20 min. (2S,3S,4S)[(R)(3-Chlorofluoro-phenyl)-ethylcarbamoyl]fluoromethoxy- pyrrolidine-1 -carboxylic acid tert-butyl ester was prepared according to the same protocols described in Scheme B25 using (R)(3- chlorofluoro-phenyl)-ethylamine in Step D. Separation of two regioisomers was performed by flash column chromatography on silica gel (c-hexane/EtOAc 6:4) to give ((2S,3S,4S)[(R)- 1-(3-chlorofluoro-phenyl)-ethylcarbamoyl]fluoromethoxy-pyrrolidinecarboxylic acid tert-butyl ester. MS : 405/407 [M+H]+; t (HPLC conditions f): 2.14 min. (2S,3S,4S)[1-(3-Chlorofluoro-phenyl)-cyclopropylcarbamoyl]fluoromethoxypyrrolidinecarboxylic acid utyl ester was ed according to the same protocols described in Scheme B25 using 1-(3-chloro fluoro-phenyl)-cyclopropylamine in Step D. 1-(3-chlorofluoro-phenyl)-cyclopropylamine is ed as described in Part C. Separation of two regioisomers was performed by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) to give (2S,3S,4S)[1-(3-chloro- 2-fluoro-phenyl)-cyclopropylcarbamoyl]fluoromethoxy-pyrrolidinecarboxylic acid tert- butyl ester. MS : 431/433 [M+H]+; t (HPLC conditions ) : 2.21 min. ,4S)(3-Chlorofluoro-benzylcarbamoyl)ethoxyfluoro-pyrrolidine carbox lic acid tert-butyl ester was prepared according to the same protocols described in Scheme B25 using EtOH instead of MeOH in Step A . Separation of two regioisomers was performed by flash column chromatography on silica gel (c-hexane/EtOAc 6:4) to give(2S,3S,4S)(3-chlorofluorobenzylcarbamoyl )ethoxyfluoro-pyrrolidinecarboxylic acid tert-butyl ester. MS (UPLC): 419/421 [M+H]+; t (HPLC conditions f): 2.23 min. (2S,3S,4S)Fluoro(2-fluorotrifluoromethoxy-phenylcarbamoyl)methoxypyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,3S,4S)fluoromethoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 1.00 g , 3.80 mmol) in CH C I (10 mL) at 0°C under 2 2 nitrogen atmosphere was added 1-chloro-N,N,2-trimethylpropenamine (609 mg, 4.56 mmol) and the e was stirred at this temperature for 1 h . 2-Fluoro (trifluoromethoxy)aniline (0.815 mg, 4.18 mmol) was then added, followed by DIPEA ( 1 .327 mL, 7.60 mmol) and the mixture was stirred at RT for 1 h . The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 1:1) to give (2S,3S,4S) fluoro(2-fluorotrifluoromethoxy-phenylcarbamoyl)methoxy-pyrrolidinecarboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d ) 2:1 mixture of rotamers d (ppm): 10.15 (m, 1H), 7.87 (m, 1/3H), 7.77 (m, 2/3H), 7.31 (m, 2H), .1 1 (m, 1H), 4.76 (d, 1/3H), 4.70 (d, 2/3H), 4.29 (m, 1H), 3.80-3.53 (m, 2H), 3.39 (m, 3H), 1.39 (s, 3H), 1.31 (s, 6H). MS (UPLC-MS): 441 [M+H]+; t (HPLC conditions f): 2.14 min. (2S,3S,4S)(3-Bromofluoro-phenylcarbamoyl)fluoromethoxy-pyrrolidine ylic acid tert-butyl ester To a solution of (2S,3S,4S)fluoromethoxy-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 100 mg, 0.380 mmol) in CH C I (2.4 mL) at 0°C under 2 2 nitrogen atmosphere was added ro-N,N,2-trimethylpropenamine (50.8 mg, 0.38 mmol) and the mixture was stirred at this temperature for 2 h . 3-Bromofluoroaniline (144 mg, 0.76 mmol) was then added, followed by DIPEA (0.265 mL, 1.52 mmol) and the mixture was stirred at RT for 1 h . The reaction mixture was concentrated and the crude residue was ed by preparative HPLC (Waters Sunfire C18-ODB, 5mhi , 30x1 00mm, : 0-0.5 min 5% CH CN in H 0 Flow: 5mL/min, 0.5-18.5 min 5 to 100% CH CN/H 0 Flow: 40mL/min, 18.5-20 3 2 3 2 min 100% CH CN, CH CN and H 0 both containing 0.1% TFA). The purified HPLC fractions 3 3 2 were neutralized by addition of a saturated s solution of Na C0 , the layer were 2 3 separated and the aqueous layer was ted with CH C I (x2). The combined organic 2 2 extracts were dried (Na S0 ) , filtered and concentrated. White solid. R , TLC (c-hexane/EtOAc 2 4 f 1:1) = 0.75; MS (UPLC): 435.1/437.1 [M+H]+, 433.1/435.1 [M-H]-; t (HPLC conditions ) : 2.06 min. (2S,3S,4S)(6-Bromo-pyridinylcarbamoyl)fluoromethoxy-pyrrolidine carboxylic acid tert-butyl ester was prepared according to the same protocols described for the synthesis 3S,4S)(3- bromofluoro-phenylcarbamoyl)fluoromethoxy-pyrrolidine-1 -carboxylic acid tert-butyl ester. White solid. R , TLC ) = 0.8; 418.1/420.1 [M+H]+, 416.2/418.1 [M-H]-; t (HPLC f R conditions ) 2.0 min.
Scheme B26: Preparation of (2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)(2- dimethylamino-ethoxy)fluoro-pyrrolidinecarboxylic acid tert-butyl ester A. (2S,3S,4S)fluorohydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester To a solution of (2S,3S,4S)fluorohydroxy-pyrrolidine-1 ,2-dicarboxylic acid dibenzyl ester (390 mg, 1.04 mmol) in MeOH (10 ml_) was added Pd/C 10% (39 mg). The reaction was placed under hydrogen atmosphere and stirred 2 h then was filtered over glass-fiber and rinsed with water. After concentration, the residue was dissolved in THF/Water 2/1 (30 ml_), aqueous NaOH ( 1 N , 2.09 ml_, 2.09 mmol) and Boc anhydride (456 mg , 2.09 mmol) were added and the on mixture was stirred 16 h at RT. THF was removed under reduced pressure and the aqueous layer was extracted with Et 0 (x2), acidified by addition of KHS0 2 4 (10% in water) and extracted with EtOAc (x2). The combined EtOAc extracts were dried (Na S0 ) , filtered and concentrated. The material thus obtained was used in the next step 2 4 without further purification.
B. (2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)fluorohydroxy-pyrrolidine ylic acid tert-butyl ester To a solution of (2S,3S,4S)fluorohydroxy-pyrrolidine-1 ,2-dicarboxylic acid -butyl ester (195 g , 0.782 mmol) in CH C I (10 ml_) were added 3-chlorofluoro-benzylamine (150 2 2 mg, 0.94 mmol), propylphosphonic ide (50% in EtOAc, 0.346 ml_, 1.17 mmol) and DIPEA (0.41 ml_, 2.35 mmol). The reaction mixture was stirred 1 h at RT, then quenched by addition of a saturated aqueous solution of NaHC0 and extracted with CH C I (x2). The 3 2 2 combined organic extracts were dried (Na S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC): 393.1 [M+H]+, 437.4 O]-; t (HPLC conditions ) : 1.95 min.
C. (2S,3S,4S)allyloxy(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester To a solution of NaH (60 % in mineral oil, 8.6 mg, 0.2 15 mmol) in DMF (5 mL) cooled with an ice-bath and under argon was added (2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl) fluorohydroxy-pyrrolidine-1 -carboxylic acid tert-butyl ester (70 mg, 0 .179 mmol) . The on mixture was stirred for 20 min before addition of allyl iodide (0.025 mL, 0.269 mmol) at 0°C. The reaction mixture was stirred for 30 min then quenched by addition of water and extracted with EtOAc (x2). The organic extracts were combined, washed with brine, dried (Na S0 ) , filtered and concentrated. The crude residue was ed by flash column 2 4 chromatography on silica gel ane/EtOAc 3:2). MS (UPLC): 431 .4/433. 1 [M+H]+, 475.5/577.5 O]-; t (HPLC conditions f) : 2.29 min.
D. (2S,3S,4S)(3-Chlorofluoro-benzylcarbamoyl)fluoro(2-oxo-ethoxy)- pyrrolidine carboxylic acid tert-butyl ester Ozone was bubbled through a solution of (2S,3S,4S)allyloxy(3-chlorofluorobenzylcarbamoyl )fluoro-pyrrolidine- 1-carboxylic acid tert-butyl ester (59 mg, 0 .137 mmol) in CH C I (20 mL) at -78°C. When the solution turned blue, ozone addition was stopped and 2 2 nitrogen was passed through the solution until the blue color was discharged.
Triphenylphosphine (35.9 mg, 0 .137 mmol) was added to the ozonide solution at -78°C and the reaction mixture was allowed to slowly reach RT. The reaction mixture was concentrated and the material thus obtained used without r purification in the next step. MS (UPLC): 433.4/435.4 , 477.4/579.5 [M+HCOO]-.
E. (2S,3S,4S)(3-Chlorofluoro-benzylcarbamoyl)(2-dimethylamino-ethoxy) fluoro-pyrrolidinecarboxylic acid utyl ester To a solution of the crude material ed in the previous step and dimethylamine (2 N in MeOH , 173 m I, 0.347 mmol) in MeOH (3 mL) at 25°C were successively added AcOH ( 100 m ) and sodium triacetoxyborohydride (73.5 mg, 0.347 mmol) . The reaction mixture was stirred 2 h and concentrated. The crude residue was purified by preparative HPLC ((Waters Sunfire, C 18- ODB, 5 [Jim, 30x1 00 mm, 5-1 00% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 3 2 3 3 2 ning 0 .1% TFA, flow: 40 mL/min) . MS (UPLC) : 462.4/464.4 [M+H]+, 506.5/508.5 [M+HCOO]-; t (UPLC conditions m): 0.70 min.
Scheme B27: Preparation of (2S,3S,4S)-2 -ri -(3-Chlorofluoro-phenyl)- cvclopropylcarbamovnfluorohvdroxy-pyrrolidinecarboxylic acid tert-butyl ester A. (2S,3S,4S)(tert-Butyl-dimethyl-silanyloxy)f luoro-pyrrolidine-1 ,2-dicarboxylic acid dibenzyl ester To a solution of (2S,3S,4S)fluorohydroxy-pyrrolidine-1 ,2-dicarboxylic acid dibenzyl ester ( 1 .90 g , 5.09 mmol) in DMF (40 ml_) were added tert-butyldimethylchlorosilane (0.844 g , 5.60 mmol), triethylamine (0.709 ml, 5.09 mmol) and DMAP (0.062 g , 0.509 mmol). The on mixture was stirred 25°C for 1 week. Then quenched by addition of a saturated aqueous solution of NaHC0 . The layers were separated and the organic extract was dried (Na S0 ) , 3 2 4 filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1). MS (UPLC): 588.4 [M+H]+, 505.5 [M+NH ]+, 510.4 [M+Na]+; t (HPLC conditions f): 2.90 min.
B. (2S,3S,4S)(tert-Butyl-dimethyl-silanyloxy)f pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester was prepared from (2S,3S,4S)(tert-butyl-dimethyl-silanyloxy)fluoro-pyrrolidine-1 ,2- dicarboxylic acid dibenzyl ester according to the protocol described in Scheme B26 step A . t (UPLC ions m): 1.21 min.
C. (2S,3S,4S)(tert-Butyl-dimethyl-silanyloxy)[1-(3-chlorofluoro-phenyl)- cyclopropyl carbamoyl]fluoro-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,3S,4S)(tert-butyl-dimethyl-silanyloxy)fluoro-pyrrolidine-1 ,2- dicarboxylic acid 1-tert-butyl ester (300 mg, 0.825 mmol), 1-(3-chlorofluoro-phenyl)- cyclopropylamine (prepared as described in Part C, 272 mg, 0.908 mmol) and HBTU (376 mg, 0.99 mmol) in DMF (10 mL) was added DIPEA (0.432 ml, 2.476 mmol) under nitrogen atmosphere. The reaction mixture was stirred 2 h at 25°C. Then quenched by addition of a saturated aqueous solution of NaHC0 and extracted with EtOAc (x2). The combined organic extracts were dried (Na S0 ) , filtered and concentrated. The crude e was ed by flash column chromatography on silica gel (c-hexane/EtOAc1 :1). MS : 531 .5 [M+H]+, 505.5 [M+NH ]+, 510.4 [M+Na]+; t (UPLC conditions m): 1.55 min. 4 R (2S,3S,4S)[1-(3-Chlorofluoro-phenyl)-cyclopropylcarbamoyl]fluorohydroxypyrrolidinecarboxylic acid tert-butyl ester TBAF ( 1 N in THF, 0.547 ml, 0.547 mmol) was added to a solution of (2S,3S,4S)(tert-butyldimethyl-silanyloxy )[1-(3-chlorofluoro-phenyl)-cyclopropyl oyl]fluoro-pyrroli dinecarboxylic acid tert-butyl ester (242 mg, 0.456 mmol) in THF (10 mL) and the reaction mixture was stirred 30 min at 25°C. Then poured into water, ted with EtOAc (x2), dried (Na S0 ) , filtered and concentrated. The material thus obtained was used without further 2 4 purification in the next step. MS (UPLC): 417.5/419.5 [M+H]+, 461 .5/463.5 [M+HCOO]-; t (HPLC conditions f): 2.04 min.
Scheme B28: preparation of (1R.3S.5S) and (1S.3S.5R)(3-Chlorofluorobenzylcarbamoyl )hvdroxymethylaza-bicyclo r3.1.01hexanecarboxylic acid tert- butyl ester A. (S)Formyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester POCIs (7.59 mL, 83 mmol) was added in 25 min at 0°C under N atmosphere to DMF (6.39 mL, 83 mmol) and the mixture was stirred at RT for 20 min. Dry CH C I (150 mL) was added at 2 2 0°C, ed by a solution of (S)-2,3-dihydro-pyrrole-1 ,2-dicarboxylic acid 1-tert-butyl ester 2- ethyl ester (10 g , 41.4 mmol) in CH C I (50 mL). The mixture was stirred 30 min at RT until 2 2 completion. The mixture was slowly poured into an ice cold s solution of NaOH 10 N (150 mL) and extracted with CH C I (x3). The combined organic extracts were washed with 2 2 brine (x2), with water, dried (Na S0 ) , ed and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 9:1) to give the desired material as a yellow oil. R , TLC (c-hexane/EtOAc 4:1) = 0.2; MS (UPLC-MS): 270 [M+H]+, 170 [M-Boc]-; t (HPLC conditions f): 1.93 min.
B. Hydroxymethyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2- ethyl ester A solution of (S)formyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester l ester (3.32 g , 12.3 mmol) in CH C I (51.4 mL) was cooled at -78°C under nitrogen atmosphere, 2 2 solid NaBH ( 1 g , 24.7 mmol) was added portionwise maintaining the temperature at -78°C.
MeOH (25.7 ml_) was added dropwise and the on mixture was allowed to reach 0°C and was stirred 1h30 at 0°C. The reaction was quenched with an aqueous saturated solution of NH C I and extracted with CH C I (x3). The combined c layers were washed with brine, 4 2 2 dried (Na S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1 to EtOAc) to give the desired material as a yellow oil. R , TLC (c-hexane/EtOAc 1:1) = 0.30; MS (UPLC-MS): 272.2 [M+H]+, 316 [M+HCOO]-; t (HPLC conditions f): 1.74 min.
C. (1R,3S,5S) and (1S,3S,5R)Hydroxymethylaza-bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 2-tert-butyl ester 3-ethyl ester To a solution of (S)hydroxymethyl-2,3-dihydro-pyrrole-1 ,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1.12 g , 4.13 mmol) in CH C I ( 1 15 ml_) under argon at -20°C were slowly added 2 2 diethylzinc (1M in hexanes, 8.26 ml_, 8.26 mmol) and methane (0.73 ml_, 9.08 mmol) and the on mixture was further stirred at -10°C for 2 h . lzinc (1M in hexanes, 8.26 ml_, 8.26 mmol) and diiodomethane (0.73 ml_, 9.08 mmol) were again added and the reaction mixture was further stirred at -10°C for 2 h to complete the reaction. A saturated aqueous solution of NH C I was added slowly (exothermic) at -20°C followed by CH C I . The layers were 2 2 separated and the aqueous layer was extracted with CH C I (x2). To the combined organic 2 2 layers were added few crystals of Na S and water (ratio CH C I /H 0 20:1) and the ic 2 2 2 2 e was stirred for 30 min. Water was added, the layers were separated, dried (Na S0 ) , filtered and trated to give a e of diastereoisomers. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) to give a mixture of diastereoisomers (4:6 (1R,3S,5S)/(1S,3S,5R)). The absolute stereochemistry of the diastereoisomers was determined by NMR. R , TLC (c-hexane/EtOAc 1:1) = 0.25; MS (UPLC- MS): 186.1[MH-Boc]+, 230.2 [MH-tBu]+, 286.3 [MH+H]+, 308.2 [MH+Na]+, 330.3 [M+HCOO]-; t (HPLC conditions f): 1-75 min.
Alternatively (1R,3S,5S) and (1S,3S,5R)hydroxymethylaza-bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 2-tert-butyl ester l ester were prepared according to the procedure below derived from J. Amer. Chem. Soc, 1998, 120, 46, 11943.
To a solution of dry DME (198 m , 1.91 mmol) in dry CH C I (4 mL) under argon atmosphere 2 2 and cooled at -10°C was added diethylzinc ( 1 M in s, 2.05 mL, 2.05 mmol) followed by chloroiodomethane (330 m , 4.1 mmol) over a 15-20 min period while maintaining the internal temperature at -10°C. The solution was stirred for an additional 10 min at -10°C and a solution of butylboronic acid N,N,N',N'-tetramethyl-D-tartaric acid diamide ester (346 m , 1.36 mmol) in anhydrous CH C I ( 1 mL) was added over a 5 min period immediately followed by the addition 2 2 of a solution of (S)hydroxymethyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (185 mg, 0.68 mmol) in dry CH C I ( 1 mL). The reaction mixture was stirred at - 2 2 °C. The reaction was quenched with 1 mL of a saturated aqueous NH C I and 10 % KHS0 (3 mL), EtOAc was added, the layers were ted and the aqueous layer back-extracted with EtOAc (x2). To the combined organic layers was added a solution containing 6 mL of 2 N aqueous NaOH and 1 mL of 30 % aqueous H 0 and the resulting biphasic solution was 2 2 vigorously d for 5 min. The two layers were separated and the organic layer was successively washed with saturated aqueous Na S0 , NaHC0 and brine, dried over Na S0 , 2 3 3 2 filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 6-4) to give a mixture of diastereoisomers (approximatively 70/30 (1R,3S,5S)/(1S,3S,5R)).
D. (1R,3S,5S) and (1S,3S,5R)Hydroxymethylaza-bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 2-tert-butyl ester To a reoisomeric mixture of ( 1 R,3S,5S) and (1S,3S,5R)hydroxymethylaza- bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid -butyl ester 3-ethyl ester (ratio 4:6, 100 mg, 0.31 mmol) in THF (1.5 mL) and H 0 (0.15 mL) at 0°C was added NaOH ( 1 M in water, 0.63 mL, 0.63 mmol). The solution was stirred 1 h at RT and poured into 10 % KHS0 (until pH 1), EtOAc was added and the layers were separated (x3). The combined c layers were dried (Na S0 ) , filtered and trated. The crude residue was used t further cation in the next step. MS (HPLC/MS): 256.2 [M-H]-, 258.3 [M+H]+, 280.3 [M+Na]+, 200.2 [MH-tBu]+, 515.54 [2M+H]+, 537.4 [2M+Na]+; t (HPLC conditions ) : 1.28 min.
E. (1R,3S,5S) and (1S,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)hydroxymethyl aza-bicyclo [3.1.0]hexanecarboxylic acid tert-butyl ester To a diastreoisomeric mixture of (1R,3S,5S) and (1S,3S,5R)hydroxymethylaza- bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (312 mg, 1.21 mmol), 3-chloro fluorobenzylamine (232 mg, 1.46 mmol), HBTU (690 mg, 1.82 mmol) in CH C I (6 mL) was 2 2 added DIPEA (0.623 mL, 3.64 mmol). The resulting solution was stirred at RT under en overnight. DIPEA (0.21 mL, 1.21 mmol), HBTU (230 mg, 0.6 mmol) and 3-chloro fluorobenzylamine (97 mg, 0.606 mmol) were added and the mixture was further stirred overnight at RT under N2. The mixture was poured into an aqueous solution of HCI 1N (pH-1) and extracted with CH C I (2x). The combined organic layers were washed with brine, dried 2 2 (Na S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 40:60) to give (1S,3S,5R)(3- chlorofluoro-benzylcarbamoyl)hydroxymethylaza-bicyclo [3. 1.0]hexanecarboxylic acid utyl ester: TLC, R (EtOAc) = 0.55 (stained with ninhydrine); MS MS): 399.2/401 .2 [M+H]+, 299.2/301.2 [MH-Boc]+, 343.2/345.2 u]+, 443.2/445.3 [M+HCOO]- ; tR (HPLC conditions f): 1.95 min, and (1R,3S,5S)(3-chlorofluoro-benzylcarbamoyl) hydroxymethylaza-bicyclo [3.1.0]hexanecarboxylic acid tert-butyl ester: TLC, Rf (EtOAc) = 0.45 (stained with rine); MS MS): 399.2/401 .2 [M+H]+, 299.2/301 .2 [MH-Boc]+, 343.2/345.2 u]+, 443.2/445.3 [M+HCOO]-; tR (HPLC conditions f): 1.89 min. ( 1R,3S,5S)Hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-tert- butyl ester was obtained using the same ols as described in Scheme B28 step D from ( 1 R,3S,5S)- -hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester. 1H NMR (400 MHz, DMSO-d 6) d (ppm): 12.5 (m, 1H), 4.71 (m, 1H), 3.92 (m, 1H), 3.42 - 3.35 (m, 2H), 3.17 (m, 1H), 2.31 (m, 1H), 2.08 (m, 1H), 1.41 and 1.33 (2 s , 9H), 0.79 (m, 1H), 0.67 (m, 1H). ( 1R,3S,5S)Hvdroxymethylaza-bicyclor3.1 .01hexane-2,3-dicarboxylic acid 2-tert- butyl ester 3-ethyl ester The mixture of ( 1 R,3S,5S) and (1S,3S,5R)hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3- dicarboxylic acid 2-tert-butyl ester l ester (360 g) was separated into its diastereoisomers by preparative chiral HPLC column: 8 SMB s Chiralpak AD, 20 urn, 250 x 30 mm; eluent: heptane-EtOH 80:20) to give (1R,3S,5S)hydroxymethylaza-bicyclo[3.1 .0]hexane- 2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester: tR (Chiralpak AD-prep, 20 uM, 250 x 4.6 mm, n-heptane/EtOH 80/20, flow rate 1 mL/min, detection: UV at 210 nm): 6.94 min and (1S,3S,5R)hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester: tR lpak AD-prep, 20 uM, 250 x 4.6 mm, n-heptane/EtOH 80/20, flow rate 1 mL/min, detection: UV at 210 nm): 4.20 min. (1R.3S.5S) and (1S,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)methoxymethyl aza-bic clo 3.1.0 hexanecarbox lic acid tert-butyl ester were obtained using the same protocols as described in Scheme B28 steps D and E for the preparation of ,5S) and (1S,3S,5R)(3-chlorofluoro-benzylcarbamoyl) hydroxymethylaza-bicyclo [3.1 .0]hexanecarboxylic acid tert-butyl ester starting from ( 1 S) and (1S,3S,5R)methoxymethylaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester. NaOH was replaced by LiOH.H 0 in step D. The diastereoisomers were separated by flash column tography on silica gel (c- hexane/EtOAc 1:1 to EtOAc) to give (1S,3S,5R)(3-chlorofluoro-benzylcarbamoyl) methoxymethylaza-bicyclo[3.1 .0]hexanecarboxylic acid tert-butyl ester as a colorless oil: TLC, R (c-hexane/EtOAc 1:1) = 0.50; MS (UPLC/MS): 413.3/415.2 [M+H]+, 457.3/459.3 [M+HCOO]-; t (HPLC conditions a): 3.74 min and ( 1 R,3S,5S)(3-chlorofluoro- carbamoyl)methoxymethylaza-bicyclo[3. 1.0]hexanecarboxylic acid tert-butyl ester as a colorless oil: TLC, R ane/EtOAc 1:1) = 0.30; MS (UPLC/MS): 413.2/415.3 [M+H]+, 457.3/459.3 [M+HCOO]-; t (HPLC conditions a): 3.57 min. ( 1R,3S,5S) and ( 1S,3S,5R)Methoxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester l ester ( 1 R,3S,5S) and ,5R)hydroxymethylaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester l ester as mixture of diastereoisomers (35:65 (1R,3S,5S)/(1S,3S,5R)) (840 mg, 2.94 mmol) were slowly added at 0°C under Argon to a suspension of NaH (60 % in mineral oil, 141 mg, 3.53 mmol) in THF (9 mL). The reaction mixture was stirred at 0°C for 30 min and iodomethane (0.28 mL, 4.42 mmol) was added slowly at 0°C. The reaction mixture was further stirred at RT overnight. Saturated NaHC0 and CH C I were added, the layers 3 2 2 were separated and the aqueous one back-extracted twice with CH C I . The combined organic 2 2 extracts were dried (Na S0 ) , ed and concentrated. The crude material was purified by 2 4 flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 2:8) to give the title compound as an unseparable mixture of diastereosisomers. TLC, R (c-hexane/EtOAc 1:1) = 0.70; MS (UPLC/MS): 300.3 [M+H]+, 599.5 [2M+H]+; t (HPLC ions a): 3.45 min. The absolute stereochemistry of the reoisomers was tentatively assigned by NMR and based on the test results for the final compounds Example 214 and Example 184 in the biological assay. (1R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)methylaza-bicyclo[3.1.0]hexane- 2-carbox lic acid tert-butyl ester Lithium triethylborohydride (1N in THF, 2.06 mL, 2.06 mmol) was added at 0°C to a solution of ( 1 R,3S,5S)(3-chlorofluoro-benzylcarbamoyl)methanesulfonyloxymethylaza- bicyclo[3.1.0]hexanecarboxylic acid tert-butyl ester (385 mg, 0.67 mmol) in THF (6.8 mL) under argon atmosphere. The solution was stirred 10 min at 0°C, then poured into cold water and extracted with EtOAc (x2). The combined c extracts were dried (Na S0 ) , filtered 2 4 and concentrated. The crude e was purified by flash column chromatography on silica gel ane to c-hexane/EtOAc 75:25). TLC, R (c-hexane/EtOAc 1:1) = 0.55; MS (UPLC/MS): 383.3/385.3 [M+H]+, 427.5/429.4 [M+HCOO]-; t (HPLC conditions ) : 2.24 min. (1R,3S,5S)(3-Chlorofluoro-benzylcarbamoyl)methanesulfonyloxymethylaza- bicyclor3.1.01hexanecarboxylic acid tert-butyl ester To a solution of ( 1 R,3S,5S)(3-chlorofluoro-benzylcarbamoyl)hydroxymethylaza- bicyclo[3.1 .0]hexanecarboxylic acid tert-butyl ester (290 mg, 0.72 mmol) and Et N (144 m I_ , 1.04 mmol) in CH C I (6.5 ml_) at 0°C under nitrogen atmosphere was added methanesulfonyl 2 2 chloride (81 m I_ , 1.04 mmol) and the mixture was stirred at RT for 1 h . Et N (48 m I_ , 0.35 mmol) and methanesulfonyl chloride (27 m I_ , 0.35 mmol) were again added and the mixture was further stirred for 0.5 h to complete the reaction. A ted aqueous solution of NaHC0 was added, the layers were separated and the aqueous layer extracted with CH C I (x2), dried 2 2 (Na S0 ) , filtered and concentrated. The material thus obtained was used in the next step without further purification. TLC, R (EtOAc) = 0.65; MS (UPLC/MS): 477.3/479.3 [M+H]+, 521.3/523.3 O]- (1R,3S,5R)Methylaza-bicvclor3.1.01hexane-2,3-dicarboxylic acid 2-tert-butyl ester To a on of ( 1 R,3S,5R)methylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-tertbutyl ester 3-ethyl ester (185 mg, 0.69 mmol) in MeOH (1.1 mL), THF ( 1 . 1 mL) and H 0 (1.1 mL) was added KOH (77 mg, 1.37 mmol). The on was stirred 2.5 h at RT, HCI (0.1 N) was added (until pH 1), CH C I was added and the layers were separated (x2). The combined 2 2 organic layers were dried (Na S0 ) , ed and concentrated. The material (yellow oil) thus obtained was used without further purification in the next step. 1H NMR (400 MHz, DMSO- ) d (ppm): 12.46 (m, 1H), 3.86 (m, 1H), 3.06 (m, 1H), 2.40 (dd, 1H), 1.86 (m, 1H), 1.37 (m, 9H), 1.18 (s, 3H) 0.65 (m, 2H). (1R,3S,5R)Methylaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3- ethyl ester To a solution of ( 1 R,3S,5S)methanesulfonyloxymethylaza-bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 2-tert-butyl ester (100 mg, 0.24 mmol) in DME (2.6 mL) were successively added Nal (355 mg, 2.37 mmol) and zinc powder (155 mg, 2.37 mmol). The reaction mixture was refluxed 30 min under argon atmosphere, cooled to RT and quenched by addition of a saturated aqueous solution of NH C I ( 1 .6 ml_). CH C I (1.6 mL) and few Na S s were 4 2 2 2 added and the biphasic mixture was stirred at RT for 1 h . The layers were separated, the organic extracts were washed with brine, dried (Na S0 ) , filtered and trated under 2 4 reduced pressure. The crude residue was purified by flash column chromatography on silica gel t: c-hexane to c-hexane/ EtOAc). TLC, R (c-hexane/ EtOAc 2:1) = 0.60; MS (UPLC/MS): 270.3 [M+H]+, 214.2 [MH-tBu]+, 170.2 [MH-Boc]+; 1H NMR (400 MHz, DMSO-d ) d (ppm): 4.1 1 (m, 2H), 3.95 (m, 1H), 3.10 (m, 1H), 2.42 (m, 1H), 1.84 (m, 1H), 1.38 (m, 9H), 1.20 (t, 3H), 1.18 (s, 3H) 0.69 (dd, 1H), 0.64 (m, 1H). (1R,3S,5S)methanesulfonyloxymethylaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester To a solution of ( 1 R,3S,5S)hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (500 mg, 1.75 mmol) and Et N (366 m I_ , 2.63 mmol) in CH C I 3 2 2 (16 mL) was added methanesulfonyl de (205 m I_ , 2.63 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was slowly allowed to reach RT and stirred 1 h . The reaction was quenched by on of a saturated aqueous solution of NaHC0 , the layers were separated and the aqueous layer extracted twice with CH C I . The combined organic extracts 2 2 were dried (Na S0 ) , filtered and concentrated. The material thus obtained was used without r cation in the next step. Yellow oil, TLC, R (EtOAc) = 0.80.
Scheme B29: Preparation of (1R,3S,5S)Hvdroxymethylaza-bicyclor3.1.01hexane carbox lic acid (2-fluorotrifluoromethoxy-phenyl)-amide hydrochloride A. ( 1R,3S,5S)(Tetrahydro-pyranyloxymethyl)aza-bicyclo[3.1 .0]hexane-2,3- dicarboxylic acid 2-tert-butyl ester 3-ethyl ester A mixture of ( 1 R,3S,5S)hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylicacid 2- tert-butyl ester 3-ethyl ester (500 mg, 1.75 mmol), 3,4-dihydro-2H-pyran (176 m , 1.93 mmol) and TsOH.H 0 (33 mg, 0.17 mmol) in CH C I (6 mL) was stirred 3 h at RT. Then poured into a 2 2 2 saturated aqueous solution of NaHC0 and extracted with CH C I (x2). The combined organic 3 2 2 extracts were dried (Na S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). ess oil.
TLC, R (EtOAc) = 0.85; MS (UPLC/MS): 370.4 [M+H]+, 387.4 [M+H 0]+; t (HPLC conditions f 2 R f): 2.28 min.
B. ( 1R,3S,5S)(Tetrahydro-pyranyloxymethyl)aza-bicyclo[3.1 .0]hexane-2,3- oxylic acid 2-tert-butyl ester To a solution of ( 1 R,3S,5S)(tetrahydro-pyranyloxymethyl)aza-bicyclo[3.1.0]hexane- 2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (510 mg, 1.38 mmol) in MeOH (2.3 mL), THF (2.3 mL) and water (2.3 mL) was added KOH (155 mg, 2.76 mmol). The reaction was stirred at 60°C for 45 min. Then allowed to cool to RT and diluted with EtOAc. The layers were separated, the s layer was acidified by addition of HCI (0.1 N , until pH 1) and extracted with EtOAc (x2). The organics were dried (Na S0 ) , filtered and concentrated. MS (UPLC/MS): 2 4 359.4 [M+NH ]+, 340.4 [M-H]-, 386.4 [M+HCOO]-, 681.5 -; t (HPLC conditions ) : 1.84 4 R min.
C. (1R,3S,5S)(2-Fluorotrifluoromethoxy-phenylcarbamoyl)(tetrahydro-pyran yloxymethyl)aza-bicyclo[3.1.0]hexanecarboxylic acid tert-butyl ester To a solution of ( 1 R,3S,5S)(tetrahydro-pyranyloxymethyl)aza-bicyclo[3.1.0]hexane- 2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.29 mmol) in dry CH C I ( 1 mL) under argon 2 2 at 0°C was added 1-chloro-N,N,2-trimethylpropenylamine (58 m , 0.44 mmol) and the reaction mixture was stirred at 0°C for 1.5 h . 2-Fluoro(trifluoromethoxy)aniline (86 mg, 0.44 mmol) was added, followed by DIPEA (100 m , 0.59 mmol) and the mixture was stirred at RT overnight. Then poured into water and extracted with CH C I (x2), the organics were dried 2 2 (Na S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to ne/EtOAc 85:15). TLC, R (c- hexane/EtOAc 2:1) = 0.45; MS (UPLC/MS): 519.3 [M+H]+, 536.3 [M+NH ]+, 517.4 , 563.3 [M-HCOO]-; t (HPLC conditions f): 2.51 min.
D. (1R,3S,5S)Hydroxymethylaza-bicyclo[3.1.0]hexanecarboxylic acid (2- fluorotrifluoromethoxy-phenyl)-amide hydrochloride To a solution of ( 1 S)(2-fluorotrifluoromethoxy-phenylcarbamoyl)(tetrahydro- pyranyloxymethyl)aza-bicyclo[3.1.0]hexanecarboxylic acid tert-butyl ester (105 mg, 0.19 mmol) in dioxane (0.5 mL) was added HCI (4 N in dioxane, 481 m , 1.92 mmol). The mixture was stirred at RT for 4 h , solvent was removed under reduced pressure and the material thus obtained was used without further purification in the next step. MS MS): 335.2 [M+H]+, 333.2 , 379.6 [M+HCOO]-. ( 1R,3S,5R)r3-(3-Chlorofluoro-phenyl)-oxetanylcarbamovnaza-bicyclor3. 1.01 To a solution of ( 1 R,3S,5R)aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (220 mg, 0.968 mmol) , propylphosphonic anhydride (50% in EtOAc, 0.856 ml, 1.45 mmol) and hlorofluoro-phenyl)-oxetanylamine (prepared as described in Part C, 358 mg, 1.06 mmol) in CH C I ( 10 ml_) was added D IPEA (0.507 ml, 2.90 mmol) under en atmosphere. 2 2 The reaction mixture was stirred 2 h at RT and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:2). MS (LC/MS): 4 11.2/41 3.2 [M+H]+, 455.2/457.2 [M+HCOO]-; t (HPLC conditions ) : 2.02 min.
Scheme B30: Preparation of ( 1 R,3S,5R)r2-(3-Acetyl-pyrazolor3,4-blpyridin-1 -yl)- acetyl1azabicyclor3.1.01- carboxylic acid A. ( 1R,3S,5R)Azabicyclo [3.1.0]hexane-2 ,3-dicarboxylic acid 3-allyl ester 2-tert-butyl ester To a on of ( 1 R,3S,5R)azabicyclo[3. 1.0]hexane-2,3-dicarboxylic acid -butyl ester ( 1 .5 g , 3.6 mmol) and Cs C0 (2.26 g , 6.9 mmol) in DMF (20 ml_) allyl bromide (0.6 ml_, 3.9 2 3 mmol) was added. The reaction mixture was stirred for 40 h at RT. DMF was evaporated. The residue was dissolved in EtOAc and washed with HCI 1N, dried over Na S0 , filtered and 2 4 concentrated. The crude residue was purified by flash column chromatography on silica gel (c- hexane to c-hexane/EtOAc 4:6). MS (LCMS): 167.9 [MH-Boc]+, 290.0 [M+Na]+.
B. ( 1R,3S,5R)Azabicyclo [3.1.0]hexane carboxylic acid allyl ester hydrochloride To ( 1 R)azabicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 3-allyl ester 2-tert-butyl ester ( 1 .69 g , 6.32 mmol) was added HCI 4N in dioxane ( 15.8 ml_, 63.2 mmol). The reaction mixture was stirred for 6 h at RT and subsequently lyophilized. MS: 168.0 [M+H]+.
C. (1R,3S,5R)[2-(3-Acetyl-pyrazolo[3,4-b]pyridinyl)-acetyl]aza-bicyclo[3.1.0] carboxylic acid allyl ester To a solution of ( 1 R,3S,5R)azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-allyl ester hydrochloride (1.03 g , 6.43 mmol), (3-acetyl-pyrazolo[3,4-b]pyridinyl)-acetic acid (prepared as described in Part A , 1.3 g , 5.93 mmol) and HBTU (2.70 g , 7.12 mmol) in DMF (19.7 mL) was added DIPEA (3.1 1 mL, 17.8 mmol). The on mixture was stirred for 16 h at RT. DMF was evaporated. The residue was poured into NH C I ated aqueous solution) and extracted with EtOAc (3 x 50 mL). The organic phases were ed, dried over Na S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 0:10). R , TLC (EtOAc) = 0.6; MS (LCMS): 369.0 [M+H]+, 391 .0 [MH+Na]+; t (HPLC conditions k): 2.78 min.
D. (1R,3S,5R)[2-(3-Acetyl-pyrazolo[3,4-b]pyridinyl)-acetyl]aza-bicyclo[3.1.0] hexanecarboxylic acid Allyl palladium chloride dimer (0.084 g , 0.231 mmol) and 2-di-tert-butylphosphino-2'- methylbiphenyl (0.288 g , 0.923 mmol) were dissolved in DMF (7.69 mL) under argon atmosphere. The reaction mixture was stirred at RT for 10 min. After cooling the reaction mixture to 10°C, formic acid (0.513 mL, 13.38 mmol) was added followed by TEA ( 1.865 mL, 13.38 mmol) and a solution of (1R,3S,5R)[2-(3-acetyl-pyrazolo[3,4-b]pyridinyl)acetyl] azabicyclo[3.1.0]hexanecarboxylic acid allyl ester ( 1 g , 2.3 mmol) in DMF (15.38 mL). The reaction e was stirred at 10°C during 1 h . DMF was evaporated. The residue was poured into NH C I (saturated aqueous solution) and extracted with EtOAc (3 x 50 mL). The c phases were combined, dried over Na S0 , filtered and concentrated. The residue was dissolved in MeOH and filtered over a PL-Thiol cartridge. The filtrate was concentrated. The crude residue was purified by preparative HPLC (Waters e C18-OBD, 5 mhi , 30x1 00mm, flow: 40 mL/min, eluent: 5% to 80% CH CN in H 0 in 20 min, CH CN and H 0 containing 0.1% 3 2 3 2 TFA) and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M+H]+, 351.0 [MH+Na]; t (HPLC conditions I): 1.84 min. H NMR (400 MHz, DMSO-d ) : d R 6 (ppm) 8.66 (dd, J=4.52, 1.59 Hz, 1 H), 8.58 (m, J=6.36 Hz, 1 H), 7.35 - 7.50 (m, 1 H), 8.54 - 8.61 (m, 1 H), 5.88 (d, 7 Hz, 1 H), 5.55 (d, J=17.12 Hz, 1 H), 4.14 - 4.24 (m, 1 H), 3.75 - 3.83 (m, 1 H), 2.64 (s, 3 H), 2.26 - 2.36 (m, 1 H), 2.10 - 2.23 (m, 1 H), 1.80 - 1.95 (m, 1 H), 0.95 - 1.07 (m, 1 H), 0.67 - 0.81 (m, 1 H).
Scheme B31 : Preparation of (1R,3S,5R)r2-(3-Carbamoyl-indazolyl)-acetyl1azabicycloP.I .OIhexanecarboxylic acid A. (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-benzyl ester 2-tert- butyl ester To a solution of ( 1 R,3S,5R)azabicyclo[3.1 ane-2,3-dicarboxylic acid 2-tert-butyl ester (2.5 g , 11.0 mmol) and Cs2C0 3 (3.94 g , 12.1 mmol) in DMF (50 ml_) at 0°C benzylbromide (2.26 g , 13.2 mmol) was added dropwise. The reaction mixture was stirred ght at RT.
DMF was evaporated. The residue was dissolved in EtOAc and washed with a saturated aqueous on of NaHC0 3, the layers were separated and the aqueous phase was extracted with EtOAc (x2). The combined organic extracts were dried over Na2S0 4, ed and concentrated. The crude residue was purified by flash column chromatography on silica gel (c- hexane/EtOAc 100:0 to 0:100) to give the desired material as a ess oil. MS (LCMS): 318.2 [M+H]+; tR (HPLC conditions f): 2.23 min.
B. (1R,3S,5R)Aza-bicyclo[3.1.0]hexanecarboxylic acid benzyl ester trifluoroacetate To ( 1 R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (3.27 g , 9.79 mmol) in CH2C I2 (50 ml_) was added was added TFA (7.54 ml_, 98 mmol).
The reaction mixture was stirred overnight at RT and subsequently concentrated under reduced pressure to give the desired material as a yellow oil. MS (UPLC): 218.1 [M+H]+; tR (HPLC conditions f): 1.24 min.
C. (1R,3S,5R)[2-(3-Carbamoyl-indazolyl)-acetyl]aza-bicyclo[3.1.0]hexane carboxylic acid benzyl ester To a solution of ( 1 R,3S,5R)aza-bicyclo[3.1.0]hexanecarboxylic acid benzyl ester trifluoroacetate (3.9 g , 9.77 mmol), (3-carbamoyl-indazolyl)-acetic acid (prepared as described in Scheme A25, 2.26 g , 9.77 mmol), HBTU (5.56 g , 14.66 mmol) in CH C I (60 mL) 2 2 was added DIPEA (5.12 mL, 29.3 mmol). The reaction mixture was stirred for 48 h at RT. The reaction mixture was poured into water and ted with CH C I (x3). The combined organic 2 2 extracts were dried over Na S0 , filtered and concentrated. The crude residue was purified by 2 4 flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 0:10). R , TLC (EtOAc) = 0.85; MS (UPLC): 436.3 [M+NH ]+, 463.2 [M+HCOO]-; t (HPLC ions f): 1.82 min. 4 R D. (1R,3S,5R)[2-(3-Carbamoyl-indazolyl)-acetyl]aza-bicyclo[3.1.0]hexane carboxylic acid ( 1 R,3S,5R)[2-(3-carbamoyl-indazolyl)-acetyl]aza-bicyclo[3.1.0]hexanecarboxylic acid benzyl ester (3.9 g , 8.85 mmol) was dissolved in THF (120 mL) and EtOAc (120 mL). Air was d from the flask and replaced with nitrogen three times. Pd/C 10 % (390 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere, and d at RT for 4 h . The st was removed through a pad of Celite and washed with EtOAc. Solvents were removed under reduced pressure and the foam thus obtained was used without further purification in the next step. MS : 346.2 [M+NH ]+, 327.1 [M-H]-; t 4 R (HPLC conditions f): 1.12 min.
Scheme B32: ,5R)aminomethylaza-bicvclor3.1.01hexanecarboxylic acid tert -but l ester A. (1R,3S,5R)Hydroxymethylaza-bicyclo[3.1.0]hexanecarboxylic acid tert-butyl ester To a solution of ( 1 R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (0.5 g , 2.2 mmol) in dry THF (10 mL), cooled to 0°C, was added under an argon atmosphere dropwise a 1M solution of boran-tetrahydrofuran-complex (4.40 mL, 4.40 mmol). The reaction mixture was kept at 0°C for an additional 2 h and then allowed to warm up to RT overnight.
The reaction was quenched by careful addition of water and subsequently EtOAc. The organic layer was subsequently washed with saturated aqueous solutions of NaCI, NaHC0 , water and NaCI. The organic phase was dried (phase separator) and concentrated to give the title compound as a colorless oil. MS (LC-MS): 214.0 ; t (HPLC conditions k): 2.99 min.
The material thus obtained was used in the next step without further purification.
B. ( 1R,3S,5R)(Toluenesulfonyloxymethyl)aza-bicyclo [3.1 .0]hexanecarboxylic acid tert-butyl ester To an ice-cooled solution of ( 1 R,3S,5R)hydroxymethylaza-bicyclo[3.1 .0]hexane carboxylic acid tert-butyl ester (0.480 g , 2.15 mmol) in pyridine (5 ml_) was added 4- toluenesulfonyl chloride (0.490 g , 2.58 mmol). The reaction mixture was stirred at RT for 6 h and then diluted with Et 0 . The organic phase was washed with 1N HCI (3x), aqueous NaHC0 (3x) and NaCI, then dried (phase separator) and concentrated under reduced pressure. The residue was purified by flash column tography on silica gel (eluent gradient: c-hexane to ne/EtOAc 4:1) to afford the title compound as a colorless wax.
TLC, R (c-hexane/EtOAc 4:1) = 0.2. MS (LC-MS): 390.0 [M+Na]+, 757.0 [2M+H]+. t (HPLC f R conditions k): 4.07 min.
C. (1R,3S,5R)Azidomethylaza-bicyclo [3.1 .0]hexanecarboxylic acid tert-butyl ester A e of (1R,3S,5R)(toluenesulfonyloxymethyl)aza-bicyclo[3.1 .0]hexane carboxylic acid utyl ester (0.400 g , 1.08 mmol) and NaN (0.420 g , 6.47 mmol) in dry DMSO (8 ml_) was stirred at 65°C overnight. After cooling, the mixture was diluted with Et 0 and washed with water (x3) and brine (x2). The organics were dried (phase separator) and concentrated in vaccuo to give the title compound as a colorless oil. MS (LC-MS): 239.0 [M+H]+; t (HPLC conditions k): 3.78 min. The material thus obtained was used in the next step without further purification.
D. ,5R)Aminomethylaza-bicyclo [3.1 .0]hexanecarboxylic acid tert-butyl ester ( 1 R,3S,5R)azidomethylaza-bicyclo[3.1.0]hexanecarboxylic acid tert-butyl ester (195 mg, 0.82 mmol) was suspended in THF (10 mL). Air was d from the flask and replaced with nitrogen three times. Pd/C 10 % (20 mg) was added to the solution which was again degassed, placed under a en atmosphere, and stirred at RT overnight. The catalyst was d through a 0.45 microns filter, and the filtrate was concentrated in vacuo to give the title compound. MS (LC-MS): 213.0 [M+H]+; t (HPLC conditions k): 2.51 min. The material thus obtained was used in the next step without further purification.
Part C : sis of aniline and benzylamine intermediates: 4-Aminobromo-benzoic acid methyl ester To a suspension of 2-bromonitro-benzoic acid methyl ester 96] (350 mg, 1.35 mmol) in MeOH (60 mL) were subsequently added tin powder ( 1 .6 g , 13.5 mmol) and 3N s HCI (27.8 mL, 83 mmol). The mixture was stirred overnight at RT. The liquid phase was decanted from the excess tin and neutralized by adding a saturated aqueous NaHC0 solution. An equal amount of water by volume was added and the water phase was extracted with EtOAc (3x). The combined organics were dried (Phase Separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane 1:4) to give the title compound as yellow solid. MS (LC/MS): 230 [M+H]+; t (HPLC conditions b): 2.89 min. 3'-Aminofluoro-biphenylcarbonitrile 3-Aminophenylboronic acid (200 mg, 1.29 mmol), 3-fluoroiodobenzonitrile (319 mg, 1.29 mmol), TBACI (35.9 mg, 0.129 mmol) and Pd(PPh ) (74.6 mg, 0.064 mmol) were suspended in a mixture of toluene (4mL) and K C0 1M in water (4mL). The biphasic mixture was 2 3 vigorously stirred under argon at 90°C for 20 h . The organic layer was separated and the aqueous phase was extracted with toluene (x2). The organic layers were combined, washed with water, dried over Na S0 , filtered and trated. The crude residue was purified by column chromatography ane/EtOAc 3:1) to give the desired material. MS ) [M+H]+ = 213; t (HPLC, Waters Atlantis, 2.1x30mm, flow 0.6mL/min, CH CN/H 0 5 to 95% in R 3 2 2.5 min, 95% CH CN 2 min, 95 to 5% CH CN, H 0 and CH CN both containing 0.1% 3 3 2 3 HCOOH): 2.84 min. 2-Fluoro(trifluoromethoxy)aniline hydrochloride A. 2-Fluoro-1 -iodo(trifluoromethoxy)benzene To a solution of 1-fluoro(trifluoromethoxy)benzene 18-5] (20.0 g , 111 mmol) in dry THF (200 mL), cooled to -78°C, was added dropwise n-BuLi (2.5 M solution in n-hexane; 65 mL, 160 mmol) and subsequently TMEDA (60 mL). The reaction mixture was stirred for additional 60 min at -78°C, followed by addition of a solution of iodine (30.2 g , 120 mmol) in dry THF (50 mL). The resulting mixture was stirred for 1 h and then quenched by addition of a saturated aqueous NH C I solution (20 mL). The organic layer was washed with 1N HCI, water and brine, and dried over MgS0 . Volatiles were d in vacuo to afford the title compound as yellow oil. The t was used in the next on step without further purification. MS (LC/MS): 306.0 [M+H]+.
B. Benzhydrylidene-(2-fluorotrifluoromethoxy-phenyl)-amine To a solution of 2-fluoroiodo(trifluoromethoxy)benzene (25 g , 8 1 mmol) in dry toluene (200 mL) was added Cs C0 (38.7 g , 120 mmol), Pd (dba) (7.42 g , 8.1 mmol), BINAP (10.8 g , 2 3 2 3 16.2 mmol) and benzhydrylideneamine (19.6 g , 108 mmol). The reaction mixture was refluxed for 8 h with stirring and then cooled to RT. The organic layer was washed with water and brine and then dried over MgS0 . After removal of solvent in vacuo, the residue was purified by column chromatography on silica gel (solvent gradient from 100% n-hexane to n- hexane/EtOAc 20:1) to afford the title compound as a pale yellow oil. H NMR (CDCI , 400 MHz) : d 7.72 (s, 1H , ArH,), 7.70 (s, 1H , ArH), 7.45-7.42 (m, 1H, ArH,), 7.37-7.33 (m, 2H, ArH), 7.25-7.17 (m, 3H, ArH), 7.06 (s, 1H, ArH), 7.05 (s, 1H , ArH,), 6.84 (t, 1H , J = 8 Hz, ArH), 6.78 (t, 1H, J = 8 Hz, ArH), 6.67-6.64 (m, 1H , ArH).
C. 2-Fluoro(trifluoromethoxy)aniline hydrochloride To a mixture of benzhydrylidene-(2-fluorotrifluoromethoxy-phenyl)-amine (7.5 g , 20 mmol) in Et 0 (40 mL) was added 3N aqueous HCI (10 mL). The on mixture was d for 4 h at RT, followed by addition of water. The aqueous layer was extracted with Et 0 (2x10 mL), the combined organic layers were washed with brine and then dried over MgS0 . After removal of solvent in vacuo, the e was purified by preparative HPLC (stationary phase: Gimini 300x50 mm, particle size 10 mhi ; solvent: A H 0 + B CH CN, pressure: 60-70 bar). The 2 3 product was extracted with Et 0 as the free base from the ed fractions. HCI gas was d through the organic phase, and the solvent was removed under vacuum to afford the title compound. Recrystallisation from EtOH/diisopropylether gave a white solid. H NMR (D 0 , 400 MHz) : d 7.40-7.35 (m, 1H, ArH), 7.32-7.27 (m, 1H, ArH), 7.27-7.19 (m, 1H, ArH). HRMS: 196.03801 [M]+ (calcd. 196.03800 for C H F NO); Anal. Calcd. for C H F NO: C, 36.31; H , 7 5 4 5 4 2.61; N , 6.05; CI, 15.31; F, 32.82; Found: C, 35.78; H , 2.63; N , 6.14; CI, 15.69; F, 31.99. 3-Difluoromethoxyfluoro-phenylamine A. 1-Difluoromethoxyfluoronitro-benzene To a mixture of sodium 2-chloro-2,2-difluoroacetate (7.14 g , 46.8 mmol) and potassium ate (3.50 g , 25.3 mmol) in DMF (10 mL) and water (2.5 mL) at 110°C was added a solution of 2-fluoronitrophenol (2 g , 12.65 mmol) in DMF (10 mL) and the mixture was d at 110°C for 6 h . After cooling down, the mixture was quenched with water and extracted with EtOAc. The organic layer was then washed with water, brine and dried over Na S0 , filtered and trated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). 1H NMR (400 MHz, DMSO- c ) d (ppm): 7.79 (td, 1H), 7.45 (t, 1H), 5.15 (m, 1H), 7.44 (m, 1H). t (HPLC conditions ) : 2.09 e R B. 3-Difluoromethoxyfluoro-phenylamine To a mixture of 1-difluoromethoxyfluoronitro-benzene (2.16 g , 10.43 mmol) and tin(ll) chloride (6.92 g , 36.5 mmol) in 2-propanol (100 ml) was added lly HCI (37%, 10.28 ml, 125 mmol) and the mixture was stirred for 30 min at 110°C. The reaction mixture was cooled to RT, diluted with water and the pH adjusted to 10 by addition of 2N NaOH. The mixture was extracted with EtOAc and the organic layer was dried over Na S0 , filtered and concentrated 2 4 to afford the titled compound. 1H NMR (400 MHz, DMSO-d ) d (ppm): 7.06 (t, 1H), 6.95 (m, 1H), 6.87 (m, 1H), 6.55 (td, 1H), 5.04 (bs, 2H). t (HPLC conditions ) : 1.93 min. 3-Cyclopropylfluoro-phenylamine To a solution of 3-bromofluoroaniline (200 mg, 1.05 mmol), ropylboronic acid ( 118 mg, 1.37 mmol), potassium phosphate (782 mg, 3.68 mmol), and lohexylphosphine (29.5 mg, 0.105 mmol) in toluene (2.4 mL) and water (120 m ) was added Pd(OAc) ( 1 1.8 mg, 0.05 mmol). The reaction mixture was degassed by repeating alternating application of vacuum and positive en pressure (3x), and then heated at 100°C under nitrogen overnight. The mixture was cooled to RT, diluted with water, and ted twice with EtOAc. The ed organic layers were dried (Na S0 ) , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel ane to c-hexane/EtOAc 93-7). TLC, R (c- / EtOAc 2:1) = 0.7; MS (UPLC/MS): 152.0 [M+H]+. 2,3-Difluoromethoxy-benzylamine A. 2,3-Difluoromethoxy-benzoic acid methyl ester To a solution of 2,3-difluorohydroxy-benzoic acid [7492301] ( 1 .00 g , 5.74 mmol; Melford Laboratories Ltd) in DMF (20 mL) was added K C0 ( 1 .99 g , 14.4 mmol) and Mel (0.79 mL, 2 3 12.6 mmol), followed by stirring at RT overnight. The reaction mixture was diluted with EtOAc, the organics were washed with a saturated aqueous NH C I solution (50 mL) and a saturated aqueous NaHC0 solution, dried (Phase separator) and evaporated under reduced pressure.
The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:1) to afford the title compound as a colorless oil. TLC, R (c-hexane/EtOAc 3:1) (LC/MS): 203.0 [M+H]+; t (HPLC conditions c): 4.72 min.
B. (2,3-Difluoromethoxy-phenyl)-methanol To a solution of 2,3-difluoromethoxy-benzoic acid methyl ester (925 mg, 4.58 mmol) in THF (25 mL), cooled to 0°C, was added a solution of LiBH (199 mg, 9.15 mmol) in THF (5 mL).
The reaction e was stirred at RT for ght. An additional aliquot of LiBH (4 equiv) was added and stirring was continued at RT for 6 h , and uently at 60°C overnight. The mixture was diluted with EtOAc, the organics were washed with 1N aqueous NaOH solution (50 mL), dried (Phase separator) and ated in vacuo to afford the title compound as a white solid. TLC R (c-hexane/EtOAc 1:1) = 0.57; MS (LC/MS): 198.0 [M+Na]+; t (HPLC f R conditions c): 3.74 min.
C. 1-Azidomethyl-2,3-dif luoromethoxy-benzene To a solution of (2,3-difluoromethoxy-phenyl)-methanol (715 mg, 4.1 1 mmol) in toluene (10 mL) was added DPPA ( 1 .04 mL, 4.93 mmol) and DBU (0.805 mL, 5.34 mmol), followed by stirring at RT for 1 h . The reaction mixture was diluted with EtOAc, the organics were washed with diluted brine (20 mL), dried (Phase separator) and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1) to afford the title compound as a colorless oil. TLC R (c-hexane/EtOAc 3:1) = 0.55; MS (LC/MS): 208.0 [M+NH ]+; t (HPLC ions c): 5.46 min. 4 R D. 2,3-Difluoromethoxy-benzylamine To a solution of 1-azidomethyl-2,3-difluoromethoxy-benzene (710 mg, 3.57 mmol) in EtOH (20 mL) was added Pd/C 10% (70 mg) and the reaction mixture was stirred at RT overnight under an H atmosphere. The reaction mixture was filtered through Celite, followed by washing with EtOH and CH C I . The combined filtrates were evaporated in vacuo and the e was 2 2 purified by flash column tography on silica gel (CH C I ne 9:1, then CH C I /MeOH 2 2 2 2 9:1) to afford the title compound as a yellowish oil. TLC R (CH C I /MeOH 9:1) = 0.32; MS f 2 2 (LC/MS): 174.0 [M+H]+; t (HPLC conditions c): 2.30 min. 3-Aminobromofluoro-benzoic acid ethyl ester C0 2H C0 2H C0 2H C0 Et C0 Et A. 4-Fluoronitro-benzoic acid Cone. HNO3 (79 mL) was dropwise added to a on of 4-fluoro-benzoic acid (70 g , 0.5 mol) in cone. H S0 (500 mL) at 0°C. The mixture was stirred for 4 h at RT and then poured into 2 4 ice-water (3.0 L). The precipitate was ed off, washed twice with water (0.5 L) and dried to give the title compound as a white solid. 1H-NMR (300 MHz, CDCI ) : d (ppm) 11.0 (s, br, 1H), 8.86 (m, 1H), 8.42 (m, 1H), 7.47 (m, 1H).
B. 3-Bromofluoronitro-benzoic acid NBS (47.9 g , 0.268 mol) was added portion-wise to a solution of 4-fluoronitro-benzoic acid (41.5 g , 0.224 mol) in cone. H S0 (0.35 L). The on e was stirred for 5 h at 65°C 2 4 and then poured into ice-water (1.5 L). The precipitate was filtered off, washed twice with water (300 mL) and dried to give the title compound as a white solid. 1H-NMR (300 MHz, CDCI 3) : d (ppm) 10.7 (s, br, 1H), 8.76 (m, 1H), 8.62 (m, 1H).
C. 3-Bromofluoronitro-benzoic acid ethyl ester SOCI (33.7 g , 0.283 mol) was added dropwise to a solution of 3-bromofluoronitro- benzoic acid (37.4 g , 0.142 mol) in EtOH (300 mL). The reaction mixture was refluxed overnight, cooled to RT and subsequently concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL), washed twice with water (50 mL), dried (Na S0 ) and concentrated to give the title compound as yellow solid. 1H-NMR (300 MHz, CDCI ) : d (ppm) 8.65 (m, 1H), 8.53 (m, 1H), 4.46 (m, 2H), 1.45 (m, 3H).
D. 3-Aminobromofluoro-benzoic acid ethyl ester A mixture of 3-bromofluoronitro-benzoic acid ethyl ester (20 g , 2.2 mol) and 3 g of Raney- Ni in EtOH (250 mL) was hydrogenated at RT ( 1 atm) overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was washed with petrol ether to afford the title nd as a white solid. (400 MHz, DMSO-d ) : d (ppm) 7.38 (dd, 1H), 7.26 (dd, 1H), 5.81 (s, 2H), 4.26 (q, 2H), 1.29 (t, 3H). (1H-tetrazolyl)-phenylamine dihydrochloride A. 3-Aminobromo-benzonitrile To a solution of 3-bromonitrobenzonitrile ( 1 g , 4.4 mmol) in MeOH (50 mL) was added tin (5.23 g , 44 mmol) and 3N HCI (44 mL, 132 mmol). The reaction mixture was stirred at RT for 2 h , the filtered off and washed with MeOH. The filtrate was concentrated in vacuo, and the remaining water phase was basified to pH=12 by addition of 4N NaOH. The aqueous layer was extracted twice with EtOAc (100 ml_), the combined organics were dried (Na2S0 4) and evaporated in vacuo to afford the title nd as a yellowish solid. MS ): 197.0 [M+H]+; tR (HPLC conditions c): 4.30 min.
B. 3-Bromo(1H-tetrazolyl)-phenylamine hloride To a solution of 3-aminobromo-benzonitrile (200 mg, 1.02 mmol) in toluene (2 ml_) was added 6N HCI (0.220 ml_, 1.32 mmol), triethylamine (0.184 ml_, 1.32 mmol) and sodium azide (86.0 mg, 1.32 mmol). The reaction mixture was stirred at 100°C for 30 min in a microwave apparatus (Personal try, Biotage), and after cooling to RT was then d with CH2C I2/MeOH (4:1) and washed with 10 ml_ of water. The organic phase was discarded, and the water phase was acidified to pH=1 by adding 12N HCI. The aqueous layer was freezedried overnight to afford the title compound as a yellowish solid. MS ): 239.3 [M+H]+; tR (HPLC conditions c): 3.23 min. 3-Bromofluoro-benzylamine, hydrochloride A mixture of 3-bromofluoro-benzonitrile (1.0 g , 5.0 mmol) and Raney-Ni in EtOH (4% NH3) (30 mL) was stirred under a hydrogen atmosphere ( 1 atm) at RT for 6.5 h . The reaction mixture was filtered through Celite, rinsed down with CH2C I2, and the te was concentrated under reduced re. The crude mixture was taken up in 1M aqueous HCI, the organic layer was separated, and the water phase was freeze-dried overnight to afford the title compound as a white solid. MS (LC/MS): 206.0 [M+H]+; tR (HPLC conditions c): 2.21 min.
C-(3-Fluoro-pyridinyl)-methylamine A. (2-Chlorofluoro-pyridinyl)-methanol Carbonyldiimidazole ( 1 .80 g , 11.1 mmol) was added to a solution of 2-chlorofluoroisonicotinic acid ( 1 .3 g , 7.41 mmol) in THF (21 .2 mL). The reaction mixture was stirred at RT overnight and was then added to a cold (0°C) solution of NaBH (1.40 g , 37 mmol) in water (52.9 mL). The mixture was stirred for 10 min at 0°C, and 1M HCI was then added carefully to quench the reaction (caution: H2 evolving). Volatiles were removed via rotary evaporation and the residue was dissolved in saturated s NaHC0 3. The mixture was extracted repeatedly with CH2C I2, the combined organics were dried (phase separator) and concentrated in vaccuo. Purification by flash column chromatography on silica gel (eluent gradient: c- hexane/EtOAc 4:1 to 2:1) afforded the title compound as a white solid. TLC, Rf (c- hexane/EtOAc 1:1) = 0.37; MS (LC/MS): 162.0 [M+H]+; tR (HPLC conditions b): 1.60 min.
B. 2-Chlorofluoro-pyridinecarbaldehyde A e of (2-chlorofluoro-pyridinyl)-methanol (0.9 g , 5.76 mmol) and activated Mn0 2 (5.76 g , 66.2 mmol) in CH2C I2 was stirred at RT overnight. The solid was filtered off and washed with CH2C I2, and the filtrate was concentrated under mildly reduced pressure to afford the title compound as a colorless liquid. MS (LC/MS): 191.0 [M+MeOH]+; tR (HPLC conditions b): 2.02 min.
C. 2-Chlorofluoro-pyridinecarbaldehyde oxime To a solution of 2-chlorofluoro-pyridinecarbaldehyde (1.20 g , 5.64 mmol) in MeOH (48 mL) and water (8 mL) were added hydroxylamine hydrochloride (0.59 g , 8.46 mmol) and ammonium acetate ( 1 .30 g , 16.9 mmol), and stirring was continued at RT ght. The reaction mixture was concentrated in vacuo, and the residue was suspended in CH2C I2/MeOH 9:1 . The precipitate was filtered off, washed with CH2C I2 and dried to afford the title compound as a white solid. MS (LC/MS): 175.0 [M+H]+; tR (HPLC ions b): 2.78 min.
D. C-(3-Fluoro-pyridinyl)-methylamine Zinc dust (2.52 g , 38.6 mmol) was added at RT to a solution of rofluoro-pyridine carbaldehyde oxime (1.34 g , 6.29 mmol) in acetic acid (30 mL). The reaction mixture was stirred at RT for 2 h , then concentrated in vacuo. The colored oily residue was partitioned between CH2C I2 and 1N HCI. The layers were separated and the aqueous phase was extracted twice with CH2C I2. The pH of the aqueous layer was then adjusted to pH=9 with 1N NaOH, and the ing white suspension was extracted repeatedly with CH2C I2. The combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow oil. MS ): 127.0 [M+H]+; tR (HPLC conditions c): 0.50 min.
C-(3-Fluorotrifluoromethyl-pyridinyl)-methylamine A. (3-Fluorotrifluoromethyl-pyridinyl)-methanol Carbonyldiimidazole ( 1 .16 g , 7.17 mmol) was added to a solution of 3-fluorotrifluoromethylisonicotinic acid (1.00 g , 4.78 mmol) in THF (13.7 mL). The on mixture was d at RT overnight and was then added to a cold (0°C) solution of NaBH4 (0.905 g , 23.9 mmol) in water (34.2 ml_). The mixture was stirred for 10 min at 0°C, and 1M HCI was then added carefully (caution: H evolving). les were d under reduced pressure, and the residue was dissolved in saturated aqueous NaHC0 . The mixture was extracted repeatedly with CH C I , 3 2 2 the ed organics were dried (phase separator) and concentrated in vacuo. Purification by flash column tography on silica gel (eluent gradient: c-hexane/EtOAc 1:1 to 0:1) afforded the title compound as a yellow oil. TLC, R (c-hexane/EtOAc 1:1) = 0.27; MS (LC/MS): 196.0 ; t (HPLC conditions b): 2.62 min.
B. 3-Fluorotrifluoromethyl-pyridinecarbaldehyde A mixture of (3-fluorotrifluoromethyl-pyridinyl)-methanol (0.620 g , 3.18 mmol) and activated Mn0 (3.20 g , 36.5 mmol) in CH C I was stirred at RT overnight. The solid was 2 2 2 filtered off, washed with CH C I , and the filtrate was concentrated under mildly d 2 2 pressure to afford the title compound as a yellow . MS (LC/MS): 212.0 [M+NH ]+, 226.0 [M+MeOH]+. t (HPLC conditions c): 3.26 min.
C. rotrifluoromethyl-pyridinecarbaldehyde oxime To a solution of 3-fluorotrifluoromethyl-pyridinecarbaldehyde (0.495 g , 2.05 mmol) in MeOH (17.6 mL) and water (2.9 mL) were added hydroxylamine hydrochloride (0.214 g , 3.08 mmol) and ammonium acetate (0.474 g , 6.15 mmol), and the resulting mixture was stirred ar RT overnight. Volatile were removed in vacuo, and the residue was suspended in CH C I /MeOH 9:1. The precipitate was filtered off, washed with CH C I and dried to afford the 2 2 2 2 title compound as a white solid. MS (LC/MS): 209.0 [M+H]+; t (HPLC conditions c): 4.28 min.
D. C-(3-Fluorotrifluoromethyl-pyridinyl)-methylamine Zinc dust (0.63 g , 9.62 mmol) was added at RT to a solution of 3-fluorotrifluoromethylpyridinecarbaldehyde oxime (0.460 g , 1.57 mmol) in acetic acid (8 mL). The reaction mixture was stirred at RT for 3 h , then filtered through a 0.45 microns filter, and the te was concentrated in vacuo. The colored oily residue was partitioned between CH C I and 1N HCI, 2 2 the layers were separated and the aqueous phase was extracted twice with CH C I . The pH of 2 2 the aqueous layer was then adjusted to pH=9 by adding a ted aqueous NaHC0 solution, and the resulting white suspension was extracted four times with CH C I . The 2 2 combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow oil. MS (LC/MS): 195.0 [M+H]+; t (HPLC conditions c): 2.47 min. 3-Aminomethylchlorofluoro-benzoic acid methyl ester A. 5-Bromochlorofluoro-benzylamine To a solution of 5-bromochlorofluorobenzonitrile (13.2 g , 56.3 mmol) in THF (200 ml_) was added under an argon atmosphere a 1M solution of boran-tetrahydrofuran-complex (70.4 ml_, 70.4 mmol) dropwise over 30 min. The on mixture was then heated at 65°C for 1.5 h .
After cooling to RT, a 2N HCI solution (70.4 ml_, 141 mmol) was added dropwise over 30 min.
The reaction mixture was then again heated at 65°C for 1 h and subsequently cooled to RT.
Volatiles were evaporated and the residue was taken up in 1M aqueous HCI on, followed by extraction with EtOAc (3x150 ml_). The combined organics were washed with 1M aqueous HCI solution. The combined acid phases were basified to pH=12 by addition of 4M aqueous NaOH solution and then extracted with EtOAc (3x150 ml_). The organics were dried (Na S0 ) , 2 4 filtered and evaporated in vacuo to afford the title compound as a yellowish oil. MS (LC/MS): 238.0 [M+H]+; t (HPLC conditions c): 3.25 min. The material thus obtained was used directly in the next step without further cation B. (5-Bromochlorofluoro-benzyl)-carbamic acid tert-butyl ester To a solution of 5-bromochlorofluoro-benzylamine (10.6 g , 44.3 mmol) in dioxane/H 0 3:1 (280 ml_) was added Boc 0 (10.3 ml_, 44.3 mmol) and NaHC0 ( 1 1.2 g , 133 mmol). The 2 3 reaction mixture was stirred at RT for 60 h . les were then removed under reduced pressure, the residue was taken up in water, and the aqueous layer was extracted twice with EtOAc (200 ml_). The organics were dried (Na S0 ) , filtered and evaporated in vacuo to afford the title compound as a white solid. MS (LC/MS): 284.0 ; t (HPLC ions c): 5.98 min. The material thus obtained was used directly in the next step t further purification.
C. 3-(tert-Butoxycarbonylamino-methyl)chlorofluoro-benzoic acid To a solution of (5-bromochlorofluoro-benzyl)-carbamic acid tert-butyl ester (8 g , 23.6 mmol) in Et 0 (300 mL), cooled to -78°C, was added under an argon atmosphere n-BuLi ( 1 .6M in hexane; 37.5 mL, 60.1 mmol) dropwise over 30 min. The reaction mixture was stirred at - 78°C for 15 min, then C0 gas was bubbled through the e over 1 min. After ng for 15 min, a saturated solution of NH C I (50 mL) added dropwise over 15 min, and the reaction mixture was allowed to warm up to RT. The aqueous phase was basified to pH= 12 by addition of a 4M aqueous NaOH solution and then washed with EtOAc (100ml_). The aqueous layer was acidified to pH=1 by addition of a 4M aqueous HCI solution and extracted with EtOAc (3x200 ml_). The combined organics were dried (Na2S0 4) and concentrated under vacuo to give the title compound as an off-white solid. MS (LC/MS): 302.0 [M-H]- ; tR (HPLC conditions c): 4.79 min.
D. 3-(tert-Butoxycarbonylamino-methyl)chlorofluoro-benzoic acid methyl ester To a solution of t-butoxycarbonylamino-methyl)chlorofluoro-benzoic acid (4.00 g , 13.2 mmol) in CH2C I2 (100 ml_) were added MeOH (6.94 ml_, 171 mmol) and subsequently trimethylsilyldiazomethane (8.56 ml_, 17.1 mmol) in a dropwise manner over 15 min. ng was continued at RT for 4.5 h . Volatiles were then evaporated under reduced pressure to afford the title compound as a colorless oil, which was used directly in the next step t further purification. TLC Rf (c-hexane/EtOAc 6:1) = 0.40 ; tR (HPLC conditions c): 5.56 min.
E. 3-Aminomethylchlorofluoro-benzoic acid methyl ester To a solution of 3-(tert-butoxycarbonylamino-methyl)chlorofluoro-benzoic acid methyl ester (4.25 g , 13.4 mmol) in CH2C I2 (70 ml_) was added TFA (10.3 ml_, 134 mmol), and stirring was continued at RT overnight. Methanol was then added to the reaction mixture, and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure to afford the title nd as a beige solid. MS (LC/MS): 218.0 [M+H]+; tR (HPLC ions c): 3.10 min. The material thus obtained was used in the next on step without further cation. 3-Chlorofluoro(2H-tetrazolyl)-benzylamine A. (3-Chlorocyanofluoro-benzyl)-carbamic acid tert-butyl ester To a solution of (5-bromochlorofluoro-benzyl)-carbamic acid tert-butyl ester (3 g , 8.86 mmol) in DMF (45 mL) was added zinc cyanide (1.04 g , 8.86 mmol) and Pd(Ph3P) ( 1 .02 g , 0.886 mmol). The reaction mixture was stirred at 120°C for 15 min in a microwave apparatus (Personal Chemistry, e). After cooling to RT, the mixture was filtered through Celite and rinsed down with EtOAc. The filtrate was washed with saturated s NH C I solution (4x75 mL), dried (Na2S0 ) and evaporated in vacuo. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane/EtOAc 9:1 to 3:1) afforded the title compound as white solid. TLC R ane/EtOAc 3:1) = 0.35 ; t (HPLC conditions c): 5.28 min. f R B. [3-Chlorofluoro(2H-tetrazolyl)-benzyl]-carbamic acid tert-butyl ester To a on of (3-chlorocyanofluoro-benzyl)-carbamic acid tert-butyl ester ( 1 .30 g , 4.57 mmol) in toluene (35 ml_) was added tri-n-butyl-tinazide (6.26 ml_, 22.8 mmol). The reaction mixture was stirred at 135°C for 90 min in a microwave (Personal Chemistry, Biotage). After cooling to RT, the mixture was diluted with EtOAc and washed with saturated aqueous NH C I on (3x100 ml_). After washing the organic phase with 70 ml_ of a 1M aqueous NaOH solution and tion of the phases, three layers were obtained: the upper organic phase was discarded, the middle oily layer was isolated and diluted with EtOAc. The water phase was acidified with 4M s HCI solution, extracted twice with EtOAc (50 ml_). All organics were combined, dried (phase separator) and evaporated in vacuo to afford the title compound.
Yellowish solid. MS (LC/MS): 328.0 [M+H]+, 349.9 [M+Na]+, 271 .9 [MH-tBu]+ ; t (HPLC conditions c): 4.74 min. The material thus obtained was used in the next reaction step without further purification.
C. 3-Chlorofluoro(2H-tetrazolyl)-benzylamine, hydrochloride To a solution of [3-chlorofluoro(2H-tetrazolyl)-benzyl]-carbamic acid tert-butyl ester ( 1 .06 g , 3.23 mmol) in dioxane (20 ml_) was added a 4M HCI solution in dioxane (8.09 ml_, 32.3 mmol). The reaction mixture was stirred at RT for 72 h and then freeze-dried overnight to afford the title compound as a white solid. MS (LC/MS): 228.0 [M+H]+ ; t (HPLC conditions c): 2.68 min. -(1-tert-Butyl-1H-tetrazolyl)chlorofluoro-benzylamine To a solution of [3-chlorofluoro(2H-tetrazolyl)-benzyl]-carbamic acid tert-butyl ester (0.15 g , 0.46 mmol) in CH C I (4 mL) was added TFA ( 1 .5 mL). The on mixture was 2 2 stirred at RT for 2 h and the solvent was removed in vacuo to give the title compound as a 2:1 mixture of 5-(1-tert-butyl-1H-tetrazolyl)chlorofluoro-benzylamine and rofluoro- -(2H-tetrazolyl)-benzylamine which was used in the next steps without separation. MS ): 228.0 and 284.0 [M+H]+. t (HPLC conditions c): 2.16 and 2.99 min. 3-Aminomethylchlorofluoro-benzonitrile To a solution of (3-chlorocyanofluoro-benzyl)-carbamic acid utyl ester (645 mg, 2.27 mmol) in CH C I (15 mL) was added TFA ( 1 .75 mL, 22.7 mmol), and stirring was continued at 2 2 RT overnight. Volatiles were removed under reduce pressure, water was added and the mixture was washed with EtOAc. The aqueous layer was basified to pH=12 by on of 4M NaOH solution and extracted twice with EtOAc. The combined cs were dried (phase separator) and ated to afford the title compound as a beige solid. MS (LC/MS): 185.0 ; t (HPLC conditions c): 2.62 min.
Scheme C 1 : preparation of (3-Aminomethylchlorofluoro-phenyl)-(2-methoxy-ethyl)- methyl-amine A. {3-Chlorofluoro[(2-methoxy-ethyl)-methyl-amino]-benzyl}-carbamic acid tert- butyl ester A suspension of (5-bromochlorofluoro-benzyl)-carbamic acid tert-butyl ester (250 mg, 0.7 mmol), N-methoxyethyl-methylamine (99 mg, 1.1 mmol), sodium tert-butoxide (142 mg, 1.5 mmol) and di^-bromobis(tri-tert-butylphosphino)dipalladium (I) [CAS 1858126] (29 mg, 0.04 mmol) in e (5 mL) was sealed in a microwave vial and heated for 30 min at 140°C (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHC0 , extracted with EtOAc, dried (Na S0 ) and evaporated in vacuo. 3 2 4 The crude product was purified by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, 5-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 containing 3 2 3 3 2 0.1% TFA, flow: 40 mL/min) to give the title compound after lyophilization. MS (LC/MS): 347.0 [M]+. t (HPLC conditions c): 5.23 min.
B. (3-Aminomethylchlorofluoro-phenyl)-(2-methoxy-ethyl)-methyl-amine To a mixture of {3-chlorofluoro[(2-methoxy-ethyl)-methyl-amino]-benzyl}-carbamic acid tert-butyl ester (60 mg, 0.17 mmol) in MeOH (2 mL) was added a solution of 4N HCI in dioxane (2 mL). The reaction mixture was stirred for 1 h at ambient ature and the solvent was removed in vacuo to give the title compound. MS (LC/MS): 247.0 [M]+. t (HPLC conditions c): 3.15 min. minomethylchlorofluoro-phenyl)-N,N\N'-trimethyl-ethane-1,2-diamine was prepared according to Scheme C 1 (step B) from {3-chloro[(2-dimethylamino-ethyl)- methyl-amino]fluoro-benzyl}-carbamic acid tert-butyl ester and 4N HCI in dioxane. MS (LC- MS): 260.0 [M]+ {3-Chloro[(2-dimethylamino-ethyl)-methyl-amino]fluoro-benzyl}-carbamic acid tert- butyl ester was prepared ing to Scheme C 1 (step A) from (5-bromochlorofluoro-benzyl)- carbamic acid tert-butyl ester (300 mg, 0.89 mmol), N,N,N'-trimethyl-ethylenediamine (136 mg, 1.3 mmol), sodium tert-butoxide (170 mg, 1.8 mmol) and di^-bromobis(tri-tertbutylphosphino )dipalladium (I) [CAS 1858126] (34 mg, 0.04 mmol). MS (LC-MS): 360.3 [M]+; t (HPLC conditions c): 4.15 min. (3-Aminomethylchlorofluoro-phenyl)-diethyl-amine was prepared according to Scheme C 1 (step B) from (3-chlorodiethylaminofluorobenzyl )-carbamic acid tert-butyl ester and TFA in CH C I . MS (LC-MS): 231.0 [M]+; t (HPLC 2 2 R conditions c): 2.29 min. (3-Chlorodiethylaminofluoro-benzyl)-carbamic acid utyl ester was prepared according to Scheme C 1 (step A) from (5-bromochlorofluoro-benzyl)- carbamic acid tert-butyl ester (300 mg, 0.89 mmol), diethylamine (0.14 mL, 1.3 mmol), sodium utoxide (170 mg, 1.8 mmol) and di^-bromobis(tri-tert-butylphosphino)dipalladium (I) [CAS 1858126] (34 mg, 0.04 mmol). MS (LC-MS): 331 .2 [M]+; t (HPLC conditions c): 4.08 min. 3-Chlorofluoro(4-methyl-piperazinyl)-benzylamine was prepared according to Scheme C 1 (step B) from [3-chlorofluoro(4-methyl-piperazin- 1-yl)-benzyl]-carbamic acid utyl ester and 4N HCI in dioxane. MS (LC-MS): 258.0 [M]+; t (HPLC conditions f): 0.74 min. [3-Chlorofluoro(4-methyl-piperazinyl)-benzyl]-carbamic acid tert-butyl ester was prepared according to Scheme C 1 (step A) from (5-bromochlorofluoro-benzyl)- carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methylpiperazine (71 mg, 0.71 mmol), caesium carbonate (269 mg, 0.83 mmol), palladium (II) acetate (6.6 mg, 0.03 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.04 mmol). MS (LC-MS): 358.0 [M]+; t (HPLC conditions c): 3.98 min. rofluoro(4-methoxy-piperidinyl)-benzylamine was prepared ing to Scheme C 1 (step B) from [3-chlorofluoro(4-methyl-piperazin- 1-yl)-benzyl]-carbamic acid tert-butyl ester and 4N HCI in dioxane. MS (LC-MS): 273.0 [M]+; t (HPLC conditions c): 2.97 min. [3-Chlorofluoro(4-methoxy-piperidinyl)-benzyl]-carbamic acid tert-butyl ester was prepared according to Scheme C 1 (step A) from (5-bromochlorofluoro-benzyl)- carbamic acid tert-butyl ester (250 mg, 0.74 mmol), 1-methoxypiperidine (102 mg, 0.89 mmol), caesium carbonate (337 mg, 1.0 mmol), palladium (II) acetate (8.3 mg, 0.04 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg, 0.05 mmol). MS (LC-MS): 373.0 [M]+; t (HPLC conditions c): 4.68 min. 3-Chlorofluoromorpholinyl-benzylamine A. 3-Chlorofluoromorpholinyl-benzonitrile A suspension of 5-Bromochlorofluoro-benzonitrile (200 mg, 0.85 mmol), morpholine (74 mg, 0.85 mmol), caesium carbonate (389 mg, 1.2 mmol), palladium(ll) acetate (10 mg, 0.04 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.06 mmol) in toluene (5 mL) was sealed in a microwave vial and heated for 30 min at 140°C (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHC0 , ted with EtOAc, dried (Na S0 ) and the solvent was removed in vacuo to give 3 2 4 the title compound which was used without further purification in the next step. TLC R (hexane/EtOAc 1:1) = 0.60 ; t (HPLC conditions c): 5.28 min.
B. 3-Chlorofluoromorpholinyl-benzylamine To a solution of 3-Chlorofluoromorpholinyl-benzonitrile (215 mg, 0.85 mmol) in THF (2 mL) was added dropwise a solution of BH -THF. The on mixture was heated under reflux for several hours, cooled to ambient ature and quenched carefully by addition of methanol. The solvent was removed in vacuo and the crude t was purified by RP- preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, 5-100% CH CN/H O/20 min, 3 2 100% CH CN/2 min, CH CN and H 0 containing 0.1% TFA, flow: 40 mL/min) to give the title 3 3 2 compound. MS (LC/MS): 244.9 [M]+ ; t (HPLC conditions c): 3.02 min.
Scheme C2: preparation of (3-Aminomethylchlorofluoro-benzyl)-diethyl-amine A. (3-Chlorofluorovinyl-benzyl)-carbamic acid tert-butyl ester To a solution of (5-bromochlorofluoro-benzyl)-carbamic acid tert-butyl ester (6 g , 17.7 mmol) in DME (100 ml_) was added Pd(Ph ) ( 1 .0 g , 0.9 mmol) under argon atmosphere and the mixture was stirred for 30 min at t temperature. After addition of vinyl boronic anhydride pyridine x (4.3 g , 17.7 mmol), water (25 ml_) and K C0 (2.45 g , 17.7 mmol) 2 3 the reaction was heated under reflux for 7 h . The reaction mixture was concentrated in vacuo to half of the volume, quenched by addition of saturated aqueous NaHC0 and extracted wit EtOAc. After drying (Na S0 ) the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (eluent: hexane/EtOAc 9:1 to 4:1) to afford the title compound as a colorless oil. 1H-NMR (500 MHz, DMSO): d (ppm) 7.62 (d, 1H), 7.45 (m, 1H.-L ) , 7.35 (d, 1H), 6.68 (dd, 1H), 5.82 (d, 1H), 5.32 (d, 1H), 4.18 (d, 2H), 1.39 (s, 9H).
B. (3-Chlorofluoroformyl-benzyl)-carbamic acid tert-butyl ester To a on of (3-chlorofluorovinyl-benzyl)-carbamic acid tert-butyl ester (2.7 g , 9.5 mmol) in acetone (20 ml_) was added N-methylmorpholine-N-oxide monohydrate ( 1 .5 g , 11 mmol) and a solution of 4% aq. osmiumtetraoxide (3.7 ml_, 0.5 mmol). The reaction was stirred for 1 h , saturated aqueous Na S 0 -solution was added and stirring was continued for one 2 2 3 hour. After extraction with EtOAc and removal of the solvent in vacuo, the residue was dissolved in acetone/water (3:1, 40 ml_) and Nal0 (4.0 g , 19 mmol) was added. After stirring for 2 h at ambient temperature, the reaction mixture was filtered, washed with EtOAc, ted with EtOAc, dried (Na S0 ) and the t was removed in vacuo to give the title compound which was used t further purification. t (HPLC conditions c): 5.22 min.
C. (3-Chlorodiethylaminomethylfluoro-benzyl)-carbamic acid tert-butyl ester A on of (3-chlorofluoroformyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.7 mmol), diethylamine (51 mg, 0.7 mmol) and acetic acid (0.06 ml_) in THF (ml_) was stirred for min at ambient temperature. After on of sodium triacetoxyborohydride (368 mg, 1,7 mmol) the reaction was d overnight, quenched by addition of of saturated aqueous NaHC0 and extracted wit EtOAc. The solvent was d in vacuo and the residue was purified by RP-preparative HPLC s Sunfire, B, 5 m h , 30x100 mm, 5-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 containing 0.1% TFA, flow: 40 3 2 3 3 2 mL/min) to give the title compound. MS (LC-MS): 345.0 [M]+; t (HPLC conditions c): 4.09 min.
D. (3-Aminomethylchlorofluoro-benzyl)-diethyl-amine To a mixture of (3-chlorodiethylaminomethylfluoro-benzyl)-carbamic acid tert-butyl ester ( 1 15 mg, 0.33 mmol) in MeOH ( 1 mL) was added a solution of 4N HCI in dioxane (3 mL). The reaction mixture was stirred for 2 h at ambient temperature and the solvent was removed in vacuo to give the title nd. MS (LC/MS): 245.0 [M]+ ; t (HPLC conditions c): 2.13 min. 3-Chlorofluoromorpholinylmethyl-benzylamine was prepared according to Scheme C2 (step D) from (3-chlorofluoromorpholin ylmethyl-benzyl)-carbamic acid tert-butyl ester (231 mg, 0.64 mmol) and 4N HCI in dioxane.
MS (LC-MS): 259.0 [M]+. (3-Chlorofluoromorpholinylmethyl-benzyl)-carbamic acid tert-butyl ester was prepared according to Scheme C2 (step C) from (3-chlorofluoroformyl-benzyl)- carbamic acid tert-butyl ester (220 mg, 0.65 mmol), morpholine (57 mg, 0.65 mmol), acetic acid (0.056 mL, 0.9 mmol) and sodium triacetoxyborohydride (344 mg, 1.6 mmol) in THF (8 mL). TLC, R (EtOAc) = 0.44 ; MS (LC-MS): 359.0 [M]+. 3-Chlorofluoro(4-methyl-piperazinylmethyl)-benzylamine was prepared according to Scheme C2 (step D) from [3-chlorofluoro(4-methyl-piperazin- 1-ylmethyl)-benzyl]-carbamic acid utyl ester (225 mg, 0.61 mmol) and 4N HCI in dioxane.
MS (LC-MS): 272.0 [M]+; t (HPLC conditions c): 2.07 min. [3-Chlorofluoro(4-methyl-piperazin-1 -ylmethyl)-benzyl]-carbamic acid utyl ester was prepared according to Scheme C2 (step C) from (3-chlorofluoroformyl-benzyl)- carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methylpiperazine (59 mg, 0.59 mmol), acetic acid (0.053 mL, 0.89 mmol) and sodium triacetoxyborohydride (313 mg, 1.5 mmol) in THF (8 mL). MS (LC-MS): 372.0 [M]+; t (HPLC conditions c): 3.64 min. 3-Chlorofluoro(4-methoxy-piperidinylmethyl)-benzylamine was prepared according to Scheme C2 (step D) from [3-chlorofluoro(4-methoxy-piperidin- 1-ylmethyl)-benzyl]-carbamic acid tert-butyl ester (225 mg, 0.61 mmol) and 4N HCI in dioxane.
MS (LC-MS): 287.0 [M]+; t (HPLC conditions c): 2.34 min. [3-Chlorofluoro(4-methoxy-piperidin-1 -ylmethyl)-benzyl]-carbamic acid tert-butyl ester was prepared according to Scheme C2 (step C) from (3-chlorofluoroformyl-benzyl)- carbamic acid utyl ester (200 mg, 0.59 mmol), 1-methoxypiperidine (68 mg, 0.59 mmol), acetic acid (0.051 mL, 0.89 mmol) and sodium triacetoxyborohydride (313 mg, 1.5 mmol) in THF (8 mL). MS (LC-MS): 387.0 [M]+ (3-Aminomethylchlorofluoro-benzyl)-(2-methoxy-ethyl)-methyl-amine was prepared according to Scheme C2 (step D) from (3-chlorofluoro{[(2-methoxy-ethyl)- methyl-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (222 mg, 0.47 mmol) and 4N HCI in dioxane. MS (LC-MS): 261 .0 [M]+. (3-Chlorofluoro{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester was prepared ing to Scheme C2 (step C) from (3-chlorofluoroformyl-benzyl)- ic acid tert-butyl ester (200 mg, 0.59 mmol), N-methoxyethyl-methylamine (74 mg, 0.83 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 362.3 ; t (HPLC conditions c): 4.04 min.
N-(3-Aminomethylchlorofluoro-benzyl)-N,N\N'-trimethyl-ethane-1,2-diamine was prepared according to Scheme C2 (step D) from (3-chloro{[(2-dimethylamino-ethyl)- methyl-amino]-methyl}fluoro-benzyl)-carbamic acid tert-butyl ester (228 mg, 0.51 mmol) and 4N HCI in dioxane. MS (LC-MS): 274.0 [M]+. (3-Chloro{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}fluoro-benzyl)-carbamic acid tert-butyl ester was prepared according to Scheme C2 (step C) from (3-chlorofluoroformyl-benzyl)- carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N,N,N'-trimethyl-ethylendiamine (71 mg, 0.70 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS ): 374.0 [M]+; t (HPLC conditions c): 3.53 min.
N-(3-Aminomethylchlorofluoro-benzyl)-N\N'-dimethyl-ethane-1,2-diamine was prepared according to Scheme C2 (step D) from (3-chloro{[(2-dimethylamino-ethyl)- methyl-amino]-methyl}fluoro-benzyl)-carbamic acid tert-butyl ester (165 mg, 0.46 mmol) and 4N HCI in e (3 mL). MS (LC-MS): 260.0 [M]+. {3-Chloro[(2-dimethylamino-ethylamino)-methyl]fluoro-benzyl}-carbamic acid tert- butyl ester was ed according to Scheme C2 (step C) from (3-chlorofluoroformyl-benzyl)- carbamic acid tert-butyl ester (200 mg, 0.70 mmol), N,N-dimethyl-ethylendiamine (67 mg, 0.77 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 360.3 [M+H]+; t (HPLC conditions c): 3.49 min.
Scheme C3 : preparation of 3-Aminomethylchlorofluoro-N,N-dimethyl-benzamide A. (3-Chlorodimethylcarbamoylfluoro-benzyl)-carbamic acid tert-butyl ester A mixture of 3-(tert-butoxycarbonylamino-methyl)chlorofluoro-benzoic acid (100 mg, 0.3 mmol), HATU (188 mg, 0.5 mmol), ylamine (0.2 ml_, 2M in THF) and DIPEA (0.23 ml_, 1.3 mmol) in DMF (2 ml_) was stirred for 16 h at ambient temperature. The crude product was ed without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, 5-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 containing 3 2 3 3 2 0.1% TFA, flow: 40 ) to give the title compound. MS (LC-MS): 275.0 [M-55]+; t (HPLC conditions c): 4.68 min.
B. 3-Aminomethylchlorofluoro-N,N-dimethyl-benzamide To a mixture of orodimethylcarbamoylfluoro-benzyl)-carbamic acid tert-butyl ester ( 1 15 mg, 0.33 mmol) in CH C I (4 ml_) was added TFA ( 1 ml_). The reaction mixture was 2 2 stirred for 1 h at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC/MS): 231.0 [M]+. t (HPLC conditions c): 2.59 min. 3-Aminomethylchlorofluoro-N-methyl-benzamide was prepared ing to Scheme C3 (step B) from (3-chlorofluoromethylcarbamoylbenzyl )-carbamic acid tert-butyl ester (99 mg, 0.3 mmol) and TFA (0.5 mL) in CH C I . MS (LC- 2 2 MS): 217.0 [M]+; t (HPLC conditions c): 2.39 min. (3-Chlorofluoromethylcarbamoyl-benzyl)-carbamic acid tert-butyl ester was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl) chlorofluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.6 mmol), methylamine (0.25 mL, 2M in THF) and DIPEA (0.29 mL, 1.6 mmol) in DMF (2 mL). MS (LC-MS): 633.0 [2M]+; t (HPLC conditions c): 4.55 min. (3-Aminomethylchlorofluoro-phenyl)-(3-methoxy-azetidinyl)-methanone was prepared according to Scheme C3 (step B) from [3-chlorofluoro(3-methoxyazetidinecarbonyl )-benzyl]-carbamic acid tert-butyl ester (99 mg, 0.3 mmol) and TFA (0.5 ml_) in CH C I . MS (LC-MS): 273.0 [M]+; t (HPLC conditions c): 2.73 min. 2 2 R [3-Chlorofluoro(3-methoxy-azetidine-1 -carbonyl)-benzyl]-carbamic acid tert-butyl ester was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl) chlorofluoro-benzoic acid ( 1 16 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), 3-methoxyazetidine (57 mg, 0.57 mmol) and DIPEA (0.27 ml_, 1.5 mmol) in DMF (2 ml_). MS (LC-MS): 373.0 [M]+ 3-Aminomethylchloro-N-(2-dimethylamino-ethyl)fluoro-benzamide was prepared according to Scheme C3 (step B) from [3-chloro(2-dimethylaminoethylcarbamoyl )fluoro-benzyl]-carbamic acid tert-butyl ester (120 mg, 0.3 mmol) and TFA ( 1 ml_) in CH C I . MS (LC-MS): 274.0 [M]+; t (HPLC conditions c): 2.17 min. 2 2 R [3-Chloro(2-dimethylamino-ethylcarbamoyl)fluoro-benzyl]-carbamic acid tert-butyl ester was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl) chlorofluoro-benzoic acid ( 116 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), N,N- ylethylenediamine (40 mg, 0.46 mmol) and DIPEA (0.2 mL, 1.1 mmol) in DMF (2 mL).
MS ): 374.2 [M]+; t (HPLC ions c): 3.87 min. (3-Aminomethylchlorofluoro-phenyl)-morpholinyl-methanone was prepared according to Scheme C3 (step B) from [3-chlorofluoro(morpholine carbonyl)-benzyl]-carbamic acid tert-butyl ester (72 mg, 0.19 mmol) and TFA ( 1 mL) in CH C I . 2 2 MS (LC-MS): 273.0 [M]+; t (HPLC conditions c): 2.64 min. [3-Chlorofluoro(morpholinecarbonyl)-benzyl]-carbamic acid tert-butyl ester was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl) chlorofluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.62 mmol), morpholine (43 mg, 0.49 mmol) and DIPEA (0.22 mL, 1.2 mmol) in DMF (2 mL). MS (LC-MS): 317.0 [M-55]+; t (HPLC conditions c): 4.65 min. (3-Aminomethylchlorofluoro-phenyl)-(4-methyl-piperazinyl)-methanone was ed according to Scheme C3 (step B) from [3-chlorofluoro(4-methyl-piperazine- 1-carbonyl)-benzyl]-carbamic acid tert-butyl ester (165 mg, 0.43 mmol) and TFA (2 mL) in CH C I . MS (LC-MS): 286.0 [M]+; t (HPLC ions c): 1.47 min. 2 2 R [3-Chlorofluoro(4-methyl-piperazine-1 -carbonyl)-benzyl]-carbamic acid tert-butyl ester was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl) fluoro-benzoic acid (150 mg, 0.49 mmol), HATU (282 mg, 0.74 mmol), 4- methylpiperazine (59 mg, 0.59 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (2 mL). MS (LC- MS): 386.0 [M]+; t (HPLC conditions c): 3.77 min.
S)(3-Bromo-phenyl)fluoro-ethylamine hydrochloride A. 2-Methyl-propanesulfonic acid 1-(3-bromo-phenyl)-meth-(Z)-ylideneamide To a solution of 3-bromo-benzaldehyde ( 1 .27 mL, 10.8 mmol) in THF (50 mL) were added titanium(IV) ethoxide (0.786 mL, 2 1.6 mmol) and tert-butylsulfonamide (1.31 g , 10.8 mmol), and stirring was continued for 16 h at 65°C. After cooling to RT, volatiles were evaporated, and the residue was purified by flash column chromatography on silica gel ane/EtOAc 3:1) to afford the title compound. MS (LC/MS): 289 ; t (HPLC conditions f): 2.35 min.
B. 2-Methyl-propanesulfonic acid [2-benzenesulfonyl(3-bromo-phenyl)fluoro-eth- (Z)-ylidene]-amide To a mixture of 2-methyl-propanesulfonic acid 1-(3-bromo-phenyl)-meth-(Z)-ylideneamide (2.16 g , 7.49 mmol) and (fluoromethylsulfonyl)benzene ( 1 .31 g , 7.49 mmol) in THF (50 mL), cooled to -78°C, was added LiHMDS (1M in THF; 7.87 mL, 7.87 mmol). The reaction mixture was stirred for 40 min at -78°C, followed by quenching ted s NH C I (10 mL) at - 78°C. The mixture was extracted with EtOAc (3x), dried over Na S0 , filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (c- hexane/EtOAc 3:1) afforded the title compound. MS (LC/MS): 462/464 [M+H]+; t (HPLC ions ) 2.20 min.
C. (S)(3-Bromo-phenyl)fluoro-ethylamine hydrochloride To a mixture of 2-methyl-propanesulfonic acid [2-benzenesulfonyl(3-bromo-phenyl) fluoro-eth-(Z)-ylidene]-amide (1.74 g , 3.76 mmol) and sodium phosphate dibasic (4.27 g , 30.1 mmol) in methanol (50 mL), cooled to -20°C, was added Na/Hg amalgam (6.92 g , 30.1 mmol).
The reaction mixture was stirred for 1 h at -20°C, followed by tion. To the filtrate was added a 4N HCI solution in dioxane (9.41 mL, 37.6 mmol), followed by stirring for 30 min at °C. After evaporation of volatiles, Et 0 was added to the residue and the resulting precipitate was filtered off. The title compound thus obtained was used in the next on step without further purification. MS (LC/MS): 218/220 [M+H]+; t (HPLC conditions ) : 1.05 min.
Scheme C4: ation of (S)(3-Chlorofluoro-phenyl)-N*2*,N*2*-dimethyl-ethane- 1,2-diamine A. [(S)(3-Chlorofluoro-phenyl)hydroxy-ethyl]-carbamic acid tert-butyl ester To a solution of (2S)amino(3-chlorofluorophenyl)ethanol (517 mg, 2.29 mmol) in MeOH (35 mL) were added (Boc) 0 (0.54 mL, 2.31 mmol) and sodium carbonate (970 mg, 9.15 mmol) and the reaction mixture was stirred at RT overnight. Organic volatiles were removed and the crude material was purified by flash column tography on silica gel (c- hexane to c-hexane/EtOAc 1:1). TLC, R (c-hexane/EtOAc 1:1): 0.55; MS MS): 290.2/292.2 , 334.2/336.3 [M+HCOO]-; t (HPLC conditionsa): 3.36 min.
B. Methanesulfonic acid (S)tert-butoxycarbonylamino(3-chlorofluoro-phenyl)- ethyl ester To a solution of -(3-chlorofluoro-phenyl)hydroxy-ethyl]-carbamic acid utyl ester (550 mg, 1.9 mmol) and triethylamine (0.29 mL, 2.09 mmol) in CH C I (5.5 mL) cooled at -10°C 2 2 was added under nitrogen atmosphere mesylchloride (0.16 mL, 2.09 mmol) and the reaction mixture was stirred at 0°C for 1.5 h . The reaction mixture was quenched with ice and water then extracted twice with EtOAc. The combined organic layers were washed with water, dried (Na S0 ) , filtered and concentrated. The crude al was used without purification in the 2 4 next step. MS (UPLC/MS): 412.3/414.3 [M+HCOO]-; t (HPLC conditions a): 3.66 min.
C. [(S)(3-Chlorofluoro-phenyl)dimethylamino-ethyl]-carbamic acid tert-butyl ester A solution of methanesulfonic acid (S)tert-butoxycarbonylamino(3-chlorofluorophenyl )-ethyl ester (690 mg, 1.88 mmol) in 33% dimethylamine in EtOH (5.6 M , 7.5 mL, 42 mmol) was heated at 80°C for 2 h in a sealed tube. The reaction mixture was concentrated and the crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give a pale yellow oil. TLC, R (EtOAc): 0.60; MS (UPLC/MS): 317.3/319.3 [M+H]+; t (HPLC conditions a): 3.19 min.
D. (S)(3-Chlorofluoro-phenyl)-N*2*,N*2*-dimethyl-ethane-1,2-diamine To a solution of [(S)-1 -(3-chlorofluoro-phenyl)dimethylarnino-ethyl]-carbarnic acid tert- butyl ester (31 5 mg, 0.99 mmol) in dioxane (6 mL) was added HCI 4N in dioxane (9.94 mL, 39.8 mmol). The on mixture was stirred at RT for 1 h and concentrated to give the desired material as a HCL salt which was used without further purification in the next step. MS (UPLC/MS): 2 17.2/21 9.2 [M+H]+; 1H NMR (400 MHz, DMSO-d ) d (ppm): 9 .17 (bs, 2H), 7.75 (m, 2H) , 7.40 (t, 1H) , 5 .16 (m , 1H), 3.85 (m , 1H), 3.60 (m, 1H), 2.87 (s, 3H).
(R)(3-Chlorofluoro-phenvn-N*3*.N*3*-dimethyl-propane-1.3-diamine was prepared using similar ures as bed for the synthesis of (3-acetyl-pyrrolo[2,3- c]pyridin-1 -yl)-acetic acid in Scheme C4 from (R)amino(3-chlorofluoro-phenyl)-propan- 1-ol. 1H-NM R (400 MHz, DMSO): d (ppm) : 8.89 (m, 2H) , 7.73 (m, 2H), 7.39 (t, 1H), 4.69 (m , 1H), 3 .13 (m , 1H), 2.98 (m, 1H), 2.73 (s, 6H), 2.47 (m, 1H), 2.34 ( , 1H). 1-(3-chloro-phenyl)-cyclopropylamine To a solution of 3-chlorobenzonitrile ( 1 g , 7.27 mmol) and titanium (IV) isopropoxide (2.34 mL, 8 mmol) in Et 0 (35 mL) at -78°C was added ethyl magnesium chloride in THF (5.71 mL, 15.99 mmol). The solution was stirred for 10 min at -78°C then at 25°C for 1 h . BF .Et 0 ( 1 .82 mL, 3 2 14.54 mmol) was added and the solution was stirred for 1 h at 25°C. The reaction mixture was quenched with 1N HCI (22 mL) Et 0 was added ( 100 mL). Then 10% aq. NaOH (70 mL) was added and the layers were separated. The organic layer was dried over Na S0 , filtered and 2 4 concentrated. The crude residue was purified by preparative HPLC (Waters e C 18- ODB, 5 [Jim, 19x50 mm, 5% CH CN/H 0 2.5 min, 5-1 00% CH CN/H 0 in 10 min, CH CN/H 0 3 2 3 2 3 2 containing 0 .1 % HCOOH flow: 20 ) to give after lyophilization of the purified ons the title compound. MS (UPLC-MS) : 170 [M+H]+, 168 [M-H]-; t (HPLC conditions f): 1.22 min. 1-(4-chloro-phenyl)-cyclopropylamine was prepared using the same procedure as for the preparation of 1-(3-chloro-phenyl)- cyclopropylamine starting from 4-chlorobenzonitrile. MS MS): 170 [M+H]+, 168 [M-H]; t (HPLC conditions f): 1 2 1 min. hlorofluoro-phenyl)-cvclopropylamine was prepared using the same procedure as for the preparation of 1-(3-chloro-phenyl)- cyclopropylamine starting from 3-chlorofluroro-benzonitrile. MS (UPLC-MS): 186/188 [M+H]+; t (HPLC conditions f): 1.13 min. 3-(3-Chlorofluoro-phenyl)-oxetanylamine hydrochloride A solution of 2-methyl-propanesulfinic acid [3-(3-chlorofluoro-phenyl)-oxetanyl]-amide (940 mg, 2.46 mmol) and hydrochloric acid (4 N in dioxane, 0.922 ml, 3.69 mmol) in MeOH (5 mL) was stirred 30 min at 0°C and concentrated. The material thus obtained was used without further purification in the next step. MS (UPLC-MS): 202/204 [M+H]+; t (HPLC conditions ) : 0.86 min. 2-methyl-propanesulfinic acid [3-(3-chlorofluoro-phenyl)-oxetanyl]-amide To a solution of ochlorofluorobenzene (896 mg, 4.28 mmol) in THF (100 mL) was added at -78°C under nitrogen atmosphere n-butyllithium ( 1 .6 N in hexanes, 2.67 ml, 4.28 mmol). The reaction mixture was stirred 1 h at -78°C and a solution of yl-N-(oxetan ylidene)propanesulfinamide (500 mg, 2.85 mmol) in THF (17.5 ml) was added dropwise.
The reaction mixture was r stirred 1 h at -78°C then allowed to reach RT and quenched by slow addition of a saturated aqueous solution of NH CI, extracted with EtOAc (x2). The combined organic extracts were washed with water and brine, dried (Na S0 ) , filtered and concentrated. The material thus obtained was used t further purification in the next step.
MS (UPLC-MS): 306.1/308.1 [M+H]+; t (HPLC conditions ) : 1.85 min.
Scheme C5: Preparation of 2,2'-difluoro-biphenylylamine A. 2,2'-Difluoronitro-biphenyl To a on of ofluoronitrobenzene [585344] (150 mg, 0.68 mmol) and 2- fluorophenylboronic acid [ 1 1939 ] (191 mg, 1.36 mmol) in dioxane (4 mL) and water ( 1 mL) was added potassium carbonate (236 mg, 1.70 mmol) and Pd(dppf)Cl2CH Cl2 adduct (55.7 mg, 0.068 mmol). The solution was heated for 30 min at 100°C under microwave irradiation.
The reaction mixture was diluted with CH C I and the resulting on was washed 2 2 successively with ted aqueous NaHC0 solution, 1N HCI solution and brine, then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 m h , 30x100 mm, flow: 40 mL/min, : 20- 100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 containing 0.1% TFA) to give 3 2 3 3 2 after lyophilization of the purified fractions the title compound. MS (LC-MS): 236 [M+H]+; t (HPLC conditions k): 3.81 min.
B. 2,2'-Difluoro-biphenylylamine To a sion of 2,2'-difluoronitro-biphenyl (100 mg, 0.36 mmol) in methanol (5 mL) were added a 3N s HCI solution (7.23 mL, 21.7 mmol) and Zn powder (426 mg, 6.51 mmol).
The mixture was stirred 4 h at RT. The reaction mixture was trated and neutralized with saturated aqueous NaHC0 solution, then diluted with an equal volume of water and extracted (x3) with CH C I .The combined organics were dried (Phase Separator) and concentrated in 2 2 vacuo to give the title compound. MS (LC-MS): 206 [M+H]+; t (HPLC conditions k): 3.30 min. 2'-Chlorofluoro-biphenylylamine was prepared by using the same procedures as described for the preparation of 2,2'-difluorobiphenylylamine in Scheme C5, starting from 2-chlorophenylboronic acid [16791]. MS (LC-MS): 222 [M+H]+; t (HPLC conditions k): 3.42 min.
Scheme C6: Pre aration of 3-(3-chloro-pyridinyl)fluoro-phenylamine A. 3-Chloro(2-fluoronitro-phenyl)-pyridine To a solution of 2-bromochloropyridine [964249] (144 mg, 0.75 mmol) and 2-fluoro nitrophenylboronic acid pinacol ester [ 1 1890423] (200 mg, 0.75 mmol) in dioxane (4 mL) and water ( 1 mL) was added potassium ate (259 mg, 1.87 mmol) and Pd(dppf)CI CH C I adduct (61 .2 mg, 0.075 mmol). The solution was heated for 60 min at 2 2 2 120°C under microwave irradiation. The on mixture was diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHC0 solution and brine, then dried (Phase separator) and concentrated under reduced pressure. The e was purified by flash chromatography on silica gel (c-hexane/EtOAc 4:1) to give the title compound. MS (LC-MS): 253 ; t (HPLC conditions k): 3.45 min.
B. 3-(3-Chloro-pyridinyl)fluoro-phenylamine was prepared by using the same procedure as described for the preparation of 2,2'-difluorobiphenylylamine in Scheme C5 step B. MS (LC-MS): 223 [M+H]+; t (HPLC conditions k): 2.63 min. 2-Fluoro(3-methyl-pyridinyl)-phenylamine was prepared by using the same procedures as described for the preparation of 3-(3-chloropyridinyl )fluoro-phenylamine in Scheme C6, starting from 2-bromomethylpyridine
[34309]. MS (LC-MS): 203 [M+H]+; t (HPLC conditions k): 1.36 min. 2-Fluoro(3-fluoro-pyridinyl)-phenylamine was prepared by using the same procedures as described for the ation of 3-(3-chloropyridinyl )fluoro-phenylamine in Scheme C6, starting from 2-bromofluoropyridine
[402738] and 2-fluoronitrophenylboronic acid [ 1 1501 146]. MS (LC-MS): 207 [M+H]+; t (HPLC conditions k): 2.39 min. 6-(2,6-difluoro-phenyl)-pyridinylamine A. 2-(2,6-Difluoro-phenyl)nitro-pyridine To a solution of 2-bromonitropyridine [212031] (200 mg, 0.99 mmol) and 2,6- rophenylboronic acid [1621019] (31 1 mg, 1.97 mmol) in dioxane (4 mL) and water ( 1 mL) was added potassium ate (340 mg, 2.46 mmol) and Pd(PPh ) ( 114 mg, 0.099 mmol). The on was heated for 60 min at 120°C under ave irradiation. More 2,6- difluorophenylboronic acid (622 mg, 3.94mmol) was added to the mixture followed by heating at 120°C for 120 min under microwave irradiation. The reaction mixture was then diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHC0 solution and brine, the organics were then dried (Phase tor) and concentrated under reduced pressure. The residue was purified by flash column tography on silica gel (c- /EtOAc 9:1) to give the title compound. MS (LC-MS): 237 [M+H]+, 259 [M+Na]+; t (HPLC conditions k): 3.44 min.
B . 6-(2,6-Difluoro-phenyl)-pyridinylamine was prepared by using the same procedure as described for the preparation of 2,2'-difluorobiphenylylamine in Scheme C5 step B. MS (LC-MS): 207 [M+H]+; t (HPLC conditions k): 2.39 min. 2'-chloro-6'-fluorobiphenylamine A . 2-Chlorofluoro-3'-nitro-1,1'-biphenyl To a solution of 1-bromonitrobenzene [5855] (400 mg, 1.98 mmol) and 2-chloro fluorophenylboronic acid [3135453] (414 mg, 2.37 mmol) in dioxane (12 mL) and water (3 mL) was added potassium de (460 mg, 7.92 mmol) and Pd(PPh ) (229 mg, 0.20 mmol).
The solution was heated for 60 min at 120°C under microwave irradiation. More 2-chloro fluorophenylboronic acid (414 mg, 2.37 mmol) was added to the mixture followed by heating at 120°C for 45 min under microwave ation. The reaction mixture was then diluted with EtOAc and the ing solution was washed successively with saturated aqueous NaHC0 solution and brine, the organics were then dried (Phase separator) and concentrated under reduced pressure. The residue was ed by ative HPLC (Waters Sunfire, C18-ODB, mhi , 30x100 mm, flow: 50 mL/min, eluent: 20-100% CH CN/H O/20 min, 100% CH CN/2 min, 3 2 3 CH CN and H 0 containing 0.1% TFA) to give the title compound. t (HPLC conditions c): 5.42 3 2 R min.
B . 2'-Chloro-6'-fluorobiphenylamine was prepared by using the same procedure as described for the preparation of 2,2'-difluorobiphenylylamine in Scheme C5 step B. MS (LC-MS): 222 [M+H]+; t (HPLC conditions c): 3.58 min.
Part D : Synthesis of examples 1 to 773 1H NMR and HRMS data for selected compounds can be found at the end of Part D.
Scheme D 1 : l protocol described for the ation of Example 1 : (2S.4FQ Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-r(1-carbamoyl-1H-indolyl)-amide1 2-(3- chlorofluoro-benzylamide) (2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidinecarboxylic acid (80 mg, 0.24 mmol, ed as described in PartB), 3-chlorofluorobenzylamine (76 mg, 0.48 mmol) and HBTU (136 mg, 0.36 mmol) were dissolved in DMF (7.98 mL). DIPEA (125 m I, 0.718 mmol) was added and the reaction mixture was stirred at 25°C for 1 h . The crude reaction mixture was diluted with EtOAc and successively washed with HCI 1N and NaHC0 (5% in water). The organic layer was dried (Na S0 ) , filtered and concentrated. The crude material 2 4 was purified by preparative HPLC (Waters Sunfire C18-ODB, 5um, 19x50mm, flow: 20 mL/min, gradient: 0-2.5 min 20% CH CN, 2.5-12.5 min 20 to 100% CH CN, 12.5-15 min 100% 3 3 CH CN, H 0 and CH CN containing 0.1% HCOOH) the pure fractions were ed, 3 2 3 extracted with EtOAc and trated. The residue was finally taken up in Et 0 and the desired nd was obtained after filtration. MS: 475.9 [M+H]+, 498 [M+Na]+; t (HPLC conditions b): 3.64 min.
The examples below were ed according to the general procedures described in Scheme D 1 for Example 1 using commercially ble building blocks, if not otherwise stated (see notes at the end of table 1): Table 1: Characterization (end-table notes), TLC, R (eluent); Example Structure Name f MS (LC/MS); t (HPLC conditions) (2S,4R)Fluoro-pyrrolidine- 424 [M+H]+; t (b): 1,2-dicarboxylic acid 2- R 2 3.15 min. benzylamide 1-[(1-carbamoyl- o=( 1H-indolyl)-amide] (2S,4R)-4—F|uoro—pyrrolidine- 425.0 [M+H]+, 1,2-dicarboxylic acid 1-[(1- 423.1 [M-H]-; tR (a): carbamoyI-1H-indoIy|)- 1.05 min. amide] 2-[(pyridiny|methyl)- amide] (2S,4R)-4—F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (1 [02]) 577.3 [M]+; amide] 2-(3-chlorofluoro—5- tR (c): 3.67 min. {[(2-methoxy-ethy|)-methy|- amino]-methy|}-benzy|amide) )-4—F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- 505.4 [M+H], 504.3 carbamoyI-1H-indoIy|)- [M-H]-; tR (a): 2.87 amide] 2-{[(S)(3-ch|oro min. fluoro-phenyI)hydroxy- ethy|]-amide} 425.2 [M+H]+, )-4—F|uoro—pyrrolidine- 447.1 [M+Na]+, 1,2-dicarboxylic acid 1-[(1- 871.3 [2M+Na]+, oyI-1H-indoIy|)- 423.1 [M-H]—, 380 amide] 2-[(pyridin-4—y|methyl)- [M-CONH2]-, tR (a): amide] 1.27 min. (2S,4R)-4—F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- (1[c1]) 574.2/577.3 carbamoyI-1H-indoIy|)- [M+H]+; tR (c): 3.53 amide] 2-[3-chlorofluoro—5- min. (4—methyI-piperaziny|)- benzylamide] )-4—F|uoro—pyrrolidine- 458.2 [M+H]+ 455.1 1,2-dicarboxylic acid 1-[(1- [M-H]-; tR (a): 3.05 carbamoyI-1H-indoIy|)- min; tR (b): 3.34 amide] 2-(3-chloro- min. benzylamide) (2S,4R)F|uoro—pyrrolidine- carboxylic acid 1-[(1- 440 [M+H]+; tR (b): carbamoyI-1H-indoIy|)- 2.66 min. amide] 2-(3-hydroxy- benzylamide) (2S,4R)F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (1[C2]) 588 [M+H]+; amide] hlorofluoro—5- tR (c): 3.31 min. (4—methyI-piperazin y|methy|)-benzy|amide] (2S,4R)F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- 463.9 [M+H]+; tR carbamoyI-1H-indoIy|)- (b): 3.55 min. amide] 2-[(5-ch|oro-thiophen- 2-y|methy|)-amide] )F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (1[C2]) 561.3 [M]+; amide] 2-(3—chloro—5- tR (c): 3.72 min. diethylamino-methyIfluorobenzyI-amide (2S,4R)F|uoro—pyrrolidine- 454.3 [M+H]+, carboxylic acid 1-[(1- 452.3 [M-H]-; tR (a): 00 carbamoyI-1H-indoIy|)- 2.63 min. amide] 2-[((S)hydroxy phenyI-ethyI)-amide] (2S,4R)F|uoro—pyrrolidine- 460.1 [M+H]+; 415 1,2-dicarboxylic acid 1-[(1- [M-CONH2]-, tR (a): carbamoyI-1H-indoIy|)- 2.95 min. amide] 2-(2,3—difluorobenzylamide (2S,3S){[(2S,4R)(1- Rf (EtOAc) = 0.7; Carbamoyl-1H-indoI 504.3 [M+H]+, y|carbamoy|)f|uoro— 526.3 [M+Na]+, pyrrolidinecarbony|]- 448.1 [MH-tBu]+, amino}-3—methy|—pentanoic 502.2 [M-H]—, 459.2 [M-CONH2]-, tR (a): 3.42 min. (2S,4R)-4—F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- (1[c1]) 5893/5923 carbamoyI-1H-indoIy|)- [M+H]+, tR (c): 3.76 amide] 2-[3—chlorofluoro—5- min. (4-methoxy-piperidiny|)- amide] (2S,4R)-4—F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- ) 590.2 [M]+; amide] 2-(3—chloro—5—{[(2- tR (c): 3.25 min. dimethylamino—ethyl)-methy|— amino]-methy|}f|uoro— benzylamide) (2S,4R)-4—F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (1[C2]) 575.2 [M]+; amide] 2-(3-chlorofluoro—5- tR (c): 3.57 min. morpholin-4—ylmethyl- amide) (2S,4R)-4—F|uoro—pyrrolidine- (1) 561.3/564 1,2-dicarboxylic acid 1-[(1- [M+H]+,tR (c): 4.26 carbamoyI-1H-indoIy|)- min. amide] 2-(3-chlorofluoro—5- morpholin-4—yI-benzylamide) (2S,4R)-4—F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- ) 603 [M+H]+; amide] 2-[3—chlorofluoro—5- tR (c): 3.72 min. (4-methoxy-piperidin y|methy|)-benzy|amide] e su s u e enzy am ne or an ne er va ve use n s ep was prepare as escr e n ar [Scheme].
Example 23: 2-({[(2S,4R)-1 -(1 -Carbamoyl-1 lylcarbamoyl)fluoro-pyrrolidine yl]-amino}-methyl)-benzoic acid To a solution of 2-({[(2S,4R)(1-carbamoyl-1 H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-methyl)-benzoic acid tert-butyl ester (prepared according to Scheme D 1 using 2-aminomethyl-benzoic acid tert-butyl ester) (76 mg, 0.145 mm) in CH C I ( 1 ml_) was 2 2 added TFA (168 m I, 2.18 mmol) and the resulting solution was stirred at RT overnight. The crude mixture was concentrated to give a solid which was suspended in Et 0 and filtered to give the desired material. MS (LC-MS): 468.1 [M+H]+, 490.1 +, 957.2 [2M+Na]+, 466.1 [M-H]-, 423.1 [M-CONH ]-, t (HPLC conditions a): 2.64 min. 2 R Example 24: 2-({[(2S,4R)-1 -(1 -Carbamoyl-1 H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-methyl)-benzoic acid To a solution of 3-({[(2S,4R)(1-carbamoyl-1 H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-methyl)-benzoic acid tert-butyl ester (prepared according to Scheme D 1 using 3-aminomethyl-benzoic acid tert-butyl ester) (21 mg, 0.04 mmol) in CH C I (0.5 ml_) was 2 2 added TFA (31 m I, 0.4 mmol) and the solution was stirred at RT for 24 h . The solvent was concentrated and the crude residue was purified by preparative HPLC (C18-ODB, 5 mhi , 19x50 mm, waters, eluent: CH CN/H 0 + 0.1 % HCOOH flow: 20 mL/min, standard 20 % method) to 3 2 give after lyophilization of the purified fractions the desired material. MS (LC-MS): 468 [M+H]+, 490 [M+Na]+, 466 [M-H]-, 423.0 [M-CONH ]-; t (HPLC ions a): 2.57 min. 2 R Example 25: (2S,3S){[(2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluororbo ny l] -am ino} -3 -m et hy l-pe nt ano ic acid To a suspension of (2S,3S){[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoropyrrolidinecarbonyl ]-amino}methyl-pentanoic acid tert-butyl ester Example 15 (64 mg, 0.127 mmol) in CH C I ( 1 ml_) was added TFA (97 m I, 1.27 mmol) and the resulting solution 2 2 was stirred at RT for 20 h . TFA ( 1 .27 mmol) was added again to ensure completion of the reaction. CH C I was concentrated and the crude residue was purified by preparative HPLC 2 2 DB, 5 mhi , 19x50 mm, waters, eluent: CH CN/H 0 + 0.1% HCOOH flow: 20 mL/min, 3 2 standard 20 % method) to give after lyophilization of the purified fractions the d material which was dissolved in CH CN and was purified again on trimethylaminopropyl cartridge (Mega Bond Elut-SAX, 1 g , from Varian, ioned with 20 mL of CH CN). The column was eluted with CH CN and the compound was finally ed with 10 mL of HCI 0.1 N in CH CN, 3 3 concentration led to a residue which was taken up in Et 0 and ed-off to give the desired material. MS (LC-MS): 448.1 [M+H]+, 446 [M-H]-; t (HPLC conditions a): 2.67 min.
Scheme D2: l protocol described for the preparation of Example 26: (2S,4S) Amino-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1H-indolyl)-amide1 2-(3- chlorofluoro-benzylamide) A. (2S,4S)- 4-(9H-fluorenylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1- [(1-carbamoyl-1H-indolyl)-amide] hlorofluoro-benzylamide) (2S,4S)[(1-carbamoyl-1H-indolyl)-amide](9H-fluorenylmethoxycarbonylamino)- pyrrolidinecarboxylic acid (400 mg, 0.723 mmol, ed as described in Scheme B10), 3- chlorofluorobenzylamine (230 mg, 1.45 mmol) and HBTU (41 1 mg, 1.08 mmol) were dissolved in DMF (2.5 mL). DIPEA (0.378 mL, 2.18 mmol) was added and the reaction mixture was stirred at 25°C for 16 h . The reaction mixture was diluted in EtOAc and successively washed with HCI 1N and NaHC0 3 (5% in . The combined organic extracts were dried (Na2S0 4) , filtered and concentrated to dryness. The crude residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 urn, mm, 20% CH3CN/2 min, 20-100% C H3CN/H2O /I8 min, 100% 2 min, CH3CN and H20 containing 0.1% TFA, flow: 40 mL/min) to give the desired nd. MS (LC/MS): 695 [M+H]+, 717 [M+Na]+; tR (HPLC conditions b): 5.16 min.
Alternative protocol: (2S,4S)[(1-carbamoyl-1H-indolyl)-amide](9H-fluorenylmethoxycarbonylamino)- pyrrolidinecarboxylic acid (40 mg, 0.072 mmol, prepared as described in Scheme B10) and amine (0.08 mmol) were dissolved in NMP (0.7 mL). DIPEA (0.025 mL, 0.143 mmol) and HBTU (40.6 mg, 0.107 mmol) were added and the reaction mixture was stirred at 25°C for 90 min. The on mixture was diluted with MeOH ( 1 mL) and filtered over a PTFE membrane (0.45 urn). The resulting filtrate was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 urn, 30x150mm, 45% CH3CN/3.0 min, 45-70% CH3CN/H 20/12 min, 70-95% CH3CN/2 min, CH3CN and H20 containing 0.1% TFA, flow: 50 mL/min) to give the d compound.
Alternative protocol 2: (2S,4S)[(1-carbamoyl-1H-indolyl)-amide](9H-fluorenylmethoxycarbonylamino)- pyrrolidinecarboxylic acid (70 mg, 0.126 mmol, prepared as described in Scheme B10), amine (0.253 mmol) and HBTU (100 mg, 0.264 mmol) were dissolved in DMF (2 mL). DIPEA (0.066 mL, 0.379 mmol) was added and the reaction mixture was stirred at 25°C for 90 min.
The reaction mixture was diluted with MeOH (2 mL), filtered over a PTFE membrane (0.45 urn) and washed with MeOH. The resulting filtrate was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 urn, 30x150mm, 20% CH3CN/1.5 min, 20-88% 9 min, 88-100% CH3CN/3 min, H20 containing 0.1% TFA, flow: 50 mL/min) to give the desired compound.
B. (2S,4S)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide) To a solution of (2S,4S)(9H-fluorenylmethoxycarbonylamino)-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) (209 mg, 0.3 mmol) in DMF (15 ml_) was added piperazine polymer bound (Aldrich CAS 526290, loading = 1.5 mmol/g, 2 g , 3.01 mmol) and the reaction mixture was stirred at 25°C for 16 h . The reaction mixture was filtered, the polymer was washed with CH2C I2 and the filtrate was concentrated to dryness. The crude residue was ed by preparative HPLC s Sunfire C18-ODB, 5 urn, 30x100mm, 20% CH3CN/2 min, 20-100% CH3CN/H 20/18 min, 100% CH3CN/2 min, CH3CN and H20 containing 0.1% HCOOH, flow: 40 mL/min) to give the title compound as a formate salt. MS (LC/MS): 473 ; tR (HPLC conditions b): 2.52 min.
Alternative protocol: atively the crude residue can be purified by catch release using silicaPrep Tosic Acid-1g column (SPE-R60530B-06S from cle). The column was conditioned with MeOH (10 ml_), and the crude residue dissolved in MeOH was added. The column was washed MeOH (10 ml_) and the compound released by elution with 2M a in MeOH (10 ml_). ative protocol 2: To solutions of (2S,4S)(9H-fluorenylmethoxycarbonylamino)-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] amides in DMF (2.0 ml_) was added piperazine polymer bound (Aldrich CAS 526290, loading = 1.5 mmol/g, 2 g , 3.01 mmol), the reaction vessels were flushed with argon and the reaction mixtures were stirred at 25°C for 48 h . The resulting ons were poured onto cartridges containing 500 mg of silicaPrep Tosic Acid (SPE-R60530B-06S from Silicycle), conditioned with MeOH (10 ml_). The columns were washed with MeOH (20 ml_) and the compounds were then released by elution with 2M ammonia in MeOH (10 ml_).
The examples below were prepared according to the general ure described for Example 26 Scheme D2, using various amines in step A: Table 2 : Characterization (end-table notes), Example Structure Name TLC, Rf (eluent); MS (LC/MS); tR (HPLC conditions) (28,4S)Amino—pyrrolidine— (1) 407 [M+H]+; tR 1,2-dicarboxylic acid 1-[(1- (d): 0.6 min. carbamoyI-1H-indoIy|)- amide] 2-phenylamide (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 2- (2) 421.3 [M+H]+; tR benzylamide 1-[(1-carbamoyl- (d): 0.62 min. 1H-indolyl)—amide] (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 454/456.1 carbamoyI-1H-indoIy|)- [M+H]+, 932.2 amide] 2-(3-chloro— [2M+Na]+, 453.1 [M- benzylamide) as a e H]-; tR (d): 2.51 min. salt (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 435 [M+H]+; tR carbamoyI-1H-indoIy|)- (b): 2.62 min. amide] 2-(3-methyl- benzylamide) (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 489 [M+H]+; tR carbamoyI-1H-indoIy|)- (b): 2.95 min. amide] rifluoromethylbenzylamide (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 439.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.75 min. amide] 2-(3—fluoro— amide) (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 446 [M+H]+; tR carbamoyI-1H-indoIy|)- (b) : 2.09 min. amide] yano— benzylamide) (2S,4S)Amino—pyrrolidine— carboxylic acid 2-(3- (1) 499/501 bromo—benzylamide) 1-[(1- [M+H]+; tR (b) : 2.78 carbamoyI-1H-indoIyl)- min. amide] (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 437.1 [M+H]+; tR carbamoyI-1H-indoIyl)- (d): 0.52 min. amide] 2-(3-hydroxy- benzylamide) )Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 451 [M+H]+; tR carbamoyI-1H-indoIyl)- (b):2.36. amide] 2-(3-methoxy- amide) (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 505.1 [M+H]+; tR carbamoyI-1H-indoIyl)- (d): 0.90 min. amide] 2-(3-trifluoromethoxy— benzylamide) (2S,4S)Amino—pyrrolidine— carboxylic acid 1-[(1- (2) 513.2 [M+H]+; tR carbamoyI-1H-indoIyl)- (d): 0.95 min. amide] 2-(3-phenoxy— benzylamide) (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 2- (1) 497.2 [M+H]+, [(biphenyIylmethyI)-amide] 495.2 [M-H]—; tR (a): 1-[(1-carbamoy|—1H-indoI 2.8 min. y|)-amide] as a formate salt (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 486.2 [M+H]+; tR carbamoyI-1H-indoIyl)- (d): 0.87 min. amide] 2-(3-pyrroIyl- benzylamide) (28,4S)Amino—pyrrolidine— (1) R (MeOH) = carboxylic acid 1-[(1- 0.25; 5871/5392 carbamoyI-1H-indoIy|)- [M+H]+, 536/538 [M- amide] 2-[3-(5-chloro— H]-; tR (a): 2.92 min. thiophenyl)-benzylamide] (28,4S)Amino—pyrrolidine— (1) R (MeOH) = 1,2-dicarboxylic acid 1-[(1- 0.28; 543.1/545 carbamoyI-1H-indoIy|)- [M+H]+, 541/5482 amide] 2-[(5'-ch|oro- [M-H]-; tR (a): 2.90 [2,2']bithiophenyl-5—ylmethyl)- min. amide] (28,4S)Amino—pyrrolidine— (3) 435.2 ; tR 1,2-dicarboxylic acid 1-[(1- (d): 0.87 min. carbamoyI-1H-indoIy|)- amide] 2-(4-methyl- benzylamide) (28,4S)Amino—pyrrolidine— carboxylic acid 1-[(1- (2) 455 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.82 min. amide] 2-(4-chloro- benzylamide) (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 489.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.88 min. amide] 2-(4—trifluoromethyl- benzylamide) (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 505.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.91 min. amide] 2-(4-trifluoromethoxy— benzylamide) (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 437.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.52 min. amide] 2-(4-hydroxybenzylamide (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 437.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.72 min. amide] 2-(2-hydroxybenzylamide (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 439.3 [M+H]+; tR carbamoyI-1H-indoIy|)- (b) : 2.12 min. amide] 2-(2-fluoro- benzylamide) (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 455.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.88 min. amide] 2-(2-chloro- benzylamide) (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 2- (3) 497.1 [M+H]+; tR enylylmethyl)—amide] (d): 1.02 min. carbamoy|—1H-indoI y|)-amide] (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 457.2 [M+H]+; tR carbamoyI-1H-indoIy|)- (b): 2.24 min. amide] —dif|uorobenzylamide (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 485 [M+H]+; tR carbamoyI-1H-indoIy|)- (b) : 2.80 min. amide] 2-(5-chloro—2-methoxy- benzylamide) (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 485 [M+H]+; tR carbamoyI-1H-indoIy|)- (b): 2.67 min. amide] 2-(3-chloro—4—methoxy- benzylamide) (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 473 ; tR carbamoyI-1H-indoIy|)- (b): 2.68 min. amide] 2-(5-chlorofluoro— benzylamide) (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 473 [M+H]+; tR carbamoyI-1H-indoIy|)- (b): 2.77 min. amide] 2-(3-chloro—4—fluoro— benzylamide) (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 469 [M+H]+; tR carbamoyI-1H-indoIy|)- (b): 2.82 min. amide] 2-(3-chloromethylbenzylamide (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 469 [M+H]+; tR carbamoyI-1H-indoIy|)- (b): 2.84 min. amide] 2-(5-chloromethylbenzylamide (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 469 [M+H]+; tR carbamoyI-1H-indoIy|)- (b) : 2.93 min. amide] 2-(3-chloromethylbenzylamide (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 489.1 ; tR oyI-1H-indoIy|)- (d): 0.96 min. amide] 2-(3,5-dich|oro— benzylamide) (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (8) 489.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.96 min. amide] 2—(3,4—dich|oro- benzylamide) (28,4S)Amino—pyrrolidine— carboxylic acid 1-[(1- (8) 491.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.88 min. amide] hloro—2,6— difluoro-benzylamide) (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (8) 471.2 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.95 min. amide] 2—[(naphthalen-2— y|)-amide] (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (8) 471.2 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.94 min. amide] 2—[(naphthalen y|)-amide] (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (8,4) 442.1 [M+H]+; carbamoyI-1H-indoIy|)- tR (d): 0.60 min. amide] 2—[(5-methy|—thiazo| y|methy|)-amide] (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (1) 461 [M+H]; tR (b) carbamoyI-1H-indoIy|)- : 2.37 min. amide] 2—[(5-ch|oro-thiophen- 2—ylmethy|)-amide] (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (3,4) 436.2 [M+H]+; carbamoyI-1H-indoIy|)- tR (e): 1.13 min. amide] 2—[(4-methy|—pyridin-2— y|methy|)-amide] (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (1) 469/471 [M+H]+, oyI-1H-indoIyl)- 424/426 [M- amide] 2-{[(S)(3—ch|oro— CONH2]-; tR (a): 2.57 phenyI)-ethy|]-amide} as a min. formate salt (2S,4S)Amino—pyrrolidine— (1) 469/471 [M+H]+, 1,2-dIcarboxyllc_ _ acnd_ 1-[(1- 424/426 [M- carbamoyI-1H-indoIyl)- CONH2]-; tR (a): 2.59 amide] )(3-ch|oro— min. phenyI)-ethy|]-amide} as a formate salt )Amino—pyrrolidine— mixture of 2 1,2-dIcarboxyllc_ _ acnd_ 1-[(1- diastereosiomers. carbamoyI-1H-indoIyl)- 519 [M+H]+; tR (b): amide] 2-{[1-(3,5-dich|oro— 2.72/2.76 min. phenyl)hydroxy-ethy|]- amide} (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 499.1 [M+H]+; tR carbamoyI-1H-indoIyl)- (d): 0.82 min. amide] 2-{[1-(3-ch|oro- phenyl)-3—hydroxy—propy|]- amide} (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 447.1 [M+H]+; tR carbamoyI-1H-indoIyl)- (d): 0.77 min._ amide] 2-[(1-pheny|— cyclopropy|)-amide] (2S,4S)Amino—pyrrolidine— (1) 497.2 [M+H]+, 1,2-dicarboxylic acid 2- 495.2 ; tR (a): benzhydry|-amide 1- [( 1- 2.80 min. carbamoyI-1H-indoIyl)- amide] as a formate salt (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 427.1 [M+H]+, tR carbamoyI-1H-indoIy|)- (d): 0.83 min. amide] 2-cyclohexylmethyl- amide (2S,4S)Amino—pyrrolidine— (2) mixture of trans 1,2-dicarboxylic acid 1-[(1- diastereoisomers: oyI-1H-indoIy|)- 443.2 [M+H]+, amide] 2-[((1R*,2S*) 465.2 [M+Na]+, hydroxy-cyclohexylmethy|)- 441.2 [M-H]-; tR (a): amide] 1.84/1.36 min. (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 443.2 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.70 min. amide] 2-[((1S,2S)hydroxy- cyclohexylmethy|)-amide] (2S,4S)Amino—pyrrolidine— (2) 413.1 [M+H]+, tR carboxylic acid 1-[(1- (d): 0.75 min. carbamoyI-1H-indoIy|)- amide] 2-cyclohexylamide (2S,4S)Amino—pyrrolidine— (2) Mixture of 1,2-dicarboxylic acid 1-[(1- diastereoisomers carbamoyI-1H-indoIy|)- 491.2 [M+H]+, tR (e): amide] 2-[(3,4,5,6—tetrahydro- 1.12/1.19 min. 2']bipyridinyl-3—yl)- amide] )Amino—pyrrolidine— (3) 481.1 [M+H]+; tR 1,2-dicarboxylic acid 1-[(1- (d): 0.94 min. carbamoyI-1H-indoIy|)- amide] 2-[(6-ch|oro-indan y|)-amide] (2S,4S)Amino—pyrrolidine— (3)497-1[M+H1+JtR 1,2-dicarboxylic acid 1-[(1- (d): 0'92 m'” carbamoyI-1H-indol-3—y|)- amide] 2-[(6—ch|oro-chroman- 4-y|)-amide] )Amino—pyrrolidine— carboxylic acid 1-[(1- (2) 435.1 [M+H]+, tR carbamoyI-1H-indoIy|)- (d): 0.77 min. amide] 2-(phenethyI-amide) (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 451.2 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.71 min. amide] 2-[(2-hydroxy phenyI-ethyI)-amide] (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 447.2 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.90 min. amide] 2-[((1R,2S)pheny|— cyclopropy|)-amide] (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 449.2 ; tR carbamoyI-1H-indoIy|)- (d): 0.90 min. amide] 2-[((R)phenyl- propy|)-amide] (2S,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (3) 449.2 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.90 min. amide] )pheny|— propy|)-amide] (2S,4S)Amino—pyrrolidine— 1,2-dlcarboxyllc. . acnd. 1-[(1- 469.1 [M+H]+; tR (d): carbamoy|-1H-indo|y)|- 0.91 min. amide] 2-{[2-(3-ch|oro- phenyl)—ethy|]—amide} (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (3) 469.1[M+H]+; tR carbamoyl-1HindoIyl)- (d): 0.91 min. amide] 2—{[2-(2-ch|oro- phenyl)—ethy|]-amide} (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (3) 453-1 ; tR carbamoyl-1HindoIyl)- (d): 0.86 min- amide] 2—{[2-(2-f|uoro—pheny|)- ethy|]-amide} )Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (3) 453.1 [M+H]+; tR carbamoyI-1Hindolyl)- (d): 0.86 min. amide] 2—{[2-(3-f|uoro—pheny|)- ethy|]-amide} (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (3) 473.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (d): 0.90 min. amide] 2—{[2-(3-ch|oro fluoro-phenyl)—ethyI]-amide} (28,4S)Amino—pyrrolidine— 1,2—dicarboxylic acid 1-[(1- (2) 451.1 [M+H]+, tR carbamoyI-1H-Indoly|)-_ (d): 0.78 min. amide] 2—[(2-phenoxy—ethy|)- amide] (28,3S){[(28,4S)Amino- 1-(1-carbamoyI-1H-indoI (2) 459.1 [M+H]+, tR y|carbamoy|)-pyrro|idine (d): 0.79 min. carbonyl]-amino}-3—methylpentanoic acid methyl ester (S){[(28,4S)—4—Amino—1-(1- carbamoyl-1H-indol-3— (3) 445.2 [M+H]+; tR amoy|)-pyrro|idine (d): 0.80 min. carbonyI]-amino}-pentanoic acid methyl ester (R)—2-{[(28,4S)—4-Amino—1-(1- carbamoyl-1H-indol-3— (3)4452 [M+H]+; tR ylcarbamoyl)—pyrrolidine (d): 0.76 min. carbonyl]—amino}-3—methyl- butyric acid methyl ester (S){[(28,4S)—4—Amino—1-(1- carbamoyl-1H-indol-3— (3)4592 [M+H]+; tR ylcarbamoyl)—pyrrolidine (d): 0.87 min. carbonyl]—amino}-4—methylpentanoic acid methyl ester (S){[(28,4S)—4—Amino—1-(1- carbamoyl-1H-indol-3— (3)4892 [M+H]+; tR ylcarbamoyl)—pyrrolidine (d): 0.87 min. carbonyl]—amino}-3—tert— butoxy-propionic acid methyl ester (S){[(28,4S)—4—Amino—1-(1- oyl-1H-indol-3— (3)4932 [M+H]+; tR ylcarbamoyl)—pyrrolidine (d): 0.88 min. carbonyl]—amino}-3—phenylpropionic acid methyl ester (S)-{[(28,4S)Amino(1- oyl-1H-indol-3— (3) 479.1 [M+H]+; tR amoyl)—pyrrolidine (d): 0.84 min. carbonyl]—amino}-phenyl- acetic acid methyl ester (28,4S)Amino—pyrrolidine— 1,2-dicarboxylic acid 1-[(1- (2) 444.1 [M+H]+, tR carbamoyl-1H-indol-3—yl)— (d): 0.61 min. amide] 2-[((1S,28)—1- carbamoylmethyl-butyl)— amide] butyl)-amide] ( 1) Compound prepared according to the l procedure described for Example 26 Scheme D2; (2) Compound prepared according to the alternative protocol described for step A and using silica gel derivatized piperazine (SPE-R60530B-06S from Silicycle) in step B ; (3) Compound ed using the alternative protocols 2 for both step A and B ; (4) In Step B stirring was ued at 60°C for additional h .
Example 102: (2S,4S)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- 3-yl)-amide] 2-[(3-isopropyl-phenyl)-amide] was prepared according to the general procedure described in Scheme D2 using 5 equivalents of 3-isopropylaniline in step A and silica gel tized piperazine (Silicycle, loading = 0.9 mmol/g, cat. Number: SPE-R60030B) in step B. MS (LC/MS): 449.2 [M+H]+, 920.3 [2M+Na]+, 447.3 [M-H]-; t (HPLC conditions a): 2.74 min.
Example 103: (2S,4S)Amino-pyrrolidine-1,2-dicarboxylic acid 2-biphenylylamide 1- [(1-carbamoyl-1H-indolyl)-amide] was prepared according to the general procedures described in Scheme D2 using 10 equivalents of biphenylylamine in step A . MS (LC/MS): 483.3 [M+H]+, 481.2 [M-H]-; t (HPLC conditions a): 2.83 min.
Scheme D3: general protocol described for the preparation Example 104: 3-(f(2S,4R) Fluoro-2 -r(2-fluoro-benzenesulfonylamino)-methvn-pyrrolidinecarbonylVamino)- indolecarboxylic acid amide To a mixture of 3-[((2S,4R)aminomethylfluoro-pyrrolidinecarbonyl)-amino]-indole carboxylic acid amide (52 mg, 0.163 mmol) red as described Scheme B 11) and 2- fluorobenzenesulfonyl de (24 m I_ , 0.179 mmol) in CH C I (0.5 ml_), was added 2 2 triethylamine (25 m I_ , 0.179 mmol) and the resulting suspension was stirred at RT under nitrogen overnight. The mixture was poured into water and extracted twice with CH C I . The 2 2 combined organic layers were dried over Na S0 , filtered and concentrated. The crude e 2 4 was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, eluent: 20% to 100% CH CN in H 0 in 15 min, CH CN and H 0 containing 0.1% HCOOH, flow: 20 mL/min) to 3 2 3 2 give after lization of the purified fractions the desired material. R , TLC (EtOAc) = 0.55; MS (LC-MS): 478.1 [M+H]+, 500 [M+Na]+, 516 [M+K]+, 977.2 [2M+Na]+, 476 [M-H]-; t (HPLC conditions ) 1.73 min.
The examples below were prepared according to the procedure described in Scheme D3 for Example 104, using various sulfonyl chlorides: Table 3 : terization TLC, R (eluent); Example Structure Name MS (LC/MS); (HPLC conditions) Rf (EtOAc) = 0.65; 3-{[(28,4R) 460 [M+H]+, 482 (Benzenesulfonylamino— [M+Na]+, 919 methy|)f|uoro-pyrrolidine [2M+H]+, 941 carbonyl]—amino}-indole—1- [2M+Na]+, 458.2 carboxylic acid amide ; tR (f): 1.71 min. 3-({(28,4R)-4—FIuoro[(3- fluoro- Rf (EtOAc) = 0.7; benzenesulfonylamino)- 478 [M+H]+, 476 methyl]—pyrrolidine—1 - [M-H]-; tR (f): 1.79 carbonyI}-amino)-indole min. carboxylic acid amide 3-({(28,4R)-4—FIuoro[(3- Rf (EtOAc) = 0.7; chloro- 6 [M+H]+, benzenesulfonylamino)- 516.1/5182 methyl]-pyrrolidine—1 - [M+Na]+, 492/494 yI}-amino)-indole [M-H]—; tR (f): 1.99 carboxylic acid amide min.
Rf (EtOAc) = 0.70; 3-({(28,4R)-4—FIuoro[(3- 537.9/5399 bromo— [M+H]+, benzenesulfonylamino)- 559.9/561.8 methyl]-pyrrolidine—1 - [M+Na]+, 356/538 yI}-amino)-indole [M-H]—; tR (f): 1.89 carboxylic acid amide min. 3-({(28,4R)-4—FIuoro[(3- trifl uoromethoxy- Rf (EtOAc) = 0.75; esulfonylamino)- 544.2 [M+H]+, 566 methyl]-pyrrolidine—1 - [M+Na]+, 542 [M- carbonyI}-amino)-indole H]-; tR (f): 2.08 min. carboxylic acid amide 3-({(28,4R)[(3-Chloro—2- 512/514 [M+H]+, fluoro- 534.1/536 +, benzenesulfonylamino)- 510/512 [M-H]-; tR methyl]—4-f|uoro—pyrro|idine (6:192 min. carbonyI}-amino)-indole carboxylic acid amide Example 113: 3-{[(2S,4R)Fluoro(phenylacetylamino-methyl)-pyrrolidine-1 - carbonyl]-amino}-indole-1 -carboxylic acid amide To a mixture of 3-[((2S,4R)aminomethylfluoro-pyrrolidinecarbonyl)-amino]-indole carboxylic acid amide (50 mg, 0.16 mmol, prepared as bed in Scheme B 1 1) and phenylacetyl chloride (23 m I_ , 0.17 mmol) in CH C I (0.5 ml_), was added ylamine (24 m I_ , 2 2 0.17 mmol) and the resulting suspension was stirred at RT under N overnight. The mixture was poured into water and extracted with CH C I (x2). The combined organic layers were dried 2 2 (Na S0 ) , filtered and concentrated. The crude residue was purified by preparative HPLC 2 4 (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, : 20% to 100% CH CN in H 0 in 15 min, 3 2 CH CN and H 0 containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the 3 2 purified fractions the desired material. R , TLC (EtOAc) = 0.1; MS (LC-MS): 438.1 [M+H]+, 897.2 [2M+Na]+, 393.1 [M-CONH ]-; t (HPLC conditions ) : 1.70 min. 2 R e 114: [(2S,4R)(1-Carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidin ylmethyl]-carbamic acid phenyl ester To a mixture of S,4R)aminomethylfluoro-pyrrolidinecarbonyl)-amino]-indole carboxylic acid amide (50 mg, 0.157 mmol, prepared as described in Scheme B 1 1) and phenyl chloroformate (22 m I_ , 0.17 mmol) in CH C I (0.5 mL), was added triethylamine (24 m I_ , 0.17 2 2 mmol) and the resulting suspension was d at RT under nitrogen overnight. The mixture was poured into water and extracted with CH C I (x2). The combined organic layers were dried 2 2 (Na S0 ) , filtered and concentrated. The crude residue was purified by preparative HPLC 2 4 (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, eluent: 20% to 100% CH CN in H 0 in 15 min, 3 2 C H3C I and H 0 containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the purified fractions the desired material. R , TLC (EtOAc) = 0.45; MS (LC-MS): 440 [M+H]+, 901.3 ]+; t (HPLC conditions f): 1.77 min.
Example 115 : [(1 R,3S,5R)(1 -Carbamoyl-1 H-indolylcarbamoyl)azabicyclo [3.1.0]hexylmethyl]-carbamic acid rofluoro-phenyl ester To a solution of S,5R)(2-aza-bicyclo[3.1 .0] hexyl)methyl]-carbamic acid 3-chloro fluoro-phenyl ester, trifluoroacetate (60.0 mg, 0.21 1 mmol) and Et N (88 m I, 0.62 mmol) in THF (5 mL) was added 3-isocyanato-indolecarboxylic acid amide (43.0 mg, 0.21 1 mmol ; prepared as described in Scheme A1). The solution was stirred at RT under a nitrogen atmosphere for 3 days. Purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, eluent: 5-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 3 2 3 3 2 containing 0.1% TFA, flow: 40 mL/min) afforded after lization of the purified HPLC fractions the title compound. MS (LC/MS): 486.0 [M+H]+; t (HPLC conditions k): 3.57 min. ,5R)-3 -r(3-Chlorofluoro-phenoxycarbonylamino)-methvnaza-icvclor3.1.01- hexanecarboxylic acid tert-butyl ester To a solution of 3-chlorofluorophenol (180 mg, 1.20 mmol) in dry CH C I (10 mL), cooled to 2 2 at 0°C, was added triphosgene (120 mg, 0.4 mmol) followed by dropwise addition of a solution of DIPEA (210 m , 1.20 mmol) in CH C I (5 mL). The mixture was allowed to warm to RT and 2 2 stirring was ued for 1 h . The reaction mixture was then added dropwise to a on of ( 1 R,3S,5R)aminomethylaza-bicyclo[3.1 .0]hexanecarboxylic acid utyl ester (170 mg, 0.80 mmol) (prepared as described in Part B) and DIPEA (168 m I_ , 0.96 mmol) in CH C I 2 2 (10 mL) at RT. After stirring for 2 h , the reaction was quenched by addition of methanol (2 mL) and water with vigorous stirring. The mixture was ted with CH C I (2x), the ed 2 2 organics were washed with brine, dried (phase separator) and concentrated under reduced pressure. Purification by flash column tography on silica gel (eluent gradient: c- hexane/EtOAc 9:1 to c-hexane/EtOAc 1:1) afforded the title compound as a colorless wax. MS (LC/MS): 385.0 [M+H]+; t (HPLC conditions k): 4.03 min. r(1R,3S,5R)(2-Aza-bicyclor3.1.01 hexyl)methvn-carbamic acid 3-chlorofluorophenyl ester, trifluoroacetate To a solution of ( 1 R,3S,5R)[(3-chlorofluoro-phenoxycarbonylamino)-methyl]aza- icyclo[3.1.0]hexanecarboxylic acid tert-butyl ester (130 mg, 0.34 mmol) in CH C I (4 mL) 2 2 was added TFA (2 mL, 26 mmol) and solution was stirred at RT for 2 h . Methanol was then added and volatiles were removed under reduced pressure. The residue was taken up in MeOH and concentrated in vacuo to afford the crude title nd as a colorless wax. MS (LC/MS): 285.0 [M+H]+; t (HPLC conditions k): 2.66 min. The material thus obtained was used directly in the next step without further purification.
Example 116 : 3-({(2S,4R)[(3-Chlorofluoro-benzylamino)-methyl]fluoropyrrolidinecarbonyl }-amino)-indolecarboxylic acid amide 3-[((2S,4R)Aminomethylfluoro-pyrrolidinecarbonyl)-amino]-indolecarboxylic acid amide (50 mg, 0.157 mmol) and 3-chlorofluorobenzaldehyde (25 mg, 0.157 mmol, prepared as described in Scheme B 1 1) were mixed in dichloroethane ( 1 mL), sodium triacetoxyborohydride (46.5 mg, 0.22 mmol) was added and the mixture was stirred at RT under en for 2 days. 3-Chlorofluorobenzaldehyde (25 mg, 0.157 mmol) and triacetoxyborohydride (46.5 mg, 0.219 mmol) were added to te the reaction. The reaction mixture was poured into a saturated aqueous solution of NaHC0 and extracted with CH C I . The combined organic extracts were dried (Na S0 ) , filtered and condentrated. The 2 2 2 4 crude residue diluted in MeOH was purified by SiliaPrep Tosic g (SPE-R60530B-06S from Silicycle), the column was washed with 10 mL of MeOH and the compound released with mL of 2M ammonia in MeOH to give after concentration the desired material which was further purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 m h , 19x50 mm, eluent: 20% to 100% CH3CN in H20 in 15 min, CH3CN and H20 containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the purified fractions the d material as a formic acid salt. MS (LC-MS): 462.1/464 [M+H]+, 460/462 [M-H]-; tR (HPLC, condditons f): 1.54 min.
Example 117: 3-({(S)[(3-Trifluoromethoxy-phenylamino)-methyl]-pyrrolidine-1 - carbonyl}-amino)-indolecarboxylic acid amide A. (S)[(3-Trifluoromethoxy-phenylamino)-methyl]-pyrrolidinecarboxylic acid tert- butyl ester N-(tert-Butoxycarbonyl)-L-prolinal (200 mg, 1,00 mmol) and 3-trifluoromethoxy-phenylamine (186,8 mg, 1,05 mmol) were mixed in 1,2-dichloroethane (10 mL) and treated with sodium triacetoxyborohydride (314 mg, 1,41 mmol). The mixture was d at RT under nitrogen overnight, then quenched by addition of water, extracted with CH2C I2, dried over Na2S0 4, filtered and concentrated. The crude oil was ed by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give the desired material. MS ): 361,1 [M+H]+.
B. (S)Pyrrolidinylmethyl-(3-trifluoromethoxy-phenyl)-amine A on of [(3-trifluoromethoxy-phenylamino)-methyl]-pyrrolidinecarboxylic acid tertbutyl ester (100 mg, 0.277 mmol) and TFA ( 1 mLI) in CH2C I2 (2 mL) was stirred at RT for 2 h .
Solvent was concentrated and the residue was co-evaporated twice with CH2C I2 and dried under high vacuum overnight to give the crude title compound as a TFA salt. MS: 261.1 [MH- Boc]+, tR (HPLC conditions a): 2.61 min.
C. 3-({(S)[(3-Trifluoromethoxy-phenylamino)-methyl]-pyrrolidinecarbonyl}-amino)- indolecarboxylic acid amide To a solution of (S)pyrrolidinylmethyl-(3-trifluoromethoxy-phenyl)-amine (49 mg, 0.131 mmol) and Et3N (55 m I, 0.393 mmol) in THF (1.5 mL) was added a solution of 3-isocyanato methyM H-indole (26 mg, 0.393 mmol, prepared as described in Scheme A1) in THF ( 1 .5 mL).
The resulting solution was stirred at RT under nitrogen for 1 h . The e was poured into water and extracted twice with EtOAc. The combined c layers were dried (Na2S0 ) , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters C18- ODB, 5 mhi , 19x50 mm, eluent: CH CN /H 0 + 0.1 % HCOOH, flow: 20 ml/min) to give after 3 2 lyophilisation of the purified fraction the title compound. TLC, R (c-hexane/EtOAc 1:2) = 0.23; MS (LC/MS): 462.1 [M+H]+, 484.1 [M+Na]+; t (HPLC conditions a): 3.75 min.
Example 118: xo[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl]- A. 1-{2-Oxo[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl]-ethyl}-1H- indolecarboxylic acid ethyl ester The title compound was prepared according to the general ure described in Scheme D6 using 1-carboxymethyl-1 H-indolecarboxylic acid ethyl ester (prepared as described in Part A) and DMF as t. TLC, R (EtOAc) = 0.56; MS (LC/MS): 526 [M+Na]+, 502 [M-H]-; t f R (HPLC conditions a): 3.90 min.
B. 1-{2-Oxo[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl]-ethyl}-1H- indolecarboxylic acid To a solution of 1-{2-oxo[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl]-ethyl}- 1H-indolecarboxylic acid ethyl ester (314 mg, 0.62 mmol) in MeOH (12 mL) and water (1.2 mL) was added NaOH 1N ( 1 .87 mL, 1.87 mmol) and the mixture was heated at 80°C for 6 h .
MeOH was concentrated, HCI 1N was added and the residue was extracted with EtOAc. The organic ts were dried with Na S0 , filtered and concentrated. The crude e was 2 4 purified by preparative HPLC (Interchrom C18-ODB, 10 mhi , 28x250 mm, 20% CH CN in H 0 3 2 2.5 min, then 20% to 100 % CH CN in H 0 in 32.5 min, CH CN and H 0 containing 0.1 % 3 2 3 2 HCOOH; flow: 40 mL/min) to give after lyophilization of the purified fractions the desired compound. TLC, R (EtOAc) = 0.05; MS (LC/MS): 498.1 [M+Na]+, 474.1 [M-H]- ; t (HPLC f R conditions a): 3.48 min.
C. Example 118: 1-{2-Oxo[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl]- ethyl}-1H-indolecarboxylic acid amide 1-{2-Oxo[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl]-ethyl}-1 H-indole carboxylic acid ( 1 1 mg, 0.023 mmol), was d with PyBOP (12 mg, 0.023 mmol), HOBt (3.54 mg, 0.023 mmol), DIPEA (16 m , 0.092 mmol), and NH C I ( 1 mg, 0.069 mmol) in DMF ( 1 mL) and the reaction mixture was d at RT under nitrogen for 3 h , then poured into an aqueous saturated on of NaHC0 , EtOAc (20 ml_) was added and the layers were separated. The aqueous layer was back-extracted twice with EtOAc and the combined organic ts were dried (Na S0 ) , filtered and concentrated. The crude residue was purified by 2 4 preparative HPLC (Waters SunFire C18-ODB, 5 mhi , 19x50 mm, 20% CH CN/H 0 2.5 min, 3 2 -100% CH CN/H 0 in 10 min, CH CN/H 0 containing 0.1 % HCOOH flow: 20 mL/min) to 3 2 3 2 give after lyophilization of the purified fractions the desired compound. TLC, R (CH C I /MeOH f 2 2 95:5) = 0.17; MS (LC/MS): 473.2 [M-H]-; t (HPLC conditions a): 3.24 min.
Example 119 (S)[2-(1-Acetyl-1H-indolyl)-acetyl]-pyrrolidinecarboxylic acid (3- A. (S)(2-1H-lndolyl-acetyl)-pyrrolidinecarboxylic acid (3-trifluoromethoxyphenyl )-amide The title compound was prepared according to the general procedure described in Scheme D6 using (1H-indolyl)-acetic acid using DMF as solvent. TLC, R (c-hexane/EtOAc 1:1) = 0.14; MS ): 432.3 [M+H]+, 454.1 +; t (HPLCconditions a): 3.68 min.
B. Example 119: (S)[2-(1-Acetyl-1H-indolyl)-acetyl]-pyrrolidinecarboxylic acid (3- trifluoromethoxy-phenyl)-amide To a solution of (S)(2-1H-indolyl-acetyl)-pyrrolidinecarboxylic acid (3-trifluoromethoxyphenyl )-amide (100 mg, 0.232 mmol) in DMF (1.5 mL) under nitrogen atmosphere were added acetyl chloride (148 m I, 2.09 mmol) followed by DMAP (85 mg, 0.7 mmol) and the reaction mixture was heated at 80°C for 18 h . After completion of the reaction, the mixture was poured into citric acid (10% solution), and extracted three times with EtOAc. The combined organic layers were washed twice with water, dried over Na S0 , ed and concentrated. The crude al was purified by preparative HPLC (Waters SunFire C18-ODB, 5 mhi , 19x50 mm, 20% CH CN/H 0 2.5 min, 20-100% CH CN/H 0 in 10 min, CH CN/H 0 containing 0.1 % HCOOH 3 2 3 2 3 2 flow: 20 mL/min) to give after lyophilization of the ed fractions the desired compound.
TLC, R (c-hexane/EtOAC 3:7) = 0.16; MS (LC/MS): 474.1 [M+H]+, 496 [M+Na]+, 472 [M-H]- ; t (HPLC conditions a): 3.80 min. e 120: (2S,4R)[2-(1-Acetyl-1H-indolyl)amino-acetyl]fluoro-pyrrolidine- 2-carboxylic acid 3-chlorofluoro-benzylamide A solution of {1-(1-acetyl-1 H-indolyl)[(2S,4R)(3-chlorofluoro-benzylcarbamoyl) -pyrrolidinyl]oxo-ethyl}-carbamic acid tert-butyl ester (102 mg, 0.173 mmol) and TFA (66.7 m I_ , 0.866 mmol) in CH C I (0.58 ml_) was stirred at 23°C overnight. TFA (66.7 m I_ , 2 2 0.866 mmol) was again added and the on mixture was stirred at 23°C for an additional 4 h to complete the reaction. Solvents were removed in vacuo and the crude residue was ed by preparative HPLC (Waters SunFire C180DB, 5 mhi , 19x50, eluent: 5% CH CN /95% H 0 to 100% CHsCN in 17 min, CH CN and H 0 containing 0.1% of TFA, flow 20 2 3 2 mL/min) to give after lyophilization of the purified fractions the desired material. MS (LC-MS): 487.1 [M-H]-; t (HPLC ions b): 3.19 min. f1-(1-Acetyl-1H-indolyl )r(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro- pyrrolidinvnoxo-ethyl)-carbamic acid tert-butyl ester To a solution of [2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] ( 1 H-indolyl)oxo-ethyl]-carbamic acid tert-butyl ester diastereosiomer P2 (prepared as described in Part B) (150 mg, 0.274 mmol) in dry THF (1.37 ml_) was added under argon and at 0°C, tBuOK (40 mg, 0.356 mmol). The on mixture was stirred 5 min at 0°C then acetyl chloride (25.3 m I_ , 0.356 mmol) was added and the reaction mixture was allowed to warm up to 23°C and stirred overnight. The mixture was quenched by on of an aqueous saturated solution of NaHC0 and extracted with EtOAc (x3). The organic layers were dried (Na S0 ) , 3 2 4 filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 0:100) to give the desired material. TLC, R (EtOAc) = 0.65; MS (LC-MS): 587.2 [M-H]-, 6 11 +; t (HPLC conditions b) : 5.18 min.
Scheme D4: preparation of Example 121 : (S)-Pyrrolidine-1,2-dicarboxylic acid 1-G(3- carbamoyl-indolizinyl)-amide1 2-r(3-trifluoromethoxy-phenyl)-amide1 A. 1-{[(S)(3-Trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarbonyl]-amino}- indolizinecarboxylic acid benzyl ester To a solution of (S)-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide TFA salt (328 mg, 0.845 mmol) and triethylamine (353 m I, 2.54 mmol) in THF (10 ml_) was added the crude yanato-indolizinecarboxylic acid benzyl ester (247 mg, 0.845 mmol, prepared as described in Scheme A6). The resulting mixture was stirred at RT under nitrogen over the week-end then poured into HCI 1 N and extracted with EtOAc (x3). The ed organic extracts were washed with an aqueous saturated solution of NaHC0 , dried (Na S0 ) , filtered 3 2 4 and concentrated. The crude mixture was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to c-hexane/EtOAc 3:7) to afford the desired compound. TLC, R (c- hexane/EtOAc 1:1) = 0.3; MS (LC/MS): 567.3 [M+H]+ 565.2 [M-H]-; t (HPLC conditions a ) : 4.16 min. - 1-{[(S)(3-Trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarbonyl]-amino}- indolizinecarboxylic acid To 1-{[(S)(3-Trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarbonyl]-amino}-indolizine carboxylic acid benzyl ester (100 mg, 0.177 mmol) dissolved in THF (3 ml_) was added Pd/C % (20 mg). Air was removed from the flask under vacuum and replaced with nitrogen three times, finally en was removed and replaced with en and the mixture was stirred at RT for 5 h . Hydrogen was removed and replaced by nitrogen, the catalyst was removed by filtration through a pad of Celite and washed with THF. Solvents were concentrated to give a mixture containing the desired compound contaminated with 20% of the decarboxylated analog. The mixture was used t further purification in the next step. LC/MS : 475 ; t (HPLC conditions a): 3.41 min.
C. Example 121 : (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizinyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide] To a solution of 1-{[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarbonyl]-amino}- indolizinecarboxylic acid ning 20% of the decarboxylated analog (65 mg, 0.136 mmol), NH C I (8.80 mg, 0.164 mmol) and HBTU (78 mg, 0.205 mmol) in DMF (2.5 mL) was added DIPEA (49 m I, 0.287 mmol) and the resulting solution was stirred at RT under en overnight. After completion of the reaction, the mixture was poured into HCI 1 N and extracted with EtOAc (x3). The combined organic extracts were washed with water (x2), dried (Na S0 ) , filtered and concentrated. The crude residue was purified by preparative HPLC s SunFire C18-ODB, 5 m , 19x50 mm, 20% CH CN/H 0 2.5 min, 20-100% CH CN/H 0 in 10 3 2 3 2 min, CH CN/H 0 containing 0.1 % HCOOH flow: 20 mL/min) to give after lyophilization of the 3 2 purified ons the desired compound as a powder. TLC, R (CH C I /MeOH 9:1) = 0.4; MS f 2 2 (LC/MS): 476 [M+H]+, 498.1 [M+Na]+, 474.1 [M-H]-; t (HPLC conditions a): 3.30 min.
Example 122: (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoylindolizin-1 -yl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] The title compound was prepared according to the same procedure as described in Scheme D4 starting from (S)-pyrrolidine-1 ,2-dicarboxylic acid 1-[(3-carbamoyl-indolizinyl)-amide] 2- [(3-trifluoro methoxy-phenyl)-amide]. MS: 494 [M+H]+, 492.1 [M-H]-; t (HPLC conditions a): 1.87 min.
Example 123: (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-indolizinyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] The title compound was prepared from yanato-indolizinecarboxylic acid benzyl ester (prepared as described in Scheme A7) using the ol described in Scheme D4. TLC, R (CH C I /MeOH 9:1) = 0.4; MS (LC/MS): 476 [M+H]+, 498.1 [M+Na]+, 474.1 ; t (HPLC 2 2 R conditions a): 3.13 min.
Scheme D5: general protocol described for the preparation of Example 124: (S)- pyrrolidine-1,2-dicarboxylic acid 1-r(1-carbamoyl-1H-indolyl)-amide1 2-G(3- trifluoromethoxy-phenvD-amidel A . (S)(3-Trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarboxylic acid tert-butyl ester To a mixture of Boc-L-proline (5 g , 23.23 mmol), 3-(trifluoromethoxy)aniline (3.73 ml_, 27.88 mmol) and HBTU (13.2 g , 34.8 mmol) in DMF (60 ml_) was added DIPEA (7.95 ml_, 46.5 mmol) and the resulting yellow solution was stirred at RT under nitrogen. The solvent was concentrated under vacuum and the residue dissolved in EtOAc and washed with HCI 1N. The combined organic layers were lized by addition of an aqueous saturated solution of NaHC0 . The layers were separated and the aqueous one back-extracted twice with CH C I . 3 2 2 The combined organic extracts were dried (Na S0 ) , filtered and concentrated. The crude 2 4 residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:1 to 2:1) to give the desired compound. TLC, R (c-hexane/EtOAc 1:1) = 0.57; MS (LC/MS): 397.1 [M+Na]+, 275.2 [MH-Boc]+, 373.3 [M-H]-; t (HPLC conditions a) 3.81 min.
Dichloromethane can also be used instead of DMF.
B. rrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide To a solution of (S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarboxylic acid tertbutyl ester (8.52 g , 22.6 mmol) in CH C I (50 ml_) was added TFA (8.65 ml_, 113 mmol) and 2 2 solution was d at RT for 12 h . The crude reaction mixture was concentrated under , Et 0 was added and the white precipitate was filtered off to give the desired compound as a TFA salt. MS (LC/MS): 275.2 [M+H]+, 273.3 [M-H]-; t (HPLC conditions a) 2.47 min.
C. Example 124: (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide] To a on of (S)-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide trifluoroacetate (328 mg, 0.845 mmol) and Et N (353 m I, 2.53 mmol) in THF (7.5 mL) was added a suspension of 3-isocyanato-indolecarboxylic acid amide (170 mg, 0.845 mmol, prepared as described in Scheme A1) in THF (7.5 mL). The resulting solution was d at RT under nitrogen for 1 h , poured into water and the e was extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 mhi , 19x50 mm, 20% CH CN/H 0 2.5 min, 20-100% CH CN/H 0 in 10 min, CH CN/H 0 containing 0.1 % HCOOH 3 2 3 2 3 2 flow: 20 mL/min) to give after lyophilization of the purified HPLC fractions the title compound.
TLC, R (c-hexane/EtOAc 1:2) = 0.1 1; MS ): 476.2 [M+H]+, 973.2 ]+.
The es below were prepared according to the general procedures described in Scheme D5 for the preparation of e 124 from commercially available building blocks, if not otherwise stated (see notes at the end of table 4): Table 4 :Table 4: Characterization (end—table notes), TLC, Rf (eluent); MS (LC/MS); Example Structure Name tR (HPLC conditions); 19F NMR (100 MHz, solvent) 6 (ppm): )Cyano-pyrro|idine- 1,2 dicarboxylic acid 1-[(1- 501.1 [M+H]+; tR (b): carbamoyI-1H-indoIy|)- 4.07 min. amide] 2-[(3-trif|uoromethoxy- pheny|)-amide] (2S,3R)—3-Methy|—pyrrolidine- (7) R (EtOAc) = 0.5; 1,2-dicarboxylic acid 1-[(1- 472.1/474.2 [M+H]+, carbamoyI-1H-indoIy|)- 427/429 [M-CONH2]- amide] 2-(3-chlorofluoro— ;tR (a): 3.24 min. benzylamide) (9) R (EtOAc) = (1 -CarbamoyI{[(1 R,3S,5R)- 0.44; 584.4/586.4 3-(3-chlorofluoro- [M+H]+, 582.7/584.4 benzylcarbamoyl)—2-aza- [M-H]-, 539.4/541.4 o[3.1.0]hexane [M-CONH2]-, carbony|]-amino}-1H-indol-6— 6284/6304 etic acid tert-butyl ester [M+HCOO]-; tR (f): 2.20 min. (2S,4S)Methoxy-pyrro|idine- 1,2-dicarboxylic acid 1-[(1- 506.2 , 504.1 carbamoyI-1H-indoIy|)- [M-H]-; tR (a): 3.43 amide] 2-[(3-trif|uoromethoxy- min. pheny|)-amide] (5, 8[B9],9[A1]) Rf (EtOAc) = 0.45; (1 R,3S,5R) 499.4/501.3 , Azabicyclo[3.1.0]hexane-2,3- 521.3/523.4 dicarboxylic acid 2-[(1-acety|- [M+Na]+, 1H-indol-3—yI)-amide] 3-{[(S) 543.3/545.4 orofluoro—phenyl)- [M+HCOO]—, 2hydroxy-ethy|]-amide} 497.5/499.8 [M-H]—; tR (a): 1.95 min. (1 R,3S,5R) Azabicyclo[3.1.0]hexane-2,3- (9[A2]) Rf (EtOAc) = dicarboxylic acid hloro 0.3; 484.4 [M+H]+, fluoro-benzylamide) 2-[(1- 484.4 [M+HCOO]—; tR methylcarbamoyI-1H-indol-3— (a): 3.34 min. y|)-amide] (2S,4R)Hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(1- 492.1 , 490.1 carbamoyI-1H-indoIy|)- [M-H]-; tR (a): 3.08 amide] 2-[(3—trif|uoromethoxy- min. phenyI)-amide] (8[B13],9) Rf(EtOAc) (2S,4R)-4—FIuoro—4—methyl- = 0.35; 550.5/552.4 pyrrolidine-1,2-dicarboxylic [M+H]+, 572.3/574.5 acid carbamoy|(2- [M+Na]+, methoxy-ethoxy)-1H-indol-3— 548.4/550.4 [M-H]-, y|]-amide} 2-(3—chlorofluoro— 594.4/596.4 amide) [M+HCOO]-; tR (f): 1.82 min. (1-Carbamoyl-3—{[(1R,3S,5R)- (9) R (EtOAc) = 0.2; 3-(3-chlorofluoro— 558.1/560.2 [M+H]+, benzylcarbamoyI)aza- 580/582.1 [M+Na]+, bicyc|o[3.1.0]hexane 513.1/515 [M- carbonyl]-amino}-1H-indoI CONH2]-; tR (f): 1.87 y|oxy)-acetic acid methyl ester min. (1 S,3S,5S)Aza— bicyclo[3.1.0]hexane-2,3- Rf (c-hexane/EtOAc dicarboxylic acid 2-[(1- 1:2) = 0.15, 488.2 carbamoyI-1H-indoIyl)- [M+H]+, 486.1 [M-H]— amide] 3-[(3-trifluoromethoxy- ;tR (a): 3.59 min. phenyI)-amide] (1 S,2S,5R)Azabicyclo [3.1.0]hexane-2,3- 470 , 425 [M- dicarboxylic acid 3-[(1- CONH2]-; tR (f): 1.84 carbamoyI-1H-indoIyl)- min. amide] 2-(3-chlorofluoro— benzylamide) 2-Aza-bicyc|o[2.1.1]hexane- (1) White solid. 1,2-dicarboxylic acid 2-[(1- Rf (EtOAc) = 0.2; carbamoyI-1H-indoIyl)- 470/473 [M]+; tR (c): amide] 1-(3-chlorofluoro— 4.51 min. benzylamide) ) Rf (C- (2S,4S)Methyl-pyrrolidine- hexane/EtOAc 1:3) = 1,2-dicarboxylic acid 1-[(1- 0.44; 487.9 [M-H]-, carbamoyI-1H-indoIyl)- 446.0 [M-CONH2]-; amide] 2-[(3-trifluoromethoxy- tR (c): 4.51 min. phenyI)-amide] (2S,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 2-(3- (1,6) 522.0 [M+H]+; bromo—2-fluoro-benzylamide) tR (c): 4.38 min. 1-[(1-carbamoy|—1H-indoIyl)- amide] (2S,5R)(Acety|amino— methyl)-pyrrolidine—1,2- (8[B4]) 547 [M+H]+; oxylic acid 1-[(1- tR (b): 4.05 min. carbamoyI-1H-indoIyl)- amide] 2-[(3-trifluoromethoxyphenyI )-amide] (R)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyI-1H-indol- 476.1 [M+H]+, 498.1 3-yI)-amide] 2-[(3- +, 474.1 [M- trifluoromethoxy-pheny|)- H]-; 1R (a): 8.47 min. amide] (1 S*,28*,5R*)Azabicyclo [3.1.0]hexane-2,3- 488.2 , 510.1 dicarboxylic acid 3-[(1- [M+Na]+; 1R (a): 8.52 carbamoyI-1H-indoIyl)- amide] 2-[(3-trifluoromethoxy- phenyI)-amide] (S)-Thiazolidine-2,3- oxylic acid 3-[(1- (1,6) White solid. carbamoyI-1H-indoIyl)- 510 [M+H]+; tR (b) amide] 2-[(2-f|uoro 4.36 min. trifluoromethoxy-pheny|)- amide] 3-Chloro{[(28,4R)(1- carbamoyI-1H-indol (1) 500 [M+H]+; tR y|carbamoy|)f|uoro— (b): 3.96 min. pyrrolidinecarbonyI]-amino}- benzoic acid methyl ester 3-({[(28,4R)(1-Carbamoyl- 1H-indoIylcarbamoyI) (8) 520.0 [M]+; tR (c): fluoro-pyrrolidinecarbonyl]- 3.05 min amino}-methy|)ch|oro—4— fluoro-benzoic acid (8)-2,5-Dihydro-pyrrole-1,2- 474.1 [M+H]+, 969.2 dicarboxylic acid 1-[(1- [2MH+Na]+, 472.1 carbamoyI-1H-indoIyl)- [M-H]-; tR (a): 8.88 amide] 2-[(3-trifluoromethoxy- min. phenyI)-amide] (1 R,2S,5S)-6—Oxa-3—azabicyc |o[3.1.0]hexane-2,3- (8[B19]) 472 [M+H]+; dicarboxylic acid 3-[(1- tR (f): 1.76 min; 19F carbamoyI-1H-indoIy|)- NMR (CD30D): -124. amide] 2-(3-chlorofluoro— benzylamide) (2S,4S)-4—Trif|uoromethyl- (1) Off-white solid. Rf pyrrolidine-1,2-dicarboxylic (EtOAc) = 0.30; acid 1-[(1-carbamoy|-1H-indol- 526.0 ; tR (c): amide] 2-(3—chloro—2- 4.88 min. fluoro-benzylamide) (1 R,3S,5R)Aza— (1) 4819/4830 bicyc|o[3.1.0]hexane-2,3- [M+H]+, 4819/4828 dicarboxylic acid bromo- [M-H]-, 4369/4389 )-amide] 2-[(1- [M-CONH2]-; tR (b) carbamoyI-1H-indoIy|)- 4.20 min. amide] (1 S,5R)Azabicyc |o[3.1.0]hexane-1,2- (1) White solid. Rf dicarboxylic acid 2-[(1- (EtOAc) = 0.43; 470 carbamoyI-1H-indoIy|)- [M+H]+; tR (c): 4.49 amide] hlorofluoro— min. benzylamide) (2S,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 2-[(3— (1) 487/489 [M+H]+; bromo—phenyI)-amide] 1-[(1- tR (b): 3.64 min. carbamoyI-1H-indoIy|)- amide] (R)-2,2-DimethyI-thiazolidine- Rf (c-hexane/EtOAc 3,4-dicarboxy|ic acid 3-[(1- 1:3) = 0.51; 522.1 carbamoyI-1H-indoIy|)- [M+H]+, 520.2 [M-H]— amide] 4-[(3—trifluoromethoxy- ;tR (c): 5.39 min. phenyI)-amide] (S)-Pyrro|idine—1,2—dicarboxylic 493 [M+H]+; tR (j) acid carbamoyI-1H-indol- 2.90 min. amide] 2—[(4'-cyano— biphenyl-3—yI)-amide] Rf (EtOAc) = 0.75; 3-Bromo{[(28,4R)(1- 546.1/548.1 [M+H]+, carbamoyl-1H-indol-3— 568.1/570 [M+Na]+, y|carbamoy|)f|uoro— 544/546 [M-H]—, pyrrolidine—2—carbonyI]-amino}- 500/502 [M-CONH2]- benzoic acid methyl ester ;tR (a): 3.33 min. (28,4R)F|uoro-pyrro|idine— 1,2—dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (3,6[C3]) 590.2 [M]+; amide] 2—[3—chloro(2— tR (c): 3.59 min. dimethylamino—ethylcarba— moy|)f|uoro-benzylamide] (1 R,3S,5R)-2—Aza— bicyclo[3.1.0]hexane-2,3- 458 , 455 [M- dicarboxylic acid 2—[(1- H]-, 413 HZ]; carbamoyI-1H-indoIy|)- tR (f): 1.99 min. amide] 3-[(5-ch|oro-thiophen- 2—ylmethy|)-amide] 2—Bromo-4—{[(28,4R)(1- carbamoyl-1H-indol-3— (1) 546/548 [M+H]+; y|carbamoy|)f|uoro— tR (b): 3.55 min. pyrrolidine—2—carbonyI]-amino}- benzoic acid methyl ester (28,4R)Methy|—pyrro|idine- (8[82]) Rf(c' 1,2—dicarboxylic acid 1-[(1- hexane/EtOAc 1:3) = carbamoyI-1H-indoIy|)- 0.44; 489.1 [M-H], amide] 2—[(3—trifluoromethoxy- 445.0 [M-CONH2]-; phenyI)-amide] tR (c): 4.65 min. (1 R,3S,5R)-2—Aza— 433.1 [M+H]+ 432.1 bicyclo[3.1.0]hexane-2,3- [M-H]-; tR (a): 2.49 dicarboxylic acid 2—[(1- min. carbamoyI-1H-indoIy|)- -3o4- amide] 3—[(6-ethy|-pyridiny|)- amide] (8[B7]) Rf (CHZCIZ/MeOH 4:1) 3—Bromo{[(28,4R)—1-(1- = 0.23; 532.0/534.0 carbamoyl-1H-indol-3— [M+H]+, 554.0/556.0 y|carbamoy|)f|uoro— [M+Na]+, pyrrolidine—2—carbonyI]-amino}- 322 [M-H]-, benzoic acid 486.9/489.0 [M- CONH2]-; tR (a): 2.98 min.
Rf (c-hexane/EtOAc (S)-Pyrro|idine—1,2—dicarboxylic 1:2) = 0.32; 455.2 acid 2-[(4-tert-butyI-thiazol [M+H]+, 909.2 y|)-amide] 1-[(1-carbamoy|—1H- +, 453.1 [M- indoIy|)-amide] H]-; tR (H a): 3.5 min.
(R)—Thiazolidine—3,4— Rf (c-hexane/EtOAc dicarboxylic acid 3—[(1- 1:3) = 0.42; 494.0 carbamoyI-1H-indoIy|)- [M+H]+, 492.1 [M-H]— amide] 4-[(3-trif|uoromethoxy- ;tR (c): 5.03 min. pheny|)-amide] (1 R)—2-Aza— (9) Rf(EtOAc) = 0.3; o[3.1.0]hexane-2,3- 5442/546.1 [M+H]+, dicarboxylic acid 2—{[1- 566/568.1 [M+Na]+, carbamoyI(2-methoxy- 542 [M-H]—, 499.1 ethoxy)-1H-indoIy|]-amide} [M-CONH2]-; tR (f): 3—(3-chloro-2—fluoro— 1.85 min. benzylamide) )—4—F|uoro-pyrro|idine— 1,2—dicarboxylic acid 1-[(1- 439.1 [M+H]+, 899.2 carbamoyI-1H-indoIy|)- [2M+Na]+, 437.0 [M- amide] 2—[(6-ethy|-pyridiny|)- H]-; tR (a): 2.32 min. amide] (28,4S)-4—Hydroxymethy|— (8[B13]) Rf (EtOAc) pyrrolidine-1,2-dicarboxylic = 0.21; 901 acid 1-[(1-carbamoyI-1H-indol- [M+H]+, 488.1 3-y|)-amide] 2-(3—chloro—2- [M-H]-; 1R (f): 1.75 fluoro-benzylamide) min. (28,4R)F|uoro-pyrro|idine— (4) R (EtOAc) = 1,2-dicarboxylic acid 1-[(1- 0.38; 508/505 carbamoyI-1H-indoIy|)- [M+H]+; 1R (c): 3.70 amide] 2-[(5-bromomethy|— pyridinyI)-amide] (1 R,3S,5R)Aza— bicyc|o[3.1.0]hexane-2,3- dicarboxylic acid 2-[(1- 470 [M+H]+; tR(b): oyI-1H-indoIy|)- 3.87 min. amide] 3-(3-chlorofluoro— benzylamide) (1 R*,28*,5S*)Aza- bicyc|o[3.1.0]hexane-2,3- 452.0 [M+H]+, 407.0 dicarboxylic acid 3-[(1- [M-CONH2]-; tR (a): carbamoyI-1H-indoIy|)- 3.16 min. amide] hloro- amide) (28,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 2-[(5- 505.0 [M+H]+; tR (c): bromomethyl-pyridin-3—yl)- 3.67 min. amide] 1-[(1-carbamoyI-1 H- indoIyI)-amide] (S)-Thiazolidine-2,3- 460.1 [M+H]+, 941.2 dicarboxylic acid 3-[(1- [2M+Na]+, 415.0 [M- carbamoyI-1H-indoIy|)- CONH2]-; 1R (a): 8.11 amide] 2-(2,3-dif|uoro— min. benzylamide) (S)-Pyrro|idine—1,2-dicarboxylic acid 1-[(1-carbamoyI-1H-indol- 458.0 [M+H]+, 1R 3-y|)-amide] 2-(3—chloro—2- (b): 8.70 min. fluoro-benzylamide) (1 R,3S,5R)—2—Aza— bicyclo[3.1.0]hexane-2,3- (4) White solid. Rf oxylic acid 2—[(1- (EtOAc) = 0.48; oyl-1H-indolyl)- 483/485 ; tR amide] 3-[(5-bromo-pyridin (c): 4.08 min. yl)-amide] (1 R,3S,5R)—2—Aza— bicyclo[3.1.0]hexane-2,3- (4) ite solid. Rf dicarboxylic acid 2—[(1- (CHzClz/MeOH 95/5) carbamoyl-1H-indolyl)- = 0.21; 423 [M+H]+; amide] 3-[(3—fluoro-pyridin-2— be (c): 3.59 min. yl)-amide] Rf (EtOAc) = 0.5; (1 R,3S,5R)—2— 436.4/438.5 [M+H]+, Azabicyclo[3.1.0]hexane-2,3- 871 .7/873.7 dicarboxylic acid 2—[(1- [2M+H]+, carbamoyl-1H-indolyl)- 480.4/482.4 amide] 3-(2-fluoro- [M+HCOO]-; tR (f): benzylamide) 1.77 min.
(S)—Thiazolidine-2,3- dicarboxylic acid 3-[(1- 458 [M+H]+; tR (a): carbamoyl-1H-indolyl)- 3.17 min. amide] 2—(3-chlorobenzylamide (1 R,3S,5R)—2—Aza— bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 2—[(1- (1,6) White solid. carbamoyl-1H-indolyl)- 506 [M+H]+; tR (b) amide] 3-[(2-fluoro 4.47 min. trifluoromethoxy-phenyl)- amide] (1 R)—2—Aza— bicyclo[3.1.0]hexane-2,3- (1) White solid. dicarboxylic acid 2—[(1- 456 [M+H]+; tR (b): carbamoyl-1H-indolyl)- 4.14 min. amide] 3-[(3-chlorofluoro- phenyl)-amide] (28,3R)—3-Hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(1- (1) White solid. 456 carbamoyI-1H-indoIy|)- [M+H]+; tR (b): 2.84 amide] 2-(3-chloro- min. benzylamide) (S)-Thiazo|idine-2,3- oxylic acid 3-[(1- 475.9 [M+H]+, 498 carbamoyI-1H-indoIy|)- [M+Na]+; 1R (b): 3.89 amide] hlorofluoro— min. benzylamide) (28,5R)—5-Azidomethyl- pyrrolidine-1,2-dicarboxylic (8[B3]) 531.1 acid 1-[(1-carbamoyI-1H-indol- [M+H]+; tR (b): 4.85 3-y|)-amide] 2-[(3- min. trifluoromethoxy-pheny|)- amide] (S)Aza-spiro[2.4]heptane— ,6-dicarboxylic acid 5-[(1- 466.1 [M+H]+, 421.1 carbamoyI-1H-indoIy|)- [M-CONH2]-, tR (a): amide] 6-(3-chloro— 3.26 min. benzylamide) (28,4R)—4-F|uoro-4— (8[B12]) Rf (EtOAc) ymethyI-pyrrolidine-1,2- = 0.15; 508.1 dicarboxylic acid 1-[(1- [M+H]+, 528.1/530.2 carbamoyI-1H-indoIy|)- [M+Na]+, 504.1/506 amide] 2-(3-chlorofluoro— [M-H]-; tR (f): 1.69 benzylamide) min.
)Methyl-pyrrolidine- (1, 8[B2]) Rf (EtOAc) 1,2-dicarboxylic acid 1-[(1- = 0.51; 472.0 carbamoyI-1H-indoIy|)- [M+H]+; tR (c): 4.62 amide] 2-(3-chlorofluoro— min. benzylamide) (1 R,3S,5R)—2-Aza— bicyclo[3.1.0]hexane-2,3- 452/454 [M+H]+; tR dicarboxylic acid 2-[(1- (a): 3.16 min; tR (b): carbamoyI-1H-indoIy|)- 3.78 min. amide] 3-(3-chloro- (1 R,3S,5S)Methoxymethyl- (5,8) Rf (EtOAc) = 2-aza-bicyc|o[3.1.0]hexane- 0.20; 514.4/516.4 carboxylic acid 2-[(1- [M+H]+, 512.3 [M-H]— carbamoyI-1H-indoIy|)- ;tR (a): 3.27 min. amide] 3-(3-chlorofluoro— benzylamide) (1 R,3S,5R)Aza— bicyc|o[3.1.0]hexane-2,3- (4) R (EtOAc) = dicarboxylic acid 2-[(1- 0.23; 423 [M+H]+; tR carbamoyI-1H-indoIy|)- (c): 3.4 min. amide] 3-[(3-f|uoro-pyridin-4— y|)-amide] (2S,3R)Methoxy-pyrrolidine- (8) White solid. 488 1,2-dicarboxylic acid 1-[(1- [M+H]+; tR (b): 3.61 carbamoyI-1H-indoIy|)- min. amide] 2-(3-chlorofluoro— benzylamide) (S)-Piperidine-1,2-dicarboxylic Rf (c-hexane/EtOAc acid 1-[(1-carbamoyI-1H-indol- 1:2) = 0.21; 490.1 3-y|)-amide] 2-[(3- [M+H]+, 1001.2 trifluoromethoxy-pheny|)- [2M+Na]+, 488.1 [M- amide] H]-; tR (a): 3.75 min. (2S,4S)Cyano-pyrro|idine- (2 at 50°C,3,6) 1,2-dicarboxylic acid 1-[(1- Rf (EtOAc) = 0.45; oyI-1H-indoIy|)- 519.1 [M+H]+, 541.0 amide] 2-[(2-f|uoro [M+Na]+, 517.2 [M- trifluoromethoxy-pheny|)- H]-; 1R (f): 1.93. amide] (2R,3S,4R)Dimethylamino— (8[320]) Rf ro-pyrrolidine—1 ,2- (CHZCIZ/MeOH 95/5) dicarboxylic acid 1-[(1- = 0.26; 519 [M+H]+, oyI-1H-indoIy|)- 563 [M-HCOO]—; tR amide] 2-(3-chlorofluoro— (f): 1.51 min. benzylamide) (2R,3R)F|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- (8) White solid. 476 carbamoyI-1H-indoIy|)- [M+H]+; tR (b): 3.66 amide] 2-(3-chlorofluoro— min. benzylamide) (2S,4R)F|uoro-pyrro|idine— Rf (c-hexane/EtOAc 1,2-dicarboxylic acid 1-[(1- 1:2) = 0.33; 494.0 carbamoyI-1H-indoIy|)- [M+H]+, 492.1 [M-H]— amide] 2-[(3-trifluoromethoxy- ;tR (a): 3.41 min. phenyI)-amide] (S)Methy|—pyrrolidine-1,2- dicarboxylic acid 1-[(1- 490.1 [M+H]+, 512.2 carbamoyI-1H-indoIy|)- [M+Na]+; 1R (a): 3.61 amide] 2-[(3-trifluoromethoxy- min. phenyI)-amide] (2S,4R)F|uoro-pyrro|idine— (4) Rf (C- 1,2-dicarboxylic acid 1-[(1- hexane/EtOAc 1:3) = oyI-1H-indoIy|)- 0.12; 445 [M+H]+; tR amide] ch|oro-pyridin (b): 3.79 min. y|)-amide] (2S,4R)F|uoro-pyrro|idine— (4) Rf (C- 1,2-dicarboxylic acid 1-[(1- hexane/EtOAc 1:3) = carbamoyI-1H-indoIy|)- 0.1; 491 [M+H]+; tR amide] 2-[(5-bromo-pyridin (c): 3.85 min. y|)-amide] (1 R,3S,5R)Aza— bicyc|o[3.1.0]hexane-2,3- 454.1 [M+H]+, 929.3 dicarboxylic acid 2-[(1- [2M+Na]+, 409.1 [M- carbamoyI-1H-indoIy|)- CONH2]-; tR (a): 3.09 amide] 3-(2,3-difluoro- min. benzylamide) (2S,4R)Hydroxy-4— hydroxymethyI-pyrrolidine-1,2- (8[B12]) 504 [M+H]+, dicarboxylic acid 1-[(1- 502 [M-H]—; tR (f): oyI-1H-indoIy|)- 1.57 min. amide] hlorofluoro— benzylamide) (1 S,28,5R)-6—Oxaazabicyclo [3.1.0]hexane-2,3- (8[B19]) 472 [M+H]+; dicarboxylic acid 3-[(1- 1R (f): 1.54 min; 19F carbamoyI-1H-indoIyl)- NMR ): -124. amide] 2-(3-chloro—2-fluoro— benzylamide) 3-Bromo{[(S)(1- carbamoyI-1H-indol (1) 5442/5462 y|carbamoy|)-thiazo|idine [M+H]+; 1R (b): 4.26 carbonyI]-amino}-benzoic acid min. methyl ester (S)-Pyrro|idine-1,2-dicarboxylic Rf (EtOAc) = 0.26; acid carbamoyI-1H-indol- 472.1 , 470.2 3-yI)-amide] 2-[(2-methy| [M-H]-; 1R (a): 3.07 -2H-pyrazoIyI)-amide] min. (3S,5S)(1-CarbamoyI-1H- (8) 516 [M+H]+, 54o indoIylcarbamoyI)(3- [M+Na]+; 1R (b): 3.37 chlorofluoro— min. benzylcarbamoyI)-pyrro|idine- 3-carboxylic acid methyl ester 4,5-Dihydro—pyrazoIe-1,5- (8[B5]) Rf dicarboxylic acid 1-[(1- (CHZCIZ/acetone 1:1) carbamoyI-1H-indoIyl)- = 0.53; 457.0 amide] 5-(3-chlorofluoro— [M+H]+; tR (b) : 3.77 benzylamide) min. (28,4S)Hydroxy hydroxymethyI-pyrrolidine-1,2- (8[B12]) 504 [M+H]+, dicarboxylic acid 1-[(1- 502 [M-H]—; tR (f): carbamoyI-1H-indoIyl)- 1.60 min. amide] 2-(3-chloro—2-fluoro— benzylamide) (1 R,3S,5R)Aza— (5,8[BQ]) Rf bicyclo[3.1.0]hexane-2,3- (CHZCIZ/MeOH 955) dicarboxylic acid 2-[(1- = 0.2; 498.1/500.4 carbamoyI-1H-indoIyl)- [M-H]-, 543.8 amide] 3-{[(S)(3-chloro—2- [M+HCOO]-, 500.2 -phenyI)hydroxy- [M+H]+, 522/5227 ethy|]-amide} [M+Na]+; 1R (a): 1.81 min. (28,38,4S)Fluor0 methoxy-pyrrolidine—1,2- (8[B24]) 506 [M+H]+, dicarboxylic acid 1-[(1- 550 [M+HCOO]-; tR carbamoyI-1H-indoIy|)- (f): 1.87 min. amide] 2-(3-chlorofluoro— benzylamide) (8[B13]) TLC, Rf (2S,4R)-4—FIuoro—4—methyl- (EtOAc) = 0.45; pyrrolidine-1,2-dicarboxylic 490.1/492.1 [M+H]+, acid 1-[(1-carbamoyI-1H-indol- 488/490 , 3-y|)-amide] 2-(3—chloro—2- 445/447.1 [M- fluoro-benzylamide) CONH2]-; 1R (f): 1.89 min. (2S,3S,4S)Acetylamino—4- (8[BZ3]) Rf -pyrrolidine—1,2- (CHZCIZ/MeOH 95/5) dicarboxylic acid 1-[(1- = 0.26 ; 531 , carbamoyI-1H-indoIy|)- 533 [M-H]—; tR (f): amide] 2-(3-chlorofluoro— 1.72 min. benzylamide) (1 S,2S,5R)-3— Azabicyclo[3.1.0]hexane-2,3- (5,8[BQ]) Rf (EtOAc) dicarboxylic acid 3-[(1- = 0.25; 500.3 carbamoyI-1H-indoIy|)- [M+H]+, 544.3/546.4 amide] 2-{[(S) [M+HCOO]-; tR (a): (3-ch|orof|uoro—phenyI) 2.93 min. hydroxy-ethy|]-amide} (2R,3S)F|uoro-pyrro|idine— (8) White solid. 476 1,2-dicarboxylic acid 1-[(1- [M+H]+; 1R (b): 3.86 oyI-1H-indoIy|)- min. amide] 2-(3-chlorofluoro— benzylamide) (2S,4R)F|uoromorpho|in- 4-y|methy|-pyrro|idine-1,2- (8[B14]) 575 [M+H]+, dicarboxylic acid 1-[(1- 502 [M-H]—; tR (f): carbamoyI-1H-indoIy|)- 1.53 min. amide] 2-(3-chlorofluoro— benzylamide) (1 R,2S,5S)Aza- Rf ) = 0.45; bicyc|o[3.1.0]hexane-2,3- 470.4/472.4 [M+H]+, dicarboxylic acid 3-[(1- 468.3/470.3 [M-H]-, oyI-1H-indoIy|)- 514.4/516.5 amide] 2-(3-chlorofluoro— O]-; tR (a): benzylamide) 3.21 min. ,4R)Acety|amino—3- (8[B23]) Rf (EtOAc) fluoro-pyrrolidine—1,2- = 0.26 ; 531 [M+H]+, dicarboxylic acid 1-[(1- 533 [M-H]—; tR (f): carbamoyI-1H-indoIy|)- 1.74 min. amide] 2-(3-chlorofluoro— benzylamide) (1 R,2S,5S) Azabicyclo[3.1.0]hexane-2,3- (5,8[BQ]) Rf (EtOAc) dicarboxylic acid 3-[(1- = 0.3; 520.3 [M+H]+, carbamoyI-1H-indoIy|)- 564.3/566.3 amide] 2-{[(S)(3-ch|oro—2- [M+HCOO]-; tR (a): -phenyI)hydroxy- 3.0 min. ethy|]-amide} (2S,3R)Hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(1- (1) White solid. 474 carbamoyI-1H-indoIy|)- [M+H]+; 1R (b): 3.11 amide] 2-(3-chlorofluoro— min. benzylamide) (5,8) White solid. Rf (1 R)-5—Methoxymethyl- (EtOAc) = 0.20; 2-aza-bicyc|o[3.1.0]hexane- 514.4/516.4 [M+H]+, 2,3-dicarboxy|ic acid 2-[(1- 512.4 [M-H]-, carbamoyI-1H-indoIy|)- 558.3/560.3 amide] 3-(3-chlorofluoro— [M+HCOO]-; tR (a): benzylamide) 3.27 min. (28,4R)F|uoro-pyrro|idine— 1,2—dicarboxylic acid 1-[(1- (1) White solid. 443 carbamoyI-1H-indoIyl)- [M+H]+; tR (b): 3.15 amide] 2—[(5—f|uoro-pyridin min. y|methy|)-amide] (1 R,3S,5R)-2—Aza— (9[A1]) Rf (EtOAc) = bicyclo[3.1.0]hexane-2,3- 0.45; 500/502.2 dicarboxylic acid 2—[(1- [M+H]+, 455.2/457.2 carbamoyImethoxy-1H- [M-CONH2]-; tR (f): indoIyI)-amide] 3-(3-chloro— 1.90 min. 2—fluoro-benzylamide) (1 R)-2— (5) R (EtOAc) = Azabicyclo[3.1.0]hexane-2,3- 0.25; 5263/5283 oxylic acid 3-{[(S) [M+H]+, 570.4/572.4 (3-bromo—phenyI)hydroxy- [M+HCOO]-; tR (a): ethy|]-amide} 2—[(1-carbamoy|— 3.1 min. 1H-indoIyI)-amide] (1 R,3S,5R)-2—Aza— bicyclo[3.1.0]hexane-2,3- (1) White solid. oxylic acid 2—[(1- 490 [M+H]+; tR (b): carbamoyI-1H-indoIyl)- 4.39 min. amide] 3-[(2-f|uoro—3- trifluoromethyI-phenyI)-amide] 3-{[(S)(1-Carbamoy|—1H- 450.1 [M+H]+, 473.0 indol-3—ylcarbamoyl)- [M+Na]+, 899.2 idine—2—carbonyl]—amino}- [2M+H]+, 448.1 [M- c acid methyl ester H]-; tR (a): 3.03 min.
(S)-Piperidine-1,2—dicarboxylic (1) 472 [M+H]+, 494 acid 1-[(1-carbamoyI-1H-indol- [M+Na]+; tR (c): 4.72 3-y|)-amide] 2—(3-chloro—2— min. fluoro-benzylamide) (28,4S)(Acety|amino- (8) 531 [M+H]-, 533 methy|)f|uoro—pyrrolidine- [M+H]+; tR (f): 0.56 1,2—dicarboxylic acid 1-[(1- min; 19F NMR oyI-1H-indoIy|)- (DMSO-de): -121, - amide] 2—(3-chlorofluoro— 150. benzylamide) (28,4R)F|uoro-pyrro|idine— carboxylic acid 1-[(1- (1) White solid. 51o carbamoyI-1H-indoIy|)- [M+H]+; tR (b): 3.88 amide] 2—(2-fluoro-3— min. trifluoromethyI-benzylamide) (1 R,3S,5R)—2— Azabicyclo[3.1.0]hexane-2,3- (5,8[B9]) Rf ) dicarboxylic acid 2—[(1- = 0.1; 5143/5163 carbamoyI-1H-indoIy|)- [M+H]+, 5583/5602 amide] 3-{[(R) [M+HCOO]-; tR (a): (3-ch|orof|uoro—phenyI) 3.15 min. hydroxy-propy|]-amide} (28,4S)F|uoro—pyrrolidine- (1) Rf (C- 1,2—dicarboxylic acid 1-[(1- hexane/EtOAc 1:3) = carbamoyI-1H-indoIy|)- 0.19; 494 [M+H]+; tR amide] 2—[(3—trifluoromethoxy- (c): 4.78 min. phenyI)-amide] (S)—Thiazolidine-2,3- (2,3) White solid. Rf dicarboxylic acid 3-[(1- (c-hexane/EtOAc carbamoyI-1H-indoIy|)- 1:3) = 0.33; 490.1 amide] 2—(2,3-dif|uoro-4— [M+H]+; tR (c): 4.39 methoxy-benzylamide) min. (1 R,3S,5R)— 2Azabicyclo[3.1.0]hexane—2,3— dicarboxylic acid 2—[(1- (1) 419.3 [M+H]+; tR oyl-1H-indol-3— (a): 1.83 min. y|)amide] 3-[(pyridin-3— y|methy|)-amide] )Methyl-pyrrolidine- 1,2—dicarboxylic acid 1-[(1- 490 [M+H]+; tR (b): carbamoyI-1H-indoIy|)- 4.51 min. amide] 2—[(3—trifluoromethoxy- phenyI)-amide] (1 R,3S,5R)—2—Aza— bicyc|o[3.1.0]hexane-2,3- dicarboxylic acid 2—[(1- 453 [M+H]+; tR (a): carbamoyI-1H-indoIy|)- 2.70 min. amide] 3-[(5—ch|oro-pyridin y|methy|)-amide] (28,4R)-4—FIuoro—4—methyl- (5,8[BQ]) Rf (EtOAc) pyrrolidine-1,2—dicarboxylic = 0.1; 514.3/516.3 acid 1-[(1-carbamoy|-1H-indol- [M+H]+, 558.3/560.2 3-y|)-amide] 2-{[(R)(3- [M+HCOO]-; tR (a): chlorofluoro—phenyl)-3— 3.15 min. hydroxy-propy|]-amide} (28,4R)F|uoro-pyrro|idine— 1,2—dicarboxylic acid 1-[(1- (1,6). 443.0 [M+H]+; oyI-1H-indoIy|)- tR (c): 3.05 min. amide] f|uoro-pyridin-4— y|methy|)-amide] (1 R,28,5S)Aza- (5,8[BQ]) White bicyc|o[3.1.0]hexane-2,3- powder. Rf oxylic acid 3-[(1- (CHZCLz/MeOH 9:1): oyI-1H-indoIy|)- 0.60; 514.3/516.3 amide] 2—{[(S)—1-(3-chloro—2— [M+H]+, 558.3/560.3 fluoro-phenyl)—2—methoxy- [M+HCOO]-; tR (a): ethy|]-amide} 3.31 min. (28,4R)F|uoro-pyrro|idine— 1,2—dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (1,6). 511.0 [M+H]+; amide] 2—[(3-f|uoro tR (c): 4.16 min. trifluoromethyI-pyridin y|methy|)-amide] (S)-Pyrro|idine—1,2-dicarboxylic 471.1 [M+H]+, 963.3 acid 1-[(1-carbamoy|-1H-indol- [2M+Na]+; tR (a): 3-y|)-amide] 2-[(3—su|famoy|- 2.58 min. phenyI)-amide] (1 R,3S,5R)—2-Aza— bicyc|o[3.1.0]hexane-2,3- (1) 470.0 [M+H]+, dicarboxylic acid 2-[(1- 468.9 [M-H]- 425.0 carbamoyI-1H-indoIy|)- [M-CONH2]-; tR (b) amide] 3-[(3-dif|uoromethoxy- 4.05 min. HCOZ phenyI)-amide] (S)—Thiazolidine-2,3- (2,3,6) Solid. R (cdicarboxylic acid 3-[(1- hexane/EtOAc 1:3) = carbamoyI-1H-indoIy|)- 0.33; 490 [M+H]+; tR amide] 2-(2,3—dif|uoro (c): 4.48 min. methoxy-benzylamide) (1 R,3S,5R)—2-Aza— (5,8[B9]) White bicyc|o[3.1.0]hexane-2,3- powder. 514.4/516.4 dicarboxylic acid 2-[(1- , 531.4/533.4 carbamoyI-1H-indoIy|)- [M+Na]+, amide] )—1-(3-chloro—2- 558.4/560.4 fluoro-pheny|)methoxy- [M+HCOO]-; tR (f): -amide} 1.97 min. (2S,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 1-[(1- 459.1/461 [M+H]+; tR oyI-1H-indoIy|)- (f): 1.30 min. amide] 2-[(5-ch|oro-pyridin y|methy|)-amide] (S)-Pyrro|idine—1,2-dicarboxylic Rf (CHZCIZ/iPrOH acid 1-[(1-carbamoy|-1H-indol- 95:5) = 0.13; 421.1 3-y|)-amide] ethy|—pyridin- [M+H]+, 419.2 [M-H]— 2-y|)-amide] ;tR (a): 2.42 min. (2S,4R)-4—FIuoro—4—methyl- (5,8[B9]) Rf pyrrolidine-1,2-dicarboxylic (CHZCIZ/MeOH 9:1) acid 1-[(1-carbamoyI-1H-indol- = 0.3; 502.4 3-y|)-amide] 2-{[(S) [M+H]+, 544.2/546.2 (3-ch|orof|uoro—phenyI) [M+HCOO]-; tR (a): hydroxy-ethy|]-amide} 3.02 min. (2S,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (3,6[C3]) 533.0 [M]+; amide] 2-(3-chlorofluoro—5— tR (c): 3.86 min. methylcarbamoylbenzylamide (8) R (EtOAc) = (2S,4S)F|uoro—4- 0.38; 508/510 fluoromethyI-pyrrolidine—1,2- [M+H]+, 530/532 oxylic acid 1-[(1- [M+Na]+, 506/508 carbamoyI-1H-indoIy|)- [M-H]-, 463.1/465.1 amide] 2-(3-chlorofluoro— [M-CONH2]-; tR (f): benzylamide) 1.92 min. 1R,3S,5R)Aza- bicyc|o[3.1.0]hexane-2,3- 437.2 [M+H]+, 895.3 oxylic acid 2-[(1- [2M+Na]+; tR (a): oyI-1H-indoIy|)- 2.36 min. amide] 3-[(3-f|uoro-pyridin y|methy|)-amide] (28,4S)FIuoro—4-morpholin- 4-y|methy|-pyrro|idine-1,2- (8[B14]) 575 [M+H]+, dicarboxylic acid 1-[(1- 502 [M-H]—; tR (f): carbamoyI-1H-indoIy|)- 1.51 min. amide] 2-(3-chlorofluoro— benzylamide) 2S,4R)(1-Carbamoyl- 1H-indoIylcarbamoyI) fluoro-pyrrolidine—2-carbony|]- (3,6) 534.0 [M]+; tR amino}-methy|)ch|oro—4— (c): 3.24 min. fluoro-benzoic acid methyl ester (1 S,2S,5R)Aza- (5,8[B9]) White o[3.1.0]hexane-2,3- powder. Rf (EtOAc): dicarboxylic acid 3-[(1- 0.20; 514.4/516.4 carbamoyI-1H-indoIy|)- [M+H]+, 558.4/560.3 amide] 2-{[(S)(3-ch|oro—2- [M+HCOO]-; tR (a): fluoro-pheny|)methoxy- 3.25 min. ethy|]-amide} (8) (mixture of diastereosisomers) {[(2S,4R)(1-CarbamoyI-1H- Rf (CHZCIZ/MeOH indoIylcarbamoyI)fluoro— 4:1) = 0.2; 502/504, idine—2-carbonyI]-amino}- [M+H]+, 500/502 [M- (3-chloro-pheny|)-acetic acid H]-; tR (a): 2.86 and 2.92 min. (1 R,3S,5R)Aza— bicyc|o[3.1.0]hexane-2,3- (4) White solid. Rf oxylic acid 2-[(1- (EtOAc) = 0.46; carbamoyI-1H-indoIy|)- 439.0 [M+H]+; tR (c): amide] 3-[(5—ch|oro-pyridin 4.01 min. y|)-amide] (2S,4R)F|uoro-pyrro|idine— (5,6[C4D 1,2-dicarboxylic acid 1-[(1- 533.4/535.5 [M+H]+, carbamoyI-1H-indoIy|)- 577.5/579.4 amide] 2-{[(S)(3-ch|oro—2- [M+HCOO]; tR (a): fluoro-pheny|) 2.60 min. dimethylamino-ethy|]-amide} (2S,4S)-4—Hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(1- 492.1 [M+H]+, 514.2 carbamoyI-1H-indoIy|)- [M+H]+, 490.1 [M-H]— amide] 2-[(3—trif|uoromethoxy- ;tR (a): 3.19 min. phenyI)-amide] (2S,4R)F|uoro-pyrro|idine— carboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (3,6[C3]) 589.3 [M]+; amide] 2-[3—chloro—2-fluoro-5— tR (c): 3.96 min. (morpholinecarbonyl)- benzylamide] (1 R,3S,5R)-2—Aza— bicyc|o[3.1.0]hexane-2,3- (1) 434.0 [M+H]+, dicarboxylic acid 2—[(1- 388.9 [M-CONH2]-; carbamoyI-1H-indoIyl)- tR (b) 3.64 min. amide] 3-[(3-methoxy-phenyl)- amide] (28,4R)F|uoro-pyrro|idine— 1,2—dicarboxylic acid 1-[(1- carbamoyI-1H-indoIyl)- (3,6[C1]) 547.2 [M]+; amide] 2—(3-chloro-5— tR (c): 3.67 min. diethylamino—2—fluoro— amide) (S)-Thiazolidine-2,3- (5) R (EtOAc) = 0.2; dicarboxylic acid 3-[(1- 506.3/5082 [M+H]+, carbamoyI-1H-indoIyl)- 5502/5522 amide] 2—{[(S)(3-chloro—2— O]-; tR (a): fluoro-phenyI)hydroxy- 3.06 min. ethy|]-amide} (1 R,3S,5R)-2—Aza— (1) 4330/4400 bicyc|o[3.1.0]hexane-2,3- , 437.8 [M-H]— dicarboxylic acid 2—[(1- 393/395 [M- carbamoyI-1H-indoIyl)- CONH2]-; tR (b) 4.12 amide] 3-[(3-chloro—phenyl)- min. amide] (28,4R)F|uoro-pyrro|idine— 1,2—dicarboxylic acid 1-[(1- carbamoyI-1H-indoIyl)- (3,6[C3]) 589.3 [M]+; amide] 2—[3-chloro—2—fluoro-5— tR (c): 4.06 min. (3-methoxy-azetidine—1 - carbonyI)-benzylamide] (28,4R)Cyano—pyrro|idine— 1,2—dicarboxylic acid 1-[(1- 501.1 [M+H]+; tR (b): oyI-1H-indoIyl)- 4.22 min. amide] 2—[(3-trifluoromethoxy- phenyI)-amide] (28,3S)Hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(1- (1) White solid. 456 oyI-1H-indoIyl)- [M+H]+; tR (b): 2.99 amide] 2-(3-chloro— min. benzylamide) (1 R,3S,5R)Aza— 418.3 [M+H]+, 416.3 bicyclo[3.1.0]hexane-2,3- [M-H]-; tR (a): 2.94 dicarboxylic acid 3- min. benzylamide 2-[(1-carbamoy|- 1H-indoIyI)-amide] (28,3R)Hydroxy-pyrrolidine- carboxylic acid 1-[(1- (1) White solid. carbamoyI-1H-indoIyl)- 462/463 [M+H]+; tR amide] ch|oro-thiophen- (b): 2.92 min. 2-ylmethyI)-amide] (8,9[A1]) Rf(EtOAc) (28,4S)Hydroxymethyl- = 0.15; 4874/4894 pyrrolidine-1,2-dicarboxylic [M+H], 485.4/486.4 acid 1-[(1-acety|-1H-indo| [M-H]-; tR (a): 3.11 y|)-amide] 2-(3-chloro—2-fluoro— min. amide) (1 R,3S,5R)Aza— bicyclo[3.1.0]hexane-2,3- (1) White solid. 504 dicarboxylic acid 2-[(1- [M+H]+; tR (b): 4.08 carbamoyI-1H-indoIyl)- min. amide] 3-(2-fluoro—3— trifluoromethyI-benzylamide) (S)-Thiazolidine-2,3- (2,3) White solid. Rf dicarboxylic acid 3-[(1- (c-hexane/EtOAc carbamoyI-1H-indoIyl)- 1:3) = 0.19; 490.1 amide] 2-(2,3-difluoro-6— [M+H]+; tR (c): 4.45 methoxy-benzylamide) min.
(S)—Thiazolidine-2,3- dicarboxylic acid 3-[(1- (1) White solid. 465 carbamoyI-1H-indoIy|)- [M+H]+; tR (b): 3.06 amide] 2-[(2-ch|oro-thiazo| min. y|methy|)-amide] (S)—Thiazolidine-2,3- dicarboxylic acid 3-[(1- (9[A4]) 494 [M+H]+; carbamoyl-5—fluoro—1H-indoI tR (b): 4.01 min. y|)-amide] 2-(3—chlorofluoro— benzylamide) 28],9[A2]) (1 R,3S,5S)Hydroxymethy|- White solid. Rf bicyc|o[3.1.0]hexane- (EtOAc) = 0.20; carboxylic acid 3-(3- 514.4/516.4 [M+H]+, chlorofluoro-benzylamide) 558.4/560.3 2-[(1-methy|carbamoy|-1H- [M+HCOO]-; tR (f): indoIy|)-amide] 1.80 min.
(S)—4-Methylene-pyrrolidine— (1) Rf (C- 1,2-dicarboxylic acid 1-[(1- hexane/EtOAc 1:3) = carbamoyI-1H-indoIy|)- 0.38; 486. [M-H]—, amide] 2-[(3—trif|uoromethoxy- 443 [M-CONH2]-; tR phenyI)-amide] (i): 3.52 min.
(S)—Thiazolidine-2,3- dicarboxylic acid 3-[(1- 494.0 , 492.1 carbamoyI-1H-indoIy|)- [M-H]-; tR (a): 3.52 amide] 2-[(3—trif|uoromethoxy- min. phenyI)-amide] (1 R,3S,5R)—2-Aza— (9) Rf(EtOAc) = o[3.1.0]hexane-2,3- 0.47; 526/528 dicarboxylic acid 2-[(5-a||y|oxy- [M+H]+, 481.1/483.3 1-carbamoyI-1H-indoIy|)- [M'CONH21'J tR(f)3 amide] 3-(3-chlorofluoro— 2.01 min. benzylamide) (flAM)Rd0 S)-Pyrro|idine-1,2-dicarboxylic hexane/EtOAc 8:2): acid 1-[(1-carbamoy|—6-methy|— 0.4; 490.1 [M+H]+, 1H-indol-3—yI)-amide] 2-[(3- 488 [M-H]—; tR (a): oromethoxy-pheny|)- 3.57 min. amide] (1 R,3S,5R)Aza— (5,8[BQ],9[A2]) White bicyc|o[3.1.0]hexane-2,3- powder. Rf (EtOAc): dicarboxylic acid 3-{[(S)(3- 0.30; 528.4/530.4 chlorofluoro—phenyI) [M+H]+, 572.4 methoxy-ethy|]-amide} 2-[(1- [M+HCOO]-; tR (a): methylcarbamoyI-1H-indol-3— 3.41 min. y|)-amide] (S)-Pyrro|idine—1,2-dicarboxylic (flAH)RNG acid 1-[(1-acety|-1H-indo| /EtOAc 1:2) = y|)-amide] 2-[(3— 0.35; 475.1 , trifluoromethoxy-pheny|)- 473.2 [M-H]-; tR (a): amide] 3.94 min. 3-Bromo{[(1R,3S,5R)(1- carbamoyl-1H-indol-3— (1) White solid. y|carbamoy|)aza- 538.0 [M+H]+; tR (b): bicyclo[3.1.0]hexane 4.3 min. carbonyI]-amino}-benzoic acid methyl ester (2S,5R)Pheny|—pyrrolidine- 1,2-dicarboxy|ic acid 1-[(1- (1) 552.1 [M+H]+; tR carbamoyI-1H-indoIy|)- (c): 5.53 min. amide] 2-[(3—trif|uoromethoxyphenyI )-amide )F|uoro-pyrro|idine— 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- 512 [M+H]+; tR (b) amide] 2-[(2-f|uoro 4.15 min. trifluoromethoxy-pheny|)- amide] (5,8[B28],9[A1]) White solid. Rf (1 R38,5S)Hydroxymethy|— (EtOAc) = 0.25; bicyc|o[3.1.0]hexane- 4993/5013 [M+H]+, 2,3-dicarboxylic acid 2-[(1- 5213/5232 acetyI-1H-indoIyI)-amide] 3- [M+Na]+, (3-chlorofluoro— 4973/4993 [M-H]—, benzylamide) 543.2/5453 [M+HCOO]-; tR (f): 1.90 min. (1 -CarbamoyI{[(1 R3S,5R)- (9) R (EtOAc) = 0.6; 3-(3-trifluoromethoxy- 576.3 [M+H]+, 574.3 carbamoyI)aza- [M-H]-, 620.3 bicyclo[3.1.0]hexane [M+HCOO]-; tR (f): carbonyl]-amino}-1H-indol-6— 2.12 min. y|oxy)-acetic acid methyl ester (2S,4R)F|uoro-pyrro|idine— carboxylic acid 1-[(1- carbamoyI-1H-indoIyl)- (3,6[C3]) 547.2 [M]+; amide] 2-(3-chloro tR (c): 3.97 min. ylcarbamoyIfluoro- benzylamide) 2-Bromo-4—{[(2S,4R)(1- carbamoyI-1H-indol (8) 530/531 [M+H]+; y|carbamoy|)f|uoro— tR (b): 3.0 min. pyrrolidine—2-carbonyl]—amino}- benzoic acid (S)-Pyrro|idine—1,2-dicarboxylic acid 2-[(5-tert—butyImethyl- 452.2 [M+H]+, 450.2 2H-pyrazoIyI)-amide] 1-[(1- [M-H]-; tR (a): 2.79 carbamoyI-1H-indoIyl)- min. amide] (2S,4R)F|uoro-pyrro|idine— (9[A4]) Rf (EtOAc) = 1,2-dicarboxylic acid 1-[(6- 0.55; 532 [M+H]+; tR a||y|oxycarbamoy|-1H-indol- (b): 4.08 min. 3-y|)-amide] hloro—2- fluoro-benzylamide) (1 R,3S,5R)—2-Aza— (5,6[C4],9[A1]) Rf bicyc|o[3.1.0]hexane-2,3- (CHZCIZ/MeOH 9:1) dicarboxylic acid 2-[(1-acety|- = 0.65; 526.3/528.3 1H-indoIy|)-amide] 3-{[(S)—1- [M+H]+, 570.3/572.3 (3-chlorofluoro—phenyI) [M+HCOO]; tR (a): ylamino-ethy|]-amide} 3.06 min.
(S)-Pyrro|idine—1,2-dicarboxylic acid 1-[(1-methy|carbamoy|- ) 490.1 1H-indoIy|)-amide] 2-[(3- [M+H]+, 488.2 [M-H]— trifluoromethoxy-pheny|)- ;tR (a): 3.65 min. amide] (2S,3R)Hydroxy-pyrrolidine- 1,2-dicarboxylic acid 1-[(1- (1) White solid. 463 carbamoyI-1H-indoIy|)- [M+H]+; tR (b): 2.03 amide] 2-[(2-ch|oro-thiazo| min. y|methy|)-amide] (1 R,3S,5S)Methoxymethyl- (5,8,9[A2]) White 2-aza-bicyc|o[3.1.0]hexane- solid. 528.4 [M+H]+, 2,3-dicarboxy|ic acid 3—(3— 526.2 [M+H]-, 572.3 chlorofluoro-benzylamide) O]-; tR (a): 2-[(1-methy|carbamoy|-1H- 3.34 min. indoIy|)-amide] Rf (c-hexane/EtOAc (1 R)—2-Aza— 1:2) = 0.29; 446.2 bicyc|o[3.1.0]hexane-2,3- [M+H]+, 891.3 dicarboxylic acid 2-[(1- [2M+H]+, 913.3 carbamoyI-1H-indoIy|)- ]+, 401.2 [M- amide] 3-[(3—isopropy|—phenyl)- CONH2]-; tR (a): 3.54 amide] min.
(S)-Pyrro|idine—1,2-dicarboxylic (9[A4]) Rf (C- acid 1-[(6-bromocarbamoy|- hexane/EtOAc 1:1) = 1H-indoIy|)-amide] 2-[(3- 0.5; 554/556 [M+H]+; trifluoromethoxy-pheny|)- tR (a): 3.74 min. amide] (1 R,3S,5R) Azabicyclo[3.1.0]hexane-2,3- (5, 9[A2]) Rf dicarboxylic acid 3-{[(S)(3- (EtOAc) = 0.2; 514.4 chlorofluoro—phenyI) [M+H]+ 558.4 hydroxy-ethy|]-amide}2-[(1- [M+HCOO]-; tR (a): carbamoyI-1H-indol-3— 3.12 min. y|)-amide] (S)-Pyrro|idine—1,2-dicarboxylic (9[A3]) 504.1 acid 1-[(1-carbamoyIethyl- [M+H]+, 526.2 1H-indol-3—yI)-amide] 2-[(3- [M+Na]+, 502 [M-H]-; trifluoromethoxy-pheny|)- tR (a): 3.68 min. amide] (1 R,3S,5R)Aza— (5,6[C4],9 [A2]) bicyc|o[3.1.0]hexane-2,3- White solid. Rf dicarboxylic acid 3-{[(S)(3- (EtOAc) = 0.25; chlorofluoro—phenyI) 541 .4 [M+H]+, dimethylamino-ethyl]—amide} 2- 585.3/587.2 [(1-methylcarbamoyI-1H-indol- O]; tR (a): 3-y|)-amide] 2.88 min.
(S)-Pyrro|idine—1,2-dicarboxylic acid 1-[(1-carbamoy|—6- (9) 499 [M-H]- ; tR trifluoromethyI-1H-indoIy|)- (a): 4.15 min. amide] 2-[(3—trifluoromethoxyphenyI )-amide] (9[A4]) Rf (C- (S)-Pyrro|idine—1,2-dicarboxylic hexane/EtOAc 1:1)= acid 1-[(1-carbamoyIchloro- 0.5; 510.1 [M+H]+, 1H-indol-3—yI)-amide] 2-[(3- 532 +, 508 trifluoromethoxy-pheny|)- ; tR (a): 3.67 amide] min. (9[A4]) Rf (EtOAc) = (2S,4R)F|uoro-pyrro|idine— 0.45; 506.0/508.0 1,2-dicarboxylic acid 1-[(1- [M+H]+, 504.1/506.1 carbamoyImethoxy-1H- [M-H]-, 461.0/463.0 indoIyI)-amide] 2-(3-chloro- [M-CONH2]-; tR (f): 2-quoro—benzylamide) 1.80 min. iazolidine-2,3- 464.0 [M+H]+, 462.0 dicarboxylic acid 3-[(1- [M-H]-, 419.0 [M- carbamoyI-1H-indoIyl)- CONH2]-; tR (f): 2.02 amide] 2—[(5-ch|oro-thiophen- min. 2—ylmethy|)-amide] (1 R,3S,5R)—2—Aza— bicyclo[3.1.0]hexane-2,3- (9[A4]) Rf (EtOAc) = oxylic acid 2—[(1- 0.47; 488 [M+H]+; 1R carbamoyl-5—fluoro—1H-indoI (b): 4.01 min. y|)-amide] 3-(3-chloro-2—fluoro— benzylamide) (1 R,3S,5R)—2—Aza— o[3.1.0]hexane-2,3- (1) White solid. 459 dicarboxylic acid 2—[(1- [M+H]+; tR (b): 3.11 carbamoyI-1H-indoIyl)- min. amide] 3-[(2-ch|oro-thiazo|—5— y|methy|)-amide] (28,4R)F|uoro-pyrro|idine— (4) Rf (C- 1,2—dicarboxylic acid 1-[(1- hexane/EtOAc carbamoyI-1H-indoIyl)- /75): 0.55; 526.0 amide] 2—{[(S)(3-chloro- ; tR (c): 4.80 pheny|)-2,2,2—trifluoro-ethyl]- min. amide} (1 R,3S,5R)—2—Aza— bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 2—[(1- (9[A4]) 506 [M+H]+; carbamoyl-6—fluoro—1H-indoI tR (b): 4.62 min. y|)-amide] 3-[(3— trifluoromethoxy-pheny|)- amide] (28,4R)F|uoro-pyrro|idine— 1,2—dicarboxylic acid 1-[(1- (6,9[A4]) 542.0 carbamoyImethoxy-1H- [M+H]+, 564.0 indoIy|)-amide] 2—[(2-f|uoro- [M+Na]+; tR (k): 3.47 3-trifluoromethoxy—phenyl)— min amide] (S)-Azetidine-1,2-dicarboxylic acid 1-[(1-carbamoy|-1H-indol- 462.1 [M+H]+, 460.1 3-yI)-amide] 2-[(3- [M-H]-; 1R (a): 3.52 trifluoromethoxy-pheny|)- min. amide] (1 R,3S,5R)Aza— (9[A4]) Rf ) = bicyclo[3.1.0]hexane-2,3- 0.45; 500/502.1 dicarboxylic acid 2-[(1- [M+H]+, 455/457 [M- carbamoyImethoxy-1H- CONH2]-; 1R (f): 1.91 indoIyI)-amide] 3-(3-chloro— min. 2-fluoro-benzylamide) (S)-4,4-Dif|uoro—pyrrolidine- Rf (EtOAc) = 0.65; 1,2-dicarboxylic acid 1-[(1- 492 [M+H]+, 494 [M- carbamoyI-1H-indoIyl)- H]-; 1R (f): 1.96 min. amide] 2-(3-chloro—2-fluoro— benzylamide) (S)-5,5-Dimethyl-pyrrolidine— (1) Off-white solid. Rf 1,2-dicarboxylic acid 1-[(1- ) = 0.53; oyI-1H-indoIyl)- 486.2 [M+H]+; tR (c): amide] 2-(3-chloro—2-fluoro— 4.87 min. benzylamide) )F|uoro-pyrro|idine— (9) R (EtOAc) = 03; 1,2-dicarboxylic acid 1-{[1- 5502/5521 [M+H]+, carbamoyI(2-methoxy- 572/5741 [M+Na]+, ethoxy)-1H-indoIyI]-amide} 548 [M-H]—, 505 [M- 2-(3-chloro—2-fluoro— CONH2]-; 1R (f): 1.76 benzylamide) min. (28,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 1-[(1- (1) 457.0 [M+H]+; tR carbamoyI-1H-indoIyl)- (c): 3.20 min. amide] 2-[(3-f|uoro—4-methy|— pyridinylmethyI)-amide] (28,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 1-[(1- (1) White solid. 493 oyI-1H-indoIyl)- [M+H]+; tR (b): 3.76 amide] 2-[(5-trif|uoromethy|— min. pyridinylmethyI)-amide] (1-Carbamoyl-3—{[(1R,3S,5R)- (9) R (EtOAc) = 3-(3-chlorofluoro— 0.45; 556.3/558.4 benzylcarbamoyI)aza- [M+H]+, 554.3/556.3 bicyclo[3.1.0]hexane , 511.3/513.3 carbony|]-amino}-1H-indoI [M'CONH21'J tR (f): etic acid ethyl ester 2.02 min. (1 S,5R)—2-Azabicyc |o[3.1.0]hexane-1,2- Rf (c-hexane/EtOAc dicarboxylic acid 2-[(1- 1:2) = 0.15; 488 carbamoyI-1H-indoIyl)- [M+H]+, 486.1 [M-H]— amide] trif|uoromethoxy- ;tR (a): 3.51 min. phenyI)-amide] (2S,4R)F|uoro-pyrro|idine— (9[A4]) White solid. carboxylic acid 1-[(1- 542.0 [M+H]+; 554.0 carbamoyIdifluoromethoxy- [M+Na]+; tR (k): 3.41 1H-indoIy|)-amide] 2-(3- min. chlorofluoro-benzylamide) (2S,4R)F|uoro-pyrro|idine— (3,4) Off-white solid. 1,2-dicarboxylic acid 1-[(1- Rf (c-hexane/EtOAc carbamoyI-1H-indoIyl)- 1:1) = 0.42; 441.2 amide] methoxy-pyridin- [M+H]+; tR (c): 3.28 4-y|)-amide] min.
(S)—Thiazolidine-2,3- (3,4) Off-white solid. dicarboxylic acid 3-[(1- Rf (EtOAc) = 0.47; carbamoyI-1H-indoIyl)- 445.0 [M+H]+; tR (c): amide] 2-[(5-ch|oro-pyridin 4.03 min. y|)-amide] (1 R,3S,5R)—2-Aza— bicyc|o[3.1.0]hexane-2,3- (9[A4]) Rf (EtOAc) = dicarboxylic acid 2-[(6-a||y|oxy- 0.4; 525 [M+H]+; tR 1-carbamoyI-1H-indoIy|)- (b) : 4.33 min. amide] 3-(3-chlorofluoro— benzylamide) (2S,4S)Hydroxymethy|— (8) 488.2 [M+H]+, pyrrolidine-1,2-dicarboxylic 433.0 [M-CONH2]-; acid 1-[(1-carbamoyI-1H-indol- tR (f): 1.63 min. 3-y|)-amide] 2-(3—chloro—2- fluoro-benzylamide) (S)-Pyrro|idine—1,2-dicarboxylic (9[A4]) Rf )= acid 1-[(6-benzyloxy 0.44; 582.1 [M+H]+, carbamoyI-1H-indoIy|)- 580.2 [M-H]—; tR (a): amide]2-[(3-trif|uoromethoxy- 3.91 min. )-amide] (1 R,3S,5R)Aza— bicyc|o[3.1.0]hexane-2,3- (5,6[C4]) White solid. dicarboxylic acid 2-[(1- Rf (EtOAc) = 0.1; carbamoyI-1H-indoIy|)- 527.3/529.3 [M+H]+, amide] 3-{[(S)(3-chloro—2- 571.3 [M+HCOO]; tR fluoro-pheny|) (a): 2.84 min. dimethylamino-ethyl]—amide} (9) R (EtOAc) = 0.4; 556.3/558.4 [M+H]+, (1-Carbamoyl-3—{[(1R,3S,5R)- 573.4/575.2 3-(3-chlorofluoro— [M+H30]+, benzylcarbamoyI)aza- 1111.7/1113.7 bicyc|o[3.1.0]hexane +, carbonyl]-amino}-1H-indoI 556.4 [M-H]—, y|)-acetic acid ethyl ester 600.3/602.8 [M+HCOO]-; tR (f): 2.02 min. (2S,4R)Methoxy-pyrrolidine- Rf (c-hexane/EtOAc 1,2-dicarboxylic acid 1-[(1- 1:2) = 0.1; 506.0 carbamoyI-1H-indoIy|)- [M+H]+, 504.1 [M-H]; amide] trifluoromethoxy- tR (a): 3.36 min. phenyI)-amide] (2S,4R)F|uoro-pyrro|idine— (4) Off-white solid. Rf 1,2-dicarboxylic acid tert— (c-hexane/EtOAc butyI-pyridiny|)-amide] 1-[(1- 1:1) = 0.42; 467.3 carbamoyI-1H-indoIy|)- [M+H]+; tR (c): 3.58 amide] min. (1-CarbamoyI{[(2S,4R) (8[B13],9) Rf (EtOAc) orofluoro— = 0.6; 580.4 benzylcarbamoyI)fluoro [M+H]+, 576.3/578.2 methyl-pyrrolidine—1-carbony|]- [M-H]-, 533.5/535.5 amino}-1H-indoIyloxy)- [M-CONH2]-; tR (f): acetic acid methyl ester 1.90 min. (2S,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 1-[(1- (4) Rf (C- carbamoyI-1H-indoIy|)- hexane/EtOAc 1:3)= amide] 2-{[(R)(3-ch|oro— 0.56; 526.0 [M+H]+; phenyI)-2,2,2-trifluoro-ethyl]- tR (c): 4.79 min. amide} (1 R,3S,5R)Aza— bicyc|o[3.1.0]hexane-2,3- dicarboxylic acid 2-[(1- (5) 482.4 [M+H]+; tR carbamoyI-1H-indoIy|)- (a): 3.05 min. amide] 3-{[(S)(3-chloro- pheny|)hydroxy-ethy|]- amide} (S)-Thiazolidine-2,3- (3,4) Off-white solid. dicarboxylic acid 3-[(1- Rf (EtOAc) = 0.38; carbamoyI-1H-indoIy|)- 489.0 [M+H]+; tR (c): amide] 2-[(5-bromo-pyridin 4.10 min. y|)-amide] )F|uoro-pyrro|idine— carboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (3,6[C3]) 602.2 [M]+; amide] 2-[3-chloro—2-fluoro tR (c): 3.47 min. (4-methyI-piperazine carbonyI)-benzylamide] (2S,4R)F|uoro-pyrro|idine— (4) White foam. Rf 1,2-dicarboxylic acid 1-[(1- (EtOAc) = 0.18; carbamoyI-1H-indoIy|)- 429.0 [M+H]+; tR (c): amide] 2-[(3-f|uoro-pyridin-4— 3.14 min. y|)-amide] (S)-Pyrro|idine—1,2-dicarboxylic 435.1 [M+H]+, 891.3 acid 1-[(1-carbamoyI-1H-indol- [2M+Na]+, 433.1 [M- 3-y|)-amide] 2-[(3-carbamoy|— H]-; tR (a): 2.39 min. phenyI)-amide] (S)-Pyrro|idine—1,2-dicarboxylic 470.0 , 939.1 acid carbamoyI-1H-indol- [2MH]+, 961.2 3-y|)-amide] 2-[(3- [2M+Na]+, 468.1 [M- methanesulfonyI-phenyl)- H]-; tR (a): 2.70 min. amide] (2S,4R)F|uoro-pyrro|idine— 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (3) 500.0 [M]+; tR (c): amide] 2-[(6-ch|oro-chroman- 4.39 min. 4-y|)-amide] (mixture of 2 diastereoisomers) (2S,4R)F|uoro-pyrro|idine— (4) White solid. Rf 1,2-dicarboxylic acid 1-[(1- (EtOAc) = 0.25; carbamoyI-1H-indoIy|)- 429.0 [M+H]+; tR (c): amide] 2-[(3-f|uoro-pyridin 3.42 min. y|)-amide] (2S,4S) (8[B15]) 532 [M+H]+, ylaminomethyl-4—fluoro— 530 [M-H]—; tR (f): pyrrolidine-1,2-dicarboxylic 1.62 min, 19F NMR acid 1-[(1-carbamoyI-1H-indol- de): 3-y|)-amide] 2-(3-chloro—2- -120, -149. fluoro-benzylamide) (2S,4R)F|uoro-pyrro|idine- 1,2-dicarboxylic acid 1-[(1- carbamoyI-1H-indoIy|)- (3,6[C1]) 576.2 [M]+; amide] hloro[(2- tR (c): 3.91 min. dimethylamino—ethyl)-methy|— amino]f|uoro-benzy|amide} (1 R,3S,5R)Aza— bicyc|o[3.1.0]hexane-2,3- (1) 460.1 , dicarboxylic acid 3-[(3—tert- 415.1 [M-CONH2]-; butyI-phenyI)-amide] 2-[(1- tR (b) 4.68 min. carbamoyI-1H-indoIy|)- amide] Rf (EtOAc) = 0.2; )-4—Hydroxy-pyrrolidine- 474.1/476.2 [M+H]+, 1,2-dicarboxylic acid 1-[(1- 496.1/498 [M+Na]+, carbamoyI-1H-indoIy|)- 472/4741 [M-H]—, amide] 2-(3-chlorofluoro— 429.1/431 [M- benzylamide) -; 1R (a): 2.88 min.
(S)-4,4-Dif|uoro—pyrrolidine- 1,2-dicarboxylic acid 1-[(1- 512.2 [M+H]+, 510.1 carbamoyI-1H-indoIy|)- [M-H]-; 1R (a): 3.63 amide] 2-[(3—trifluoromethoxy- min. phenyI)-amide] 3-Bromo{[(2S,4R)(1- carbamoyl-1H-indol-3— (4,6) 578/580 y|carbamoy|)f|uoro— [M+H]+, 576/578 [M- pyrrolidinecarbonyI]-amino}- H]-; 1R (b): 4.3 min. 4-fluoro-benzoic acid ethyl ester Rf (c-hexane/EtOAc (1 R,3S,5R)Aza— 1:2) = 0.40; 488 bicyc|o[3.1.0]hexane-2,3- [M+H]+, 997.2 dicarboxylic acid 2-[(1- ]+, 486.1 [M- carbamoyI-1H-indoIy|)- H]-, 443.2 [M- amide] 3-[(3—trifluoromethoxy- CONH2]-; tR (a): 3.55 phenyI)-amide] min.
OCF (S)-Pyrrolidine-1 ,2-dicarboxylic (9[A4]) R (EtOAc)= acid 1-[(5-allyloxy 0.51; 532.2 [M+H]+, 335 carbamoyl-1 H-indolyl)- 530 [M-H]-; t (a): amide] 2-[(3-trifluoromethoxy- 3.64 min. )-amide] ( 1) CH2CI2 was used instead of DMF in step A ; (2) CH3CN was used instead of DMF in step A ; (3) HATU was used as the ng reagent in step A ; (4) The reaction mixture in step A was heated at 70°C; (5) HCI (4 M in dioxane) in dioxane was used instead of TFA in CH2CI2 in step B ; (6) The substituted benzylamine or e derivative used in step A was prepared as described in Part C [Scheme]; (7) The substituted proline derivative used in step A was prepared as described in Part B [Scheme]; (8) The title compound was prepared according to the general procedure described in Scheme D5 steps B and C starting from the substituted proline derivative prepared as described in Part B [Scheme]; (9) The isocyanate reagent used in step C was ed as described in Part A .
Example 336: (2S,5R)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- 2-[(3-trifluoromethoxy-phenyl)-amide] The title compound was prepared according to the general procedure described in Scheme D5 except that CH C I was used instead of DMF in step A , ng from a e of (2S.5R)- and 2 2 (2S,5S)methyl-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester in a 7:1 ratio (prepared as described in Scheme B1). The diastereoisomers were separated by chiral HPLC (Chiracel OJ, mM, 185 x 48 mm, flow: 100 mL/min, mobile phase: n-hexane/EtOH 9:1) to give the title compound: TLC, R (c-hexane/EtOAc 1:3) = 0.45; MS ): 490.0 [M+H]+, 488.0 ; t f R (HPLC conditions c): 4.99 min.
Example 337: (2S,5S)Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] The title compound was prepared according to the general procedure described in Scheme D5 except that CH C I was used instead of DMF in step A , starting from a (7:1)-mixture of 2 2 (2S.5R)- and (2S,5S)methyl-pyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester (prepared as bed in Scheme B1). The reoisomeric product was separated by chiral HPLC (Chiracel OJ, 20 mM, 185 x 48 mm, flow: 100 mL/min, mobile phase: n-hexane/EtOH 9:1) to give the title compound. TLC R ane/EtOAc 1:3) = 0.45; MS (LC/MS): 490.0 [M+H]+, 488.0 [M-H]-; t (HPLC conditions c): 5.21 min.
Example 338: (2S,5R)Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol- -yl)-amide] 2-[(3-trifluoromthoxy-phenyl)-amide] The title compound was prepared according to the general ure described in Scheme D5 except that CH C I was used instead of DMF in step A , starting from a >9:1 diastereoisomeric 2 2 mixture of (2S.5R)- and (2S,5S)ethyl-pyrrolidine-1 ,2-diarboxylic acid 1-tert-butyl ester (prepared as described in Part B). Purification of the product in the final on step by chiral preparative HPLC (Chiralcel OJ H 5 mM stationary phase) gave the title compound as single reomer. TLC R (EtOAc) = 0.60; MS (LC/MS): 504.1 [M+H]+; t (Chiralcel OJ H 5 mM, f R column 250 x 4.0 mm, n-hexane/EtOH 8:2, flow 1.1 mL/min, 25°C, detection 200 nm): 4.73 min; t (HPLC conditions c): 5.21 min.
Example 339: 3-Chloro{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoropyrrolidinecarbonyl ]-amino}-benzoic acid The title compound was prepared according to the general procedure described in Scheme D5 (Steps B and C) starting from (2S,4R)(3-carboxychloro-phenylcarbamoyl)fluoropyrrolidinecarboxylic acid tert-butyl ester)(prepared by using similar protocols as described in Scheme B7). White solid. MS (LC/MS): 486 [M-H]+; t (HPLC conditions b): 3.31 min. e 340: 3-Bromo{[(1R,3S,5R)(1-carbamoyl-1H-indolylcarbamoyl)aza- bicyclo[3.1 .0]hexanecarbonyl]-amino}-benzoic acid The title compound (White solid) was prepared according to the general procedure described in Scheme D5 (Steps B and C) starting from (1R,3S,5R)(3-bromocarboxyphenylcarbamoyl a-bicyclo[3.1 .0]hexanecarboxylic acid utyl (prepared by using r protocols as described in Scheme B7, except that the reaction mixture was heated at 65°C in step A and dioxane was used instead of MeOH in step B). White solid. MS (LC/MS): 524.3/525.3 [M+H]+; t (HPLC conditions b): 3.6 min.
Example 341 : 3-Bromo{[(S)(1-carbamoyl-1H-indolylcarbamoyl)-thiazolidine benzoic acid The title compound was prepared ing to the general procedure described in Scheme D5 (Steps B and C) starting from (S)(3-bromocarboxy-phenylcarbamoyl)-thiazolidine ylic acid tert-butyl ester) (prepared by using similar protocols as described in Scheme B7). MS (LC/MS): 530.2/532.2/533.1 [M-H]-; t (HPLC conditions b): 3.55 min.
Example 342: 3-Bromo{[(1 R,3S,5R)(1 -carbamoylmethoxy-1 H-indol a-bicyclo[3.1.0]hexanecarbonyl]-amino}-benzoic acid The title compound (White solid) was prepared according to the general procedure described in Scheme D5 (Steps B and C) using (1R,3S,5R)(3-bromocarboxy-phenylcarbamoyl) aza-bicyclo[3.1.0]hexanecarboxylic acid tert-butyl ester) (prepared by using similar protocols as described in Scheme B7, except that the reaction mixture was heated at 65°C in step A and e was used instead of MeOH in step B) and 3-lsocyanatomethoxy-indolecarboxylic acid amide (prepared as described in Scheme A1). MS (LC/MS): 556.0 [M+H]+; t (HPLC conditions c): 4.32 min.
Example 343: 3-Bromo{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoropyrrolidinecarbonyl ]-amino}fluoro-benzoic acid The title compound was prepared according to the general procedure described in Scheme D5 (Steps B and C) starting from (2S,4R)(3-bromocarboxyfluoro-phenylcarbamoyl) fluoro-pyrrolidinecarboxylic acid tert-butyl ester (prepared by using similar protocols as described in Scheme B7 starting from 3-aminobromofluoro-benzoic acid ethyl ester described Part C). MS ): 550/552 [M+H]+; t (HPLC conditions b): 3.3 min. e 344: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-{[3-bromo- -(1H-tetrazolyl)-phenyl]-amide} 2-[(1-carbamoyl-1H-indolyl)-amide] The title compound was prepared according to the general procedure described in Scheme D5 step C from a mixture of (1R,3S,5R)aza-bicyclo[3.1 anecarboxylic acid [3-bromo ( 1 H-tetrazolyl)-phenyl]-amide and (1R,3S,5R)aza-bicyclo[3.1.0]hexanecarboxylic acid mo(1-tert-butyl-1H-tetrazolyl)-phenyl]-amide (ratio 2:3, prepared as described in Scheme B8). Purification by preparative HPLC re, C18-ODB, 5 m h , 30x100 mm, flow: 40 mL/min, eluent: 5-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 containing 3 2 3 3 2 0.1% TFA) afforded the title compound (1R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 3-{[3-bromo(1 H-tetrazolyl)-phenyl]-amide} 2-[(1 -carbamoyl- 1H-indol yl)-amide] as a white powder, MS (LC/MS): 550.0 ; t (HPLC conditions c): 4.35 min.
Example 345: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-{[3-bromo- -(1-tert-butyl-1H-tetrazolyl)-phenyl]-amide} 2-[(1-carbamoyl-1H-indolyl)-amide] The title compound was prepared ing to the l procedure described in Scheme D5 step C from a mixture of (1R,3S,5R)aza-bicyclo[3.1 .0]hexanecarboxylic acid [3-bromo ( 1 H-tetrazolyl)-phenyl]-amide and (1R,3S,5R)aza-bicyclo[3.1.0]hexanecarboxylic acid [3-bromo(1-tert-butyl-1H-tetrazolyl)-phenyl]-amide (ratio 2:3, prepared as bed in Scheme B8). Purification by preparative HPLC (Sunfire, C18-ODB, 5 m h , 30x100 mm, flow: 40 mL/min, eluent: 5-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 containing 3 2 3 3 2 0.1% TFA) afforded the title compound (1R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 3-{[3-bromo(1-tert-butyl-1 H-tetrazolyl)-phenyl]-amide} 2-[(1-carbamoyl- 1H-indolyl)-amide] as a white solid. MS ): 606.0 [M+H]+; t (HPLC conditions c): .60 min.
Example 346: )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-[3-chlorofluoro(1H-tetrazolyl)-benzylamide] The title compound was prepared according to the general procedure described in Scheme D5 step C from a 2:1 mixture of (2S,4R)fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro trazolyl)-benzylamide and (2S,4R)fluoro-pyrrolidinecarboxylic acid 5-(1-tert- butyl-1 H-tetrazolyl)chlorofluoro-benzylamide (prepared as described in Part B). The crude products were purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 m , 30x100 mm, 5-80% CH CN/H O/20 min, 100% CH CN/2 min, 3 2 3 CH CN and H 0 containing 0.1% TFA, flow: 40 mL/min) to give the title compound (2S,4R) 3 2 fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-[3-chloro fluoro(1H-tetrazolyl)-benzylamide]: MS (LC/MS): 544.0 [M]+; t (HPLC ions c): 3.09 min.
Example 347: (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[5-(1-tert-butyl-1H- tetrazolyl)chlorofluoro-benzylamide] 1-[(1-carbamoyl-1H-indolyl)-amide] The title compound was prepared according to the general procedure described in Scheme D5 step C from a 2:1 mixture of )fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro (2H-tetrazolyl)-benzylamide and (2S,4R)fluoro-pyrrolidinecarboxylic acid ert- butyl-1 H-tetrazolyl)chlorofluoro-benzylamide (prepared as described in Part B). The crude products were purified t aqueous workup by RP-preparative HPLC (Waters Sunfire, B, 5 m , 30x100 mm, 5-80% CH CN/H O/20 min, 100% CH CN/2 min, 3 2 3 CHsCN and H 0 containing 0.1% TFA, flow: 40 mL/min) to give the title compound (2S,4R) fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[5-( 1-tert-butyl- 1H-tetrazolyl)chlorofluorobenzylamide ] 1-[(1-carbamoyl-1 H-indolyl)-amide]: MS (LC/MS): 600.2 [M]+; t (HPLC conditions c): 3.63 min.
Example 348: (2R,3S)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] hloro-benzylamide) The title compound was ed according to the general procedure described in Scheme D5 (Steps B and C) starting from )(3-chloro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester (prepared by using similar protocols as described for the ation of (2R,3S)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester in Part B). White solid. MS (LC/MS): 458 [M+H]+; t (HPLC conditions b): 3.56 min.
Example 349: (2R,3R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-(3-chloro-benzylamide) The title compound was prepared according to the general procedure described in Scheme D5 (Steps B and C) by starting from (2R,3R)(3-chloro-benzylcarbamoyl)fluoro-pyrrolidine carboxylic acid tert-butyl ester (prepared by using similar protocols as described for the preparation of (2R,3R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester in Part B). White solid. MS (LC/MS): 458 [M+H]+; t (HPLC conditions b): 3.42 min.
Example 350: (2S,5R)Methyl-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1H- 2-(3-chlorofluoro-benzylamide) The title compound (cis/trans ratio 1:1 1) was prepared according to the general procedure described in Scheme D5 except that CH C I was used instead of DMF in step A , and ng 2 2 (2S,5R)methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared in cis/trans ratio of 1:1 1 as described in Scheme B1). White solid. TLC R (EtOAc) = 0.35; MS (LC/MS): 472 [M+H]+, 494 [M+Na]+; t (HPLC conditions c): 4.52 min.
Example 351 : (2S,5R)Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol- -yl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared according to the general procedure described in Scheme D5 except that CH C I was used instead of DMF in step A , starting from a >9:1 diastereoisomeric 2 2 mixture of (2S.5R)- and (2S,5S)ethyl-pyrrolidine-1 ,2-diarboxylic acid 1-tert-butyl ester (prepared as described in Part B). The crude diastereoisomeric t e was purified by chiral preparative HPLC cel OJ, 10 mM, 250 x 4.6 mm, flow: 1.0 mL/min, mobile phase: heptane/EtOH 8:2; t = 5.61 min (major) and 14.3 min (minor) in a peak ratio of 87:13) to give the title compound as single diastereomer. TLC, R (EtOAc/c-hexane 4:1) = 0.31; MS (LC/MS): 486.1 ; t (HPLC conditions c): 4.76 min.
Example 352: (2S,4R)Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared according to Scheme D5 (steps B and C) from (2S,4R)(3- chlorofluoro-benzylcarbamoyl)hydroxymethyl-pyrrolidinecarboxylic acid tert-butyl ester prepared using the same protocol as for the ation of (2S,4S)(3-chlorofluorobenzylcarbamoyl )hydroxymethyl-pyrrolidinecarboxylic acid tert-butyl ester (prepared as described in Part B). TLC, R (EtOAc) = 0.05; MS (LC/MS): 488.1/490.1 , 510.1/512.1 [M+Na]+, 443.0/445.0 [M-CONH ]-; t (HPLC conditions a): 2.87 min. 2 R Example 353: (3S,5S)-1 -(1 -Carbamoyl-1 H-indolylcarbamoyl)(3-chloro-2,6-difluoro- yrrolidinecarboxylic acid methyl ester The title compound was prepared according to Scheme D5 (steps B and C) from (3S,5S)(3- chloro-2,6-difluoro-benzylcarbamoyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3- methyl ester prepared using the protocols described for the ation of (3S,5S)(3-chloro- 2-fluoro-benzylcarbamoyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester in Part B. R , TLC (CH C I /MeOH, 95:5) = 0.2; MS (LC-MS): 534.3/536.2 [M+H]+, 532.2 [M-H]-; t f 2 2 R (HPLC conditions a): 2.96 min.
Example 354: (3S,5S)-1 -(1 -Carbamoyl-1 H-indolylcarbamoyl)(3-chloro-2,6-difluoro- benzylcarbamoyl)-pyrrolidinecarboxylic acid To a solution of (3S,5S)(1 moyl-1 H-indolylcarbamoyl)(3-chloro-2,6-difluoro- benzylcarbamoyl)-pyrrolidinecarboxylic acid methyl ester e 353 (50 mg, 0.094 mmol) in THF (0.3 mL)/ Et 0 (3 mL)/ H 0 (0.3 mL) was added potassium trimethylsilanolate 2 2 (19.5 mg, 0.2 mmol) and the resulting suspension was stirred at RT for 1.30 h . The reaction was diluted with EtOAc (15 mL) and H 0 (3 mL), and the biphasic mixture was vigorously d for 5 min. The layers were separated, and the aqueous one was extracted with EtOAc (x2). The aqueous layer was acidified by addition of 1N HCI and ted with EtOAc, the combined organic layers were dried over Na S0 , filtered and concentrated. The crude 2 4 material was purified by preparative HPLC (Waters e, C18-ODB, 5 mhi , 19x50 mm, eluent: 20% to 100% CH CN in H 0 in 25 min, CH CN and H 0 containing 0.1% HCOOH, 3 2 3 2 flow: 20 mL/min) to give, after lyophilization of the purified fractions the title nd as a white solid. MS (LC-MS): 518.4 [M-H]-, 520.1 [M+H]+, 1039.3 [2M+H]+; t (HPLC conditions ) : 1.70 min.
Example 355: )Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-(3-bromo e) 1-[(1-carbamoyl-1H-indolyl)-amide] To a solution of (3S,5S)(3-bromofluoro-benzylcarbamoyl)(1-carbamoyl-1 H-indol ylcarbamoyl)-pyrrolidinecarboxylic acid methyl ester (85 mg, 0.14 mmol) in THF (1.5 mL) under nitrogen atmosphere was added LiBH (2 M in THF, 0.14 mL, 0.29 mmol). The reaction mixture was stirred at RT for 30 min, and then it was slowly poured into an aqueous saturated solution of NaHC0 and extracted twice with EtOAc. The combined c layers were dried over Na S0 , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel t: 100% CH C I to CH C I / MeOH 91-9) to give the desired 2 2 2 2 material as white solid. R , TLC (EtOAc) = 0.2; MS (UPLC-MS): 532.3/534.4 [M+H]+, 576.3/578.3 [M+HCOO]-, 532.5 [M-H]-; t (HPLC conditions ) : 1.69 min. )(3-Bromof luoro-benzylcarbamoyl)-1 -(1 -carbamoyl-1 H-indolylcarbamoyl)- pyrrolidinecarboxylic acid methyl ester The title compound was prepared according to Scheme D5 (steps B and C) from (3S,5S)(3- bromofluoro-benzylcarbamoyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester prepared using the protocols as for the preparation of (3S,5S)(3-chlorofluorobenzylcarbamoyl )-pyrrolidine-1 ,3-dicarboxylic acid -butyl ester 3-methyl ester described in Part B. R , TLC (EtOAc) = 0.45, MS (UPLC-MS): 560.5/562.4 [M+H]+, 577.3/579.4 [M+NH4]+, 582.3/584.3 [M+Na]+, 604.4/606.3 [M+HCOO]-, 558.2/560.2 [M-H]-; t (HPLC conditions ) 1.88 min.
Example 356: (2S,4S)Fluorohydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1- olyl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared according to Scheme D5 (steps B and C) from (2S,4S)(3- chlorofluoro-benzylcarbamoyl)fluorohydroxymethyl-pyrrolidinecarboxylic acid tert- butyl ester (prepared using similar protocols as described in Scheme B12). TLC, R (EtOAc) = 0.15; MS (LC-MS): 506.0/508.0 , 528.1/530.1 [M+Na]+, 506.1 [M-H], 461.0/463.0 [M-CONH ]-; t (HPLC conditions f): 1.71 min. 2 R Example 357: (1S,3S,5R)Hydroxymethylaza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indolyl)-amide] hlorofluoro-benzylamide) The title compound was prepared according to Scheme D5 (steps B and C) using in step B HCI 4N in dioxane d of TFA from a mixture of (1S,3S,5R) and (1R,3S,5S) hydroxymethylaza-bicyclo[3. 1.0]hexanecarboxylic acid 3-chlorofluorobenzylamide.HCI salt (prepared as described in Part B Scheme B28). The mixture of diastereoisomers was purified by flash column chromatography on silica gel (CH C I to 2 2 CH C I /MeOH:90:10) to give: ( 1 R,3S,5S)hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3- 2 2 dicarboxylic acid 2-[(1-carbamoyl-1 H-indolyl)-amide] hlorofluoro-benzylamide) and (1S,3S,5R)hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl- 1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) which was again purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, : 20% to 100% (CHsCN/MeOH 1:4)/H 0 in 30 min, (CH CN/MeOH 1:4) and H 0 containing 0.1% HCOOH, 2 3 2 flow: 20 mL/min): UPLC-MS: 500 [M+H]+, 544.3/546.4 O-]-; t (HPLC conditions ) : 1.78 min. The absolute stereochemistry was tentatively assigned by NMR and based on the test results for the final compounds Example 357 and Example 358.
Example 358: ( 1R,3S,5S)Hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic oyl-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) The title compound was prepared according to Scheme D5 (steps B and C) using in step B HCI 4N in dioxane instead of TFA from a mixture of (1S,3S,5R) and (1R,3S,5S) hydroxymethylaza-bicyclo[3. 1.0]hexanecarboxylic acid 3-chlorofluorobenzylamide.HCI salt red as described in Part B Scheme B28). The mixture of diastereoisomers was purified by flash column chromatography on silica gel (CH C I to 2 2 CH C I /MeOH:90:10) to give: ( 1 S)hydroxymethylaza-bicyclo[3.1 .0]hexane-2,3- 2 2 oxylic acid 2-[(1-carbamoyl-1 H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) which was again ed by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, eluent: 20% to 100% (CH CN/MeOH 1:4)/H 0 in 30 min, (CH CN/MeOH 1:4) and H 0 3 2 3 2 containing 0.1% HCOOH, flow: 20 mL/min) to give a white solid: 502.4 [M+H]+, 544.4/546.5 O]-; t (HPLC conditions f): 1.72 min. The absolute stereochemistry was tentatively assigned by NMR and based on the test results for the final compounds Example 357 and Example 358.
Example 359: (2S,4S)Difluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared according to Scheme D5 from (2S,4S)difluoromethylpyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester (prepared following the procedure described in J. Org. Chem. 2002, 67, 7162). White solid. MS (LC/MS): 508 [M+H]+; t (HPLC conditions b) 4.03 min.
Example 360: (2S,5R)Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] was prepared according to Scheme D5 (step C) using (2S,5R)(tert-butyl-dimethylsilanyloxymethyl )-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide (prepared as described in Part B). Except that after completion of the reaction, the mixture was poured into HCI 1N and EtOAc was added. The layers were separated and the aqueous one was back extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and 2 4 concentrated. The crude residue was purified by preparative HPLC (Waters e C 18- ODB, 5 [Jim, 19x50 mm, 20% CH CN/H 0 2.5 min, 20- 100% CH CN/H 0 in 10 min, 3 2 3 2 CH CN/H2O containing 0 .1 % HCOOH flow: 20 mL/min) to give after lyophilization of the purified HPLC fractions the title compound. MS (LC-MS): 506 [M+H]+; t (HPLC conditions b) 4 .13 min.
Example 361 : hydro-pyrazole-1 arboxylic acid 1-[(1 moyl-1 H-indolyl)- -benzylamide) The title compound was prepared according to Scheme D5 (step C) from 3,4-dihydro-2H- pyrazolecarboxylic acid 3-chloro-benzylamide (prepared using similar protocols as described in Scheme B5). MS (LC-MS): 439.0 [M+H]; t (HPLC conditions b): 3.55 min. e 362: (S Dihydro-pyrazole-1 ,5-dicarboxylic acid 1-[(1 -carbamoyl-1 H-indol- -yl)-amide] 5-(3-chlorofluoro-benzylamide) Obtained from racemic 4,5-dihydro-pyrazole-1 arboxylic acid 1-[(1 -carbamoyl-1 H-indol yl)-amide] 5-(3-chlorofluoro-benzylamide) Example 201 by separation by chiral HPLC (Chiralpak ADi 5 m , 1mL/min, solvent: TBM E/CH C I /EtOH 50:30:20, t = 9.08 min). MS (LC- 2 2 R MS): 457 [M+H]+; t (HPLC conditions b): 3.73 min. The absolute stereochemistry has been assigned tentatively based on the test results for the final compounds Example 362 and Example 363 in the biological assay.
Example 363: ,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol- -yl)-amide] 5-(3-chlorofluoro-benzylamide) Obtained from racemic 4,5-dihydro-pyrazole-1 ,5-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol yl)-amide] 5-(3-chlorofluoro-benzylamide) Example 201 by separation by chiral HPLC (Chiralpak ADi 5 m , 1ml_/min, solvent: H 2C I2/EtOH 50:30:20, tR = 6.49 min). MS (LC- MS): 457 [M+H]+; tR (HPLC conditions b): 3.73 min. The absolute stereochemistry has been assigned tentatively based on the test results for the final compounds e 362 and Example 363 in the biological assay.
Example 364: (2S,3R)Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] §)(3-chlorofluoro-phenyl)-ethyl]-amide} The title compound was prepared according to the general procedure described in Scheme D5 (CH2C I2 was used instead of DMF in step A) from a ca. ( 1 :1)-mixture of diastereomers (2S.3R)- 3-hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-{[(R) and (S)(3-chlorofluoro-phenyl)-ethyl]-amide} and purification of the title compound by preparative chromatographic separation on a Chiralpak IA 5 mhi nary phase (column 250 x 10 mm) using heptane/TBME/MeOH/TFA 50:35:15:0.05 as the eluent (flow: 8 mL/min, ion 254 nm, 25°C). White solid. MS (LC/MS): 488 [M+H]+; tR (HPLC conditions b): 3.28 min. tR (chiral HPLC conditions: Chiralpak IA 5 mhi ; column 250 x 4.6 mm; heptane/TBME/MeOH/TFA 15:0.05; flow: 2.00 mL/min; ion 254 nm, 25°C): 10.1 min. The absolute stereochemistry has been assigned ively based on the test results for the final compounds Example 364 and Example 365 in the biological assay.
Example 365: (2S,3R)Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-{[(S§)(3-chlorofluoro-phenyl)-ethyl]-amide} The title compound was prepared according to the general ure described in Scheme D5 (CH C I was used d of DMF in step A) from a ca. ( 1 :1)-mixture of diastereomers (2S.3R)- 2 2 3-hydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] ) and (S)(3-chlorofluoro-phenyl)-ethyl]-amide} by preparative chromatographic separation on a Chiralpak IA 5 mhi stationary phase (column 250 x 10 mm) using heptane/TBME/MeOH/TFA 50:35:15:0.05 as the eluent (flow: 8 mL/min, detection 254 nm, 25°C). White solid. MS (LC/MS): 488 [M+H]+; t (HPLC conditions b): 3.28 min. t l HPLC conditions: Chiralpak R R IA 5 mhi ; column 250 x 4.6 mm; heptane/TBME/MeOH/TFA 50:35:15:0.05; flow: 2.00 mL/min; detection 254 nm, 25°C): 14.3 min. The absolute stereochemistry has been assigned tentatively based on the test results for the final compounds Example 364 and Example 365 in the biological assay.
Example 366: (S)-Pyrrolidine-1,2-dicarboxylic acid 1-{[1-(2-hydroxy-acetyl)-1H-indol -amide} 2-[(3-trifluoromethoxy-phenyl)-amide] (S)-Pyrrolidine-1 arboxylic acid (2-benzyloxy-acetyl)-1H-indolyl]-amide} 2-[(3- trifluoromethoxy-phenyl)-amide] (55 mg, 0.095 mmol) was dissolved in MeOH ( 1 mL) and Pd/C % (12 mg) was added and the solution was degassed 3 times replacing air by nitrogen and finally en by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere overnight and the catalyst was d through a pad of Celite and washed with MeOH. Solvent was concentrated and the crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 m , 19x50 mm, 20% CH CN/H 0 2.5 min, 20-100% 3 2 C H3CN/H2O in 10 min, CH CN/H 0 containing 0.1 % HCOOH flow: 20 mL/min) to give after 3 2 lyophilization of the pure fractions the desired compound. TLC, R (CH C I /MeOH 9:1) = 0.49; f 2 2 MS (LC/MS): 491 .1 [M+H]+, 513.2 [M+Na]+, 489.1 ; t (HPLC conditions a): 3.47 min.
(S)-Pyrrolidine-1,2-dicarboxylic acid (2-benzyloxy-acetyl)-1H-indolyl1-amide) 2- ifluoromethoxy-phenyl)-amide1 To a solution of (S)-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide TFA salt (177 mg, 0.457 mmol) and Et N (191 m I, 1.37 mmol) in dry THF (3.5 mL) was added a solution of 2-benzyloxy(3-isocyanato-indolyl)-ethanone (140 mg, 0.457 mmol, ed as described in Scheme A5) in dry THF (3.5 mL). The solution was stirred at RT under nitrogen for 15 min until completion. The e was poured into water, extracted twice with EtOAc.
The combined organic layers were dried over Na S0 , filtered and concentrated. The crude 2 4 material was ed by flash column chromatography on silica gel (c-hexane to c- hexane/EtOAc 65:35) to afford the desired compound. TLC, R ane/EtOAc 1:1) = 0.3; MS (LC/MS): 581 .2 [M+H]+, 579.1 [M-H]-; t (HPLC ions a): 4.18 min.
Example 367: (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetylcyano-1H-indolyl)- methoxy-phenyl)-amide] To a solution of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(6-cyano-1 lyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide] (60 mg, 0.131 mmol) in dry THF ( 1 mL) at 0°C under nitrogen atmosphere was added potassium tert-butoxide (17.7 mg, 0.157 mmol). The suspension was stirred at 0°C for 5 minutes before addition of acetyl chloride (0.01 1 mL, 0.157 mmol) and the resulting solution was stirred at RT under nitrogen overnight. The mixture was poured into an aqueous saturated solution of NaHC0 and extracted twice with CH C I . The combined 3 2 2 organic layers were dried over Na S0 , filtered and concentrated. The crude material was successively purified by flash column chromatography on silica gel (CH C I to CH C I /MeOH 2 2 2 2 95:5) and preparative HPLC (Waters Sunfire B, 5um, 19x50mm, flow: 20 mL/min, gradient: 0-2.5 min 20% CH CN, 2.5-12.5 min 20 to 100% CH CN, 12.5-15 min 100% CH CN, 3 3 3 H 0 and CH CN containing 0.1% HCOOH) to give after lyophilization of the purified fractions 2 3 the desired compound. MS (LC/MS): 500 [M+H]+, 498.1 [M-H]-; t (HPLC conditions a): 3.69 min.
(S)-Pyrrolidine-1,2-dicarboxylic acid 1-r(6-cyano-1H-indolyl)-amide1 2-G(3- trifluoromethoxy-phenvD-amidel A solution of (S)-pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide TFA salt (315 mg, 0.81 mmol) in THF (10 mL) was added to a solution of 3-isocyanato-1H-indole carbonitrile (270 mg, prepared as described in Part A , 70% purity as measured by NMR) in toluene (4 mL). Triethylamine (338 m I, 2.43 mmol) was added and the resulting solution was stirred at RT under nitrogen overnight. The mixture was poured into HCI 1 N and extracted with EtOAc (x3). The combined organic layers were washed with a saturated aqueous NaHC0 solution, dried over Na S0 , ed and trated. The crude material was purified by flash 2 4 column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give the title compound. TLC, R ane/EtOAc 1:1) = 0.5; MS (LC-MS): 554.0 [M+H]+, 556.0 [M-H]-; t f R (HPLC conditions a): 3.74 min.
Example 368: )Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1 -acetyl difluoromethoxy-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) To a solution of (2S,4R)fluoro-pyrrolidine-1 arboxylic acid 2-(3-chlorofluorobenzylamide ) 1-[(6-difluoromethoxy-1H-indolyl)-amide] (105 mg, 0.210 mmol) in dry THF (5 mL) was added Ac 0 ( 1 mL, 10.5 mmol) and DMAP (26 mg, 0.210 mmol). The reaction mixture was stirred at 60°C for 18 h . The volatiles were evaporated under reduced pressure, and the residue was purified by ative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 mhi , 40x250 mm, flow: 40 mL/min, eluent: 5-100% CH CN/H O/20 min, 100% CH CN/2 min, 3 2 3 CH CN and H 0 containing 0.1% TFA) to afford after lyophilization of purified ons the title 3 2 compound as a white solid. MS (LC/MS): 541 [M+H]+, 563 [M+Na]+; t (HPLC conditions k): 3.65 min. (2S,4R)fluoro-pyrrolidine-1,2-dicarboxylic acid 2-(3-chlorofluoro-benzylamide) 1- r(6-difluoromethoxy-1H-indolyl)-amide1 The title compound was prepared according to the general protocol described in Scheme D5.
In Step C, uoromethoxyisocyanato-1H-indole (prepared as described in Part A) was used and after completion of the reaction, the mixture was concentrated and directly purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, flow: 40 ml/min, eluent: 5- 100% CH CN/H O/20 min, 100% CH3CN/2 min, CH CN and H 0 containing 0.1% TFA). White 3 2 3 2 solid. MS ): 499 [M+H]+, 521 [M+Na]+; t (HPLC conditions k): 3.49 min).
Example 369: (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoylhydroxy-1H-indol- 3-yl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] (S)-Pyrrolidine-1 ,2-dicarboxylic acid 1-[(6-benzyloxycarbamoyl-1 H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide] Example 313 (75 mg, 0.129 mmol) was ved in a mixture of THF/DMF 1-1 (3 ml_), Pd/C 10 % (20 mg) was added to the solution and the solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The on mixture was further stirred under hydrogen atmosphere for 3 h and the catalyst was removed through a pad of Celite and washed with THF. Solvents were trated and the resulting oil was poured into water and extracted with EtOAc (x3). The combined organic layers were washed twice with water, dried over Na S0 , filtered and concentrated. The crude residue was 2 4 purified by preparative HPLC (Waters SunFire C18-ODB, 5 m h , 19x50 mm, 20% to 100 % CH CN in H 0 in 25 min, CH CN/H 0 containing 0.1 % HCOOH flow: 20 mL/min) to give after 3 2 3 2 lyophilization of the purified fractions the desired compound. TLC, R (EtOAc) = 0.39; MS (LC/MS): 492.1 [M+H]+, 490.1 [M-H]-; t (HPLC conditions a): 3.22 min.
Example 370: rrolidine-1,2-dicarboxylic acid 1-[(1-carbamoylhydroxy-1H-indol- mide] 2-[(3-trifluoromethoxy-phenyl)-amide] A e of (S)-pyrrolidine-1,2-dicarboxylic acid 1-[(5-allyloxycarbamoyl-1 H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide] Example 335 (30 mg, 0.056 mmol), palladium acetate ( 1 .4 mg, 2.82 mhioI ) and triphenylphosphine ( 1 .5 mg, 5.64 mhioI ) in formic acid (0.7 mL) was heated at 90°C for 30 min under nitrogen. The mixture was poured into water and extracted twice with EtOAc. The combined c layers were dried over Na S0 , filtered and trated. The crude material was purified by flash column chromatography on silica gel (c- hexane/EtOAc 1:1 to EtOAc) to give the desired compound. TLC, R (EtOAc) = 0.56; MS (LC/MS): 492 [M+H]+, 514.2 [M+Na]+, 490 [M-H]-, 447.1 [M-CONH ]-; t (HPLC conditions a): 2 R 3.13 min.
Example 371 : ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1- carbamoylhydroxy-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) Allyl palladium chloride dimer (4.9 mg, 0.013 mmol) and 2-di-tert-butylphosphino-2'- methylbiphenyl (16.6 mg, 0.053 mmol) were dissolved in DMF (0.4 mL) and the e was stirred for 5 min under nitrogen atmosphere. Formic acid (30 m I_ , 0.772 mmol), triethylamine (107 m I_ , 0.772 mmol) and (1R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(5- allyloxycarbamoyl-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) Example 268 (70 mg, 0.133 mmol) in DMF ( 1 mL) were added in that order. The mixture was d at 10°C for 1 h , then at RT for 2 days. The mixture was poured into water and extracted twice with EtOAc.
The combined organic layers were dried over Na S0 , filtered and concentrated. The crude 2 4 material was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, eluent: 20% to 100% CH CN in H 0 in 15 min, CH CN and H 0 containing 0.1% HCOOH, 3 2 3 2 flow: 20 mL/min) to give the desired nd after lyophilization of the purified fractions.
TLC, R (EtOAc) = 0.4 ; MS (LC-MS): 486.0 [M+H]+, 441 .1 [M-CONH ]-; t (HPLC conditions f): f 2 R 1.65 min.
Example 372: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1- H-indolyl)-amide] 3-(2-fluoro-benzylamide) Allyl palladium de dimer (17.8 mg, 0.048 mmol) and 2-di-tert-butylphosphino-2'- methylbiphenyl (60.6 mg, 0.194 mmol) were ved in DMF (2 mL) and the mixture was stirred for 5 min. Formic acid (108 m , 2.81 mmol), triethylamine (391 m , 2.81 mmol) and ( 1 R,3S,5R)aza-bicyclo[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(5-allyloxycarbamoyl-1H- 3-yl)-amide] 3-(3-chlorofluoro-benzylamide) Example 268 (255 mg, 0.485 mmol) in DMF (3 mL) were added in that order and the resulting solution was stirred at RT overnight under nitrogen. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and concentrated. The crude residue was ed by flash column chromatography on silica gel (c-hexane 100% to 100% EtOAc to CH C I /MeOH 90-10) to give a mixture of the desired compound together with the 2 2 deschlorinated analog. The mixture was purified by preparative HPLC (Interchrom, C18-ODB, mhi , 28x250 mm, eluent: 20% to 100% CH CN in H 0 in 40 min, CH CN and H 0 3 2 3 2 containing 0 .1% HCOOH , flow: 40 mL/min) to give after extraction of the purified fractions with EtOAc ( 1 R,3S,5R)aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 2-[(1 -carbamoyl hydroxy- 1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) and ( 1 R,3S,5R)aza- o[3. 1.0]hexane-2,3-dicarboxylic acid 2-[(1 -carbamoylhydroxy-1 H-indolyl)-amide] 3- (2-fluoro-benzylamide). TLC, R (EtOAc) = 0.3; MS (LC-MS) : 452. 1 [M+H]+, 474. 1 [M+Na]+, 407 [M-CON H ]-; t (HPLC conditions f) : 1.81 min. 2 R e 373: ( 1R,3S,5R)Aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 2-[(1 - omethoxy-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) To a solution of Example 371 ( 1 R,3S,5R)aza-bicyclo[3. xane-2,3-dicarboxylic acid 2- [(1 -carbamoylhydroxy- 1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) (50 mg, 0 .103 mmol) in acetone (0.5 ml_) were added cesium carbonate (36.9 mg, 0 .11 mmol) and cetonitrile (8. 13 m I_ , 0 .11 mmol) and the reaction mixture was stirred at RT under nitrogen for 4 h . Acetone was concentrated. The residue was dissolved in water and extracted twice with EtOAc. The combined organic ts were dried over Na S0 , filtered and 2 4 concentrated. The crude material was purified by prep HPLC (Waters Sunfire, C 18-ODB, 5 [Jim , 19x50 mm, eluent: 20% to 100% (CH CN/MeOH 1-4) / H 0 in 15 min, (CH CN/MeOH 1-4) 3 2 3 and H 0 containing 0 .1% HCOOH , flow: 20 mL/min). TLC, Rf (EtOAc) = 0.45; MS (UPLC/MS): 525.4/527.2 [M+H]+, 542.4/544.7 [M+N H ]+, 571 .4 O]-; t (HPLC conditions f) : 4 R 1.89 min.
Example 374: ( 1-Carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- necarbonyl]-amino}-1H-indolyloxy)-acetic acid To a solution of ( 1-carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3. 1.0]hexanecarbonyl]-amino}-1 H-indolyloxy)-acetic acid methyl ester Example 133 (85 mg, 0 .145 mmol) in THF ( 1 .2 mL) and H 0 ( 120 m I_) was added NaOH 1N (290 m I_, 0.29 mmol) and the reaction mixture was d at RT for 20 min. The crude was directly purified using trimethylaminopropyl cartridge (Mega Bond Elut-SAX, 1 g from Varian) pre- washed with CH CN (10 mL) and the compound was released with 10 mL of HCI 0.1 N in CH CN. The resulting solution was concentrated and purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, : 20% to 100% CH CN in H 0 in 15 min, CH CN 3 2 3 and H 0 containing 0.1% HCOOH, flow: 20 mL/min) to give the desired material after lization of the purified fractions. MS MS): 544.3/546.3 [M+H]+, 566.4/568.3 [M+Na]+, 542.3/544.4 [M-H]-; t (HPLC conditions f): 1.72 min.
Example 375: ( 1-Carbamoyl{[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro- 4-methyl-pyrrolidinecarbonyl]-amino}-1H-indolyloxy)-acetic acid The title compound was prepared according to the protocol described for the preparation of Example 374 from (1-carbamoyl{[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro methylpyrrolidinecarbonyl]-amino}-1H-indolyloxy)-acetic acid methyl ester e 318.
MS (UPLC): 564.2 [M+H]+, 562.3 [M-H]-; t (HPLC conditions f): 1.72 min.
Example 376: (1-Carbamoyl{[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azanecarbonyl ]-amino}-1H-indolyloxy)-acetic acid The title compound was prepared according to the protocol described for the preparation of Example 374 from (1-carbamoyl{[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza bicyclo[3.1 .0] hexanecarbonyl]-amino}-1H-indolyloxy)-acetic acid methyl ester Example 394. MS : 544.3/546.3 , 542.3/544.3 [M-H]-; t (HPLC conditions ) : 1.78 min.
Example 377: (1-Carbamoyl{[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexanecarbonyl]-amino}-1H-indolyl)-acetic acid The title compound was prepared ing to the protocol described for the preparation of Example 374 from (1-carbamoyl{[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)3 Example 306. TLC, R (EtOAc) = 0.2; MS (UPLC): 528.3/530.2 [M+H]+, 528.6 [M-H]-, 483.3/485.3 [M-CONH ]-; t (HPLC conditions f): 1.74 min. 2 R Example 378: (1-Carbamoyl{[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azanecarbonyl ]-amino}-1H-indolyl)-acetic acid to a on of (1-carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0] hexanecarbonyl]-amino}-1 H-indolyl)-acetic acid tert-butyl ester Example 127 (30 mg, 0.051 mmol) in CH C I (0.5 ml_) was added TFA (157 m I_ , 2.05 mmol) and the 2 2 e was stirred at RT for 1 h . Then concentrated and the crude residue was taken up in Et 0 and filtered-off to give the d material. MS (UPLC): 528.2/530.3 [M+H]+, 1055.6/1057.2 [2M+H]+, 483.1/485.1 [M-CONH ]-, 1053.6/1055.6 [2M-H]-; t (HPLC conditions 2 R f): 1.75 min.
Example 379: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1- droxy-ethoxy)-1H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide) To a solution of (1-carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza bicyclo[3.1.0]hexanecarbonyl]-amino}-1 H-indolyloxy)-acetic acid methyl ester Example 133 (344 mg, 0.573 mmol) in THF (3 mL) under nitrogen was added LiBH 2M in THF (573 m , 1.15 mmol). The resulting solution was stirred at RT under nitrogen for 30 min, then slowly poured into an s saturated solution of NaHC0 and extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and concentrated. The crude residue was taken up in CH C I and filtered-off then purified by preparative HPLC (Waters e, 2 2 C18-ODB, 5 m , 19x50 mm, eluent: 20% to 100% CH CN in H 0 in 15 min, CH CN and H 0 3 2 3 2 containing 0.1% HCOOH, flow: 20 mL/min) to give the desired material after lyophilization of the purified fractions. R , TLC (EtOAc) = 0.15; MS (LC-MS): 530/532 , 552.1/554.1 [M+Na]+, 528.1/530.1 [M-H]-, 485/487 [M-CONH ]-; t (HPLC conditions ) : 1.64 min. 2 R Example 380: (S)-Thiazolidine-2,3-dicarboxylic acid 3-{[1-carbamoyl(2-hydroxy- 3-yl]-amide} 2-(3-chlorofluoro-benzylamide) The title compound was prepared according to the protocol described for the preparation of e 379 from (1-carbamoyl{[(S)(3-chlorofluoro-benzylcarbamoyl)-thiazolidine carbonyl]-amino}-1H-indolyloxy)-acetic acid methyl ester (prepared using r protocols as for Example 133). TLC, R (EtOAc) = 0.45; MS (UPLC): 564.2/566.2 [M+H]+, 581.2/583.2 [M+NH ]+, 562.3/564.3 [M-H]-, 608.4/610.4 [M+HCOO]-; t (HPLC conditions f): 1.82 min. 4 R Example 381 : (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1- carbamoyl(2-hydroxy-ethoxy)-1H-indolyl]-amide} 3-[(3-trifluoromethoxy-phenyl)- The title compound was prepared according to the protocol described for the preparation of Example 379 from (1-carbamoyl{[(1 R,3S,5R)(3-trifluoromethoxy-phenylcarbamoyl) aza-bicyclo[3.1.0] hexanecarbonyl]-amino}-1H-indolyloxy)-acetic acid methyl ester (prepared using similar protocols as for Example 133). MS (UPLC): 548.3 [M+H]+, 546.3 [M- H]-, 592.3 [M+HCOO]-; t (HPLC conditions ) : 1.80 min. e 382: S*,5R*)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-{[1- carbamoyl(2-hydroxy-ethoxy)-1H-indolyl]-amide} 2-(3-chlorofluoro-benzylamide) The title compound was prepared according to the protocol described for the preparation of e 379 from (1-carbamoyl{[(1S*,2S*,5R*)(3-chlorofluoro-benzylcarbamoyl) aza-bicyclo[3.1.0] carbonyl]-amino}-1 H-indolyloxy)-acetic acid methyl ester ester (prepared using similar protocols as for Example 133). MS (UPLC): 530.3/532.2 [M+H]+, 528.2/530.4 [M-H]-, 574.3/576.3 [M+HCOO]-; t (HPLC conditions f): 1.58 min. e 383: (2S,4R)Fluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-{[1- carbamoyl(2-hydroxy-ethoxy)-1H-indolyl]-amide} 2-(3-chlorofluoro-benzylamide) The title nd was prepared according to the protocol described for the preparation of Example 379 from bamoyl{[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro methyl-pyrrolidine carbonyl]-amino}-1 H-indolyloxy)-acetic acid methyl ester Example 318. TLC, R (EtOAc) = 0.30; MS (UPLC): 550.3/552.5 [M+H]+, 505.7/507.1 H ]-; t f 2 R (HPLC conditions f): 1.72 min.
Example 384: ,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1- droxy-ethyl)-1H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide) The title compound was prepared according to the protocol described for the preparation of Example 379 from (1-carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- bicyclo[3.1 .0] hexanecarbonyl]-amino}-1H-indolyl)-acetic acid ethyl ester Example 315.
MS (UPLC): 514.3/516.3 [M+H]+, 512.3/514.3 [M-H]-, 560.2 [M+HCOO]-; t (HPLC conditions ) 1.75 min.
Example 385: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1- droxy-ethyl)-1H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide) The title compound was prepared according to the protocol described for the preparation of Example 379 from bamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- bicyclo[3.1 .0] hexanecarbonyl]-amino}-1H-indolyl)-acetic acid ethyl ester Example 306.
TLC, R (EtOAc) = 0.2; MS (UPLC): 514.2/516.3 [M+H]+, 512.3/514.1 [M-H]-, 558.3/560.2 [M+HCOO]-, 469.2/471.4 H ]-; t (HPLC conditions f): 1.72 min. 2 R Example 386: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1- carbamoyl(2-hydroxymethyl-propoxy)-1H-indolyl]-amide} 3-(3-chlorofluoro- To a solution of bamoyl{[(1 R)(3-chlorofluoro-benzylcarbamoyl)aza bicyclo[3.1.0]hexanecarbonyl]-amino}-1 H-indolyloxy)-acetic acid methyl ester Example 133 (50 mg, 0.083 mmol) in dry THF (0.5 mL) at 0°C was added methylmagnesium bromide (3M in Et 0 , 6 1 m I_ , 0.183 mmol). The mixture was stirred under nitrogen at 0°C for 10 min, then allowed to reach RT and further stirred for 24 h . Water was added (2 mL) and the precipitate was filtered-out. The te was extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and concentrated. The crude residue was purified by 2 4 preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, eluent: 20% to 100% CH CN in H 0 in 15 min, CH CN and H 0 ning 0.1% HCOOH, flow: 20 mL/min) to give the 2 3 2 desired material after lyophilization of the purified ons. TLC, R (EtOAc) = 0.25; MS (LC- MS): 0 [M+H]+, 513.1/515.2 [M-CONH ]-; t (HPLC conditions ) : 1.84 min. 2 R Example 387: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1- carbamoyl(2-dimethylamino-ethoxy)-1H-indolyl]-amide} 3-(3-chlorofluoro- A solution of methanesulfonic acid 2-(1-carbamoyl{[(1 R,3S,5R)(3-chlorofluorobenzylcarbamoyl )aza-bicyclo[3.1 .0]hexanecarbonyl]-amino}-1H-indolyloxy)-ethyl ester (35 mg, 0.054 mmol) and dimethylamine 5.6 M in EtOH (0.5 mL) was heated at 70°C for 4 h in a sealed tube. The reaction was poured into an aqueous saturated on of NaHC0 and extracted twice with EtOAc. The combined organic layers were dried over Na S0 , filtered and concentrated. The crude residue was purified by preparative HPLC (Nucleosil, C18-HD, 5 mhi , 2 1x50 mm, eluent: 20% to 100% CH3CN in H 0 in 15 min, CH CN and H 0 containing 0 .1% 2 3 2 HCOOH , flow: 20 ) to give after lization of the purified fractions the desired material as a formic acid salt. MS (UPLC): 557.3/559.3 [M+H]+, 555.6/558.4 [M-H]-, 12.3/51 4.5 [M-CON H ]-; t (HPLC conditions f : 1.47 min. 2 R Methanesulfonic acid 2-( 1-carbamoylf IT 1R.3S.5R)(3-chlorof luorobenzylcarbamoyl )aza-bicvclor3. 1.01hexanecarbonvn-aminoV1 H-indolyloxy)-ethyl ester To a solution of ( 1 R,3S,5R)aza-bicyclo[3. xane-2,3-dicarboxylic acid 2-{[1 -carbamoyl- -(2-hydroxy-ethoxy)- 1H-indolyl]-amide} hlorofluoro-benzylamide) e 379 (50 mg, 0.09 mmol) and Et N (62 m I_ , 0.448 mmol) in CH C I ( 1 mL) at 0°C under nitrogen 3 2 2 atmosphere, was added methanesulfonyl chloride (35 m I_ , 0.448 mmol) . The resulting solution was stirred at RT overnight. Et N (31 m I_ , 0.224 mmol) and methanesulfonyl chloride ( 17 m I_ , 0.224 mmol) were added and the e was further stirred at RT for 1.5 h to te the reaction. The reaction was poured into a saturated aqueous solution of NaHC0 , extracted twice with CH C I , dried over Na S0 , filtered and concentrated. The crude residue was 2 2 2 4 purified by flash column chromatography on silica gel (c-hexane/EtOAc 1- 1 to 100% EtOAc) to give the desired material . TLC, R (EtOAc) = 0.25; MS (UPLC): 608.5/61 0.2 , 563.4 [M- CON H ]-, 606.4/608.0 [M-H]-; t (HPLC conditions ) : 1.88 min. 2 R Example 388: ( 1 R,3S,5R)Aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 2-{[1 - carbamoyl(2-pyrrolidin-1 -yl-ethoxy)-1 H-indolyl]-amide} 3-(3-chlorofluoro- The title compound was prepared as a formic acid salt from methanesulfonic acid 2-(1 - carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3. 1.0]hexane- 2-carbonyl]-amino}-1 H-indolyloxy)-ethyl ester and pyrrolidine according to the procedure described for the preparation of Example 387: ( 1 R)Aza-bicyclo[3. 1.0]hexane-2,3- dicarboxylic acid 2-{[1 -carbamoyl(2-dimethylamino-ethoxy)- 1H-indolyl]-amide} 3-(3- chlorofluoro-benzylamide). TLC, R (CH C I / MeOH 8-2) = 0.3; MS (UPLC/MS): 583.5/585.5 f 2 2 [M+H]+, 627.5/629.3 [M+HCOO]-; t (HPLC conditions ) : 1.51 min.
Example 389: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1- carbamoyl(2-imidazolyl-ethoxy)-1H-indolyl]-amide} 3-(3-chlorofluoro- The title compound was prepared from methanesulfonic acid 2-(1-carbamoyl{[(1R,3S,5R) (3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hexanecarbonyl]-amino}-1 H-indol- y)-ethyl ester and imidazole according to the procedure described for the preparation of Example 387: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl- -(2-dimethylamino-ethoxy)-1H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide). TLC, R (CH C I / MeOH 8-2) = 0.60; MS (UPLC/MS): 580.5/582.5 , 578.5/580.7 , 2 2 624.5/626.5 [M+HCOO]-; t (HPLC conditions f): 1.49 min.
Example 390: bamoyl{[(1R,3S,5R)(2-fluoro-benzylcarbamoyl)azanecarbonyl ]-amino}-1H-indolyloxy)-acetic acid tert-butyl ester To ( 1 R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoylhydroxy- 1H-indolyl)-amide] 3-(2-fluoro-benzylamide) Example 372 (38 mg, 0.084 mmol) in acetone (0.45 ml_) was added cesium carbonate (30.2 mg, 0.093 mmol) and utyl bromoacetate (14 m I_ , 0.093 mmol), and the resulting suspension was stirred at RT under nitrogen overnight. e was concentrated and to the residue water was added and the mixture was extracted twice with EtOAc. The combined oragnic layers were dried (Na S0 ) , filtered and 2 4 concentrated. The crude residue was purified by preparative HPLC s Sunfire, C18-ODB, mhi , 19x50 mm, eluent: 20% to 100% CH CN in H 0 in 15 min, CH CN and H 0 containing 3 2 3 2 0.1% HCOOH, flow: 20 mL/min) to give the desired material after lyophilization of the purified fractions. MS (LC-MS): 588.3 [M+Na]+, 510.1 [MH-tBu]+, 521 .2 [M-CONH ]-; t (HPLC 2 R conditions ) 2.04 min.
Example 391 : (1-Carbamoyl{[(1R,3S,5R)(2-fluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexanecarbonyl]-amino}-1H-indolyloxy)-acetic acid To (1-carbamoyl{[(1 R,3S,5R)(2-fluoro-benzylcarbamoyl)aza-bicyclo[3.1.0]hexane carbonyl]-amino}-1H-indolyloxy)-acetic acid tert-butyl ester Example 390 (18 mg, 0.032 mmol) in CH C I (0.5 mL) was added TFA (97 m I_ , 1.27 mmol) and the mixture was stirred at 2 2 RT overnight. Then concentrated, taken up in CH C I and ed-off to give the desired 2 2 material which was further dried under high vacuum. MS (LC-MS): 510.1 [M+H]+, 532.2 [M+Na]+, 508.1 [M-H]-, 465.1 [M-CONH ]-; t (HPLC conditions ) : 1.52 min. 2 R Example 392: (1R,3S,5R)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1- xy-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) The title compound was prepared from (1R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(6-allyloxycarbamoyl-1H-indolyl)-amide] 3-(3-chlorofluoro-benzylamide) according to the procedure bed for the preparation of ( 1 R,3S,5R)aza- o[3.1 .0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoylhydroxy-1H-indolyl)-amide] 3- (3-chlorofluoro-benzylamide) Example 371 . MS (LC-MS): 486.0 [M+H]+; t (HPLC conditions b) : 3.39 min. e 393: (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl hydroxy-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared from (2S,4R)fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(6- allyloxycarbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) according to the procedure described for the preparation of ( 1 R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3- dicarboxylic acid 2-[(1-carbamoylhydroxy-1H-indolyl)-amide] hlorofluorobenzylamide ) e 371 . MS (LC-MS): 492 [M+H]+; t (HPLC conditions b): 3.12 min.
Example 394: ( 1-Carbamoyl{[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl) necarbonyl]-amino}-1H-indolyloxy)-acetic acid methyl ester To ( 1 R,3S,5R)aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 2-[(1 -carbamoylhydroxy- 1H-indolyl)-amide] hlorofluoro-benzylamide) Example 392 (70 mg, 0 .144 mmol) in acetone (720 m I_) were added Cs C0 (56.3 mg, 0 .173 mmol) and methyl bromoacetate ( 16.4 2 3 m I_ , 0 .173 mmol) and the reaction mixture was stirred at 23°C overnight. 0.5 eq of methyl cetate and 0.5 eq of Cs C0 were added and the reaction e was stirred at 23°C 2 3 for 4 hr to complete the reaction. The crude mixture was poured in water and ted with EtOAc (x2) . The combined organic layers were dried (Na S0 ) , ed and evaporated to 2 4 dryness. The crude material was purified by preparative HPLC (Waters SunFire C 180DB, 5 [Jim, 30x1 00, eluent: 20% CH CN/80% H 0 to 100% CH CN in 20 min, CH CN and H 0 3 2 3 3 2 containing 0 .1% of TFA, flow 40 mL/min) to give the desired material after lyophilization of the ed fractions. MS (LC-MS): 558 [M+H]+; t (HPLC conditions b) : 3.84 min.
Example 395: ( 1R,3S,5R)Aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 2-{[1 - droxy-ethoxy)-1H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide) The title compound was prepared from ( 1-carbamoyl{[(1 R,3S,5R)(3-chlorofluorobenzylcarbamoyl )aza-bicyclo[3. 1.0]hexanecarbonyl]-amino}-1 H-indolyloxy)-acetic acid methyl ester Example 394 according to the procedure described for the preparation of ( 1 R,3S,5R)aza-bicyclo[3. xane-2,3-dicarboxylic acid 2-{[1 -carbamoyl(2-hydroxy- ethoxy)-1 H-indolyl]-amide} 3-(3-chlorofluoro-benzylamide) Example 379. TLC, Rf (EtOAc) = 0 .12 ; MS (UPLC): 532.3 [M+H]+, 528.2/530.5 [M-H]-, 574.2/576.4 [M+HCOO]-; t (HPLC conditions f): 1.71 min.
Example 396: (2S,4S)Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -carbamoyl-1 H- indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] (2S,4S)N-fmoc-Amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-[(3-trifluoromethoxy-phenyl)-amide] (380 mg, 0.533 mmol) was dissolved in a solution of piperidine 20 % in DMF (2 ml_). The mixture was stirred at RT for 1 h and directly purified by ative HPLC (Interchrom C18-ODB, 10 mhi , 28x250 mm, 5% CH CN in H 0 2.5 min, 3 2 then 5% to 100 % CH CN in H 0 in 32.5 min, CH CN and H 0 ning 0.1 % HCOOH; flow: 3 2 3 2 40 mL/min). To the ed HPLC fractions was added NaOH 1 N and the compound was extracted with EtOAc (x3). The combined organic extracts were dried over Na S0 , ed and 2 4 concentrated and this material was purified again by preparative HPLC (Water e C18- ODB, 5 mhi , 19x50 mm, eluent: 5 % to 60% CH CN in H 0 in 18 min, CH CN and H 0 3 2 3 2 containing 0.1 % HCOOH; flow: 20 ) to give after lyophilization of the purified fractions the desired compound as a formate salt. MS (LC-MS): 491.2 [M+H]+, 489.1 [M-H]-. (2S,4S)N-fmoc-Amino-pyrrolidine-1,2-dicarboxylic acid 1-r(1-carbamoyl-1H-indolyl)- amidel 2-r(3-trifluoromethoxy-phenyl)-amide1 The title compound was prepared as described in Scheme D5 from (4S)N-Fmoc-amino Boc-L-proline. TLC, R (CH C I /MeOH 9:1) = 0.45; t (HPLC conditions a): 4.20 min. f 2 2 R Example 397: (2S,3S,4R)Aminomethoxy-pyrrolidine-1,2-dicarboxylicacid 1-[(1- o l-3 -y l)-a m ide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared according to Scheme D5 (steps B and C) from (2S,3S,4R)- 2-(3-chlorofluoro-benzylcarbamoyl)(9H-fluorenylmethoxycarbonylamino)methoxypyrrolidinecarboxylic acid tert-butyl ester (described in Scheme B21) followed by Fmoc deprotection using the same protocol as described for Example 396. MS MS): 547 [M+H]+; t (HPLC conditions ) : 1.50 min; 19F NMR (100 MHz, DMSO-d ) d (ppm): -120.
R 6 Example 398: (2S,4S)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(6-benzyloxy carbamoyl-1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] The title compound was prepared as described in Scheme D5 using (4S)N-Fmoc-amino Boc-L-proline in step A and 6-benzyloxyisocyanato-indolecarboxylic acid amide (prepared as described in Part A4) in step C, followed by Fmoc deprotection as described in Scheme D2 step B. MS (LC/MS): 597.1 [M+H]+, 595.2 [M-H]; t (HPLC conditions a): 3.16 min.
Example 399: (S)-Piperazine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chloro-benzylamidel The title compound as a formate salt was prepared as described in Scheme D5 using (S)NBocN-Fmoc-piperazinecarboxylic acid and 1 equivalent of 3-chlorobenzylamine in step A followed by Fmoc deprotection as described in Scheme D2 step B. MS (LC/MS): 455.2/457.2 [M+H]+, 410/412 [M-CONH ]-; t (HPLC ions a): 2.58 min. 2 R Example 400: (S)-Pyrrolidine-1,2-dicarboxylic acid 2-[(4'-aminomethyl-biphenylyl)- amide 1-[(1-carbamoyl-1H-indolyl)-amide] Ta on of (S)-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] - cyano-biphenylyl)-amide] Example 152 (25 mg, 0.051 mmol) in EtOH ( 1 mL) containing 5% of NH , was added a drop of Ni Raney ved in EtOH (0.5 mL). The resulting mixture was stirred at RT under hydrogen atmosphere for 26 h , then filtered through Celite, and trated. The crude residue was purified by preparative HPLC (Waters SunFire C180DB, m , flow 20 mL/min, eluent: 5% CH CN/95% H 0 to 100% CH CN in 15 min, CH CN and 3 2 3 3 H 0 containing1% of HCOOH) to give after lyophilization of the purified fractions the desired nd as a formate salt. MS ): 497 [M+H]+; t (Waters Symmetry C18, 3.5um, 2.1x50mm, 5-95% CH CN/H 0/3.5 min, 95% CH CN/2 min, CH CN and H 0 containing 0.1% 3 2 3 3 2 TFA, flow: 0.6 mL/min) 3.04 min.
Example 401 : (S)-Pyrrolidine-1,2-dicarboxylic acid -aminomethyl-2'-fluoro-biphenyl- 3- l)-amide] 1-[(1-carbamoyl-1H-indolyl)-amide] To a solution of (S)-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2- [(4'-cyano-2'-fluoro-biphenylyl)-amide] (140 mg, 0.274 mmol) (prepared according to the general procedure described in Scheme D5, using in step A 3'-Aminofluoro-biphenyl carbonitrile (prepared as described in Part C) in EtOH (15 mL) containing 4% of NH was added Ra-nickel (70 mg) and the e was stirred under H atmosphere for 18 h . The reaction mixture was filtered on Celite and concentrated. The crude residue was purified by ative HPLC (Waters e (C18 ODB, 5mhi , 19x50, flow = 20ml_/min, 20% CH CN/ 80% water to 100% CH CN) to give the desired compound. MS (LC/MS): 515 [M+H]+; t 3 R (Waters Symmetry C18, 3.5um, 2.1x50mm, 5-95% CH CN/H 0/3.5 min, 95% CH CN/2 min, 3 2 3 CH CN and H 0 containing 0.1% TFA, flow: 0.6 mL/min) 3.1 min. 3 2 Example 402: (2S,5R)Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl- H-indolyl)-amide] trifluoromethoxy-phenyl)-amide] A mixture of (2S,5R)azidomethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indol- 3-yl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] Example 179 (50 mg, 0.094 mmol) and triphenylphosphine (29.7 mg, 0.1 13 mmol) in THF ( 1 mL) was stirred at RT overnight. After completion of the on MeOH ( 1 mL) and water ( 1 mL) were added and the solution was stirred for 1 h , then the crude reaction mixture was concentrated and purified by preparative HPLC (Waters SunFire C18-ODB 5 m , 19x50, 5-100% CH CN/H 0 in 17 min, 100% CH CN 3 2 3 for 3 min, CH CN and H 0 containing 0.1% TFA, flow: 20 mL/min) to give the title compound. 3 2 MS: 505 [M+H]+; t (HPLC conditions b): 3.24 min.
Example 403: (2S,4R)Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl- 1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] (2S,4S)Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-[(3- trifluoromethoxy-phenyl)-amide] Example 125 (20 mg, 0.04 mmol) was dissolved in MeOH (0.2 ml_). Ammonia (25% in water, 0.02 ml_) and Raney Nickel (7.1 1 mg) were added. Air was removed from the flask and replaced with nitrogen three times. Finally the flask was again degassed and the mixture was placed under a hydrogen here, and d at RT overnight. The catalyst was removed through a pad of Celite and washed with MeOH. The filtrate was concentrated, and the residue purified by preparative HPLC (Waters SunFire C18- ODB, 5 mhi , 19x50 mm, eluent: 5-100 % CH CN/H 0 in 17 min, CH CN and H 0 containing 3 2 3 2 0.1% TFA, flow: 20 mL/min) to give the title nd as a TFA salt. MS (LC-MS): 505 [M+H]+; t (HPLC conditions b): 3.1 min.
Example 404: (2S,4S)Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl- 1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] The title compound was obtained from (2S,4R)cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1 H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] Example 256 using the protocol bed for the preparation of Example 403. MS (LC/MS): 505 [M+H]+; t (HPLC conditions b): 3.1 min.
Example 405: (2S,4R)Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl- olyl)-amide] 2-(3-chlorof luoro-benzylamide) The title compound was prepared analogously as described for the title compound Example 403 using (2S,4S)cyano-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -carbamoyl-1 H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide) prepared according to scheme D5. MS (LC/MS): 487 [M+H]+, 442 [M-CON H ]-; t (HPLC conditions f): 1.46 min. 2 R Example 406: )Dimethylaminomethyl-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 - o l-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) To a solution of Example 405 ( 132 mg, 0.271 mmol) in MeOH (0.9 ml_) was added formaldehyde 20 % in MeOH (373 m I_ , 2.71 mmol), sodium cyanoborohydride (56 mg, 0.895 mmol) and acetic acid (31 .5 m I_ , 0.542 mmol). The reaction mixture was stirred for 16 h at RT then concentrated. The crude material was purified by preparative HPLC (Waters e C 18-ODB, 5 [Jim, 19x50 mm, eluent: 10- 100 % CH CN/H 0 in 30 min, CH CN and H 0 3 2 3 2 containing 0 .1% TFA, flow: 20 mL/min) to give the desired material. TLC, R (EtOAc)= 0.02; MS (LC/MS): 5 15 [M+H]+, 470 [M-CON H ]-; t (HPLC conditions ) : 1.47 min. 2 R Example 407: (2S,4S)Aminomethylhydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 - olyl)-amide] 2-(3-chlorofluoro-benzylamide) To a on of (2S,4R)azidomethylhydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 - carbamoyl- 1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) (300 mg, 0.567 mmol) (prepared according to Scheme D5 from (2S,4R)azidomethyl(3-chlorofluorobenzylcarbamoyl droxy-pyrrolidine-1 -carboxylic acid tert-butyl ester (described in Part B) in EtOAc ( 10 mL) was added Pd/C ( 10 mg). Air was d from the flask and replaced with nitrogen three times. Finally the flask was again degassed and the mixture was placed under a hydrogen atmosphere, and stirred at RT overnight. The catalyst was removed through a pad of Celite and washed with EtOAc. The filtrate was concentrated, and the residue purified by preparative HPLC (Waters e C 18-ODB, 5 mhi , 19x50 mm, eluent: 5-1 00 % CH CN/H 0 3 2 in 17 min, CH CN and H 0 containing 0 .1% TFA, flow: 20 mL/min) to give the title compound 3 2 as a TFA salt. MS (LC-MS): 503 [M+H]+; tR (HPLC conditions c): 3.57 min; 19F NMR (100 MHz, DMSO-d 6) d (ppm): -122.
Example 408: (2S,4R)Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1- olyl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared ously as described for Example 407 using (2S,4S) ethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2- (3-chlorofluoro-benzylamide) prepared according to scheme D5 from (2S,4S) azidomethyl(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tertbutyl ester (described in Part B). MS ): 505/507 ; tR (HPLC conditions f): 1.46 min; 19F NMR (100 MHz, DMSO-d 6) d (ppm): -121 , -150.
Example 409: (2S,4S)Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1- olyl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared analogously as described for Example 407 using (2S,4R) azidomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2- (3-chlorofluoro-benzylamide) ed according to scheme D5 from (2S,4R) azidomethyl(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tertbutyl ester (described Scheme B15). MS (LC-MS): 505/507 [M+H]+; tR (HPLC conditions f): 1.47 min; 19F NMR (100 MHz, DMSO- ) d (ppm): -121 , -150.
Example 410: (2S,4S)Fluoroformylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1- [(1-carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was obtained from Example 409 (2S,4S)aminomethylfluoropyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluorobenzylamide ) as formylation occurred during the concentration of the purified e 409 HPLC fractions from the preparative HPLC containing 1% HCOOH. MS (LC-MS): 531 [M-H]-, 533 [M+H]+; tR (HPLC ions f): 0.56 min; 19F NMR (100 MHz, DMSO-d 6) d (ppm): -121, - 150.
Example 411 : )Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] hloro-2,6-difluoro-benzylamide) To a solution of (2S,4R)azidomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1- oyl-1H-indolyl)-amide] 2-(3-chloro-2,6-difluoro-benzylamide) (100 mg, 0.182 mmol) (prepared according to scheme D5 using (2S,4R)azidomethyl(3-chloro-2,6-difluorobenzylcarbamoyl )fluoro-pyrrolidinecarboxylic acid tert-butyl ester prepared analogously as described in Scheme B15) in THF (5 mL) and water (6.56 m ) under N2 atmosphere at RT was added 1M PMe3 in THF (0.219 mL, 0.219 mmol). The reaction mixture was d for 16 h then quenched with water and extracted twice with EtOAc. The combined organic layers were dried (Na2S0 4) , filtered and concentrated. The crude residue was purified preparative HPLC (Waters SunFire C18-ODB, 5 m , 19x50 mm, 5% CH3CN/H 20 2.5 min, 5-100% CH3CN/H20 in 10 min, CH3CN/H20 ning 0.1 % HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the title compound (formic acid salt). MS (UPLC-MS): 523/525 [M+H]+, 521/523 [M-H]-; tR (HPLC conditions ) : 1.42 min; 19F NMR (100 MHz, DMSO- ) d (ppm): - 115 (2F), -150.
Example 412: (2S,4S)Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1- acetyl-1 H-indolyl)-amide] 2-(3-chlorof luoro-benzylamide) The title compound was prepared analogously as described for Example 411 using (2S,4R) azidomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-acetyl-1 H-indolyl)-amide] 2-(3- chlorofluoro-benzylamide) prepared according to scheme D5 from (2S,4R)azidomethyl (3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester (described Scheme B15) and 1-(3-isocyanato-indolyl)-ethanone (described in Scheme A1).
MS (UPLC-MS): 504/506 [M+H]+, 502/504 [M-H]-; t (HPLC conditions f): 1.62 min; 19F NMR (100 MHz, DMSO-d ) d (ppm): -121 , -153. e 413: (2S,4S)Aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 2-{[(S) (3-bromo-phenyl)f luoro-ethyl]-amide} 1-[(1 -carbamoyl-1 lyl)-amide] The title compound was prepared ously as described for Example 411 from (2S,4R) azidomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 2-{[(S)(3-bromo-phenyl)fluoroethyl ]-amide} 1-[(1 -carbamoyl-1 H-indolyl)-amide] (82 mg, 0.1 15 mmol) red according to scheme D5 step C using (2S,4R)azidomethyl[(S)(3-bromo-phenyl)fluoroethylcarbamoyl ]fluoro-pyrrolidinecarboxylic acid tert-butyl ester prepared as described in Scheme B16). cation on preparative HPLC (Waters SunFire C18-ODB, 5 mhi , 19x50 mm, % C H3CN/H2O 2.5 min, 5-100% CH CN/H 0 in 10 min, CH CN/H 0 containing 0.1 % 3 2 3 2 HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the title compound (formic acid salt). MS (UPLC-MS): 561/563 [M+H]+, 561/563 [M-H]-; t (HPLC conditions f): 1.42 min. e 414: (2S,4S)Aminomethylfluoro-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide] The title compound was prepared ously as described for Example 411 from (2S,4R) azidomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2- [(3-trifluoromethoxy-phenyl)-amide] (43 mg, 0.078 mmol) (prepared according to scheme D5 Step C using (2S,4R)azidomethylfluoro(3-trifluoromethoxy-phenylcarbamoyl)- pyrrolidinecarboxylic acid tert-butyl ester prepared as described Scheme B16 using 2- trifluoromethoxy-phenylamine in step G instead of 3(S)(3-bromo-phenyl)fluoroethylamine ). Purification by preparative HPLC (Waters e C18-ODB, 5 mhi , 19x50 mm, % C H3CN/H2O 2.5 min, 5-100% CH CN/H 0 in 10 min, CH CN/H 0 containing 0.1 % 3 2 3 2 HCOOH flow: 20 mL/min) gave after lyophilization of the purified fractions the title compound (formic acid salt). MS (UPLC-MS): 523 [M+H]+, 521 [M-H]-; t (HPLC conditions ) : 1.59 min; 19F NMR (100 MHz, DMSO-d ) d (ppm): -57 (3F), -150.
Example 415: (2S,3S,4S)Aminofluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl- H-indolyl)-amide] 2-(3-chlorof luoro-benzylamide) The title compound was prepared according to Scheme D5 from ,4S)azido(3- chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid utyl ester (described in scheme B19) followed by ion of the azide as described for the preparation of Example 411 . TLC, R (CH C I /MeOH 95/5) = 0.2 ; MS (LC-MS): 491 [M+H]+, 489 [M-H]-; t f 2 2 R (HPLC conditions f): 1.55 min.
Example 416: (2S,3R,4S)Aminohydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1- oyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) The title nd was prepared according to Scheme D5 from (2S,3S,4S)azido(3- fluoro-benzylcarbamoyl)hydroxy-pyrrolidinecarboxylic acid tert-butyl ester (described in scheme B19) followed by reduction of the azide as described for the preparation of Example 411 . TLC, R (CH C I /MeOH 95/5) = 0.2; MS (LC-MS): 489 [M+H]+, 487 ; t f 2 2 R (HPLC conditions f): 1.34 min.
Example 417: (2S,3R)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- 2-(3-chlorofluoro-benzylamide) A on of (2S,3R)azido-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- amide] 2-(3-chlorofluoro-benzylamide) red according to scheme D5 step C using (2S,3R)azido-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide trifluoroacetate (prepared as described in Part B) (70 mg, 0.140 mmol) in MeOH (10 mL) was enated at RT ( 1 atm) over Pd/C 10% (14 mg, 20% w/w) for 4 h . The reaction mixture was filtered through a 0.45 microns filter and trated under reduced pressure. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 m h , 30x100 mm; flow: 40 mL/min; eluent: -60% C H3CN/H2O for 20 min, 60% CH CN for 2 min, CH CN and H 0 containing 0.1% TFA) 3 3 2 to afford the title compound as a white solid. MS (LC/MS): 473 [M+H]+; t (HPLC conditions b): 2.75 min.
Example 418: (2S,3R)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol -amide] 2-(3-chlorofluoro-benzylamide) Prepared as described for Example 417 from (2S,3R)azido-pyrrolidine-1,2-dicarboxylic acid acetyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) prepared according to Scheme D5 by using (2S,3R)azido-pyrrolidinecarboxylic acid 3-chlorofluorobenzylamide trifluoroacetate (prepared as described in Part B) and 1-(3-isocyanato-indolyl)- ethanone (prepared as described in Scheme A1). White solid. MS (LC/MS): 473 [M+H]+; t (HPLC conditions b): 2.91 min. e 419: (2S,3R)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-{[(S)(3-chlorofluoro-phenyl)-2,2,2-trifluoro The title compound was prepared as described for Example 417 starting from (2S,3R) azido-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1-carbamoyl-1 lyl)-amide] 2-{[(S)(3- fluoro-phenyl)-2,2,2-trifluoro-ethyl]-amide} (prepared according to Scheme D5 (step C) from (2S,3R)azido-pyrrolidinecarboxylic acid [(S)(3-chlorofluoro-phenyl)-2,2,2- trifluoro-ethyl]-amide (prepared in a similar manner as described in Part B for (2S,3R)azidopyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide trifluoroacetate starting from (S) (3-chlorofluorophenyl)-2,2,2-trifluoroethanamine. White solid. MS ): 541.0 [M+H]+; t (HPLC conditions c): 4.07 min.
Example 420: (2S,3S)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide) Prepared as described for Example 417 from )azido-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) (prepared according to scheme D5 step C by using (2S,3S)azido-pyrrolidinecarboxylic acid 3-chlorofluorobenzylamide (prepared as described in Part B). White solid. MS (LC/MS): 473 [M+H]+; t (HPLC conditions b): 2.91 min.
Example 421 : (2S,3S)Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-(3-chloro-benzylamide) Prepared as described for Example 4 17 from (2S,3S)azido-pyrrolidine- 1,2-dicarboxylic acid 1-[(1 -carbamoyl-1 H-indolyl)-amide] 2-(3-chloro-benzylamide) (prepared according to scheme D5 step C by using (2S,3S)azido-pyrrolidinecarboxylic acid 3-chlorobenzylamide (prepared using similar protocols as described in Part B for )azidopyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide). White solid. MS (LC/MS): 455 [M+H]+; t (HPLC conditions b): 2.79 min.
Example 422: (2S,3R)Acetylamino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -carbamoyl- lyl)-amide] hlorof luoro-benzylamide) To an ice-cooled on of (2S,3R)amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -carbamoyl- 1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) Example 4 17 (27.0 mg, 0.057 mmol) in dry CH C I (5 ml_) and dry THF (2.5 ml_) were added triethylamine (0.024 ml_, 0 .17 1 mmol) 2 2 and acetic anhydride (0. 108 ml_, 1.14 mmol) under an argon atmosphere. The reaction mixture was stirred at RT for 16 h . Volatiles were removed under d pressure, and the residue was purified by preparative HPLC (Waters Sunfire, C 18-ODB, 5 mhi , 19x50 mm, : 5- 100% CH CN/H2O/2O min, 100% CH CN/2 min, CH CN and H 0 containing 0 .1% TFA, flow: 3 3 3 2 mL/min) to give after lyophilization the title compound as a white solid. MS (LC/MS): 5 15.0 [M+H]+; t (HPLC conditions k) : 2.96 min.
Example 423: )(2-Methoxy-ethylamino)-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 - carbamo l-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) To a solution of (2S,3R)amino-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1 -carbamoyl-1 H-indol yl)-amide] 2-(3-chlorofluoro-benzylamide) Example 4 17 (36 mg, 0.076 mmol) in dry DMF ( 1 .5 mL) were added triethylamine (0.032 mL, 0.228 mmol) and 1-bromomethoxyethane (0.014 ml_, 0.144 mmol) under an argon atmosphere, followed by ng at RT for 60 h .
UPLC-MS showed formation of product and the presence of unreacted starting al )amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3- chlorofluoro-benzylamide). An excess of 1-bromomethoxyethane (10 eq) and triethylamine (10 eq) were added to the reaction mixture, and stirring was continued at RT for 18 h , and then at 50°C for 24 h . The crude material was directly ed by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H20 containing 0.1% TFA, flow: 20 mL/min) to give after lization the title nd as a solid. MS (LC/MS): 531 [M+H]+; tR (HPLC conditions k): 2.97 min.
Example 424: (2S,4S)Fluoromethylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1- [(1-carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) [(3R,5S)(1-carbamoyl-1 H-indolylcarbamoyl)(3-chlorofluoro-benzylcarbamoyl) fluoro-pyrrolidinylmethyl]-methyl-carbamic acid 2,2,2-trichloro-ethyl ester (prepared according to scheme D5 Steps B and C using )fluoro{[methyl-(2,2,2-trichloroethoxycarbonyl )-amino]-methyl}-pyrrolidine-1,2-dicarboxylic acid yl ester 1-tert-butyl ester (prepared as described in Scheme B17) (56 mg, 0.08 mmol) was dissolved in MeOH (5 mL) under N2 atmosphere at RT. Zinc dust was added (0.24 mg, 3.7 mmol), the pH was adjusted to pH 5-6 by adding some acetic acid. The reaction mixture was stirred for 1 h then filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 m , 19x50 mm, 5% CH3CN/H20 2.5 min, 5-100% CH3CN/H20 in 10 min, CH3CN/H20 containing 0.1 % HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the title compound. MS (UPLC-MS): 519 [M+H]+ ; tR (HPLC conditions f): 1.32 min; 19F NMR (100 MHz, DMSO- ) d (ppm): -120, -150.
Example 425: (2S,4S)Methylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl- 1H-indolyl)-amide] 2-(3-chlorof luoro-benzylamide) The title compound was prepared according to Scheme D5 Steps B and C from )(3- chlorofluoro-benzylcarbamoyl)[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine- 1-carboxylic acid tert-butyl ester (37 mg, 0.05 mmol) (prepared as described in Scheme B6) followed by the deprotection of the Troc protecting group as described for Example 424.
Purification by preparative HPLC (Waters SunFire C18-ODB, 5 m h , 19x50 mm, 5% C H3CN/H2O 2.5 min, 5-100% CH3CN/H20 in 10 min, CH3CN/H20 containing 0.1 % HCOOH flow: 20 mL/min) gave after lyophilization of the purified ons the title compound (formic acid salt). MS MS): 489 [M+H]+; tR (HPLC conditions ) : 1.48 min; 19F NMR (100 MHz, DMSO- ) d (ppm): -120.
Example 426: (2S,4S )(2-Methoxy-ethylamino)-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) To a solution of 2-methoxyethylamine (219 m , 2.54 mmol) in MeOH (265 m ) was added HCI 1.25 N in MeOH (339 m I_ , 0.424 mmol) followed by (S)oxo-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) (100 mg, 0.212 mmol) (prepared as described in scheme D5 from (S)oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert- butyl ester) and NaBH3CN (16 mg, 0.254 mmol) and the reaction e was stirred at 23°C during 1 week. 2-Methoxyethylamine (219 m I_ , 2.54 mmol) and NaBH3CN (16 mg, 0.254 mmol) were added again and the reaction mixture was stirred at 23°C for 2 days. The crude e was d in EtOAc and washed with NaHC0 3 ted aqueous solution. The layers were separated and the aqueous one re-extracted with EtOAc. The combined c layers were dried, filtered and concenrated to dryness. The crude residue was purified by flash column chromatography on silica gel (CH2C I2/MeOH gradient 100:0 to 9:1) followed by preparative HPLC (Waters SunFire C180DB, 5 m , 30x100, : 5% CH3CN/95% H20 to 100% CH3CN in 20 min, CH3CN and H20 containing 0.1% of TFA, flow 40 mL/min) to give after lyophlisation of the purified fractions the desired material. MS: 531.1 [M+H]+; tR (HPLC conditions b): 3.1 min. The te stereochemistry has been assigned tentatively based on the test results for the final compound Example 426 in the biological assay.
Example 427: (2S,4S)Dimethylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) To a solution of (2S,4S)amino-pyrrolidine-1 arboxylic acid 1-[(1-carbamoyl-1 H-indol ide] hlorofluoro-benzylamide) Example 26 (20 mg, 0.042 mmol) in MeOH (140 m I) was added dehyde (58.3 m I, 0.423 mmol), NaBH CN (8.77 mg, 0.140 mmol) and AcOH (4.84 m I, 0.085 mmol), and the reaction mixture was stirred at 23°C under nitrogen for 16 h . After completion, the crude reaction mixture was purified by ative HPLC (Waters SunFire C180DB, 5 m , 19x50, eluent: 5% CH CN/95% H 0 to 100% CH CN in 17 min, 3 2 3 CH CN and H 0 containing 0.1% of TFA, flow 20 mL/min) to give after lization of the 3 2 purified fractions the desired material. MS (LC/MS): 501 .1 [M+H]+; t (HPLC conditions b): 2.75 min.
Example 428: (S)-4,4-Dimethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-(3-chlorofluoro-benzylamide) To a solution of methylamine hydrochloride (14.3 mg, 0.212 mmol) in MeOH (300 m I_) was added HCI 1.25 N in MeOH (400 m I, 0.50 mmol), (S)oxo-pyrrolidine-1 ,2-dicarboxylic acid 1- [(1-carbamoyl-1 H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) (100 mg, 0.212 mmol)(prepared as described in scheme D5 from (S)oxo-pyrrolidine-1 ,2-dicarboxylic acid 1- tert-butyl ester) and NaBH CN (8 mg, 0.127 mmol) and the reaction mixture was stirred at 23°C for 16 h . The crude on mixture was diluted with EtOAc and washed with aqueous saturated NaHC0 solution. The organic layer was dried, filtered and concentrated to dryness, finally purified by preparative HPLC (Waters SunFire C180DB, 5 m h , 19x50, eluent: 20% CH CN/80% H 0 to 100% CH CN in 12.5 min, CH CN and H 0 containing 0.1% HCOOH, flow 3 2 3 3 2 mL/min) to give after lyophilization of the purified fractions the desired material. MS: 518 [M+H]+; t (HPLC conditions b): 3.79 min.
Example 429: (2S,3S,4R)Aminohydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1- o ly l)-a m ide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared as described for Example 411 using (2S,3R,4R)azido hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chloro fluoro-benzylamide). TLC, R (EtOAc)= 0.02; MS (LC-MS): 489 [M+H]+, 487 [M-H]-; t (HPLC f R conditions g): 1.96 min. ,4R)azidohvdroxy-pyrrolidine-1,2-dicarboxylic acid 1-r(1-carbamoyl-1H-indol- 3-yl)-amide1 2-(3-chlorofluoro-benzylamide) The title compound was ed according to scheme D5 (steps B and C) from a mixture of (2S,3R,4R)azido(3-chlorofluoro-benzylcarbamoyl)hydroxy-pyrrolidinecarboxylic acid tert-butyl ester and (2S,3S,4S)azidohydroxy-pyrrolidine-1 ,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) in ratio 6:4 (described Scheme B19). The regioisomers were separated by flash column tography on silica gel (c-hexane 100% to EtOAc 100%) to give the title compound. TLC, R (EtOAc)= 0.23; MS (LC- MS): 515/517 [M+H]+, 513 [M-H]-; t (HPLC conditions ) : 1.81 min.
Example 430: (2R,3S,4R)Aminofluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1- o ly l)-a m ide] hlorofluoro-benzylamide) The title compound was prepared according to Scheme D5 (steps B and C) from (2R,3R,4R)- o(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester (described in scheme B19) followed by ion of the azide as described for the ation of Example 4 11 . TLC, R (EtOAc)= 0.12; MS (LC-MS): 491 [M+H]+, 489 [M-H]-; t f R (HPLC conditions f): 1.45 min. e 431 : (2S,3S,4S)Aminofluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1- olyl)-amide] 2-(3-chlorofluorobenzylamide) The title compound was prepared according to Scheme D5 (steps B and C) from (2S,3S,4S) azido(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester (described in scheme B19) followed by ion of the azide as described for the preparation of Example 411 . (Absolute stereochemistry tentatively assigned by NMR). TLC, R (CH C I /MeOH 95/5) = 0.2; MS (LC-MS): 491 [M+H]+, 489 [M-H]-; t (HPLC conditions f): 1.46 2 2 R Example 432: 3-{2-[(S)(3-Chlorofluoro-benzylcarbamoyl)-pyrazolidinyl]oxorboxylic acid amide To a solution of (S)(1-carbamoyl-1 H-indolylcarbamoyl)(3-chlorofluorobenzylcarbamoyl )-pyrazolidinecarboxylic acid tert-butyl ester (20 mg, 0.036 mmol) in CH C I 2 2 (200 m I_), TFA (27.6 m I_ , 0.358 mmol) was added, and the reaction mixture was stirred at 23°C for 20 h . The solvents were concentrated and the crude residue was purified by preparative HPLC (Waters SunFire C180DB, 5 m , 19x50, eluent: 20% CH CN/80% H 0 to 100% CH CN 3 2 3 in 12.5 min, CH CN and H 0 both containing 0.1% of HCOOH, flow 20 mL/min) to give the 3 2 desired al after lization of the purified fractions. MS (LC-MS): 459 [M+H]+; t (HPLC conditions b): 3.72 min. (S)(1-carbamoyl-1H-indolylcarbamoyl)(3-chloro -benzylcarbamoyl)-pyrazolidinecarboxylic acid tert-butyl ester was prepared as bed in Scheme D5 step C using (S)(3-chlorofluoro-benzylcarbamoyl)-pyrazolidine- 1-carboxylic acid tert-butyl ester (prepared as described in Scheme B5).
Example 433: 3-{2-[(R)(3-Chlorofluoro-benzylcarbamoyl)-pyrazolidin-1 -yl]oxoethyl }-indolecarboxylic acid amide The title compound was prepared from (R)(1 -carbamoyl- 1H-indolylcarbamoyl)(3- chlorofluoro-benzylcarbamoyl)-pyrazolidinecarboxylic acid tert-butyl ester according to the procedure described for the preparation of e 432 using 10 equivalents of TFA for the Boc deprotection. MS: 459 [M+H]+; t (HPLC conditions b): 3.73 min. (R)(1-Carbamoyl- 1H-indolylcarbamoyl)(3-chlorofluoro-benzylcarbamoyl)-pyrazolidinecarboxylic acid tert-butyl ester was prepared as described in Scheme D5 step C using (R)(3-chlorofluorobenzylcarbamoyl )-pyrazolidinecarboxylic acid tert-butyl ester (prepared as described in Scheme B5).
Example 434: Pyrazolidine-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 5- -chloro-benzylamide) The title nd was prepared from 2-(1 -carbamoyl- olylcarbamoyl)(3-chloro- benzylcarbamoyl)-pyrazolidinecarboxylic acid tert-butyl ester according to the procedure described for the preparation of Example 432. MS (LC/MS) 441.1 [M+H]+; t (HPLC conditions b): 3.67 min. 2-(1-Carbamoyl-1 H-indolylcarbamoyl)(3-chloro-benzylcarbamoyl)- lidinecarboxylic acid tert-butyl ester was prepared as described in Scheme D5 step C using 3-(3-chloro-benzylcarbamoyl)-pyrazolidinecarboxylic acid tert-butyl ester (prepared using similar protocols as described Scheme B5).
Example 435: (3S,5S)-1 -(1 -Carbamoyl-1 H-indolylcarbamoyl)(2-fluoro rbamoyl)-pyrrolidinecarboxylic acid methyl ester Chlorotrimethylsilane (537 m I_ , 4.24 mmol) was added dropwise to dry MeOH (700 m I_) at 0°C, followed by a solution of (2S,4S)cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H- indolyl)-amide] 2-[(2-fluorotrifluoromethoxy-phenyl)-amide] Example 188 ( 1 10 mg, 0.212 mmol) in dry CH C I (600 m I_). The reaction mixture was stirred at RT under N ght. Then 2 2 2 cooled to 0°C, water and CH C I were added. The layers were separated and the aqueous one 2 2 extracted back with CH C I . The combined organic extracts were neutralized with an aqueous 2 2 solution ted with NaHC0 and brine, dried over Na S0 , filtered and concentrated. The 3 2 4 crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to c-hexane/EtOAc 1:3 to EtOAc) to give the desired compound. R , TLC (EtOAc) = 0.6; MS (LC-MS): 552.1 [M+H]+, 574.2 +, 550.2 [M-H]-; t (HPLC conditions f): 1.98 min. e 436: (2S,4S)Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1- oyl-1H-indolyl)-amide] 2-(3-chloro-2,6-difluoro-benzylamide) To a solution of (3S,5S)(1-carbamoyl-1 H-indolylcarbamoyl)(3-chloro-2,6-difluorobenzylcarbamoyl )-pyrrolidinecarboxylic acid methyl ester e 353 (88 mg, 0.165 mmol) in THF (2 ml_) was added Lithium borohydride 2 M in THF (0.18 ml_, 0.36 mmol) and the reaction mixture was stirred at RT for 2 h under N atmosphere. After completion, the mixture was quenched with brine and extracted twice with CH C I . The combined organic 2 2 layers were dried (Na S0 ) , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, eluent: 20% to 100% CH CN in H 0 in 15 min, CH CN and H 0 containing 0.1% HCOOH, flow: 20 mL/min) to give after 2 3 2 lization of the purified fractions the desired material. R , TLC (CH C I /MeOH 90:10) = f 2 2 0.65; MS (LC-MS): 506.2 [M+H]+, 101 1.4 [2M+H]+, 504.2 [M-H]-; t (HPLC conditions ) : 1.62 Example 437: (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid bromo carbamoyl-phenyl)-amide] 1-[(1 -carbamoyl-1 H-indolyl)-amide] To a solution of 3-bromo{[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoropyrrolidinecarbonyl ]-amino}-benzoic acid Example 159 (100 mg, 0.188 mmol), ammonium chloride (12 mg, 0.225 mmol) and HBTU (107 mg, 0.282 mmol) in DMF (3 mL) was added DIPEA (64 m I, 0.374 mmol) and the resulting solution was stirred at RT under nitrogen for 7 h .
The on mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed water (x2), dried (Na S0 ) , filtered and concentrated. The crude 2 4 residue was purified by preparative HPLC (C18-ODB, 5 mhi , 19x50 mm, waters, eluent: CH CN/H 0 + 0.1 % HCOOH flow: 20 mL/min, standard 20 % method) to give the desired 3 2 material after lyophilization of the purified fractions. TLC, R (EtOAc) = 0.3; MS (LC-MS): 531/533 [M+H]+, 553/555 [M+Na]+, 529/531 [M-H]-; t (HPLC ions a): 2.79 min.
Example 438: (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid carbamoyl-1H- indolyl)-amide] 2-[3-chlorofluoro(2-methoxy-ethylcarbamoyl)-benzylamide] To a mixture of 3-({[(2S,4R)(1-carbamoyl-1H-indolylcarbamoyl)fluoro-pyrrolidine carbonyl]-amino}-methyl)chlorofluoro-benzoic acid Example 144 (30 mg, 0.06 mmol), 2- methoxyethylamine (5 mg, 0.07 mmol) and HATU (33 mg, 0.09 mmol) in DMF ( 1 mL) was added DIPEA (0.04 mL, 0.23 mmol) and the resulting solution was stirred at RT under nitrogen. The crude product was ed without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 m , 30x100 mm, 5-100% CH CN/H O/20 min, 100% CH CN/2 3 2 3 min, C H3C N and H 0 containing 0.1% TFA, flow: 40 ml/min) to give the title compound. MS ): 577.0 [M]+; t (HPLC conditions c): 3.95 min.
Example 439: (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-[(3-isopropyl-isoxazolyl)-amide] The title compound was ed as described in steps B and C Scheme D5 using (S)(3- isopropyl-isoxazolylcarbamoyl)-pyrrolidinecarboxylic acid tert-butyl ester. MS (LC-MS): 425.2 [M+H]+, 447.1 [M+Na]+, 871.3 [2M+Na]+ , 423.1 [M-H]-; t (HPLC conditions a): 3.06 (S)(3-lsopropyl-isoxazolylcarbamoyl)-pyrrolidinecarboxylic acid tert-butyl ester To a mixture of Boc-L-proline (150 mg, 0.697 mmol), 3-isopropylisoxazolamine (88 mg, 0.697 mmol) and HBTU (264 mg, 0.697 mmol) in DMF (7 ml_) was added 2-tert-butylimino diethylamino-1 ,3-dimethylperhydro-1 ,3,2-diazaphosphorine (BEMP) (201 m I, 0.697 mmol) and the reaction e was stirred at RT under en for 48 h . The mixture was poured into HCI 1N and extracted three times with EtOAc. The ed organic layers were washed with an aqueous saturated solution of NaHC0 , with water, dried over Na S0 , filtered and 3 2 4 concentrated. The crude residue was purified by flash column chromatography on silica gel (c- hexane to c-hexane/EtOAc 7-3) to give the title compound. TLC, R (c-hexane/EtOAc 1:1) = 0.6; MS (LC-MS): 324.1 [M+H]+, 346.1 [M+Na]+, 669.2 [2M+Na]+, 322.1 [M-H]-; t (HPLC conditions a): 3.42 min.
Example 440: (S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)- 2-[(3-phenyl-isoxazolyl)-amide] The title compound was prepared in 3 steps as described for the preparation of e 439.
MS (LC/MS): 459.1 [M+H]+, 481.1 +, 918.3 [2M+H]+, 940.2 [2M+Na]+, 457.1 [M-H]-; t (HPLC conditions a): 3.29 min.
Scheme D6: general protocol described for the preparation of Example 441 : 3-f2 2- (3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidin-1 -vnoxo-ethylVindolecarboxylic acid amide A. (S)(3-Trifluoromethoxy-phenylcarbamoyl)-pyrrolidinecarboxylic acid tert-butyl ester The title compound was prepared according to the general procedures bed in Scheme D5 Step A . TLC, R (c-hexane/EtOAc 1:1) = 0.57; MS (LC/MS): 397.1 [M+Na]+, 275.2 [MH- Boc]+, 373.3 [M-H]-; t (HPLC conditions a) 3.81 min.
Dichloromethane can also be used instead of DMF.
B. rrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide The title compound as a TFA salt was prepared according to the general procedures described in Scheme D5 Step B. MS (LC/MS): 275.2 [M+H]+, 273.3 [M-H]-; t (HPLC conditions a) 2.47 min.
C. Example 441 : 3-{2-[(S)(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidinyl]oxo- ethyl}-indolecarboxylic acid amide (S)-Pyrrolidinecarboxylic acid (3-trifluoromethoxy-phenyl)-amide TFA salt (59.3 mg, 0.153 mmol, prepared as described in Sheme D5 steps A and B), (1-carbamoyl-1 H-indolyl)-acetic acid (40 mg, 0.183 mmol, prepared as described in Scheme A8) and HBTU (86.9 mg, 0.229 mmol) were dissolved in CH C I (4 ml_) under nitrogen, DIPEA (52.3 m I, 0.306 mmol) was 2 2 added and the on mixture was stirred at RT for 5 h . After completion of the reaction aqueous 1 N HCI and EtOAc were added, the layers were separated and the aqueous one back-extracted twice with EtOAc. The combined organic extracts were washed with an aqueous ted on of NaHC0 , dried over Na S0 , filtered and concentrated. The 3 2 4 crude residue was ed by preparative HPLC (Waters SunFire C18-ODB, 5 mhi , 19x50 mm, % C H3CN/H2O 2.5 min, % CH CN/H 0 in 10 min, CH CN/H 0 ning 0.1 % 3 2 3 2 HCOOH flow: 20 mL/min) to give after extraction of the pure fractions the d compound.
MS (LC/MS): 475 [M+H]+, 497 [M+Na]+; t (HPLC conditions a) 3.47 min.
DMF can also be used instead of Dichloromethane.
The examples below were prepared according to the general procedures described in Scheme D6 for the preparation of Example 441, from commercially available building blocks, if not otherwise stated (see notes at the end of table 5): Table 5 : Characterization (end-table notes), TLC, R (eluent); Example Structure Name MS (LC/MS); t (HPLC conditions); 19F NMR (100 MHz, solvent) d (ppm) 3-{2—[(28,4R)—4-F|uoro(2- fluoro—3-trifluoromethoxy- (2,3) 511 [M+H]+, 533 phenylcarbamoyl)—pyrro|idin [M+Na]+; tR (b): 3.88 min. y|]oxo-ethy|}-indo|e carboxylic acid amide 3-(2-{(1S,28,5R)—2—[(S)—1-(3- (5[B9]) Rf (EtOAc) = Chlorofluoro—phenyI) 0.15; 4993/5013 hydroxy-ethylcarbamoy|] [M+H]+, 543.3/545.3 azabicyc|o[3.1.0]hexy|} [M+HCOO]-; 1R (a): 3.0 oxo—ethyI)-indolecarboxylic min. acid amide 3-{2—[(28,3R)—2—(3-Chloro-2— fluoro—benzylcarbamoyl)—3- (2) 473 [M+H]+; tR (b): hydroxy-pyrrolidiny|]oxo- 3.20 min. ethy|}-indo|ecarboxy|ic acid amide (28,4S)(3-Ch|oro—2— (5[B15],6) 532/534 fluoro—benzylcarbamoyl)—4— [M+H]+; 1R (f): 1.53 min; dimethylaminomethylfluoro— 19F NMR (DMSO-de): pyrrolidiny|]oxo-ethy|}- -120, -149. indoIecarboxylic acid amide 3-{2—[(1R,3S,5R)—3-(3-Ch|oro—2— fluoro—benzylcarbamoy|)aza- White solid. Rf (EtOAc/n- o[3.1.0]hexy|]oxo- hexane 3:1) = 0.11; 469 ethy|}-indo|ecarboxy|ic acid ; tR (b): 3.94 min. amide 3-(2-{(28,4R)-2—[(R)(3- (5[B9]) White solid, Rf Chlorofluoro—phenyI) (CHZCIZ/MeOH 9:1) = y-propylcarbamoy|] 0.6; 519.3/521.3 [M+H]+, fluoro—4-methyI-pyrrolidiny|}- 563.3/565.3 [M+HCOO]—; 2-oxo-ethy|)-indo|ecarboxy|ic tR (a): 3.1 min. acid amide 3-{2—[(28,4R)—2—(3-Chloro-2— fluoro—benzylcarbamoyl)—4— 475/477 [M+H]+; tR (b): fluoro-pyrrolidiny|]oxo- 3.76 min. ethy|}-indo|ecarboxy|ic acid amide 3-(2-{(1R,3S,5R)-3—[(S)(3— Chloro—2-fluoro—phenyI) (5[891) 499.1 , hydroxy-ethyl carbamoy|] 520.7/5214 [M+Na]+, aza—bicyc|o[3. 1 .0]hexy|} 5432/5452 [M+HCOO]—; oxo—ethyI)-indolecarboxylic tR (f): 1.79 min. acid amide 3-{2-[(S)(3-ChIorofluoro- 475/477 [M+H]+; tR (b): benzylcarbamoyI)-thiazolidin-3— 3.95 min. y|]oxo-ethy|}-indo|e—1 - carboxylic acid amide (5[B12]). Rf (EtOAc) = 3-{2-[(2S,4R)(3-Chloro 0.1; 505.1/507.2 [M+H]+, fluoro—benzylcarbamoyl)-4— 527.0/529.2 [M+Na]+, fluorohydroxymethyl- 503/505 [M-H]—, pyrrolidiny|]oxo-ethy|}- 551 [M+HCOO]—; indoIecarboxylic acid amide tR (a): 2.96 min. (1R,3S,5R)-3—(3—Ch|oro—2- (1[A4],6) Rf (EtOAc) = fluoro—benzylcarbamoy|)aza- 0.3; 499.1/501.1 [M+H]+, bicyc|o[3.1.0]hexy|]oxo- 543.1/545 [M+HCOO]—, ethy|}methoxy-indo|e 454/456 H2]-; tR carboxylic acid amide (a): 2.25 min. (1 [A9]) 5292/531 .1 3-{2-[(1R,3S,5R)-3—(3—Ch|oro—2- [M+H]+, 551/5532 fluoro—benzylcarbamoy|)aza- [M+Na]+, 573.1/575 bicyc|o[3.1.0]hexy|]oxo- [M+HCOO]—, 484.1/486.1 (2-hydroxy-ethoxy)- [M-CONH2]-; tR (a): 1.54 indoIecarboxylic acid amide min. (1R,3S,5S)-3—(3—Chloro (4,5) White solid. Rf fluoro—benzylcarbamoyI) ) = 0.25; methoxymethyIaza- 513.3/515.3 [M+H]+, bicyc|o[3.1.0]hexy|]oxo- 557.4/559.4 [M+HCOO]—; ethy|}-indo|ecarboxy|ic acid tR (a): 3.23 min. amide —(2-Hydroxy-ethoxy){2-oxo- (1[A9]) 547.2 [M+H]+, 2-[(1R,3S,5R)(3- 564.3 [M+NH4]+, 545.2 oromethoxy- [M-H]-, 591.2 phenylcarbamoyI)aza- [M+HCOO]—; tR (f): 1.85 bicyclo[3.1.0]hexy|]-ethy|}- min. indoIecarboxylic acid amide 3-(2-{(1R,3S,5R)-3—[(5—Chloro— thiophenylmethyl)- Rf (CH2C|2/MeOH 9.1) = oy|]aza- 0.43; 457 [M+H]+; tR (b): bicyclo[3.1.0]hexy|}oxo- 3.84 min. -indo|ecarboxy|ic acid amide 3-(2-{(1R,3S,5R)-3—[(R)(3- Chloro—2-fluoro—phenyl)-3— (5[B9]) Rf (EtOAc) = 0.2; y-propylcarbamoy|] 513.3 [M+H]+, azabicyclo[3.1.0]hex—2-y|} 557.3/559.2 [M+HCOO]—; oxo—ethyI)-indolecarboxylic 1R (f): 1.86 min. acid amide 3-(2-{(1R,3S,5R)-3—[(S)(3— (3 [0414) White solid. Rf Chlorofluoro—phenyI) (CHZClz/MeOH 9:1) = dimethylamino- 0.45; 526.4/528.4 ethylcarbamoyl]—2-aza— [M+H]+, 570.4/5722 bicyclo[3.1.0]hexy|}oxo- [M+HCOO]; 1R (a): 2.80 ethyI)-indo|ecarboxy|ic acid min. amide 3-{2-[(28,4R)(3-Chloro (1[A9],5[B13]) Rf (EtOAc) fluoro—benzylcarbamoyl)-4— = 0.2; 549.3/551.2 fluoro—4-methyI-pyrrolidiny|]- [M+H]+, 593.2/595.3 2-oxo-ethy|}(2-hydroxy- [M+HCOO]—; tR (f): 1.70 ethoxy)-indo|ecarboxy|ic acid min. amide 3-{2-[(28,4R)(3-Chloro fluoro—benzylcarbamoyl)-4— (1[A4]) 493 [M+H]+; 1R fluoro-pyrrolidiny|]oxo- (b):3.9 min. ethy|}f|uoro-indo|e carboxylic acid amide indolecarboxylic acid amide ( 1) The ( 1-carbamoyl-1 H-indolyl]-acetic acid derivative used in step C was prepared as described in Part A ; (2) CH2CI2 was used instead of DMF in step A ; (3) The substituted benzylamine or aniline tive used in step A was prepared as described in Part C [Scheme]; (4) HCI (4 M/dioxane) in e was used instead of TFA in CH2CI2 in step B; (5) The title compound was prepared according to the general procedure described in Scheme D6 steps B and C starting from the tuted proline derivative prepared as described in Part B [Scheme]; (6) DMF was used as solvent in step C.
Example 466: 3-{2-[(2S,3S,4S)Amino(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinyl ]oxo-ethyl}-indolecarboxylic acid amide The title compound was prepared according to Scheme D6 from (2S,3S,4S)azido(3- chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester (described in scheme B19) followed by reduction of the azide as described for the preparation of Example 411 (2S,4S)aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-(3-chloro-2,6-difluoro-benzylamide). TLC, R (CH C I /MeOH f 2 2 95/5) = 0.3; MS (LC-MS): 490 [M+H]+, 488 [M-H]-; t (HPLC conditions f): 1.42 min.
Example 467: 3-{2-[(1R,3S,5S)(3-Chlorofluoro-benzylcarbamoyl)hydroxymethyl - 2-aza-bicyclo[3.1.0]hexyl]oxo-ethyl}-indolecarboxylic acid amide A solution of (1-carbamoyl-1H-indolyl)-acetic acid (1R,3S,5S)[2-(1-carbamoyl-1 l yl)-acetyl](3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3. .0]hexylmethyl ester (65 mg, 0.084 mmol) and NaOH 1 N (0.5 ml_, 0.5 mmol) in THF (0.4 ml_) / water (40 m I_) was stirred at RT for 1 h . Water and CH C I were added, the layers were separated and the 2 2 aqueous one back-extracted with CH C I (x3). The ed organic extracts were dried 2 2 (Na S0 ) , filtered and concentrated. The crude material was purified by preparative HPLC 2 4 (Waters Sunfire C18-ODB, 5 mhi , 30x100 mm, eluent: 5% to 100% CH CN in H 0 in 25 min, 3 2 CH CN and H 0 containing 0.1% TFA, flow: 40 ). EtOAc and ted aqueous 3 2 NaHC0 were added to the ed purified fractions, the layers were separated and the aqueous one back-extracted with EtOAc (x3). The combined organic extracts were dried (Na S0 ) , filtered and concentrated to give the desired material.
TLC, R (CH C I / MeOH 4-1) = 0.35; MS (UPLC/MS): 499.4/501.4 [M+H]+, 523.3 f 2 2 [M+Na]+, 543.3/545.2; t (HPLC conditions f): 1.75 min. (1-Carbamoyl-1H-indolyl)-acetic acid (1R,3S,5S)r2-(1-carbamoyl-1H-indolyl)- acetvn(3-chlorofluoro-benzylcarbamoyl)aza-bicvclor3.1.01hexylmethyl ester The title compound N,0 bis-acylated was prepared according to Scheme D6 from ,5S)- 3-(3-chlorofluoro-benzylcarbamoyl)hydroxymethylaza-bicyclo[3.1 .0] hexane carboxylic acid tert-butyl ester (prepared as described in Part B Scheme B28) using HCI 4N in dioxane d of TFA in Step B. (46.2 mg, 0.14 mmol) using (1-carbamoyl-1H-indolyl)- acetic acid (60.2 mg, 0.28 mmol), HBTU (105 mg, 0.28 mmol) and DIPEA (94 m I_ , 0.55 mmol) in CH C I ( 1 ml_). TLC, R ) = 0.25; MS MS): 699.4/701.3 [M+H]+, 721.3/723.3 2 2 f [M+Na]+, 743.4/745.5 [M+HCOO]-; t (HPLC conditions ) : 2.05 min.
Example 468: 3-{2-[(2S,4S)Amino(3-chlorofluoro-benzylcarbamoyl)-pyrrolidin-1 - oxo-ethyl}-indolecarboxylic acid amide A solution of (2S,4S)azido(3-chlorofluoro-benzylcarbamoyl)-pyrrolidinyl] oxo-ethyl}-indole-1 -carboxylic acid amide (80 mg, 0.161 mmol) in MeOH (8 ml_) was hydrogenated over Pd/C 10% (8 mg, 10% w/w) at RT ( 1 atm). The reaction mixture was filtered through a 0.45 microns filter and concentrated under reduced pressure to give the title compound as colorless foam. MS (LC/MS): 472 [M+H]+; t (HPLC conditions b) 2.94 min. 3-f2 -r(2S,4S)Azido(3-chlorofluoro-benzylcarbamoyl)-pyrrolidinvnoxo-ethylV indole-1 -carboxylic acid amide The title compound was prepared as described in Scheme D6 using (2S,4S)azidopyrrolidine-1 ,2-dicarboxylic acid 1-tert-butyl ester. TLC, Rf (EtOAc) = 0.4; MS MS): 583.5/585.4 [M+H]+, 600.5/602.7 [M+NH4]+, 605.5/607.4 [M+Na]+, 629.4 O]-; t (HPLC conditions f) 2.20 min.
Example 469: 3-{2-[5-(3-Chloro-benzylcarbamoyl)-pyrazolidin-1 -yl]oxo-ethyl}-indole-1 - carboxylic acid amide A solution of 2-[2-(1-carbamoyl-1H-indolyl)-acetyl](3-chloro-benzylcarbamoyl)- pyrazolidine-1 -carboxylic acid tert-butyl ester (15 mg, 0.03 mmol) in HCI 4N in dioxane (69.4 m , 0.278 mmol) was stirred at 23°C for 1 h . The crude material was directly purified by preparative HPLC (waters SunFire C18 ODB 5um, 19x50, 5-100% CH CN/H 0/15min, 3 2 100%CH CN/2.5min, CH CN and H 0 containing 0.1% of TFA, flow : 20 mL/min) to give after 3 3 2 lyophilization of the purified fractions the desired material. MS (LC-MS): 440 [M+H]+; t (HPLC conditions b) : 3.49 min. 2-r2-(1-carbamoyl-1H-indolyl)-acetvn(3-chloro-benzylcarbamoyl)-pyrazolidine carboxylic acid utyl ester The title compound was prepared as described in Scheme D6 using 3-(3-chlorobenzylcarbamoyl )-pyrazolidine-1 xylic acid tert-butyl ester (prepared using a similar ure as the one described in Scheme B5 for the ation of 3-(3-chlorofluorobenzylcarbamoyl )-pyrazolidine-1 -carboxylic acid tert-butyl ester).
Example 470: 3-{2-[(2S,4S)Aminomethyl(3-chlorofluoro-benzylcarbamoyl) fluoro-pyrrolidin-1 -yl]oxo-ethyl}-indole-1 -carboxylic acid amide The title compound was ed according to Scheme D6 from (2S,4R)azidomethyl(3- chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidine-1 -carboxylic acid tert-butyl ester (prepared as described scheme B15) using DMF as solvent followed by azide reduction as described for the preparation of Example 4 11 . MS (LC-MS): 504/506 [M+H]+; t (HPLC conditions ) : 1.42 min; 19F NMR (100 MHz, DMSO-d ) d (ppm): -120, -152.
Example 471 : 3-{2-[(2S,4S)Aminomethyl(3-chloro-2,6-difluoro-benzylcarbamoyl) fluoro-pyrrolidin-1 -yl]oxo-ethyl}-indole-1 xylic acid amide The title compound was ed according to Scheme D6 from (2S,4R)azidomethyl(3- chloro-2,6-difluoro-benzylcarbamoyl)fluoro-pyrrolidine-1 -carboxylic acid tert-butyl ester (prepared using similar protocols as described for (2S,4R)azidomethyl(3-chlorofluorobenzylcarbamoyl )fluoro-pyrrolidinecarboxylic acid tert-butyl ester scheme B15) using DMF as solvent followed by azide ion as described for the preparation of Example 411 .
MS (UPLC-MS): 522/524 [M+H]+; t (HPLC conditions ) : 1.47 min; 19F NMR (100 MHz, DMSO-d ) d (ppm): - 1 17 (2F), -150.
Example 472: 3-{2-[(1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo yl]oxo-ethyl}(2-dimethylamino-ethoxy)-indolecarboxylic acid amide Methanesulfonic acid 2-(1-carbamoyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)- 2-aza-bicyclo[3.1.0]hexyl]oxo-ethyl}-1 H-indolyloxy)-ethyl ester in a solution of dimethylamine 5.6 M in EtOH ( 1 ml_) was sealed in a microwave vial and heated at 70°C for 2 h (Emrys Optimizer; al chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHC0 , extracted with EtOAc, dried (Na S0 ) and evaporated in vacuo. 3 2 4 Then crude residue was purified by catch-release (SCX Tosic Acid-1g from Silicycle; eluent MeOH (10 ml_) to 2M ammonia in MeOH (10 ml_)) to give the desired material which was precipitated in Et 0 . MS (UPLC/MS): 556.5/558.5 [M+H]+, 600.4/602.5 [M+HCOO]-; t (HPLC 2 R conditions ) 1.46 min.
Methanesulfonic acid 2-(1-carbamoylf2 -r(1R,3S,5R)(3-chlorofluoro-benzyl carbamoyl)aza-bicvclor3.1.01hex-2 -vnoxo-ethyl)-1H-indolyloxy)-ethyl ester To a solution of e 453: 3-{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo ]hexyl]oxo-ethyl}(2-hydroxy-ethoxy)-indolecarboxylic acid amide (45 mg, 0.08 mmol) and Et N (56 m I_ , 0.41 mmol) in CH C I ( 1 ml_) at 0°C was added 3 2 2 methanesulfonyl chloride (31 m I_ , 0.41 mmol) and the white suspension was stirred at RT under nitrogen overnight. Et3N (56 m I_ , 0.41 mmol) and methanesulfonyl chloride (31 m I_ , 0.41 mmol) were added and the mixture was r stirred for 1.5 h to complete the reaction. The reaction mixture was quenched by addition of saturated s NaHC0 , extracted with CH C I , dried 3 2 2 (Na S0 ) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel t: EtOAc to EtOAc/ e 1-1). TLC, Rf (EtOAc) = 0.2; MS (UPLC/MS): 607.4/609.3 [M+H]+, 629.2/631.2 [M+Na]+, 562.2/564.1 [M-CONH ]-, 651 .3/653.3 [M+HCOO]-; t (HPLC conditions f): 1.88 min.
Example 473: ( amoyl{2-[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl) aza-bicyclo[3.1 .0]hexyl]oxo-ethyl}-1 H-indolyl)-acetic acid A solution of ( amoyl{2-[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3. 1.0]hexyl]oxo-ethyl}- 1H-indolyl)-acetic acid tert-butyl ester (265 mg, 0.46 mmol) and TFA ( 1.05 ml_, 23.5 mmol) in CH C I (4.8 ml_) was stirred at RT for 3 h . The 2 2 on mixture was concentrated taken up in EtOAC, c-hexane was added until a itate formed and was filtered. Further purification on tnmethylaminopropyl cartridge (Mega Bond Elut-SAX, 1 g 6 ml_, from Varian) (eluent: CH CN 10 ml_ then HCI 0 .1 N in CH CN 10 ml_) gave 3 3 a solid which was precipitated in Et 0 . MS (UPLC): 527.4/529.5 [M+H]+, 544.4/546.3 [M+N H ]+, 571 .3/573.4 [M+HCOO]-; t (HPLC conditions f : 1.74 min. 4 R (1-Carbamoylf2 -r(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- bicvclor3.1.01hex-2 -vnoxo-ethylV1H-indolyl)-acetic acid tert-butyl ester The title compound was prepared according to the protocol described in Scheme D6 using 6- tert-butoxycarbonylmethyl-1 -carbamoyl-1 H-indolyl)-acetic acid (prepared as described in Part A) and (2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoromethyl-pyrrolidine- 1- carboxylic acid tert-butyl ester (prepared as bed in Scheme B 13). TLC, R (EtOAc) = 0.2; MS (UPLC): 549.3/551 .2 [M+H]+, 593.2/595.3 [M+HCOO]-; t (HPLC conditions f): 1.70 min.
Example 474: (1 R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo yl]oxo-ethyl}(2-hydroxy-ethyl)-indolecarboxylic acid amide To a solution of ( 1-carbamoyl{2-[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3. xyl]oxo-ethyl}-1 H-indolyl)-acetic acid methyl ester (35 mg, 0.047 mmol) in THF (0.25 mL) was added LiBH (2 M in THF, 47 m , 0.094 mmol) under nitrogen atmosphere. And the reaction mixture was stirred at RT for 2 h . LiBH4 (2 M in THF, 47 m , 0.094 mmol) was added again and the mixture was further stirred at RT for 2 h , then poured into s NaHC0 , extracted twice with EtOAc, dried (Na S0 ) and the solvent was 3 2 removed in vacuo. The crude material was purified by prep HPLC (Waters Sunfire, C 18-ODB, [Jim, 19x50 mm, : 20% to 100% (CH CN/MeOH 1-4) / H 0 in 15 min, (CH H 1- 3 2 3 4) and H 0 containing 0 .1% HCOOH , flow: 20 mL/min) to give after lyophilization of the purified on the desired material as a white powder. TLC, R (EtOAc) = 0.25; MS (UPLC/MS): 5 13.4/51 5.5 [M+H]+, 530.5/532.7 [M+N H ]+, 557.4/559.4 [M+HCOO]-; t (HPLC 4 R conditions ) 1.74 min. ( amoyl-3 - 2-r(1 R,3S,5R)(3-chloro fluoro-benzylcarbamoyl )aza- bicvclor3.1 .01hexvnoxo-ethylV1 H-indol yl)-acetic acid methyl ester To a suspension of Example 473: ( 1-carbamoyl{2-[(1 R,3S,5R)(3-chlorofluorobenzylcarbamoyl )aza-bicyclo[3. xyl]oxo-ethyl}-1 lyl)-acetic acid (98 mg, 0 .18 mmol) in CH C I ( 1 mL) were added (40 mg, 0 .195 mmol), DMAP (2.2 mg, 0.01 8 mmol) 2 2 and MeOH (7. 17 m I_ , 0 .177 mmol) and the mixture was stirred at RT under nitrogen for 1.5 h .
The mixture was poured into water and extracted twice with CH C I . The combined organic 2 2 layers were dried over Na S0 , filtered and concentrated. The crude material was taken up in 2 4 MeOH and filtered. The filtrate was concentrated and purified by prep HPLC (Waters Sunfire, C 18-ODB, 5 [Jim, 19x50 mm, eluent: 20% to 100% (CH CN/MeOH 1-4) / H 0 in 22.5 min, 3 2 /MeOH 1-4) and H 0 containing 0 .1% HCOOH , flow: 20 mL/min) . TLC, R (EtOAc) = 2 f 0.35; MS MS): 541 .4/543.4 [M+H]+, 558.5/560.5 [M+N H ]+, 563.4/565.0 [M+Na]+, 585.3/587.3 [M+HCOO]-; t (HPLC conditions f) : 1.92 min.
Scheme D7: ation of Example 475: (1 R,3S,5R)(3-Chlorofluorobenzylcarbamoyl )aza-bicvclor3. 1.01hexvnoxo-ethyl)-1 H-indolecarboxylic acid amide A. ( 1R,3S,5R )(3-Chlorofluoro-benzylcarbamoyl)aza-bicyclo [3 .1.0]hexane carboxylic acid tert-butyl ester To a mixture of ( 1R,3S,5R)aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (4 g , 17.6 mmol), 3-chlorofluorobenzylamine (3.09 g , 19.36 mmol) and HBTU ( 10.01 g , 26.4 mmol) in CH C I (88 mL) was added D IPEA (6.03 mL, 35.2 mmol) and the resulting yellow 2 2 solution was stirred at RT under nitrogen. The reaction mixture was poured into HCI 1N and extracted twice with CH C I . The combined organic layers were neutralized with sat. NaHC0 , 2 2 3 dried over Na S0 , filtered and concentrated. The crude residue was purified by fish chromatography (c-hexane to c-hexane/ EtOAc 1-9) to give the desired al as a white solid. TLC, R (EtOAc) = 0.75; MS (LC/MS): 391 .1/393. 1 [M+Na]+, 269.0/271 .0 [MH-Boc]+, 4 13.0/41 5 .1 [M+HCOO]-; t (HPLC conditions f) 2 .1 min.
DMF can also be used instead of Dichloromethane.
B. (1R,3S,5R)Aza-bicyclo [3.1 .0]hexanecarboxylic acid 3-chlorofluorobenzylamide To a solution of (1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0]hexane- 2-carboxylic acid utyl ester (6.35 g , 17.22 mmol) in CH2C I2 (60 ml_) was added TFA (13.18 ml_, 172 mmol) and the solution was stirred at RT for 3 h . The crude reaction mixture was concentrated under vacuum, Et20 was added and the white itate was filtered off to give the desired compound as a TFA salt. MS (LC/MS): 287.0 [M+H]+, 285.1 ; tR (HPLC conditions f) 1.27 min.
C. Example 475: 1-{2-[(1R,3S,5R)(3-Chlorofluoro-benzylcarbamoyl)azabicyclo [3.1 .0]hexyl]oxo-ethyl}-1 H-indolecarboxylic acid amide The mixture of (1R,3S,5R)aza-bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluorobenzylamide oroacetate (70.2 mg, 0.183 mmol), (3-carbamoyl-indolyl)-acetic acid
[10166895] (40.0 mg, 0.183 mmol), HBTU (104 mg, 0.275 mmol) and DIPEA (0.128 ml_, 0.733 mmol) in CH2C I2 (8 ml_) was stirred at RT over 60 h . The reaction e was then diluted with CH2C I2, and the solution was washed twice with 0.1N HCI. The precipitate formed in the aqueous layer was filtered off, washed with CH2C I2 and dried in vacuo to afford the title product as a white solid. MS ): 469 [M+H]+, 491 [M+Na]+; tR (HPLC conditions b): 3.56 min.
Alternatively, for final compounds containing a basic residue the pure HPLC fractions were neutralized with an aqueous saturated solution of Na2C0 3, extracted with EtOAc, dried (Na2S0 4) , filtered and concentrated to give the desired material as a free base.
The examples below were prepared according to the general procedure bed in Scheme D7 for the preparation of Example 475 commercially ble building blocks if not otherwise mentioned (see notes at the end of table 6): Table 6 : Characterization (end-table notes), Example Structure Name TLC, Rf (eluent); MS (LC/MS); tR (HPLC conditions) 1-{2-[(2S,4R)(3-Chloro White solid. 475 fluoro-benzylcarbamoyl) [M+H]+; t (b): 4.19 476 fluoro-pyrrolidinyl]oxo- min. -1 H-indolecarboxylic NH2 acid amide F 1-{2-[(2S,4R)(3-Chloro (4[A1 1],5) Solid. 505 fluoro-benzylcarbamoyl) [M+H]+, 527 [M+Na]+; fluoro-pyrrolidinyl]oxo- t (c): 4.27 min ethyl}methoxy-1 H-indole NH2 carboxylic acid amide White solid. 470 [2-(3-Acetyl-indolyl)- [M+H]+, 492 [M+Na]+; acetyl]-piperidinecarboxylic 478 t (c): 5.01 min. acid 3-chlorofluorobenzylamide 6-Bromo{2-[(2S,4R)(3- (4,5) Solid. 573.0 F chlorofluoro- [M+H]+; t (k): 3.35 benzylcarbamoyl)fluoro- min. pyrrolidinyl]oxo-ethyl} fluoro-1 H-indolecarboxylic NH2 acid amide 3-[({(1 R,3S,5R)[2-(3- (1) White solid. R Acetyl-indolyl)-acetyl] (EtOAc 100) = 0.35; aza-bicyclo[3. 1.0]hexane 526.0 [M+H]+, 548.0 480 carbonyl}-amino)-methyl]- [M+Na]+; t (c): 4.90 -chlorofluoro-benzoic acid min. methyl ester F 1-{2-[(2S,4R)(3-Bromo (1,5) R fluoro-benzylcarbamoyl) (CH C I /MeOH 95:5) = 2 2 fluoro-pyrrolidinyl]oxo- 0.24; 521.0 [M+H]+; t -1 H-indolecarboxylic (k): 3.10 min.
NH2 acid amide (28,4R)[2—(3-Acetyl- (3[B13],4[A15]) Rf pyrro|o[2,3-c]pyridiny|)- (CHZCIZ/MeOH 9:1)= acety|]f|uoro—4-methyl- 0.40; 489.2/491.2 pyrrolidine—2—carboxylic acid [M+H]+, 533.3/535.2 rofluoro—benzylamide [M+HCOO]-; tR (f): 1.49 min. (4[A13]) Rf (EtOAc) = (1 R,3S,5R)-2—[2—(3-Acetyl- 0.10; 469.3/4713 pyrro|o[2,3-b]pyridiny|)- [M+H]+, 937.5/9395 acety|]aza- [2M+H]+, 513.3/515.3 bicyclo[3.1.0]hexane—3- [M+HCOO]-, carboxylic acid 3-chloro—2— 981 .4/983.5 fluoro-benzylamide OO]—; tR (f): 1.90 min. (4[A13]) Rf (1 R,3S,5R)-2—[2—(3-Acetyl- Z/MeOH 4:1) = pyrro|o[2,3-b]pyridiny|)- 0.45; 4573/4592 acety|]aza- [M+H]+, 479.2/481,1 bicyclo[3.1.0]hexane—3- [M+Na]+, 5013/5032 carboxyl ic acid (5-chloro- [M+HCOO]-; thiophen-2—ylmethyI)-amide tR (f): 1.86 min. (3[BZ4],4) 578 (28,38,4S)[2-(3-AcetyI [M+HCOO]-, 534 y-indoIy|)-acety|] [M+H]+; tR (f): 1.99 methoxy-pyrrolidine— min. 2—carboxylic acid 3-chloro—2— fluoro-benzylamide 461 [M+H]+; tR (b): 1-{2-[(28,4R)(3-Ch|oro—2— 4.25 min. fluoro-phenylcarbamoy|) fluoro-pyrrolidiny|]oxo- ethy|}-1H-indole—3-carboxylic acid amide (3[B24],4[A13]) and (3—acetylmethoxy- ,4S)—1-[2-(3-Acetyl indolyl)-acetic acid methoxy-indolyl)-acetyl] (prepared as fluoro-3—methoxy-pyrrolidine— described in Part A). 2-carboxylic acid 3—chloro 578 [M+HCOO]—, 534 fluoro-benzylamide [M+H]+; tR (f): 2.03 min.
-Chloro{2-[(2S,4R)—2-(3— (4[A11]) White solid. chlorofluoro- 509/510 [M+H]+, benzylcarbamoyl)—4-fluoro- 532/533 [M+Na]+; tR pyrrolidinyl]oxo-ethyl}- (b): 4.50 min. ole—3-carboxylic acid amide 7-Chloro{2-[(2S,4R)—2-(3— (4[A11]) White solid. chlorofluoro- 509/510 [M+H]+, carbamoyl)—4-fluoro- 3 [M+Na]+; tR pyrrolidinyl]oxo-ethyl}- (b): 4.42 min. 1H-indole—3-carboxylic acid amide (1 R,3S,5S)[2-(3—Acetyl- (2,3,4[A13]) White pyrrolo[2,3—b]pyridiny|)- solid. Rf (EtOAc) = acetyl]methoxym ethyl 0.25; 513.3/515.3 aza-bicyclo[3.1.0]hexane-3— [M+H]+, 557.4/559.4 carboxylic acid 3—chloro [M+HCOO]-; tR (a): fluoro-benzylamide 3.23 min. (4) White solid. 6-Chloro{2-[(2S,4R)—2-(3— 509/510 [M+H]+; chlorofluoro-benzyl- 532/533 [M+Na]+; tR carbamoyl)-4—fluoro-pyrrolidin- (b): 4.52 min. 1-yl]—2-oxo-ethyl}-1H-indole—3— carboxylic acid amide 1-{2-[(2S,4R)—2-(3—Chloro (4,5) Solid. 511 -benzylcarbamoyl)—4- [M+H]+; tR (k): 3.28 fluoro-pyrrolidinyl]oxo- min. ethyl}-5,6—difluoro-1H-indole— 3-carboxylic acid amide (2S,4R)(3-Chloro (4,5) Solid. 560.0 fluoro-benzylcarbamoyl) [M+H]+; t (k): 3.45 fluoro-pyrrolidinyl]oxo- min. 493 ethyl}trifluoromethoxy-1 H- indolecarboxylic acid NH2 amide ( 1 R,3S,5R)[2-(3-Acetyl (4[A15]) R methoxy-pyrrolo[2,3-b]pyridin- (CH C I /MeOH 9:1) = 2 2 1-yl)-acetyl]aza- 0.50; 499.3/501 .3 bicyclo[3. 1.0]hexane [M+H]+, 543.3/545.3 ° > carboxylic acid 3-chloro [M+HCOO]-; -benzylamide t (f): 2.08 min. ( 1 R,3S,5R){2-[3-(2,2,2- (4[A13],5) White solid.
Trifluoro-acetyl)-i ndol- 1-yl]- 522.0 [M+H]+; t (c): acetyl}aza- 5.53 min. 495 bicyclo[3. 1.0]hexane carboxylic acid 3-chloro fluoro-benzylamide 1-{2-[(2S,4R)(3-Chloro (3[B13],5) White solid. fluoro-benzylcarbamoyl) 489 [M+H]+; t (c): methyl-pyrrolidin 4.35 min. yl]oxo-ethyl}-1 H-indole NH2 carboxylic acid amide 'r-v H 1-{2-[(2S,4R)(3-Chloro ],5) White solid. fluoro-benzylcarbamoyl) 505 [M+H]+; t (c): fluoro-pyrrolidinyl]oxo- 4.17 min. ethyl}methoxy-1 H-indole NH / carboxylic acid amide CI (2S,4R)[2-(3-Acetyl-indol- (1) White solid. 499.0 1-yl)-acetyl]fluoro- [M+H]+, 497.0 [M-H]-; idinecarboxylic acid t (c): 4.55 min. 498 3-chlorocyanofluorobenzylamide F 1-{2-[(2S,4R)(3-Chloro (4[A10],5) White solid. fluoro-benzylcarbamoyl) 505 [M+H]+; t (c): fluoro-pyrrolidinyl]oxo- 4.19 min. ethyl}methoxy-1 H-indole NH2 carboxylic acid amide )[2-(3-Acetyl (4[A13],5) Solid. 504 methoxy-indolyl)-acetyl] [M+H]+, 526 [M+Na]+; 500 -pyrrolidinecarboxylic t (k): 3.43 min. acid 3-chlorofluorobenzylamide (4) White solid. 500 (S)[2-(3-Acetylmethoxy- ; t (c): 4.96 indolyl)-acetyl]-piperidine- R 501 min. 2-carboxylic acid 3-chloro fluoro-benzylamide (3[B13], 4 [A15]) R (2S,4R)[2-(3-Acetyl- f (CH C I /MeOH 9:1) = pyrrolo[3,2-c]pyridinyl)- 2 2 0.40; 489.3/491 .3 502 acetyl]fluoromethyl- [M+H]+, 533.3/535.3 pyrrolidinecarboxylic acid O]-; t (f): 3-chlorofluoro-benzylamide R 1.50 min.
-Benzyloxy{2-[(2S,4R) (4[A1 1]) White solid. (3-chlorofluoro- R (EtOAc/MeOH carbamoyl)fluoro- 95:5) = 0.27; 581/582 pyrrolidinyl]oxo-ethyl}- [M+H]+; t (b): 4.90 NH 1H-indolecarboxylic acid min. amide ( 1 R,3S,5R)[2-(3-Acetyl- (3[B9]) R (EtOAc)= indolyl)-acetyl]aza- 0.15; 512.3 [M+H]+, bicyclo[3. 1.0]hexane 556.3/558.4 carboxylic acid [(R)(3- [M+HCOO]-; t (a): chlorofluoro-phenyl) 3.22 min. hydroxy-propyl]-amide (2S,3S,4S)[2-(3-Acetyl- (3[B24]) 504 [M+H]+; 1-yl)-acetyl]fluoro t (f): 2.01 min. ° y-pyrrolidine carboxylic acid ro fluoro-benzylamide ( 1 R,2S,5S)[2-(3-Acetyl- (4[A15]) R pyrrolo[2,3-c]pyridinyl)- (CH C I /MeOH 9:1)= 2 2 acetyl]aza- 0.30; 469.3/471 .3 bicyclo[3. 1.0]hexane [M+H]+, 513.2/515.2 carboxylic acid 3-chloro O]-; fluoro-benzylamide t (f): 1.48 min.
White solid. 474 (2S,4R)[2-(3-Acetyl-indol- [M+H]+; t (b): 3.90 1-yl)-acetyl]fluoro- R 507 min. pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide (2S,4R)[2-(3-Acetyl (4[A13],5) White solid. benzyloxy-indolyl)-acetyl]- 580/582 [M+H]+; t 4-fluoro-pyrrolidine (k): 3.81 min. 508 carboxylic acid 3-chloro fluoro-benzylamide (2S,4R)[2-(3-Acetyl (4,5) White solid. R trifluoromethoxy-indolyl)- (CH C I /MeOH 95:5) = 2 2 acetyl]fluoro-pyrrolidine 0.31; 558.0 ; t 509 ocF R carboxylic acid 3-chloro (c): 5.26 min. fluoro-benzylamide ( 1 R,3S,5R)[2-(3-Acetyl- (5) White solid. 468.0 indolyl)-acetyl]aza- [M+H]+; t (c): 4.77 bicyclo[3. 1.0]hexane min. carboxylic acid 3-chloro fluoro-benzylamide (2S,4R)[2-(3-Acetyl-indol- (3[B13],5) White solid. 1-yl)-acetyl]fluoromethyl- R (CH C I /MeOH f 2 2 pyrrolidinecarboxylic acid 95:5) = 0.31; 488.0 11 3-chlorofluoro-benzylamide [M+H]+; t (c): 4.82 min. ( 1 R,3S,4S)[2-(3-Acetyl- 482 [M+H]+, 480 [M- indolyl)-acetyl]aza- H]-; tR (f): 0.98 min. 512 bicyclo[2.2. 1]heptane carboxylic acid 3-chloro fluoro-benzylamide (4[A13]) Rf (EtOAc)= (S)[2-(3-Acetyl-pyrrolo[2,3- - S 0.80; 475.3/477.2 b]py ridinyl)-acetyl]- [M+H]+, 949.4/951.3 513 thiazolidine [2M+H]+, 519.2/521.2 carboxylic acid ro [M+HCOO]-; fluoro-benzylamide tR (f): 1.91 min. (2S,4R)[2-(3-Acetyl-indol- (1,5) White solid. 510 1-yl)-acetyl]fluoro- [M+H]+, 532 [M+Na]+; pyrrolidinecarboxylic acid tR (k): 3.62 min (2-fluorotrifluoromethoxyphenyl )-amide ( 1 R,3S,5R)[2-(3-Acetyl- ( 1 ,2) White solid. indolyl)-acetyl]aza- 548.0 [M+H]+; tR (c): bicyclo[3. 1.0]hexane 4.51 min. 515 carboxylic acid [3-bromo (2H-tetrazolyl)-phenyl]- amide (2S,4R)[2-(3-Acetyl-indol- (1,5) White solid. Rf 1-yl)-acetyl]fluoro- (CH2C I2/MeOH 95:5) = pyrrolidinecarboxylic acid 0.41; 518.0 [M+H]+; tR 3-bromofluoro-benzyl (k): 3.45 min amide 1-{2-[(2S,4R)Fluoro(2- (5,6) White solid. 495 fluorotrifluoromethyl- [M+H]+, 989 [2M+1]+; carbamoyl)-pyrrolidin- tR (c): 4.46 min. 1-yl]oxo-ethyl}-1 H-indole NH2 ylic acid amide F HO (2S,4R)[2-(3-Acetyl-indol- (5) White solid. Rf 1-yl)-acetyl]fluoro- (CH2C H 95:5) = 518 pyrrolidinecarboxylic acid 0.32; 504.0 [M+H]+; tR [(S)(3-chlorofluoro- (c): 4.21 min. phenyl)hydroxy-ethyl]- amide 1-{2-[(2S,4R)(3-Chloro (4) 489 [M+H]+; t (b): F R fluoro-benzylcarbamoyl) 3.57 min. 519 fluoro-pyrrolidinyl]oxo- ethyl}-1 H-indolecarboxylic NH acid methylamide \ (2S,3S,4S)[2-(3-Acetyl- (3[B24], 4[A13]) 549 pyrrolo[2,3-b]pyridinyl)- [M+HCOO]-, 505 ° acetyl]fluoromethoxy- [M+H]+; t (f): 1.90 520 N - pyrrolidinecarboxylic acid min. 3-chlorofluoro-benzylamide (2S,4R)[2-(3-Acetyl-indol- (1,2) White solid. 1-yl)-acetyl]fluoro- 542.3 [M+H]+, 540.3 N- pyrrolidinecarboxylic acid [M-H]-; t (c): 4.27 min 521 °° 3-chlorofluoro(1 H- olyl)-benzylamide ( 1 R,3S,5R)[2-(3-Acetyl- (1[C4],2) R (EtOAc) = indolyl)-acetyl]aza- 0.1 ; 527/527 [M+H]+; bicyclo[3. 1.0]hexane t (f): 1.66 min. 522 carboxylic acid [(S)(3- chlorofluoro-phenyl) dimethylamino-ethyl]-amide 3-[({(2S,4R)[2-(3-Acetyl- (1,5) White solid. indolyl)-acetyl]fluoro- 530.0 [M-H]-; t (c): pyrrolidinecarbonyl}- 4.73 min. -methyl]chloro fluoro-benzoic acid methyl ester ( 1 R)[2-(3-Acetyl- ]) R pyrrolo[3,2-c]pyridinyl)- (CH C I /MeOH 4:1)= 2 2 acetyl]aza- 0.35, 469.3/471 .3 bicyclo[3. 1.0]hexane , 513.3/515.3 carboxylic acid 3-chloro [M+HCOO]-; fluoro-benzylamide t (f): 1.46 min.
CI ( 1 R,3S,5R)[2-(3-Acetyl- (1,2) White solid. 1-yl)-acetyl]aza- 536.3 [M+H]+, 534.3 bicyclo[3. 1.0]hexane [M-H]-; tR (c): 4.41 525 carboxylic acid ro min. fluoro(1 H-tetrazolyl)- benzylamide 3-Acetyl{2-[(1R,3S,5R) (4[A13],5) Solid. 526 (3-chlorofluoro- , 1021 benzylcarbamoyl)aza- [2M+H]+; tR (k): 3.52 526 bicyclo[3. 1.0]hexyl]oxo- min. ethyl}-1 H-indolecarboxylic acid methyl ester CI ( 1 R,3S,5R)[2-(3-Acetyl- (1) White solid. 493.0 indolyl)-acetyl]aza- [M+H]+; tR (c): 4.68 bicyclo[3. 1.0]hexane min 527 carboxylic acid 3-chloro cyanofluoro-benzylamide F 1-{2-[(2S,4R)(3-Chloro (4,5) Solid. 541/543 fluoro-benzylcarbamoyl) [M+H]+; tR (k): 3.33 fluoro-pyrrolidinyl]oxo- min. 528 difluoromethoxy-1 H- NH2 indolecarboxylic acid amide 6-Benzyloxy{2-[(2S,4R) (4[A1 1]) White solid. (3-chlorofluoro- 581/582 [M+H]+, benzylcarbamoyl)fluoro- 603/604 [M+Na]+; tR idinyl]oxo-ethyl}- (b): 4.94 min. 1H-indolecarboxylic acid amide (2S,4R)[2-(3-Acetyl- (3[B13], 4[A13]) Rf 530 pyrrolo[2,3-b]pyridinyl)- (EtOAc) = 0.35; acetyl]fluoromethyl- 489.3/491.2 [M+H]+, pyrrolidinecarboxylic acid 533.3/535.2 3-chlorofluoro-benzylamide [M+HCOO]-; tR (f): 1.93 min. (2S,4R)[2-(3-Acetyl (4[A13],5) Solid. chloro-indolyl)-acetyl] 0 [M+H]+, 530 531 fluoro-pyrrolidinecarboxylic [M+Na]+; t (k): 3.63 acid rofluoro- min. benzylamide ( 1 R,3S,5R)[2-(3-Acetyl (4[A15]) R (EtOAc) = cyano-pyrrolo[2,3-b]pyridin 0.25; 494.3/496.3 yl)-acetyl]aza- , 538.2/540.2 bicyclo[3. 1.0]hexane [M+HCOO]-; ylic acid 3-chloro t (f): 2.03 min. fluoro-benzylamide ( 1 R,3S,5R)[2-(3-Acetyl- (2,3[B9],4[A13]) White pyrrolo[2,3-b]pyridinyl)- solid. R (EtOAc) = acetyl]aza- 0.50; 513.2/515.2 533 bicyclo[3. 1.0]hexane [M+H]+, 5 11.2 [M-H]-, ylic acid [(S)(3- 557.2/559.2 chlorofluoro-phenyl) [M+HCOO]-; t (a): methoxy-ethyl]-amide 3.26 min. (2S,4R)[2-(3-Acetyl (4[A13],5) Solid. 534 benzyloxy-indolyl)-acetyl]- 580/581 [M+H]+; t ° 4-fluoro-pyrrolidine (k): 3.83 min. carboxylic acid 3-chloro fluoro-benzylamide ( 1 R,3S,5R)[2-(3-Acetyl- (2,3[B9],4[A15]) R 535 pyrrolo[2,3-c]pyridinyl)- (CH C I / MeOH 9:1) = 2 2 acetyl]aza- 0.45; 513.3/515.3 bicyclo[3. 1.0]hexane [M+H]+, 557.2/559.2 ylic acid [(S)(3- [M+HCOO]-; t (f): chlorofluoro-phenyl) 1.50. methoxy-ethyl]-amide ( 1 R,3S,5R)[2-(3-Acetyl (4[A13],5) Solid. 574 benzyloxy-indolyl)-acetyl]- ; t (k): 3.89 536 2-aza-bicyclo[3. 1.0]hexane min. carboxylic acid 3-chloro fluoro-benzylamide -4o4— (1 R,28,5S)[2-(3—Acetyl- (4[A15l) Rf pyrrolo[3,2-c]pyridinyl)- (CHZClz/MeOH 9:1): acetyl]aza- 0.40, 469.3/471.3 bicyclo[3.1.0]hexane [M+H]+, 513.3/515.3 carboxylic acid 3-chloro [M+HCOO]—; -benzylamide tR (f): 1.47 min. (1 R,28,5S)[2-(3—Acetyl- (4[A13l) Rf pyrrolo[2,3—b]pyridinyl)- (CHZClz/MeOH 4:1)= acetyl]aza- 0.35; 469.3/471.3 bicyclo[3.1.0]hexane [M+H]+, 513.3/515.2 carboxylic acid 3-chloro M+HCOO]—; fluoro-benzylamide tR (a): 3.15 min. (28,4R)[2-(3—Acetyl (4[A13],5) White solid. trifluoromethoxy-indolyl)- 558.0 [M+H]+; tR (c): acetyl]fluoro—pyrrolidine 5.25 min. carboxylic acid 3-chloro -benzylamide 3-Acetyl{2-[(1R,3S,5R)-3— (4[A13],5) Solid. (3-chlorofluoro— 8 [M+H]+, benzylcarbamoyl)aza- 548/550 +; tR bicyclo[3.1.0]hexyl]oxo— (k): 3.54 min. ethyl}-1H-indolecarboxylic acid methyl ester 3-Acetyl{2-[(1R,3S,5R)-3— (4[A13],5) Solid. MS (3-chloro (LC/MS): 525 [M+H]+, fluorobenzylcarbamoyl) 1051 [2M+H]+; tR (k); aza-bicyclo[3.1.0]hex—2-yl]—2- 3.68 min. oxo-ethyl}-1H-indole-7— ylic acid methyl ester 3-Acetyl{2-[(28,4R)(3— (4[A13],5) Solid. 532 chlorofluoro— [M+H]+, 554 [M+Na]+; carbamoyl)fluoro- tR (k): 3.44 min. pyrrolidinyl]oxo-ethyl}- 1H-indole—6-carboxylic acid methyl ester -4o5- (28,4R)Fluoro{2-[3-(2- (3[B13],4[A13],5) hydroxy-acetyl)-indolyl]- White solid. 504.0 acetyl}methyl-pyrrolidine—2- [M+H]+; tR (C): 4.56 carboxylic acid 3-chloro min. fluoro-benzylamide (1S28,5R)[2-(3-Acetyl- (4[A15]) Rf pyrrolo[2,3-c]pyridinyl)- (CHZClz/MeOH 9:1): acetyl]aza- 0.45; 4592/4712 bicyclo[3.1.0]hexane [M+H]+, 513.2/5153 carboxylic acid 3-chloro [M+HCOO]-; fluoro-benzylamide tR (f): 1.49 min. tyl{2-[(1R,3S,5R) (4,5) Solid. 54o (3-chlorofluoro- [M+H]+, 552 [M+Na]+; benzylcarbamoyl)aza- tR (k): 3.51 min. bicyclo[3.1.0]hexyl]oxoethyl }-1H-indol-6—yl)-acetic acid methyl ester (28,4R)Fluoro{2-[3- (1,4[A13],5) White (2,22-trifluoro-acetyl)-indol solid. Rf yl]-acetyl}-pyrrolidine Z/Acetone 9:1) ylic acid 3-bromo = 0.41; 573.0 [M+H]+; fluoro-benzylamide tR (k): 3.87 min (4[A13]) Rf (28,4R)[2-(3-Acetyl- z/MeOH 4:1): pyrrolo[2,3-b]pyridinyl)- 0.80; 475.3/477.3 acetyl]fluoro-pyrrolidine [M+H]+, 5192/5212 ylic acid 3-chloro [M+HCOO]—; fluoro-benzylamide tR (f): 1.84 min. 3-Acetyl{2-[(28,4R)(3- (3[B13],4[A13],5) chlorofluoro- Solid. 546 [M+H]+, benzylcarbamoyl)fluoro- 568 [M+Na]+; tR (k): 4-methyl-pyrrolidinyl] 3.58 min. oxo-ethyl}-1H-indole-6— carboxylic acid methyl ester (3-Acetyl{2-[(2S,4R)(3- (4,5) Solid. 546 fluoro- [M+H]+, 568 [M+Na]+; carbamoyl)fluoro- t (k): 3.46 min. pyrrolidinyl]oxo-ethyl}- 1H-indolyl)-acetic acid methyl ester ( 1 R)[2-(3-Acetyl- (4[A15]) White solid. pyrrolo[2,3-c]pyridinyl)- 469.3/471.3 [M+H]+, acetyl]aza- 513.2/515.2 bicyclo[3. 1.0]hexane [M+HCOO]-; carboxylic acid 3-chloro t (f): 1.48 min. fluorobenzylamide (2S,4R)Fluoro{2-[3-(2- (1,4[A13],5) White hydroxy-acetyl)-indolyl]- solid. 548.0 [M+H]+; t acetyl}-pyrrolidine (c): 4.47 min. carboxylic acid [(S)(3- bromo-phenyl)fluoro-ethyl]- amide (4[A15]) R F (2S,4R)[2-(3-Acetyl- (CH C I /MeOH 9:1)= pyrrolo[2,3-c]pyridinyl)- 2 2 0.40; 475.4/477.3 acetyl]fluoro-pyrrolidine , 521 .4 carboxylic acid 3-chloro [M+HCOO]-; fluoro-benzylamide t (f): 1.45 min. ( 1 R,3S,5R)[2-(3-Acetyl- (4[A13]) R pyrrolo[3,2-b]pyridinyl)- (CH C I /MeOH 4:1)= 2 2 acetyl]aza- 0.35, 469.2/471 .3 bicyclo[3. 1.0]hexane [M+H]+, 513.3/515.3 carboxylic acid 3-chloro [M+HCOO]-; fluoro-benzylamide t (f): 1.45 min. (2S,4R)Fluoromethyl ],4[A13],5) {2-[3-(2,2,2-trifluoro-acetyl)- White solid. R indolyl]-acetyl}-pyrrolidine- (CH C I /MeOH 95:5) = 2 2 2-carboxylic acid 3-chloro 0.56; 542.0 [M+H]+; t F3 fluoro-benzylamide (c): 5.54 min. -4o7- (2R,3S,4R)[2-(3—Acetyl- (3[820]) Rf (C- indoIy|)-acety|] hexane/EtOAc 1/1) = dimethylamino—3-fluoro— 0.17; 517 [M+H]+, 561 pyrrolidine—2-carboxylic acid [M-H]-; tR (f): 1.63 3-chlorofluoro—benzylamide min. (1 R,3S,5R){2-[3—(2- (4[A13],5) White solid. y-acetyI)-indoly|]- 484.0 [M+H]+; tR (c): acety|}aza- 4.50 min. bicyc|o[31.0]hexane carboxylic acid 3-chloro -benzylamide (1 R,3S,5R)[2-(3—Acetyl- (3[B9],4 [A13]) Rf o[2,3—b]pyridiny|)- (CHZCIZ/MeOH 9:1): acety|]aza- 0.7; 5133/5153 bicyc|o[31.0]hexane [M+H]+, 557.2 carboxylic acid [(R)(3- [M+HCOO]—; tR (a): chlorofluoro—phenyl)-3— 302min. hydroxy-propy|]-amide (1 R,3S,5R)[2-(3—Acetyl- (4[A13]) Rf (EtOAc) = pyrrolo[2,3—b]pyridiny|)- 0.30; 487.3 [M+H]+, acety|]aza- 9735 [2M+H]+, 485.3 bicyc|o[31.0]hexane [M-H]—, 531.3 carboxyl ic acid (3- [M+HCOO]—, 1017.5 trifluoromethoxy-pheny|)- [2M+HCOO]—; amide tR (f): 2.08 min.
Rf (c-hexane/EtOAc (S)[2-(3—FormyI-indoly|)- 1:2)= 0.04; 460.1 ]-pyrro|idine [M+H]+, 482 [M+Na]+, carboxylic acid (3- 941.2 [2M+Na]+, trifluoromethoxy-pheny|)- 458.2 [M-H]—; tR (a): amide 358 min. (2S,4R)Fluoro[2-(3- MS (LC/MS): 490.0 formyl-5—methoxy-indoIy|)- [M+H]+; tR (l): 1.77 ]-pyrro|idine min. carboxylic acid 3-chloro—2- fluoro-benzylamide )Fluoro{2-[3- (4[A13],5) White solid. (2,2,2—trifluoro—acetyl)-indol Rf (c-hexane/EtOAc etyl}-pyrrolidine 1:1) = 0.18; 528.0 carboxylic acid ro—2— [M+H]+; tR (c): 5.44 fluoro-benzylamide min. (1 R)-2—[2—(3—Acetyl- (1,4[A13]) Rf (EtOAc) pyrrolo[2,3-b]pyridinyl)- = 0.45; 505.4 [M+H]+, acetyl]—2—aza— 1009.6 [2M+H]+, bicyclo[3.1.0]hexane 503.3 [M-H]-, 549.3 carboxylic acid (2-fluoro [M+HCOO]—, 1007.7 trifluoromethoxy-phenyl)- [2M+HCOO]-; amide tR (f): 2.08 min. (28,4R)Fluoro{2-[3-(2- (4[A13],5) White solid. hydroxy-acetyl)-indolyl]- 490.1 [M+H]+, 485.5 acetyl}-pyrrolidine-2— [M-H]-; tR (c): 4.39 carboxylic acid 3-chloro min. fluoro-benzylamide (28,4R)Fluoro{2-[3-(2- (1,4[A13],5) Solid. Rf hydroxy-acetyl)-indolyl]- (CHZClz/MeOH 9:1) = acetyl}-pyrrolidine-2— 0.50; 534.0 [M+H]+; tR carboxylic acid 3-bromo (k): 3.25 min. fluoro-benzylamide (28,4R)Fluoro{2-[3-(2- (4[A13],5) White solid. methoxy-acetyl)-indolyl]- 504.0 [M+H]+; tR (c); }-pyrrolidine-2— 4.63 min. carboxylic acid 3-chloro fluoro-benzylamide 1-{2-[(28,4R)(3-Chloro—2— (3[B12]) 503 [NI-H], fluoro-benzylcarbamoyl) 505 [M+H]+; tR (f): fluoro-4—hydroxymethyl- 1.66 min. pyrrolidinyl]oxo-ethyl}- 1H-indole—3-carboxylic acid amide methoxy-ethyl]-amide 3.43 min. ( 1) The substituted benzylamine or aniline derivative used in step A was prepared as described in Part C ; (2) HCI (4M in dioxane) was used instead of TFA in step B ; (3) The title compound was prepared according to the general procedure described in Scheme D6 steps B and C starting from the substituted proline derivative prepared as described in Part B e]; (4) Compound was prepared as described in Scheme D7 using (3-carbamoyl-indol-1 -yl)-acetic acid derivative or (3-acetyl-indol-1 -yl)-acetic acid tive (prepared as bed in Part A); (5) DMF was used instead of CH2CI2 in step C ; (6) HATU was used as the coupling t in step C.
Example 569: (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoroethoxy-pyrrolidine- -carboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared according to Scheme D7 from (2S,3S,4S)fluoroethoxypyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide (prepared as described in Scheme B24 using ethyl iodide instead of methyl iodide in Step B). MS (UPLC-MS): 518 [M+H]+, 562 [M+HCOO]-; t (HPLC conditions f): 2.1 1 min.
Example 570: ,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxypyrrolidinecarboxylic acid [(R)(3-chlorofluoro-phenyl)-ethyl]-amide The title compound was prepared according to Scheme D7 from (2S,3S,4S)fluoro methoxy-pyrrolidinecarboxylic acid (R)(3-chlorofluoro-phenyl)-ethyl]-amide prepared as described in Scheme B24 using (R)(3-chlorofluorophenyl)ethanamine in Step D. MS MS): 562 [M+HCOO]-, 518 [M+H]+; t (HPLC conditions f): 2.1 1 min.
Example 571 : (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxypyrrolidinecarboxylic acid [(S)-1 -(3-chlorofluoro-phenyl)-ethyl]-amide The title compound was prepared ing to Scheme D7 from (2S,3S,4S)fluoro methoxy-pyrrolidinecarboxylic acid (S)(3-chlorofluoro-phenyl)-ethyl]-amide prepared as described in Scheme B24 using (S)(3-chlorofluorophenyl)ethanamine in Step D. MS (UPLC-MS): 562 [M+HCOO]-, 518 [M+H]+; t (HPLC conditions f): 2.09 min.
Example 572: (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxypyrrolidinecarboxylic acid [1-(3-chloro-phenyl)-cyclopropyl]-amide The title compound was prepared according to Scheme D7 from (2S,3S,4S)[1-(3-chlorophenyl )-cyclopropylcarbamoyl]fluoromethoxy-pyrrolidinecarboxylic acid tert-butyl ester (prepared using the same protocols as described in Scheme B24 using 1-(3-chloro-phenyl)- cyclopropylamine in Step D). Preparation of hloro-phenyl)-cyclopropylamine was described in Part C. MS MS): 556 [M+HCOO]-, 512 [M+H]+; t (HPLC conditions f): 2.05 min.
Example 573: (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]fluoromethoxypyrrolidinecarboxylic acid chloro-phenyl)-cyclopropyl]-amide The title compound was prepared according to Scheme D7 from (2S,3S,4S)[1-(3-chlorophenyl )-cyclopropylcarbamoyl]fluoromethoxy-pyrrolidinecarboxylic acid utyl ester (prepared using the same protocols as bed in Scheme B24 using 1-(4-chloro-phenyl)- cyclopropylamine in Step D). Preparation of 1-(4-chloro-phenyl)-cyclopropylamine was described in Part C. MS (UPLC-MS): 556 [M+HCOO]-, 512 ; t (HPLC conditions f): 2.05 min.
Example 574: 1-{2-[(2S,3S,4S)Amino(3-chlorofluoro-benzylcarbamoyl)fluorooxo-ethyl }-1H-indolecarboxylic acid amide The title compound was prepared according to Scheme D7 from (2S,3S,4S)azido(3- chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester (described in scheme B19) followed by reduction of the azide as described for the preparation of Example 411 (2S,4S)aminomethylfluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-(3-chloro-2,6-difluoro-benzylamide). TLC, R (CH C I /MeOH f 2 2 95/5) = 0.2 ; MS ): 490 [M+H]+, 488 [M-H]-; t (HPLC conditions ) : 1.46 min.
Example 575: (2S,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]aminofluoro-pyrrolidine 3-chlorofluoro-benzylamide The title compound was prepared according to Scheme D7 starting from a mixture of (2R,3S,4R) and (2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)(9H-fluoren oxycarbonylamino)fluoro-pyrrolidinecarboxylic acid tert-butyl ester in a 2:1 ratio (prepared as bed in Scheme B22) followed by Fmoc deprotection using the protocol described for the preparation of Example 396. The regioisomers were separated by preparative HPLC to give the title compound: MS (UPLC-MS): 489 [M+H]+, 533 [M-H]-; t (HPLC conditions f): 1.62 min.
Example 576: (2R,3S,4R)[2-(3-Acetyl-indolyl)-acetyl]aminofluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared according to Scheme D7 starting from a mixture of ,4R) and (2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)(9H-fluoren ylmethoxycarbonylamino)fluoro-pyrrolidinecarboxylic acid tert-butyl ester in a 2:1 ratio (prepared as described in Scheme B22) followed by Fmoc deprotection using the protocols bed for the preparation of Example 396. TLC, R (CH C I /MeOH 95/5) = 0.26 ; MS f 2 2 MS): 489 [M+H]+ , 533 [M+HCOO]-; t (HPLC conditions f): 1.63 min. e 577: 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin xy-1H-indolecarboxylic acid amide To a suspension of 5-benzyloxy{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinyl ]oxo-ethyl}-1 lecarboxylic acid amide Example 503 (148 mg, 0.255 mmol) in TFA (2.5 mL), cooled to 0°C, was added thioanisole (0.301 mL, 2.55 mmol), and the reaction mixture was stirred at RT for 3h. Volatiles were evaporated under reduced pressure, and the residue was suspended in a saturated aqueous NaHC0 solution, followed by freeze- drying in vacuo. The residue was suspended in a small amount of methanol and the solid was filtered off. The filtrate was purified by preparative HPLC (Sunfire, C18-ODB, 5 m h , 30x100 mm, flow: 40 mL/min, 20-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 3 2 3 3 2 containing 0.1% TFA). The title compound was obtained as a white solid. MS (LC/MS): 491 [M+H]+; 983 [2M+H]+; t (HPLC, conditions b): 3.75 min.
Example 578: 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin yl]oxo-ethyl}hydroxy-1H-indolecarboxylic acid amide The title compound was prepared in a similar manner as described above for Example 577 from (6-benzyloxy{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]- 2-oxo-ethyl}-1 lecarboxylic acid amide Example 529 (220 mg, 0.379 mmol). White solid. MS (LC/MS): 491 [M+H]+; t (HPLC conditions b): 3.76 min.
Example 579: (2S,4R)[2-(3-Acetylhydroxy-indolyl)-acetyl]fluoro-pyrrolidine carbox lic acid 3-chlorofluoro-benzylamide The title compound was prepared in a similar manner as described for Example 577 from (2S,4R)[2-(3-acetylbenzyloxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3- chlorofluoro-benzylamide Example 508 (167 mg, 0.288 mmol). White solid. MS (LC/MS): 490 [M+H]+; t (HPLC conditions k): 3.03 min. e 580: (2S,4R)[2-(3-Acetylhydroxy-indolyl)-acetyl]fluoromethylrrolidinecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared in a similar manner as described above for Example 577 from )[2-(3-acetylbenzyloxy-indolyl)-acetyl]fluoromethyl-pyrrolidine carboxylic acid rofluoro-benzylamide (57.0 mg, 0.096 mmol), TFA (3 mL), and thioanisole (0.1 14 mL, 0.960 mmol). Solid. MS (LC/MS): 504 [M+H]+; t (HPLC, conditions k): 3.22 min. (2S,4R)r2-(3-acetylbenzyloxy-indolyl)-acetvnfluoromethyl-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide was prepared as described in Scheme D7 from (3-acetylbenzyloxy-indolyl)-acetic acid red as described in Part A) using DMF instead of CH C I in Step C. White solid. MS 2 2 (LC/MS): 594 [M+H]+; t (HPLC conditions k): 3.89 min.
Example 581 : (1R,3S,5R)[2-(3-Acetylhydroxy-indolyl)-acetyl]aza- ecarboxylic acid 3-chlorofluoro-benzylamide The title compound was ed in a similar manner as described above for Example 577 from ,5R)[2-(3-acetylbenzyloxy-indolyl)-acetyl]aza-bicyclo [3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide (79.0 mg, 0.138 mmol), TFA (3 ml_) and thioanisole (0.163 ml_, 1.38 mmol). Solid. MS (LC/MS): 484 [M+H]+; t (HPLC, conditions k): 3.18 min. (1R,3S,5R)r2-(3-acetylbenzyloxy-indolyl)-acetvnaza-bicyclor3.1.01hexane carboxylic acid 3-chlorofluoro-benzylamide was prepared as described in Scheme D7 from (3-acetylbenzyloxy-indolyl)-acetic acid (prepared as bed in Part A) using DMF instead of CH C I in Step C. White solid. MS 2 2 ): 574 [M+H]+; t (HPLC conditions k): 3.88 min.
Example 582: (2S,4R)[2-(3-Acetylhydroxy-indolyl)-acetyl]fluoromethylrrolidinecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared in a similar manner as described above for Example 577 from (2S,4R)[2-(3-acetylbenzyloxy-indolyl)-acetyl]fluoromethyl-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide (96.0 mg, 0.137 mmol), TFA (2 mL) and thioanisole (0.162 mL, 1.374 mmol). Solid. MS (LC/MS): 504 [M+H]+; t (HPLC, conditions k): 3.26 min. )r2-(3-acetylbenzyloxy-indolyl)-acetvnfluoromethyl-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide was prepared as described in Scheme D7 from (3-acetylbenzyloxy-indolyl)-acetic acid (prepared as described in Part A) using DMF instead of CH C I in Step C. Solid. MS (LC/MS): 2 2 594 [M+H]+; t (HPLC conditions k): 3.94 min.
Example 583: (2S,4R)[2-(3-Acetylhydroxy-indolyl)-acetyl]fluoro-pyrrolidine carbox lic acid 3-chlorofluoro-benzylamide The title compound was prepared in a similar manner as described for Example 577 from )[2-(3-acetylbenzyloxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3- chlorofluoro-benzylamide Example 534 (100 mg, 0.172 mmol). White solid. MS (LC/MS): 490 [M+H]+, 512 [M+Na]+; t (HPLC conditions k): 3.15 min.
Example 584: ( 1R,3S,5R)[2-(3-Acetylhydroxy-indol-1 -yl)-acetyl]aza- bic clo[3.1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared in a similar manner as described for Example 577 from ( 1 R,3S,5R)[2-(3-acetylbenzyloxy-indolyl)-acetyl]aza-bicyclo[3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide Example 536 (360 mg, 0.527 mmol). Solid. MS (LC/MS): 484 [M+H]+; t (HPLC conditions k): 3.21 min. e 585: 1-{2-[(2S,4R)(3-Chlorof luoro-benzylcarbamoyl)fluoro-pyrrolidin-1 - oxo-ethyl}(1 H-tetrazolylmethoxy)-1 H-indolecarboxylic acid amide A solution of 1-{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl] oxo-ethyl}hydroxy-1 H-indolecarboxylic acid amide e 578 (148 mg, 0.283 mmol) in DMSO (3 mL) was treated with Cs C0 (0.28 g , 0.85 mmol). The mixture was stirred at RT for 2 3 min, followed by addition of 5-(chloromethyl)-1 H-tetrazole (35 mg, 0.098 mmol) and stirring at RT for 36 h . The reaction mixture was neutralised by addition of 1N HCI. Water was then added to the mixture to form a precipitate. The solid material was filtered off, washed with water, and dried in vacuo to afford the title compound as a solid. MS ): 573 [M+H]+; t (HPLC conditions k): 2.92 min.
Example 586: (2S,4R)-1 -{2-[3-Acetyl(1 azolylmethoxy)-indol-1 -yl]-acetyl} fluoro-yrrolidinecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared in a r manner as described above for Example 585 from (2S,4R)[2-(3-acetylhydroxy-indolyl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide Example 583 (60.0 mg, 0.122 mmol), cesium carbonate (120 mg, 0.367 mmol) and 5-(chloromethyl)-1 H-tetrazole (44.0 mg, 0.366 mmol) in DMSO (2.5 mL).
Solid. MS ): 572 [M+H]+; t (HPLC conditions k): 3.23 min.
Example 587: ( 1 R,3S,5R){2-[3-Acetyl(1 H-tetrazolylmethoxy)-indol-1 -yl]-acetyl} aza-bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide A solution of ( 1 R,3S,5R)[2-(3-Acetylhydroxy-indolyl)-acetyl]aza-bicyclo[3.1 .0]- hexanecarboxylic acid 3-chlorofluoro-benzylamide Example 584 (80.0 mg, 0.165 mmol) in DMSO (2 mL) was treated with cesium carbonate (162 mg, 0.496 mmol). After stirring at RT for 5 min, 5-(chloromethyl)-1H-tetrazole (21 .0 mg, 0.174 mmol) was added and stirring was continued at RT for 36 h . The mixture was neutralised by addition of 1N HCI, diluted with water ted with EtOAc (2x). The combined organic layers were washed with water (2x) and brine. The ing suspension was filtered over phase separator and concentrated. The ed solid was triturated with methanol, decanted and dried in vacuo to give the title compound. The filtrate was purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 m h , 40x250 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H20 ning 0.1% TFA) to afford after lyophilization of the purified fractions a second batch of the title nd as a white solid. MS (LC/MS): 566 [M+H]+; tR (HPLC conditions k): 3.22 min.
Example 588: (2S,4R)[2-(3-Acetylmethoxy-indolyl)-acetyl]fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide A solution of (2S,4R)[2-(3-acetylhydroxy-indolyl)-acetyl]fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide Example 579 (28.0 mg, 0.057 mmol) in DMSO (2 mL) was treated with potassium hydroxide (15.0 mg, 0.257 mmol). The mixture was stirred at RT for 5 min, followed by addition of iodomethane (0.006 mL, 0.089 mmol) and stirring at RT for 60 h . The reaction mixture was partitioned between water and CH2C I2 and the s layer was extracted with CH2C I2 (2x). The combined organics were washed with brine (3x), dried (phase separator) and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 19x50 mm, flow: 20 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H20 containing 0.1% TFA) to afford after lization of the purified fractions the title compound as a solid. MS (LC/MS): 504 [M+H]+, 526 [M+Na]+; tR (HPLC conditions k): 3.38 min.
Example 589: )-1 -{2-[3-Acetyl(pyridinylmethoxy)-indol-1 -yl]-acetyl}f luoropyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide A on of (2S,4R)-1 -[2-(3-acetylhydroxy-indol-1 -yl)-acetyl]fluoro-pyrrolidine ylic acid 3-chlorofluoro-benzylamide Example 579 (60.0 mg, 0 .122 mmol) in DMSO (2.5 mL) was treated with cesium carbonate ( 160 mg, 0.490 mmol) . After stirring at RT for 5 min, 2-(bromomethyl)pyridine (31 .0 mg, 0 .122 mmol) was added to the reaction mixture and stirring was continued at RT for 16 h . Water was then added to the mixture to form a solid precipitate which was filtered off, washed with water and dried in vacuo. Purification by preparative HPLC s Sunfire, C 18-ODB, 5 m h , 30x1 00 mm, flow: 40 mL/min, eluent: 20- 100% CH CN/H2O/2O min, 100% CH CN/2 min, CH CN and H 0 containing 0 .1% TFA) 3 3 3 2 afforded after lyophilization of the ed fractions the title compound as a white solid. MS (LC/MS): 580/581 [M+H]+; t (HPLC conditions k): 3.00 min.
Example 590: (2S,4R)-1 -{2-[3-Acetyl(pyrimidinylmethoxy)-indol-1 -yl]-acetyl} fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide The title compound was ed according to procedure described for the preparation of Example 589 (2S,4R)-1 -{2-[3-acetyl(pyridinylmethoxy)-indol-1 -yl]-acetyl}fluoropyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide from (2S,4R)-1 -[2-(3-acetyl hydroxy-indol-1 -yl)-acetyl]fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide Example 579 (23.0 mg, 0.047 mmol), cesium carbonate (61 mg, 0 .188 mmol) and 2- (chloromethyl)pyrimidine (0.01 2 mg, 0.070 mmol) in DMSO (2 mL). White solid. MS (LC/MS): 582/583 [M+H]+; t (HPLC conditions k): 3 .19 min.
Example 591 : 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin-1 - yl]oxo-ethyl}(2-methoxy-ethoxy)-1 H-indolecarboxylic acid amide A solution of 1-{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin- 1-yl] oxo-ethyl}hydroxy-1 lecarboxylic acid amide Example 578 (50 mg, 0 .102 mmol) in DMSO ( 1 mL) was d with KOH (26.0 mg, 0.458 mmol). The mixture was stirred at RT for min, followed by addition of (2-bromoethyl)methyl ether (0.01 5 mL, 0 .158 mmol) and stirring at RT for 2 h . The mixture was partitioned between water and CH C I , and the s phase 2 2 was extracted twice with CH C I . The combined organics were washed with brine (3x) , dried 2 2 (phase separator) and trated under reduced pressure. cation by preparative HPLC (SunFire C 18-ODB, 5 m , 30x1 00 mm, eluent: 20-1 00% CH CN/H O/20 min, 100% CH CN/2 3 2 3 min, CH CN and H 0 containing 0 .1% TFA, flow: 40 mL/min) afforded after lyophilization of the 3 2 purified fractions the title compound as a white solid. MS : 549 [M+H]+; t (HPLC conditions c): 4 .17 min.
Example 592: (3-Carbamoyl-1 -{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidin-1 -yl]oxo-ethyl}-1 lyloxy)-acetic acid methyl ester A solution of 1-{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin- 1-yl] hyl}hydroxy-1 H-indolecarboxylic acid amide Example 578 ( 140 mg, 0.285 mmol) in DMSO (3 mL) was treated with Cs C0 (0.28 g , 0.85 mmol). The mixture was stirred at RT for 2 3 min, followed by on of methyl 2-bromoacetate (0.039 mL, 0.428 mmol) and stirring at RT for 4 h . The mixture was partitioned between water and CH C I , and the organic phase was 2 2 washed twice with brine (the combined aqueous washings were filtered and the solid thus obtained was dried in vacuo to give an aliquot of the title compound), dried (phase separator) and concentrated under reduced pressure. Purification by preparative HPLC (SunFire C 18- ODB, 5 [Jim, 30x1 00 mm, eluent: 20-1 00% CH CN/H O/20 min, 100% CH CN/2 min, CH CN 3 2 3 3 and H 0 containing 0 .1% TFA, flow: 40 mL/min) afforded after lyophilization of the purified fractions the title compound as a white solid. MS : 563 [M+H]+; t (HPLC conditions c) : 4 .17 min.
Example 593: (3-Carbamoyl-1 -{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl) fluoro-pyrrolidin-1 -yl]oxo-ethyl}-1 H-indolyloxy)-acetic acid To a solution of (3-carbamoyl- 1-{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidin-1 -yl]oxo-ethyl}-1 H-indolyloxy)-acetic acid methyl ester Example 592 ( 18 mg, 0.032 mmol) in a mixture of THF (2 mL) and water (0.2 mL) was added 1N NaOH (0.064 mL), followed by stirring at RT for 4 h . The reaction mixture was partitioned between CH C I and 2 2 water. The aqueous phase was adjusted to pH = 2 by on of 1N HCI, followed by extraction with CH C I (3x). The combined organics were dried (phase separator) and 2 2 concentrated under reduced pressure to afford the title compound as a white solid. MS: 549 [M+H]+; t (HPLC conditions c): 3.74 min.
Example 594: 1-{2-[(2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidin yl]oxo-ethyl}(2-hydroxy-ethoxy)-1H-indolecarboxylic acid amide To a solution of (3-carbamoyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinyl ]oxo-ethyl}-1 lyloxy)-acetic acid methyl ester Example 592 (30.0 mg, 0.049 mmol) in THF ( 1 ml_) was added LiBH (2M in THF; 0.049 ml_, 0.098 mmol) and stirring was continued at RT for 2 h . The reaction mixture was partitioned between CH C I and water, 2 2 and the aqueous layer was extracted with CH C I (3x). The combined organics were dried 2 2 (phase separator) and concentrated under reduced pressure. Purification by ative HPLC (SunFire B, 5 m , 19x50 mm, eluent: 5-100% CH CN/H O/20 min, 100% CH CN/2 3 2 3 min, CH CN and H 0 containing 0.1% TFA, flow: 20 mL/min) afforded after lyophilization of the 3 2 purified fractions the desired compound as a white solid. MS: 535 [M+H]+; t (HPLC conditions c): 3.72 min.
Example 595: tyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinyl ]oxo-ethyl}-1H-indolyl)-acetic acid To a solution of tyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinyl o-ethyl}-1H-indolyl)-acetic acid methyl ester Example 549 (200 mg, 0.366 mmol) in THF (5 mL) and water (0.5 mL) was added 1N NaOH ( 1 .46 mL, 1.46 mmol) and the reaction was stirred at RT for 60 h . The mixture was partitioned between diethylether and water. The layers were separated and the aqueous phase was adjusted to pH = 2 by addition of a 1N HCI solution to form a precipitate. The solid was filtered off, washed with water and diethylether and dried in vacuo to afford the title compound as a solid. MS (LC/MS): 532 [M+H]+; t (HPLC conditions k): 3.19 min.
Example 596: (3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- 2-yl]oxo-ethyl}-1H-indolyl)-acetic acid The title compound was prepared in a similar manner as bed for Example 595 from (3- {2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1.0]hexyl] oxo-ethyl}-1 H-indolyl)-acetic acid methyl ester Example 545 (200 mg, 0.370 mmol). Solid.
MS (LC/MS): 526 [M+H]+; t (HPLC conditions k): 3.24 min.
Example 597: 3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro- pyrrolidin-1 -yl]oxo-ethyl}-1 H-indolecarboxylic acid The title compound was prepared in a similar manner as described for Example 595 from 3- acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo- ethyl}-1 H-indolecarboxylic acid methyl ester Example 542 (200 mg, 0.370 mmol). Solid. MS (LC/MS): 518 ; t (HPLC conditions k): 3.14 min.
Example 598: 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- 2-yl]oxo-ethyl}-1H-indolecarboxylic acid Example 599: 3-Acetyl-1 -{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)f luoro methyl-pyrrolidinyl]oxo-ethyl}-1H-indolecarboxylic acid The title compound was prepared in a similar manner as described for Example 595 from 3- acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoromethyl-pyrrolidinyl] oxo-ethyl}-1 H-indolecarboxylic acid methyl ester Example 548 (70 mg, 0.128 mmol). Solid.
MS (LC/MS): 532 [M+H]+; t (HPLC conditions c): 4.34 min.
Example 600: (2S,3S,4S)Fluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1- carbamoyl-1H-indolyl)-amide] 2-(3-chlorofluoro-benzylamide) The title compound was prepared in a similar manner as described for e 595 starting from (2S,3S,4S)fluoromethoxy-pyrrolidinecarboxylic acid rofluorobenzylamide (prepared as described in Scheme D7 from 3-acetylcarboxymethyl-1H-indole- 6-carboxylic acid methyl ester ibed in Part C) and (2S,3S,4S)fluoromethoxypyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide ibed Scheme B24). MS (UPLC-MS): 548 [M+H]+, 592 [M+HCOO]-; t (HPLC conditions f): 1.84 min.
Example 601 : 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azal ]oxo-ethyl}-1H-indolecarboxylic acid To a solution of 3-acetyl{2-[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexyl]oxo-ethyl}-1 H-indolecarboxylic acid methyl ester Example 541 ( 1 10 mg, 0.209 mmol) in THF (3 mL) and water (0.3 mL) was added 2N LiOH (1.05 mL, 2.09 mmol). Stirring of the reaction mixture was continued at RT for 18 h . A 1N HCI on was added to adjust to pH=2-3 and the resulting aqueous suspension was filtered. The solid was washed with water then dried in vacuo. The e was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, flow: 40 mL/min, eluent: 20-100% CH CN/H O/20 min, 3 2 100% C H3C N/2 min, CH CN and H 0 containing 0.1% TFA) to afford after lyophilization of the 3 2 purified fractions the title nd as a white solid. MS (LC/MS): 512 [M+H]+; t (HPLC conditions k): 3.34 min.
Example 602: 4-(3-Acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoropyrrolidinyl o-ethyl}-1H-indolyloxymethyl)-benzoic acid The title nd was prepared in a similar manner as described for Example 595 from 4-(3- acetyl{2-[(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinyl]oxo- ethyl}-1 H-indolyloxymethyl)-benzoic acid methyl ester (37.0 mg, 0.058 mmol) and 1N NaOH (0.928 ml_, 0.928 mmol) in THF (5 ml_) and water (0.5 ml_). Solid. MS (LC/MS): 624/626 [M+H]+; t (HPLC conditions k): 3.48 min. 4-(3-Acetylf2 -r(2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinvn- 2-oxo-ethylV1H-indolyloxymethyl)-benzoic acid methyl ester A solution of (2S,4R)[2-(3-acetylhydroxy-indolyl)-acetyl]fluoro-pyrrolidine ylic acid 3-chlorofluoro-benzylamide Example 583 (60.0 mg, 0.122 mmol) in DMSO (2.5 mL) was treated with cesium ate (160 mg, 0.490 mmol). After stirring at RT for 5 min, methyl 4-(bromomethyl)benzoate (28.0 mg, 0.122 mmol) was added and the reaction was stirred at RT for 1 h . The mixture was neutralised with 1N HCI and diluted with water to form a precipitate. The solid was filtered off, washed with water and dried in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, flow: 40 mL/min, eluent: 20-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 3 2 3 3 2 containing 0.1% TFA) to afford after lyophilization the title compound as a white solid. MS (LC/MS): 639 [M+H]+; t (HPLC conditions k): 3.82 min.
Example 603: 3-Acetyl-1 -{2-[(1 R)(3-chlorof luoro-benzylcarbamoyl)azabicyclo [3.1 .0]hexyl]oxo-ethyl}-1 H-indolecarboxylic acid To a solution of 3-acetyl{2-[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexyl]oxo-ethyl}-1 H-indolecarboxylic acid methyl ester (141 mg, 0.268 mmol) in THF (3 mL) and water (0.3 mL) was added 2N LiOH ( 1 .07 mL, 2.14 mmol). Stirring of the reaction e was continued at 50°C for 60 h . After g to RT, a 1N HCI solution was added to adjust to pH= 2-3, and the resulting aqueous suspension was extracted with CH C I 2 2 (3x). The ed organics were dried (phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters e, B, 5 mhi , 30x100 mm, flow: 40 , eluent: 20-100% CH CN/H O/20 min, 100% CH CN/2 min, 3 2 3 CH CN and H 0 containing 0.1% TFA) to afford after lyophilization of the ed fractions the 3 2 title compound as a white solid. MS (LC/MS): 512 [M+H]+; t (HPLC conditions c): 4.33 min. 3-Acetylf2 -r(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza-bicyclor3.1.01hex- 2-yl1oxo-ethylV1H-indolecarboxylic acid methyl ester The title compound was prepared as described in Scheme D7 from 3-acetylcarboxymethyl- 1H-indolecarboxylic acid methyl ester (prepared as described in Part A) and by using DMF instead of CH C I . Solid. MS (LC/MS): 526 , 548 [M+Na]+; t (HPLC conditions k): 3.54 2 2 R min.
Example 604: (2S,4R)-1 -[2-(3-Acetylhydroxymethyl-indol-1 -yl)-acetyl]f yrrolidinecarboxylic acid 3-chlorofluoro-benzylamide To a solution of (2S,4R)[2-(3-acetyltriisopropylsilanyloxymethyl-indolyl)-acetyl] fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide (50.0 mg, 0.057 mmol) in THF (5 mL), cooled to at 0°C, was added TBAF (1M in THF, 0.057 mL, 0.057 mmol), and stirring was continued for 3 h . The reaction was quenched with saturated aqueous NaHC0 followed by addition of EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with water (1x) and brine, dried (phase separator) and concentrated in vacuo. Purification by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, flow: 40 mL/min, eluent: 20% CH CN/H O/20 min, 3 2 100% CH CN/2 min, CH CN and H 0 containing 0.1% TFA) afforded after lyophilization of the 3 3 2 purified fractions the title compound as a white solid. MS (LC/MS): 504 [M+H]+; t (HPLC conditions k): 3.10 min. (2S,4R)r2-(3-Acetyltriisopropylsilanyloxymethyl-indolyl)-acetvnfluoropyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared as described in Scheme D7 from (3-acetyl triisopropylsilanyloxymethyl-indolyl)-acetic acid red as described in Scheme A14) and by using DMF instead of CH C I . Yellow wax. MS (LC/MS): 683 [M+Na]+; t (HPLC conditions 2 2 R k): 4.72 min.
Example 605: 3-[({(2S,4R)[2-(3-Acetyl-indolyl)-acetyl]fluoro-pyrrolidine carbonyl}-amino)-methyl]chlorofluoro-benzoic acid To 3-[({(2S,4R)[2-(3-acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarbonyl}-amino)- methyl]chlorofluoro-benzoic acid methyl ester Example 523 (35.0 mg, 0.066 mmol) in OH-H 0 (ratio 2:1:1; 1 mL) was added LiOH.H 0 (2.76 mg, 0.066 mmol). The reaction 2 2 mixture was stirred at RT for 4 h . Volatiles were evaporated and the residue was taken up in water, Acidification to pH=1 by addition of a 6M HCI solution formed a precipitate which was filtered and dried at 50°C in vacuo for 1 h to afford the title nd as a solid. MS: 518.0 [M+H]+; t (HPLC conditions c): 4.26 min.
Example 606: 3-[({(1R,3S,5R)[2-(3-Acetyl-indolyl)-acetyl]azabicyclo [3.1.0]hexanecarbonyl}-amino)-methyl]chlorofluoro-benzoic acid The title compound was prepared according to procedure bed for the preparation of 3- [({(2S,4R)[2-(3-acetyl-indolyl)-acetyl]fluoro-pyrrolidinecarbonyl}-amino)-methyl] fluoro-benzoic acid Example 605 starting from 3-[({(1 R,3S,5R)[2-(3-acetyl-indol yl)-acetyl]aza-bicyclo[3.1 .0]hexanecarbonyl}-amino)-methyl]chlorofluoro- benzoic acid methyl ester Example 480. MS: 512.0 [M+H]+; t (HPLC conditions c): 4.41 min.
Example 607: (2S,4S)[2-(3-Acetyl-indolyl)-acetyl]aminomethylfluoropyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide The title nd was prepared according to Scheme D7 from (2S,4R)azidomethyl(3- chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester (described in scheme B15) using DMF as solvent in step C, followed by azide reduction as described for the preparation of Example 411 (2S,4S)aminomethylfluoro-pyrrolidine-1,2- dicarboxylic acid 1-[(1-carbamoyl-1H-indolyl)-amide] 2-(3-chloro-2,6-difluoro-benzylamide).
MS MS): 503 [M+H]+; tR (HPLC conditions f): 1.60 min; 19F NMR (100 MHz, DMSO-d 6) d (ppm): - 117 , -150.
Example 608: (2S,4S)[2-(3-Acetyl-indolyl)-acetyl]methylamino-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared according to Scheme D7 from )(3-chlorofluorobenzylcarbamoyl )[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidinecarboxylic acid tert-butyl ester (prepared as described in Scheme B6) followed by the deprotection of the Troc protecting group as described for Example 424. Purification by preparative HPLC (Waters SunFire C18-ODB, 5 m , 19x50 mm, 5% CH3CN/H 20 2.5 min, 5-100% CH3CN/H20 in 10 min, H20 containing 0.1 % HCOOH flow: 20 mL/min) gave after lyophilization of the purified fractions the title compound (formic acid salt). MS (UPLC-MS): 487 [M+H]+; tR (HPLC conditions ) : 1.60 min; 19F NMR (100 MHz, DMSO- ) d (ppm): -120.
Example 609: (2S,4S)[2-(3-Acetyl-indolyl)-acetyl](2-methoxy-ethylamino)- idinecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared according to Scheme D7 from (2S,4S)(3-chlorofluorobenzylcarbamoyl )[(2-methoxy-ethyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine carboxylic acid tert-butyl ester (prepared as described in Scheme B6 using 1-bromo methoxyethane instead of methyl iodide in step B) followed by deprotection of the Troc protecting group as described for Example 424. Purification on ative HPLC (Waters SunFire C18-ODB, 5 m , 19x50 mm, 5% CH CN/H 0 2.5 min, 5-100% CH CN/H 0 in 10 min, 3 2 3 2 CH CN/H 0 containing 0.1 % HCOOH flow: 20 mL/min) gave after lization of the purified 3 2 ons the title compound (formic acid salt). MS (UPLC/MS): 531 [M+H]+; t (HPLC conditions f): 1.66 min; 19F NMR (100 MHz, DMSO-d ) d (ppm): -120. e 6 10 : ( 1 R,3S,5S)[2-(3-Acetyl-pyrrolo[2,3-b]pyridin-1 -yl)-acetyl]hydroxy clo[3.1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide A solution of (3-acetyl-pyrrolo[2,3-b]pyridinyl)-acetic acid (1R,3S,5S)[2-(3-acetylpyrrolo [2,3-b]pyridinyl)-acetyl](3-chlorofluoro-benzylcarbamoyl)aza-bicyclo[3.1 .0] hexylmethyl ester (90 mg, 0.1 15 mmol) and NaOH 1 N (0.58 ml_, 0.58 mmol) in THF (0.55 ml_) / water (55 m I_) was stirred at RT for 1 h . Water and CH C I were added, the layers were 2 2 separated and the aqueous one back-extracted with CH C I (x3). The combined organic 2 2 extracts were dried (Na S0 ) , filtered and concentrated. The crude material was purified by 2 4 preparative HPLC (Waters Sunfire C18-ODB, 5 mhi , 30x100 mm, eluent: 5% to 100% CH CN in H 0 in 25 min, CH CN and H 0 containing 0.1% TFA, flow: 40 mL/min). EtOAc and 2 3 2 saturated aqueous NaHC0 were added to the combined purified fractions, the layers were separated and the aqueous one back-extracted with EtOAc (x3). The combined organic ts were dried (Na S0 ) , filtered and concentrated to give the desired al. TLC, R 2 f (CH C I / MeOH 9-1) = 0.45; MS (UPLC/MS): 499.3/501 .3 [M+H]+, 521 .1/523.2 [M+Na]+; t 2 2 R (HPLC conditions f): 1.73 min. (3-Acetyl-pyrrolor2,3-blpyridinyl)-acetic acid (1R,3S,5S)r2-(3-acetyl-pyrrolor2,3- blpyridin-1 -yl)-acetvn(3-chlorofluoro-benzylcarbamoyl)aza-bicyclor3.1 .01 hex l ester The title compound N,0 bis-acylated was ed according to Scheme D7 Steps B and C from ( 1 R,3S,5S)(3-chlorofluoro-benzylcarbamoyl)hydroxymethylaza- bicyclo[3.1 anecarboxylic acid tert-butyl ester (prepared as described in Part B Scheme B28) using HCI 4N in dioxane instead of TFA in Step B and 2 equivalents of tylpyrrolo [2,3-b]pyridinyl)-acetic acid ibed in Part A) in Step C. cation by flash column chromatography on silica gel (CH C I to CH C I /MeOH 94-6). TLC, R (CH C I / MeOH 2 2 2 2 f 2 2 9-1) = 0.48; MS (UPLC/MS): 699.4/701.3 [M+H]+, 743.4/745.4 [M+HCOO]-; t (HPLC conditions ) 2.05 min.
Example 6 11: ( 1 R,3S,5S)[2-(3-Acetyl-indol-1 -yl)-acetyl]hydroxymethylazanecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 ( 1 S)[2-(3-acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl] hydroxymethylaza-bicyclo[3. xanecarboxylic acid rofluoro-benzylamide using (3-acetyl-indolyl)-acetic acid instead of (3-acetyl-pyrrolo[2,3-b]pyridinyl)-acetic acid.
White powder. TLC, R (EtOAc) = 0.05; MS (LC/MS): 498/500 [M+H]+, 520/522 [M+Na]+; t f R (HPLC conditions f): 1.84 min.
Example 612: (1S,2S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hexane carbox lic acid [(S)-1 -(3-chlorof luoro-phenyl)-2hydroxy-ethyl]-amide The title compound was prepared in 2 steps according to the ure described for the preparation of Example 610 ( 1 R,3S,5S)[2-(3-acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl] hydroxymethylaza-bicyclo[3. 1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide from (1S,2S,5R)[(S)(3-chlorofluoro-phenyl)hydroxy-ethylcarbamoyl]aza- bicyclo[3.1 .0]hexanecarboxylic acid tert-butyl ester (prepared using similar protocols as described in Scheme B9) and (3-acetyl-indolyl)-acetic acid. White powder. TLC, R (EtOAc) = 0.10; MS (UPLC/MS): 498.3/500.4 [M+H]+, 542.4/544.3 [M+HCOO]-; t (HPLC conditions a): 3.10 min.
Example 613: (1R,3S,5R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]aza-bicyclo [3.1.0]hexanecarboxylic acid [(S)(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 ( 1 R,3S,5S)[2-(3-acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl] hydroxymethylaza-bicyclo[3. 1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide from (1R,3S,5R)[(S)(3-chlorofluoro-phenyl)hydroxy-ethylcarbamoyl]aza- bicyclo[3.1 .0]hexanecarboxylic acid utyl ester red as described in Scheme B9).
White powder. TLC, R (CH /CI /EtOAc 9:1) = 0.70; MS (UPLC/MS): 499.3/501 .3 [M+H]+, f 2 2 543.2/545.3 [M+HCOO]-; t (HPLC conditions a): 3.02 min.
Example 614: (2S,4R)[2-(3-Acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl]fluoromethylrrolidinecarboxylic acid [(S)-1 -(3-chlorofluoro-phenyl)hydroxy-ethyl]-amide The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 ( 1 R,3S,5S)[2-(3-acetyl-pyrrolo[2,3-b]pyridinyl)-acetyl] ymethylaza-bicyclo[3. 1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide from (2S,4R)[(S)(3-chlorofluoro-phenyl)hydroxy-ethylcarbamoyl]fluoromethylpyrrolidinecarboxylic acid tert-butyl ester (prepared using similar protocols as described in Scheme B9). White powder. TLC, R (CH /CI /EtOAc 9:1) = 0.60; MS (UPLC/MS): 519.3/521.3 f 2 2 [M+H]+, 563.3/565.3 [M+HCOO]-; t (HPLC conditions a): 2.96 min.
Example 615: ,5R){2-[3-Acetyl(N,N-dimethyl-carbamimidoyl)-indolyl]- 1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide HCI (gaz) was slowly bubbled for 3 h in a suspension of ( 1 R,3S,5R)[2-(3-acetylcyano- indolyl)-acetyl]aza-bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide (50 mg, 0.1 mmol) in MeOH (3 mL) cooled at 0°C. The reaction e was allowed to reach RT and further stirred for 1 h . After completion argon was bubbled to remove the excess of HCI and the reaction mixture was concentrated. Crude 3-acetyl{2-[(1 R,3S,5R)(3-chloro fluoro-benzylcarbamoyl)aza-bicyclo[3. 1.0]hexyl]oxo-ethyl}-1 H-indolecarboximidic acid methyl ester (MS MS): 525.3/527.3 [M+H]+) was diluted in MeOH (2 mL), dimethylamine (2 M in MeOH, 0.26 mL, 0.524 mmol) was added and the mixture refluxed overnight. The reaction mixture was concentrated and the crude material was purified by preparative HPLC s Sunfire C18-ODB, 5 mhi , 30x100 mm, 5-95% CH CN /H 0 , CH CN 3 2 3 and H 0 containing 0.1% TFA flow: 40 ) to give after lyophilization of the purified fractions the desired material as a TFA salt. TLC, R (CH C I /MeOH 9:1): 0.65; MS (UPLC/MS): f 2 2 539.3/541 .3 [M+H]+, 583.3/585.4 [M+HCOO]-; t (HPLC conditions a): 3.05 min. (1R,3S,5R)r2-(3-Acetylcvano-indolyl)-acetvnaza-bicyclor3.1.01hexane ylic acid rofluoro-benzylamide The title compound was prepared according to Scheme D7 from (3-acetylcyano-indolyl)- acetic acid (prepared as described in Part C). TLC, R (CH C I / MeOH 9-1) = 0.40; MS f 2 2 (UPLC/MS): 493.3/495.3 [M+H]+, 537.3/539.3 [M+HCOO]-; t (HPLC conditions a): 3.42 min.
Example 616: (1R,3S,5R){2-[3-Acetyl(N,N-dimethyl-carbamimidoyl)-indolyl]- acetyl}aza-bicyclo[3.1 .0]hexanecarboxylic acid 3-chlorofluoro-benzylamide The title nd was prepared in a similar manner as described above for Example 615 from (3-acetylcyano-indolyl)-acetic acid (prepared as described in Part C). TLC, R (CH C I /MeOH 9:1): 0.65; MS (UPLC/MS): 539.3/541 .3 [M+H]+ 583.3/585.3 [M+HCOO]-; t 2 2 R (HPLC conditions a): 3.13 min. (2S,4R)r2-(3-acetylcvano-indolyl)-acetvnfluoro-pyrrolidinecarboxylic acid 3- chlorofluoro-benzylamide The title compound was prepared according to Scheme D7 from (3-acetylcyano-indolyl)- acetic acid (prepared as described in Part C). . TLC, R (CH C I / MeOH 9-1) = 0.40; MS f 2 2 (UPLC/MS): 495.3 , 537.3/539.3 [M+HCOO]-; t (HPLC conditions a): 3.46 min.
Example 617: (2S,4R){2-[3-Acetyl(1H-tetrazolyl)-indolyl]-acetyl}fluoropyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide To a suspension of (2S,4R)[2-(3-acetylcyano-indolyl)-acetyl]fluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide (prepared as described in Example 616 (45.0 mg, 0.09 mmol) in water (2 ml_) and isopropanol ( 1 ml_) at RT were added sodium azide (24.0 mg, 0.360 mmol) and zinc bromide (40.0 mg, 0.180 mmol). The mixture was heated to 130°C for 10 h in a microwave apparatus (Personnal Chemistry, Biotage). After g to RT, a 6N HCI solution was added to the mixture, followed by extraction with EtOAc (3x). The combined organics were washed with brine, dried (phase separator) and concentrated in vacuo.
Purifcation of the residue by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, eluent: 20-100% CH CN/H O/20 min, 100% CH CN/2 min, CH CN and H 0 ning 0.1% 3 2 3 3 2 TFA, flow: 40 mL/min) afforded after lyophilization the title compound as solid. MS (LC/MS): 542.0 [M+H]+; t (HPLC ions k): 3.15 min. e 618: (1R,3S,5R){2-[3-Acetyl(1H-tetrazolyl)-indolyl]-acetyl}aza- bic clo[3.1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide The title compound was ed in a r manner as described above for Example 617 from (1R,3S,5R)[2-(3-acetylcyano-indolyl)-acetyl]aza-bicyclo [3.1 .0]hexane carboxylic acid 3-chlorofluoro-benzylamide (prepared as described in Example 616 (100.0 mg, 0.203 mmol), sodium azide (66.0 mg, 1.014 mmol) and zinc bromide (228.0 mg, 1.014 mmol) in water (2 ml_) and isopropanol ( 1 ml_). White solid. MS (LC/MS): 536.0 [M+H]+; t (HPLC conditions k): 3.21 min.
Example 619: (2S,3S,4S)[2-(3-Acetyl-c/3-indolyl)-acetyl]fluoromethoxypyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide The title compound was prepared according to Scheme D7 from (2S,3S,4S)fluoro methoxy-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide (prepared as described in Scheme B24) and (3-acetyl-d3-indolyl)-acetic acid (prepared in a similar manner as described in Scheme A13 using acetyl-d3-chloride in step A) using DMF as solvent in step C.
MS (UPLC-MS): 507/509 [M+H]+, 551/553 [M+HCOO]-; t (HPLC conditions f): 2.01 min.
Example 620: (2S,3S,4S)-1 -[2-(3-Acetyl-indol-1 -yl)-acetyl]fluoromethoxy-c/3- oxylic acid 3-chlorofluoro-benzylamide The title compound was prepared according to Scheme D7 from (2S,3S,4S)fluoro methoxy-d3-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide (prepared as described in Scheme B24 using methyl-d3-iodide instead of methyl iodide in Step B). MS (UPLC-MS): 507/509 [M+H]+, 551/553 O]-; t (HPLC conditions f): 2.01 min.
Example 621 : (1R,3S,5R)[2-(1-Acetyl-imidazo[1,5-a]pyridinyl)-acetyl]aza-bicyclo boxylic acid rofluoro-benzylamide The title compound was prepared according to Scheme D7 using in Step C (1-acetylimidazo ]pyridinyl)-acetic acid (prepared as described in Scheme A19) and DMF as solvent. MS (UPLC-MS): 469.3/471.4 [M+H]+, 513.4/515.5 [M+HCOO]-; t (HPLC conditions a): 3,08 min.
Example 622: S,5R)[2-(3-Acetyl-indolyl)-acetyl]aza-bicyclo[3.1.0]hex yl}-carbamic acid 3-chlorofluoro-phenyl ester To a solution of [(1R,3S,5R)(2-aza-bicyclo[3.1 .0] hexyl)methyl]-carbamic acid 3-chloro fluoro-phenyl ester, trifluoroacetate red as described in Example 115) (60.0 mg, 0.21 1 mmol) in THF (3 ml_) was added HBTU (120 mg, 0.316 mmol), DIPEA (0.147 ml_, 0.843 mmol) and (3-acetyl-indolyl)-acetic acid (50 mg, 0.232 mmol). The reaction mixture was stirred at RT for 60 h . Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, eluent: 20-100% C 2O /2O min, 100% CH CN/2 min, CH CN and H 0 containing 0.1% TFA, flow: 40 3 3 2 mL/min) to give after lyophilization of the ed HPLC fractions the title compound. MS (LC/MS): 484.0 [M+H]+; t (HPLC conditions k): 3.69 min.
Scheme D8: preparation of Example 623: (2S,4R)r2-(3-Acetyl-pyrazolor3,4-clpyridin- 1-yl)-acetvnfluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide formate A. (2S,4R)(3-Chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid tert-butyl ester To a solution of (2S,4R)fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.97 g , 17.02 mmol) in CH C I (34 mL) were successively added 3-chlorofluoro-benzylamine (2.35 2 2 mL, 18.72 mmol), HBTU (9.68 g , 25.5 mmol) and DIPEA (8.92 mL, 51.1 mmol). The reaction mixture was stirred at RT for 16 h . Water was added and the phases were separated. The organic layer was washed successively with 0.1 N HCI (2x), sat. aq. NaHC0 (2x) and brine, then dried (phase separator) and concentrated in vacuo. The residual oil was ed via flash column chromatography on silica gel (c-hexane/ EtOAc 9-1 to 1-1). MS (LC/MS): 397 +, 319 [MH-tBu]+; 275 [MH-Boc]+; t (HPLC ions k): 3.52 min.
DMF can also be used instead of Dichloromethane.
B. (2S,4R)fluoro-pyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide trifluoroacetate To a solution of (2S,4R)(3-chlorofluoro-benzylcarbamoyl)fluoro-pyrrolidinecarboxylic acid utyl ester (7.94 g , 2 1.18 mmol) in CH C I (70.5mL) was added TFA (16.32 ml_, 212 2 2 mmol) and the solution was stirred at RT for 16 h . The crude reaction mixture was concentrated under vacuum and the material this obtained was used without further purification in the next step. MS (LC/MS): 274.9 [M+H]+; t (HPLC conditions b): 2.13 min.
C. Example 623: (2S,4R)[2-(3-Acetyl-pyrazolo[3,4-c]pyridinyl)-acetyl]fluoropyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide e To a solution of (2S,4R)fluoro-pyrrolidinecarboxylic acid rofluoro-benzylamide trifluoroacetate (50 mg, 0.13 mmol), propylphosphonic anhydride (50% in EtOAc, 0.057 ml, 0.19 mmol) and (3-acetyl-pyrazolo[3,4-c]pyridinyl)-acetic acid trifluoroacetate red as described in Scheme A20, 42.9 mg, 0.13 mmol) in CH C I (5 ml_) was added DIPEA (0.067 ml, 2 2 0.386 mmol) under nitrogen atmosphere. The reaction mixture was stirred 2 h at RT and quenched by addition of a saturated aqueous solution of NaHC0 . The layers were separated, the aqueous layer was extracted with CH C I (x2), the combined organic extracts were dried 2 2 (Na S0 ) , filtered and concentrated. The crude residue was purified by preparative HPLC 2 4 (Waters Sunfire (C18 ODB, 5mhi , 19x50, flow = in, 5% CH CN in water for 2.5 min, 5 to 100% CH CN in water in 10 min to 100% CH CN for 2.5 min, both CH CN and water 3 3 3 containing 0.1% HCOOH) and the pure HPLC fractions were concentrated and lyophilized. MS (LC/MS): 476/478 [M+H]+, t (HPLC conditions ) : 1.51 min.
Alternatively, the pure HPLC fractions were neutralized with an s saturated on of Na C0 , extracted with EtOAc, dried (Na S0 ) , filtered and concentrated to give the desired 2 3 2 material as a free base.
The examples below were prepared according to the general procedures described in Scheme D8 for the preparation of Example 623 from commercially available building blocks if not otherwise mentioned (see notes at the end of table 7): Table 7 : Characterization (end-table notes), Example Structure Name TLC, R (eluent); MS (LC/MS); t (HPLC conditions) (2S,3S,4S)[2-(3-Acetylpyrazolo [3,4-b]pyridinyl)- (1,2) 520 [M+H]+, acetyl]fluoromethoxy- 564 [M+HCOO]-; t pyrrolidinecarboxylic acid R (f): 2.04 min.
[(R)(3-chlorofluoro- o )-ethyl]-amide ( 1S,2S,5R)[2-(3-Acetyl A methyl-pyrazolo[3,4-c]pyridin- (2) 484 [M+H]+, 528 1-yl)-acetyl]aza-bicyclo [M+HCOO]-; tR (f): ° [3. 1.0]hexanecarboxylic 1.59 min. acid 3-chlorofluoro- o benzylamide (2S,4R)[2-(3-Acetyl ' H methyl-pyrazolo[3,4-c]pyridin- (2) 490 [M+H]+, 534 1-yl)-acetyl]fluoro- [M+HCOO]-; t (f): ° R pyrrolidinecarboxylic acid 1.54 min. 3-chlorofluoro-benzylamide ( 1 R,3S,5R)[2-(3-Acetyl- lo[3,4-c]pyridinyl)- acetyl]aza-bicyclo (2) 470/472 [M+H]+; [3. 1.0]hexanecarboxylic t (f): 1.58 min. acid 3-chlorofluoro- o benzylamide 1-{2-[(2S,3S,4S)Fluoro (2-fluorotrifluoromethoxy- (1,2) 542.3 [M+H]+, phenylcarbamoyl)methoxy- 559.3 [M+NH ]+, idinyl]oxo-ethyl}- 440.3 [M-H]-; t (f): 1H-indazolecarboxylic acid 1.97 min amide 1-{2-[(2S,3S,4S)Fluoro (2-fluorotrifluoromethoxyphenylcarbamoyl )methoxy- (1,2) 543.2 [M+H]+, pyrrolidinyl]oxo-ethyl}- 541 .2 [M-H]-; t (f): 1H-pyrazolo[3,4-c]pyridine 1.52 min carboxylic acid amide trifluoroacetate ,4S)[2-(3-Acetyl- (1,2) 506.2/5082 pyrazolo[4,3-c]pyridiny|)- [M+H]+, 504.2 [M- ]f|uoromethoxy- H]-, 5502/5522 pyrrolidine—2—carboxylic acid [M+HCOO]-; tR (f): 3-chlorofluoro—benzylamide 1.49 min. (2S,3S,4S)[2-(3-Acetyl- pyrazolo[3,4-c]pyridiny|)- (1,2) 532.4/534.5 acety|]f|uoromethoxy- [M+H]+, 576.6/578.5 pyrrolidine—2—carboxylic acid [M+HCOO]-; tR (f): [1-(3-ch|orof|uoro-pheny|)— 1.64 min. cyclopropy|]-amide 3-AcetyI{2-[(1R,3S,5R)-3— (2) 5441/5461 (3-chlorofluoro-benzyl carbamoy|)aza-bicyc|o 5712/5732 [3.1 .0]hexy|]oxo-ethy|}- [M+HCOO]—; tR (m): 1H-indazole—6—carboxylic acid 1.08 min. methyl ester (1 R,3S,5R)[2-(3-Acetyl- pyrazolo[3,4-b]pyridiny|)- (1,2) 512.1/514.1 acetyl]—2—aza—bicyclo [M+H]+, 351 [3.1 .0]hexanecarboxy|ic [M+Na]+; 1R (f): 1.89 acid [3-(3-chlorofluoro— min. phenyl)—oxetan-3—yI]-amide (2S,3S,4S)[2-(3-Acetyl- indoIy|)-acety|](2- (1) 5614/5634 dimethylamino—ethoxy)—4— [M+H]+, 605.5/607.5 -pyrrolidine—2—carboxylic [M+HCOO]-; tR (f): acid 3-chlorofluoro— 1.62 min. benzylamide formate (2S,3S,4S)[2-(3-Acetyl- pyrazolo[3,4-c]pyridiny|)- (1,2) 518.4/520.4 acety|]f|uorohydroxy- [M+H]+, 562.5 pyrrolidine—2—carboxylic acid [M+HCOO]-; tR (f): [1-(3-ch|orof|uoro-pheny|)— 1.51 min. cyclopropy|]-amide formate 1-{2-[(2S,3S,4S)Fluoro (2-fluorotrifluoromethoxyphenylcarbamoyl )methoxy- (1,2) 557.2 , 636 pyrrolidinyl]oxo-ethyl} 555.2 [M-H]-; t (f): methyl-1 H-pyrazolo[3,4- 1.50 min NH2 c]pyridinecarboxylic acid amide triflate -Ethyl{2-[(2S,3S,4S) fluoro(2-fluorotrifluoro methoxy-phenyl carbamoyl)- (1,2) 571.3 [M+H]+, 637 3-methoxy-pyrrolidinyl] 569.3 [M-H]-; t (f): oxo-ethyl}-1 H-pyrazolo[3,4-c] 1.55 min pyridinecarboxylic acid amide triflate (2S,3S,4S){2-[3-Acetyl (pyrimidinylmethoxy)- indazolyl]-acetyl}fluoro- (1,2) 649.3 [M+H]+, 638 oxy-pyrrolidine- 647.3 [M-H]-; t (f): oxylic acid oro 1.99 min trifluoromethoxy-phenyl)- amide ( 1) The title compound was prepared according to the general procedure described in Scheme D8 steps B and C starting from the substituted proline derivative ed as described in Part B ; (2) The acid reagent used in step C was prepared as described in Part A .
Example 639: 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- oxo-ethyl}-1H-indazolecarboxylic acid A solution of Example 632 (65 mg, 0.123 mmol) in MeOH (5 mL) and sodium ide (d= 1 g/mL, 0.247 mL, 0.617 mmol) was stirred for 16 h at RT. The reaction was quenched by addition of HCI (1N, until pH = 1) and concentrated under reduced pressure. The aqueous residue was extracted with CH C I (x3) and concentrated. The crude material was purified by 2 2 preparative HPLC (Waters Sunfire C18-ODB, 5 mhi , 30x100 mm, eluent: 5% to 100% CH CN in H 0 in 25 min, CH CN and H 0 containing 0.1% TFA, flow: 40 mL/min). MS (LC/MS): 2 3 2 530.2/532.2 [M+H]+; 5 11.1/513.1 [M-H]-, 557.2/559.2 O]-; t (UPLC conditions m): 0.91 min.
Example 640: 3-Acetyl-1 -{2-[(2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)fluoro methoxy-pyrrolidin-1 -oxo-ethyl}-1 H-indazolecarboxylic acid yl{2-[(2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)fluoromethoxy-pyrroli dinyl]oxo-ethyl}-1 H-indazolecarboxylic acid benzyl ester (47 mg, 0.063 mmol) was dissolved in MeOH (5 ml_), Pd/C (10%, 5 mg) was added and the solution was ed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for 1 h . The catalyst was removed through a pad of Celite and washed with MeOH. The solvent was concentrated under d pressure and the crude residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 mhi , 30x100 mm, eluent: 5% to 100% CH CN in H 0 in 25 min, CH CN and H 0 containing 0.1% TFA, flow: 40 3 2 3 2 mL/min). MS (LC/MS): 549.5 [M+H]+; 547.5 [M-H]-; t (HPLC conditions ) : 1.93 min. 3-Acetylf2-r(2S,3S,4S)(3-chlorofluoro-benzylcarbamoyl)fluoromethoxypyrrolidin-1 -vnoxo-ethylV1H-indazolecarboxylic acid benzyl ester was ed using similar protocols as described in Scheme D8 Step C for the preparation of Example 623 from 3-acetylcarboxymethyl-1 H-indazolecarboxylic acid benzyl ester (prepared as described in Part A) and (2S,3S,4S)fluoromethoxy-pyrrolidinecarboxylic acid rofluoro-benzylamide trifluoroacetate (prepared as described in Scheme B24).
White solid. MS (UPLC/MS): 683.6/685.7 [M+HCOO]-; t (HPLC conditions ) : 2.43 min.
Scheme D9: preparation of e 641 : (1R,3S,5R)r2-(3-Acetyl-pyrrolor2,3- clpyridinyl)-acetvnaza-bicvclor3.1.01hexanecarboxylic acid r(R)(3-chloro fluoro-phenvD-ethyll-amide A. ,5R)[(R)(3-Chlorofluoro-phenyl)-ethylcarbamoyl]aza-bicyclo [3.1.0]hexanecarboxylic acid tert-butyl ester To a solution of (R)(3-chlorofluoro-phenyl)-ethylamine (1.85 g , 8.80 mmol) in CH C I (44 2 2 mL) were successively added ,5R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2- utyl ester (2 g , 8.80 mmol), DIPEA (4.61 mL, 26.4 mmol) and HBTU (4.01 g , 10.56 mmol). The reaction mixture was stirred at RT for 16 h . Water was added and the phases were ted. The organic layer was washed successively with 1N HCI (2x), sat. aq. NaHC0 (2x) and brine, then dried (phase separator) and concentrated in vacuo. The residual oil was purified via flash column chromatography on silica gel (c-hexane/ EtOAc 9-1 to 9-4). MS (LC/MS): 405 [M+Na]+, 283 [MH-Boc]+; t (HPLC conditions c): 4.93 min.
DMF can also be used instead of Dichloromethane.
B. (1R,3S,5R)Aza-bicyclo[3.1.0]hexanecarboxylic acid [(R)(3-chlorofluorophenyl )-ethyl]-amide trifluoroacetate To a solution of ( 1 R,3S,5R)[(R)(3-chlorofluoro-phenyl)-ethylcarbamoyl]aza- bicyclo[3.1.0]hexanecarboxylic acid tert-butyl ester (3.2 g , 8.36 mmol) in CH C I (30 mL) 2 2 was added TFA (15 mL, 195 mmol) and the solution was stirred at RT for 1 h . The crude reaction mixture was concentrated under vacuum, the residue was suspended in MeOH and concentrated again under vacuum. The crude product was used without further purification in the next step. MS (LC/MS): 283.0 [M+H]+; t (HPLC ions c): 3.41 min.
C. Example 641 : ,5R)[2-(3-Acetyl-pyrrolo[2,3-c]pyridinyl)-acetyl]azabicyclo [3.1.0]hexanecarboxylic acid [(R)(3-chlorofluoro-phenyl)-ethyl]-amide To a solution of (3-acetyl-pyrrolo[2,3-c]pyridinyl)-acetic acid trifluoroacetate (prepared as described Scheme [A15], 52 mg, 0.157 mmol) in DMF ( 1 .5 mL) were added sively ( 1 R,3S,5R)aza-bicyclo[3.1 anecarboxylic acid [(R)(3-chlorofluoro-phenyl)- ethyl]-amide trifluoroacetate (62.3 mg, 1.57 mmol), HBTU (89 mg, 0.235 mmol) and DIPEA (107 m , 0.626 mmol). The reaction mixture was stirred at RT for 16 h and poured into water.
The layers were separated and the aqueous layer extracted with CH C I (x2). The combined 2 2 organic extracts were dried (Na S0 ) , filtered and concentrated in vacuo. The residual oil was 2 4 purified by preparative HPLC (Waters Sunfire C18-ODB, 5 mhi , 30x100 mm, eluent: 5% to 100% CH CN in H 0 in 25 min, CH CN and H 0 containing 0.1% TFA, flow: 40 ). The 3 2 3 2 pure fractions were combined, neutralized by filtration through a Varian VariPure HC0 -MP cartridge and lyophilized to give the d material as a white powder. TLC, R (CH C I /MeOH 9:1) = 0.42; MS (LC/MS): 483.4/485.3 [M+H]+, 527.4/529.4 [M+HCOO]-; t 2 2 R (HPLC conditions a): 2.74 min. atively, the pure HPLC fractions were lized with an aqueous saturated solution of Na C0 , extracted with EtOAc (x2), dried (Na S0 ) , filtered and concentrated to give the 2 3 2 4 desired material.
Alternatively, the crude residue was purified by preparative HPLC (Waters Sunfire (C18 ODB, m , 19x50, flow = in, 5% CH CN in H 0 for 2.5 min, 5 to 100% CH CN in H 0 in 10 3 2 3 2 min to 100% CH CN for 2.5 min, CH CN and H 0 both containing 0.1% HCOOH) and the pure 3 3 2 HPLC ons were concentrated and lyophilized to give the desired compound as a formate salt.
The examples below were prepared according to the general procedures described in Scheme D9 for the preparation of Example 641 from commercially available building blocks if not otherwise mentioned (see notes at the end of table 8): Table 8 : Characterization (end-table notes), Example Structure Name TLC, R (eluent); MS ); t (HPLC conditions) (1,2,4) White solid. ( 1 R,3S,5R)[2-(3-Acetyl- R (CH C I /MeOH indazolyl)-acetyl]aza- f 2 2 9:1) = 0.55; bicyclo[3. 1.0]hexane 540.5/542.5 [M+H]+, 642 carboxylic acid [(R)(3- 584.5/586.5 chlorofluoro-phenyl) [M+HCOO]-; t (a): ° \ dimethylamino-propyl]-amide R 2.93 min. 1-(2-{(2S,3S,4S)[(R)(3- Chlorofluoro-phenyl)- ethylcarbamoyl]fluoro (3,4) 521 [M+H]+, methoxy-pyrrolidinyl} 543 [M+Na]+; t 643 R (k): oxo-ethyl)-1 H-pyrazolo[3,4- 3.10 min. b]pyridinecarboxylic acid amide (1 R,3S,5R)—2-[2-(1-Acetyl- (2,3,4) Rf imidazo[1,5-a]pyridinyl)- (CHZCIZ/MeOH 9:1) acetyl]aza-bicyclo = 0.75; 499.1/501.1 [3.1 .0]hexane-3—carboxylic [M+H]+, 543.2/544.3 acid [(S)(3-chlorofluoro- [M+HCOO]-; tR (a): )hydroxy-ethyl]- 2.74 min. amide (1 R,3S,5R)—2-[2-(3—Propionyl- (4) White solid. pyrrolo[2,3—c]pyridinyl)- 483.4/485.4 [M+H]+, acetyl]aza-bicyclo 527.3/529.4 [3.1 .0]hexane-3—carboxylic [M+HCOO]-; tR (f): acid 3-chlorofluoro- 1.56 min. benzylamide (1 R,3S,5R)—2-[2-(3—Acetyl (4) White solid. Rf methyl-pyrrolo[2,3-c]pyridin (CHZCIZ/MeOH 9:1) yl)-acetyl]aza-bicyclo = 0.4; 483.4/485.4 [3.1 .0]hexane-3—carboxylic [M+H]+, 527.5/529.4 acid 3-chlorofluoro- [M+HCOO]-; tR (f): benzylamide 1.52 min. (1 R)—2-[2-(3—Acetyl-5,6— dimethoxy-indazolyl)- ]aza-bicyclo (4) 529 [M+H]+; tR [3.1 .0]hexane-3—carboxylic (k): 3.46 min. acid 3-chlorofluoro- amide (2S,4R)—1-[2-(3-Acetyl methyl-pyrrolo[2,3-c]pyridin (4,5) White solid. yl)-acetyl]—4-fluoro - 587.1 [M-H]—; tR (c): pyrrolidine—2-carboxylic acid 3.71 min. rofluoro-benzylamide (1 R,3S,5R)—2-[2-(5—Acetyl- (4) White solid. Rf pyrrolo[2,3-d]pyrimidinyl)- (CHZCIZ/MeOH 9:1) acetyl]aza-bicyclo = 0.4; 470.4/472.4 [3.1 .0]hexane-3—carboxylic [M+H]+, 514.4/516.5 acid 3-chlorofluoro- [M+HCOO]-; tR (f): benzylamide 1.54 min. 1-{2—[(1R,3S,5R)(3-Chloro- 2-fluoro-benzylcarbamoy|) aza-bicyclo[3.1.0]hexy|] (4) 471 [M+H]+; tR oxo—ethyI}-1 H-pyrazolo[4,3- (k): 2.69 min. c]pyridinecarboxy|ic acid amide 1-{2—[(1R,3S,5R)(3-Chloro- 2-fluoro-benzylcarbamoy|) aza-bicyclo[3.1.0]hexy|] (4) 485 [M+H]+; tR oxo-ethy|}methyI-1H- (k): 2.71 min. lo[3,4-c]pyridine—3- carboxylic acid amide (1 R,3S,5R)-2—{2—[3-(2— Hydroxy-acety|)-indazo|y|]- (4) 485 [M+H]+, 507 acety|}aza-bicyc|o [M+Na]+; tR (k): 8.24 [3.1 .0]hexane—3-carboxylic min. acid 3-chloro—2—fluoro— benzylamide 1-{2—[(1R,3S,5R)(3-Chloro- ro-benzylcarbamoy|) aza-bicyclo[3.1.0]hexy|] (4) 485 [M+H]+; tR hy|}methy|-1 H- (k): 2.73 min. pyrazolo[4,3-c]pyridine—3- carboxylic acid amide 1-{2—[(1R,3S,5R)(3-Chloro- 2-fluoro-benzylcarbamoy|) aza-bicyclo[3.1.0]hexy|] (4)471 [M+H]+; tR oxo—ethyI}-1 H-pyrazolo[3,4- (k): 2.99 min. dine—3-carboxy|ic acid amide (1 R,3S,5R)-2—[2—(5—Acetyl- (4) R (CHZCIZ/MeOH pyrro|o[2,3-c]pyridazin-7—y|)- 9:1) = 0.4; acetyl]—2—aza—bicyclo 470.1/472.2 [M+H]+, [3.1 .0]hexane—3-carboxylic 5142/5162 acid 3-chloro—2—fluoro— [M+HCOO]-; tR (f): benzylamide 1.51 min. 1-{2-[(S)(3-Ch|orofluoro- (4) White solid. benzylcarbamoyI)-piperidin 473.0 [M+H]+, 495.0 yI]oxo-ethy|}-1H- [M+Na]+; tR (c): 3.63 pyrazolo[3,4-c]pyridine—3- min. carboxylic acid amide 1-{2-[(S)(3-Ch|orofluoro- (4) White solid. benzylcarbamoyI)-thiazolidin- 477.0 [M+H]+, 498.9 3-y|]oxo-ethy|}-1H- [M+Na]+; tR (c): 3.50 pyrazolo[3,4-c]pyridine—3- min. carboxylic acid amide (28,38,4S)[2-(3—AcetyI methyl-pyrrolo[2,3-c]pyridin (3,4) 519/521 y|)-acety|]f|uoromethoxy- [M+H]+; 1R (f): 1.51 idine—2-carboxylic acid min. 3-chlorofluoro—benzylamide formate 1-(2-{(28,3S,4S)[1-(3— Chlorofluoro—pheny|)- ropyl carbamoy|] (3,4) 533 ; tR fluoromethoxy-pyrrolidin (k): 3.16 min. y|}oxo-ethyI)-1 H- lo[3,4-b]pyridine-3— carboxylic acid amide 1-(2-{(28,3S,4S)[1-(3— Chlorofluoro—pheny|)- cyclopropyl carbamoy|] (3,4) 533 [M+H]+; tR fluoromethoxy-pyrrolidin (k): 2.84 min. y|}oxo-ethyI)-1 H- pyrazolo[4,3-c]pyridine—3- carboxylic acid amide 1-{2-[(28,3S,4S)(3—Chloro- 2-fluoro-benzylcarbamoy|) fluoromethoxy-pyrrolidin (3,4) 521 [M+H]+; tR y|]oxo-ethy|}methyl-1H- (k): 2.73 min. pyrazolo[3,4-c]pyridine—3- carboxylic acid amide 1-{2-[(2S,3S,4S)(3-Chloro- F O- 2-fluoro-benzylcarbamoyl) fluoromethoxy-pyrrolidin (3,4) 507 [M+H]+; t 2 oxo-ethyl}-1 H- (k): 2.71 min. pyrazolo[3,4-c]pyridine NH2 carboxylic acid amide 1-{2-[(2S,3S,4S)(3-Chloro- F O- 2-fluoro-benzylcarbamoyl) fluoromethoxy-pyrrolidin (3,4) 507 [M+H]+; t yl]oxo-ethyl}-1 H- (k): 2.71 min. - r s pyrazolo[4,3-c]pyridine ylic acid amide 1-(2-{(2S,3S,4S)[(R)(3- fluoro-phenyl)- ethylcarbamoyl]fluoro (3,4) 521 [M+H]+; t methoxy-pyrrolidinyl} R 4 (k): 2.78 min. oxo-ethyl)-1 H-pyrazolo[3,4- c]pyridinecarboxylic acid amide 1-(2-{(2S,3S,4S)[(R)(3- Chlorofluoro-phenyl)- ethylcarbamoyl]fluoro (3,4) 521 [M+H]+; t o methoxy-pyrrolidinyl} , (k): 2.79 min. oxo-ethyl)-1 H-pyrazolo[4,3- c]pyridinecarboxylic acid amide ( 1 R,3S,5R){2-[3-Acetyl (pyrimidinylmethoxy)-indol- 1-yl]-acetyl}aza-bicyclo (4) 576/578 [M+H]+; [3. 1.0]hexanecarboxylic t (k): 3.48 min. acid 3-chlorofluorobenzylamide (28,38,4S)[2-(3-Acety| methyl-pyrrolo[2,3-c]pyridin (3,4) 533/535 y|)-acety|]ethoxyf|uoro- [M+H]+; tR (f): 1.51 pyrrolidine—2-carboxylic acid min. 3-chlorofluoro—benzylamide formate 1-{2-[(1R,3S,5R)(3-Bromo- (4) R (EtOAc) = 0.1; ro-phenylcarbamoy|) 501 .1/503.0 [M+H]+, aza-bicyc|o[3.1.0]hexy|] 5012 [M-H]—, oxo—ethyI}-1 zolo[3,4- 545.1/548.3 c]pyridinecarboxy|ic acid [M+HCOO]-; tR (a): amide 2.42 min. 1-{2-[(1R,3S,5R)(3-Bromo- (4) R (EtOAc) = 0.6; 2-fIuoro-phenylcarbamoy|) 517.1/519.1 aza-bicyc|o[3.1.0]hexy|] ]+, oxo-ethyI}-1H-indazole—3- 4982/5001 [M-H]—; carboxylic acid amide tR (a): 3.18 min. 1-{2-[(1R,3S,5R)(3-Bromo- (4) R (EtOAc) = 0.1; 2-fIuoro-phenylcarbamoy|) 5152/517.1 [M+H]+, aza-bicyc|o[3.1.0]hexy|] 5132/515.1 [M-H]—, oxo-ethyI}methyI-1H- 561.2 [M+HCOO]—; tR pyrazolo[3,4-c]pyridine—3- (a): 2.48 min. carboxylic acid amide (1R,3S,5R)(3-Bromo- (4) R (EtOAc) = 2-fIuoro-phenylcarbamoy|) 0.15; 529.1/531.1 aza-bicyc|o[3.1.0]hexy|] [M+H]+, 5272/529.1 oxo-ethy|}ethy|-1H- [M-H]-, 5732/575.3 pyrazolo[3,4-c]pyridine—3- [M+HCOO]-; tR (a): ylic acid amide 2.55 min. 1-{2-[(1R,3S,5R)(6— (4,5) Rf (EtOAc) = CyclopropyI-pyridin 0.4; 445.3/4463 y|carbamoy|)aza-bicyc|o [M+H]+, 489.4/491.4 [3.1 .0]hexy|]oxo-ethy|}- [M+HCOO]-; tR (a): 1H-indazole—3-carboxylic acid 2.53 min. amide -mm- 1-{2-[(1R,3S,5R)-3—(6— (4,5) Rf (EtOAc) = IsopropyI-pyridin 0.1; 448.3 [M+H]+, y|carbamoy|)aza-bicyc|o 446.0 [M-H]-, 492.3 [3.1 .0]hexy|]oxo-ethy|}- [M+HCOO]-; tR (a): azo|o[3,4-c]pyridine—3— 1.31 min. carboxylic acid amide (1R,3S,5R)-3—(3— (1A)Rd0 Cyclopropylfluoro— hexane/EtOAc 2:1) = phenylcarbamoyI)aza- 0.6; 361.2 [M+H]+, bicyc|o[3.1.0]hexy|]oxo- 738.4 [2M+Na]+; tR ethyl}-1H-indazole—3- (f): 2.29 min. carboxylic acid amide (2,3,4) Rf 1-{2-[(1R,3S,5R)—3-(3-Chloro- (CHZCIZ/MeOH 9:1) 2-f|uoro-benzylcarbamoy|) = 0.4; 485.3/487.3 methylaza-bicyclo [M+H]+, 507.2/509.2 [3.1 .0]hexy|]oxo-ethy|}- [M+Nat 1H-pyrazo|o[3,4-c]pyridine—3— 529.3/531.3 carboxylic acid amide O]-; tR (f): 1.47 min. (1 R,3S,5R)—2-[2-(3—AcetyI (4) R (CHZCIZ/MeOH amino-pyrro|o[2,3-b]pyridin-1 - 9:1) = 0.5; y|)-acety|]aza-bicyc|o 503.1/505.1 [M+H]+, [3.1 .0]hexane-3—carboxylic 547.1/549.1 acid 3-chlorofluoro— O]-; tR (f): amide 2.11 min. (2,3,4) Rf (1 R,3S,5R)—2-[2-(3—Acetyl- (CHZCIZ/MeOH 9:1) pyrazolo[3,4—b]pyridiny|)- = 0.55; 500.1/502.1 acetyl]—2-aza—bicyclo [M+HH, [3.1 .0]hexane-3—carboxylic 1000.3/1001.3 acid [(S)(3-ch|orof|uoro— [2M+H]+, pheny|)hydroxy-ethy|]- 544.1/546.1; tR (f): amide 1.81 min. (1 R,3S,5R)—2-[2-(1-Acetyl- (2,3,4) Rf imidazo[1,5-a]pyridiny|)- (CHZCIZ/MeOH 9:1) acetyl]—2-aza—bicyclo = 0.7; 513.2/515.2 [3.1 .0]hexanecarboxy|ic [M+H]+, 557.2/558.3 acid [(S)(3-ch|orof|uoro— [M+HCOO]-; tR (a): phenyI)methoxy-ethy|]- 3.15 min. amide (1 R,3S,5R)—2-[2-(1-Acetylimidazo [1,5-a]pyridiny|)- (4) Rf (EtOAc) = 0.2; acety|]aza- 508.3 [M+H]+, 506.2 bicyc|o[3.1.0]hexane [M-H]-; tR (a): 3.05 carboxylic acid [(R)(3— min. fluoro—phenyI) cyano—ethyl]—amide (2S,3S,4S)—1-[2-(3—Acetyl- (3) 5052/5072 indazoIy|)-acety|]f|uoro- [M+H]+, 549.3/551.4 3-methoxy-pyrrolidi ne—2- [M+HCOO]-; tR (f): carboxylic acid 3-chloro—2- 2.09 min. fluoro-benzylamide (2S,3S,4S)—1-[2-(3—Acetyl- (3,4) 507.2 pyrrolo[2,3-c]pyridiny|)- [M+H]+, 549.2/551.2 ]f|uoromethoxy- [M+HCOO]-; tR (f): pyrrolidine—2-carboxylic acid 1.49 min. 3-chlorofluoro—benzylamide (2S,3S,4S)—1-[2-(3—Acetyl- (3,4) 506.4/508.4 pyrazolo[3,4-c]pyridiny|)- [M+H]+, 550.5/552.6 acety|]f|uoromethoxy- [M+HCOO]-; tR (f): pyrrolidine—2-carboxylic acid 1.59 min. 3-chlorofluoro—benzylamide (1 R,3S,5R)—2-{2-[3—AcetyI (4,7) 451.0 [M+Na]+, (pyrimidinylmethoxy)- 328.9 ]+, Iy|]-acety|}aza- 427.1 [M-H]—; tR (c): bicyc|o[3.1.0]hexane .29 min. carboxylic acid (3- sulfur pentafluoride -phenyI)-amide 1-{2—[(1R,3S,5R)(2,2'- Difluoro—biphenyI y|carbamoy|)aza- ) 517 [M+H]+; bicyclo[3.1.0]hexy|]oxo— tR (k): 3.01 min. ethy|}-1H-pyrazolo[3,4-c] pyridinecarboxylic acid amide (1R,3S,5R)(2'-Chloro— 2-fluoro-biphenyI y|carbamoy|)aza- (1,4,7) 533 [M+H]+; bicyclo[3.1.0]hexy|]oxo— tR (k): 3.05 min. ethy|}-1H-pyrazolo[3,4-c] pyridinecarboxylic acid amide (1R,3S,5R)—3-[2—Fluoro- 3-(3-fluoro-pyridin-2—y|)- phenylcarbamoyl]—2—aza- (1,4,7) 517 [M+H]+; bicyclo[3.1.0]hexy|}oxo— 1R (k): 3.10 min. ethyl)-1H-indazole—3- carboxylic acid amide 1-(2-{(1R,3S,5R)—3-[2—Fluoro- 3-(3-methyI-pyridiny|)- phenylcarbamoyl]—2—aza- (1,4,7) 514 [M+H]+; bicyclo[3.1.0]hexy|}oxo— 1R (k): 2.32 min. ethy|)-1H-pyrazolo[3,4—c] pyridinecarboxylic acid amide (1R,3S,5R)[3—(3— —pyridiny|)f|uoro- phenylcarbamoyl]—2-aza- (1,4,7) 534 [M+H]+; bicyc|o[3.1.0]hexy|}oxo- tR (k): 2.72 min. -1H-pyrazolo[3,4—c] pyridinecarboxylic acid amide 3-AcetyI{2-[(1R,3S,5R)-3— (3-chlorofluoro— benzylcarbamoyI)aza- (4) 527 [M+H]+, 549 bicyc|o[3.1.0]hexy|]oxo- [M+Na]+; tR (k): 3.43 ethyl}-1H-pyrro|o[2,3-b] min. pyridine-6—carboxylic acid methyl ester 1-(2-{(28,4R)[(R)(3- Chlorofluoro—pheny|)- (4) 489/491 [M+H]+, ethylcarbamoy|]f|uoro- 513[M+Na]+; tR (c): pyrrolidiny|}oxo-ethy|)- 3.43 min. 1H-pyrazo|o[3,4-c]pyridine-3— carboxylic acid amide 1-(2-{(28,4R)[(R)(3- Chlorofluoro—pheny|)- ethylcarbamoy|]f|uoro- (4) 505 [M+H]+; tR idiny|}oxo-ethy|)- (k): 2.74 min. -methyI-1H-pyrazolo[3,4—c] pyridinecarboxylic acid amide 1-{2-[(1R,3S,5R)(3-Chloro- 2-fluoro-benzylcarbamoy|) (4) 470 [M+H]+, 492 aza-bicyc|o[3.1.0]hex—2-yl]—2- [M+Na]+; tR (c): 4.17 oxo-ethyI}-1H-indazole—3- min. carboxylic acid amide 1-(2-{(1R,3S,5R)[(R)(3— Chlorofluoro—pheny|)- (4)499[M+H]+; tR ethylcarbamoyl]—2-aza- (c): 3.51 min. bicyc|o[3. 1 .0]hex—2-yl}oxo— ethyI)methyI-1H- -45o- pyrazolo[3,4-c]pyridine—3- carboxylic acid amide 1-{2—[(1R,3S,5R)(3-Chloro- 2-fluoro-benzylcarbamoy|) aza-bicyclo[3.1.0]hex—2—yl]—2— (4) 485 [M+H]+; tR oxo-ethyI}methyI-1H- (c): 3.39 min. pyrazolo[3,4-c]pyridine—3- carboxylic acid amide 1-{2—[(1R,3S,5R)(3-Chloro- 2-fluoro-benzylcarbamoy|) aza-bicyclo[3.1.0]hex—2—yl]—2— (4) 499 [M+H]+; tR oxo-ethyI}-5,7-dimethyI-1 H- (c): 3.46 min. pyrazolo[3,4-c]pyridine—3- carboxylic acid amide (1R,3S,5R)[(R)(3- Chlorofluoro—pheny|)- ethylcarbamoyl]—2—aza- (4) 513 [M+H]+, 511 bicyclo[3. 1 .0]hex—2-y|}oxo- [M-H]-; 1R (c): 3.58 ethyI)-5,7-dimethyI-1H- min. pyrazolo[3,4-c]pyridine—3- carboxylic acid amide 1-{2-[(28,3S,4S)-2—(3-Chloro- 2-fluoro-benzylcarbamoy|) fluoromethoxy-pyrrolidin (3,4) 535 [M+H]+; tR oxo—ethyI}ethyl-1H- (k): 2.82 min. pyrazolo[3,4-c]pyridine-3 -carboxy|ic acid amide 1-(2-{(1R,3S,5R)[(S)(3- Chlorofluoro—pheny|)- ethylcarbamoyl]—2 (4) 485 [M+H]+; tR -aza-bicyc|o[3.1 —2-y|} (c): 3.59 min. oxo—ethyI)-1H-pyrazolo[3,4- c]pyridinecarboxy|ic acid amide carboxylic acid amide ( 1) The amine t used in step A was prepared as described in Part C ; (2) HCI (4M in dioxane) was used instead of TFA in step B; (3) The title compound was prepared according to the general procedure described in Scheme D9 steps B and C starting from the substituted proline derivative prepared as described in Part B; (4) The acid reagent used in step C was ed as described in Part A ; (5) CH2CI2 was used d of DMF in step C ; (6) T3P was used instead of HBTU in step C and the reaction was performed in CH2CI2; (7) In step A , DMF was used instead of CH2C I2 and the reaction was performed at 50-70°C.
Example 702: 1-(2-{(1 R,3S,5R)[(R)-1 -(3-Chlorofluoro-phenyl)-ethylcarbamoyl] aza-bicyclo[3.1 .0]hexyl}oxo-ethyl)-1 H-pyrazolo[3,4-c]pyridinecarboxylic acid amide To a solution of (3-carbamoyl-pyrazolo[3,4-c]pyridin-1 -yl)-acetic acid trifluoroacetate salt (2.65 g , 7.94 mmol, ed as described in Scheme A26) in DM F (30 ml_) were added successively ( 1 R,3S,5R)aza-bicyclo[3.1 .0]hexanecarboxylic acid, -(3-chloro fluoro-phenyl)-ethyl]-amide trifluoroacetate salt (3.00 g , 7.56 mmol), HBTU (3.44 g , 9.07 mmol) and DIPEA (5.28 mL, 30.2 mmol). The reaction e was stirred at RT for 16 h and then was concentrated under vacuum. The al oil was partitioned between CH C I and a sat. 2 2 aq. NaHC0 solution. A solid precipitated from the resulting emulsion and was filtered off, washed with water and dried under vacuum. The solid was suspended in a mixture of water (150 mL) and MeOH (3 mL), stirred for 1 h at RT, filtered, washed with water and finally dried under vacuum to give the title material as a white powder. MS (LC/MS): 485 ; t (HPLC conditions c): 3.54 min.
Example 703: 1-(2-((1 R,3S,5R)((3-Chlorofluorobenzyl)carbamoyl)azabicyclo yl)oxoethyl)-1H-pyrazolo[3,4-c]pyridinecarboxamide To a solution of (3-carbamoyl-pyrazolo[3,4-c]pyridinyl)-acetic acid trifluoroacetate salt (2.12 g , 6.35 mmol, prepared as described in Scheme A26) in DMF (32 mL) were sively added ( 1 R,3S,5R)-N-(3-chlorofluorobenzyl)azabicyclo[3. 1.0]hexanecarboxamide trifluoroacetate salt (2.70 g , 6.35 mmol), HBTU (3.37 g , 8.89 mmol) and DIPEA (4.44 mL, 25.4 mmol). The reaction mixture was stirred at RT for 16 h , and then was concentrated under vacuum. The residual oil was partitioned between CH C I and a sat. aq. NaHC0 solution. A 2 2 3 solid precipitated from the resulting on and was filtered off, washed with water and dried under . The solid was suspended in a mixture of water (150 mL) and MeOH (3 mL), stirred for 1 h at RT, filtered, washed with water and finally dried under vacuum to give the title material as a white powder. MS (LC/MS): 471 [M+H]+; t (HPLC conditions c): 3.41 min.
Example 704: 3-Acetyl{2-[(1R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)aza- 2-yl]oxo-ethyl}-1H-pyrrolo[2,3-b]pyridinecarboxylic acid To a solution of 3-acetyl{2-[(1 R,3S,5R)(3-chlorofluoro-benzylcarbamoyl)azabicyclo [3.1.0]hexyl]oxo-ethyl}-1 H-pyrrolo[2,3-b]pyridinecarboxylic acid methyl ester (Example 689, 70 mg, 0.133 mmol) in THF (3 mL) and water (0.3 mL) was added a 2N aqueous LiOH solution (0.664 mL, 1.33 mmol). The reaction mixture was stirred at 25°C for 16 h , then a 1N HCI aqueous solution was added to y the reaction mixture to pH = 2 to 3 .
The resulting aqueous suspension was filtered, the solid was washed with water and then dried in vacuo. The crude solid was ed by preparative HPLC (Waters Sunfire C18-OBD, 5 m , 30x100mm, flow: 40 mL/min, : 20% to 100% CH CN in H 0 in 20 min, 100% CH CN 3 2 3 2 min, CH CN and H 0 containing 0.1% TFA). The pure fractions were combined, CH CN was 3 2 3 evaporated under reduced pressure and the resulting aqueous on was lyophilized to give the title compound as a white solid. MS: 513 [M+H]+, 535 [M+Na]+; t (HPLC conditions k): 3.14 min.
Example 705: 3-Carbamoyl(2-((1R,3S,5R)(3-chlorofluorobenzylcarbamoyl) azabicyclo[3.1.0]hexanyl)oxoethyl)-1H-pyrazolo[3,4-c]pyridine 6-oxide To a solution of 1-(2-((1 R,3S,5R)(3-chlorofluorobenzylcarbamoyl) azabicyclo[3. 1.0]hexanyl)oxoethyl)-1 H-pyrazolo[3,4-c]pyridinecarboxamide (Example 703, 100 mg, 0.21 mmol) in acetic acid (4 mL) was added 3-chlorobenzoperoxoic acid (58 mg, 0.34 mmol) at 55°C. The reaction mixture was stirred at 55°C for 18 h and then cooled to RT.
Volatiles were evaporated and the residue was purified by preparative HPLC (Waters e, C18-ODB, 5 m , 30x100 mm, flow: 40 mL/min, eluent: 5-100% CH CN/H O/20 min, 100% 3 2 CH CN/2 min, CH CN and H 0 containing 0.1% TFA) to afford the title nd as a white 3 3 2 solid. MS: 487 ; t (HPLC conditions c): 3.44 min.
Example 706: 3-Carbamoyl(2-((1R,3S,5R)((R)(3-chlorofluorophenyl)ethylcarbamoyl )azabicyclo[3.1 .0]hexanyl)oxoethyl)-1 H-pyrazolo[3,4-c]pyridine 6- oxide To a solution of 1-(2-((1R,3S,5R)((R)(3-chlorofluorophenyl)ethylcarbamoyl) azabicyclo[3. 1.0]hexanyl)oxoethyl)-1 H-pyrazolo[3,4-c]pyridinecarboxamide (Example 702, 150 mg, 0.31 mmol) in acetic acid (4 mL) was added 3-chlorobenzoperoxoic acid (85 mg, 0.50 mmol) at 55°C. The reaction mixture was stirred at 55°C for 18 h and then cooled to RT.
Volatiles were evaporated and the residue was purified by ative HPLC (Waters Sunfire, C18-ODB, 5 mhi , 30x100 mm, flow: 40 mL/min, eluent: 5-100% CH CN/H O/20 min, 100% 3 2 CH CN/2 min, CH CN and H 0 containing 0.1% TFA) to afford the title compound as a white 3 3 2 solid. MS: 501 [M+H]+; t (HPLC conditions c): 3.64 min.
Scheme D10: general protocol described for the preparation of Example 707: 1 r(1R,3S,5R)(2-Fluorotrifluoromethoxy-phenylcarbamoyl)aza-bicyclor3.1.01 hex vnoxo-ethylV1H-indazolecarboxylic acid amide A. ( 5R)(2-Fluorotrif luoromethoxy-phenylcarbamoyl)aza-bicyclo[3.1 .0] hexanecarboxylic acid tert-butyl ester To a solution of ( 1 R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester ( 1 .83 g , 8.07 mmol) in dry THF (45 mL) at -20°C under nitrogen atmosphere was added triethylamine (3.32 mL, 23.8 mmol) followed by ethylchloroformate (0.775 mL, 8.07 mmol) dropwise. The reaction mixture was stirred at -20°C for 90 min and a solution of ro (trifluoromethoxy)aniline (prepared as described in Part C, 1.5 g , 7.69 mmol) in dry THF (5 mL) was added. The reaction e was further stirred at -20°C for 1 h , warmed up to RT and stirred at 65°C for 16 h until completion of the reaction. The reaction mixture was diluted with EtOAC, washed with a saturated aqueous solution of NaHC0 (x3) and brine, dried (phase separator) and concentrated under reduced pressure. The crude residue was purified via flash column chromatography on silica gel (EtOAc/c-hexane 1:1) to give the desired material as a colorless oil. MS: 427 [M+Na]+, 304.9 [MH-Boc]+; t (HPLC conditions c): 5.23 min.
B. (1R,3S,5R)Aza-bicyclo[3.1.0]hexanecarboxylic acid (2-fluorotrifluoro methoxyphenyl )-amide trifluoroacetate To a solution of ((1 R,3S,5R)(2-fluorotrifluoromethoxy-phenylcarbamoyl)aza- o[3.1 .0] hexanecarboxylic acid tert-butyl ester (2.56 g , 6.33 mmol) in CH C I (20 mL) 2 2 was added TFA (10 mL, 130 mmol) and the solution was stirred at RT for 16 h . CH C I was 2 2 trated, the residue was ed in MeOH, concentrated again and dried under high vacuum to give the desired material which was used without further purification in the next step. MS: 305 [M+H]+; t (HPLC conditions c): 3.55 min.
C. Example 707: 1-{2-[(1R,3S,5R)(2-Fluorotrifluoromethoxy-phenylcarbamoyl) aza-bicyclo[3.1 .0]hexyl]oxo-ethyl}-1 H-indazolecarboxylic acid amide To a solution of (3-carbamoyl-indazolyl)-acetic acid (73.4 mg, 0.335 mmol, prepared as described in Scheme A25) in DMF (2 ml_) were successively added (1R,3S,5R)azabicyclo [3.1 .0]hexanecarboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide oroacetate (140 mg, 0.335 mmol), DIPEA (0.234 ml_, 1.34 mmol) and HBTU (152 mg, 0.402 mmol). The reaction mixture was stirred at 25°C for 2 h , concentrated and the residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 mhi , 30x100mm, flow: 40 mL/min, eluent: 5% to 100% CH CN in H 0 in 20 min, 100% CH CN 2 min, CH CN and H 0 3 2 3 3 2 containing 0.1% TFA). The pure fractions were combined, CH CN was evaporated under reduced pressure and the resulting aqueous solution was lyophilized. White powder: MS: 506 [M+H]+; t (HPLC ions k): 3.40 min.
Alternatively, for final compounds containing a basic residue : the pure HPLC ons were combined, CH CN was evaporated under reduced pressure, the resulting s solution was ed to pH 8-9 by addition of an aqueous saturated solution of NaHC0 , extracted with CH C I (x3), the combined organic extracts were dried (phase separator) and 2 2 concentrated under .
The examples below were prepared according to the general procedures bed in Scheme D10 for Example 707 using commercially available building blocks if not otherwise stated (see note at the end of table 9): Table 9 : terization (end-table notes), TLC, R Example Structure Name (eluent); MS (LC/MS); t (HPLC conditions) 1-(2-((2S,4R)fluoro(2-fluoro (trifluoromethoxy)phenylcarbamoyl) (1) 512 [M+H]+; t (k): 708 R pyrrolidinyl)oxoethyl)-1H- 3.31 min. indazolecarboxamide 1-(2-((1R,3S,5R)-3—(2-f|uoro—3— (trifluoromethoxy)phenylcarbamoyl)- (1) 507 ; tR (k): 2-azabicyc|o[3.1.0]hexany|) 2.90 min. oxoethy|)-1H-pyrazolo[4,3-c] pyridinecarboxamide Methyl 3-acetyI(2-((1R,3S,5R)—3- (2-fluoro—3-(trifluoromethoxy) (1) 563 [M+H]+, 585 phenylcarbamoy|)azabicyc|o [M+Na]+; tR (k): 3.89 min. [3.1 .0]hexanyI)oxoethy|)-1H- indazole—6-carboxylate (1 R,3S,5R)[2-(3—AcetyI-pyrazolo[ 3,4—b]pyridiny|)-acety|]aza- bicyc|o[3.1.0]hexane—3-carboxylic (1) 506 [M+H]+; tR (k): acid (2-fluorotrifluoromethoxy- 3.67 min. phenyI)-amide I{2-[(1R,3S,5R)—3-(2-fluoro- 3-trifluoromethoxyphenylcarbamoyl )—2-aza- (1) 535 [M+H]+; tR (k): o[3.1 .0]hexy|]oxo-ethy|}- 2.97 min. 1H-pyrazolo[3,4-c]pyridine-3— carboxylic acid amide 1-{2-[(1R,3S,5R)—3-(2-F|uoro—3- trifluoromethoxy-phenylcarbamoy|)- 2-aza-bicyc|o[3. 1 .0]hexy|]oxo- (1)521 [M+H]+; tR (k): ethyl}-6—methyI-1H-pyrazolo[4,3- 2.92 min. c]pyridinecarboxy|ic acid amide 1-{2-[(1R,3S,5R)—3-(2-F|uoro—3- trifluoromethoxy-phenylcarbamoy|)- 2-aza-bicyc|o[3. 1 .0]hexy|]oxo- (1) 537 [M+H]+; tR (k): ethy|}methoxy-1 H-pyrazolo[3,4- 3.24 min. c]pyridinecarboxy|ic acid amide -EthyI{2-[(2S,4R)f|uoro—2-(2- fluoro—3-trifluoromethoxy-phenyl (1)541 [M+H]+; tR (k): carbamoyl)—pyrrolidiny|]oxo- 2.95 min. -1H-pyrazolo[3,4-c]pyridine-3— carboxylic acid amide 1-{2-[(1R,3S,5R)(2-F|uoro—3- trifluoromethoxy-phenylcarbamoy|)- 2-aza-bicyc|o[3. 1 y|]oxo- (1)521 [M+H]+; tR (k): ethyl}-7—methyI-1H-pyrazolo[3,4— 2.90 min. c]pyridinecarboxy|ic acid amide 1-{2-[(1R,3S,5R)(2-F|uoro—3- trifluoromethoxy-phenylcarbamoy|)- 2-aza-bicyc|o[3. 1 .0]hexy|]oxoethyl }-5,7—dimethy|—1H-pyrazolo (1) 535 ; tR (c): [3,4-c]pyridinecarboxylic acid 3.84 min. amide (1 R,3S,5R){2-[3-AcetyI (pyrimidinylmethoxy)-indazo|—1- y|]-acety|}aza- (1) 613 [M+H]+, 635 bicyclo[3.1.0]hexane—3-carboxylic [M+Na]+; tR (c): 4.81 min. acid (2-fluorotrifluoromethoxy- phenyI)-amide -CyclopropyI(2-((1R,3S,5R) ((2-fIuoro(trifluoromethoxy) phenyl)carbamoyI)azabicyclo (1) 547 [M+H]+; tR (c): [3.1 anyI)oxoethy|)-1H- 3.97 min. pyrazolo[3,4—c] pyridine carboxamide (1R,3S,5R)((2-Fluoro (trifluoromethoxy)phenyl)carbamoyl) (1) 508.0 [M+H]+, 529.9 azabicyc|o[3.1.0]hexany|) [M+Na]+; tR (c): 4.08 min. oxoethy|)-1H-pyrazolo[3,4—c] pyridazine—3-carboxamide 1-(2-{(1R,3S,5R)[6-(2,6—Dif|uoro— phenyI)-pyridinylcarbamoy|] (1,2) 518 [M+H]+; tR (k): aza—bicyclo[3. 1 .0]hexy|}oxo- 2.90 min. ethyI)-1H-pyrazolo[3,4—c]pyridine—3- carboxamide 1-(2-((1R,3S,5R)(2'-Chloro-6'- fluorobiphenylylcarbamoyl) (1,2) 533 [M+H]+; t (c): yclo[3. 1.0]hexanyl) R 722 4.12 min. oxoethyl)-1 H-pyrazolo[3,4-c] NH2 pyridinecarboxamide ( 1) The acid derivative used is step C was prepared as described in Part A ; (2) The amine derivative used in step A was prepared as described in Part C.
Example 723: 1-{2-[(1R,3S,5R)(2-Fluorotrifluoromethoxy-phenylcarbamoyl)azabicyclo [3.1.0]hexyl]oxo-ethyl}methyl-1H-pyrazolo[3,4-c]pyridinecarboxylic acid amide To a solution of (3-carbamoylmethyl-pyrazolo[3,4-c]pyridinyl)-acetic acid trifluoroacetate salt (3.87 g , 11.1 mmol; prepared as bed in Scheme A27) in DMF (45 ml_) were successively added (1R,3S,5R)aza-bicyclo[3.1.0]hexanecarboxylic acid (2-fluoro trifluoro methoxy-phenyl)-amide trifluoroacetate salt (5.00 g , 11.1 mmol), DIPEA (7.77 ml_, 44.5 mmol) and HBTU (5.06 g , 13.3 mmol). The reaction mixture was stirred at 25°C for 2 h and was then concentrated in vacuo. The e was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 mhi , 30x1 00mm, flow: 50 , eluent: 5% to 100% CH CN in H 0 in 3 2 min, 100% CH CN 2 min, CH CN and H 0 containing 0.1% TFA). The pure fractions were 3 3 2 combined and volatiles were evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 8 to 9 by addition of an aqueous saturated solution of NaHC0 , and then was extracted with CH C I (x3). The combined organic extracts were dried (phase 2 2 separator) and concentrated under vacuum to afford the title compound as a white solid. MS: 521 [M+H]+; t (HPLC conditions c): 3.81 min. e 724: 1-(2-((1 R,3S,5R)((2-Fluoro(trifluoromethoxy)phenyl)carbamoyl) azabicyclo[3.1.0]hexanyl)oxoethyl)-1H-pyrazolo[3,4-c]pyridinecarboxamide To a solution of (3-carbamoyl-pyrazolo[3,4-c]pyridinyl)-acetic acid trifluoroacetate salt (1.60 g , 4.78 mmol; prepared as bed in Scheme A26) in DMF (40 ml_) were successively added ( 1 R)aza-bicyclo[3.1.0]hexanecarboxylic acid (2-fluorotrifluoro methoxyphenyl e trifluoroacetate salt (2.50 g , 4.78 mmol), DIPEA (3.34 ml_, 19.1 mmol) and HBTU (2.17 g , 5.74 mmol). The reaction mixture was stirred at 25°C for 2 h and then was concentrated. The residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 mhi , 30x100mm, flow: 50 mL/min, : 5% to 100% CH3CN in H20 in 20 min, 100% CH3CN 2 min, CH3CN and H20 containing 0.1% TFA). The pure fractions were combined and les were removed under reduced pressure. The resulting aqueous solution was adjusted to pH 8 to 9 by addition of an aqueous saturated solution of NaHC0 3 and was then extracted with CH2C I2 (x3). The combined organic extracts were dried (phase tor) and concentrated under vacuum. The residual solid was suspended in Et20 and stirred at RT for 16 h . The solid was filtered and dried under vacuum to afford the title compound as a white solid. MS: 507 [M+H]+; tR (HPLC conditions c): 3.77 min.
Example 725: 3-Acetyl{2-[(1R ,3S,5R)(2-fluoro fluoromethoxy)phenylcarbamoyl )aza-bicyclo [3.1 .0]hexyl]oxo-ethyl}-1H-indazole carboxylic acid To a solution of methyl 3-acetyl(2-((1 R,3S,5R)(2-fluorotrifluoromethoxy)phenylcarbamoyl )azabicyclo[3.1 .0]hexanyl)oxo-ethyl)-1 H-indazolecarboxylate (Example 710, 25 mg, 0.044 mmol) in THF (2 ml_) and water (0.2 ml_) was added a 2N aqueous LiOH solution (0.089 ml_, 0.178 mmol). The reaction mixture was stirred at 25°C for 4 h , then a 1N HCI aqueous solution was added to acidify the reaction mixture to pH = 2 to 3 . The resulting s solution was extracted with CH2C I2 (x3), the combined organic extracts were dried (Phase separator) and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 mhi , 30x1 00mm, flow: 40 mL/min, eluent: 5% to 100% CH3CN in H20 in 20 min, 100% CH3CN 2 min, CH3CN and H20 containing 0.1% TFA). The pure fractions were combined, volatiles were d under reduced pressure and the resulting aqueous solution was lyophilized to afford the title compound as a white solid.
MS: 549 [M+H]+; t (HPLC conditions c): 4.76 min.
Example 726: 3-Carbamoyl(2-((1R,3S,5R)((2-fluorohydroxyphenyl)carbamoyl) anyl)oxoethyl)methyl-1H-pyrazolo[3,4-c]pyridine 6-oxide To a solution of (1 R,3S,5R)(2-fluorotrifluoromethoxy-phenylcarbamoyl)aza- o[3. 1.0]hexyl]oxo-ethyl}methyl-1 H-pyrazolo[3,4-c]pyridinecarboxylic acid amide le 723, 50 mg, 0.096 mmol) in acetic acid (3 ml_) was added 3- chlorobenzoperoxoic acid (38 mg, 0.154 mmol) at 55°C. The reaction mixture was stirred at 55°C for 18 h and then cooled to RT. Volatiles were ated, the residue was then dissolved in EtOAc and washed with a sat. aq. NaHC0 solution (x3) and brine, dried (Phase separator) and trated under d pressure to afford the title compound as a white solid. MS: 537 [M+H]+; t (HPLC conditions k): 3.00 min.
Scheme D 11: general protocol described for the ation of Example 727: 1 r(1R,3S,5R)(6-Bromo-pyridinylcarbamoyl)aza-bicyclor3.1.01hexvnoxo- ethyl)-1H-indazolecarboxylic acid amide A. ( 1R,3S,5R)(6-Bromo-pyridinylcarbamoyl)aza-bicyclo [3.1 .0]hexane carboxylic acid tert-butyl ester To a solution of ( 1 R,3S,5R)aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (500 mg, 2.2 mmol) in dry CH C I (2 ml_) was added 1-chloro-N,N,2-trimethylpropenylamine 2 2 (349 m I_ , 2.64 mmol) at 0°C under nitrogen atmosphere. Formation of the acyl chlorid intermediate was monitored by TLC after quenching of an aliquot with MeOH. After completion (1-1.5 h), 2-aminobromopyridine (457 mg, 2.64 mmol) was added at 0°C, followed by DIPEA (1.13 ml_, 6.60 mmol) and the reaction mixture further stirred 2 h at RT. The reaction mixture was poured into water and extracted twice with CH C I . The combined organic extracts 2 2 were dried (Na S0 ) , filtered and concentrated. CH C I was added to the crude residue and the 2 4 2 2 precipitate filtered to give the desired al as a white solid. TLC, R ) = 0.85; MS: 382.1/384.1 [M+H]+, 380.2/382.3 [M-H]-, 426.7/428.3 [M+HCOO]-; t (HPLC conditions h): 2.19 min.
B. (1R,3S,5R)Aza-bicyclo[3.1.0]hexanecarboxylic acid (6-bromo-pyridinyl)-amide di(trifluoroacetate) salt To a solution of ( 1 R,3S,5R)(6-bromo-pyridinylcarbamoyl)aza-bicyclo[3.1.0]hexane carboxylic acid tert-butyl ester (561 mg, 1.47 mmol) in CH C I ( 1 1 ml_) was added TFA (1.13 2 2 ml_, 14.7 mmol) and the solution was stirred at RT overnight. CH C I was concentrated and the 2 2 crude residue was dried under high vacuum to give the desired material which was used without further purification in the next step. MS: 282.1/284.1 [M+H]+, 304.0/306.1 [M+Na]+, 563.1/565.2 [2M+H]+; t (HPLC conditions f): 0.96 min.
C. Example 727: 1-{2-[(1R,3S,5R)(6-Bromo-pyridinylcarbamoyl)aza-bicyclo [3.1.0]hexyl]oxo-ethyl}-1H-indazolecarboxylic acid amide (3-Carbamoyl-indazolyl)-acetic acid (130 mg, 0.59 mmol, prepared as described in Scheme A25), ( 1 R,3S,5R)aza-bicyclo[3.1.0]hexanecarboxylic acid (6-bromo-pyridinyl)-amide (2 TFA salt, 303 mg, 0.59 mmol) and HBTU (337 mg, 0.89 mmol) were dissolved in DMF (3 mL).
DIPEA (406 m , 2.37 mmol) was added and the reaction mixture was stirred at 25°C for 1 h .
The crude reaction mixture was purified by ative HPLC (Waters Sunfire C18-OBD, 5 mhi , 30x100mm, flow: 40 mL/min, eluent: 20% to 100% CH CN in H 0 in 25 min, CH CN and H 0 3 2 3 2 containing 0.1% TFA). The pure fractions were combined, neutralized with an aqueous saturated solution of NaHC0 and extracted with CH C I to give the desired compound. TLC, 3 2 2 R (CH C I /MeOH 9:1) = 0.55; MS: 483.1/485.1 [M+H]+, 965.4/967.4 [2M+H]+, 982.4/984.3 f 2 2 [2M+NH ]+, 481 .1/483.2 [M-H]-, 527.2/529.1 [M+HCOO]-; t (HPLC conditions a): 2.79 min. 4 R Alternatively, for final nds containing a basic residue: the pure HPLC ons were combined, CH CN was evaporated under reduced pressure, the resulting aqueous solution was adjusted to pH 8-9 by addition of an s saturated on of NaHC0 , extracted with CH C I (x3), the combined c extracts were dried (Na S0 ) and concentrated under 2 2 2 vacuum.
The examples below were prepared ing to the general procedures described in Scheme D11 for Example 727 using commercially available building blocks if not otherwise stated (see notes at the end of table 10): Table 10: 1-{2-Oxo[(1 R,3S,5R)(6- (1) R (EtOAc) = 0.1; trifluoromethyl-pyridin f 474.2 , 472.2 ylcarbamoyl)aza-bicyclo [M-H]-, 518.3 732 [3.1.0]hexyl]-ethyl}-1 [M+HCOO]-; t (a): H-pyrazolo[3,4-c]pyridine R NH2 2.09 min. carboxylic acid amide (1R,3S,5R)[2-(3-Acetyl- (1) R (EtOAc) = 0.25; pyrazolo[3,4-c]pyridinyl)- f 473.2 [M+H]+, 471.2 acetyl]aza-bicyclo[3.1 .0] [M-H]-, 517.2 733 hexanecarboxylic acid (6- [M+HCOO]-; t (a): trifluoromethyl-pyridinyl)- R 2.30 min. amide 1-{2-[(1 R,3S,5R)(6-Bromo- (1) R (EtOAc) = 0.1; pyridinylcarbamoyl)aza- 498.1/500.1 [M+H]+, bicyclo[3. 1.0]hexyl]oxo- 498.1 [M-H]-, ethyl}methyl-1 H-pyrazolo 542.3/544.1 [3,4-c]pyridinecarboxylic acid [M+HCOO]-; t (a): NH2 R amide 2.27 min. 1-{2-[(1 R,3S,5R)(6-Bromo- (1) R (EtOAc) = 0.26; pyridinylcarbamoyl)aza- 12.2/514.2 [M+H]+, bicyclo[3. 1.0]hexyl]oxo- 510.2/512.2 [M-H]-, ethyl}ethyl-1 H-pyrazolo[3,4- 556.2/558.2 dinecarboxylic acid [M+HCOO]-; t (a): NH2 R amide 2.35 min. (1R,3S,5R)[2-(3-Acetyl- (1) R (CH C I /MeOH f 2 2 pyrazolo[3,4-c]pyridinyl)- 9:1) = 0.5; 736 acetyl]aza-bicyclo[3.1 .0] 485.1 , hexanecarboxylic acid (6- 481 .1/483.1 [M-H]-; t bromo-pyridinyl)-amide (f): 1.38 min. 1-{2-[(1 R,3S,5R)(2-Fluoro (1,4) 419.2 [M+H]+, trifluoromethoxy- 436.2 [M+NH ]+, phenylcarbamoyl)methyl 4 737 417.2 [M-H]-, 463.2 aza-bicyclo[3. 1.0]hexyl] [M+HCOO]-; t (f): hyl}-1 zole R NH 2.46 min. carboxylic acid amide 1-{2-[(1 R,3S,5R)(2-Fluoro (1,4) R oromethoxy-phenyl (CH C I /MeOH 9:1) = 2 2 carbamoyl)methylaza- 0.5; 521.2 [M+H]+, 738 bicyclo[3.1.0]hexyl]-2 1041.5 [2M+H]+, -oxo-ethyl}-1 zolo[3,4-c] 519.2 [M-H]-, 1039.5 necarboxylic acid [2M-H]-; t (f): 1.49 amide min. 1-{2-[(2S,4R)(6-Bromo- (1) R (CH C I /MeOH f 2 2 pyridinylcarbamoyl)fluoro- 9:1) = 0.5; 739 pyrrolidinyl]oxo-ethyl}-1H- 489.2/491.1 , - indazolecarboxylic acid 487.1/489.3 [M-H]-; t amide (f): 1.56 min. (1) R (CH C I /MeOH (1R,3S,5R)[2-(3-Acetyl- f 2 2 9:1) = 0.6; pyrazolo[4,3-c]pyridinyl)- 483.1/485.2 [M+H]+, 740 acetyl]aza-bicyclo[3.1 .0] 965.3/697.3 [2M+H]+, hexanecarboxylic acid (6- 481 .1/483.2 [M-H]-; t bromo-pyridinyl)-amide R (f): 1.34 min. (1) R (CH C I /MeOH 1-{2-[(1 R,3S,5R)(6-Bromo- f 2 2 9:1) = 0.6; pyrazinylcarbamoyl)aza- 501 .2/503.2 741 bicyclo[3. 1.0]hexyl]oxo- [M+NH ]+, to ethyl}-1 H-indazolecarboxylic 4 482.1/484.1 [M-H]-; t acid amide R (f): 1.51 min. (1) R (CH C I /MeOH 1-{2-[(1 R,3S,5R)(4-Bromo- f 2 2 9:1) = 0.5; thiazolylcarbamoyl)aza- 489.1/491.1 [M+H]+, 742 bicyclo[3. xyl]oxo- 11.1/513.1 [M+Na]+, ethyl}-1 H-indazolecarboxylic 487.1/489.1 [M-H]-; t acid amide R (f): 1.59 min. 1-{2-[(1 R,3S,5R)(6-Bromo- (1) R (CH C I /MeOH nylcarbamoyl)aza- f 2 2 9:1) = 0.45; G bicyclo[3. 1.0]hexyl]oxo- 743 ° , 512.2/514.2 [M+H]+, ethyl}-5,7-dimethyl-1H- 510.2/512.2 [M-H]-; t pyrazolo[3,4-c]pyridine R (f): 1.25 min. carboxylic acid amide 1-{2—[(1R,3S,5R)—3-(6—Bromo— (1,4) Rf pyridinylcarbamoy|) (CHZCIZ/MeOH 9:1) = methylaza-bicyc|o[3.1.0] 744 0.4; 4972/4992 y|]oxo-ethy|}-1H- [M+H]+, 4952/4972 le—3-carboxylic acid [M-H]—; tR (f): 1.82 min. amide (1,4) Rf 1-{2—[(1R,3S,5R)—3-(6—Bromo— (CHZCIZ/MeOH 9:1) = pyridinylcarbamoy|) 0.4; 512.2/514.2 methylaza-bicyc|o[3.1.0] 745 , 510.1/512.2 hexy|]oxo-ethy|}methyl- [M-H]—, 556.3/5582 1H-pyrazolo[3,4—c]pyridine [M+HCOO]—; tR (f): carboxylic acid amide 1.37 min. (1) R (CHZCIZ/MeOH 1-{2—[(1R,28,5S)—2—(6—Bromo- 9:1) = 0.55; pyridinylcarbamoy|)aza- 483.1/485.1 [M+H]+, 746 bicyclo[3.1.0]hexy|]oxo— 481.1/483.1 [M-H]-, ethy|}-1H-indazoIecarboxylic 527.3/529.1 acid amide [M+HCOO]—; tR (f): 1.74 min. 1-{2—[(1R,3S,5R)—3-(6—Bromo— (1) R Z/MeOH pyridinylcarbamoy|)aza- 9:1) = 0.4; bicyclo[3.1.0]hexy|]oxo— 747 500.2 [M+H]+, ethyl}-7—methy|—1H-pyrazolo 496.7/498.4 [M-H]—; tR [3,4-c]pyridinecarboxylic acid (f): 1.26 min. amide (1 R,38,5R){2—[3-AcetyI (1) R (CHZCIZ/MeOH (pyrimidinylmethoxy)- 9:1) = 0.75; indazoIy|]-acety|}aza- 590.2/5922 [M+H]+, bicyclo[3.1.0]hexane 1179.5/1181.4 carboxylic acid (6-bromo- [2M+H]+, 588.3/590.4 pyridiny|)-amide [M-H]—; 1R (f): 1.80 min. 1-{2—[(1R,3S,5R)—3-(6—Bromo— (1) R (CHZCIZ/MeOH pyridinylcarbamoy|)aza- 9:1) = 0.55; 749 bicyclo[3.1.0]hexy|]oxo— 519.1 [M+H]+, ethyl}chloro—1H-indazole—3- 515.1/517.1 [M-H]-, carboxylic acid amide 5511/5632 [M+HCOO]—; tR (f): 1.88 min. (1) R (CHZCIZ/MeOH (1 R,3S,5R)—2—[2—(3-Acetyl- 9:1) = 0.75; pyrrolo[2,3-b]pyridiny|)- 482.1/484.2 [M+H]+, 750 acety|]aza-bicyc|o[3.1 .0] 480.1/482.1 [M-H]—, hexanecarboxylic acid (6- 526.0/528.1 bromo-pyridiny|)-amide O]—; tR (f): 1.75 min. (1) R (CHZCIZ/MeOH (1 R,3S,5R)—2—[2—(3-Acetyl- 9:1) = 0.5; pyrrolo[3,2—c]pyridiny|)- 484.2 [M+H]+, 751 acety|]aza-bicyc|o[3.1 .0] 480.0/482.1 [M-H]—, hexanecarboxylic acid (6- 526.1/5282 bromo-pyridiny|)-amide [M+HCOO]—; tR (f): 1.27 min. (1 R,3S,5R)—2—[2—(5-Acetyl- (1) R (CHZCIZ/MeOH pyrro|o[2,3-c]pyridazin-7—y|)- 9:1) = 0.55; 752 acety|]aza-bicyc|o[3.1 .0] 483.2/485.1 , hexanecarboxylic acid (6- 481.1/483.1 [M-H]—; tR bromo-pyridiny|)-amide (f): 1.29 min. (1) R (CHZCIZ/MeOH 1-{2—[(1R,3S,5R)—3-(6—Bromo— 9:1) = 0.45; pyridinylcarbamoy|)aza- 482.1/484.1 [M+H]+, 753 bicyclo[3.1.0]hexy|]oxo— 499.2/501.2 ethy|}-1H-indole—3-carboxylic [M+NH4]+, acid amide 480.1/482.1 [M-H]—; tR (f): 1.64 min. 1-{2-[(28,3S,4S)(6-Bromo- pyridinylcarbamoy|)f|uoro— (wwwmwm 754 3-methoxy-pyrrolidiny|] wmhm1wwn hyI}-1H-indazole—3- Wflhm®1Mmm carboxylic acid amide (1,5) R (AcOEt) = 0.5; 1-{2-[(2S,3S,4S)(3-Bromo 553.2/555.2 fluoro-phenylcarbamoyl) [M+NH ]+, 755 fluoromethoxy-pyrrolidin 534.2/536.1 [M-H]-, yl]oxo-ethyl}-1 H-indazole 580.1/582.2 ylic acid amide [M+HCOO]-; t (f): 1.76 min. (1,5) R (AcOEt) = 0.9; (2S,3S,4S)[2-(3-Acetyl- f 518.2/520.1 [M+H]+ indazolyl)-acetyl]fluoro 516.1/518.1 [M-H]- 756 methoxy-pyrroIidine 562.2/564.2 ylic acid (6-bromo- [M+HCOO]-; t (f): pyridinyl)-amide R 1.92 min. (1) R (CH C I /MeOH f 2 2 (1R,3S,5R)[2-(3-Acetyl- 9:1) = 0.85; indazolyl)-acetyl]aza- 483.1/485.1 [M+H]+, 757 bicyclo[3. xane 500.2/502.2 carboxylic acid (6-bromo- [M+NH ]+, pyrazinyl)-amide 481 .1/483.1 [M-H]-; t (f): 1.91 min. ( 1) The acid derivative used is step C was prepared as described in Part A ; (2) The amine derivative used in step A was prepared as described in Part C ; (3) Step C was performed using T3P and DIPEA as described in Scheme D8 Step C ; (4) The acid derivative used is step A was prepared as described in Part B ; (5) The title compound was prepared according to the general procedure described in Scheme D 11 steps B and C starting from the tuted proline derivative prepared as described in Part B.
Example 758: 1-{2-[(1 R,3S,5S)(2-Fluorotrif luoromethoxy-phenylcarbamoyl) hydroxymethylaza-bicyclo[3.1 yl]oxo-ethyl}-1 H-indazolecarboxylic acid amide A solution of (3-carbamoyl-indazolyl)-acetic acid ( 1 R,3S,5S)[2-(3-carbamoyl-indazol yl)-acetyl](2-fluorotrifluoromethoxy-phenylcarbamoyl)aza-bicyclo[3.1.0]hexylmethyl ester (69.2 mg, 0.085 mmol) and NaOH ( 1 N , 188 m I_ , 0.19 mmol) in THF (0.45 mL) and water (43 m I_) was stirred at RT 1 h . Water and EtOAc were added, the layers were separated and the s one extracted with EtOAc (x2). The combined c extracts were dried (Na2S0 4) , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 mhi , 30x100 mm, eluent: 20% to 100% CH3CN in H20 in 25 min, C H3C I and H20 containing 0.1% TFA, flow: 40 mL/min). Rf, TLC (CH2C I2/MeOH 9:1) = 0.45; MS (UPLC/MS): 536.4 [M+H]+, 553.3 [M+NH 4]+, 558.2 [M+Na]+, 534.3 [M-H]-, 580.3 [M+HCOO]-; tR (HPLC ions f): 1.82 min. (3-Carbamoyl-indazolyl)-acetic acid (1R,3S,5S)r2-(3-carbamoyl-indazolyl)-acetvn- luorotrifluoromethoxy-phenylcarbamoyl)aza-bicvclor3.1.01hexylmethyl ester To a mixture of (3-carbamoyl-indazolyl)-acetic acid (prepared as described in Scheme A25, 4 1 mg, 0.18 mmol, 2 eq.), (1R,3S,5S)hydroxymethylaza-bicyclo[3.1.0]hexane carboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide hydrochloride (prepared as described in Scheme B29, 5 1 mg, 0.09 mmol, 1 eq.), and HBTU (106 mg, 0.28 mmol) in DMF (0.45 mL) was added DIPEA (64 m , 0.37 mmol). The reaction mixture was stirred at RT for 30 min, then poured into water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2S0 ) , filtered and concentrated. The material thus obtained was used in the next step without further purification. MS (UPLC/MS): 737.3 [M+H]+, 759.3 [M+Na]+, 735.2 [M-H]-; tR (HPLC conditions f): 2.03 min.
Example 759: 1-{2-[(1R,3S,5S)(3-Bromofluoro-phenylcarbamoyl)hydroxymethyl - 2-aza-bicyclo[3.1 .0]hexyl]oxo-ethyl}-1 H-indazolecarboxylic acid amide was ed using the protocols described for the preparation of Example 758 using 3- bromofluoro-phenylamine instead of 2-fluorotrifluoromethoxy-phenylamine. Rf, TLC (CH2C I2/MeOH 9:1) = 0.45; MS (UPLC/MS): 549.2 [M+NH 4]+, 552.2/554.1 +, 1081 .3/1083.3 [2M+Na]+, 574.3/576.0 [M+HCOO]-, 1057.3/1059.3 [2M-H]-; tR (HPLC conditions ) 1.62 min.
Example 760: 1-{2-[(1 S)(6-Bromo-pyridinylcarbamoyl)hydroxymethyl aza-bicyclo[3.1 .0]hexyl]oxo-ethyl}-1 H-indazolecarboxylic acid amide was prepared using the protocols described for the preparation of Example 758 using 6- bromo-pyridinylamine instead of 2-fluorotrifluoromethoxy-phenylamine. R , TLC (CH C I /MeOH 9 :1) = 0.4; MS MS) : 5 13.2/51 5.2 [M+H]+, 530.3/532.2 [M+N H ]+, 2 2 4 535.3/537.2 [M+Na]+; t (HPLC conditions f): 1.47 min.
Example 761 : ( 1 R,3S,5S)[2-(1 -Acetyl-imidazo[1 ,5-a]pyridinyl)-acetyl]hydroxy clo[3.1.0]hexanecarboxylic acid 3-chlorofluoro-benzylamide was ed using the ols bed for the preparation of Example 758 from ( 1 R,3S,5S)(3-chlorofluoro-benzylcarbamoyl)hydroxymethylaza-bicyclo[3. 1.0]- hexanecarboxylic acid tert-butyl ester (prepared as described in Scheme B28) and ( 1- acetyl-imidazo[1 ,5-a]pyridinyl)-acetic acid (prepared as described in Scheme A 19) . R , TLC (CH C I /MeOH 9 :1) = 0.40; MS (UPLC/MS): 499.4/501 .4 [M+H]+, 521 .4/523.4 [M+Na]+, 2 2 543.5/545.5 [M+HCOO]-; t (HPLC conditions f) : 1.66 min.
Example 762: ( 1R,3S,5R)Aza-bicyclo[3. 1.0]hexane-2,3-dicarboxylic acid 3-[(6-bromo - e] 2-[(1 -carbamoyl-1 H-indolyl)-amide] To a solution of ((1 R,3S,5R)aza-bicyclo[3. 1.0]hexanecarboxylic acid (6-bromo-pyridin ide (2 TFA salt, 40 mg, 0.08 mmol) and Et N (44 m I, 0.31 mmol) in THF (0.4 mL) was added a suspension of 3-isocyanato-indole-1 -carboxylic acid amide (25 mg, 0.08 mmol , prepared as described in Scheme A 1) in THF (0.8 mL) . The resulting on was d at RT under nitrogen for 45 min, concentrated and purified by preparative HPLC (Waters SunFire C 18-ODB, 5 [Jim , 19x50 mm, 20-1 00% CH CN/H 0 in 25 min, CH CN and H 0 both 3 2 3 2 containing 0 .1 % TFA flow: 40 mL/min) to give the desired material after neutralization (saturated aqueous solution of NaHC0 ) and extraction of the purified fractions (CH C I ) . TLC, 3 2 2 R (CH C I /MeOH 9:1) = 0.45; MS (LC/MS): 483.1/485.2 [M+H]+, 965.3/967.3 [2M+H]+, f 2 2 481.1/483.1 ; t (HPLC conditions f): 1.83 min.
Example 763: ,5S)Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid bromoe ] 3-[(1 -carbamoyl-1 H-indolyl)-amide] was prepared using the ol described for the synthesis of Example 762; TLC, R (CH C I /MeOH 9:1) = 0.55; 483.1/485.1 [M+H]+, 965.3/967.3 [2M+H]+, 481 .1/483.2 [M-H]-; t 2 2 R (HPLC conditions f): 1.72 min.
Example 764: (2S,4R)Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(6-bromo-pyridin yl)-amide] 1-[(1 moyl-1 H-indolyl)-amide] was prepared using the protocol described for the synthesis of Example 762; TLC, R (CH C I /MeOH 9:1) = 0.45; 489.1/491 . 1 [M+H]+, 506.1/508.2 [M+NH ]+, 487.1/489.1 [M-H]-; t 2 2 4 R (HPLC conditions f): 1.70 min.
Scheme D12: general protocol described for the preparation of Example 765: (S) ({(1R,3S,5R)r2-(3-Acetyl-pyrazolor3,4-blpyridinyl)-acetvnaza-bicvclor3.1.01 hexanecarbonyl)-amino)cvclohexyl-propionic acid ethyl ester (1R,3S,5R)[2-(3-Acetyl-pyrazolo[3,4-b]pyridinyl)-acetyl]aza-bicyclo[3.1.0]hexane carboxylic acid (20 mg, 0.061 mmol, prepared as described in Scheme B30), (S)amino cyclohexyl-propanoic acid ethyl ester (17.3 mg, 0.073 mmol) and HBTU (34.7 mg, 0.091 mmol) were dissolved in DMF (0.2 mL). DIPEA (32 m I, 0.18 mmol) was added and the reaction mixture was stirred at 25°C for 20 h . The crude material was purified by preparative HPLC (XBridge C180DB, 5 m , 30x100, eluent: 20% CH CN/ 80% H 0 to 100% CH CN in 12 min, 3 2 3 CH CN and H 0 containing 7.3 mM of NH , flow 45 mL/min). The pure fractions were 3 2 3 combined and lyophilized to give the desired material as a white powder. MS: 510.1 [M+H]+, 532.0 +; t (HPLC conditions I): 3.42 min.
The examples below were prepared ing to the general procedures described in Scheme D12 for e 765 using commercially available building , if not otherwise stated: Table 1 1 : ( 1) The reaction was performed at 40°C, (2) The acid derivative used as starting material was prepared according to Scheme B31 .
Example 769: ( 1R,3S,5R)[2-(3-Acetyl-pyrazolo[3,4-b]pyridin-1 -yl)-acetyl]azaecarboxylic acid (4-trifluoromethyl-pyrimidinyl)-amide To a solution of ( 1 R,3S,5R)[2-(3-acetyl-pyrazolo[3,4-b]pyridinyl)-acetyl]aza- bicyclo[3.1 .0]hexanecarboxylic acid (50 mg, 0.15 mmol, ed as described in part B) in CH C I (3 mL) was added 1-chloro-N,N,2-trimethylpropenamine (81 mg, 0.609 mmol) at 2 2 0°C under en atmosphere. After stirring at 0°C for 1h, 4-(trifluoromethyl)pyrimidin amine (27.3 mg, 0.17 mmol) followed by DIPEA (0.053 ml, 0.305 mmol) were added and the mixture was stirred at RT for 16 h . The mixture was trated and the residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5um, 30x100mm, flow: 40 , gradient: 0-18.5 min 5% to 100% CH CN, 18.5-20 min 100% CH CN, H 0 and CH CN containing 0.1% 3 3 2 3 TFA). The pure fractions were combined, neutralized with an aqueous saturated solution of Na C0 , ted with EtOAc, dried (Na S0 ) , filtered and concentrated. MS (UPLC-MS): 2 3 2 4 474.3 [M+H]+, 472.3 [M-H]-; t (HPLC conditions ) : 1.81 min.
Scheme D13: general protocol described for the preparation of Example 770: (1R,3S,5R)f2-r3-Acetyl(2-methoxy-ethoxy)-indazolvn-acetylV2-azabicycloP.1 .01hexanecarboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide A. ( 1R,3S,5R)[2-(3-Acetylbenzyloxy-indazol-1 -yl)-acetyl]aza-bicyclo[3.1 .0] hexanecarboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide To a solution of tylbenzyloxy-indazolyl)-acetic acid (1.38 g , 4.30 mmol, prepared as described in Part A), ( 1 R,3S,5R)aza-bicyclo[3.1 anecarboxylic acid (2-fluoro trifluoro methoxy-phenyl)-amide trifluoroacetate ( 1 .80 g , 4.30 mmol) and propylphosphonic anhydride (50% in EtOAc, 3.80 ml, 6.46 mmol) in CH C I (40 ml) was added DIPEA (2.25 mL, 2 2 12.91 mmol) and the resulting mixture was d at RT for 2 h . The mixture was concentrated and the crude residue was purified by flash column chromatography on silica gel (c- hexane/EtOAc 1:0 to 0:1). MS (UPLC-MS): 6 11 ; t (HPLC conditions ) : 2.40 min.
B. (1R,3S,5R)[2-(3-Acetylhydroxy-indazolyl)-acetyl]aza-bicyclo[3.1.0]hexane carboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide A mixture of (1R,3S,5R)[2-(3-acetylbenzyloxy-indazolyl)-acetyl]azabicyclo [3.1.0]hexanecarboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide (2.0 g , 3.28 mmol) and Pd/C (10%, 165 mg) in MeOH (40 mL) was stirred under a H atmosphere for 1 h .
The mixture was filtered through a celite pad and concentrated. The product was used in the next step without further purification. MS (UPLC-MS): 521 [M+H]+; t (HPLC conditions ) : 2.02 min.
C. Example 770: (1R,3S,5R){2-[3-Acetyl(2-methoxy-ethoxy)-indazolyl]-acetyl} cyclo [3.1.0]hexanecarboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide To a suspension of sodium hydride (60% in Mineral oil, 4.8 mg, 0.121 mmol) in DMF (5 mL) at 0°C was added 1R,3S,5R)[2-(3-acetylhydroxy-indazolyl)-acetyl]azabicyclo [3.1 .0]hexanecarboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide (60 mg, 0.1 15 mmol). After stirring for 5 min, 1-bromomethoxyethane (0.016 mL, 0.173 mmol) was added and the reaction mixture was stirred at RT for 16 h . The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na S0 , filtered and 2 4 concentrated. The crude residue was ed by preparative HPLC s Sunfire C18-ODB, 5um, 30x100mm, flow: 40 mL/min, gradient: 0-18.5 min 5% to 100% CH CN, 18.5-20 min 100% CH CN, H 0 and CH CN containing 0.1% TFA). r purification by flash 3 2 3 chromatography on silica gel (c-hexane/EtOAc 1:0 to 0:1) afforded the title nd. MS (UPLC-MS): 579.3. t (HPLC conditions ) : 2.07 min.
Example 771 : ( 1R,3S,5R){2-[3-Acetyl(cyano-methyl-methoxy)-indazol-1 -yl]-acetyl}- 2-aza-bicyclo[3.1 .0]hexanecarboxylic acid (2-fluorotrifluoromethoxy-phenyl)-amide was prepared using the protocol described for the synthesis of e 770 in Scheme A13.
The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 0:1). MS MS): 572.2 [M-H]-; t (HPLC conditions ) : 2.15 min.
Example 772: (1R,3S,5R){2-[3-Acetyl(tetrahydro-furanylmethoxy)-indazolyl]- acetyl}aza-bicyclo[3.1 .0]hexanecarboxylic acid (2-fluorotrifluoromethoxy- was prepared using the protocol described for the synthesis of Example 770 in Scheme D13 with the following ure for Step C. To a suspension of sodium hydride (60% in Mineral oil, 4.8 mg, 0.121 mmol) in DMF (5 ml_) at 0°C was added 1R,3S,5R)[2-(3-acetylhydroxyindazolyl )-acetyl]aza-bicyclo[3.1 .0]hexanecarboxylic acid (2-fluorotrifluoromethoxyphenyl )-amide (60 mg, 0.1 15 mmol). After stirring for 5 min, 2-(bromomethyl)tetrahydrofuran (28.5 mg, 0.173 mmol) was added and the reaction e was stirred at RT for 16 h .
Additional portions of NaH (60% in Mineral oil, 4.6 mg, 0.1 15 mmol) and 2-(bromomethyl) tetrahydrofurane (19.0 mg, 0.1 15 mmol) were added and the resulting mixture was d at RT for 16 h . The reaction mixture was ed with water and extracted with EtOAc. The organic layer was dried over Na S0 , filtered and concentrated. The crude residue was purified 2 4 by preparative HPLC (Waters Sunfire C18-ODB, 5um, 30x100mm, flow: 40 mL/min, gradient: 0-18.5 min 5% to 100% CH CN, 18.5-20 min 100% CH CN, H 0 and CH CN containing 0.1% 3 3 2 3 TFA). MS (UPLC-MS): 605.4. t (HPLC conditions ) : 2.20 min.
Scheme D14: general protocol described for the preparation of Example 773: (2R,3S,4S)r2-(3-Acetyl-indolyl)-acetvn-3,4-difluoro-pyrrolidinecarboxylic acid 3- A. (3S,4S)-3,4-Difluoro-pyrrolidine To a on of (3S,4S)-3,4-Difluoro-pyrrolidinecarboxylic acid benzyl ester (ACS Scientific Inc., cat # 6-051 1 , 3 g , 12.44 mmol) in MeOH (41 mL) was added Pd/C 10 % (500 mg) and the solution was degassed 3 times ing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for 3 days. After completion, the solution was degassed 3 times replacing hydrogen by nitrogen and the catalyst was d through a pad of Celite. The ing solution of volatil (3S,4S)-3,4-difluoropyrrolidine in MeOH (approx. 0.209 mol/L) was stored in the fridge and used t further treatment in the next step. R (EtOAc): 0.1 .
B. (3S,4S)-3,4-difluoro-3,4-dihydro-2H-pyrrole To a solution of (3S,4S)-3,4-difluoro-pyrrolidine (0.209 M in MeOH, 2.5 ml_, 0.52 mmol) in a flask protected with an aluminium sheet at 0°C under argon was added tBuOCI (73 m I_ , 0.52 mmol). The reaction mixture was stirred at 0°C for 1 h ; until TLC (CH C I /MeOH 9:1) indicated 2 2 consumption of the starting material. DBU (79 m I_ , 0.52 mmol) was then added at 0°C to the resulting solution of (3S,4S)chloro-3,4-difluoro-pyrrolidine and the mixture was allowed to reach RT and further stirred for 3 h . The solution thus obtained was used in the next step.
C. Example 773: (2R,3S,4S)[2-(3-Acetyl-indolyl)-acetyl]-3,4-difluoro-pyrrolidine carboxylic acid 3-chlorofluoro-benzylamide To the crude solution of (3S,4S)-3,4-difluoro-3,4-dihydro-2H-pyrrole (0.52 mmol) in MeOH under argon were successively added (3-acetyl-indolyl)-acetic acid (57 mg, 0.26 mmol) and rofluoro(isocyanomethyl)benzene (44 mg, 0.26 mmol) in MeOH (0.2 ml_). The reaction mixture was d at RT for 60 h and poured into a ted aqueous solution of NaHC0 and extracted with CH C I (x2). The combined organic extracts were dried (Na S0 ) , 3 2 2 2 4 filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (Gold RediSep column, 24 g , CH C I to CH C I / MeOH 95-5), the fractions containing 2 2 2 2 the desired material as a mixture of 2 diastereosiomers were concentrated and the residue was purified again by preparative HPLC (Waters Sunfire C18-OBD, 5 mhi , 30x100 mm, eluent: % to 100% CH CN in H 0 in 25 min, CH CN and H 0 ning 0.1 % TFA, flow: 40 3 2 3 2 mL/min) to give (2S,3S,4S)[2-(3-acetyl-indolyl)-acetyl]-3,4-difluoro-pyrrolidine carboxylic acid rofluoro-benzylamide: R (EtOAc): 0.60; MS (UPLC): 492.2/494.2 [M+H]+, 536.2/538.2 O]- and (2R,3S,4S)[2-(3-acetyl-indolyl)-acetyl]-3,4-difluoropyrrolidinecarboxylic acid 3-chlorofluoro-benzylamide; R (EtOAc): 0.50; MS (UPLC): 492.2/494.2 [M+H]+, 536.2/538.2 [M+HCOO]-; t (HPLC conditions a): 3.37 min. The absolute stereochemistry has been assigned tentatively based on comparison of H-NMR spectra and test results in the biological assay measured for both diastereosiomers. 1H NMR and HRMS data for selected compounds: H NMR a were recorded using a Bruker Avance DPX 400 and I I 600 Spectrometers.
Example 1: H NMR (400 MHz, DMSO- ) d (ppm): 8.65 (t, 1H), 8.35 (s, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.74 (d, 1H), 7.34 - 7.54 (m , 4H), 7.26 (m, 1H), 7.08 - 7.21 (m, 2H), 5.51-5.38 (m, 1H), 4.55 (t, 1H), 4.27 - 4.46 (m, 2H), 3.92 - 4.07 (m, 1H), 3.89-3.96 (m, 1H), 2.5 (m, 1H), 1.97 - 2.19 (m, 1H).
Example 26: H NMR (400 MHz, DMSO- ) d (ppm): 8.28 (m, 2H), 8.20 (s, 1H), 7.98 (s, 1H), 7.72 (d, 1H), 7.34 - 7.57 (m, 4H), 7.26 (t, 1H), 7.06 - 7.23 (m, 2H), 4.24 - 4.52 (m, 3H), 3.82 (dd, 1H), 3.69 (m, 1H), 3.53 (dd, 1H), 2.4 (m, 1H), 1.78 (m, 1H).
Example 73: HRMS: 497.2294 [M+H]+ (calcd 497.2296 for CzsHzsNeOs).
Example 107: H NMR (400 MHz, DMSO- ) d (ppm) : 8.19 - 8.34 (m, 2H), 7.98 (s, 2H), 7.69 - 7.86 (m, 4H), 7.64 (t, 1H), 7.41 (br.s, 2H), 7.26 (t, 1H), 7.18 (t, 1H), .30 (m , 1H), 4.16 (m, 1H), 3.93 (m, 1H), 3.49 - 3.76 (m, 1H), 3.18 (m, 1H), 3.03 (m , 1H), 2.29 (m, 1H), 1.94 - 2.20 (m, 1H). e 124: HRMS: 476.1539 [M+H]+ (calcd 476.1540 for C22H20F3N5O4) , 498.1358 [M+Na]+ (calcd 498.1360 for C22H2oF3N50 4Na), 493.1805 [M+NH 4]+ (calcd 493.1806 for C22H2oF3N50 4NH4) ; tR (HPLC conditions a) 3.46 min.
Example 133: H NMR (400 MHz, DMSO- ) d (ppm) : 8.42 - 8.56 (m, 2H), 8.18 (d, 1H), 8.01 (s, 1H), 7.29 - 7.53 (m, 5H), 7.16 (t, 1H), 6.93 (dd, 1H), 4.75 (dd, 2H), 4.23 - 4.46 (m, 1H), 4.16 (dd, 1H), 3.81 (m, 1H), 3.71 (s, 3H), 2.34 (m, 1H), 2.10 (m, 1H), 1.80 (m, 1H), 0.84 (m, 1H), 0.56 (m, 1H).
Example 134: HRMS: 488.1539 [M+H]+ (calcd 488.1540 for C H oF NsO , 510.1358 [M+Na]+ (calcd 510.1360 for C H oF NsC Na) , 505.1805 [M+NH 4]+ (calcd 505.1806 for e 136: H NMR (400 MHz, DMSO-d 6) d (ppm) : 8.38 - 8.54 (m, 2H), 8.17 (d, 1H), 7.99 (s, 1H), 7.46 (t, 1H), 7.25 - 7.42 (m, 4H), 7.16 (t, 1H), 6.89 (dd, 1H), 4.23 - 4.46 (m, 2H), 4.16 (dd, 1H), 3.83 (m, 1H), 3.78 (s, 3H), 2.33 (dd, 1H), 2.09 (m , 1H), 1.78 (m, 1H), 0.84 (m , 1H), 0.56 (m, 1H).
Example 141 : HRMS: 488.1539 [M+H]+ (calcd 488.1540 for CzsHzoFsNsO^, 510.1358 [M+Na]+ (calcd 510.1360 for C 23H N40 .
Example 148: H NMR (400 MHz, DMSO-d 6) d (ppm): 10.07 (s, 1H), 8.64 (s, 1H), 8.27 (d, 1H), 8.00 (s, 2H), 7.80 (d, 1H), 7.49 - 7.59 (m, 1H), 7.38 (br.s, 2H), 7.1 1 - 7.30 (m , 4H), 4.18 (t, 1H), 3.88 - 3.97 (m, 1H), 2.29 - 2.41 (m, 1H), 2.08 - 2.21 (m, 1H), 1.74 - 1.88 (m, 1H), 0.77 - 0.89 (m, 1H), 0.50 - 0.65 (m , 1H).
Example 155: H NMR (400 MHz, DMSO- ) d (ppm): 8.55 (m, 2H), 8.28 (d, 1H), 8.00 (s, 1H), 7.79 (d, 1H), 7.43 (br.s, 2H), 7.27 (t, 1H), 7.19 (t, 1H), 6.94 (d, 1H), 6.84 (d, 1H), 4.35 (m, 1H), 4.14 (dd, 1H), 3.80 (m, 1H), 2.30 (dd, 1H), 2.09 (m, 1H), 1.77 (m, 1H), 0.84 (m , 1H), 0.54 (m , 1H).
Example 158: H NMR (400 MHz, DMSO-d 6) d (ppm): 10.16 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.92 (d, 1H), 7.80 (d, 1H), 7.70 (t, 1H), 7.40 (br.s, 2H), 7.23 - 7.32 (m, 1H), 7.20 (t, 1H), 6.99 (d, 1H), 4.38 (t, 1H), 3.93 (m, 1H), 2.68 (q, 2H), 2.39 (m, 1H), 2.19 (m, 1H), 1.80 (m, 1H), 1.22 (t, 3H), 0.84 (m, 1H), 0.54 (m, 1H).
Example 166: H NMR (400 MHz, DMSO- ) d (ppm): 8.57 (s, 1H), 8.46 (t, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.79 (d, 1H), 7.39 - 7.55 (m, 3H), 7.35 (t, 1H), 7.27 (m, 1H), 7.18 (m, 2H), 4.25 - 4.48 (m, 2H), 4.17 (dd, 1H), 3.83 (m, 1H), 2.33 (dd, 1H), 2.1 1 (m, 1H), 1.79 (m, 1H), 0.85 (m, 1H), 0.56 (m, 1H). e 170: H NMR (400 MHz, DMSO- ) d (ppm): 8.49 (t, 1H), 8.25 (d, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.72 (d, 1H), 7.36 - 7.54 (m, 3H), 7.33 (t, 1H), 7.23 (t, 1H), 7.12 (m, 2H), 4.20- 4.49 (m, 3H), 3.69 (m, 1H), 3.53 (m, 1H), 2.13 (m, 1H), 1.73-2.02 (m, 3H).
Example 175: H NMR (400 MHz, DMSO-d 6) d (ppm): 9.98 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 7.91 - 8.04 (m, 2H), 7.80 (d, 1H), 7.43 (br.s, 2H), 7.24 - 7.36 (m, 3H), 7.20 (t, 1H), 4.40 (dd, 1H), 3.84 - 3.96 (m, 1H), 2.31 - 2.43 (m, 1H), 2.17 - 2.27 (m, 1H), 1.77 - 1.88 (m, 1H), 0.81 - 0.92 (m, 1H), 0.53 - 0.64 (m, 1H).
Example 176: H NMR (400 MHz, DMSO-d 6) d (ppm): 9.88 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.88 (t, 1H), 7.80 (d, 1H), 7.43 (br.s, 2H), 7.16 - 7.37 (m, 4H), 4.35 - 4.44 (m, 1H), 3.87 - 3.95 (m, 1H), 2.32 - 2.43 (m, 1H), 2.16 - 2.27 (m, 1H), 1.78 - 1.87 (m, 1H), 0.82 - 0.91 (m, 1H), 0.55 - 0.63 (m, 1H).
Example 178: H NMR (400 MHz, DMSO- ) d (ppm): 8.65 (br.s, 1H), 8.50 (br.s, 1H), 8.26 (d, 1H), 7.97 (br.s, 1H), 7.71 (d, 1H), 6.99 - 7.57 (m, 7H), 5.54 (br.s, 1H), 4.17 - 4.50 (m, 2H), 4.00 (br.s, 2H), 3.20 (br.s, 2H).
Example 181 : H NMR (400 MHz, DMSO-d 6) d (ppm): 8.65 (t, 1H), 8.34 (br.s, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.76 (d, 1H), 7.41 - 7.55 (m, 3H), 7.37 (t, 1H), 7.26 (t, 1H), 7.04 - 7.21 (m, 2H), 5.36 (t, 1H), 4.59 (t, 1H), 4.37 - 4.49 (m, 1H), 4.21 - 4.37 (m, 1H), 3.81 - 3.94 (m, 1H), 3.53 - 3.81 (m, 3H), 2.34-2.40 (m, 1H), 1.97 - 2.18 (m, 1H).
Example 183: H NMR (400 MHz, DMSO- ) d (ppm): 8.56 (s, 1H), 8.45 (t, 1H), 8.28 (d, 1H), 8.02 (s, 1H), 7.80 (d, 1H), 7.44 (m, 2H), 7.22 - 7.38 (m, 5H), 7.18 (t, 1H), 4.30 (m, 1H), 4.17 (dd, 1H), 3.82 (m, 1H), 2.33 (dd, 1H), 2.12 (m, 1H), 1.78 (br.s, 1H), 0.86 (m, 1H), 0.56 (dt, 1H).
Example 184: H NMR (400 MHz, DMSO-d 6) : 8.54 (s, 1H), 8.47 (m, 1H), 8.28 (d, 1H), 8.01 (s, 1H), 7.81 (d, 1H), 7.47 (t, 1H), 7.44 (m, 2H), 7.36 (t, 1H), 7.27 (t, 1H), 7.18 (t, 2H), 4.36 (m, 2H), 4.23 (m, 1H), 3.77 (m, 1H), 3,45 (d, 1H), 3.36 (d, 1H), 3.29 (s, 3H), 2.39 (dd, 1H), 2.10 (dd, 1H), 0.95 (m, 1H), 0.82 (m, 1H).
Example 186: H NMR (400 MHz, DMSO- ) d (ppm): 8.47 (t, 1H), 8.27 (d, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.73 (d, 1H), 7.34 - 7.52 (m, 4H), 7.26 (t, 1H), 7.09 - 7.20 (m, 2H), 4.59 (d, 1H), 4.27 - 4.47 (m, 2H), 4.1 1 - 4.19 (m, 1H), 3.72 - 3.82 (m, 1H), 3.50 - 3.61 (m, 1H), 3.34 (s, 3H), 2.03 - 2.23 (m, 2H).
Example 190: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.56 (t, 1H), 8.37 (s, 1H), 8.28 (d, 1H), 8.02 (s, 1H), 7.80 (d, 1H), 7.33 - 7.52 (m, 4H), 7.26 (t, 1H), 7.10 - 7.20 (m, 2H), 5.32 - 5.58 (m, 1H), 4.59 - 4.71 (m, 1H), 4.30 - 4.48 (m, 2H), 3.81 - 3.91 (m, 1H), 3.69 - 3.79 (m, 1H), 2.15 - 2.32 (m, 2H).
Example 194: H NMR (400 MHz, DMSO-d 6) d (ppm): 10.63 (s, 1H), 8.68 (d, 1H), 8.45 (s, 1H), 8.39 - 8.43 (m, 2H), 8.26 (d, 1H), 7.97 (s, 1H), 7.76 (d, 1H), 7.41 (br.s, 2H), 7.25 (t, 1H), 7.17 (t, 1H), 5.51 (d, 1H), 4.55 - 4.68 (m, 1H), 3.74 - 4.14 (m, 2H), 2.53 - 2.64 (m, 1H), 2.04 - 2.28 (m, 1H).
Example 195: H NMR (400 MHz, DMSO- ) d (ppm): 8.56 (s, 1H), 8.45 (t, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.79 (d, 1H), 7.44 (br.s, 2H), 7.23 - 7.36 (m, 2H), 7.1 1 - 7.23 (m, 3H), 4.27 - 4.48 (m, 2H), 4.18 (dd, 1H), 3.81 (m, 1H), 2.33 (dd, 1H), 2.12 (m, 1H), 1.78 (m, 1H), 0.87 (m, 1H), 0.56 (m, 1H).
Example 200: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.52 (m, 1H), 8.23 (m, 2H), 7.97 (s, 1H), 7.75 (d, 1H), 7.28 - 7.51 (m, 4H), 7.22 (t, 1H), 7.04 - 7.18 (m, 2H), 4.32 - 4.50 (m, 2H), 4.18 - 4.32 (m, 1H), 3.96 (t, 1H), 3.80 (t, 1H), 3.61 (s, 3H), 3.31 (m, 2H), 2.08 (m, 1H).
Example 203: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.53 (s, 1H), 8.19 - 8.33 (m, 2H), 7.95 (s, 1H), 7.74 (d, 1H), 7.34 - 7.52 (m, 4H), 7.27 (t, 1H), 6.96 - 7.23 (m, 2H), 5.12 (m, 1H), 5.02 (t, 1H), 4.24 (dd, 1H), 3.79 (m, 1H), 3.58 (m, 2H), 2.21 - 2.31 (m, 1H), 2.07 - 2.17 (m, 1H), 1.77 (m, 1H), 0.85 (m, 1H), 0.53 (m, 1H). e 205: H NMR (400 MHz, DMSO- ) d (ppm): 8.65 (t, 1H), 8.32 (s, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.75 (d, 1H), 7.32 - 7.57 (m, 4H), 7.26 (t, 1H), 7.06 - 7.21 (m, 2H), 4.57 (t, 1H), 4.38 - 4.50 (m, 1H), 4.23 - 4.38 (m, 1H), 3.97 (dd, 1H), 3.61 - 3.80 (m, 1H), 2.4 (m, 1H), 1.86 - 2.14 (m, 1H), 1.57 (d, 3H).
Example 208: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.87 (t, 1H), 8.24 - 8.32 (m, 2H), 7.99 (s, 1H), 7.73 (d, 1H), 7.38 - 7.52 (m, 3H), 7.31 - 7.37 (m, 1H), 7.23 - 7.30 (m, 1H), 7.1 1 - 7.20 (m, 2H), 5.13 - 5.36 (m, 1H), 4.62 - 4.74 (m, 1H), 4.29 - 4.45 (m, 2H), 3.87 - 3.97 (m, 1H), 3.60 - 3.72 (m, 1H), 2.07 - 2.36 (m, 2H).
Example 210: H NMR (400 MHz, DMSO- ) d (ppm): 8.41 (t, 1H), 8.27 (d, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.74 (d, 1H), 7.45 (m, 4H), 7.25 (t, 1H), 7.15 (m, 2H), 4.37 - 4.49 (m, 2H), 4.25 - 4.37 (m, 1H), 3.93 (d, 1H), 3.64 (dd, 1H), 1.91 (m, 1H), 1.78 (m, 1H), 0.73 (q, 1H), 0.63 (m, 1H).
Example 213: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.24 - 8.33 (m, 2H), 8.08 (s, 1H), 7.99 (s, 1H), 7.73 (d, 1H), 7.53 (t, 1H), 7.37 - 7.48 (m, 3H), 7.26 (t, 1H), 7.16 (t, 1H), 7.08 (t, 1H), .35 (d, 1H), 4.30 - 4.52 (m, 4H), 3.74 - 3.84 (m, 1H), 3.50 - 3.60 (m, 1H), 1.96 - 2.16 (m, 2H).
Example 216: H NMR (400 MHz, DMSO- ) d (ppm): 8.53 (s, 1H), 8.46 (t, 1H), 7.88 (m, 2H), 7.68 (d, 1H), 7.27 - 7.57 (m, 4H), 7.18 (t, 1H), 6.83 (dd, 1H), 4.22 - 4.47 (m, 2H), 4.16 (dd, 1H), 3.79 (m, 4H), 2.32 (m, 1H), 2.02 - 2.17 (m, 1H), 1.77 (m, 1H), 0.84 (m, 1H), 0.54 (m, 1H).
Example 218: H NMR (400 MHz, DMSO-d 6) d (ppm): 10.00 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 8.17 - 8.25 (m, 1H), 8.00 (s, 1H), 7.80 (d, 1H), 7.34 - 7.57 (m, 4H), 7.23 - 7.31 (m, 1H), 7.16 - 7.23 (m, 1H), 4.34 - 4.46 (m, 1H), 3.85 - 3.95 (m, 1H), 2.31 - 2.43 (m, 1H), 2.19 - 2.29 (m, 1H), 1.77 - 1.88 (m, 1H), 0.81 - 0.92 (m, 1H), 0.55 - 0.64 (m, 1H).
Example 223: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.52 (s, 1H), 8.34 (d, 1H), 8.27 (d, 1H), 7.95 (s, 1H), 7.74 (d, 1H), 7.48 - 7.41 (m, 4H), 7.27 (t, 1H), 7.22 - 7.16 (m, 2H), 5.19 (m, 1H), 4.18 (dd, 1H), 3.79 (m, 1H), 3,40 (2H under H20 signal), 2.28 (dd, 1H), 2.10 - 2.04 (m, 1H), 1.92 - 1.73 (m, 3H), 0.85 (m, 1H), 0.53 (m, 1H).
Example 237: H NMR (400 MHz, DMSO- ) d (ppm): 8.71 (br.s, 1H), 8.48 (s, 2H), 8.35 (s, 1H), 8.26 (d, 1H), 8.02 (s, 1H), 7.88 (br.s, 1H), 7.75 (d, 1H), 7.42 (br.s, 2H), 7.26 (t, 1H), 7.16 (t, 1H), 5.27 - 5.66 (m, 1H), 4.53 (m, 1H), 4.37 (m, 2H), 4.01 (m, 1H), 3.73 - 3.93 (m, 1H), 2.08 - 2.24 (m, 1H), 1.94 - 2.08 (m, 1H).
Example 258: H NMR (400 MHz, DMSO- ) d (ppm): 8.53 (s, 1H), 8.37 (t, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.79 (d, 1H), 7.44 (br.s, 2H), 7.15 - 7.34 (m, 5H), 4.22 - 4.39 (m, 2H), 4.20 (dd, 1H), 3.81 (m, 1H), 2.31 (m, 1H), 2.13 (m, 1H), 1.77 (m, 1H), 0.85 (m, 1H), 0.54 (td, 1H).
Example 274: H NMR (400 MHz, DMSO- ) d (ppm): 10.22 (br.s, 1H), 8.43 (br.s, 1H), 8.27 (d, 1H), 7.94 - 8.06 (m, 2H), 7.77 (d, 1H), 7.41 (br.s, 2H), 7.13 - 7.34 (m, 4H), 5.39 - 5.62 (m, 1H), 4.83 (t, 1H), 3.79 - 4.14 (m, 2H), 2.58 - 2.65 (m, 1H), 2.06 - 2.30 (m, 1H).
Example 285: HRMS: 446.2186 [M+H]+ (calcd 446.2187 for C25H27N5O3F3) , 05 [M+Na]+ (calcd 468.2006 for CzsHzyNsOsNa); H NMR (400 MHz, DMSO- ) d (ppm): 9.83 (s, 1H), 8.62 (s, 1H), 8.29 (d, 1H), 8.02 (s, 1H), 7.81 (d, 1H), 7.53 (br. s , 1H), 7.47 (d, 1H), 7.38 (br. s , 2H), 7.12 - 7.31 (m, 3H), 6.93 (d, 1H), 4.23 (t, 1H), 3.93 (br. s , 1H), 2.85 (m, 1H), 2.35 (m, 1H), 2.20 (m, 1H), 1.82 (br. s , 1H), 1.20 (d, 6H), 0.86 (br. s , 1H), 0.58 (br. s , 1H).
Example 294: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.56 (s, 1H), 8.47 (t, 1H), 8.26 - 8.32 (m, 1H), 8.09 (s, 1H), 7.61 - 7.66 (m, 1H), 7.42 - 7.58 (m, 3H), 7.35 (t, 1H), 7.08 - 7.20 (m, 2H), 4.26 - 4.45 (m, 2H), 4.13 - 4.20 (m, 1H), 3.75 - 3.82 (m, 1H), 2.28 - 2.37 (m, 1H), 2.06 - 2.15 (m, 1H), 1.74 - 1.84 (m, 1H), 0.82 - 0.90 (m, 1H), 0.52 - 0.60 (m, 1H).
Example 298: H NMR (400 MHz, DMSO-cfe): d (ppm): 10.22 (s, 1H), 8.33 (s, 1H), 8.15 (d, 1H), 7.93 - 8.05 (m, 2H), 7.22 - 7.41 (m, 5H), 6.83 - 6.91 (m, 1H), 5.39 - 5.62 (m, 1H), 4.83 (t, 1H), 3.80 - 4.13 (m, 2H), 3.78 (s, 3H), 2.54 - 2.66 (m, 1H), 2.07 - 2.29 (m, 1H).
Example 300: H NMR (400 MHz, DMSO- ) d (ppm): 8.41 - 8.49 (m, 2H), 8.16 (d, 1H), 8.00 (s, 1H), 7.46 (m, 1H), 7.27 - 7.42 (m, 4H), 7.16 (t, 1H), 6.90 (dd, 1H), 4.24 - 4.45 (m, 2H), 4.16 (dd, 1H), 3.98 - 4.13 (m, 2H), 3.84 (m, 1H), 3.67 (t, 2H), 3.32 (s, 3H), 2.35 (m, 1H), 2.05 - 2.17 (m, 1H), 1.71 - 1.86 (m, 1H), 0.86 (m, 1H), 0.55 (m, 1H).
Example 302: H NMR (400 MHz, DMSO- ) d (ppm): 8.49 (t, 1H), 8.27 (d, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.34 - 7.52 (m, 4H), 7.19 - 7.32 (m, 2H), 7.1 1 (t, 1H), 6.85 (t, 1H), 4.67 - 4.85 (m, 1H), 4.28 - 4.50 (m, 2H), 2.14 - 2.32 (m, 1H), 1.83 - 1.98 (m, 2H), 1.70 - 1.82 (m, 1H), 1.58 (s, 3H), 1.44 (s, 3H).
Example 306: 1H NMR (400 MHz, DMSO- ) d (ppm): 8.56 (s, 1H), 8.45 (t, 1H), 8.21 (d, 1H), 8.01 (s, 1H), 7.69 (s, 1H), 7.40 - 7.54 (m, 3H), 7.34 (t, 1H), 7.1 1 - 7.21 (m, 2H), 4.27 - 4.45 (m, 2H), 4.18 (dd, 1H), 4.09 (q, 2H), 3.82 (m, 1H), 3.70 (s, 2H), 2.35 (m, 1H), 2.12 (m, 1H), 1.80 (m, 1H), 1.19 (t, 3H), 0.85 (m, 1H), 0.56 (m, 1H).
Example 312: H NMR (400 MHz, DMSO- ) d (ppm): 8.50 (t, 1H), 8.27 (d, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.77 (d, 1H), 7.31 - 7.53 (m, 4H), 7.25 (t, 1H), 7.14 (m, 2H), 4.76 (t, 1H), 4.35 - 4.49 (m, 2H), 4.30 (dd, 1H), 3.83 (t, 1H), 3.37 - 3.52 (m, 3H), 2.41 (m, 1H), 2.30 (m, 1H), 1.62 (m, 1H).
Example 315: H NMR (400 MHz, DMSO- ) d (ppm): 8.55 (s, 1H), 8.46 (t, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.72 (d, 1H), 7.41 - 7.55 (m, 3H), 7.35 (m, 1H), 7.17 (t, 1H), 7.08 (dd, 1H), 4.26 - 4.46 (m, 2H), 4.17 (dd, 1H), 4.09 (q, 2H), 3.80 (m, 1H), 3.75 (s, 2H), 2.28 - 2.34 (m, 1H), 2.10 (m, 1H), 1.78 (m, 1H), 1.19 (t, 3H), 0.85 (m, 1H), 0.56 (m, 1H).
Example 331 : H NMR (400 MHz, DMSO- ) d (ppm): 8.57 (t, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.76 (d, 1H), 7.31 - 7.56 (m, 4H), 7.26 (t, 1H), 7.07 - 7.21 (m, 2H), 5.33 (d, 1H), 4.44 (dd, 1H), 4.26 - 4.40 (m, 3H), 3.76 (dd, 1H), 3.57 (dd, 1H), 2.30 - 2.42 (m, 1H), 1.82 - 1.94 (m, 1H). e 332: HRMS: 512.1350 [M+H]+ (calcd 512.1352 for C22H 18F5N50 4) , 534.1 169 [M+Na]+ (calcd 534.1 171 for C22H 18F5N50 4Na), 529.1617 [M+NH 4]+ (calcd 529.1617 for Example 333: H NMR (400 MHz, DMSO-d 6) d (ppm): 10.31 (s, 1H), 8.59 - 8.69 (m, 1H), 8.43 (s, 1H), 8.26 (d, 1H), 7.98 (s, 1H), 7.90 - 7.96 (m, 1H), 7.76 (d, 1H), 7.30 - 7.51 (m, 2H), 7.25 (t, 1H), 7.17 (t, 1H), 5.50 (d, 1H), 4.83 (t, 1H), 4.31 (q, 2H), 3.77 - 4.12 (m, 2H), 2.53 - 2.66 (m, 1H), 2.09 - 2.30 (m, 1H), 1.30 (t, 3H).
Example 334: HRMS: 488.1539 [M+H]+ (calcd 488.1540 for C H oF NsO , 510.1358 [M+Na]+ (calcd 510.1360 for CzsHzoFsNsC^Na). H NMR (400 MHz, DMSO-d 6) d (ppm): 10.22 (s, 1H), 8.66 (s, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.80 (d, 1H), 7.54 (d, 1H), 7.43 (t, 1H), 7.40 (m, 2H), 7.26 (t, 1H), 7.19 (t, 1H), 7.03 (d, 1H), 4.18 (t, 1H), 3.95 (m, 1H), 2.30 (m, 1H), 2.10 (m, 1H), 1.80 (m, 1H), 0.83 (m, 1H), 0.59 (m, 1H). e 340: H NMR (400 MHz, DMSO-d 6) d (ppm): 10.27 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 8.15 - 8.24 (m, 2H), 8.01 (s, 1H), 7.82 (d, 1H), 7.71 (s, 1H), 7.39 (br.s, 2H), 7.28 (t, 1H), 7.21 (t, 1H), 4.18 (t, 1H), 3.86 - 4.00 (m, 1H), 2.30 - 2.44 (m, 2H), 2.10 - 2.24 (m, 1H), 1.74 - 1.89 (m, 1H), 0.77 - 0.92 (m, 1H), 0.54 - 0.68 (m, 1H).
Example 343: H NMR (400 MHz, DMSO-d 6) d (ppm): 10.32 - 10.48 (m, 1H), 8.51 - 8.59 (m, 1H), 8.48 (s, 1H), 8.25 (d, 1H), 7.97 (s, 1H), 7.86 - 7.92 (m, 1H), 7.77 (d, 2H), 7.40 (br.s, 2H), 7.23 (t, 1H), 7.15 (t, 1H), 5.48 (d, 1H), 4.87 (t, 1H), 3.76 - 4.12 (m, 2H), 2.54 - 2.65 (m, 1H), 2.03 - 2.29 (m, 1H).
Example 344: H NMR (400 MHz, DMSO-d 6) d ppm 10.37 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 8.28 (d, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.82 (d, 1H), 7.40 (br. s , 2H), 7.27 (t, 1H), 7.20 (t, 1H), 4.21 (t, 1H), 3.90 - 4.01 (m, 1H), 2.41 (dd, 1H), 2.19 (dt, 1H), 1.78 - 1.91 (m, 1H), 0.86 (dt, 1H), 0.58 - 0.68 (m, 1H).
Example 350: H NMR (400 MHz, DMSO- ) d (ppm): 8.45 (t, 1H), 8.27 (d, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H), 7.37 - 7.48 (m, 3H), 7.21 - 7.33 (m, 2H), 7.14 (t, 1H), 6.99 (br.s, 1H), 4.27 - 4.57 (m, 4H), 2.26 - 2.42 (m, 1H), 2.08 - 2.23 (m, 1H), 1.77 - 1.89 (m, 1H), 1.55 - 1.66 (m, 1H), 1.22 (d, 2H).
Example 358: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.53 (s, 1H), 8.39 - 8.45 (m, 1H), 8.28 (d, 1H), 8.00 (s, 1H), 7.81 (d, 1H), 7.31 - 7.54 (m, 4H), 7.27 (t, 1H), 7.17 (t, 2H), 4.29 - 4.44 (m, 2H), 4.17 - 4.26 (m, 1H), 3.69 (m, 1H), 3.49 - 3.44 (m, 2H under DMSO signal), 2.30 - 2.37 (m, 1H), 2.04 - 2.16 (m, 1H), 0.97 (m, 1H), 0.75 (m, 1H).
Example 359: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.6 (t, 1H), 8.26 (m, 2H), 7.97 (s, 1H), 7.75 (d, 1H), 7.45-7.34 (m, 4H), 7.24 (t, 1H), 7.14 (m, 2H), 6.28 - 6.05 (tt, 1H), 4.46 - 4.27 (m, 3H), 3.89 (m, 1H), 3.65 (m,1 H), 2.88 (m, 1H), 2.39 (m, 1H), 1.8 (m, 1H).
Example 362: H NMR (400 MHz, DMSO- ) d (ppm): 8.80 (s, 1H), 8.75 (m, 1H), 8.27 (d, 1H), 7.98 (s, 1H), 7.66 (d, 1H), 7.41 - 7.56 (m, 3H), 7.37 (t, 1H), 7.25 (t, 1H), 7.03 - 7.22 (m, 3H), 4.72 (dd, 1H), 4.21 - 4.47 (m, 2H), 3.30 (m, 1H), 2.88 (dd, 1H).
Example 371 : H NMR (400 MHz, DMSO-d 6) d (ppm): 9.09 (br.s, 1H), 8.44 (m, 2H), 8.06 (d, 1H), 7.92 (s, 1H), 7.46 (t, 1H), 7.24 - 7.40 (m, 3H), 7.19 (t, 1H), 7.1 1 (d, 1H), 6.75 (dd, 1H), 4.24 - 4.47 (m, 2H), 4.16 (dd, 1H), 3.80 (m, 1H), 2.31 (dd, 1H), 2.00 - 2.20 (m, 1H), 1.77 (m, 1H), 0.85 (m, 1H), 0.54 (m, 1H). e 374: H NMR (400 MHz, DMSO-d 6) d (ppm): 12.95 (br.s, 1H), 8.46 (m, 2H), 8.17 (d, 1H), 8.01 (s, 1H), 7.25 - 7.55 (m, 5H), 7.17 (t, 1H), 6.92 (dd, 1H), 4.66 (m, 2H), 4.27 - 4.43 (m, 2H), 4.17 (dd, 1H), 3.82 (m, 1H), 2.33 (dd, 1H), 2.10 (m, 1H), 1.78 (m, 1H), 0.86 (m, 1H), 0.55 ( , 1H).
Example 377: H NMR (400 MHz, DMSO- ) d (ppm): 8.56 (s, 1H), 8.45 (t, 1H), 8.21 (d, 1H), 8.01 (s, 1H), 7.69 (s, 1H), 7.27 - 7.57 (m, 4H), 7.17 (m, 2H), 4.26 - 4.45 (m, 2H), 4.18 (dd, 1H), 3.83 (m, 1H), 3.62 (s, 2H), 2.31 - 2.37 (m, 1H), 2.04 - 2.17 (m, 1H), 1.78 (m, 1H), 0.85 (m, 1H), 0.55 (m, 1H).
Example 378: H NMR (400 MHz, DMSO-d 6) d (ppm): 12.28 (br.s, 1H), 8.54 (s, 1H), 8.45 (t, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.71 (d, 1H), 7.41 - 7.54 (m, 3H), 7.35 (t, 1H), 7.17 (t, 1H), 7.08 (dd, 1H), 4.27 - 4.45 (m, 2H), 4.17 (dd, 1H), 3.81 (m, 1H), 3.66 (s, 2H), 2.24 - 2.33 (m, 1H), 2.12 (m, 1H), 1.77 (m, 1H), 0.84 (m, 1H), 0.55 (m, 1H).
Example 379: H NMR (400 MHz, DMSO- ) d (ppm): 8.48 (m, 2H), 8.16 (d, 1H), 8.00 (s, 1H), 7.46 (m, 1H), 7.24 - 7.42 (m, 4H), 7.17 (t, 1H), 6.90 (dd, 1H), 4.89 (t, 1H), 4.22 - 4.46 (m, 2H), 4.16 (dd, 1H), 3.99 (m, 2H), 3.84 (m, 1H), 3.74 (q, 2H), 2.34 (m, 1H), 2.10 (m, 1H), 1.73 (m, 1H), 0.85 (m, 1H), 0.55 (m, 1H).
Example 384: H NMR (400 MHz, DMSO- ) d (ppm): 8.51 (s, 1H), 8.45 (t, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.68 (d, 1H), 7.27 - 7.55 (m, 4H), 7.18 (t, 1H), 7.05 (dd, 1H), 4.65 (t, 1H), 4.25 - 4.46 (m, 2H), 4.17 (dd, 1H), 3.81 (m, 1H), 3.63 (m, 2H), 2.83 (t, 2H), 2.26 - 2.33 (m, 1H), 2.10 (m, 1H), 1.77 (m, 1H), 0.84 (m, 1H), 0.54 (m, 1H).
Example 385: H NMR (400 MHz, DMSO- ) d (ppm): 8.39 - 8.53 (m, 2H), 8.17 (d, 1H), 7.98 (s, 1H), 7.63 (s, 1H), 7.46 (t, 1H), 7.27 - 7.40 (m, 3H), 7.09 - 7.21 (m, 2H), 4.65 (t, 1H), 4.26 - 4.45 (m, 2H), 4.17 (dd, 1H), 3.83 (m, 1H), 3.64 (m, 2H), 2.81 (t, 2H), 2.27 - 2.34 (m, 1H), 2.12 (m, 1H), 1.77 (m, 1H), 0.87 (m, 1H), 0.55 (m, 1H).
Example 387: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.46 (m, 2H), 8.16 (m, 2H), 7.99 (s, 1H), 7.46 (m, 1H), 7.25 - 7.41 (m, 3H), 7.15 (t, 1H), 6.89 (dd, 1H), 4.25 - 4.45 (m, 2H), 4.16 (dd, 1H), 3.96 - 4.12 (m, 2H), 3.84 (m, 1H), 2.59 - 2.72 (m, 2H), 2.34 (m, 1H), 2.24 (s, 6H), 2.1 1 (m, 1H), 1.71 - 1.83 (m, 1H), 0.84 (m, 1H), 0.55 (m, 1H).
Example 388: H NMR (400 MHz, DMSO- ) d (ppm): 8.47 (m, 2H), 8.17 (s, 2H), 7.98 (s, 1H), 7.45 (t, 1H), 7.34 (m, 4H), 7.14 (t, 1H), 6.90 (dd, 1H), 4,36 (m, 3H), 4,16 (m, 1H), 4.24 (dd, 1H), 4,06 (m, 3H), 3.82 (m, 1H), 2,82 (m, 2H), 2,34 (m, 1H), 2,10 (m, 1H), 1,78 (m, 1H), 1,70 (m, 4H), 0,85 (m, 1H), 0,56 (m, 1H).
Example 392: H NMR (400 MHz, DMSO-d 6) d (ppm): 9.28 (s, 1H), 8.43 (m, 2H), 7.78 (m, 2H), 7.56 (d, 1H), 7.47 (t, 1H), 7.35 (t, 1H), 7.30 (br.s, 2H), 7.18 (t, 1H), 6.66 (dd, 1H), 4.25 - 4.48 (m, 2H), 4.16 (m, 1H), 3.79 (m, 1H), 2.31 (dd, 1H), 2.03 - 2.13 (m, 1H), 1.70 - 1.83 (m, 1H), 0.85 (m, 1H), 0.52 (m, 1H).
Example 394: H NMR (400 MHz, DMSO- ) d (ppm): 8.53 (s, 1H), 8.44 (t, 1H), 7.88 (s, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.27 - 7.49 (m, 4H), 7.16 (t, 1H), 6.85 (dd, 1H), 4.79 (s, 2H), 4.22 - 4.45 (m, 2H), 4.14 (dd, 1H), 3.78 (m, 1H), 3.70 (s, 3H), 2.32 (m, 1H), 1.98 - 2.15 (m, 1H), 1.77 (m, 1H), 0.83 (m, 1H), 0.54 (m, 1H).
Example 395: H NMR (400 MHz, DMSO- ) d (ppm): 8.52 (s, 1H), 8.45 (t, 1H), 7.88 (m, 2H), 7.68 (d, 1H), 7.26 - 7.55 (m, 4H), 7.18 (t, 1H), 6.84 (dd, 1H), 4.88 (br.s, 1H), 4.26 - 4.46 (m, 2H), 4.16 (dd, 1H), 4.00 (t, 2H), 3.70 - 3.85 (m, 3H), 2.32 (dd, 1H), 2.02 - 2.18 (m, 1H), 1.77 (m, 1H), 0.85 (m, 1H), 0.55 (m, 1H).
Example 396: HRMS: 48 [M+H]+ (calcd 491.1649 for C22H21 F3N604).
Example 409: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.57 (t, 1H), 8.28 (m, 3H), 8.02 (s, 1H), 7.8 (d, 1H), 7.4 (t, 2H), 7.3 (t, 1H), 7.2 (t, 1H), 7.15 (m, 2H), 4.7 (d, 1H), 4.4 (d, 2H), 3.94 (m, 2H), 3.0 (d, 2H), 2.4 (t, 1H), 2.3 (t, 1H).
Example 412: H NMR (400 MHz, DMSO- ) d (ppm): 8.7 (t, 1H), 8.53 (s, 1H), 8.35 (d, 1H), 7.87 (m, 2H), 7.47 (t, 1H), 7.41 (t, 1H), 7.36 (t, 1H), 7.28 (t, 1H), 7.12 (t, 1H), 4.60 (t, 1H), 4.37 (m, 2H), 3.97 (dd, 1H), 3.80 (dd, 1H), 3.0 (dd, 2H), 2.61 (s, 3H), 2.45 (m, 1H), 2.07 (m, 1H).
Example 415: H NMR (400 MHz, DMSO-d 6) d ppm 7.81 - 7.92 (m, 3H), 7.41 - 7.57 (m, 2H), 7.33 - 7.41 (m, 1H), 7.23 - 7.33 (m, 1H), 7.04 - 7.17 (m, 1H), 4.54 - 4.64 (m, 2H), 4.40 (dd, 2H), 4.09 - 4.17 (m, 1H), 3.94 - 3.66 (m, 2H), 2.61 (s, 3H).
Example 417: H NMR (400 MHz, DMSO- ) d (ppm): 8.80 (t, 1H), 8.26 - 8.32 (m, 2H), 8.16 (br.s, 2H), 7.95 (s, 1H), 7.72 (d, 1H), 7.41 - 7.51 (m, 4H), 7.22 - 7.30 (m, 1H), 7.10 - 7.17 (m, 2H), 4.49 - 4.62 (m, 2H), 4.31 - 4.42 (m, 1H), 3.84 - 3.99 (m, 2H), 3.56 - 3.67 (m, 1H), 2.28 - 2.37 (m, 1H), 2.01 - 2.14 (m, 1H).
Example 430: H NMR (400 MHz, DMSO- ) d (ppm): 8.88 (br. s , 1H), 8.23 - 8.32 (m, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.73 (d, 1H), 7.37 - 7.51 (m, 2H), 7.24 (t, 1H), 7.09 - 7.18 (m, 2H), 4.90 (d, 1H), 4.57 (d, 1H), 4.29 - 4.47 (m, 2H), 3.81 - 3.88 (m, 1H), 3.51 - 3.64 (m, 1H).
Example 431: H NMR (400 MHz, DMSO- ) d (ppm): 8.78 (br. s , 1H), 8.42 (s, 1H), 8.25 (d, 1H), 7.93 (s, 1H), 7.67 (d, 1H), 7.38 - 7.56 (m, 2H), 7.25 (t, 1H), 7.06 - 7.19 (m, 2H), 5.18 - .40 (m, 1H), 4.69 (d, 1H), 4.25 - 4.48 (m, 2H), 4.02 - 4.25 (m, 2H), 3.77 - 3.92 (m, 1H).
Example 432: H NMR (400 MHz, DMSO- ) d (ppm): 8.80 (s, 1H), 8.54 (t, 1H), 8.27 (d, 1H), 8.03 (s, 1H), 7.60 (d, 1H), 7.37 - 7.54 (m, 3H), 7.34 (t, 1H), 7.27 (t, 1H), 7.06 - 7.23 (m, 2H), .43 (dd, 1H), 4.48 (t, 1H), 4.24 - 4.44 (m, 2H), 3.22 (m, 1H), 2.63 - 2.80 (m, 1H), 1.95 (m, 1H).
Example 446: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.44 (t, 1H), 8.22 - 8.28 (m, 1H), 7.77 (s, 1H), 7.55 - 7.60 (m, 1H), 7.42 - 7.54 (m, 3H), 7.21 - 7.31 (m, 2H), 7.09 - 7.20 (m, 2H), 4.28 - 4.47 (m, 2H), 4.22 - 4.28 (m, 1H), 3.94 (s, 2H), 3.64 - 3.72 (m, 1H), 2.08 - 2.29 (m, 2H), 1.75 - 1.85 (m, 1H), 0.75 - 0.92 (m, 1H), 0.51 - 0.57 (m, 1H).
Example 452: H NMR (400 MHz, DMSO- ) d (ppm): 8.46 (t, 1H), 8.13 (d, 1H), 7.74 (s, 1H), 7.33 - 7.54 (m, 3H), 7.28 (t, 1H), 7.03 - 7.19 (m, 2H), 6.87 (dd, 1H), 4.29 - 4.42 (m, 2H), 4.25 (dd, 1H), 3.90 (s, 2H), 3.75 (s, 3H), 3.68 (m, 1H), 2.19 - 2.31 (m, 1H), 2.04 - 2.19 (m, 1H), 1.78 (m, 1H), 0.94 (m, 1H), 0.54 (m, 1H).
Example 466: H NMR (400 MHz, DMSO- ) d (ppm): 8.40 - 8.82 (m, 1H), 8.1 1 - 8.37 (dd, 1H), 7.73 (s, 1H), 7.54-7.55 ( dd, 1H), 7.07-7.46 (m, 8H), 4.90-5.04 (m, 1H), .47 (m, 3H), 4.08-4.16 (m, 1H), 3.61-3.87 (m, 4H) Example 476: H NMR (400 MHz, DMSO- ) d (ppm): 4:1 mixture of rs d (ppm): 9.02 (t, 0.2H), 8.63 (t, 0.8H), 8.1 1 - 8.21 (m, 1H), 7.89 - 7.96 (m, 1H), 7.36 - 7.51 (m, 2H), 6.96 - 7.29 (m, 4H), 5.41 - 5.61 (m, 1H), 5.08 - 5.40 (m, 2H), 4.88 (t, 0.2H), 4.13 - 4.56 (m, 3.8H), 3.81 - 4.1 1 (m, 1H), 2.43 - 2.49 (m, 1H), 1.97 - 2.18 (m, 1H).
Example 483: H NMR (400 MHz, DMSO-d 6) : 8.51-8.46 (m, 3H), 8.35 (m, 1H), 7.46 (m, 1H), 7,31 (dd, 1H), 7.21 (m, 1H), 7.09 (t, 1H), 5,53 (d, 1H), 5,37 (d, 1H), 4.41-4.27 (m, 3H), 3.72 (m, 1H), 2.47 (s, 3H), 2,26 (m, 1H), 2.19-2.13 (m, 1H), 1.89 (m, 1H), 1.08 (m, 1H), 0.75 (m, 1H).
Example 491: H NMR (400 MHz, DMSO- ) d (ppm): 4:1 mixture of rotamers d (ppm): 9.03 (t, 0.2H), 8.64 (t, 0.8H), 8.1 1 - 8.19 (m, 1H), 7.91 - 7.99 (m, 1H), 7.61 (m, 0.8H), 7.48 - 7.58 (br s , 1H), 7.34 - 7.48 (m, 1.2H), 7.1 1 - 7.28 (m, 2H), 6.97 (t, 1H), 5.43 - 5.63 (m, 1H), 5.09 - 5.43 (m, 2H), 4.89 (t, 0.2H), 4.10 - 4.59 (m, 3.8H), 3.83 - 4.05 (m, 0.8H), 3.42 - 3.59 (m, 0.2H), 2.71 - 2.85 (m, 0.2H), 2.42 - 2.47 (m, 0.8H), 1.98 - 2.27 (m, 1H).
Example 496: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.01 (t, 0.2H), 8.63 (t, 0.8H), 8.12 - 8.19 (m, 1H), 7.89 - 7.94 (m, 1H), 7.36 - 7.49 (m, 2H), 7.20 - 7.27 (m, 0.8H), 7.09 - 7.19 (m, 3H), 6.90 - 7.04 (m, 0.8H), 6.74 - 6.81 (m, 0.2H), 6.54 - 6.61 (m, 0.2H), .33 (d, 0.8H), 5.22 (d, 0.2H), 5.07 (d, 0.8H), 4.88 (t, 0.2H), 4.56 (d, 0.2H), 4.33 - 4.52 (m, 2H), 4.1 1 - 4.31 (m, 1.8H), 3.90 - 4.03 (m, 0.2H), 3.70 - 3.87 (m, 0.8H), 2.46 - 2.54 (m, 1H, overlapped by DMSO residual signal) 1.90 - 2.27 (m, 1H), 1.47 - 1.66 (m, 3H). e 497: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.02 (t, 0.2H), 8.82 (br. s , NH2) 8.63 (t, 0.8H), 7.83 - 7.90 (m, 1H), 7.66 (s, 1H), 7.12 - 7.51 (m, 3H), 7.02 (t, 1H), 6.72 - 6.80 (m, 1H), 5.39 - 5.58 (m, 0.8H), 5.00 - 5.37 (m, 2H), 4.86 (t, 0.2H), 4.23 - 4.62 (m, 3.4H), 4.09 - 4.22 (m, 0.8H), 3.81 - 4.05 (m, 0.8H), 3.78 (s, 3H), 2.71 - 2.85 (m, 0.2H), 1.97 - 2.26 (m, 0.8H), (NH2 s partially exchanged with deuterium).
Example 499: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.03 (t, 0.2H), 8.65 (t, 0.8H), 8.00 (d, 1H), 7.72 - 7.84 (m, 1H), 7.33 - 7.48 (m, 1H), 7.24 (t, 0.8H), 7.14 (t, 0.2H), 6.88 - 7.01 (m, 1.6H), 6.69 - 6.82 (m, 1.4H), 5.40 - 5.61 (m, 1H), 5.30 (d, 0.8H), 5.14 - .22 (m, 0.2H), 5.05 (d, 0.8H), 4.88 (t, 0.2H), 4.23 - 4.57 (m, 3.2H), 4.09 - 4.23 (m, 0.8H), 3.80 - 4.06 (m, 1H), 3.68 - 3.77 (m, 3H), 3.42 - 3.61 (m, 1H), 2.71 - 2.84 (m, 0.2H), 1.98 - 2.28 (m, 0.8H), (NH2 s exchanged with deuterium).
Example 500: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.05 (t, 0.2H), 8.65 (t, 0.8H), 8.06 - 8.12 (m, 1H), 8.01 - 8.05 (m, 1H), 7.35 - 7.47 (m, 1.2H), 7.1 1 - 7.27 (m, 1H), 6.98 (d, 0.8H), 6.92 (t, 0.8H), 6.80 - 6.88 (m, 1.2H), 5.40 - 5.61 (m, 1H), 5.28 - 5.39 (m, 0.8H), 5.08 - 5.24 (m, 1H), 4.88 (t, 0.2H), 4.59 (d, 0.2H), 4.24 - 4.53 (m, 2.8H), 4.08 - 4.20 (m, 1H), 3.83 - 4.05 (m, 1H), 3.68 - 3.77 (m, 3H), 2.70 - 2.84 (m, 0.2H), 2.40 (s, 3H), 1.99 - 2.27 (m, 0.8H).
Example 505: H NMR (400 MHz, DMSO-d 6) d (ppm): 8.72 (t, 1H), 8.23 (s, 1H), 8.20 (m, 1H), 7.45 (m, 2H), 7.27 (t, 1H), 7.21 (m, 2H), 7.03 (t, 1H), 5.37 (d, 1H), 5.2 (m, 2H), 4.65 (d, 1H), 4.4 (dd, 1H), 4.3 (m, 3H), 4.1 (m, 2H), 3.4 (s, 3H), 2.42 (s, 3H).
Example 507: H NMR (400 MHz, DMSO- ) d (ppm): 4:1 mixture of rotamers d (ppm): 9.03 (t, 0.2H), 8.63 (t, 0.8H), 8.15 - 8.29 (m, 2H), 7.38 - 7.51 (m, 2H), 7.13 - 7.31 (m, 3.2H), 6.97 (t, 0.8H), 5.43 - 5.61 (m, 1H), 5.14 - 5.43 (m, 1.8H), 4.87 (t, 0.2H), 4.64 (d, 0.2H), 4.10 - 4.54 (m, 3.8H), 3.84 - 4.05 (m, 0.8H), 3.43 - 3.61 (m, 0.2H), 2.44 (s, 3H and m , 1H), 1.96 - 2.30 (m, 1H).
Example 508: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 9.02 (t, 0.2H), 8.62 (t, 0.8H), 8.12 - 8.22 (m, 1H), 7.75 - 7.83 (m, 1H), 7.30 - 7.53 (m, 7H), 7.24 (t, 0.8H), 7.16 (t, 0.2H), 7.10 (d, 0.2H), 6.96 - 7.03 (m, 0.8H), 6.88 - 6.96 (m, 1H), 5.41 - 5.61 (m, 0.8H), 5.27 - .41 (m, 1H), 5.19 - 5.26 (m, 0.2H), 5.09 - 5.19 (m, 2.8H), 4.85 (t, 0.2H), 4.59 (d, 0.2H), 4.22 - 4.51 (m, 2.8H), 4.07 - 4.21 (m, 0.8H), 3.80 - 4.05 (m, 1H), 3.43 - 3.60 (m, 0.2H), 3.35 (m, 1H, overlapping with H20 residual signal) 2.68 - 2.84 (m, 0.2H), 2.41 (s, 3H), 1.98 - 2.19 (m, 0.8H).
Example 510: H NMR (400 MHz, DMSO-d 6) d ppm 8.49 (t, 1H), 8.31 (s, 1H), 8.16 - 8.24 (m, 1H), 7.41 - 7.55 (m, 2H), 7.15 - 7.28 (m, 3H), 7.04 (t, 1H), 5.39 (dd, 2H), 4.37 - 4.46 (m, 1H), 4.21 - 4.35 (m, 2H), 3.68 - 3.80 (m, 1H), 2.45 (s, 3H), 2.23 - 2.33 (m, 1H), 2.1 1 - 2.22 (m, 1H), 1.80 - 1.95 (m, 1H), 1.00 - 1.13 (m, 1H), 0.70 - 0.82 (m, 1H).
Example 514: 1H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 10.54 (s, 0.2H), 10.20 (s, 0.8H), 8.23 - 8.31 (m, 1H), 8.15 - 8.21 (m, 1H), 7.84 - 8.00 (m, 1H), 7.39 - 7.49 (m, 1H), 7.18 - 7.39 (m, 4H), 5.33 - 5.66 (m, 2H), 5.13 - 5.28 (m, 1H), 4.69 - 4.89 (m, 1H), 4.15 - 4.28 (m, 1H), 3.89 - 4.14 (m, 1H), 2.56 - 2.66 (m, 1H), 2.44 (s, 3H), 2.08 - 2.30 (m, 1H).
Example 515: H NMR (400 MHz, DMSO-d 6) d ppm 10.31 (s, 1H), 8.27 - 8.41 (m, 2H), 8.18 (d, 1H), 8.04 - 8.1 1 (m, 1H), 7.88 (s, 1H), 7.52 (d, 1H), 7.10 - 7.32 (m, 2H), 5.45 (dd, 2H), 4.31 (dd, 1H), 3.86 (t, 1H), 2.44 (s, 3H), 2.32 - 2.40 (m, 1H), 2.21 - 2.32 (m, 1H), 1.83 - 2.02 (m, 1H), 0.98 - 1.13 (m, 1H), 0.73 - 0.89 (m, 1H).
Example 521: H NMR (400 MHz, DMSO-d 6) d (ppm): 3:1 mixture of rotamers 9.23 (t, , 8.75 (t, 0.75H), 8.24 (s, 0.75H), 8.05 - 8.18 (m, 2.25H), 7.97 (m, 1H), 7.41 (m, , 7.01 - 7.21 (m, 2.25H), 5.13 - 5.63 (m, 2.75H), 4.91 (t, 0.25H), 3.83 - 4.64 (m, 5H), 2.37 - 2.46 (m, 3H), 1.96 - 2.20 (m, 1H).
Example 524: H NMR (400 MHz, DMSO-d 6) : 9.35 (s, 1H), 8.50 (t, 1H), 8.40 (s, 1H), 8.32 (d, 1H), 7.54 (d, 1H), 7.46 (m, 1H), 7.19 (t, 1H), 7.03 (t, 1H), 5.53 (d, 1H), 5.33 (d, 1H), 4.43 (dd, 1H), 4.31-4.26 (m, 2H), 3.71 (m, 1H), 2.49 (s, 3H), 2.34-2.26 (m, 1H), 2.20-2.14 (m, 1H), 1.90 (m, 1H), 1.06 (m, 1H), 0.78 (m, 1H).
Example 525: H NMR (400 MHz, DMSO-d 6) d ppm 8.61 (t, 1H), 8.30 (s, 1H), 8.14 - 8.20 (m, 1H), 8.1 1 (dd, 1H), 7.97 - 8.02 (m, 1H), 7.41 - 7.51 (m, 1H), 7.18 (dd, 2H), 5.39 (dd, 2H), 4.39 - 4.46 (m, 2H), 4.33 (dd, 1H), 3.71 - 3.79 (m, 1H), 2.44 (s, 3H), 2.13 - 2.37 (m, 2H), 1.86 - 1.98 (m, 1H), 1.02 - 1.15 (m, 1H), 0.74 - 0.84 (m, 1H).
Example 526: H NMR (400 MHz, DMSO-cfe): d (ppm): 8.51 - 8.61 (m, 2H), 8.26 - 8.33 (m, 1H), 8.22 (s, 1H), 7.85 (dd, 1H), 7.37 - 7.44 (m, 1H), 7.16 (t, 1H), 6.91 (t, 1H), 5.63 (d, 1H), .40 (d, 1H), 4.38 - 4.47 (m, 1H), 4.24 - 4.33 (m, 2H), 3.67 - 3.91 (m, 4H), 2.47 (s, 3H), 2.26 - 2.35 (m, 1H), 2.13 - 2.22 (m, 1H), 1.85 - 1.96 (m, 1H), 1.04 - 1.13 (m, 1H), 0.73 - 0.80 (m, 1H).
Example 534: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.05 (t, 0.2H), 8.67 (t, 0.8H), 8.13 (s, 0.8H), 8.05 (m, 1.2H), 7.29 - 7.50 (m, 6.2H), 7.22 (t, 0.8H), 7.08 - 7.15 (m, 1H), 6.83 - 6.98 (m, 2H), 5.41 - 5.63 (m, 0.8H), 5.28 - 5.40 (m, 1H), 4.87 - 5.25 (m, 3.2H), 4.23 - 4.67 (m, 3H), 3.83 - 4.21 (m, 1.8H), 3.43 - 3.61 (m, 0.2H), 2.54 - 2.60 (m, 1H), 2.41 (s, 3H), 1.99 - 2.21 (m, 1H).
Example 536: H NMR (400 MHz, DMSO-cfe): d (ppm): 8.53 (t, 1H), 8.21 (s, 1H), 8.00 - 8.09 (m, 1H), 7.30 - 7.42 (m, 6H), 7.14 - 7.21 (m, 2H), 6.88 - 6.97 (m, 2H), 5.20 - 5.48 (m, 2H), 4.89 - 5.07 (m, 2H), 4.38 - 4.50 (m, 1H), 4.23 - 4.33 (m, 2H), 3.70 - 3.78 (m, 1H), 2.42 (s, 3H), 2.26 - 2.36 (m, 1H), 2.12 - 2.22 (m, 1H), 1.84 - 1.94 (m, 1H), 1.01 - 1.09 (m, 1H), 0.70 - 0.79 (m, 1H).
Example 542: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.05 (t, 0.2H), 8.66 (t, 0.8H), 8.38 - 8.46 (m, 1H), 8.28 (d, 1H), 7.95 - 8.20 (m, 1H), 7.84 (dd, 1H), 7.34 - 7.48 (m, 1.2H), 7.10 - 7.22 (m, 1H), 6.85 (t, 0.8H), 5.28 - 5.63 (m, 2.8H), 4.92 (t, 0.2H), 4.72 (d, 0.2H), 4.1 1 - 4.55 (m, 3.8H), 3.88 - 4.06 (m, 1H), 3.78 - 3.88 (m, 3H), 3.35 (m, 1H, pping with H20 residual signal) 2.56 - 2.61 (m, 0.2H), 2.46 (s, 3H), 2.02 - 2.23 (m, 0.8H).
Example 545: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.51 (t, 1H), 8.27 - 8.33 (m, 1H), 8.12 (d, 1H), 7.40 - 7.50 (m, 2H), 7.10 - 7.23 (m, 2H), 6.96 - 7.09 (m, 1H), 5.46 (d, 1H), 5.29 (s, 1H), 4.36 - 4.50 (m, 1H), 4.22 - 4.36 (m, 2H), 3.56 - 3.78 (m, 5H), 2.44 (s, 3H), 2.24 - 2.37 (m, 1H), 2.12 - 2.22 (m, 1H), 1.84 - 1.95 (m, 1H), 1.26 (d, 1H), 1.02 - 1.10 (m, 1H), 0.73 - 0.80 (m, 1H).
Example 548: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 9.04 (t, 0.2H), 8.67 (t, 0.8H), 8.38 - 8.46 (m, 1H), 8.25 - 8.31 (m, 1H), 8.16 (s, 0.8H), 7.95 (s, 0.2H), 7.84 (d, 1H), 7.34 - 7.46 (m, 1.2H), 7.1 1 - 7.22 (m, 1H), 6.84 (t, 0.8H), 5.47 - 5.58 (m, 0.8H), 5.35 - 5.44 (m, 0.2H), 5.28 (d, 0.8H), 4.89 - 4.99 (m, 0.2H), 4.70 (d, 0.2H), 4.35 - 4.58 (m, 2H), 4.09 - 4.29 (m, 1.6H), 3.92 - 4.04 (m, 0.2H), 3.84 - 3.91 (m, 1H), 3.72 - 3.84 (m, 3H), 3.35 (m, 1H , overlapping with H20 residual signal) 2.55 - 2.60 (m, 0.2H), 2.46 (s, 3H), 1.93 - 2.18 (m, 0.8H), 1.47 - 1.69 (m, 3H).
Example 549: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rs d (ppm): 8.99 - 9.09 (m, 0.2H), 8.64 (t, 0.8H), 8.15 - 8.24 (m, 1H), 8.12 (d, 1H), 7.35 - 7.50 (m, 2H), 7.22 (t, 0.8H), 7.04 - 7.19 (m, 1.4H), 6.95 (t, 0.8H), 5.28 - 5.61 (m, 1.8H), 5.1 1 - 5.28 (m, 1H), 4.88 (t, 0.2H), 4.62 (d, 0.2H), 4.23 - 4.54 (m, 3H), 4.09 - 4.23 (m, 0.8H), 3.81 - 4.05 (m, 1H), 3.56 - 3.75 (m, 6H), 2.54 - 2.60 (m, 0.2H), 2.39 - 2.45 (m, 3H), 1.97 - 2.29 (m, 0.8H). e 550: H NMR (400 MHz, DMSO-d 6) : 8.90 (m, 1H), 8.51 (t, 1H), 8.49 (s, 1H), 8.33 (d, 1H), 8.06 (m, 1H), 7.45 (m, 1H), 7.20 (m, 1H), 7.06 (t, 1H), 5.63 (d, 1H), 5.42 (d, 1H), 4.42 (dd, 1H), 4.32-4.28 (m, 2H), 3.72 (m, 1H), 2.48 (s, 3H), 2.34-2.26 (m, 1H), 2.21-2.14 (m, 1H), 1.90 (m, 1H), 1.08 (m, 1H), 0.81 (m, 1H).
Example 551: H NMR (400 MHz, DMSO- ) d (ppm): 3:1 mixture of rotamers 9.24 (d, 0.25H), 8.78 (d, 0.75H), 8.31 (s, 0.75H), 8.23 (s, 0.25H), 8.13 - 8.21 (m, 1H), 7.69 (s, 0.25H), 7.62 (s, 0.75H), 7.32 - 7.50 (m, 3H), 7.10 - 7.27 (m, 3.25H), 7.04 (d, 0.25H), 5.43 - 5.63 (m, 1H), 5.06 - .43 (m, 3H), 4.94 (t, 0.25H), 4.74 (d, 0.25H), 4.40 - 4.67 (m, 5H), 4.09 - 4.24 (m, 0.75H), 3.81 - 4.06 (m, 1.25H), 2.00 - 2.21 (m, 1H).
Example 556: H NMR (400 MHz, DMSO-d 6) d ppm 8.49 (t, 1H), 8.39 (s, 1H), 8.15 - 8.26 (m, 1H), 7.40 - 7.55 (m, 2H), 7.13 - 7.30 (m, 3H), 7.05 (t, 1H), 5.40 (dd, 2H), 4.55 (s, 2H), 4.36 - 4.45 (m, 1H), 4.20 - 4.35 (m, 2H), 3.67 - 3.78 (m, 1H), 2.23 - 2.32 (m, 1H), 2.12 - 2.21 (m, 1H), 1.81 - 1.95 (m, 1H), 1.06 (ddd, 1H), 0.71 - 0.82 (m, 1H).
Example 561 : H NMR (400 MHz, DMSO-d 6) d ppm: 4:1 mixture of rotamers 9.04 (t, 0.2H), 8.63 (t, 0.8H), 8.42 - 8.57 (m, 1H), 8.1 1 - 8.29 (m, 1H), 7.59 (d, 0.8H), 7.29 - 7.50 (m, 3.4H), 7.09 - 7.27 (m, 1H), 6.94 (t, 0.8H), 5.23 - 5.68 (m, 2.8H), 4.86 (t, 0.2H), 4.78 (d, 0.2H), 3.82 - 4.57 (m, 4.4H), 3.43 - 3.63 (m, 0.2H), 2.57 (d, 0.2H), 1.97 - 2.24 (m, 1H).
Example 563: H NMR (400 MHz, DMSO- ) d ppm 4:1 mixture of rs 9.03 (t, 0.2H), 8.63 (t, 0.8H), 8.34 (s, 0.8H), 8.29 (s, 0.2H), 8.20 (d, 1H), 7.34 - 7.51 (m, 2H), 7.1 1 - 7.30 (m, 3.2H), 6.98 (t, 0.8H), 5.14 - 5.63 (m, 2.8H), 4.87 (t, 0.2H), 4.64 (d, 0.2H), 4.54 (s, 2H), 3.79 - 4.52 (m, 4.8H), 1.97 - 2.20 (m, 1H).
Example 564: H NMR (400 MHz, DMSO-d 6) d ppm 4:1 mixture of rotamers 9.02 (t, 0.2H), 8.62 (t, 0.8H), 8.34 (s, 0.8H), 8.29 (s, 0.2H), 8.14 - 8.25 (m, 1H), 7.51 - 7.62 (m, 1H), 7.38 - 7.50 (m, 1H), 7.17 - 7.31 (m, 3H), 7.10 (t, 0.2H), 6.91 (t, 0.8H), 5.1 1 - 5.65 (m, 2.8H), 4.87 (t, 0.2H), 4.63 (d, 0.2H), 4.54 (s, 2H), 3.82 - 4.51 (m, 4.8H), 1.97 - 2.21 (m, 1H).
Example 565: H NMR (400 MHz, DMSO- ) d (ppm): 4:1 mixture of rotamers 9.04 (t, 0.2H), 8.63 (t, 0.8H), 8.33 (s, 0.8H), 8.29 (s, 0.2H), 8.15 - 8.25 (m, 1H), 7.37 - 7.50 (m, 2H), 7.19 - 7.28 (m, 3H), 7.16 (t, 0.2H), 6.97 (t, 0.8H), 5.15 - 5.63 (m, 2.8H), 4.87 (t, 0.2H), 4.64 (d, 0.2H), 3.78 - 4.54 (m, 6.8H), 3.39 (s, 3H), 1.98 - 2.20 (m, 1H).
Example 568: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.41 (d, 1H), 8.29 (s, 1H), 8.19 (m, 1H), 7.48 - 7.42 (m, 2H), 7.30 (t, 1H), 7.26 - 7.20 (m, 2H), 7.10 (t, 1H), 5.47 (d, 1H), 5.28 - 4.21 (m, 2H), 4.33 (dd, 1H), 3.72 (m, 1H), 3.48 (d, 1H), 3.33 (d, 1H), 3.22 (s, 3H), 2.43 (s, 3H), 2.27 - 2.22 (m, 1H), 2.18 - 2.12 (m, 1H), 1.87 (m, 1H), 1.05 (m, 1H), 0.73 (m, 1H).
Example 577: H NMR (400 MHz, DMSO- ) d (ppm): 4:1 mixture of rotamers d (ppm): 8.99 (t, 0.2H), 8.62 (t, 0.8H), 7.78 - 7.85 (m, 1H), 7.56 (m, 1H), 7.35 - 7.51 (m, 1.2H), 7.25 (t, 0.8H), 7.14 - 7.20 (m, 1H), 7.04 (t, 0.8H), 6.93 (d, 0.2H), 6.59 - 6.66 (m, 1H), 5.38 - 5.59 (m, 1H), 4.96 - 5.31 (m, 1.8H), 4.85 (t, 0.2H), 4.09 - 4.52 (m, 4H), 3.96 - 4.04 (m, 0.2H), 3.78 - 3.95 (m, 0.8H), 2.40 - 2.49 (m, 1H , under DMSO residual peak), 1.96 - 2.25 (m, 1H).
Example 578: H NMR (400 MHz, DMSO- ) d (ppm): 4:1 mixture of rotamers d (ppm): 8.93 - 9.19 (m, 1H), 8.63 (t, 1H), 7.90 (d, 1H), 7.67 - 7.74 (m, 1H), 7.22 - 7.53 (m, 2H), 7.01 - 7.22 (m, 1H), 6.55 - 6.75 (m, 2H), 5.27 - 5.62 (m, 1H), 4.79 - 5.26 (m, 2H), 4.10 - 4.54 (m, 3.8H), 3.96 - 4.05 (m, 0.2H), 3.78 - 3.95 (m, 0.8H), 3.42 - 3.58 (m, 0.2H), 2.70 - 2.84 (m, 0.2H), 2.40 - 2.49 (m, 0.8H), 1.97 - 2.31 (m, 1H).
Example 579: H NMR (400 MHz, fe): 4:1 mixture of rotamers d (ppm): 8.96 - 9.10 (m, 1.2H), 8.63 (t, 0.8H), 8.05 - 8.14 (m, 1H), 7.57 - 7.64 (m, 1H), 7.36 - 7.51 (m, 1.2H), 7.1 1 - 7.29 (m, 1.8H), 6.95 - 7.05 (m, 1H), 6.67 (dd, 1H), 5.40 - 5.60 (m, 0.8H), 5.04 - 5.35 (m, 2H), 4.84 (t, 0.2H), 4.23 - 4.62 (m, 3H), 3.96 - 4.22 (m, 1H), 3.79 - 3.96 (m, 0.8H), 3.42 - 3.59 (m, 0.2H), 3.35 (m, 1H, overlapping with H20 residual signal) 2.70 - 2.83 (m, 0.2H), 2.38 (s, 3H), 1.97 - 2.17 (m, 0.8H).
Example 580: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 8.59 - 9.06 (m, 1H), 8.06 - 8.15 (m, 1H), 7.57 - 7.64 (m, 1H), 7.33 - 7.51 (m, 1.2H), 7.13 - 7.30 (m, 1.8H), 6.94 - 7.07 (m, 1H), 6.67 (dd, 1H), 4.95 - 5.31 (m, 2H), 4.85 (t, 0.2H), 4.39 - 4.58 (m, 1.8H), 4.06 - 4.39 (m, 2H), 3.90 - 4.03 (m, 0.2H), 3.68 - 3.84 (m, 0.8H), 3.35 (m, 1H , overlapping with H20 residual signal) 2.70 - 2.84 (m, 0.2H), 2.38 (s, 3H), 1.90 - 2.27 (m, 0.8H), 1.48 - 1.65 (m, 3H), (OH proton ged with deuterium).
Example 581: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.48 (t, 1H), 8.18 (s, 1H), 7.61 (d, 1H), 7.43 - 7.51 (m, 1H), 7.17 - 7.30 (m, 2H), 7.07 (t, 1H), 6.69 (dd, 1H), 5.15 - 5.44 (m, 2H), 4.23 - 4.50 (m, 3H), 3.65 - 3.74 (m, 1H), 2.39 (s, 3H), 2.21 - 2.32 (m, 1H), 2.10 - 2.21 (m, 1H), 1.81 - 1.94 (m, 1H), 0.99 - 1.10 (m, 1H), 0.70 - 0.79 (m, 1H), (OH proton exchanged with deuterium).
Example 582: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 8.60 - 9.04 (m, 1H), 7.98 - 8.07 (m, 0.8H), 7.90 - 7.98 (m, 1H), 7.84 - 7.90 (m, 0.2H), 7.37 - 7.52 (m, 1.2H), 7.14 - 7.29 (m, 1H), 7.03 (t, 0.8H), 6.70 - 6.79 (m, 1.8H), 6.59 (d, 0.2H), 4.93 - 5.30 (m, 1.8H), 4.85 (t, 0.2H), 4.40 - 4.57 (m, 1.8H), 4.09 - 4.40 (m, 2H), 3.91 - 4.05 (m, 0.2H), 3.66 - 3.85 (m, 1H), 3.35 (m, 1H , overlapping with H20 residual signal) 2.71 - 2.85 (m, 0.2H), 2.32 - 2.42 (m, 3H), 1.88 - 2.25 (m, 0.8H), 1.47 - 1.66 (m, 3H), (OH proton exchanged with deuterium).
Example 583: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.18 - 9.36 (m, 1H), 9.00 (t, 0.2H), 8.63 (t, 0.8H), 7.89 - 8.17 (m, 2H), 7.37 - 7.53 (m, 1.2H), 7.22 - 7.31 (m, 0.8H), 6.99 - 7.21 (m, 1H), 6.58 - 6.82 (m, 2H), 5.40 - 5.61 (m, 0.8H), 5.27 (d, 1H), 4.98 - 5.20 (m, 1H), 4.85 (t, 0.2H), 4.23 - 4.58 (m, 3.2H), 4.09 - 4.23 (m, 0.8H), 3.78 - 4.07 (m, 1H), 3.35 (m, 1H, overlapping with H20 residual ) 2.69 - 2.83 (m, 0.2H), 2.38 (s, 3H), 1.95 - 2.25 (m, 0.8H).
Example 584: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.51 (t, 1H), 8.10 (s, 1H), 7.87 - 8.00 (m, 1H), 7.45 (t, 1H), 7.23 (t, 1H), 7.10 (t, 1H), 6.69 - 6.85 (m, 2H), 5.08 - 5.42 (m, 2H), 4.23 - 4.53 (m, 3H), 3.64 - 3.78 (m, 1H), 2.39 (s, 3H), 2.21 - 2.31 (m, 1H), 2.1 1 - 2.21 (m, 1H), 1.83 - 1.94 (m, 1H), 1.01 - 1.1 1 (m, 1H), 0.69 - 0.77 (m, 1H), (OH proton ged with deuterium). e 585: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.04 (t, 0.2H), 8.66 (t, 0.8H), 8.03 - 8.1 1 (m, 1H), 7.80 - 7.88 (m, 1H), 7.34 - 7.49 (m, 1.2H), 7.23 (t, 0.8H), 7.1 1 - 7.19 (m, 1H), 6.88 - 7.04 (m, 2H), 5.27 - 5.60 (m, 3.8H), 5.21 (d, 0.2H), 5.08 (d, 0.8H), 4.88 (t, 0.2H), 4.23 - 4.60 (m, 3.2H), 4.09 - 4.23 (m, 0.8H), 3.82 - 4.06 (m, 1H), 3.51 - 3.60 (m, 1H), 2.70 - 2.87 (m, 0.2H), 1.95 - 2.31 (m, 0.8H), (NH2 protons exchanged with deuterium).
Example 586: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 9.22 - 9.34 (m, 1H), 8.95 - 9.10 (m, 0.2H), 8.59 - 8.79 (m, 0.8H), 7.90 - 8.24 (m, 2H), 7.34 - 7.51 (m, 1.2H), 7.14 - 7.29 (m, 1.6H), 6.95 - 7.14 (m, 1.2H), 6.70 - 6.95 (m, 1H), 5.28 - 5.62 (m, 3H), 5.01 - .27 (m, 1H), 4.82 - 4.92 (m, 0.2H), 4.53 - 4.65 (m, 0.2H), 4.23 - 4.53 (m, 2.8H), 4.07 - 4.23 (m, 0.8H), 3.76 - 4.07 (m, 1H), 3.35 (m, 1H, overlapping with H20 al signal) 2.37 - 2.44 (m, 3H), 1.94 - 2.28 (m, 1H).
Example 587: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.51 (t, 1H), 8.23 (s, 1H), 8.02 - 8.14 (m, 1H), 7.33 - 7.46 (m, 1H), 7.10 - 7.25 (m, 2H), 6.89 - 7.05 (m, 2H), 5.37 - 5.53 (m, 2H), 5.20 - 5.35 (m, 2H), 4.34 - 4.54 (m, 1H), 4.21 - 4.34 (m, 2H), 3.67 - 3.78 (m, 1H), 2.40 - 2.45 (m, 3H), 2.26 - 2.37 (m, 1H), 2.1 1 - 2.23 (m, 1H), 1.90 (d, 1H), 1.00 - 1.15 (m, 1H), 0.73 - 0.86 (m, 1H).
Example 588: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 9.02 (t, 0.2H), 8.63 (t, 0.8H), 8.1 1 - 8.22 (m, 1H), 7.67 - 7.73 (m, 1H), 7.30 - 7.53 (m, 2H), 7.12 - 7.28 (m, 1H), 6.96 - 7.1 1 (m, 1H), 6.80 - 6.87 (m, 1H), 5.40 - 5.61 (m, 0.8H), 5.08 - 5.39 (m, 2H), 4.85 (t, 0.2H), 4.59 (d, 0.2H), 4.22 - 4.52 (m, 2.8H), 4.08 - 4.21 (m, 0.8H), 3.81 - 4.05 (m, 1H), 3.79 (s, 3H), 3.53 - 3.62 (m, 0.2H), 3.35 (m, 1H, overlapping with H20 residual signal) 2.70 - 2.85 (m, 0.2H), 2.41 (s, 3H), 1.98 - 2.19 (m, 0.8H).
Example 589: H NMR (400 MHz, DMSO-cfe): 4:1 e of rotamers d (ppm): 8.58 - 9.07 (m, 2H), 8.14 - 8.24 (m, 1H), 7.98 (t, 1H), 7.76 - 7.82 (m, 1H), 7.66 (d, 1H), 7.35 - 7.51 (m, 3H), 7.09 - 7.28 (m, 1.2H), 6.92 - 7.03 (m, 1.8H), 5.41 - 5.63 (m, 1H), 5.10 - 5.40 (m, 3.8H), 4.85 (t, 0.2H), 4.59 (d, 0.2H), 4.22 - 4.52 (m, 2.8H), 4.08 - 4.20 (m, 1H), 3.80 - 4.05 (m, 1H), 2.40 (s, 3H), 1.96 - 2.27 (m, 1H).
Example 590: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 8.58 - 9.05 (m, 3H), 8.1 1 - 8.19 (m, 1H), 7.68 - 7.72 (m, 1H), 7.41 - 7.49 (m, 2H), 7.32 - 7.40 (m, 1H), 7.13 - 7.27 (m, 1H), 6.95 - 7.1 1 (m, 1H), 6.91 (dd, 1H), 5.40 - 5.59 (m, 1H), 5.27 - 5.39 (m, 3H), 5.09 - .25 (m, 1H), 4.85 (t, 0.2H), 4.58 (d, 0.2H), 4.42 - 4.51 (m, 1H), 4.23 - 4.42 (m, 1.8H), 4.07 - 4.20 (m, 0.8H), 3.80 - 4.04 (m, 1H), 3.35 (m, 1H , pping with H20 residual signal) 2.38 (s, 3H), 1.97 - 2.19 (m, 1H).
Example 592: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.02 (t, 0.2H), 8.65 (t, 0.8H), 8.02 (d, 1H), 7.78 - 7.84 (m, 1H), 7.34 - 7.49 (m, 1H), 7.1 1 - 7.27 (m, 1H), 6.91 - 7.02 (m, 1.8H), 6.81 (m, 1.2H), 5.25 - 5.60 (m, 1.8H), 5.18 (d, 0.2H), 5.04 (d, 0.8H), 4.87 (t, 0.2H), 4.53 - 4.76 (m, 2H), 4.24 - 4.52 (m, 3H), 4.08 - 4.23 (m, 0.8H), 3.81 - 4.06 (m, 1H), 3.69 (s, 3H), 3.42 - 3.59 (m, 0.2H), 2.71 - 2.85 (m, 0.2H), 1.97 - 2.18 (m, 0.8H). (NH2 protons partially exchanged with deuterium).
Example 593: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 12.90 (br. s , 1H), 9.01 (t, 0.2H), 8.64 (t, 0.8H), 8.02 (d, 1H), 7.77 - 7.85 (m, 1H), 7.36 - 7.50 (m, 1H), 7.24 (t, 0.8H), 7.16 (t, 0.2H), 6.94 - 7.04 (m, 1.6H), 6.76 - 6.90 (m, 1.4H), 5.39 - 5.61 (m, 0.8H), 5.24 - .35 (m, 1H), 5.19 (d, 0.2H), 5.05 (d, 0.8H), 4.87 (t, 0.2H), 4.24 - 4.68 (m, 5H), 4.09 - 4.22 (m, 1H), 3.81 - 4.05 (m, 1H), 3.43 - 3.64 (m, 0.8H), 3.35 (m, 0.2 H , overlapping with H20 residual signal) 2.71 - 2.85 (m, 0.2H), 1.98 - 2.17 (m, 0.8H). (NH2 protons exchanged with deuterium).
Example 595: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 12.29 (br. s , 1H), 9.05 (t, 0.2H), 8.64 (t, 0.8H), 8.15 - 8.22 (m, 1H), 8.1 1 (d, 1H), 7.35 - 7.49 (m, 2H), 7.23 (t, 0.8H), 7.09 - 7.19 (m, 1.4H), 6.95 (t, 0.8H), 5.41 - 5.63 (m, 1H), 5.38 (d, 0.8H), 5.22 - 5.33 (m, 0.2H), 5.16 (d, 0.8H), 4.88 (t, 0.2H), 4.61 (d, 0.2H), 4.23 - 4.53 (m, 3H), 4.10 - 4.22 (m, 0.8H), 3.81 - 4.06 (m, 1H), 3.48 - 3.64 (m, 2H), 3.35 (m, 1H, pping with H20 residual signal) 2.70 - 2.84 (m, 0.2H), 2.42 (s, 3H), 1.98 - 2.27 (m, 0.8H).
Example 596: H NMR (400 MHz, DMSO-cfe): d (ppm): 12.29 (br. s , 1H), 8.52 (t, 1H), 8.28 (s, 1H), 8.1 1 (d, 1H), 7.36 - 7.50 (m, 2H), 7.10 - 7.23 (m, 2H), 7.01 (t, 1H), 5.45 (d, 1H), 5.27 (d, 1H), 4.35 - 4.51 (m, 1H), 4.23 - 4.35 (m, 2H), 3.70 - 3.79 (m, 1H), 3.50 - 3.67 (m, 2H), 2.44 (s, 3H), 2.24 - 2.36 (m, 1H), 2.1 1 - 2.22 (m, 1H), 1.90 (q, 1H), 1.01 - 1.13 (m, 1H), 0.73 - 0.81 (m, 1H).
Example 597: H NMR (400 MHz, DMSO-d 6) : 85:15 mixture of rotamers d (ppm): 12.77 (br. s , 1H), 9.06 (t, 0.15H), 8.68 (t, 0.85H), 8.36 - 8.46 (m, 1H), 8.26 (d, 1H), 8.18 (s, 0.85H), 7.98 (s, 0.15H), 7.83 (d, 1H), 7.36 - 7.49 (m, , 7.10 - 7.27 (m, 1H), 6.92 (t, 0.85H), 5.24 - 5.64 (m, 2.85H), 4.92 (t, , 4.72 (d, 0.15H), 4.1 1 - 4.55 (m, 3.85H), 3.86 - 4.06 (m, 1H), 3.35 (m, 1H , overlapping with H20 al signal) 2.55 - 2.60 (m, 0.1 5H), 2.46 (s, 3H), 2.00 - 2.20 (m, 0.85H).
Example 598: 1H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.46 - 8.60 (m, 2H), 8.18 - 8.31 (m, 2H), 7.84 (dd, 1H), 7.42 (t, 1H), 7.19 (t, 1H), 6.98 (t, 1H), 5.61 (d, 1H), 5.38 (d, 1H), 4.35 - 4.45 (m, 1H), 4.23 - 4.35 (m, 2H), 3.74 - 3.82 (m, 1H), 2.47 (s, 3H), 2.24 - 2.35 (m, 1H), 2.1 1 - 2.22 (m, 1H), 1.85 - 1.94 (m, 1H), 1.04 - 1.13 (m, 1H), 0.73 - 0.81 (m, 1H).
Example 599: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.03 (t, 0.2H), 8.66 (t, 0.8H), 8.35 - 8.44 (m, 1H), 8.21 - 8.29 (m, 1H), 8.16 (s, 0.8H), 7.96 (s, 0.2H), 7.83 (d, 1H), 7.36 - 7.49 (m, 1.2H), 7.13 - 7.25 (m, 1H), 6.92 (t, 0.8H), 5.46 - 5.57 (m, 0.8H), 5.34 - 5.43 (m, 0.2H), 5.27 (d, 0.8H), 4.88 - 5.00 (m, 0.2H), 4.71 (d, 0.2H), 4.34 - 4.57 (m, 2H), 4.09 - 4.29 (m, 1.8H), 3.98 (dd, 1H), 3.73 - 3.91 (m, 0.8H), 3.40 - 3.48 (m, 0.2H), 2.55 - 2.60 (m, 0.2H), 2.46 (s, 3H), 1.93 - 2.27 (m, 0.8H), 1.47 - 1.67 (m, 3H), (COOH proton exchanged with deuterium).
Example 604: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 9.04 (t, 0.2H), 8.65 (t, 0.8H), 8.14 - 8.21 (m, 1H), 8.10 - 8.14 (m, 1H), 7.38 - 7.47 (m, 2H), 7.14 - 7.26 (m, 2.2H), 6.97 (t, 0.8H), 5.43 - 5.61 (m, 0.8H), 5.39 (d, 0.8H), 5.12 - 5.32 (m, 1H), 4.88 (t, 0.2H), 4.63 (d, 0.2H), 4.52 - 4.59 (m, 2H), 4.34 - 4.52 (m, 2H), 4.1 1 - 4.32 (m, 2H), 3.83 - 4.06 (m, 1H), 3.35 (m, 1H , overlapping with H20 residual signal) 2.42 (s, 3H), 1.98 - 2.27 (m, 1H).
Example 605: H NMR (400 MHz, DMSO-d 6) d (ppm): 3:1 mixture of rotamers 9.14 (t, 0.25H), 8.69 (t, 0.75H), 8.24 (s, 1H), 8.18 (d, 1.75H), 7.92 - 8.02 (m, 1.25H), 7.87 (m, 1H), 7.44 (m, 1H), 7.08 - 7.27 (m, 3H), 5.17 - 5.60 (m, 3.75H), 4.85 - 4.95 (t, 0.25H), 4.59 (d, 0.25H), 3.78 - 4.55 (m, , 2.70 - 2.85 (m, 0.25H), 1.90 - 2.16 (m, 0.75H).
Example 615: H NMR (400 MHz, DMSO-cfe): d (ppm): 9.27 (s, 1H), 8.86 (s, 1H), 8.52 (d, 1H), 8.50 (m, 1H), 8.41 (d, 1H), 7.74 (d, 1H), 7.47 - 7.40 (m, 2H), 7.20 (t, 1H), 7.05 (t, 1H), 5.60 (d, 1H), 5.37 (d, 1H), 4.40 (dd, 1H), 3.32 - 4.26 (m, 2H), 3,73 (m, 1H), 3.25 (s, 3H), 3.02 (s, 3H), 2.49 (s, 3H), 2.34 - 2.26 (m, 1H), 2.20 - 2.14 (m, 1H), 1.90 (m, 1H), 1.08 (m, 1H), 0.78 (m, 1H).
Example 617: H NMR (400 MHz, DMSO-d 6) : 85:15 mixture of rotamers d (ppm): 9.06 (t, 0.15H), 8.70 (t, 0.85H), 8.33 - 8.44 (m, 2H), 8.25 (s, , 8.09 (s, 0.15H), 7.85 (d, 1H), 7.38 - 7.49 (m, 0.15H), 7.28 - 7.35 (m, 0.85H), 7.1 1 - 7.22 (m, 1H), 6.81 (t, 1H), 5.42 - 5.65 (m, 1.85H), 5.27 - 5.42 (m, 1H), 4.93 (t, 0.15H), 4.75 (d, 0.15H), 4.1 1 - 4.58 (m, 3.85H), 3.89 - 4.09 (m, 1H), 2.54 - 2.62 (m, , 2.48 (s, 3H), 2.00 - 2.29 (m, 0.85H).
Example 621 : H NMR (400 MHz, DMSO-cfe): d (ppm): 8.51 (t, 1H), 8.34 (d, 1H), 8.18 (br. d , 1H), 7,46 (m, 1H), 7.35 (m, 1H), 7,22 (m, 1H), 7.08 (t, 1H), 6,95 (dt, 1H), 4,63 (d, 1H), 4.24 - 4.45 (m, 4H), 3,69 (m, 1H), 2,51 (s, 3H), 2,29 (m, 1H), 2,18 (m, 1H), 1,84 (m, 1H), 1,02 (m, 1H), 0,79 (m, 1H).
Example 628: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 10.51 (s, 0.2H), .16 (s, 0.8H), 8.18 (m, 1H), 7.91 (m, 0.2H), 7.83 (m, 0.8H), 7.65 (m, 1H), 7.62 (d, 0.8H), 7.56 (d, 0.2H), 7.46-7.22 (m, 5H), 5.66-5.24 (m, 3H), 5.08 (d, 0.2H), 4.95 (d, 0.8 H), 4.56 (m, 0.2H), 4.33 (ddd, 0.8H), 4.24-4.00 (m, 1.6H), 3.87-3.60 (m, 0.4H), 3.47 (s, 0.6H), 3.43 (s, 2.4H).
Example 652: H NMR (400 MHz, DMSO-cfe): d (ppm): 8.48 (br. s , 1H), 8.22 (d, 1H), 7.71 (d, 1H), 7.36 - 7.52 (m, 4H), 7.20 (t, 1H), 7.05 (t, 1H), 5.84 (d, 1H), 5.55 (d, 1H), 4.85 (s, 2H), 4.37 - 4.47 (m, 2H), 4.25 - 4.33 (m, 2H), 3.68 - 3.76 (m, 1H), 2.24 - 2.36 (m, 1H), 2.10 - 2.21 (m, 1H), 1.83 - 1.94 (m, 1H), 0.99 - 1.08 (m, 1H), 0.83 (m, 1H).
Example 657: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.17 (br. s , 1H), 8.65 (br. s , 1H), 8.38 (t, 1H), 8.07 (d, 1H), 7.85 (br. s , 1H), 7.56 (br. s , 1H), 7.46 (t, 1H), 7.22 (t, 1H), 6.99 - 7.15 (m, 1H), 5.76 (br. s , 2H), 5.45 (d, 1H), 4.38 (d, 1H), 4.28 (d, 1H), 4.15 - 4.24 (m, 1H), 4.02 - 4.12 (m, 1H).
Example 661: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rs d (ppm): 8.99 (d, 0.8H), 8.92 (s, 0.2H), 8.63 (t, 1H), 7.90 (s, 1H), 7.77 (br. s , 1H), 7.48 - 7.55 (m, 1H), 7.40 - 7.48 (m, 1H), 7.17 - 7.29 (m, 1H), 7.04 (t, 1H), 5.53 - 5.80 (m, 1.8H), 5.43 - 5.50 (m, 0.2H), 5.30 - 5.41 (m, 0.4H), 5.19 - 5.27 (m, 0.2H), 5.01 - 5.13 (m, 0.4H), 4.66 (d, 0.8H), 4.51 - 4.60 (m, 0.2H), 4.34 - 4.49 (m, 1.2H), 4.09 - 4.32 (m, 2.6H), 3.95 - 4.09 (m, 0.8H), 3.56 - 3.86 (m, 0.4H), 3.39 (s, 3H), 2.61 (s, 3H).
Example 662: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.12 (d, 0.8H), 8.97 - 9.07 (m, 0.4H), 8.64 (br. s , 0.8H), 8.37 (d, 1H), 8.07 (dd, 1H), 7.84 (br. s , 1H), 7.56 (br. s , 1H), 7.40 - 7.52 (m, 1.2H), 7.18 - 7.30 (m, 1H), 7.05 (t, 0.8H), 5.57 - 5.81 (m, 1.6H), 5.47 (m, 0.4H), 5.34 (m, 0.4H), 5.17 - 5.28 (m, 0.2H), 5.05 - 5.17 (m, 0.4H), 4.67 (d, 0.8H), 4.50 - 4.62 (m, 0.2H), 4.35 - 4.49 (m, 1.2H), 4.1 1 - 4.32 (m, 2.8H), 3.99 - 4.10 (m, 0.8H), 3.64 - 3.83 (m, 0.2H), 3.40 (s, 3H).
Example 663: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.43 (d, 0.8H), 8.99 (m, 0.2H), 8.62 (m, 1H), 8.39 - 8.48 (m, 1H), 7.89 (br. s , 1H), 7.63 (m, 1.8H), 7.40 - 7.55 (m, 1.2H), 7.17 - 7.30 (m, 1.2H), 7.04 (t, 0.8H), 5.55 - 5.71 (m, 1H), 5.43 - 5.54 (m, 1H), 5.20 - .41 (m, 0.6H), 4.90 - 5.13 (m, 0.4H), 4.65 (d, 0.8H), 4.50 - 4.60 (m, 0.2H), 4.35 - 4.48 (m, 1.2H), 4.08 - 4.32 (m, 2.8H), 3.96 - 4.08 (m, 0.8H), 3.61 - 3.85 (m, 0.2H), 3.39 (s, 3H).
Example 664: H NMR (400 MHz, DMSO-cfe): 4:1 mixture of rotamers d (ppm): 9.12 (s, 0.8H), 8.96 - 9.03 (m, 0.2H), 8.93 (s, 0.2H), 8.55 - 8.66 (m, 0.8H), 8.34 - 8.41 (m, 1H), 8.05 - 8.1 1 (m, 1H), 7.84 (br. s , 0.8H), 7.78 (br. s , 0.2H), 7.50 - 7.60 (m, 1H), 7.35 - 7.50 (m, 1.2H), 7.30 (t, 0.8H), 7.04 - 7.19 (m, 1H), 5.55 - 5.79 (m, 1.8H), 5.47 (m, 0.2H), 5.20 - 5.39 (m, 0.8H), 5.00 - .13 (m, 1.2H), 4.95 (d, 0.2H), 4.67 (d, 0.8H), 4.12 - 4.30 (m, 1.8H), 3.93 - 4.08 (m, 0.8H), 3.57 - 3.85 (m, 0.4H), 3.41 - 3.48 (m, 3H), 1.48 (d, 0.6H), 1.34 (d, 2.4H).
Example 668: H NMR (400 MHz, fe): d (ppm): 9.86 (s, 1H), 9.18 (s, 1H), 8.37 (d, 1H), 8.07 (d, 1H), 7,84 (m, 1H), 7.76 (t, 1H), 7.55 (m, 1H), 7.46 (t, 1H), 7.12 (t, 1H), 5.97 (d, 1H), .67 (d, 1H), 4.52 (m, 1H), 3.80 (m, 1H), 2.40-2.20 (m, 2H), 1.93 (m, 1H), 1.05 (m, 1H), 0.83 (m, 1H).
Example 675: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.14 (s, 1H), 8.50 (m, 1H), 8.38 (d, 1H), 8.08 (d, 1H), 7.84 (m, 1H), 7.55 (m, 1H), 7.45 (t, 1H), 7.21 (t, 1H), 7.07 (t, 1H), 5.88 (d, 1H), .57 (d, 1H), 4.41 - 4.24 (m, 3H), 3,48 (m, 1H), 2,44 (dd, 3H), 1.93 (dd, 1H), 1.28 (s, 3H), 1.01- 0.96 (m, 2H).
Example 684: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.79 (br. s , 1H), 9.19 (s, 1H), 8.37 (d, 1H), 8.08 (dd, 1H), 7.81 - 8.01 (m, 2H), 7.37 - 7.66 (m, 3H), 7.1 1 - 7.37 (m, 4H), 5.98 (d, 1H), .67 (d, 1H), 4.55 (dd, 1H), 3.75 - 3.89 (m, 1H), 2.21 - 2.41 (m, 2H), 1.87 - 2.01 (m, 1H), 0.98 - 1.13 (m, 1H), 0.82 (m, 1H).
Example 685: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.79 (br. s , 1H), 9.28 (s, 1H), 8.40 (d, 1H), 8.15 (d, 1H), 7.91 (t, 2H), 7.53 - 7.70 (m, 2H), 7.32 - 7.53 (m, 3H), 7.24 (t, 1H), 6.97 - 7.14 (m, 1H), 6.00 (d, 1H), 5.69 (d, 1H), 4.56 (dd, 1H), 3.75 - 3.86 (m, 1H), 2.23 - 2.40 (m, 2H), 1.85 - 2.01 (m, 1H), 0.94 - 1.13 (m, 1H), 0.82 (td, 1H).
Example 686: H NMR (400 MHz, DMSO-cfe): d (ppm): 9.81 (br. s , 1H), 8.58 (m, 1H), 8.19 (d, 1H), 7.81 - 8.03 (m, 2H), 7.48 - 7.73 (m, 3H), 7.23 - 7.47 (m, 4H), 5.82 (d, 1H), 5.51 (d, 1H), 4.54 (dd, 1H), 3.76 - 3.84 (m, 1H), 2.32 (m, 2H), 1.86 - 1.98 (m, 1H), 1.00 - 1.10 (m, 1H), 0.71 - 0.81 (m, 1H).
Example 688: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.81 (br. s , 1H), 9.22 (s, 1H), 8.64 (dd, 1H), 8.38 (d, 1H), 8.02 - 8.19 (m, 2H), 7.82 - 8.02 (m, 2H), 7.46 - 7.63 (m, 2H), 7.27 (t, 1H), 7.18 - 7.23 (m, 1H), 5.99 (d, 1H), 5.68 (d, 1H), 4.55 (dd, 1H), 3.75 - 3.91 (m, 1H), 2.19 - 2.41 (m, 2H), 1.84 - 2.03 (m, 1H), 0.96 - 1.17 (m, 1H), 0.75 - 0.90 (m, 1H). e 690: H NMR (400 MHz, DMSO-cfe): d (ppm): 8.42 - 8.51 (m, 1H), 7.52 (br. s , 2H), 7.46 (t, 1H), 7.28 (br. s , 1H), 7.20 (t, 1H), 7.1 1 (s, 1H), 7.06 (t, 1H), 5.62 (d, 1H), 5.35 (d, 1H), 4.37 - 4.47 (m, 1H), 4.22 - 4.35 (m, 3H), 3.63 - 3.71 (m, 1H), 2.21 - 2.32 (m, 1H), 2.09 - 2.20 (m, 1H), 1.81 - 1.92 (m, 1H), 0.97 - 1.06 (m, 1H), 0.67 - 0.76 (m, 1H).
Example 693: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.40 - 8.48 (m, 1H), 8.24 (d, 1H), 8.08 (d, 1H), 7.89 - 7.98 (m, 1H), 7.58 (br. s , 1H), 7.37 - 7.44 (m, 1H), 7.27 (t, 1H), 6.98 (t, 1H), 6.00 (d, 1H), 5.72 (d, 1H), 5.04 (m, 1H), 4.29 (dd, 1H), 3.74 - 3.81 (m, 1H), 2.78 (s, 3H), 2.29 (dd, 1H), 2.09 - 2.20 (m, 1H), 1.84 - 1.97 (m, 1H), 1.33 (d, 3H), 1.01 - 1.1 1 (m, 1H), 0.68 (m, 1H).
Example 694: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.48 (t, 1H), 8.24 (d, 1H), 8.08 (d, 1H), 7.90 (br. s , 1H), 7.61 (br. s , 1H), 7.45 (t, 1H), 7.21 (t, 1H), 7.06 (t, 1H), 6.02 (d, 1H), 5.75 (d, 1H), 4.20 - 4.40 (m, 3H), 3.71 - 3.85 (m, 1H), 2.84 (s, 3H), 2.31 (dd, 1H), 2.14 (m, 1H), 1.83 - 2.01 (m, 1H), 0.99 - 1.16 (m, 1H), 0.62 - 0.80 (m, 1H).
Example 695: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.47 (br. s , 1H), 8.00 (br. s , 1H), 7.88 (br. s , 1H), 7.61 (br. s , 1H), 7.45 (t, 1H), 7.21 (t, 1H), 7.02 - 7.12 (m, 1H), 6.01 (d, 1H), 5.73 (d, 1H), 4.22 - 4.40 (m, 3H), 3.73 - 3.82 (m, 1H), 2.85 (s, 3H), 2.62 (s, 3H), 2.31 (dd, 1H), 2.07 - 2.19 (m, 1H), 1.85 - 1.96 (m, 1H), 1.00 - 1.12 (m, 1H), 0.64 - 0.76 (m, 1H).
Example 696: H NMR (400 MHz, DMSO-cfe): d (ppm): 8.36 - 8.50 (m, 1H), 7.96 (m, 1H), 7.63 (br. s , 1H), 7.40 (t, 1H), 7.27 (t, 1H), 6.98 (t, 1H), 6.02 (d, 1H), 5.71 (d, 1H), 4.97 - 5.13 (m, 1H), 4.28 (dd, 1H), 3.72 - 3.83 (m, 1H), 2.82 (s, 3H), 2.60 - 2.72 (m, 3H), 2.21 - 2.39 (m, 1H), 2.07 - 2.19 (m, 1H), 1.83 - 1.97 (m, 1H), 1.33 (d, 3H), 1.01 - 1.13 (m, 1H), 0.62 - 0.76 (m, 1H).
Example 697: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rotamers d (ppm): 9.09 (s, 0.8H), 9.01 (br. s , 0.2H), 8.59 - 8.69 (m, 1H), 7.89 - 8.00 (m, 1H), 7.81 (br. s , 1H), 7.48 - 7.59 (m, 1.2H), 7.38 - 7.48 (m, 1H), 7.18 - 7.30 (m, 1H), 7.04 (t, 0.8H), 5.56 - 5.80 (m, 1.8H), 5.20 - 5.52 (m, 0.8H), 5.10 (m, 0.4H), 4.66 (d, 0.8H), 4.50 - 4.61 (m, 0.2H), 4.33 - 4.49 (m, 1.4H), 3.97 - 4.33 (m, 3.4H), 3.60 - 3.86 (m, 0.2H), 3.39 (s, 3H), 2.92 (m, 2H), 1.20 - 1.40 (m, 3H).
Example 702: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.14 (s, 1H), 8.30 - 8.47 (m, 2H), 8.07 (m, 1H), 7.88 (br. s , 1H), 7.53 (br. s , 1H), 7.35 - 7.46 (m, 1H), 7.28 (t, 1H), 6.94 - 7.16 (m, 1H), .90 (d, 1H), 5.62 (d, 1H), 5.06 (quin, 1H), 4.30 (dd, 1H), 3.57 - 3.78 (m, 1H), 2.20 - 2.36 (m, 1H), 2.06 - 2.20 (m, 1H), 1.76 - 1.99 (m, 1H), 1.33 (d, 3H), 0.94 - 1.10 (m, 1H), 0.70 - 0.84 (m, 1H).
Example 703: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.16 (s, 1H), 8.45 - 8.54 (m, 1H), 8.38 (d, 1H), 8.08 (dd, 1H), 7.85 (br. s , 1H), 7.55 (br. s , 1H), 7.45 (t, 1H), 7.20 (t, 1H), 7.07 (t, 1H), .92 (d, 1H), 5.63 (d, 1H), 4.36 - 4.51 (m, 1H), 4.25 - 4.33 (m, 2H), 3.68 - 3.75 (m, 1H), 2.24 - 2.37 (m, 1H), 2.10 - 2.22 (m, 1H), 1.84 - 1.95 (m, 1H), 1.00 - 1.10 (m, 1H), 0.80 (m, 1H).
Example 705: H NMR (400 MHz, DMSO-cfe): d (ppm): 8.99 (br. s , 1H), 8.40 - 8.54 (m, 1H), 8.02 (s, 2H), 7.88 (br. s , 1H), 7.61 (br. s , 1H), 7.36 - 7.53 (m, 1H), 7.17 - 7.28 (m, 1H), 7.04 - 7.17 (m, 1H), 5.75 (d, 1H), 5.45 (d, 1H), 4.24 - 4.48 (m, 3H), 3.58 - 3.71 (m, 1H), 2.21 - 2.32 (m, 1H), 2.10 - 2.21 (m, 1H), 1.82 - 1.93 (m, 1H), 0.97 - 1.07 (m, 1H), 0.82 (m, 1H).
Example 706: H NMR (400 MHz, DMSO-d 6) : d (ppm): 8.98 (s, 1H), 8.39 (m, 1H), 8.01 (d, 2H), 7.90 (br. s , 1H), 7.58 (br. s , 1H), 7.36 - 7.49 (m, 1H), 7.29 (t, 1H), 7.06 - 7.19 (m, 1H), .73 (d, 1H), 5.43 (d, 1H), 5.06 (quin, 1H), 4.28 (dd, 1H), 3.60 - 3.69 (m, 1H), 2.24 (m, 1H), 2.12 (m, 1H), 1.80 - 1.92 (m, 1H), 1.34 (d, 3H), 0.95 - 1.05 (m, 1H), 0.76 - 0.86 (m, 1H).
Example 707: H NMR (400 MHz, DMSO-cfe): d (ppm): 9.96 (br. s , 1H), 8.19 (d, 1H), 7.78 - 7.88 (m, 1H), 7.65 (d, 2H), 7.21 - 7.49 (m, 5H), 5.81 (d, 1H), 5.51 (d, 1H), 4.50 (dd, 1H), 3.78 - 3.85 (m, 1H), 2.22 - 2.39 (m, 2H), 1.92 (m, 1H), 1.04 (dt, 1H), 0.77 (m, 1H).
Example 708: H NMR (400 MHz, DMSO-d 6) : 9:1 mixture of rotamers d (ppm): 10.52 (s, 0.1 H), 10.19 (s, 0.9H), 8.12 - 8.25 (m, 1H), 7.84 - 7.98 (m, 1H), 7.63 (d, 2H), 7.34 - 7.47 (m, 2H), 7.20 - 7.34 (m, 3H), 5.54 - 5.75 (m, 2H), 5.38 - 5.54 (m, 0.9H), 4.96 - 5.27 (m, 0.2H), 4.73 (t, 0.9H), 4.16 - 4.33 (m, 1H), 4.00 (dd, 1H), 3.91 (m, 1H), 2.56 - 2.65 (m, 1H), 2.04 - 2.31 (m, 1H).
Example 709: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.97 (d, 1H), 9.49 (s, 1H), 8.50 (d, 1 H), 7.99 (br. s , 1H), 7.79 - 7.86 (m, 2H), 7.69 (br. s , 1H), 7.22 - 7.37 (m, 2H), 5.90 (d, 1H), 5.59 (d, 1H), 4.51 (dd, 1H), 3.76 - 3.83 (m, 1H), 2.21 - 2.39 (m, 2H), 1.89 - 1.98 (m, 1H), 0.99 - 1.09 (m, 1H), 0.79 (m, 1H).
Example 712: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.97 (br. s , 1H), 9.17 (br. s , 1H), 7.99 (s, 1H), 7.79 - 7.89 (m, 2H), 7.57 (br. s , 1H), 7.23 - 7.38 (m, 2H), 5.97 (d, 1H), 5.65 (d, 1H), 4.51 (dd, 1H), 3.76 - 3.86 (m, 1H), 2.93 (q, 2H), 2.23 - 2.41 (m, 2H), 1.87 - 1.99 (m, 1H), 1.30 (t, 3H), 1.01 - 1.1 1 (m, 1H), 0.82 (td, 1H).
Example 716: H NMR (400 MHz, DMSO-d 6) : d (ppm): 10.01 (br. s , 1H), 8.24 (d, 1H), 8.09 (d, 1H), 7.80 - 7.99 (m, 2H), 7.61 (br. s , 1H), 7.21 - 7.36 (m, 2H), 6.1 1 (d, 1H), 5.76 (d, 1 H), 4.52 (dd, 1H), 3.81 - 3.93 (m, 1H), 2.90 (s, 3H), 2.39 (m, 1H), 2.21 - 2.33 (m, 1H), 1.90 - 2.03 Example 717: H NMR (400 MHz, DMSO-cfe): d (ppm): 10.01 (br. s , 1H), 7.96 (m, 1H), 7.69 - 7.91 (m, 2H), 7.59 (br. s , 1H), 7.16 - 7.39 (m, 2H), 6.09 (d, 1H), 5.72 (d, 1H), 4.51 (dd, 1H), 3.73 - 3.98 (m, 1H), 2.88 (s, 3H), 2.59 (s, 3H), 2.31 - 2.45 (m, 1H), 2.20 - 2.31 (m, 1H), 1.95 (dt, 1H), 1.02 - 1.13 (m, 1H), 0.68 - 0.78 (m, 1H). e 718: H NMR (400 MHz, DMSO-cfe): d (ppm): 9.95 (br. s , 1H), 8.85 (d, 2H), 7.78 - 7.87 (m, 1H), 7.64 (d, 1H), 7.57 (s, 1H), 7.47 (t, 1H), 7.17 - 7.37 (m, 3H), 5.88 (d, 1H), 5.55 (d, 1H), 5.36 (s, 2H), 4.51 (dd, 1H), 3.77 - 3.86 (m, 1H), 2.58 (s, 3H), 2.23 - 2.37 (m, 2H), 1.84 - 1.97 (m, 1H), 0.95 - 1.09 (m, 1H), 0.74 - 0.89 (m, 1H).
Example 719: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.96 (br. s , 1H), 8.93 - 9.08 (m, 1H), 7.92 (d, 1H), 7.70 - 7.86 (m, 2H), 7.49 (br. s , 1H), 7.19 - 7.39 (m, 2H), 5.90 (d, 1H), 5.60 (d, 1H), 4.50 (dd, 1H), 3.74 - 3.85 (m, 1H), 2.15 - 2.42 (m, 3H), 1.84 - 2.03 (m, 1H), 0.99 - 1.09 (m, 1H), 0.89 - 0.99 (m, 4H), 0.76 - 0.84 (m, 1H).
Example 721: H NMR (400 MHz, DMSO-d 6) : d (ppm): 10.63 (br. s , 1H), 9.29 (s, 1H), 8.40 (d, 1H), 8.05 - 8.23 (m, 2H), 7.82 - 8.02 (m, 2H), 7.44 - 7.71 (m, 2H), 7.15 - 7.33 (m, 3H), 6.02 (d, 1H), 5.69 (d, 1H), 4.43 - 4.60 (m, 1H), 3.72 - 3.93 (m, 1H), 2.20 - 2.38 (m, 2H), 1.87 - 1.97 (m, 1H), 1.00 - 1.08 (m, 1H), 0.75 - 0.84 (m, 1H).
Example 723: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.98 (br. s , 1H), 9.25 (br. s , 1H), 8.09 (br. s , 1H), 7.90 (br. s , 1H), 7.78 - 7.87 (m, 1H), 7.61 (br. s , 1H), 7.22 - 7.39 (m, 2 H), 5.99 (d, 1H), 5.67 (d, 1H), 4.51 (dd, 1H), 3.76 - 3.86 (m, 1H), 2.67 (s, 3H), 2.21 - 2.41 (m, 2H), 1.88 - 1.99 (m, 1H), 1.05 (dt, 1H), 0.82 (m, 1H).
Example 724: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.98 (br. s , 1H), 9.22 (s, 1H), 8.39 (d, 1H), 8.1 1 (d, 1H), 7.77 - 7.93 (m, 2H), 7.47 - 7.67 (m, 1H), 7.22 - 7.36 (m, 2H), 5.99 (d, 1H), .68 (d, 1H), 4.52 (dd, 1H), 3.76 - 3.86 (m, 1H), 2.21 - 2.40 (m, 2H), 1.87 - 1.99 (m, 1H), 1.01 - 1.10 (m, 1H), 0.83 (m, 1H).
Example 726: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.98 (br. s , 1H), 9.08 (s, 1H), 8.10 (s, 1H), 7.78 - 7.90 (m, 2H), 7.57 (br. s , 1H), 7.22 - 7.36 (m, 2H), 5.79 (d, 1H), 5.47 (d, 1H), 4.50 (m, 1H), 3.60 - 3.83 (m, 1H), 2.44 (s, 3H), 2.21 - 2.38 (m, 2H), 1.91 (m, 1H), 0.97 - 1.07 (m, 1H), 0.80 - 0.90 (m, 1H). e 727: H NMR (400 MHz, DMSO-d 6) : d (ppm): 10.77 (m, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.72 (t, 1H), 7,70 (m, 1H), 7.65 (d, 1H), 7.43 (t, 1H), 7.40 (m, 1H), 7.33 (d, 1H), 7.27 (t, 1H), 5.82 (d, 1H), 5.50 (d, 1H), 4.45 (m, 1H), 3.80 (m, 1H), 2.32 (m, 1H), 2.21 (m, 1H), 1.90 (m, 1H), 1.01 (m, 1H), 0.75 (m, 1H).
Example 731: H NMR (400 MHz, DMSO-d 6) : d (ppm): 9.86 (m, 1H), 8.19 (d, 1H), 7.74 (br. t , 1H), 7.67 (m, 1H), 7.66 (d, 1H), 7.45 (br. t , 1H), 7.39 (m, 1H), 7.34 (br. t , 1H), 7.28 (td, 1H), .81 (d, 1H), 5.51 (d, 1H), 4.50 (dd, 1H), 3.80 (m, 1H), 2.30 (m, 2H), 1.92 (m, 1H), 1.04 (m, 1H), 0.77 (m, 1H).
Example 741: H NMR (400 MHz, DMSO-cfe): d (ppm): 11.14 (br.s, 1H), 9.27 (s, 1H), 8.55 (s, 1H), 8.18 (d, 1H), 7.68 (m, 1H), 7.66 (d, 1H), 7.45 (t, 1H), 7.38 (m, 1H), 7.27 (t, 1H), 5.83 (d, 1H), 5.51 (d, 1H), 4.47 (m, 1H), 3.83 (m, 1H), 2.32-2.37 (m, 1H), 2.22-2.28 (m, 1H), 1.91 (m, 1H), 1.01 (m, 1H), 0.77 (m, 1H).
Example 744: H NMR (400 MHz, DMSO-d 6) : d (ppm): 10.77 (m, 1H), 8.18 (d, 1H), 8.04 (d, 1H), 7.72 (t, 1H), 7.67 (m, 1H), 7.64 (d, 1H), 7.44 (t, 1H), 7.37 (m, 1H), 7.33 (d, 1H), 7.26 (t, 1H), 5.78 (d, 1H), 5.44 (d, 1H), 4.40 (m, 1H), 3.59 (m, 1H), 2.46 (dd, 1H), 1.98 (dd, 1H), 1.90 (m, 1H), 1.30 (s, 3H), 0.96 (br. t , 1H), 0.90 (dd, 1H).
Example 746: H NMR (400 MHz, DMSO- ) d (ppm): 90:10 mixture of rotamers, only the major rotamer is described: d (ppm): 10.85 (s, 1H), 8.16 (d, 1H), 8.01 (d, 1H), 7.70 (t, 1H), 7.64 (d, 1H), 7.62 (m, 1H), 7.43 (t, 1H), 7.37 (m, 1H), 7.31 (d, 1H), 7.25 (t, 1H), 5.44 (s, 2H), 4.62 (br. d , 1H), 4.00 (dd, 1H), 3.87 (d, 1H), 1.99 (m, 1H), 1.87 (m, 1H), 0.78 (m, 1H), 0.73 (m, 1H).
Example 754: H NMR (400 MHz, DMSO- ) d (ppm): 85:15 mixture of rotamers, only the major rotamer is bed: d (ppm): 10.98 (m, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.72 (t, 1H), 7.64 (d, 1H), 7.63 (m, 1H), 7.44 (t, 1H), 7.38 (m, 1H), 7.34 (d, 1H), 7.26 (t, 1H), 5.63 (d, 1H), .51 (d, 1H), 5.50-5.34 (m, 1H), 4.90 (m, 1H), 4.33 (m, 1H), 4.23 -4.03 (m, 2H), 3.41 (s, 3H).
Example 762: H NMR (400 MHz, DMSO-d 6) : d (ppm): 10.68 (m, 1H), 8.65 (m, 1H), 8.28 (d, 1H), 8.10 (d, 1H), 8.00 (s, 1H), 7.80 (d, 1H), 7.75 (t, 1H), 7.38 (m, 2H), 7.35 (d, 1H), 7.27 (t, 1H), 7.20 (t, 1H), 4.35 (t, 1H), 3.93 (m, 1H), 2.38 (dd, 1H), 2.17 (m, 1H), 1.80 (m, 1H), 0.85 (m, 1H), 0.55 (m, 1H).
Example 770: H NMR (400 MHz, DMSO-d 6) : 4:1 mixture of rs d (ppm): 9.95 (s, 1H), 7.81 (m, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.30 (m, 1H), 7.27 (m, 1H), 7.14 (dd, 1H), 5.89-5.52 (AB system, 2H), 4.50 (dd, 1H), 4.14 (m, 2H), 3.80 (m, 1H), 3.70 (m, 2H), 3.32 (s, 3H), 2.59 (s, 3H), 2.29 (m, 2H), 1.91 (m, 1H), 1.02 (m, 1H), 0.81 (m, 1H).
Example 773: H NMR (600 MHz, DMSO- ) d (ppm): 85:15 mixture of rotamers d (ppm): 9.15 (t, 0.15H), 8.72 (t, 0.85H), 8.32 (s, 0.15H), 8.23 (s, 0.85H), 8.19 - 8.20 (m, 1H), 7.48 - 7.49 (m, 1H), 7.44 (m, 0.85H), 7.41 (m, 0.15H), 7.20 - 7.23 (m, 2H), 7.18 (t, 0.15H), 7.01 (t, 0.85H), 5.75 (m, 0.15H), 5.67 (m, 0.15H), 5.61 (m, 0.85H), 5.52 (m, 1H), 5.45 (d, , 5.28 (d, 0.15H), .22 (d, 0.85H), 4.72 (m, 1H), 4.54 (m, 0.3H), 4.43 (dd, 0.85H), 4.31 (dd, 0.85H), 4.08-4.25 (m, 1.70H), 4.01 (m, 0.15H), 3.70 (m, 0.15H), 2.43 (s, 3H).
Factor D inhibition data using Method 1 to determine the ICgn s.
Example ICso (nM) e ICso (nM) Example ICso (nM) 1 7 3 1 12150 6 1 7100 2 25 32 3350 62 85 3 450 33 24050 63 400 4 3980 34 90 64 22450 30 35 2850 65 13100 6 2100 36 3250 66 65 7 32 37 22000 67 22200 8 9 38 6300 68 15100 9 250 39 1050 69 1050 604 40 11150 70 2575 1 1 7 4 1 3200 7 1 2900 12 11135 42 2850 72 7000 13 139 43 7750 73 325 14 55 44 2600 74 3650 1100 45 22500 75 12550 16 94 46 22800 76 15650 17 4048 47 8950 77 14550 18 815 48 7500 78 10400 19 10 49 900 79 6000 1126 50 21600 80 14950 2 1 3 1 5 1 8500 8 1 4750 22 191 52 400 82 24750 23 1850 53 1750 83 2250 24 1700 54 1850 84 6000 6750 55 125 85 350 26 25 56 1950 86 14300 27 8300 57 1350 87 4650 28 2525 58 350 88 6800 29 588 59 6400 89 7700 2700 60 800 90 50 9 1 2950 124 500 157 850 92 8650 125 5100 158 80 93 4000 126 00 159 55 94 10950 127 3 160 1400 95 1350 128 2000 161 987 96 8050 129 4 162 5 97 900 130 54 163 100 98 1850 131 4600 164 400 99 23250 132 18 165 140 100 17550 133 6 166 3 101 15200 134 500 167 108 102 567 135 59 168 250 103 550 136 17900 169 268 104 1487 137 300 170 30 105 800 138 9 171 200 106 700 139 1500 172 1050 107 75 140 18300 173 111 108 55 141 650 174 35 109 2700 142 19 175 10 110 20 143 350 176 30 1 1 1 60 144 15 177 85 112 550 145 300 178 6 113 1150 146 9 179 400 114 500 147 120 180 650 115 1536 148 45 181 20 116 1150 149 10800 182 63 117 850 150 25 183 20 118 17500 151 9323 184 9 119 4800 152 4400 185 550 120 3200 153 55 186 20 121 1250 154 1367 187 22200 122 150 155 20 188 1067 123 2930 156 50 189 942 190 20 223 12 256 4000 191 48 224 700 257 3950 192 17750 225 350 258 78 193 160 226 417 259 25 194 93 227 800 260 200 195 14 228 00 261 75 196 700 229 29 262 200 197 100 230 2550 263 400 198 357 231 103 264 10 199 8650 232 989 265 83 200 25 233 850 266 1625 201 20 234 150 267 83 202 450 235 80 268 8 203 6 236 8 269 1600 204 7 237 70 270 54 205 14 238 650 271 629 206 187 239 52 272 271 207 321 240 141 273 2263 208 29 241 250 274 14 209 1900 242 200 275 30 210 22 243 200 276 1310 2 11 1319 244 17 277 627 212 10 245 1046 278 350 213 12 246 2000 279 2900 214 1572 247 400 280 250 215 386 248 119 281 18 216 65 249 1425 282 3675 217 4 1 250 549 283 900 218 24 251 325 284 286 219 1850 252 114 285 55 220 233 253 1068 286 2650 221 23 254 150 287 112 222 137 255 434 288 1100 289 555 322 348 355 104 290 15783 323 902 356 480 291 3250 324 4250 357 389 292 3 325 2250 358 8 293 35 326 7151 359 250 294 5 327 1700 360 1000 295 150 328 102 361 25 296 218 329 181 362 5 297 350 330 250 363 9250 298 7 331 35 364 900 299 1800 332 450 365 45 300 4 333 47 366 3250 301 95 334 53 367 7950 302 75 335 550 368 66 303 8 336 750 369 850 304 653 337 250 370 95 305 1354 338 18900 371 3 306 4 339 65 372 45 307 13300 340 29 373 1 308 127 341 95 374 3 309 550 342 55 375 2 310 475 343 30 376 247 3 11 70 344 68 377 20 312 115 345 800 378 24 313 1300 346 69 379 5 314 20 347 677 380 17 315 13 348 200 381 57 316 3100 349 150 382 184 317 2800 350 85 383 4 318 3 351 600 384 32 319 548 352 200 385 7 320 7 353 252 386 8 321 85 354 1664 387 57 388 28 421 9300 454 103 389 30 422 888 455 767 390 38 423 780 456 85 391 30 424 68 457 107 392 7 425 1232 458 169 393 7 426 436 459 2 11 394 70 427 665 460 20 395 25 428 478 461 6250 396 667 429 1036 462 75 397 3161 430 58 463 3 114 398 3050 431 3 1 464 254 399 1600 432 7 465 1589 400 3950 433 1789 466 43 401 1050 434 35 467 47 402 300 435 250 468 350 403 1000 436 150 469 3350 404 1000 437 107 470 250 405 295 438 924 471 89 406 150 439 1250 472 255 407 1050 440 1050 473 463 408 1400 441 5625 474 95 409 25 442 850 475 350 410 15 443 4468 476 33 4 11 26 444 243 477 628 412 14 445 580 478 258 413 101 446 16 479 89 414 3 11 447 739 480 33 415 48 448 26 481 22 416 315 449 5 1 482 188 417 40 450 25 483 60 418 168 451 90 484 358 419 476 452 15 485 15 420 1150 453 13 486 2450 487 13 520 22 553 5297 488 250 521 37 554 44 489 124 522 415 555 2272 490 214 523 5 1 556 25 491 28 524 64 557 134 492 237 525 36 558 1986 493 108 526 54 559 15700 494 50 527 483 560 141 495 19 528 75 561 14 496 176 529 186 562 804 497 128 530 72 563 42 498 692 531 11 564 13 499 36 532 223 565 369 500 36 533 34 566 436 501 471 534 5 1 567 293 502 449 535 62 568 121 503 115 536 121 569 13 504 57 537 609 570 27 505 14 538 9 11 571 99 506 331 539 3 1 572 284 507 16 540 236 573 865 508 12 541 9 1 574 217 509 58 542 19 575 843 510 16 543 245 576 400 11 7 1 544 1110 577 7 1 512 4 11 545 113 578 50 513 193 546 10 579 39 514 95 547 38 580 252 515 268 548 363 581 60 516 8 549 69 582 134 517 1456 550 33 583 25 518 4 1 551 899 584 38 519 722 552 40 585 17 586 132 619 14 652 19 587 79 620 17 653 47 588 3 1 621 19 654 18 589 237 622 5595 655 9 1 590 10 623 24 656 358 591 109 624 26 657 78 592 115 625 19 658 24 593 56 626 36 659 25 594 85 627 16 660 16 595 4 1 628 38 661 10 596 95 629 17 662 13 597 14 630 36 663 36 598 14 631 11 664 24 599 46 632 18 665 58 600 14 633 55 666 6 601 110 634 53 667 16 602 227 635 18 668 19 603 1613 636 13 669 10 604 37 637 9 670 90 605 54 638 5 671 77 606 14 639 62 672 178 607 28 640 8 673 157 608 1835 641 32 674 75 609 1559 642 15 675 23 610 45 643 25 676 11 6 11 141 644 79 677 10 612 3433 645 132 678 40 613 215 646 12 679 134 614 245 647 16 680 16 615 42 648 17 681 19 616 123 649 441 682 12 617 28 650 22 683 48 618 39 651 2 1 684 27 685 5 715 27 745 5 686 30 716 46 746 7 687 98 717 3 1 747 13 688 10 718 24 748 4 689 156 719 13 749 4 690 34 720 140 750 34 691 68 721 98 751 8 1 692 3 722 20 752 95 693 6 723 90 753 66 694 17 724 6 1 754 5 695 15 725 18 755 17 696 101 726 169 756 7 697 3 727 9 757 3 698 29 728 8 758 64 699 118 729 62 759 9 700 6 730 143 760 12 701 15 731 53 761 70 702 10 732 44 762 5 703 10 733 25 763 14 704 23 734 4 764 4 705 2 1 735 3 765 2 11 706 45 736 18 766 216 707 88 737 36 767 346 708 54 738 93 768 146 709 144 739 23 769 378 710 52 740 13 770 9 711 71 741 5 771 8 712 38 742 37 772 7 713 260 743 5 773 28 714 300 744 4 hout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the ion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information d from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
THE

Claims (1)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A compound or salt thereof represented by one of the formulae (IIIb) or (IVb): Z 6 Z 5 Z 7 Z 2 N N G (CR21R 22)q O R 3 O R 15 R 16 R 19 R 17 Z (IIIb) N N G (CR21R 22)q O R 3 L O R 15 R 16 R 19 R 6 R 5 R 17 Z (IVb) H:\rec\Interwoven\NRPortbl\DCC\REC\7971025_1.doc-
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