NZ718056B2

NZ718056B2 - Glucosylceramide synthase inhibitors for the treatment of diseases

Info

Publication number: NZ718056B2
Application number: NZ718056A
Authority: NZ
Inventors: Alexander James Bridges; Daniel Chu; Bing Wang
Original assignee: Biomarin Pharmaceutical Inc
Priority date: 2013-09-20
Filing date: 2014-09-19
Publication date: 2022-01-06

Abstract

Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

Description

GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES CROSS REFERENCE TO RELATED ATIONS The present application claims the beneﬁt of priority of US. Provisional Application No. 61/880,752, ﬁled September 20, 2013, the t of which is hereby incorporated by reference in its ty.

FIELD Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

BACKGROUND Glucosylceramide synthase (GCS) is a key enzyme which catalyzes the initial glycosylation step in the thesis of glucosylceramide-based glycosphingolipids (GSLs) namely via the transfer of glucose from UDP-glucose (UDP-Glc) to ceramide to form glucosylceramide. GCS is a transmembrane, type III integral n localized in the cis/medial golgi. Glycosphingolipids (GSLs) are believed to be integral in many cell membrane , including cellular interactions, signaling, and trafﬁcking. Synthesis of GSL structures has been shown (Proc. Natl. Acad. Sci CJSA 1999, 96(16), 9142-9147) to be essential for embryonic development and for the differentiation of some s. Ceramide plays a central role in sphingolipid metabolism, and downregulation of GCS activity has been shown to have marked effects on the sphingolipid pattern with shed expression of phingolipids. Sphingolipids have a role in physiological as well as pathological cardiovascular conditions. In particular, sphingolipids and their regulating enzymes appear to play a role in adaptive responses to chronic hypoxia in the neonatal rat heart (Prostaglandins & Other Lipid Mediators 2005, 78(1-4), 249-263).

GCS inhibitors have been proposed for the ent of a variety of diseases (see, for example, WO2005068426). Such diseases include glycolipid e es (e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fabry diseases), diseases associated with glycolipid accumulation (e.g., Gaucher disease), diseases that cause renal hypertrophy or hyperplasia such as diabetic nephropathy, diseases that cause hyperglycemia or hyperinsulinemia, s in which glycolipid synthesis is abnormal, infectious diseases caused by organisms which use cell e glycolipids as receptors, infectious diseases in which synthesis of ylceramide is essential or ant, diseases in which excessive glycolipid synthesis occurs (e.g., sclerosis, polycystic kidney disease, and renal hypertrophy), neuronal disorders, neuronal injury, inﬂammatory diseases or disorders ated with macrophage tment and activation (e.g., rheumatoid arthritis, Crohn's disease, asthma and sepsis), pain (see W02008011483 — neuropathic pain, inﬂammatory pain, headache pain, somatic pain, visceral pain, referred pain), cognitive disorders (see W02008/109286 — agnosia; amnesia; a; an apraxia; delirium; dementia including AIDS dementia complex, Binswanger's disease, dementia with Lewy Bodies, frontotemporal dementia, mild cognitive impairment, multi-infarct dementia, Pick's disease, semantic dementia, senile dementia, and vascular dementia; and learning disorders including Asperger's syndrome, attention deﬁcit disorder, attention deﬁcit hyperactivity disorder, autism, childhood disintegrative disorder, and Rett syndrome), neurodegenerative disorders (such as Alzheimer's disease, corticobasal degeneration, Creutzfeldt-Jacob e, frontotemporal lobar degeneration, Huntington disease, multiple sclerosis, normal pressure hydrocephalus, organic chronic brain syndrome, Parkinson's disease, Pick disease, progressive supranuclear palsy, and senile dementia (Alzheimer type), glomerular disease, and diabetes mellitus and obesity (see WO 2006053043). Renal hypertrophy induced by diabetes is associated with enhanced synthesis of glycosphingolipids such as glucosylceramide and ganglioside GM3 which accumulate in the kidney of rats (J. Clin.

Invest. 1993, 91(3), 797).

It has been shown that pression of GCS is implicated in multi-drug resistance and disrupts de-induced apoptosis. For example, Turzanski et al.

(Experimental logy 2005, 33(1), 62-72) have shown that ceramide induces apoptosis in acute myeloid leukemia (AML) cells and that P-glycoprotein (p-gp) confers resistance to ceramide-induced apoptosis, with modulation of the ceramide-glucosylceramide pathway making a marked contribution to this resistance in TF-I cells. Thus, GCS inhibitors can be useful for treatment of proliferative ers (such as cancer) by inducing apoptosis in diseased cells.

Sandhoff (or type 2 GM2 gangliosidosis) is caused by a deﬁciency in B-hexosaminidase A and B activity which leads to an accumulation of the ganglioside GM2 and other glycolipids causing damage to the central nervous system and eventually is lethal (PLOS One 2011, 6(6), ). chs e (or GM2 gangliosidosis) is caused by a ncy in B-hexosaminidase A which lead to an lation of osides in the brain’s nerve cells eventually leading to their premature death. Intravenous injection of the missing enzyme(s) is not a viable option as of the enzymes does cross the blood-brain barrier (Genetics in Medicine 2009, 1(6), 425). Glucosylceramide synthase is a key enzyme in the synthesis of glucosylceramide and other glycosphingolipids. Its inhibition can decrease the amount of the glycosphingolipids which accumulate in Sandhoff disease.

Fabry disease is caused by loss of activity of the lysosomal hydrolase ugalactosidase which leads to an accumulation of glycosphingolipids (particularly globotriaosylceramide) causing pain, renal disease and failure, cerebral vascular e, and myocardial infarction (Kidney International 2000, 5 7, 446). One treatment strategy is to e the defective enzyme to the patient; however, enzyme replacement therapy can only slow the progression of the e and is not a cure. An ative or complementary strategy is one where glucosylceramide synthase, a key enzyme in the synthesis of glycosphingolipids, is inhibited with a small molecule thus decreasing the amount of globotriaosylceramide and other glucosylceramide-based lipids that need to be broken down by hydrolase (x-galactosidase.

Gaucher disease is caused by a defect in the enzyme lysosomal glucocerebrosidase which is responsible for catalyzing the breakdown of glucosylceramide which then accumulates in tissues of affected people (J. Org. Chem. 2007, 72(4), 1088) g liver malfunction, skeletal disorders, l bone lesions, hypersplenism, pancytopenia, and neurological symptoms lsions, hypertonia, mental retardation, apnea, dementia, and ocular muscle apraxia). One treatment strategy is to provide the defective enzyme to the t; however, enzyme replacement therapy is not suitable for all patients and does not address the neurological manifestations of the disease for those with type 2 and type 3. An alternative or complementary strategy is one where glucosylceramide synthase is inhibited with small molecules thus decreasing the amount of glucosylceramide that needs to be broken down by glucocerebrosidase.

Nonalcoholic fatty liver disease (NALD) is a disease where fat accumulates in the liver of people who drink little or no alcohol and results in inﬂammation and ng of the liver which can progress to liver failure. Inhibition of glucosylceramide se in ob/ob mice lowered glucose levels, lowered liver/body weight ratio, decreased the accumulation of triglycerides, and prevented and reversed steatosis (Hepatology 2009, 50(1), 85-93). Thus GCS inhibitors are useful for the prevention and treatment ofNALD. stic kidney disease (PKD) is a genetic disease terized by noncancerous cysts which are filled with fluid and cause the kidneys to e which can result in a decrease in quality of life (e.g., headaches, high blood pressure, back and side pain, colon problems, mitral valve prolapsed, and kidney stones) and can be life-threatening (e.g. kidney failure, aneurysm in the brain, and high blood pressure which can lead to heart disease and stroke). PKD can also damage the liver, spleen, pancreas, vasculature, testes, seminal vesicles, and intestines. Glucosylceramide and ganglioside GM3 levels in the kidney are higher than in normal tissue (Nat Med 2010, 16(7), 788). Thus, blocking the synthesis of glucosylceramide with an inhibitor of GCS can be useful in the treatment of PKD to reduce new cyst formation (partial or complete inhibition of cystogenesis), reduce cyst mass, reduce the size and number of cysts, and/or reduce the severity of the symptoms associated. All t treatments for PKD address symptoms and do not treat the underlying cause of the disease (Nat Med 2010, 16(7), 788).

SUMMARY OF THE INVENTION The present invention particularly relates to a compound of Formula I: where R1 is –C(O)C(R6)(R6a)R1a or –C(O)C(R6)(R6a)-X1-R1a; X1 is ne, alkenylene, or cycloalkylene; R1a is alkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R7 ; R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R8; R4 is aryl substituted with a halo and a cycloalkyloxy group; R5 is –OH, and R5a is hydrogen; R6 and R6a together with the carbon to which they are attached form C(=NOH) or C(O); each R7, when present, is independently nitro, cyano, amino, alkylamino, lamino, halo, kyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, heterocycloalkyl, , phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or heteroaryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1, 2 or 3 R7a; each R7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, yalkyl, and cycloalkyl; each R8, when present, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, kyl, or cycloalkyl; or two R8 together with the carbon to which they are attached form C(O); R12 is hydrogen or C1-5 alkyl; and optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally ally a pharmaceutically acceptable salt thereof.

In a further aspect, provided is a pharmaceutical ition comprising 1) a compound of Formula I optionally as a tautomer, a single stereoisomer or mixture of stereoisomers f and additionally optionally as a pharmaceutically acceptable salt thereof, and 2) a ceutically acceptable excipient or pharmaceutically acceptable carrier.

In a further aspect, provided is a method of treating a disease or disorder, in particularly in a non-human animal comprising administering a compound of Formula I, optionally as a tautomer, a single isomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, or the pharmaceutical ition f additionally comprising a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier. In a still further aspect, provided is the use of compound of Formula I, or a pharmaceutical composition comprising a nd of formula I and a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier in the manufacture of a ment for treating a e or disorder. [00013a] These and other aspects and embodiments are described further below.

Certain aspects and embodiments may be broader than or fall outside the scope of the present invention as described above. These aspects are included herein for completeness and may form the subject of the divisional application, NZ 756043.

In a ﬁarther aspect, it is ed a method of making a compound of Formula I, comprising a) treating an intermediate of formula 100 R{ ,R3 N OH 1 00 or a salt therof, Where R2, R3, R4, and all other groups are as deﬁned in the Summary of the Invention or as in any of the embodiments described herein; with an intermediate of formula R1C(O)OH using standard amide coupling conditions to yield a Compound of Formula I Where R5 is hydroxy and R5&1 is hydrogen and R1 is as deﬁned in the Summary of the ion or as in any of the embodiments described herein; and b) optionally separating individual isomers.

DETAILED DESCRIPTION iations Abbreviation Meanin_ ACN acetonitrile _aueous tert—butox carbon 1 concentrated dieth laminosulfur trifluoride diiso.ro leth lamine dichlorormethane diisobu num h dride dimeth lformamide Dess-Martin oeriodinane dimeth lsulfoxide l-eth l 3-dimeth lamino..ro lcarbodiimide hours HATU 0-(7-azabenzotriazol- l -yl)-N,N,N', '-tetramethyluronium hexaﬂuoro o hos 0 hate HOBt h drox benzotriazole milliram N meahertz ‘b iter microliter mes l mosuccinimideNBS NMR nuclear c resonance 2014/056555 —Abbreviation Meanin_ oetroleum ether room temoerature sat saturated TBAF tetra-n-but lammonium ﬂuoride TBDMS tert—but ldimeth lsil 1 TBS ut l-sil l trieth lamine triﬂuoroacetic acid tetrah drofuran thin layer chromatography Deﬁnitions To facilitate understanding of the disclosure set forth herein, a number of terms are deﬁned below. Generally, the nomenclature used herein and the tory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless deﬁned otherwise, all technical and scientiﬁc terms used herein generally have the same g as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

] As used throughout this application and the appended claims, the following terms have the following meanings: "About" preceding a numerical value refers to a range of values ::10% of the value speciﬁed.

"Acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

"Alkoxy" means an —OR group where R is alkyl, as deﬁned herein. In some embodiments, alkoxy includes, but are not limited to, y, ethoxy, propoxy, 2-pr0p0xy, butoxy, utoxy, pentyloxy, and hexyloxy.

"Alkoxycarbonyl" means a -C(O)R group where R is alkoxy, as deﬁned yl" means a straight or ed hydrocarbon radical having from 2 to 8 carbon atoms and at least one double bond. "Lower alkenyl" means an alkenyl group having one to six carbon atoms. In some embodiments, alkenyl includes ethenyl, propenyl, l-butenyl, l-pent-3 -enyl, l-heX-S-enyl and the like.

"Alkenylene" means a divalent alkenyl group, as deﬁned herein.

] "Alkenyloxy" means an —OR group where R is alkenyl, as deﬁned herein.

"Alkyl" means a straight or branched saturated hydrocarbon radical containing from 1-10 carbon atoms, in another example 1-6 carbon atoms. In some embodiments, alkyl es, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

"Alkylamino" means a -NHR radical where R is alkyl as deﬁned herein, or an N-oxide derivative thereof. In some embodiments, alkylamino includes methylamino, ethylamino, n-, iso-propylamino, n-, is0-, tert—butylamino, or methylamino-N-oxide, and the like.

] "Alkylaminoalkyl" means an alkyl group substituted with one or two mino groups, as deﬁned herein.

"Alkylaminocarbonyl" means a -C(O)NHR group where R is alkyl, as deﬁned herein.

"Alkylene" means a divalent alkyl group, as deﬁned herein.

"Alkynyl" means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one triple bond.

"Amino" means -NH2.

] "Aminoalkyl" means an alkyl group substituted with at least one, for e one, two, or three, amino groups.

"Aminocarbonyl" means a -C(O)NH2 group.

] "Aryl" means a monovalent six- to fourteen-membered, mono- or bi- carbocyclic ring, wherein the monocyclic ring is ic and at least one of the rings in the bicyclic ring is aromatic. In some embodiments, the examples of aryl e phenyl, naphthyl, and indanyl, and the like.

"Carboxy" means a -C(O)OH group.

] "Cycloalkyl" means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon radical of three to ten carbon ring atoms. Fused bicyclic hydrocarbon radical includes bridged rings. Cycloalkyl includes spirocycloalkyl rings. Unless stated otherwise, the y of the group may be located on any atom of any ring within the radical, y rules permitting. One or two ring carbon atoms may be ed by a -C(O)-, -C(S)-, or -C(=NH)- group.

In some embodiments, cycloalkyl includes but is not d to: "Cycloalkylene" means a divalent cycloalkyl group, as deﬁned herein. alkylalkyl" means an alkyl group, as deﬁned , substituted with at least one, in another example I or 2, cycloalkyl groups as deﬁned herein.

"Cycloalkylalkyloxy" means an -OR group where R is a cycloalkylalkyl group as deﬁned herein.

"Cycloalkyloxy" means an -OR group where R is lkyl, as deﬁned herein. alkylthio" means an -SR group where R is cycloalkyl, as deﬁned herein.

"Dialkylamino" means an -NRR’ radical where R and R’ are independently alkyl as deﬁned , or an e derivative, or a protected derivative thereof. In some embodiments, dialkylamino includes dimethylamino, diethylamino, N,N—methylpropylamino or N,N—methylethylamino, and the like.

"Dialkylaminoalkyl" means an alkyl group substituted with at least one, for example one or two, dialkylamino group(s), as deﬁned herein.

"Dialkylaminocarbonyl" means a -C(O)NRR’ group where R and R’ are alkyl, as deﬁned herein.

"Haloalkoxy" means an alkoxy group, as deﬁned herein, substituted with one or more halo atoms, in another example by l, 2, or 3 halo atoms.

"Haloalkyl" means an alkyl group substituted with one or more halo atoms, in another example by l, 2, 3, 4, 5, or 6 halo atoms, in another e by l, 2, or 3 halo atoms.

In some embodiments, haloalkyl includes, but is not limited to, triﬁuoromethyl, chloromethyl, and the like.

"Heteroaryl" means monocyclic, fused bicyclic, or fused tricyclic, radical of 5 to 14 ring atoms containing one or more, in another example one, two, three, or four ring heteroatoms independently selected from -O-, -S(O)n- (n is 0, l, or 2), -N-, -N(H)-, and N—oxide, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or lic radical is aromatic (but does not have to be a ring which contains a heteroatom, e. g. 2,3-dihydrobenzo[b][l,4]dioxinyl). One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)—, or -C(=NH)— group. Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, y rules permitting.

In some embodiments, heteroaryl es, but is not limited to, lyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, ﬁlranyl, pyrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, indolyl, 2,3-dihydro-lH—indolyl (including, for example, 2,3-dihydro-lH—indolyl or 2,3-dihydro- lH-indol-S -yl, and the like), indazolyl, phthalimidyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiazolyl, nyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolinyl or tetrahydroisoquinolinyl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridinyl or pyrrolo[3,2-c]pyridinyl, and the like), pyrrolo[l ,2- b]pyridazinyl, imidazo[ l ,2-a]pyridinyl, thiazolyl, benzo[d] [ l ,3]dioxolyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, ﬁlro[2,3-d]thiazolyl, thieno[2,3-d]oxazolyl, thieno[3,2- b]ﬁ1ranyl, ,3-d]pyrimidinyl, ﬁlro[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, 6,7-dihydro-5H— cyclopenta[b]pyridinyl, and 7,8-dihydro-6H—cyclopenta[g]quinoxalinyl; and derivatives, N- oxide and ted derivatives thereof.

"Heteroarylalkyl" means an alkyl group, as deﬁned herein, substituted with one or two heteroaryl groups, as deﬁned herein.

"Heteroaryloxy" means an —OR group where R is heteroaryl as deﬁned herein.

"Heterocycloalkyl" means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group of 3 to 9 ring atoms or a ted or partially unsaturated (but not aromatic) monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more heteroatoms, for example one, two, three, or four ring heteroatoms, independently selected from -O-, -S(O)n- (n is 0, l, or 2), -N=, -NH-, and e, the ing ring atoms being . One or two ring carbon atoms may be replaced by a , -C(S)—, or -C(=NH)— group. Fused ic radical includes d ring systems.

Unless ise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Heterocycloalkyl includes spiroheterocycloalkyl rings.

In some embodiments, heterocycloalkyl includes, but is not limited to, azetidinyl, idinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH— pyrrolinyl, oxo-lH— pyrrolyl, 2,5-dioxo-pyrrolidinyl, 2,5-dihydro-lH—pyrrolyl, piperidinyl, 2-oxopiperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, iperazinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, l,3-dioxinyl, l,3-dioxanyl, l,4-dioxinyl, l,4-dioxanyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, lidinyl, imidazolinyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl, dihydropyridinyl, ydropyridinyl, oxazolinyl, oxazolidinyl, olidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, 2-azaspiro[3.3]heptanyl, icyclo[2.2.l]heptanyl, and 8-azabicyclo[3.2. l]octanyl, and the derivatives thereof and N-oxide (for example l-oxidopyrrolidin-l-yl ) or a protected derivative thereof.

"Heterocycloalkylalkyl" means an alkyl group substituted with at least one, in another example 1 or 2, heterocycloalkyl groups, as deﬁned herein.

] "Heterocycloalkylalkyloxy" means an —OR group where R is an heterocycloalkylalkyl group, as deﬁned herein. ocycloalkyloxy" means an -OR group where R is heterocycloalkyl, as deﬁned herein.

"Hydroxyalkyl" means an alkyl group, as deﬁned herein, substituted with l, 2, or 3 hydroxy groups. xyalkyloxy" means an —OR group where R is hydroxyalkyl, as deﬁned herein.

"Phenylalkyl" means an alkyl group, as deﬁned herein, substituted with one or two phenyl groups.

"Phenyloxy" means an —OR group where R is phenyl.

The term cting group" refers to a removable group which modiﬁes the reactivity of a functional group, for example, a hydroxyl, ketone or amine, against undesirable reaction during synthetic procedures and to be later removed. Examples of hydroxy-protecting groups include, but not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, ethers such as methoxymethyl, and esters including , benzoyl, and the like. Examples of ketone protecting groups include, but not limited to, ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, l-isopropoxycyclohexyl oxime, and the like. Examples of amine protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc) and carbobenzyloxy (Cbz). oisomers" include (but are not limited to) geometric isomers, enantiomers, diastereomers, and mixtures of geometric isomers, enantiomers or diastereomers. In some embodiments, individual stereoisomers of compounds are ed synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are iﬁed by (l) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or tography and liberation of the optically pure product from the auxiliary or (2) direct separation of the e of optical enantiomers on chiral chromatographic column.

As used herein, "amelioration" of the symptoms of a particular disorder by administration of a particular nd or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, g or transient that can be attributed to or associated with administration of the compound or composition.

The term "carrier" includes pharmaceutically inert, nic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch, or derivatives thereof, talc, c acid or its salts and the like can be used, for example, as such carriers for s, coated tablets, s and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatin es, other than the soft gelatin itself. Suitable carriers for the production of solutions and syrups are, for example, water, s, glycerol, ble oils and the like. Suitable carriers for suppositories are, for e, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The term "diluent" refers to chemical nds that are used to dilute the compound of interest prior to delivery. Diluents include chemicals used to stabilize compounds because they provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in some or any embodiments, including, but not limited to a phosphate buffered saline solution.

The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufﬁcient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated.

The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically signiﬁcant decrease in disease symptoms. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

] "Excipient" or "pharmaceutically acceptable ent" means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one ment, each component is " pharmaceutically acceptable" in the sense of being ible with the other ients of a pharmaceutical formulation, and le for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a able benefit/risk ratio. See, e.g, Remington: The Science and Practice ofPharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook ofPharmaceutical Excipients, 6th ed.; Rowe et al. The Pharmaceutical Press and the American ceutical Association: 2009; , Eds.; Handbook ofPharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformalation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

"Pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

In some ces, pharmaceutically acceptable salts are obtained by reacting a nd having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a ium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, yl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not speciﬁcally limited as far as it can be used in medicaments. es of a salt that the compound of the present ion forms with a base include the following: salts thereofwith inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereofwith organic bases such as methylamine, mine and ethanolamine; salts thereof with basic amino acids such as lysine and omithine; and ammonium salt. The salts may be acid addition salts, which are speciﬁcally iﬁed by acid addition salts with the ing: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, ﬁlmaric acid, maleic acid, lactic acid, malic acid, ic acid, citric acid, esulfonic acid, and sulfonic acid; acidic amino acids such as ic acid and glutamic acid.

The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical ents, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening , and/or ents. The pharmaceutical composition facilitates administration of the nd to an sm.

Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. ct" refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

"Treat," "treating," and "treatment," in the context of treating a disease or disorder, are meant to include alleViating or abrogating a er, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the e, disorder or condition.

Embodiments The following paragraphs present a number of embodiments of the compounds disclosed herein. In each instance the embodiment es both the recited compound(s) as well as a single stereoisomer or mixture of stereoisomers thereof, as well as a pharmaceutically acceptable salt thereof. The compounds include the N-oxides or pharmaceutically acceptable salts thereof In some situations, the compounds exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

The compounds described herein, as well as their corresponding ceutically acceptable salts f, can exist in isotopically-labeled form, in which one or more atoms of the compounds are replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, , phosphorous, sulfur, ﬂuorine, and chloride, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O, 31P, 32P, 358, 18F, and 36Cl, tively. Isotopically labeled compounds of the present invention, as well as pharmaceutically acceptable salts thereof, generally can be prepared by carrying out the procedures sed in the Schemes and/or in the Examples and Preparations herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

In the compounds of the invention, unless otherwise stated, any atom not speciﬁcally designated as a particular isotope is meant to ent any stable isotope of that atom at is natural abundance. When a position is designated as "H" or "hydrogen," the position is to be understood to have hydrogen at is naturally abundant isotopic composition, with the understanding that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis.

When a particular position is designated as "D" or "deuterium," it is to be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, with is 0.015%, and lly has at least 50% deuterium incorporation at that position.

] The s sed herein also include methods of treating diseases by administering ated compounds of the invention or other isotopically-labeled compounds of the invention alone or as ceutical itions. In some of these situations, substitution of hydrogen atoms with heavier isotopes such as deuterium can afford certain therapeutic ages ing from greater metabolic stability (for e, increased in vivo half-life or reduced dosage requirements). Moreover, certain isotopically- labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays such as positron emission tomography (PET). Tritiated (3H) and carbon-l4 (14C) isotopes are useful for these embodiments.

In one aspect, provided is a compound of Formula 1: R2\ ,R3 N R5 RXR‘tR53 R1/ \R12 Formula I where R1 is —C(O)C(R6)(R6a)R1a or (R6)(R6a)-X1-R1a; X1 is alkylene, lene, or cycloalkylene; R1&1 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R7 groups; R2 is hydrogen, hydroxy, or alkyl; and R3 is alkyl, aminoalkyl, minoalkyl, or dialkylaminoalkyl; R2 and R3 together with the nitrogen to which they are attached form a 3-10 ed heterocycloalkyl ring, optionally substituted with l, 2, 3, 4, 5, 6, 7, or 8 R8; R4 is aryl or heteroaryl each of which is ally tuted with l, 2, 3, or 4 R9 groups; R5 is halo, -OH, -OTBS, -N3, -NH2, -NH(OCH3), -NHC(O)CH3, or -NHC(O)H; and R5&1 is hydrogen, alkyl, or deuterium; or R5 and R5&1 together with the carbon to which they are attached form C(O) or C(NOH); R6 is halo or deuterium; and R6&1 is hydrogen, halo, or deuterium; or R6 and R6&1 together with the carbon to which they are attached form C(=NOR10) or C(O); each R7, when present, is independently nitro, cyano, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, aryl, arylalkyl, or aryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with l, 2 or 3 R721; each R7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl; each R8, when present, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl; or two R8 together with the carbon to which they are attached form C(O); each R9, when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, -NR11C(O)NR11aR11b,hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, -l6- haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, or ; where the heterocycloalkyl and the phenyl, either alone or as part of another group, are ndently optionally substituted with l or 2 Rga; each R9a, when present, is independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino; R10 is hydrogen, alkyl, or phenyl; R11, Rlla, and R11b are independently hydrogen, alkyl, or cycloalkyl; and R12 is hydrogen or C1_5 alkyl; optionally a er, a single isomer or mixture of stereoisomers thereof and additionally ally a pharmaceutically acceptable salt thereof.

] In some or any embodiments, the compound of Formula I is that where R1 is —C(O)C(R6)(R6a)R1a or —C(O)C(R6)(R6a)-X1-R1a; X1 is alkylene, alkenylene, or cycloalkylene; R1&1 is alkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R7 groups; R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with l, 2, 3, 4, 5, 6, 7, or 8 R8; R4 is aryl or heteroaryl each of which is ally substituted with l, 2, 3, or 4 R9 groups; R5 is —OH, and R581 is hydrogen; R6 and R6&1 are halo; R6 and R6&1 are deuterium; or R6 and R6&1 together with the carbon to which they are attached form C(=NOH) or C(O); each R7, when present, is independently nitro, cyano, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or aryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with l, 2 or 3 R721; each R7a, when present, is ndently selected from cyano, halo, alkyl, l, haloalkyl, hydroxyalkyl, and cycloalkyl; each R8, when present, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl; or two R8 er with the carbon to which they are attached form C(O); each R9, when present, is independently cyano, nitro, amino, alkylamino, lamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl, cycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the cycloalkyl and the phenyl, either alone or as part of another group, are independently optionally substituted with l or 2 Rga; each R9a, when present, is independently selected from alkyl, y, alkoxy, halo, kyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino; and R12 is hydrogen or C1_5 alkyl; optionally a tautomer, a single isomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

In some or any embodiments, the compound of a I is that where R1 is —C(O)C(R6)(R6a)R1a or —C(O)C(R6)(R6a)-X1-R1a; X1 is alkylene, lene, or cycloalkylene; R1&1 is alkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R7 groups; R2 and R3 er with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl; each of which is optionally substituted with l or 2 R8; R4 is aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R9 groups; R5 is —OH, and R581 is hydrogen; R6 and R6&1 are halo; or R6 and R6&1 together with the carbon to which they are attached form C(=NOH) or C(O); each R7, when t, is independently nitro, cyano, halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or heteroaryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with l, 2 or 3 R721; each R7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl; each R8, when present, is independently amino, mino, dialkylamino, alkyl, halo, or cycloalkyl; or two R8 together with the carbon to which they are ed form C(O); each R9, when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and the phenyl, either alone or as part of another group, are independently optionally substituted with l or 2 Rga; each R9a, when present, is independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, mino, and dialkylamino; and R12 is hydrogen or CH3; optionally a tautomer, a single stereoisomer or e of stereoisomers thereof and additionally optionally a ceutically acceptable salt thereof.

In some or any ments, the compound of Formula I is that where R1 is —C(O)C(R6)(R6a)R1a or —C(O)C(R6)(R6a)-X1-R1a; X1 is alkylene or alkenylene; R1&1 is cycloalkyl, aryl or heteroaryl each of which is optionally substituted with l or 2 R7 ; R2 and R3 together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic cycloalkyl; each of which is optionally substituted with l or 2 R8; R4 is aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R9 groups; R5 is —OH, and R581 is hydrogen; R6 and R6&1 are halo; or R6 and R6&1 together with the carbon to which they are attached form C(=NOH) or C(O); each R7, when present, is independently cyano, halo, kyl, alkyl, alkynyl, cycloalkyl, cycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, or heteroaryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with l or 2 R721; each R7a, when present, is independently ed from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl; each R8, when present, is independently amino, alkyl, or halo; or two R8 together with the carbon to which they are attached form C(O); each R9, when present, is independently amino, halo, haloalkyl, alkyl, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and the phenyl, either alone or as part of r group, are independently optionally substituted with l or 2 Rga; each R9a, when present, is independently selected from alkyl or halo; R10 is hydrogen or CH3; R12 is hydrogen; and optionally a er, a single stereoisomer or mixture of stereoisomers f and onally optionally a pharmaceutically acceptable salt thereof.

In some or any embodiments, the compound of Formula I is that where R1 is —C(O)C(R6)(R6a)R1a or —C(O)C(R6)(R6a)-X1-R1a; X1 is alkylene; R1&1 is heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R7 groups; R2 and R3 together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl; each of which is optionally substituted with l or 2 R8; R4 is aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R9 groups; R5 is —OH, and R581 is hydrogen; R6 and R6&1 are halo; or R6 and R6&1 together with the carbon to which they are attached form or C(O); each R7, when present, is independently nitro, cyano, halo, haloalkyl, alkyl, alkenyl, alkynyl, lkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or aryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally tuted with l, 2 or 3 R721; each R7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl; each R8, when present, is independently amino, alkylamino, dialkylamino, alkyl, or halo; each R9, when present, is independently amino, mino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, lkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl, cycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and the phenyl, either alone or as part of r group, are independently optionally substituted with l or 2 Rga; each R9a, when present, is independently selected from alkyl and halo; and R12 is hydrogen or CH3; optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

WO 42397 In another aspect, provided is a nd of Formula II: R{ ,R3 N R5 R53 Formula II where R1 is —C(O)C(R6)(R6a)R1a or -C(O)C(R6)(R6a)-X1-R1a; X1 is ne, alkenylene, or cycloalkylene; R1&1 is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R7 ; R2 is hydrogen, hydroxy, or alkyl; and R3 is alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; or R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally substituted with l, 2, 3, or 4 R8; R4 is aryl or heteroaryl each of which is optionally substituted with l, 2, or 3 R9 groups; R5 is halo, -OH, -OTBS, -N3, -NH2, -NH(OCH3), -NHC(O)CH3, or -NHC(O)H and R581 is hydrogen, alkyl, or deuterium; or R5 and R5&1 together with the carbon to which they are attached form C(O) or C(NOH); R6 is halo or deuterium; and R6&1 is hydrogen, halo, or deuterium; or R6 and R6&1 together with the carbon to which they are attached form C(=NOR10) or C(O); each R7, when present, is independently nitro, cyano, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, haloalkoxy, carboxy, carbonyl, arbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or heteroaryl; each R8, when t, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl; each R9, when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, -NR11C(O)NR11aR11b,hydroxy, alkoxy, haloalkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy which is ally substituted with l or 2 y; R10 is hydrogen, alkyl, or ; R11, Rlla, and R11b are independently hydrogen, alkyl, or cycloalkyl; and optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

In some or any embodiments, the compound of Formula I or II is that where R1 is (R6)(R6a)R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)R1a; R6 and R6&1 are halo; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)CF2R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any ments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)R1a; R6 is halo and R6&1 is en; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of a I or II is that where R1 is -C(O)C(H)(F)R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)CD2R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)R1a; R6 and R6&1 together with the carbon to which they are attached form 10); and all other groups are as deﬁned in the Summary of the Invention or any of the ments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is (R6)(R6a)R1a; R6 and R6&1 together with the carbon to which they are attached form C(O); and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R1 is (R6)(R6a)-X1-R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)-X1-R1a; R6 and R6&1 are halo; and all other groups are as deﬁned in the Summary of the Invention or any of the ments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)CF2-X1-R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the ments described herein.

In some or any embodiments, the compound of a I or II is that where R1 is -C(O)C(R6)(R6a)-X1-R1a; X1 is ne; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)-CH2-R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments bed herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)-CH2CH2-R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any ments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)-X1-R1a; X1 is lene; and all other groups are as deﬁned in the Summary of the Invention or any of the ments described herein. In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)-X1-R1a; X2 is - or -C(=CH2)CH2-; and all other groups are as deﬁned in the Summary of the Invention or any of the ments described herein.

In some or any embodiments, the compound of Formula I or II is that where R1 is -C(O)C(R6)(R6a)-X1-R1a which is -C(O)C(halo)2CH2R1a, -C(O)C(halo)2CH2CH2R1a, -C(O)C(O)CH2CH2R1a, -C(O)C(=NOH)CH2CH2R1a, -C(O)C(=NOCH3)CH2CH2R1a, -C(O)C(halo)2-CH=CHR1a, or -C(O)C(halo)2-C(=CH2)CH2R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described . In some or any embodiments, the compound of Formula I or II is that where R1 is —C(O)C(R6)(R6a)-X1-R1a which is -C(O)CF2CH2R1a, F2CH2CH2R1a, -C(O)CF2-CH=CHR1a, or -C(O)CF2-C(=CH2)CH2R1a; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any ments, the compound of a I or II is that where R1 is -C(O)C(R6)(R6a)R1a; R6 and R6&1 together with the carbon to which they are attached form C(O); and all other groups are as deﬁned in the y of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R181 is alkyl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is methyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R181 is aryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is naphthyl optionally substituted with l or 2 R7 groups; and all other groups are as deﬁned in the Summary of the ion or any of the embodiments described herein. In some or any embodiments, the compound of a I or II is that where R181 is yl optionally tuted with l or 2 R7 groups and each R7, when present, is halo; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is indanyl optionally substituted with l or 2 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any ments, the compound of Formula I or II is that where R181 is indanyl optionally substituted with l or 2 R7 groups and each R7, when t, is independently heteroaryl (in another example pyridinyl) or halo; and all other groups are as deﬁned in the Summary of the ion or any of the embodiments bed herein. In some or any embodiments, the compound of Formula I or II is that where R181 is phenyl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is phenyl optionally tuted with l or 2 R7 groups and each R7, when present, is independently halo, haloalkoxy, or heteroaryl (in another example pyridinyl); and all other groups are as deﬁned in the Summary of the ion or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is phenyl optionally substituted with l or 2 R7 groups and each R7, when t, is independently aryl or heteroaryl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is phenyl optionally substituted with l or 2 R7 groups and each R7, when present, is independently phenyl or heteroaryl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R181 is heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is ﬁlsed bicyclic heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is benzoﬁaranyl, benzothienyl, l, benzimidazolyl, 6,7-dihydro-5H—cyclopenta[b]pyridinyl, benzothiazolyl, furo[3 ,2-c]pyridinyl, o[ l ,2-b]pyridazinyl, imidazo[ l ,2-a]pyridinyl, furo[3,2-b]pyridinyl, furo[2,3-d]pyrimidinyl, thieno[3,2-b]furanyl, thieno[2,3-d]oxazolyl, or furo[2,3-d]thiazolyl, each of which is optionally substituted with l or 2 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is benzoﬁlranyl, benzothienyl, indolyl, benzimidazolyl, 6,7-dihydro-5H— cyclopenta[b]pyridinyl, or benzothiazolyl, each of which is optionally substituted with l or 2 R7 ; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R181 is benzofuranyl optionally substituted with l or 2 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments bed herein.

In some or any embodiments, the compound of Formula I or II is that where R181 is fused bicyclic heteroaryl optionally substituted with l, 2, or 3 R7 groups where each R7, when present, is independently halo, alkyl, or haloalkyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of a I or II is that where R181 is fused bicyclic heteroaryl optionally substituted with l, 2, or 3 R7 groups where each R7, when present, is independently chloro, bromo, ﬁuoro, methyl, or triﬁuoromethyl; and all other groups are as deﬁned in the y of the Invention or any of the ments bed herein.

In some or any embodiments, the compound of Formula I or II is that where R181 is fused tricyclic heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described . In some or any embodiments, the compound of Formula I or II is that where R181 is 7,8-dihydro-6H-cyclopenta[g]quinoxalinyl; and all other groups are as deﬁned in the Summary of the ion or any of the embodiments bed herein.

In some or any embodiments, the compound of Formula I or II is that where each R7, when present, is independently optionally substituted with l, 2 or 3 R7&1 , where each R7a, when present, is independently cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and lkyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of a I or II is that where each R7, when present, is aryl or heteroaryl, either alone or as part of another group, such aryl or heteroaryl is independently optionally substituted with l, 2 or 3 R7&1 groups, as described herein. In some or any embodiments, the compound of a I or II is that where each R7, when present, is phenyl or heteroaryl, 2014/056555 either alone or as part of another group, such phenyl or heteroaryl is independently optionally substituted with l, 2 or 3 R7&1 groups, as described herein.

In some or any embodiments, the compound of Formula I or II is that where R2 is hydrogen, hydroxy, or alkyl; and R3 is alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R2 is hydroxy and R3 is alkyl; and all other groups are as deﬁned in the Summary of the ion or any of the embodiments described herein.

] In some or any embodiments, the compound of Formula I or II is that where R2 and R3 together with the en to which they are ed form a 3-10 membered heterocycloalkyl ring which is ally substituted with l, 2, 3, or 4 R8; and all other groups are as deﬁned in the Summary of the ion or any of the embodiments described herein. In some or any embodiments, the nd of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form a 4-8 membered heterocycloalkyl ring which is optionally substituted with l, 2, 3, or 4 R8; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any ments, the compound of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, 2-azabicyclo[2.2. l]heptanyl, 7-azabicyclo[2.2. l ]heptanyl, 2-azaspiro[3 .3]heptanyl, l-oxidopyrrolidinyl, piperidinyl, piperazinyl, or 8-azabicyclo[3.2.l]octanyl, each of which is optionally substituted with l or 2 R8; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the nd of Formula I or II is that where R2 and R3 er with the nitrogen to which they are attached form pyrrolidinyl optionally substituted with l, 2, 3, or 4 R8; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form pyrrolidinyl optionally substituted with l or 2 R8; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form pyrrolidinyl ally substituted with l, 2, 3, or 4 R8 where each R8, when present, is independently deuterium, amino, alkyl, halo, or cycloalkyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the nd of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form unsubstituted pyrrolidinyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form azetidinyl optionally substituted with l or 2 R8; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R2 and R3 together with the nitrogen to which they are ed form azetidinyl optionally substituted with l or 2 R8 where each R8, when present, is independently alkyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 ed heterocycloalkyl ring which is optionally tuted with l, 2, 3, or 4 R8 where each R8, when present, is ndently deuterium, amino, alkyl, halo, or lkyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally tuted with l, 2, 3, or 4 R8 where each R8, when present, is independently deuterium, amino, methyl, ﬂuoro, or cyclopropyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally substituted with l or 2 R8 where each R8, when t, is independently amino, methyl, ﬂuoro, or ropyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R4 is aryl ally tuted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R4 is phenyl ally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the nd of Formula I or II is that where R4 is phenyl optionally substituted with l, 2, or 3 R9 groups where each R9, when present, is independently halo, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, cycloalkyloxy, or heterocycloalkylalkyloxy which is optionally substituted with one hydroxy; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R4 is phenyl optionally substituted with l or 2 R9 groups where each R9, when present, is ndently bromo, chloro, ﬁuoro, methoxy, diﬁuoromethyl, triﬁuoromethyl, triﬁuoromethoxy, cyclopropyloxy, tetrahydrofuranyloxy, or tetrahydropyranylmethyl which is ally substituted with one hydroxy; and all other groups are as deﬁned in the Summary of the ion or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R4 is phenyl optionally substituted with 2 R9 groups one of which is halo, and one of which is alkoxy; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R4 is heteroaryl ally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of a I or II is that where R4 is nyl, 1H- indazolyl, benzofuranyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, or quinolinyl each of which is ally substituted with l or 2 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or any of the ments described herein. In some or any embodiments, the compound of Formula I or II is that where R4 is pyridinyl, lH-indazolyl, benzofuranyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, or quinolinyl; R9, when present, is halo, alkyl, alkoxy, haloalkoxy, cycloalkyloxy, or heterocycloalkylalkyloxy which is optionally substituted with one hydroxy; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described . In some or any embodiments, the compound of Formula I or II is that where R4 is pyridinyl, lH-indazolyl, benzofuranyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, or quinolinyl; R9, when present, is chloro, ﬁuoro, methyl, y, isopropoxy, 2,2,2-triﬁuoroethoxy, cyclopropyloxy, or tetrahydropyranylmethyl which is optionally substituted with one hydroxy; and all other groups are as deﬁned in the y of the ion or any of the embodiments described . In some or any embodiments, the compound of Formula I or II is that where R4 is unsubstituted 2,3-dihydrobenzo[b][l,4]dioxinyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R5 is R5 is halo, -OH, -OTBS, -Ng, -NH2, -NH(OCH3), -NHC(O)CH3, or -NHC(O)H and R521 is hydrogen, alkyl, or deuterium; or R5 and R5&1 together with the carbon to which they are ed form C(O) or C(NOH); and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described . In some or any embodiments, the compound of Formula I or II is that where R5 is -OH, -NH2, -NH(OCH3), -NHC(O)CH3, or -NHC(O)H and R5&1 is hydrogen, alkyl, or deuterium; or R5 and R5&1 together with the carbon to which they are attached form C(O) or ; and all other groups are as deﬁned in the y of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R5 is OH and R5&1 is hydrogen; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R5 is -NH2 and R5&1 is hydrogen; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described . In some or any embodiments, the compound of Formula I or II is that where R5 is OH and R5&1 is deuterium; and all other groups are as deﬁned in the Summary of the Invention or any of the ments described herein. In some or any embodiments, the nd of Formula I or II is that where R5 is -NH(OCH3) and R5&1 is hydrogen; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R5 is OH and R5&1 is alkyl; and all other groups are as deﬁned in the y of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R5 is -NHC(O)H and R5&1 is hydrogen; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any ments, the compound of Formula I or II is that where R5 and R5&1 er with the carbon to which they are attached form C(O); and all other groups are as deﬁned in the y of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R5 and R5&1 together with the carbon to which they are attached form C(NOH); and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments bed herein. In some or any embodiments, the compound of Formula I or II is that where R5 is OH and R5&1 is hydrogen, R5 is -NH2 and R5&1 is hydrogen, R5 is OH and R5&1 is deuterium, R5 is -NH(OCH3) and R5&1 is hydrogen, R5 is OH and R5&1 is alkyl, R5 is -NHC(O)H and R5&1 is hydrogen, R5 and R5&1 together with the carbon to which they are attached form C(O), or R5 and R5&1 together with the carbon to which they are attached form C(NOH); and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I or II is that where R10 is hydrogen; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described . In some or any embodiments, the compound of Formula I or II is that where R10 is alkyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R10 is ; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein. In some or any embodiments, the compound of Formula I or II is that where R10 is phenyl; and all other groups are as deﬁned in the Summary of the Invention or any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(a): N R5 R58 . R4 R1/NH Formula I(a) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the above embodiments. In another embodiment, the compound of a 1(a) is that where R581 is hydrogen; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In r embodiment, the compound of Formula 1(a) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula 1(a) is that where R1 is —C(O)C(R6)(R6a)R1a; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of a 1(a) is that where R4 is heteroaryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula 1(a) is that where R4 is aryl ally tuted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments bed herein. In another embodiment, the compound of Formula 1(a) is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is ally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described .

In some or any embodiments, the compound of Formula I is according to Formula I(b) or I(c): R2\N,R3R5 RaN/R385 K_/LR4 : R1.lilH R1ﬁH Formula I(b) Formula I(c) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(b) or I(c) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(b) or I(c) is that where R1 is —C(O)C(R6)(R6a)R1a; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(b) or I(c) is that where R1 is —C(O)C(R6)(R6a)R1a; R1&1 is unsubstituted indanyl; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(b) or I(c) is that where R4 is aryl optionally substituted with l, 2, or 3 R9 ; and all other groups are as deﬁned in the y of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(b) or I(c) is that where R4 is aryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the compound of Formula I(b) or I(c) is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(d): Formula I(d) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(d) is that where R5 is OH; and all other groups are as deﬁned in the y of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(d) is that where R4 is heteroaryl optionally substituted with l, 2, or 3 R9 ; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(d) is that where R4 is aryl optionally substituted with l, 2, or 3 R9 ; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another ment, the compound of Formula I(d) is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of a I(d) is that where R6 and R6&1 are halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments bed herein. In another embodiment, the compound of Formula I(d) is that where R181 is heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(d) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(e): Formula I(e) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(e) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the nd of Formula I(e) is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally tuted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the nd of Formula I(e) is that where R6 and R6&1 are halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(e) is that where R181 is heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In r embodiment, the nd of Formula I(e) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(f): Formula I(f) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the compound of Formula I(l) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of a I(f) is that where R2 and R3 er with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is ally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(f) is that where R6 and R6&1 are halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the nd of Formula I(f) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another ment, the compound of Formula I(f) is that where R4 is heteroaryl optionally tuted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(f) is that where R4 is aryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the nd of Formula I is according to Formula I(g): N R5 Formula I(g) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(g) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments bed herein. In another embodiment, the compound of Formula I(g) is that where R4 is heteroaryl optionally substituted with l, 2, or 3 R9 ; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(g) is that where R4 is unsubstituted 2,3-dihydrobenzo[b][l,4]dioxinyl; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(g) is that where R4 is aryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(g) is that where R181 is heteroaryl optionally tuted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(g) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another ment, the compound of Formula I(g) is that where R181 is benzofuranyl optionally tuted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(s): Formula I(s) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(s) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(s) is that where R4 is heteroaryl optionally tuted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(s) is that where R4 is unsubstituted 2,3-dihydrobenzo[b][l,4]dioxinyl; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(s) is that where R4 is aryl optionally tuted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments bed herein. In another embodiment, the compound of Formula I(s) is that where R181 is aryl optionally substituted with l, 2, or 3 R7 ; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(s) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments bed herein. In another embodiment, the compound of Formula I(s) is that where R181 is benzofuranyl optionally tuted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In another embodiment, the compound of a I(s) is that where R181 is benzothiophene optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments bed herein. In another embodiment, the compound of Formula I(s) is that where R181 is aryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the nd of Formula I(s) is that where R181 is phenyl optionally substituted with l, 2, or 3 R7 ; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(s) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(s) is that where R7 is phenyl or heteroaryl optionally substituted with at least one R721; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(s) is that where at least one R7&1 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(t): Formula I(t) where all groups are as deﬁned in the y of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the compound of Formula I(t) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(t) is that where R4 is heteroaryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(t) is that where R4 is unsubstituted 2,3-dihydrobenzo[b][l,4]dioxinyl; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(t) is that where R4 is aryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the y of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the compound of Formula I(t) is that where R181 is heteroaryl optionally tuted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(t) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In r embodiment, the nd of Formula I(t) is that where R181 is benzofuranyl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to a I(u): Formula I(u) where all groups are as deﬁned in the y of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(u) is that where R5 is OH; and all other groups are as deﬁned in the y of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(u) is that where R4 is heteroaryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(u) is that where R4 is unsubstituted 2,3-dihydrobenzo[b][l,4]dioxinyl; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the nd of Formula I(u) is that where R4 is aryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(u) is that where R181 is heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the nd of Formula I(u) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the nd of Formula I(u) is that where R181 is benzofuranyl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to a I(v), Formula I(v’), or Formula I(v"): Ra ,R3 R? ,R3 R’i ,R3 N R5 N 35 N R5 R4 vR4 K/LR4 0 0 g 0 ; NH NH NH Rla R’la R’la O O 0 Formula I(v) Formula I(v’) Formula I(v") where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is ally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the compound of a I(v), Formula I(v’), or Formula I(v") is that where R5 is OH; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In r embodiment, the compound of Formula I(v), Formula I(v’), or a I(v") is that where R4 is heteroaryl optionally tuted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where R4 is unsubstituted 2,3- dihydrobenzo[b][l,4]dioxinyl; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(v), a I(v’), or Formula I(v") is that where R4 is aryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(v), Formula I(v’), or a I(v") is that where at least one R9 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where at least one R9 is alkoxy; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where R181 is heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where R181 is benzoﬁlranyl optionally tuted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described . In another embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where R181 is benzothiophene optionally substituted with l, 2, or 3 R7 ; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of a I(v), Formula I(v’), or Formula I(v") is that where R181 is aryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where R181 is phenyl ally tuted with l, 2, or 3 R7 ; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In r embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another ment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where R7 is phenyl or heteroaryl optionally substituted with at least one R721; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where at least one R7&1 is WO 42397 halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(w), Formula I(w’), or a I(w"): RE ,R3 RE ,R3 R{ ,R3 N OH N oH N OH R4 VR‘l KAR4 o o g o ; NH NH NH R1a R’la R18 0 O 0 Formula I(w) Formula I(w’) Formula I(w") where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where R2 and R3 together with the en to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where R4 is heteroaryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments bed herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where R4 is unsubstituted hydrobenzo[b][l,4]dioxinyl; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the nd of Formula I(w), a I(w’), or Formula I(w") is that where R4 is aryl optionally substituted with l, 2, or 3 R9 ; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where at least one R9 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where at least one R9 is alkoxy; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where R181 is heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where R181 is benzofuranyl optionally tuted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the y of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(w), a I(w’), or Formula I(w") is that where R181 is benzothiophene optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where R181 is aryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the y of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where R181 is phenyl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described herein. In another embodiment, the compound of a I(w), Formula I(w’), or Formula I(w") is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the nd of Formula I(w), Formula I(w’), or Formula I(w") is that where R7 is phenyl or heteroaryl optionally substituted with at least one R721; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(w), Formula I(w’), or Formula I(w") is that where at least one R7&1 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. 1] In some or any embodiments, the compound of a I is according to Formula I(X), Formula I(X’), or Formula I(x"): R2 R3 R2 R3 R2 R3 ‘N’ OH ‘N’ QH \N’ OH \ \ \ NH / NH / NH / R’la R1a R18 0 o 0 Formula I(X) Formula I(X’) Formula I(X") where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the nd of Formula I(x), Formula I(X’), or Formula I(X") is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 ed heterocycloalkyl ring which is ally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments described . In another embodiment, the compound of Formula I(X), Formula I(X’), or Formula I(X") is that where at least one R9 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(x), Formula I(X’), or Formula I(X") is that where at least one R9 is alkoxy; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another ment, the compound of Formula I(v), Formula I(v’), or Formula I(v") is that where there are 2 R9 groups, where one R9 is halo and one R9 is , preferably cyclopropyloxy; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the ments bed herein. In another embodiment, the compound of Formula I(X), Formula I(X’), or Formula I(X") is that where R181 is heteroaryl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(X), Formula I(X’), or Formula I(X") is that where R181 is benzofuranyl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(x), Formula I(X’), or Formula I(X") is that where R181 is benzothiophene optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(X), Formula I(X’), or a I(X") is that where R181 is aryl optionally substituted with l, 2, or 3 R7 ; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(X), Formula I(X’), or a I(X") is that where R181 is phenyl optionally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(X), Formula I(X’), or Formula I(X") is that where at least one R7 is halo; and all other groups are as deﬁned in the y of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(X), Formula I(X’), or Formula I(X") is that where R7 is phenyl or heteroaryl optionally tuted with at least one R781; and all other groups are as deﬁned in the y of the Invention or as deﬁned in any of the embodiments described herein. In WO 42397 another embodiment, the compound of Formula I(X), Formula I(X’), or Formula I(X") is that where at least one R7&1 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments bed .

In some or any embodiments, the compound of Formula I is according to Formula I(y), Formula I(y’), or Formula I(y"): U U U N OH N QH N OH \ \ \ O moon 0 é I — In some or any embodiments, the compound of Formula I is according to Formula I(z), Formula I(z’), or Formula I(z"): Q a 6 OH N C_)H N OH \ \ \ O moan 0 g I —n o NH / NH / j— In some or any embodiments, the compound of Formula I is according to Formula I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or Formula I(ae): O a 8 N B5 N I35 N I35 K/kR4 VR4 VR4 R6 R6a é R6 R6a i R6 R6a 2 NH NH NH R’la R’la R18 0 O 0 Formula I(aa) Formula I(ab) Formula I(ac) N I35 N I35 K/KR4 VR4 R6 RSa _ R6 R68 ‘5 R1aWm R1aWM O 0 Formula I(ad) Formula I(ae) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of a I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or Formula I(ae) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another ment, the compound of Formula I(aa), a I(ab), Formula I(ac), Formula I(ad), or Formula I(ae) is that where R4 is heteroaryl optionally tuted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or Formula I(ae) is that where R4 is aryl ally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another ment, the compound of Formula I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or a I(ae) is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or Formula I(ae) is that where R6 and R6&1 are halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or Formula I(ae) is that where R181 is heteroaryl ally substituted with l, 2, or 3 R7 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(aa), Formula I(ab), Formula I(ac), Formula I(ad), or a I(ae) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(af), Formula I(ag), Formula I(ah), Formula I(ai), Formula I(aj), or Formula I(ak): R{ R3 Z X (5 N’ I35 N I35 N I35 vR4 vR4 vR4 R6 R6a 2 R6 R6a 2 R6 R6a 3 R\X1B§[(NH1a - R\X1§S]/NH1a - R\X>S(NH1a - O O 0 Formula I(af) Formula I(ag) Formula I(ah) R? ,R3 1 B 6 N I35 N I35 N 85 vR4 |\/-\ R4 vR4 0 g o g o ; 1a 1a 1a 0 O 0 Formula I(ai) Formula I(aj) Formula I(ak) where all groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(ai), Formula I(ag), Formula I(ah), Formula I(ai), Formula I(aj), or Formula I(ak) is that where X1 is ne or lene; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(af), Formula I(ag), Formula I(ah), a I(ai), Formula I(aj), or Formula I(ak) is that where R5 is OH; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(af), Formula I(ag), Formula I(ah), Formula I(ai), Formula I(aj), or Formula I(ak) is that where R4 is heteroaryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(af), Formula I(ag), Formula I(ah), Formula I(ai), a I(aj), or Formula I(ak) is that where R4 is aryl optionally substituted with l, 2, or 3 R9 groups; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described . In another embodiment, the compound of Formula I(ai) or Formula I(ai) is that where R2 and R3 together with the nitrogen to which they are attached form a 3-10 ed cycloalkyl ring which is optionally substituted with l, 2, or 3 R8; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments bed herein. In another embodiment, the compound of Formula I(ai), Formula I(ag), or a I(ah), is that where R6 and R6&1 are halo; and all other groups are as deﬁned in the Summary of the ion or as deﬁned in any of the embodiments described herein. In another embodiment, the nd of Formula I(af), Formula I(ag), Formula I(ah), Formula I(ai), Formula I(aj), or Formula I(ak) is that where R181 is aryl or heteroaryl optionally substituted with l, 2, or 3 R7 ; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein. In another embodiment, the compound of Formula I(af), Formula I(ag), Formula I(ah), Formula I(ai), a I(aj), or Formula I(ak) is that where at least one R7 is halo; and all other groups are as deﬁned in the Summary of the Invention or as deﬁned in any of the embodiments described herein.

In some or any embodiments, the compound of Formula I is according to Formula I(al), a I(am), Formula I(an), or Formula I(ao): 2 3 R3 R3 RE R3 R3 ,R3 VR" VR" K/KR4 K/KR4 R6 R6a E R6 R68 5 O E. O i R1a> In some or any embodiments, the compound is that of any one of Examples 1-74.

In some or any embodiments, the compound is that of any one of Examples 77-383.

In some or any embodiments, the nd is that of any one of Examples 384-478.

In some or any embodiments, the compound is selected from Table 1. 1] In some or any embodiments, the compound is selected from Table 2.

In some or any embodiments, the compound is selected from Table 3.

In some or any embodiments, the compound is selected from Table l, where R181 is aryl, which is optionally substituted with l, 2, or 3 R7 groups.

In some or any embodiments, the compound is selected from Table l, where R181 is heterocycloalkyl, which is optionally substituted with l, 2, or 3 R7 groups.

In some or any embodiments, the nd is selected from Table l, where R181 is heteroaryl, which is optionally substituted with l, 2, or 3 R7 groups.

In some or any embodiments, the compound is selected from Table l, where R2 and R3 together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring, which is optionally tuted with l or 2 R8.

In some or any embodiments, the compound is selected from Table l, where R2 and R3 together with the nitrogen to which they are attached form a 7-8 membered bicyclic heterocycloalkyl ring, which is optionally substituted with l or 2 R8.

In some or any embodiments, the compound is selected from Table l, where R4 is aryl, which is optionally substituted with l, 2, or 3 R9 .

In some or any embodiments, the compound is selected from Table l, where R4 is heteroaryl, which is ally substituted with l, 2, or 3 R9 groups.

In some or any embodiments, the compound is selected from Table l, where Rém—OH.

In some or any embodiments, the compound is selected from Table l, where R6 and R6&1 together with the carbon to which they are attached form C(O).

In some or any embodiments, the nd is selected from Table 2, where R181 is heterocycloalkyl, which is optionally substituted with l, 2, or 3 R7 groups.

In some or any ments, the nd is selected from Table 2, where R181 is heteroaryl, which is optionally tuted with l, 2, or 3 R7 groups. 4] In some or any embodiments, the compound is ed from Table 2, where R2 and R3 together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring, which is optionally substituted with l or 2 R8.

In some or any embodiments, the nd is selected from Table 2, where R2 and R3 together with the nitrogen to which they are ed form a 7-8 membered bicyclic heterocycloalkyl ring, which is optionally substituted with l or 2 R8.

In some or any embodiments, the compound is selected from Table 2, where R4 is aryl, which is optionally substituted with l, 2, or 3 R9 groups.

In some or any embodiments, the compound is selected from Table 2, where R4 is heteroaryl, which is optionally substituted with l, 2, or 3 R9 groups.

In some or any embodiments, the compound is selected from Table 2, where Rém—OH.

In some or any embodiments, the compound is selected from Table 2, where R6 and R6&1 together with the carbon to which they are attached form C(O).

In some or any embodiments, the compound is selected from Table 3, where R181 is heterocycloalkyl, which is optionally substituted with l, 2, or 3 R7 groups.

In some or any embodiments, the compound is selected from Table 3, where R181 is heteroaryl, which is optionally substituted with l, 2, or 3 R7 groups.

In some or any embodiments, the compound is selected from Table 3, where R2 and R3 together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring, which is ally substituted with l or 2 R8.

In some or any embodiments, the compound is selected from Table 3, where R2 and R3 together with the nitrogen to which they are attached form a 7-8 membered bicyclic heterocycloalkyl ring, which is optionally substituted with l or 2 R8.

In some or any embodiments, the compound is selected from Table 3, where R4 is aryl, which is optionally substituted with l, 2, or 3 R9 groups.

In some or any embodiments, the compound is selected from Table 3, where R4 is heteroaryl, which is optionally substituted with l, 2, or 3 R9 groups.

In some or any embodiments, the compound is selected from Table 3, where R5 is —OH. 7] In some or any embodiments, the compound is ed from Table 3, where R6 and R6&1 together with the carbon to which they are attached form C(O).

In some or any embodiments, provided is a ceutical composition sing 1) a Compound of Formula I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), I(h), I(j), I(k), 1(m), 1(11), I(p), I(CI), 1(IV), 1(S), 1(t), 1(11), 1(V), 1(V’), 1(V"), 1(W), 1(W'), 1(W"), 1(X), I(X’), I(X"), I(Y), I(Y’), I(Y"), 1(Z), 1(Z’), 1(Z"), 1(81%), 1(ab), 1(aC), 1(ad), , I(ai), I(ag), I(ah), I(ai), I(ai), I(ak), I(al), I(am), I(an), or I(ao) or a compound in Table l, 2, or 3, optionally as a er, a single isomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, and 2) a pharmaceutically acceptable ent or pharmaceutically acceptable carrier.

Pharmaceutical Composition/Formulation In some or any embodiments, optionally in combination with any or all of the above various embodiments, provided herein is a ceutical composition comprising of a compound of Formula I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), I(h), I(j), I(k), I(m), I(n), I(p), I(CI), 1(IV), 1(S), 1(t), 1(11), 1(V), 1(V’), 1(V"), 1(W), 1(W'), 1(W"), 1(X), 1(X’), 1(X"), I(Y), I(Y’), I(y"), I(z), I(z’), I(z"), I(aa), I(ab), I(ac), I(ad), I(ae), I(af), I(ag), I(ah), I(ai), I(aj), I(ak), I(al), I(am), I(an), or I(ao), or a compound of Table l, 2, or 3, or stereoisomers, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carrier(s), excipient(s), (s) or diluent(s). The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsiﬁers, sweeteners, colorants, ﬂavorants, salts for varying the osmotic pressure, buffers, coating agents or idants. 0] In some or any embodiments, disclosed herein is a ceutical composition comprising a compound, pharmaceutically acceptable salt, pharmaceutically acceptable N—oxide, pharmaceutically active lite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of any of the compounds disclosed herein. In some embodiments, the pharmaceutical compositions further comprises a pharmaceutically acceptable diluent, excipient or binder.

In some or any embodiments, pharmaceutical compositions are formulated in any manner, including using one or more physiologically acceptable carriers sing excipients and/or auxiliaries which facilitate processing of the active compounds into pharmaceutical preparations. In some embodiments, proper formulation is dependent upon the route of administration chosen. In various embodiments, any techniques, carriers, and ents are used as suitable.

A pharmaceutical ition, as used herein, refers to a mixture of a nd described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In some or any embodiments, a pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, cing the methods of treatment or use provided herein, includes administering or using a ceutical composition comprising a therapeutically effective amount of a compound ed herein. In specific embodiments, the methods of treatment provided for herein include administering such a pharmaceutical composition to a mammal having a disease or condition to be treated. In one embodiment, the mammal is a human. In some embodiments, the therapeutically effective amount varies widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In s embodiments, the compounds described herein are used singly or in combination with one or more therapeutic agents as components of es.

In a some or any embodiment, it is provided a method of g a composition, comprising ing a compound and forming the composition. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments of the ition, optionally in combination with any or all of the above various embodiments, the ition is formulated in a formulation for local or systemic delivery. Examples of such formulations are ations for oral administration, injection, l administration, pulmonary administration, or implant. In some or any embodiments, the compound is according to any of the various embodiments described above or below.

In some or any embodiments, the ceutical compositions provided herein are formulated for intravenous injections. In certain aspects, the intravenous injection formulations ed herein are formulated as aqueous solutions, and, in some embodiments, in physiologically compatible s such as Hank’s solution, Ringer’s solution, or physiological saline . In certain embodiments, the pharmaceutical compositions provided herein are formulated for transmucosal administration. In some aspects, transmucosal formulations include penetrants appropriate to the barrier to be permeated. In certain embodiments, the pharmaceutical compositions provided herein are formulated for other parenteral injections, riate formulations include aqueous or nonaqueous solutions, and in one embodiment, with physiologically compatible buffers or excipients.

In some or any embodiments, the pharmaceutical compositions provided herein are formulated for oral administration. In certain s, the oral formulations provided herein comprise compounds bed herein that are formulated with ceutically acceptable carriers or excipients. Such carriers enable the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, s, slurries, sions and the like, for oral ingestion by a patient to be treated. 6] In some or any embodiments, pharmaceutical ations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of es, after adding suitable aries, if d, to obtain tablets or dragee cores. Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or ol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. I(f) desired, disintegrating agents are optionally added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

In some or any embodiments, provided herein is a pharmaceutical composition formulated as dragee cores with suitable coatings. In some or any ments, concentrated sugar solutions are used in forming the suitable coating, and optionally contain gum arabic, talc, nylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, 2014/056555 r solutions, and suitable organic solvents or solvent mixtures. In some embodiments, dyestuffs and/or pigments are added to tablets, dragees and/or the gs thereof for, e.g., identification or to characterize different combinations of active compound doses.

In some or any embodiments, pharmaceutical preparations which are used include orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the t capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.

In some or any embodiments, in soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid in, or liquid polyethylene glycols. In addition, izers are optionally added. In some or any embodiments, the ations for oral administration are in dosages suitable for such administration.

In some or any embodiments, the ceutical compositions provided herein are formulated for buccal or sublingual administration. In some or any embodiments, buccal or sublingual compositions take the form of tablets, lozenges, or gels formulated in a conventional manner. In some or any embodiments, parenteral injections involve bolus injection or continuous inﬁlsion. In some embodiments, formulations for ion are ted in unit dosage form, e.g., in ampoules or in multi-dose ners, with an added preservative. In some embodiments, the ceutical composition described herein is in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and optionally contains formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In some embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions. le lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In some or any embodiments, aqueous injection sions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.

Optionally, the suspensions also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly trated solutions. In alternative embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In some ments, the compounds described herein are stered topically. In speciﬁc embodiments, the compounds described herein are formulated into a variety of topically administrable itions, such as solutions, suspensions, lotions, gels, , ted sticks, balms, creams or ointments. Such pharmaceutical compounds optionally contain solubilizers, stabilizers, tonicity ing , buffers and/or preservatives.

In some or any embodiments, the pharmaceutical compositions provided herein are formulated for transdermal administration of compounds described herein. In some embodiments, administration of such compositions s transdermal delivery devices and transdermal delivery patches. In some or any embodiments, the compositions are lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an ve. Such patches include those constructed for continuous, pulsatile, or on demand delivery of ceutical agents. In some embodiments, transdermal delivery of the compounds described herein is accomplished by use of iontophoretic patches and the like. In some or any embodiments, transdermal patches provide controlled delivery of the compounds provided herein, such as, for example, compounds of Formula (I). In some or any embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers are optionally used to increase absorption. Absorption enhancer and carrier e absorbable ceutically acceptable solvents that assist in e of the compound through the skin.

For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the nd to the skin of the host at a lled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

In some or any embodiments, the pharmaceutical compositions provided herein are formulated for administration by inhalation. In some or any embodiments, in such pharmaceutical compositions formulated for inhalation, the nds described herein are in a form as an aerosol, a mist or a powder. In some embodiments, pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodiﬂuoromethane, trichloroﬂuoromethane, dichlorotetraﬂuoroethane, carbon dioxide or other suitable gas. In certain aspects of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a d amount. In some or any embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufﬂator is formulated ning a powder mix of the compound described herein and a suitable powder base such as lactose or starch. 3] In some embodiments, the compounds described herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention . In some or any ments, rectal compositions optionally contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In some or any suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

In s embodiments provided herein, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and aries which facilitate sing of the active compounds into pharmaceutically acceptable preparations. In some or any embodiments, proper formulation is dependent upon the route of administration chosen. In various embodiments, any of the techniques, rs, and excipients is used as suitable. In some embodiments, pharmaceutical compositions comprising a compound described herein are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or ssion processes.

In some or any embodiments, the pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound described herein described herein as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein e the use ofN-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. In some situations, compounds described herein exist as tautomers. All tautomers are included within the scope of the compounds presented . Additionally, included herein are the solvated and unsolvated forms of the nds described herein. Solvated compounds include those that are solvated with pharmaceutically acceptable solvents such as water, ethanol, and the like. The ed forms of the compounds ted herein are also considered to be disclosed herein. In some embodiments, the pharmaceutical compositions described herein include other medicinal or ceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution ers, salts for regulating the osmotic pressure, and/or s. In additional embodiments, the pharmaceutical compositions described herein also contain other eutically valuable nces.

Methods for the preparation of compositions containing the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or rs to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. In various embodiments, the compositions are in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions optionally contain minor s of nontoxic, auxiliary substances, such as wetting or emulsifying , pH ing agents, and so forth.

In some embodiments, a composition comprising a nd described herein takes the form of a liquid where the agents are t in solution, in suspension or both. In some ments, when the composition is administered as a solution or suspension a ﬁrst portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some ments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous 8] Useful aqueous suspension optionally contain one or more polymers as suspending . Useful rs include water-soluble rs such as cellulosic polymers, e.g., hydroxypropyl cellulose, and water-insoluble polymers such as cross- linked carboxyl-containing polymers. Useful compositions optionally comprise an mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

Useful compositions optionally include solubilizing agents to aid in the solubility of a compound described herein. The term ilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent.

Solubilizing agents include certain acceptable nonionic surfactants, for example polysorbate 80, and ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Useful compositions optionally include one or more pH adjusting agents or ing , including acids such as acetic, boric, citric, lactic, phosphoric and hloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium e, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

Useful compositions optionally include one or more salts in an amount ed to bring osmolality of the ition into an able range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, , phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulﬁte and ammonium sulfate.

Certain useful compositions optionally include one or more preservatives to t microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine e; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Some useful compositions optionally include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., yethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol lO, octoxynol 40.

Certain useful compositions optionally one or more antioxidants to enhance chemical stability Where required. Suitable antioxidants include, by way of example only, ic acid and sodium metabisulﬁte.

In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. In alternative embodiments, le-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

In various embodiments, any delivery system for hobic pharmaceutical compounds is employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. In some or any ments, certain organic ts such as N-methylpyrrolidone are employed. In some embodiments, the compounds are delivered using a sustained-release system, such as semipermeable matrices of solid hobic polymers containing the therapeutic agent. Various sustained-release materials are utilized in the embodiments herein. In some or any embodiments, sustained-release es release the compounds for a few weeks up to over 100 days. In some embodiments, depending on the chemical nature and the biological stability of the therapeutic reagent, additional gies for protein stabilization are employed.

In some or any embodiments, the formulations or compositions described herein beneﬁt from and/or optionally comprise antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) an polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. s of Dosing and Treatment Regimens In some or any ments, the method can be conducted in living bodies of mammals. In such a case, the compounds may be administered to the mammals.

In some or any ments, the compounds described herein are used in the ation or manufacture of medicaments for the treatment of diseases or conditions that are ed by the enzyme GCS or in which inhibition of the enzyme GCS ameliorates the disease or condition. In some embodiments, a method for treating any of the diseases or ions described herein in a subject in need of such treatment, involves stration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, ceutically acceptable N—oxide, pharmaceutically active metabolite, pharmaceutically acceptable g, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said t.

In some or any embodiments, ed is a method of treating or ameliorating a medical condition, comprising administering to a subject in need thereof a compound according to any of the various embodiments described herein or a pharmaceutical composition according to any of the various embodiments described herein.

In some or any ments, provided herein is a method of treating or ameliorating a disease ameliorated by the inhibition of GCS comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of Formula I, 1(a), 1(b), 1(0), 1(d), 1(6), 1(0, 1(g), 1(h), 10'), 1(k), Km), 1(11), 1(1)), 1((1), 1(IV), 1(S), 1(t), 1(11), 1(V), 1(V’), 1(V"), 1(W), 1(W’), 1(W"), 1(X), 1(X’), 1(X"), 1(y), 1(y’), 1(y"), 1(Z), 1(Z’), 1(Z"), 1(aa), 1(ab), I(ac), I(ad), I(ae), I(af), I(ag), I(ah), I(ai), I(aj), I(ak), I(al), I(am), I(an), or I(ao), or a compound in Table l, 2, or 3, optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof. In some or any embodiments, the e is selected from glycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fabry diseases); diseases associated with glycolipid accumulation (e.g., Gaucher disease); diseases that cause renal hypertrophy or lasia such as diabetic nephropathy; diseases that cause hyperglycemia or hyperinsulemia; cancers in which glycolipid synthesis is al; infectious diseases caused by organisms which use cell surface glycolipids as receptors or in which synthesis of ylceramide is essential or important; a metabolic disorder such as atherosclerosis, polycystic kidney disease, renal hypertrophy, diabetes mellitus, and y; cancer such as breast cancer, renal adenocarcinoma, brain cancer, neuroblastoma, lung cancer, intestinal cancer, pancreas and prostrate cancer; neuronal disorders; neuronal injury; inﬂammatory diseases or disorders (e.g., rheumatoid arthritis, Crohn's disease, asthma and sepsis), and diabetes us and y In any of the aforementioned embodiments are further ments that include single administrations of the effective amount of the compound, including further embodiments in which the compound is administered to the subject (i) once; (ii) multiple times over the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned embodiments are further embodiments in which administration is enteral, parenteral, or both, and wherein: (a) the ive amount of the nd is systemically administered to the subject; (b) the effective amount of the compound is administered orally to the subject; (c) the effective amount of the compound is intravenously administered to the subject; (d) the effective amount of the compound administered by inhalation; (e) the effective amount of the compound is administered by nasal administration; (f) the effective amount of the compound is administered by injection to the subject; (g) the effective amount of the compound is administered topically l) to the subject; (h) the effective amount of the compound is administered by ophthalmic administration; and/or (i) the ive amount of the compound is administered ly to the subject.

In some or any embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In some or any therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufﬁcient to cure or at least partially arrest the symptoms of the disease or condition. In some embodiments, amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and se to the drugs, and the judgment of the treating physician. In certain instances, it is considered appropriate for the caregiver to determine such therapeutically effective amounts by routine experimentation (including, but not limited to, a dose escalation clinical trial).

In some or any prophylactic applications, compositions containing the compounds described herein are administered to a patient tible to or otherwise at risk of a ular disease, disorder or ion. In some ments, the amount administere is defined to be a "prophylactically effective amount or dose." In some or any ments of this use, the precise amounts of compound administered depend on the patient's state of health, weight, and the like. In some embodiments, it is considered appropriate for the caregiver to determine such prophylactically effective amounts by routine experimentation (e.g., a dose escalation clinical trial). In some or any embodiments, when used in a patient, ive amounts for this use will depend on the severity and course of the e, disorder or condition, previous therapy, the patients health status and response to the drugs, and the nt of the treating ian.

In some or any embodiments are ﬁarther embodiments that include multiple administrations of the effective amount of the compound, including r embodiments wherein: (i) the compound is administered in a single dose; (ii) the time between multiple strations is every 6 hours; (iii) the compound is administered to the subject every 8 hours.

In further or alternative embodiments, the method includes a drug holiday, wherein the administration of the compound is arily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the nd is resumed. In some embodiments, the length of the drug holiday varies from 2 days to 1 year.

In certain instances, a t’s condition does not improve or does not significantly improve following administration of a compound or composition described herein and, upon the ’s discretion the administration of the compounds is optionally administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

In certain cases wherein the patient’s status does improve or does not ntially improve, upon the doctor’s discretion the administration of the compounds are optionally given continuously; alternatively, the dose of drug being administered is optionally arily reduced or temporarily suspended for a certain length of time (i.e., a "drug y"). In some or any embodiments, the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.

The dose reduction during a drug y includes a reduction from about 10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

In some or any embodiments, once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. In some embodiments, the dosage, e.g., of the maintenance dose, or the frequency of administration, or both, are reduced, as a on of the symptoms, to a level at which the ed disease, disorder or condition is retained. In some or any embodiments, however, patients are optionally given intermittent treatment on a long-term basis upon any recurrence of symptoms.

In some or any embodiments, the amount of a given agent that ponds to an effective amount varies depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the t or host in need of treatment. In some embodiments, the effective amount is, heless, determined ing to the particular circumstances surrounding the case, including, e.g., the speciﬁc agent that is administered, the route of administration, the condition being d, and the subject or host being d. In some or any embodiments, however, doses employed for adult human treatment is in the range of about 0.02 to about 5000 mg per day, in a speciﬁc embodiment about 1 to about 1500 mg per day. In various embodiments, the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

In some or any embodiments, the pharmaceutical compositions described herein are in a unit dosage form suitable for single administration of precise s. In some instances, in unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. In some or any embodiments, the unit dosage is in the form of a package containing discrete quantities of the formulation. Non- limiting examples are packaged tablets or capsules, and powders in vials or ampoules. In some embodiments, aqueous suspension compositions are packaged in single-dose non- reclosable containers. In alternative embodiments, multiple-dose reclosable ners are used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection are, in some embodiments, presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose ners, with an added preservative. 3] In some or any embodiments, the daily dosages appropriate for the compounds described herein described herein are from about 0.01 to about 2.5 mg/kg per body weight. In some embodiments, an indicated daily dosage in the larger subject, including, but not limited to, , is in the range from about 0.5 mg to about 100 mg, iently administered in divided doses, including, but not limited to, up to four times a day or in extended release form. In some or any embodiments, suitable unit dosage forms for oral administration comprise from about 1 to about 50 mg active ingredient. The foregoing ranges are merely suggestive, as the number of les in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. In some or any embodiments, the dosages are altered depending on a number of les, not limited to the ty of the nd used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

In some or any embodiments, toxicity and therapeutic efficacy of such therapeutic ns are determined by standard ceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the tion). The dose ratio between the toxic and therapeutic s is the therapeutic index and it can be sed as the ratio between LD50 and ED50. In some or any embodiments, compounds exhibiting high therapeutic indices are preferred. In some embodiments, the data obtained from cell culture assays and animal studies is used in formulating a range of dosage for use in human. In specific embodiments, the dosage of such compounds lies within a range of circulating trations that include the ED50 with minimal toxicity. In some or any embodiments, the dosage varies within this range depending upon the dosage form ed and the route of administration utilized.

Kits/Articles of Manufacture Articles of cture, comprising packaging material, a compound provided herein that is effective for ting the activity of the enzyme GCS, or for treatment, tion or amelioration of one or more symptoms of a GCS-mediated disease or condition, within the packaging material, and a label that tes that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable N—oxide, pharmaceutically active metabolite, ceutically acceptable prodrug, or pharmaceutically acceptable e thereof, is used for modulating the activity of GCS, or for ent, prevention or amelioration of one or more symptoms of GCS-mediated disease or condition, are provided.

For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. In various embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) sing one of the separate elements to be used in a method described herein. le containers include, for example, bottles, vials, syringes, and test tubes. In some embodiments, the containers are formed from a variety of materials such as glass or c.

In some embodiments, the articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a ed formulation and intended mode of administration and treatment.

In some embodiments, the container(s) described herein comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example in some embodiments the container is an enous solution bag or a vial having a stopper pierceable by a rmic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described .

In some embodiments, a kit will comprises one or more additional containers, each with one or more of various materials (such as ts, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but are not limited to, buffers, ts, ﬁlters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and e inserts with instructions for use. A set of instructions is optionally included.

In some or any embodiments, a label is on or associated with the container. In some embodiments, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is t within a receptacle or carrier that also holds the container, e. g., as a package insert. In some or any embodiments, a label indicates that the contents are to be used for a speciﬁc therapeutic ation. In some ments, the label indicates directions for use of the contents, such as in the methods described herein.

In some or any ments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. In some embodiments, the pack contains a metal or plastic foil, such as a blister pack. The pack or ser device is optionally accompanied by instructions for administration. In some embodiments, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of ceuticals, which notice is reﬂective of approval by the agency of the form of the drug for human or nary administration. In some or any ments, such notice is, for example, the labeling approved by the US. Food and Drug Administration for prescription drugs, or the ed product insert. In some embodiments, compositions ning a compound provided herein are formulated in a compatible pharmaceutical carrier and are placed in an appropriate container labeled for treatment of an ted condition.

Any combination of the groups described above for the various variables is contemplated herein.

PREPARATION OF COMPOUNDS The following are rative examples of how the compounds can be prepared and tested. Although the examples can represent only some embodiments, it should be understood that the following examples are illustrative and not limiting.

In a ﬁlrther aspect, it is provided a method of making a compound, comprising synthesizing a compound as any of the various embodiments described above or below.

Examples of the method are further described in the Examples.

Compounds disclosed herein are commercially ble or can be y prepared from commercially available starting materials according to established methodology in the art of organic sis. General methods of synthesizing the nd can be found in, e.g., Stuart Warren and Paul Wyatt, Workbook for Organic Synthesis: The Disconnection Approach, second Edition, Wiley, 2010. sis of some of the compounds are exempliﬁed in detail below.

In some embodiments, individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are iﬁed by (l) attachment of a mixture of enantiomers to a chiral axillary, separation of the ing mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the ary or (2) direct tion of the mixture of optical omers on chiral chromatographic column.

Materials were obtained from commercial suppliers and were used without further puriﬁcation. Air or moisture sensitive reactions were conducted under argon atmosphere using oven-dried glassware and rd syringe/septa techniques. 1H NMR spectra were measured at 400 MHz unless stated otherwise and data were reported as follows in ppm (5) from the internal standard (TMS, 0.0 ppm): chemical shift (multiplicity, ation, coupling constant in Hz).

General Scheme 1 R2R‘N’ R3 R2\NR OH R10(O)OH KKKR4—> RAW NH2 1,NH 1 00 I(h) A Compound of Formula I(h) (where all groups are as deﬁned in the y of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein) can be prepared according to General Scheme 1.

A Compound of Formula I(h) can be prepared using standard amide coupling conditions. More speciﬁcally, an intermediate of formula 100, which can be prepared using procedures disclosed herein or are known to one of ordinary skill in the art, is treated with in WO 42397 a solvent such as DMF, DCM or THF, optionally in the presence of a base such as DIPEA or TEA, and in the presence of a ng agent such as EDCI and/or HOBt to yield a compound of Formula I(h). The mixture can optionally be puriﬁed using procedures known to one of ordinary skill in the art. Alternatively, the intermediate of formula R1C(O)OH can be treated with a chlorinating agent such as oxalyl chloride in a solvent such as DMF followed by treatment with the intermediate of formula 100 to yield a compound of Formula I(h). The mixture can optionally be purified using procedures known to one of ordinary skill in the art.

General Scheme 2 R? ,R3 2 R3 N OH RN" 0 KN" —. HAW ,NH ,NH R1 R1 Kb) 10) A Compound of Formula I(j) (where all groups are as deﬁned in the Summary of the Invention for a nd of Formula I or according to any of the embodiments disclosed herein) can be prepared according to General Scheme 2. A Compound of Formula I(h) is treated with a base such as NMP, in the presence ofNHCOg, and in a solvent such as DCM to yield a Compound of Formula I(j).

General Scheme 3 R1 ,R3 RE ,R3 i 3 N OH / N CI N HN’O\ R,NH 1,NH /NH R R Hm Hk) Hm) 1] A Compound of Formula I(k) or I(m) (where all groups are as d in the Summary of the ion for a compound of Formula I or according to any of the ments disclosed herein) can be prepared according to General Scheme 3. A Compound of Formula I(h) is treated with a chlorinating agent such as SOC12 in a solvent such as DCM to yield a nd of Formula I(k). A Compound of Formula I(m) is prepared by treating a Compound of Formula I(k) with NH20CH3 in a solvent such as MeOH.

General Scheme 4 Ra ,R3 Ra ,R3 / N o N NIOH VLR". —> R4 ,NH ,NH R1 R1 ') I(n) A Compound of Formula I(n) (where all groups are as deﬁned in the Summary of the Invention for a compound of Formula I or according to any of the embodiments disclosed ) can be prepared ing to General Scheme 4. A nd of Formula I(j) is treated with hydroxylamine in a solvent such as MeOH to yield a Compound of Formula I(n).

General Scheme 5 2 R3 2 R3 N H NH R1 , R1 , 1(1) I(13) A Compound of Formula I(p) (where all groups are as deﬁned in the Summary of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein) can be prepared according to General Scheme 5. A nd of Formula I(j) is treated with NaBD4 in a ated solvent such as CD301) to yield a Compound of Formula I(p).

General Scheme 6 R2\N /R R2 /R R \ N/R3N2 \N H2 RKKKR4 —’ RKKKR4 _>RKKKR4 I(k) I(q) I(r) A Compound of Formula I(q) or I(r) (where all groups are as deﬁned in the Summary of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein) can be ed according to General Scheme 6. A Compound of Formula I(k) is treated with NaN3 in a solvent such as DMF and heated to about 50 °C to yield a Compound of Formula I(q) which can be optionally worked up before proceeding to the next step. The Compound of Formula I(q) is then treated with PPh3 in a t such as THF to yield the Compound of Formula I(r).

In some or any embodiments of General Schemes l-6, intermediate of formula 100 or the Compound of Formula I(h), I(j), or I(k) is that where R2 and R3 together with the nitrogen to which they are attached form a 3membered ring which is optionally substituted with l, 2, or 3 R8 groups.

General Scheme 7 Ra R3 R2\ ,R3 R{ R3 R2\ R3 N’ OPG N OPG N’ OPG N’ OH OHK/iR" _. o K/iR" _, NH2 R18RNH RMJKWNH H O O 0 100a 100b 100c I(s) where R5 is OH and R5a is H R2\ R3 R3 , R3 100d I(u) where R5 is OH and R5a is H A Compound of Formula I(s) (where R5 is hydroxy and R581 is hydrogen and all groups are as deﬁned in the y of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein) can be prepared according to General Scheme 7. 7] An ediate of formula 100b can be prepared using standard amide coupling conditions. More speciﬁcally, an intermediate of formula 10021, which can be prepared using procedures disclosed herein or are known to one of ry skill in the art, is treated with in a solvent such as DMF, DCM or THF, optionally in the presence of a base such as DIPEA or TEA, and in the presence of a coupling agent such as EDCI and/or HOBt to yield an intermediate of formula 100e (e.g., a nd of Formula I(s) where R5 is -OTBS and R5&1 is hydrogen). The protecting group in intermediate of formula 1000 is then d in the ce of TBAF in a solvent such as THF. The mixture can optionally be puriﬁed using procedures known to one of ordinary skill in the art. Alternatively, a nd of Formula I(s) (where R5 is hydroxy and R5&1 is hydrogen and all groups are as deﬁned in the Summary of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein) can be prepared by treating an intermediate of formula 10021 with RlaC(O)C(O)OH using standard amide coupling ures described herein or known to one of ordinary skill in the art. The mixture can optionally be puriﬁed using procedures known to one of ordinary skill in the art.

A Compound of Formula I(u) (where R5 is hydroxy and R581 is en and all groups are as deﬁned in the y of the ion for a compound of Formula I or according to any of the ments disclosed herein) can be prepared according to General Scheme 7. The intermediate of formula 1000 is treated with an intermediate of a RlaONHg in the presence of sodium e in a solvent such as ethanol or methanol to yield an intermediate of formula 100d (e. g., a compound of Formula I(u) where R5 is -OTBS and R5&1 is hydrogen and all groups are as deﬁned in the Summary of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein). The intermediate of formula 100d is treated with TBAF in a t such as THF to yield a Compound of Formula I(u). The mixture can optionally be puriﬁed using procedures known to one of ordinary skill in the art. Alternatively, the Compound of Formula I(s) (where R5 is hydroxy and R5&1 is hydrogen and all groups are as deﬁned in the Summary of the Invention for a compound of Formula I or according to any of the embodiments disclosed herein) is treated with an intermediate of formula RlaONHg in a solvent such as ethanol or methanol to yield a Compound of Formula I(u). The mixture can optionally be puriﬁed using procedures known to one of ordinary skill in the art.

SYNTHETIC EXAMPLES Intermediate A 0 | O | ,JIO/"V/kOH—> m/"\E/H\OH _>Ho"\;/ﬂ‘N’O TBSO/A\E/ﬂ\N’O ; 5 | —> E | —» NH NHCbz NHCbz NHCbz A1 A2 A3 A4 TBso/\E/ﬂ\E::I:: --* TBSO --> Ho/"\/"\I::]::]--* CszN CszN CszN OMsOH N9H CszNMa:1 CszNMO:j_’ WONH2 0] A8 Benzyl formate (50 mL, 50 w.t.% on in toluene, 148 mmol) was added to a solution of (R)aminohydroxypropanoic acid (A1) (10.5 g, 100 mmol) in sat. aq NaHCOg solution (400 mL). The mixture was stirred vigorously for 4 h at 20 °C, and the aqueous solution was extracted with ether (400 mL x 2). The aqueous phase was acidiﬁed with cone. hydrochloric acid to pH = 2 and extracted with ethyl acetate (300 mL x 3). The combined organic phase was dried with Na2S04 and concentrated to afford crude product Compound A2 (20 g, yield 84%) as a white solid. LC-MS (m/z): 240 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) peaks: 5 (ppm) 3.653 (m, 2H), 4.051 (m, 1H), 4.884 (m, 1H), 5.038 (s, 2H), 7.303-7.373 (m, 6H), 12.658 (s, 1H).

To a mixture of EDCI-HCl (2.4g, 12.5 mmol), HOBt (1.7 g, 12.5 mmol), DIPEA (2.7 g, 20 mmol) in DCM (50 mL) was added Compound A2 (1 g, 4 mmol) and N,0-dimethylhydroxylamine hydrochloride (1.2 g, 12.5 mmol). The mixture was stirred at rt overnight. The mixture was washed with hydrochloric acid solution (1 M, 50 mL x 2), ted aqueous NaHC03 (20 mL), brine (20 mL), and dried over Na2S04. The crude product was d by silica gel column chromatography (ethyl acetate in petroleum, 30% v/v) to give Compound A3 (826 mg, yield 70%) as a ess liquid. LC-MS (m/z): 283 [M+1]+; 1H-NMR(CDC13, 400 MHz) peaks: 5 (ppm) 3.113 (s, 3H), 3.673 (s, 3H), 3.743 (t, J = 4.8 Hz, 2H), 4.766 (m, 1H), 4.959-5.044 (m, 2H), 6.046 (d, J: 8.0 Hz, 1H), 7.200-7.254 (m 5H).

TBDMS-Cl (800 mg, 5.31 mmol) in THF (10 mL) was added dropwise to a solution of Compound A3 (500 mg, 1.77 mmol) and imidazole (602 mg, 8.86 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at rt for 2 h, and then ﬁltered. The ﬁltrate was washed with 1N HCl (50 mL x 2) and brine (50 mL), and dried over Na2S04. The crude product was puriﬁed with silica gel column chromatography (ethyl acetate in petroleum, 13% v/v) to give nd A4 (526 mg, yield 75%) as a colorless liquid. LC-MS (m/z): 396 [M+1]+; 1H-NMR (CDC13, 400 MHz) peaks: 5 (ppm) 0.012 (s, 3H), 0.085 (s, 6H), 0.852 (s, 9H), 3.211 (s, 3H), 3.756 (s, 3H), 3.896 (m, 2H), 4.809 (m, 1H), 5.085 (q, J: 11.2 Hz, 2H), 5.662 (d, J: 8.8 Hz, 1H), 7.286-7.351 (m 5H).

To a on of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine (4.9 g, 23 mmol) in THF (100 mL) was added n-BuLi (1.6 M, 15 mL) at -60 °C under N2 and stirred for 0.5 h, before a solution of Compound A4 (3 g, 7.6 mmol) in THF (50 mL) was added slowly. The mixture was stirred at -60 °C for 1 h, and followed by on of a saturate NH4Cl solution.

The e was extracted with ethyl acetate (100 mL x 2), brine (100 mL), and then dried over Na2S04. The crude t was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to give Compound A5 (3 g, yield 84%) as a colorless liquid.

LC-MS (m/z): 472 [M+1]+; 1H-NMR(CDC13, 400 MHz) peaks: 5 (ppm) 0.000 (s, 3H), 0.024(s, 3H), 0.892 (s, 9H), 4.024-4.116 (m, 1H), 4.465 (m, 4H), 5.262(s, 2H), 5.421 (m, 1H), 6.066 (d, J: 8.0 Hz, 1H), 7.043 (d, J: 8.0 Hz, 1H), 7.444-7.505 (m, 5H), 7.618- 7.639 (m, 2H). nd A5 (2 g, 4.2 mmol) was dissolved in THF (30 mL) and the on was cooled down to -70 °C under nitrogen atmosphere. L-Selectride (8.5 mL, 1M solution in THF, 8.5 mmol) was added dropwise while keeping the temperature at -70 °C. After an hour, the reaction was quenched with saturate NH4Cl solution and extracted with ethyl acetate (50 mL x 2). The extract was dried over Na2S04 to yield a crude t which was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to afford Compound A6 (1.4 g, yield 70%) as a colorless oil. LC-MS (m/z): 474 [M+1]+; 1H-NMR (CDCl3, 400 MHz) peaks: 5 (ppm) 0.08 (m, 6H), , 9H), 3.71 (m, 1H), 3.77 (m, 2H), 4.18 (s, 4H), 4.88 (m, 1H), 4.50 (m, 2H), 5.36 (d, J: 7.6 Hz, 1H), 6.76 (s, 2H), 6.83 (s, 1H), 7.28 (m, 5H).

To a solution of Compound A6 (1.4 g, 3 mmol) in THF (50 mL) was added a solution of TBAF (155 mg, 0.6 mmol) in THF (5 mL) at 0 °C, then the mixture was stirred at rt overnight. After removal of solvent by evaporation, water (50 mL) was added to the mixture which was then extracted with ethyl acetate (2 x 50 mL), washed with brine (1 x 100 mL), and dried over Na2S04 to obtained Compound A7 (1 g, crude). LC-MS (m/z): 342 [M+1]+; 1H-NMR(CDC13, 400 MHz) peaks: 5 (ppm) 3.620-3.737 (m, 3H), 3.772-3.814 (m, 1H), 4.014 (s, 1H), 4.224 (s, 4H), 4.867 (m, 1H), 5.024 (s, 2H), 5.607 (d, J: 8.8 Hz, 1H), 6.809 (s, 2H), 6.888 (s, 1H), 7.24 (m, 5H).

To a solution of Compound A7 (3.6 g, 10 mmol) in THF (50 mL) was added Eth (3 g, 30 mmol), and then the mixture was cooled to -15 °C before adding MsCl (0.8 mL) slowly. The mixture was stirred at -15 °C about half an hour. The reaction mixture was taken up with water (30 mL), extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium e, and evaporated to get Compound A8. To a solution of the resulting mesylate ediate (A8) in THF (50 mL) was added pyrrolidine (5.7 g, 80 mmol), K2C03 (11 g, 80 mmol) and NaI (3 g). The mixture was heated at 50 °C overnight. After ﬁltration and evaporation, the crude t was purified by column chromatography on silica gel (methanol in dichloromethane, 5% v/v) to give Compound A9 (2.5 g, yield 61%) as a colorless oil. LC-MS (m/z): 413 ; 1H-NMR(CDC13, 400 MHz) peaks: 5 (ppm) 1.756 (m, 4H), 2.534 (m, 1H), 2.660 (m, 4H), 2.877 (m, 1H), 4.019 (m, 1H), 4.236 (s, 4H), 4.924 W0 2015/042397 (d, J: 2.8 Hz, 1H), 5.043 (s, 2H), 5.079 (m, 1H), 6.7756-6.892 (m, 3H), 7.266-7.361 (m, 5H).

To a solution of Compound A9 (2.5 g, 6.1 mmol) in ol (20 mL) was added Pd(OH)2 (250 mg), and then the mixture was stirred at rt under H2 ght. The mixture was ﬁltered and the ﬁltrate was evaporated to dryness to give Intermediate A (1.7 g).

LC-MS (m/z): 279 [M+1]+; 1H-NMR (CDClg, 400 MHz) peaks: 5 (ppm) 1.70 (m, 4H), 2.53 (m, 6H), 3.05 (m, 1H), 4.18(s, 4H), 4.47 (d, J: 3.6 Hz, 1H), 6.75 (m, 3H).

Intermediate B DCUS:UJ~U1~W3 ﬁUUZHﬁﬁUJ~§UJ~YUJbzO;Zlh" 0’2"". b To a solution of 5-ﬂuorohydroxybenzaldehyde (14.0 g, 0.1 mol) in THF (150 mL) was added dropwise sat. aq. NaOH solution (0.05 N, 300 mL, 15 mmol) at 0 °C, ed by 30% H2O2 solution (40 mL). After stirred for 2 h at rt, the second portion of 30% H202 (40 mL) was added dropwise and stirred for additional 4 h. The reaction mixture was cooled to 0 °C and pH was adjusted to 10-11 using aq. NaOH on (2 N, 60 mL). The mixture was stirred for 0.5 h before it was quenched with conc. HCl at 0 °C to pH 2~3. The mixture was extracted with DCM (150 mL x 3) and washed with brine (150 mL x 1), dried over sodium sulfate, and evaporated to dryness to yield Compound B1 (12.8 g, yield 100%) as a yellow oil. 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 6.38- 6.56 (m, 1H), 6.53-6.56 (m, 1H), 6.66-6.70 (m, 1H), 8.83 (s, 1H), 9.30 (s, 1H).

A mixture of Compound B1 (12.8 g, 0.1 mol), Cs2C03 (81.5 g, 0.25 mol) in DMF (200 mL) was ﬁrst stirred for 0.5 h at 40 °C and then 1,2-dibromoethane (11.7 mL, 0.135 mol) was added and the mixture was d for 16 h at 80 °C. After it was cooled down to rt, the e was ﬁltered and the cake was washed with ethyl acetate (100 mL). The ﬁltrate was diluted with water (400 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with water (200 mL x 5) and brine (200 ml x 1), dried over sodium sulfate, concentrated, and puriﬁed by column tography on silica gel (ethyl acetate/PE = 1/20, v/v) to get Compound B2 (4.3 g, yield 30%) as a yellow oil. 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 4.20-4.25 (m, 4H), 6.51-6.56 (m, 1H), 6.58-6.61 (m, 1H), 6.76-6.80 (m, 1H). 9] To a solution of Compound B2 (4.1 g, 26.5 mmol) and NBS (7.1 g, 40 mmol) in ACN (30 mL) was added TFA (302 mg, 2.65 mmol) at rt and the mixture was kept at rt with ng overnight. Upon removal of the solvents, the e was puriﬁed by column chromatography on silica gel (ethyl e/PE = 1/25, v/v) to yield Compound B3 (4.9 g, yield 79%) as a white solid. 1H NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 4.21-4.26 (m, 4H), 6.67-6.69 (d, J: 9.2 Hz, 1H), 7.02-7.04 (d, J: 6.8 Hz, 1H).

To a solution of Compound B3 (700 mg, 53.7 mmol) in THF (10 mL) was added n-BuLi (2.5M, 1.24 mL, 3.1 mmol) at -60 °C under N2. After 30 min, a solution of (R)-benzyl 4-formyl-2,2-dimethyloxazolidinecarboxylate (263 mg, 1 mmol) in THF (3 mL). The mixture was stirred at -60 °C under N2 for an additional 30 min, before it was quenched with saturated aqueous NH4Cl solution (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3), washed with brine (20 mL x 1), dried over ous Na2SO4, and puriﬁed by column chromatography on silica (ethyl acetate in petroleum, 30% v/v) to yield Compound B4 (120 mg, yield 29%) as a white foam. LCMS (m/z): 440 [M+1] +ng-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.41-1.70 (m, 6H), 3.63-3.94 (m, 1.5H), 4.09 (m, 0.5H), 4.19 (m, 4H), 4.29-4.41 (m, 1H), 4.95-4.98 (m, 1H), 5.09-5.22 (m, 2H), 6.54 (m, 1H), 6.98 (m, 1H), 7.35 (m, 5H).

To a solution of Compound B4 (2 g, 4.8 mmol) in THF (20 mL) was added 3 N HCl (8 mL) and stirred at 50 °C for 6 h. The mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (30 mL x 1), dried over anhydrous Na2SO4, and concentrated to obtain Compound B5 (1.8 g, yield 100%) as a yellow oil. LCMS (m/z): 400 [M+23]+.

To a solution of Compound B5 (1.8 g, 4.8 mmol) and Et3N (1 mL, 7.2 mmol) in THF (40 mL) was added MsCl (1.44 mL) at -50 °C. Stirred at this temperature for 2 h under N2, the reaction was quenched with sat. aqueous NaHCOg solution (50 mL). It was extracted with ethyl acetate (50 mL x 3), washed with brine (30 mL x 1), dried with ous Na2S04, purified with a silica gel column (MeOH in DCM, 3% v/v) to give nd B6 (1.2 g, yield 55%) as a colorless oil. LCMS (m/z): 478 [M+23]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.94-3.09 (m, 3H), .55 (m, 7H), .00-5.31 (m, 4H), 6.56-6.60 (m, 1H), 6.94-6.98 (m, 1H), 7.27-7.37 (m, 5H). 3] To a solution of Compound B6 (1.2 g, 2.6 mmol) in THF (40 mL) was added pyrrolidine (2 mL, 23.7 mmol) and stirred at 50 °C overnight. After the mixture was cooled down, the mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with water (100 mL x 3), brine (100 mL x 1), dried over anhydrous , and puriﬁed using silica gel column chromatography (MeOH in DCM, 4% v/v) to obtain Compound B7 (0.4 g, 36%) as a white solid. LCMS (m/z): 431 [M+1]+.

To a solution of nd B7 (400 mg, 0.93 mmol) in EtOH (20 mL) and water (2 mL) was added LiOH-HZO (120 mg, 2.79 mmol). The mixture was stirred at reﬂux for 4 h, followed by addition of water (50 mL). The mixture was extracted with ethyl acetate (30 mL x 3), washed with brine (50 mL x 1), dried over anhydrous Na2S04, and concentrated to give Intermediate B (300 mg, yield 100%) as a yellow solid. LCMS (m/z): 297 [M+1]+.

Intermediate C Elf"ii?"ill):(I? 2% F01 T880 :1 I :j M30 CszN HC(EJZHN CszN= :1 U U N OH N OH CszN= D Km, 1 C9 C ] To a solution of Compound C1 (50 g, 357 mmol) in ACN (400 mL) was added NBS (60.08 g, 360 mmol) and HC(O)O'NH4+ (2.47 mg, 39 mmol) at rt and then the mixture was stirred at rt for 2 h. After removal of the solvent and diluted with ethyl acetate (200 mL), the e was washed with brine, dried over anhydrous Na2S04, and concentrated to give Compound C2 (78 g, yield 100%) as a yellow solid. 1H-NMR(CDC13, 400 MHz) major teristic peaks: 5 (ppm) 7.48-7.23 (m, 2H), 9.87 (s, 1H), 10.89 (s, 1H).

To a solution of Compound C2 (40 g, 183 mmol) in THF (260 mL) was added se aq. NaOH solution (0.05 N, 720 mL, 37 mmol) at 0 °C, and then 30% H202 solution (90 mL). The mixture was stirred for 2 h at rt and followed by the addition of a second portion of 30% H202 (90 mL). After stirred for 4 h, it was cooled to 0 °C and aq. NaOH solution (2 N, 112 mL) was added until pH10~11 was reached, and then the mixture was stirred for 0.5 h and quenched with conc. HCl at 0 °C to pH2~3. It was extracted with romethane (250 mL x 3) and washed with brine (300 mL x 2), dried over Na2SO4, and concentrated to give Compound C3 (37 g, yield 98%) as a yellow oil. LC-MS (m/z): 205 [M- 1]".

To a mixture of Compound C3 (30 g, 146 mol), K2C03 (60.3 g, 437 mol) in DMF (450 mL) was added 1,2-dibromoethane 63 mL, 730 mol). The mixture was stirred at 80 °C for 4 h. After cooled to rt, it was ﬁltered and the cake was washed with ethyl acetate (100 mL). The ﬁltrate was diluted with water (900 mL) and extracted with ethyl e (400 mL x 3). The organic layer was washed with water (900 mL x 5) and brine (900 ml x 1), dried, concentrated, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 5 % v/v) to afford Compound C4 (20.4 g, yield 60%) as a colorless oil. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 4.35 (s, 4H), 6.91 (t, J = 8 Hz, 2H), 7.33 (s, 1H).

To a solution of nd C4 (10.5 g, 45 mmol) in THF (300 mL) was added n-BuLi (2.4 M, 20 mL, 46.5 mmol) at — 60 °C under N2 and it was stirred at under this condition for 0.5 h. It was added a solution of Compound A4 (6 g, 15 mmol) in THF (10 mL). The e was stirred at — 60 °C under N2 for 20 min, quenched with saturated aqueous NH4Cl solution (200 mL), extracted with ethyl acetate (200 mL x 3), washed with brine (200 mL x 1), dried over anhydrous Na2S04, and puriﬁed by column tography on silica gel (ethyl acetate in petroleum, 10% v/v) to obtain Compound C5 (4.87 g, yield 66%) as a colorless oil. LC-MS (m/z): 490 .

To a solution of Compound C5 (4 g, 8.1 mmol) in THF (50 mL) was added L-Selectride (16.3 mL) at — 60 °C under N2. The e was stirred under the same condition for 1 h before quenched with saturated aqueous NH4Cl on (50 mL). It was extracted with ethyl acetate (50 mL x 3), washed with brine, dried over anhydrous Na2S04, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 9% v/v) to yield Compound C6 (4 g, yield 100%) as a colorless oil. LC-MS (m/z): 474 [M+1-18]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 3.77-3.83 (m, 2H), 4.28 (t, J = 8 Hz, 4H), 4.92-5.05 (m, 2H), 5.11 (m, 1H), 5.38-5.57 (m, 1H), 6.67-6.74 (m, 2H), 7.29-7.36 (m, 5H).

To a solution of Compound C6 (4.15 g, 8.4 mmol) in THF (150 mL) was added TBAF (1.1g, 4.2 mmol) at 0 °C and it was stirred at rt overnight. The mixture was added water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 2), dried over anhydrous Na2S04, and trated to give Compound C7 (3.18 g, yield 100%) as a colorless oil. LC-MS (m/z): 360 [M+1-18]+; 1H-NMR(CDC13, 400 MHz) major 2014/056555 characteristic peaks: 5 (ppm) 4.14-4.16 (m, 6H), 4.91 (s, 2H), 4.98 (s, 1H), 5.47 (d, J: 8 Hz, 2H), 6.55-6.63 (m, 2H), 7.17-7.26 (m, 5H).

To a solution of Compound C7 (3.18 g, 8.4 mmol) and Eth (3.5 mL, 25.3 mmol) in THF (80 mL) was added MsCl (0.71 mL, 9.3 mmol) at — 40 °C and the mixture was stirred at — 40 °C for 4 h. It was added water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 1), dried over anhydrous Na2S04, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 30% v/v) to give nd C8 (1.35 g, yield 35%) as a ess oil. LC-MS (m/z): 438 [M+l-l8]+.

To a solution of Compound C8 (1 g, 3 mmol) in THF (20 mL) was added pyrrolidine (2.66 mL, 30 mmol). The mixture was d at 60 °C overnight. It was added water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (30 mL x 1), dried over anhydrous Na2S04 and concentrated in vacuum to give Compound C9 (900 mg, crude) as a yellow oil. LC-MS (m/z): 431 [M+l]+.

To a solution of Compound C9 (900 mg, 2.1 mmol) in EtOH/water (20 mL, 9:1, v/v) was added LiOH-HZO (264 mg, 6.3 mmol). The mixture was reﬂuxed for 36 h and then diluted with water (20 mL). It was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to give Intermediate C (800 mg, crude) as a yellow oil. LC-MS (m/z): 297 [M+l]+.

Intermediate D @"86 $3:(EVE? _.\Qjammmjﬁmmmjﬁ mjwMm)" "an: :3 To a solution of Compound D1 (80 g, 266 mmol) in H (400 ml) was added fuming HN03 (24 mL) at 10 °C and the mixture was d at 32 °C for l h. Water (200 mL) was added and the mixture ﬁltered. The ﬁltrate was washed with water to remove W0 2015/042397 CH3C02H and was dried to give Compound D2 (80 g, yield 82%) as a yellow solid. LC-MS (m/z): 244 [M-1]'.

To a solution of Compound D2 (40 g, 163 mmol) in THF (260 mL) was added dropwise aq. NaOH solution (0.05 N, 640 mL, 33 mmol) at 0 °C and 30% H202 solution (80 mL). The mixture was stirred for 2 h at rt. The second portion of 30% H202 (80 mL) was added se and the mixture was stirred for 4 h. After cooling to 0 °C, aq. NaOH solution (2 N, 98 mL) was added dropwise until pH10~11. The mixture was stirred for 0.5 h and quenched with conc. HCl at 0 °C until pH 2~3. The mixture was extracted with dichloromethane (250 mL x 3) and washed with brine (300 mL x 2), dried over Na2S04, and concentrated to give Compound D3 (37 g, yield 98%) as a yellow solid. LC-MS (m/z): 232 [M-1]'; 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 7.17 (s, 1H), 7.48 (s, 1H), 10.59 (s, 2H).

To a mixture of nd D3 (32 g, 137 mol) and K2C03 (73 g, 549 mol) in DMF (500 mL) was added 1,2-dibromoethane (147 mL, 343 mol). The mixture was stirred at 80 °C for 4 h. After cooling to rt, the mixture was ﬁltered and the cake was washed with ethyl acetate (100 mL). The ﬁltrate was d with water (900 mL) and extracted with ethyl acetate (400 mL x 3). The organic layer was washed with water (900 mL x 5) and brine (900 ml x 1), dried, concentrated, and puriﬁed by column chromatography on silica gel (ethyl e in petroleum, 5 % V/V) to yield nd D4 (30 g, yield 84%) as a colorless oil. 1H- NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 4.35 (s, 4H), 6.91 (t, J = 8 Hz, 2H), 7.33 (s, 1H).

To a solution of Compound D4 (11 g, 42.5 mmol) in EtOH (200 mL) was added HCl (7 mL). Fe (7.1 g, 127 mmol) was added over 0.5 h. Then HCl was added to reach pH 3-4. The e was stirred at 100 °C for 2 h. After g to rt, 10% NaOH aq was added dropwise until pH 10~11. The mixture was ﬁltered and the cake was washed with THF. The ﬁltrate was condensed and extracted with ethyl acetate (100 mL x 3), washed with brine (200 mL x 1), dried over anhydrous Na2S04, concentrated, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 20% V/V) to obtain Compound D5 (9 g, yield 93%) as a white solid. LC-MS (m/z): 230 [M+1]+; 1H-NMR (CDC13, 400 MHz) major teristic peaks: 5 (ppm) 4.23-4.27 (m, 4H), 6.46 (d, J = 8 Hz, 2H).

A solution of D5 (3.3 g, 14.7 mmol) in H20 (15 mL) and concentrated HCl (4 mL, 48 mmol) was cooled to 5 °C. A solution z (1.09 g, 15.8 mmol) in H20 (7 mL) was added dropwise. The brown solution of the diazionium salt was then added dropwise to a solution of CuCl (2.96 g, 28.4 mmol) in concentrated HCl (5 mL), maintaining the internal 2014/056555 temperature around 10 °C. The mixture was then diluted with H20 (120 ml) and the solution was stirred for an additional 1 h at rt. The product was extracted into ethyl acetate (50 mL x 3), washed with brine (200 mL x 1), dried over anhydrous Na2SO4, concentrated, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 20% V/V) to obtain Compound D6 (1.9 g, yield 53%) as a white solid. 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 4.26 (t, J: 8 Hz, 2H), 4.34 (t, J: 8 Hz, 2H), 6.95 (s, 1H), 7.08 (s, 1H).

To a solution of Compound D6 (8.05 g, 32 mmol) in THF (300 mL) was added n-BuLi (2.4 M, 14 mL, 29.4 mmol) at — 60 °C under N2 and d for 0.5 h. Then it was added a solution of nd A6 (4.3 g, 11 mmol) in THF (10 mL). The mixture was stirred at — 60 °C under N2 for 20 min, ed with saturated aqueous NH4C1 solution (200 mL), extracted with ethyl acetate (200 mL x 3), washed with brine (200 mL x 1), dried over anhydrous , puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 10% V/V) to yield Compound D7 (4.87 g, yield 66%) as a colorless oil. LC-MS (m/z): 506 [M+1]+.

To a solution of Compound D7 (4.5 g, 8.8 mmol) in THF (50 mL) was added L-selectride (17.7 mL) at — 60 °C under N2. After stirred for 1 h, the mixture was quenched with saturated aqueous NH4Cl solution (50 mL), extracted with ethyl acetate (50 mL x 3), washed with brine, dried over anhydrous Na2SO4, and puriﬁed by column chromatography on silica gel (ethyl acetate in eum, 20 % V/V) to give Compound D8 (3.8 g, yield 85 %) as a white solid. LC-MS (m/z): 490 [M+1-18]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 0.90 (s, 9H), 3.77-3.85(m, 2H), 4.25 (s, 2H), 4.34 (s, 2H), 4.90 (s, 1H), 5.01-5.12 (m, 2H), 5.40 (d, J: 8 Hz, 1H), 6.80 (s, 1H), 6.97 (s, 1H), 7.32-7.36 (m, 5H).

To a solution of Compound D8 (3.8 g, 7.5 mmol) in THF (150 mL) was added TBAF (1 g, 3.8 mmol) at 0 °C and it was stirred at rt overnight. The mixture was added water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 2), dried over anhydrous Na2SO4, and concentrated to yield D9 (2.81 g, yield 100%) as a ess oil.

LC-MS (m/z): 376 [M+1-18]+; 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.72-3.80 (m, 2H), 4.23 (s, 2H), 4.31 (s, 2H), 4.69-4.86 (m, 1H), 5.02-5.15 (m, 2H), .51 (d, J: 8 Hz, 1H), 6.75-6.96 (m, 2H), 7.29-7.36 (m, 5H).

To a solution of Compound D9 (1.4 g, 3.6 mmol) and TEA (1.5 mL, 10.8 mmol) in THF (30 mL) was added MsCl (0.31 mL, 3.9 mmol) at — 40 °C. After stirring at —0 °C for 4 h, water (50 mL) was added and the product was extracted into ethyl acetate (50 mL x 3) which was washed with brine (100 mL x 1) and dried over anhydrous Na2S04. The product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 50% v/v) to give nd D10 (756 mg, yield 45%) as a white solid. LC-MS (m/z): 454 8]+.

To a solution of Compound D10 (756 mg, 1.6 mmol) in THF (20 mL) was added pyrrolidine (1.4 mL, 16 mmol). The mixture was stirred at 60 °C overnight. It was added water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (30 mL x 1), dried over anhydrous Na2S04, and concentrated in vacuum to give crude t Compound D11 (715 mg, crude) as a white solid. LC-MS (m/z): 447 [M+1]+.

To a solution of Compound D11 (714 mg, 1.6 mmol) in EtOH/water (24 mL, 2:1, v/v) was added LiOH-HZO (672 mg, 16 mmol). The mixture was reﬂuxed for 24 h before added water (20 mL). It was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to give crude t Intermediate D (620 mg, crude) as a yellow oil. LC-MS (m/z): 313 [M+1]+.

Intermediate E BocHN’Nj Bed-WV 9H N N OH 9" . o M80 j —> ' 0 g O —> CszN 5 0 j 1le CszN 2 A8 E1 E2 A suspension of Compound A8 (1.00 g, 2.29 mmol mmol), tert—butylaza- bicyclo[3.2.1]octanylcarbamate (1.96 g, 6.86 mmol) and K2C03 (1.58 g, 11.45 mmol) in ACN (30 mL) was stirred at 60 °C overnight. The mixture was diluted with ethyl acetate (150 mL) and evaporated to give nd E1 (1.20 g, yield 92%) as a colorless oil. LCMS (m/z): 568 [M+1]+.

A mixture of nd E1 (1.20 g, 2.12 mmol) and NaOH (423 mg, 10.58 mmol) in HgO/EtOH (10/50 mL) was stirred at 80 °C overnight. The mixture was diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by prep-HPLC to yield Compound E2 (980 mg, yield 100%) as a colorless oil. LCMS (m/z): 433 [M+1]+.

To a solution of nd E2 (980 mg, 2.26 mmol) and imidazole (461 mg, 6.78 mmol) in THF (10 mL) was added TBDMSCl (678 mg, 4.53 mmol) at rt. The mixture was stirred at rt for 2 h. It was diluted with ethyl acetate (150 mL), washed with water and brine, dried with anhydrous Na2S04, and ated to afford Intermediate E (1.10 g, yield 89%) as a colorless oil, which was used for next step directly. LCMS (m/z): 548 [M+1]+.

Example 1 (3% at)? a ﬂow 4 \ O OH OH 1A 1B 1C 1D 1E o O O N 9H 0 O OH O —> \—> \—> F —> E o F F F F j 1F 1G 1H 1 To a stirred on of Compound 1A (2.75 g, 17 mmol) in DCM (40 mL) was added THF-borane (1 M, 20 mL, 20 mmol) at -78 °C. The resulting mixture was allowed to warm up to rt over 1 h. To the mixture was added MeOH (8 mL) and it was heated to reﬂux for 2 h. Diluted with aq. NaHCOg (20 mL), the mixture was poured into crash ice slowly with stirring. The e was then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2S04 and concentrated to give the crude product which was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, from 1% to 25% v/v) to yield nd IE (2.4 g, yield 96%) as a white solid. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.79-2.75 (m, 3H), 3.01-3.08 (m,2H), 3.61-3.64 (m,2H), 7.10-7.23 (m,4H).

A solution of Compound 1B (200 mg, 1.4 mmol) and Dess-Martin reagent (688 mg, 1.6 mmol) in dichloromethane (20 mL) was stirred at rt for 4 h. The resulting solution was poured into a saturated solution of sodium hydrogen ate (20 mL) in which hand sodium thiosulfate pentahydrate had been dissolved. After 15 min of vigorous stirring, the organic phase was collected and the aqueous phase was extracted with diethyl ether (10 mL x 3). The combined organic layers were dried and evaporated to give a crude product which was puriﬁed by column tography on silica gel (ethyl acetate in petroleum ether, from 1% to 4% v/v) to afford Compound 1C (190 mg, yield 96%) as a yellow oil. (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.05-3.23 (m,5H), 7.06-7.15 (m, 4 H), 9.67 (s,1H).

Compound 1C (292 mg, 2 mmol) was added to a solution of sodium metabisulfite (196 mg, 4 mmol) in water (3 mL). The mixture was vigorously stirred for 2 h at rt and after the addition of sodium e (380 mg, 2 mmol), and then stirred for 1 h. The e was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2S04, and concentrated to give a crude product 1D 2014/056555 (316 mg, yield 91%) as a yellow oil. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: (ppm) 2.89-3.01 (m,3H), 3.14-3.24 (m, 2H), 4.41-4.43 (d, J: 8 Hz, 1H), .26 (m,4H). 1] A solution of Compound ID (300 mg, 1.7 mmol) in HCl/MeOH (3 M, 2 mL) was heated to reﬂux for 18 h. The e was concentrated by evaporation and puriﬁed by column chromatography on silica gel to give Compound 1E (116 mg, yield 32%). 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.85-3.01 (m,6H), 3 .75 (s,3H), 4.28 (s,lH), 7.11-7.19 (m, 4H).

A solution of Compound 1E (550mg, 2.70 mmol) and Dess-Martin reagents (1.3 g, 3.2 mmol) in dichloromethane (20 mL) was d at rt for 4 h. The suspension was diluted with diethyl ether (60 mL) before being slowly poured into a saturated solution of sodium hydrogen carbonate (20 mL) in which contained a pre-dissolved sodium thiosulfate pentahydrate (1.6 g, 6.4 mmol). After 15 min of vigorous stirring, the organic phase was collected and the aqueous phase was extracted with diethyl ether (10 mL x 3). The combined organic layers were dried and evaporated to give a crude product 1F (500 mg, yield 92%) as a yellow oil. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.24-3.26 (d, J = 4 Hz, 4H), 3.89-3.91(m,3H), 4.01-4.05 (m,lH), 7.14-7.20 (m, 4H).

'ToasﬁnedsohunniofConmound1F(2001ng,1nnnoDin1)Ch4(4rnL)was added DAST (0.8 mL, 6 mmol) at 0 °C. The resulting mixture was stirred at rt for 24 h. The mixture was poured into crash ice slowly with stirring. The mixture was stirred for 30 min, and then extracted with DCM (10 mL x 3). The combined c layers were washed with brine (20 mL), dried over Na2S04, and concentrated to give a crude product. The crude t was puriﬁed by prep-TLC (petroleum ether as the eluent) to give Compound 1G (80 mg, yield 36%). 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 298-3. 19 (m,5H), 3.74 (s,3H), 7.07-7.17 (m, 4H).

To a stirred on of Compound 1G (140mg, 0.6mmol) in EtOH (2 mL) and H20 (2 mL) was added LiOH-HZO (50 mg, 1.2 mmol) in ice bath. The resulting e was stirred at rt for 2 h and followed by acidification to pH 2 with 2 M HCl. The e was ted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2S04, and concentrated to give Compound IH (130 mg, yield 100%) as yellow oil. LC-MS (m/z): 211 [M-1]'; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.09-3.12 (m,5H),7.13-7.18 (m, 4 H).

To a stirred e of Compound 1H (31.8mg, 0.15mmol) and Intermediate A (62.55 mg, 0.23 mmol) in DMF (3 mL) was added HOBt (30 mg, 0.25 mmol) and EDCI (43.2 mg, 0.23 mmol). The resulting mixture was stirred at rt overnight. The mixiture was diluted with water (15 mL), and extracted with EtOAc (15 mL x 3). The ed organic layers were washed with brine (15 mL), dried over NaZSO4, and concentrated to give a crude product. The crude product was puriﬁed by prep-HPLC to afford triﬂuoroacetic acid salt of Compound 1 (11.1 mg, yield 15.5%) as a white solid. LC-MS(m/z): 473 [M+l]+; lH-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.62 (s, 4H), 2.16 (s, 4H), 2.5 8-2.64 (m, 2H), .09 (m, 4H), 3.52-3.57 (m, 1H), 3.52-3.57 (m, 1H), 4.11-4.21 (m, 4H), 4.39- 4.41 (m, 1H), 5.16 (s, 1H), 6.80-6.90 (m, 3H), 7.13-7.15 (t, J: 4 Hz, 4H), 7.37-7.39 (d, J: 8 Hz, 1H).

Example 2 o F F [13%O /ﬂerEt o OEt O 03 —>[ o —>E 0 o o o o 2A 23 :N: 9H F F o F F 0 OH a [: NH ______, ______, : o 0 2c 2 6] To a d suspension of A1C13 (26.7 g, 200 mmol) in DCM (100 mL) was added dropwise ethyl 2-chlorooxoacetate (27.3 g, 200 mL) at 0 °C. After d at 0 °C for min, 2, 3-dihydrobenzo[b][l,4]dioxine (13.6 g, 100 mmol) was added dropwise at 0°C to the mixture. The resulting mixture was stirred at rt for 3 h, poured into ice water (300 mL), and then extracted with DCM (150 mL x 3). The combined organic layers were washed with aq. NaHC03 (200 mL), brine (200 mL), dried over NaZSO4, and concentrated to give a crude product. The crude product was puriﬁed by column chromatography on silica gel (ethyl e in petroleum ether, from 5% to 10% v/v) to yield Compound 2A (1 8 g, yield 76%) as a yellow solid. LC-MS (m/z): 162 [M+1]+; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 1.40-1.43 (t, J: 7.2 Hz, 3 H), 4.28-4.33 (m, 2 H), 4.34-4.36 (m, 2 H), 4.40- 4.45 (m, 2 H), 6.94-6.96 (dd, J: 7.6, 1.6 Hz, 1 H), 7.54-7.56 (m, 2 H).

To a stirred solution of Compound 2A (4.72 g, 20 mmol) in DCM (50 mL) was added DAST (16.1 g, 100 mmol) at 0°C. The resulting mixture was stirred at rt for 24 h and poured into crash ice slowly with stirring. The mixture was stirred for 30 min, and then extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (20 mL), dried over NaZSO4, and concentrated to give crude product. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 3% v/v) to afford Compound 2B (4.28 g, yield 83%) as a yellow oil. LC-MS (m/z): 259 ; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 1.29-1.33 (t, J = 7.2 Hz, 3H), 4.26-4.32 (m, 6H), 6.90-6.92 (d, J: 8.0 Hz, 1H), 7.07-7.12 (dd, J: 7.6, 2.4 Hz, 1H), 7.12-7.13 (d, J: 2.0 Hz, 1H).

To a stirred solution of Compound 2B (4.28 g, 16.59 mmol) in THF (20 mL) and H20 (20 mL) was added LiOH-HZO (1.393 g, 33.18 mmol) in an ice bath. The resulting mixture was stirred at rt for 16 h. THF was removed under reduced pressure. The residue was diluted with water (20 mL), acidiﬁed to pH 2 with 2 M HCl, and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2S04 and concentrated to give Compound 2C (3.8 g, yield 98%) as light yellow solid. LC-MS (m/z): 211 [M-19]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 4.28-4.30 (t, J: 4.4 Hz, 4H), 6.98- 7.04 (m, 3H).

To a d mixture of Compound 2C (23 mg, 0.1 mmol) and Intermediate A (41.7 mg, 0.15 mmol) in DMF (1 mL) was added HOBt (20 mg, 0.15 mmol) and EDCI (30mg, 0.15 mmol). The resulting mixture was stirred at rt overnight. The mixiture was diluted with water (10 mL) and ted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2S04, and concentrated to give crude product. The crude product was puriﬁed by PLC to give triﬂuoroacetic acid salt of Compound 2 (18.9 mg, yield 39%) as a white solid. LC-MS (m/z): 491 [M+1]+;1H-NMR (CDC13, 400 MHz) major teristic peaks: 5 (ppm) 2.07(s, 3 H), 2.86 (s, 1 H),3.00 (s, 1H), 3.46 (s, 2H),3.76 (s, 2H), 4.20-4.25 (m, 8H), 4.37 (s, 1 H), 5.05 (s, 1 H), 6.72-6.81 (m, 4PD,691(s,1}D,765(s,HHL1L67(s1H) Example3 O O /— Cl CI 0 Cl 0 —> F s s o S F 3A 3B :N: 9H 0 5 CI OH \ o NH j _> F —> O S F F 3c CI 3 To a solution of 5-chlorobenzo[b]thiophene (2.00 g, 11.83 mmol) in THF (50 mL) was added dropwise n-BuLi in THF (5.20 mL, 13.01 mmol) at -78 °C. Then it was stirred at -50 °C for 1 h. Diethyl oxalate (4.32 g, 29.58 mmol) was added to the mixture quickly at -78 °C. The mixture was stirred at -50 °C for 1 h. It was quenched with acetic acid, diluted with ethyl acetate (200 mL), washed with water and brine, dried with ous Na2S04, and evaporated to give a residue which was washed with petroleum ether to obtain Compound 3A (2.60 g, yield 82%) as a light yellow solid. LCMS: 269 [M+1] +; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 1.46 (t, J = 7.6 Hz, 3H), .51 (m, 2H), 7.48 (d, J: 8.8 Hz, 1H), 7.82 (d, J: 8.8 Hz, 1H), 7.92 (s, 1H), 8.37 (s, 1H).

To a solution of Compound 3A (600 mg, 2.25 mmol) in DCM (120 mL) was added dropwise DAST (1.5 mL, 11.19 mmol) at rt. The mixture was stirred at rt overnight. It was then quenched with ice, d with ethyl acetate (150 mL), washed with water and brine, dried with anhydrous Na2S04, and evaporated to yield Compound 3B (420 mg, yield 64%) as a yellow oil. LCMS: 291 [M+1] +; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.37 (t, J: 7.2 Hz, 3H), .41 (m, 2H), 7.38 (d, J: 8.8 Hz, 1H), 7.58 (s, 1H), 7.77-7.82 (m, 2H).

A solution of Compound 3B (420 mg, 1.45 mmol) and LiOH-HZO (122 mg, 2.90 mmol) in THF/MeOH/H20 (10/10/5 mL) was stirred at rt for 2 h. The mixture was adjusted to pH 2 with conc. HCl, diluted with ethyl acetate (150 mL), washed with water and brine, dried with anhydrous , and evaporated to give Compound 3C (400 mg, yield 10096)asaxvhﬁesohd.LCmAS:261[h44]2 A mixture of Intermediate A (80 mg, 0.29 mmol), Compound 3C (94 mg, 0.34 mmol), EDCI (84 mg, 0.44mmol), HOBt (59 mg 0.44 mmol) and DIPEA (0.2 mL) in DCM (5 mL) was stirred at rt overnight. Then it was diluted wit ethyl acetate (150 mL) washed mmwmmmMMmmmﬁmempmlCmmﬁMCmmWMB60mgﬂ$ﬂﬁ©wa white solid. LCMS: 523 [M+1]: 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.14 (br s, 4H), 2.59 (br s, 4H), .03 (m, 2H), 3.45-3.51 (m, 2H), 3.82 (br s, 2H), 4.00-4.16 (m, 4H), 4.44 (br s, 1H), 5.15 (s, 1H), 6.72-6.82 (m, 3H), 7.10 (s, 1H), 3.37 (d, J: .4 Hz, 1H), 7.70-7.78 (m, 2H), 11.95 (s, 1H).

Example 4 Br Br TBSO TBSO OH 0/ CszN CszN F F OH OH N F CF(_) N OH OH N OH —> —> —> NHCbz NHCbz 0/ "Hz 4D 4E 4F To a solution of 4-bromoﬁuorophenol (15 g, 78.5Cmmol) in DMF (200 mL) was added K2C03 (32.25 g, 235.6 mmol), CH31 (12.3 mL, 96.3 mmol). The mixture was stirred at rt overnight. Water (500 mL) was added to the e and the e was extracted with ethyl acetate (200 mL x 3), dried over anhydrous Na2SO4, and puriﬁed by column chromatography on silica gel (petroleum 100%) to obtain Compound 4A (11.3 g, 70%) as a colorless oil. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.86 (s, 3H), 6.83 (t, J: 8.8 Hz, 1H), 7.20 (m, 2H).

] To a solution of Compound 4A (11 g, 53.7 mmol) in THF (250 mL) was added n-BuLi (2.5M, 22.2 mL, 55.5 mmol) at -60°C under N2. The mixture was stirred at -0°C under N2 for 0.5 h. Then it was added a solution of Intermediate A4 (7.1 g, 17.9 mmol) in THF (50 mL). The mixture was stirred at -60°C under N2 for another 5 min before quenched with saturated aqueous NH4Cl solution (200 mL). The mixture was extracted with ethyl acetate (200 mL x 3), washed with brine (200 mL x 1), dried over anhydrous Na2SO4, and puriﬁed by column chromatography on silica (ethyl acetate in petroleum, 9% V/V) to yield Compound 4B (7.1 g, 86%) as a colorless oil. LCMS: 462 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) -0.14 (s, 3H), -0.12 (s, 3H), 0.75 (s, 9H), 3.89 (m, 1H), 3.96 (m, 4H), 5.13 (s, 2H), 5.29 (m, 1H), 5.89 (m, 1H), 7.01 (m, 1H), 7.35 (m, 5H), 7.73 (m, 2H).

To a solution of Compound 4B (7.1 g, 15.4 mmol) in THF (100 mL) was added ctride (31 mL) at -60°C under N2 and stirred at -60°C under N2 for 1 h. The mixture was quenched with saturated aqueous NH4C1 solution (100 mL) and extracted with ethyl acetate (100 mL x 3), washed with brine, dried over anhydrous Na2SO4, and then puriﬁed by column chromatography on silica gel (ethyl e in petroleum, 9% V/V) to give Compound 4C (6.7 g, 94%) as a ess oil. LCMS: 446 [M+1-18]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 0.03 (m, 6H), 0.90 (d, 9H), 3.68 (m, 1H), 3.88 (m, 51D,489(nn11D,504(nL2PD,539(nL11D,688(nn11D,703(nn1}D,712(nL11D, 7.30 (m, 5H).

To a solution of Compound 4C (6.7 g, 13.6 mmol) in THF (250 mL) was added TBAF (1.8 g, 6.8 mmol) at 0°C and d at rt overnight. The e was added water (200 mL), extracted with ethyl acetate (100 mL x 3), washed with brine (200 mL x 1), MMMWNmmeﬂhﬁmmmmmmwmdmmCmmwm4D6g9W®wawa oil. LCMS: 332 [M+1-18]+.

To a solution of Compound 4D (5 g, 14.3 mmol) and TEA (6 mL, 42.9 mmol) in THF (80 mL) was added MsCl (1.2 mL) at -60°C and stirred at -60°C for 2 h. The mixture was added pyrrolidine (12 mL, 143 mmol) and d at 50°C overnight. After the mixture was cooled down, water (200 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL x 1), and dried over anhydrous Na2S04. The crude product was d by prep-HPLC to obtain nd 4E (1.9 g, 33%) as a colorless oil. LCMS: 403 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.78 (m, 4H), 2.64 (m, 6H), 3.88 (m, 4H), 5.03 (m, 4H), 6.89 (m, 1H), 6.70 (m, 1H), 7.11 (m, 1H), 7.28 (m, 5H).

To a solution of Compound 4E (1.9 g, 4.7 mmol) in MeOH (30 mL) was added Pd(OH)2 (660 mg, 4.7 mmol). The mixture was stirred at rt ght under H2. The mixture was ﬁltered and the ﬁltrate was concentrated to obtain Compound 4F (1.2 g, 95%) as a colorless oil. LCMS: 269 [M+1]+.

To a mixture of Compound 4F (194 mg, 0.74 mmol) in DCM (10 mL) was added EDCI (213 mg, 1.11mmol), HOBt (150 mg, 1.11 mmol) and Compound 3C (200 mg, 0.74 mmol) and stirred at rt for overnight. Then it was added water (50 mL), extracted with DCM (20 mL x 3), dried over anhydrous Na2S04, puriﬁed by prep-HPLC to give 4 (50 mg, 14%) as a white solid. LCMS: 514 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.88 (m, 2H), 2.02 (m, 2H), 3.12 (m, 2H), 3.49 (s, 3H), 3.56 (m, 4H), 4.28 (m, 1H), 4.48 (d, J: 9.2 Hz, 1H), 6.06 (br, 1H), 6.71 (t, J: 8.8 Hz, 1H), 6.93 (d, J = 8Hz, 1H), 7.05 (dd, 1H), 7.20 (s, 1H), 7.52 (dd, 1H), 7.95 (d, J: 2.4 Hz, 1H), 8.07 (d, J: 8.4 Hz, 1H), 9.23 (m, 1H), 9.78 (br, 1H).

Example 5 U / {5 N OH 6%. .0 N OH 5B F F _ e 0/ and ""2 o/ o F 2 S F (33H 4F 5A F F o F + 5 To a e of Compound 4F (157 mg, 0.74 mmol) in DCM (10 mL) was added EDCI (213 mg, 1.1 lmmol), HOBt (150 mg, 1.11 mmol) and Compound IH (200 mg, 0.74 mmol) and stirred at rt overnight. Water (50 mL) was added to the mixture, which was then extracted with DCM (20 mL x 3). The combined organic phases were dried over anhydrous Na2S04 and evaporated to remove solvents. The residues were puriﬁed by prep- HPLC to yield 5 (30 mg, yield 9%) as a white solid. LCMS: 463 ; 1H-NMR(DMSO- d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.88 (m, 2H), 2.03 (m, 2H), 3.10 (m, 2H), 3.54 (m, 5H), 3.76 (s, 3H), 4.31 (m, 1H), 4.50 (d, J: 7.2 Hz, 1H), 6.09 (br, 1H), 7.13 (m, 7H), 8.86 (d, J: 8.8 Hz, 1H), 9.51 (br, 1H).

Example6 O O x— /— CIU» —» (IN CI CI N 0 N 0 —» (I F S s o S F 6A 6B ::N 9H F F OH NWNH= S j —> \ / —» 0 Cl N F CI 8 0 6C 6 To a solution of 5-chlorobenzo[d]thiazole (500 mg, 2.95 mmol) in THF (20 mL) was added n-BuLi (1.42 ml, 3.54 mmol) at — 78 °C under the protection of en. The mixture was stirred at — 78 °C for l h, and then diethyl oxalate (1.08 g, 7.37 mmol) was added to the mixture and stirred for additional one hour at — 78 °C. The reaction was quenched with sat. aqueous NH4Cl. The organic phase was separated and washed with brine, dried over anhydrous Na2S04, and puriﬁed with column chromatography on silica gel (ethyl e in petroleum 20% v/v) to give Compound 6A (200 mg, yield 25%) as a yellow solid.

LCMS (m/z): 288 [M+18]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.46 (t, J: 7.2 Hz, 3H), 4.54 (q, J: 7.2 Hz, 2H), 7.57 (dd, J: 2.0, 8.8 Hz, 1H), 7.95 (d, J: 88HL1H)827@LJ=20}h,HD.

To a solution of Compound 6A (170 mg, 0.63 mmol) in DCM (10 mL) was added DAST (305 mg, 1.89 mmol) at 0 °C under N2 and stirred at 15 °C overnight. The reaction mixture was poured into 100 mL of ice-water and extracted with DCM (50 mL x 3).

The combined c phase was washed with brine, and dried over anhydrous Na2S04, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 9% v/v) to yield Compound 6B (105 mg, yield 52%) as a yellow oil. LCMS (m/z): 292 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.27 (t, J = 7.2 Hz, 3H), 4.43 (q, J = 7.2 Hz, 2H), 7.72 (dd, J: 2.0, 8.8 Hz, 1H), 8.36 (m, 2H).

To a solution of Compound 6B (105 mg, 0.36 mmol) in THF/MeOH/water (6 mL, 1:1:1, v/v/) was added LiOH-HZO (15 mg). The mixture was d at 25 °C for 2 h.

After l of the solvents and adjust pH to 7 with 1 N HCl, the mixture was diluted with ethyl acetate (100 mL), washed with water, brine, and dried over anhydrous Na2S04. The crude product was used for next step without further puriﬁcation. Compound 6C (95 mg, yield 99%) was obtained as a yellow oil. LCMS (m/z): 264 [M+1]+; 1H-NMR(CDC13, 400 MHz) major teristic peaks: 5 (ppm) 7.51 (dd, J: 1.6, 8.8 Hz, 1H), 7.90 (d, J: 8.84 Hz, 1H), 8.14 (d, J: 1.6 Hz,1H).

To a mixture of Compound 6C (95 mg, 0.36 mmol) in DCM (10 mL) was added EDCI (104 mg, 0.54mmol), HOBt (73 mg 0.54 mmol) and ediate A (100 mg, 0.36 mmol) and stirred at 25 °C overnight. Diluted with water (5 mL), the mixture was extracted with DCM (20 mL x 3). The organic phase was dried over anhydrous Na2S04 and puriﬁed with prep-HPLC to afford Compound 6 (10 mg, yield 6%) as a colorless oil. LCMS (m/z): 524 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.91 (m, 4H), 2.75 (m, 2H), 2.93-3.01 (m, 6H), 3.23 (m, 2H), 4.24 (s, 4H), 4.63 (d, J: 9.6 Hz, 1H), 6.80 (m, 2H), 7.41 (d, J: 8.4 Hz, 1H), 7.83 (d, J: 8.8 Hz, 1H), 7.93 (d, J: 2.0 Hz, 1H).

Example 7 2m 42m:313%;3133?a OH —> CI F m aOH CI OH CI 0 F a a CI CN CI 0 CI 0 C' O\ O \ 0 O \ 7H 71 7.: 7K N 9H CI F o —> F —> F F : CI OH 1 CI 0 6] To a solution of 5,6-dichloroisobenzofuran-l,3-dione (12.00 g, 55.30 mmol) in THF (300 mL) was added LiAlH4 (3. 15 g, 82.95 mmol) carefully at 0 °C. The mixture was stirred at rt overnight. It was then quenched with water (13 mL), 15% aqueous NaOH (3.2 mL). After ﬁltration, the ﬁltrate was evaporated to dryness to yield Compound 7A (1 l .20 g, yield 98%) as a white solid. LCMS: 207 [M+l]+, 1H-NMR(DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 4.47 (d, J: 5.6 Hz, 4H), 5.34 (t, J: 5.6 Hz, 2H), 7.57 (s, 2H).

A suspension of Compound 7A (4.80 g, 23.2 mmol) in conc. HBr (100 mL) was stirred at 90 °C overnight. The mixture was diluted with ethyl acetate (100 mL) and petroleum ether (100 mL), washed with water and brine, concentrated, and then d by silica chromatography on silica gel (ethyl acetate in eum ether, 8% v/v) to give Compound 7B (5.20 g, yield 68%) as a light yellow solid. LCMS: 333 , 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 4.55 (s, 4H), 7.47 (s, 2H).

To a solution of Compound 7B (5.88 g, 36.8 mmol) in THF (300 mL) was added NaH (882 mg, 36.8 mmol). The mixture was stirred at rt for 10 min. Then diethyl te (12.20 g, 36.75 mmol) was added to the mixture. After stirring for 20 min, an additional portion ofNaH (882 mg, 36.8 mmol) was added. After stirring at rt overnight, the mixture was evaporated to dryness to give Compound 7C (126 g, yield 100%) as a white solid. LCMS: 331 [M+l]+.

A mixture of Compound 7C (12.6 g, 38.2 mmol) and LiOH-HZO (5.80 g, 0.15 mol) in THF/MeOH/HZO (100/100/50 mL) was stirred at rt overnight. The mixture was condensed by removal of solvents and adjusted to pH 1 with cone. HCl. The precipitate was ﬁltered to obtain Compound 7D (11.2 g, yield 100%) as a white solid. LCMS: 273 [M-l] ', 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 3.47 (s, 4H), 7.57 (s, 2H), 13.16 (s, 2H).

A mixture of Compound 7D (4.80 g, 17.5 mmol) and NaCl (4.80 g) in DMSO (100 mL) was stirred at 130 °C for 5 h. Diluted with ethyl acetate (200 mL), the mixture was washed with water and brine, dried with anhydrous Na2S04, and evaporated to dryness to give Compound 7E (3.40 g, yield 84%) as a white solid. LCMS: 229 [M-1]', 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 3.12-3.23 (m, 4H), 3.34-3.42 (m, 1H), 7.55 (s, 2H), 12.45 (s, 1H).

To a solution of Compound 7E (3.40 g, 1.47 mmol) in THF (100 mL) was added LiAlH4 (554 mg, 1.47 mmol). The mixture was stirred at rt overnight. After being quenched with water (2.4 mL) and aqueous NaOH (15%, 0.56 mL), the itate was ﬁltered off and the ﬁltrate was evaporated to give Compound 7F (2.80 g, yield 88%) as a white solid. LCMS: 217 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: (ppm) 2.50-2.60 (m, 1H), 2.89-2.95 (m, 2H), 3.32 (s, 4H), 4.65-4.68 (m, 1H), 7.44 (s, 2H).

To a solution of nd 7F (2.80 g, 12.96 mmol) in DCM (100 mL) was added DMP (6.60 g, 15.6 mmol). The mixture was d at rt for 2 h. The solids were ﬁltered off and the ﬁltrate was d with ethyl acetate (200 mL), washed with water and brine, and puriﬁed by silica gel chromatography (ethyl acetate in PE, 15% v/v) to give nd 7G (2.10 g, yield 76%) as a light yellow solid. LCMS: 215 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major teristic peaks: 5 (ppm) 3.06-3.12 (m, 2H), 3.19-3.24 (m, 2H), .44 (m, 1H), 7.51 (s, 2H), 9.68 (s, 1H).

A suspension of Compound 7G (2.70 g, 12.6 mmol) and Na205S2 (1.24 g, .2 mmol) in EtOH/HZO (20/20 mL) was stirred at rt for 2 h before NaCN (1.24 g, 25.24 mmol) was added. The mixture was stirred at rt ght. It was diluted with ethyl acetate (200 mL), washed with water and brine, d by silica gel chromatography (ethyl acetate mpdmbmndmm30%vN)mymM(bnmmmdﬂ1Q10gymM69%ﬂmawmwde.

LCMS: 242 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 2.79-2.87 (m, 3H), 3.01-3.08 (m, 2H), 4.57 (t, J: 6.8 Hz, 1H), 6.60 (d, J: 6.4 Hz, 1H), 7.50 @,2H) WO 42397 A solution of Compound 7H (2.10 g, 8.71 mmol) in MeOH (100 mL) was stirred at rt overnight in the presence of HCl gas. After the on of water (20 mL), the mixture was stirred at rt for 2 h and then diluted with ethyl acetate (200 mL), washed with water and brine, dried with anhydrous Na2S04. Removal of solvents by evaporation gave Compound 71 (1.80 g, yield 75%) as a white solid. LCMS: 275 [M+1]+; 1H-NMR d6, 400 MHz) major characteristic peaks: 5 (ppm) 2.76-2.92 (m, 5H), 3.63 (s, 3H), 4.08 (t, J = .6 Hz, 1H), 5.65 (d, J: 6.0 Hz, 1H), 7.44 (s, 2H).

To a solution of Compound 71 (1.00 g, 3.65 mmol) in DCM (30 mL) was added DMP (1.55 g, 3.65 mmol). The mixture was stirred at rt for 2 h. It was then diluted with ethyl acetate (200 mL), washed with water and brine, and d by silica gel chromatography (ethyl e in petroleum ether, 25% v/v) to afford Compound 7J (880 mg, yield 87%) as a white solid. LCMS: 273 [M+l]+.

To a solution of Compound 7J (272 mg, 1.00 mmol) in DCM (10 mL) was added DAST (0.66 mL, 5.00 mmol). The mixture was stirred at 25 °C overnight. It was then diluted with ethyl acetate (150 mL), washed with water and brine, and purified by silica gel tography (ethyl acetate in PE, 10% V/V) to yield Compound 7K (210 mg, yield 71%) as a white solid. LCMS: 295 [M+1]+.

A mixture of Compound 7K (120 mg, 0.41 mmol) and ZO (52 mg, 1.23 mmol) in THF/MeOH/H20 (5/5/2 mL) was stirred at rt for 2 h. After removal of ts, the residues were purified by prep-HPLC to give Compound 7L (90 mg, yield 78%) as a white solid. LCMS: 279 [M-1]'.

A mixture of Intermediate A (100 mg, 0.36 mmol), Compound 7L (100 mg, 0.36 mmol), EDCI (103 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and Eth (0.2 mL) in DCM (5 mL) was stirred at 25 °C overnight. It was diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by prep-HPLC to afford 7 (50 mg, yield 37%) as a white solid. LCMS: 541 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.14 (br s, 4H), 2.52-2.59 (m, 2H), 2.65-2.87 (m, 3H), 2.93-3.11 (m, 3H), 3.38-3.50 (m, 2H), 3.82 (br s, 2H), 4.14-4.25 (m, 4H), 4.42 (br s, 1H), 5.12 (s, 1H), 6.80-6.88 (m, 3H), 7.21 (s, 2H), 7.45 (br s, 1H), 11.99 (s, 1H).

WO 42397 Example 8 o o o o OHF HO/QKOH —>HO/\)J\O/—> oyko/—> o/W)| O E E AVNCbzE NHCbz NHCbz ﬁ’NCBz ﬁ/NCBZ A2 8A 33 so an /0 OH F OH F 1 5 / \ N CH F N OH F HO MsO _> _> _, __ CszN CszN CszN Hzﬁ /0 /O 8E 8F as / 8H /0 N OH F N OH F N OH F ::N OH F and E —’ F F —’ F F 5 F F - H2N NH ﬁH ﬁH /O O O\ o o\ O 0\ 8H 8| SJ 8 9] Acetyl de (10 g, 130 mmol) was added to methanol (100 mL) at 0 °C in an ice-water bath under N2. The mixture was stirred for 5 min before Compound A2 (10 g, 42 mmol) was added. The mixture was heated to reﬂux and stirred for 2 h. Removal of the solvent by evaporation gave Compound 8A (9 g, yield 85%) as a white solid, which was used for the next step without further puriﬁcation.

To a solution of Compound 8A (10 g, 40 mmol) in e (100 mL) was added 2,2-dimethoxypropane (37 g, 0.36 mol) and BF3.Eth (2 mL). The resulting orange solution was d at rt for 3 h. The mixture was treated with TEA (4 mL) and then evaporated to dryness. The resulted residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine, and then evaporated to give a crude product, which was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 10% v/v) to yield Compound SE (7.5 g, yield 80%) as a colorless oil. 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.49-1.57 (d, 3H), 1.64-1.71 (d, 3H), 3.64, 3.77 (s, 3H), 4.08-4.19 (m, 2H), 4.47-4.57 (m, 1H), 5.03-5.20 (m, 2H), .37 (m, 5H).

To a solution of Compound 8B (6 g, 20 mmol) in toluene (50 mL) at -78 °C was added 1.0 M DIBAL (30 mL). The mixture was stirred at this temperature for 2 h, quenched with menthol (6 mL), diluted with l N aq HCl (25 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (100 mL x 2), and evaporated to remove the volatiles. The crude product was d by silica gel column chromatography (ethyl acetate in petroleum ether, 10% v/v) to give nd 8C (2.7 g, yield 51%) as a colorless oil. 1H-NMR(CDC13, 400 MHZ) major characteristic peaks: 5 (ppm) l.5l-l.58 (d, 3H), 1.60-1.68 (d, 3H), 4.08-4.16 (m, 2H), 4.31-4.36 (m, 1H), 5.10 (m, 2H), 7.28-7.37 (m, 5H), 9.56-9.63 (s, 1H).

To a solution of 2-bromoﬁuoromethoxybenzene (3.5 g, 34 mmol) in THF (60 mL) was added n-BuLi (9.2 mL, 2.5 M) under N2 at -60 °C. Stirred for l h, Compound 8C (3 g, 11.4 mmol) in THF (10 mL) was added to the mixture. After stirring for an additional 3 h at rt, the mixture was diluted with sat. aq. NH4Cl (40 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (100 mL x 2), and then evaporated to give a crude t, which was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 30% v/v) to yield Compound 8D (1.8 g, yield 41%) as colorless oil. LC-MS (m/z): 390 [M+1]+.

A on of Compound SD (0.39 g, 1 mmol) in THF (10 mL) and 1 N aq HCl (2 mL) was stirred at rt for 5 h. The mixture was quenched with water (10 mL), ted with ethyl acetate (20 mL x 2), washed with brine (30 mL x 2), and ated to remove solvents.

The crude product was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 50% v/v) to give Compound SE (283 mg, yield 81%) as a colorless oil. LC- MS (m/z): 350 [M+1]+.

To a solution of nd SE (1 g, 2.9 mmol) in THF (25 mL) was added ylamine (0.44 g, 4.4 mmol) and MsCl (0.4 g, 3.5 mmol) under N2 at -40 °C. The mixture was stirred at this ature for 3 h before quenched with water (40 mL). It was ted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 2), and evaporated to give a crude product, which was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 50% v/v) to yield Compound SF (0.85 g, yield 69%) as a colorless oil. LC- MS (m/z): 410 +.

To a solution of Compound 8F (0.8 g, 2.3 mmol) in THF (25 mL) was added pyrrolidine (1.5 g, 21 mmol). The mixture was stirred at 60 °C overnight, quenched with water (40 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 2), and evaporated to remove solvents. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to give Compound 8G (0. 5 g, 54%) as colorless oil. LC-MS (m/z): 403 [M+1]+.

A solution of Compound 8G (0.5 g, 1.2 mmol) and LiOH'HzO (157 mg, 3.6 mmol) in ethanol (20 mL) was heated to reﬂux overnight. The mixture was quenched with water (40 mL), ted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 2), and evaporated to yield Compound 8H (0. 3 g, 93%) as a colorless oil. LC-MS (m/z): 269 [M+1]+.

To a solution of Compound 8H (0.2 g, 0.75 mmol) in romethane (15 mL) was added Compound IH (191 mg, 0.9 mmol), EDCI (216 mg, 1.13 mmol), HOBt (152 mg, 1.13 mmol). The mixture was stirred at rt overnight, quenched with water (20 mL), extracted with DCM (20 mL x 2), washed with brine (50 mL x 2), and evaporated. The crude product was puriﬁed by prep-HPLC to give 81 and ed by chiral-prep-HPLC to afford two isomers SJ (5 mg) as a white solid and 8K (105 mg) as a white solid. For 8J: LC-MS (m/z): 463 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.87 (m, 4H), 2.80 (m, 3H), 2.86 (m, 2H), 2.96 (m, 3H), 3.10 (m, 3H), 3.72 (s, 3H), 3.81 (s, 1H), 4.34 (s, 1H), 5.46 (s, 1H),6.80 (m, 1H), 6.96 (m, 2H), 7.14 (m, 5H). For 8K: LC-MS (m/z): 463 [M+1]+; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 1.84 (s, 4H), 2.80 (m, 7H), 3.02 (m, 3H), , 1H), 3.81 (s, 3H), 4.21 (s, 1H), 5.16 (m, 1H), 6.81 (m, 1H), 6.94 (m, 1H), 7.16 (m, 5H).

Example 9 N\ OH N\ /3 N\ OH N\ OH | —» | —» | —» I/ / / / CN 0003 9A 93 90 9D N\ F N\ F F mo] —> E):>— WCOOH —’ WW 9E /_\ o To a solution of Compound 9A (2.18 g, 15 mmol) in DCM (50 mL) was added DMP (7.44 g, 18 mmol). The mixture was stirred at rt for 2 h, followed by filtration. The filtrate was washed with sat.aq. NaHCOg (50 mL x 2), extracted with DCM (50 mL x 2), washed with brine (1 x 50 mL), dried over Na2S04, concentrated, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 9B (1.2 g, yield 56%) as a white solid. LC-MS (m/z): 148 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.17 (m, 1H), 3.38 (m, 4H), 7.09 (m, 1H), 7.53 (d, J: 8.0 Hz, 1H), 8.39 (d, J: 4.4 Hz, 1H), 9.82 (s,1H).

Compound 9B (1.2 g, 8.2 mmol) was added to a solution of sodium metabisulfate (1.55 g, 8.2 mmol) in water (35 mL). The mixture was vigorously stirred for 2 h at rt before the addition ofNaCN (800 mg, 16 mmol). Stirred overnight, the mixture was diluted with water (30 mL) and THF (10 mL). The mixture was extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL x 1), dried over Na2S04, and concentrated to give Compound 9C (1.15 g, yield 81%) as a white solid. LC-MS (m/z): 175 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 2.86 (m, 3H), 3.08 (m, 2H), 4.62 (m, 1H), 6.63 (t, J: 3.2 Hz, 1H), 7.13 (t, J: 7.2 Hz, 1H), 7.60 (d, J: 7.6 Hz, 1H), 8.29 (d, J = 4.8 Hz, 1H).

A solution of Compound 9C (1.15 g, 6.6 mmol) in EtOH (20 mL) was bubbled with a gentle stream of HCl (gas) (dried over conc. H2S04) for 5 h at 0 °C. The mixture was added water (20 mL), stirred at rt for 2 h, and then adjusted pH to 7 with dilute NaOH (2M). It was extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over , concentrated, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 50% v/v) to yield Compound 9D (1 g, yield 69%) as a ess oil. LC- MS (m/z): 222 [M+1]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 1.29 (m, 3H), 3.055 (m, 5H), 4.24 (m, 3H), 7.03 (m, 1H), 7.46 (m, 1H), 8.33 (d, J: 4.4 Hz, 1H) To a solution of nd 9D (500 mg, 2.26 mmol) in DCM (20 mL) was added DAST (1.1 g, 6.78 mmol) at 0 °C, then the mixture was stirred at rt overnight. The mixture was poured into ice-water, added sat. aq NaHC03 (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04 and evaporated. The crude product was puriﬁed by silica gel column tography (ethyl acetate in petroleum ether, 50% v/v) to render Compound 9E (170 mg, yield 34%) as a colorless oil. LC-MS (m/z): 224 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.29 (t, J = 7.2 Hz, 3H), 3.12 (m, 5H), 4.26 (q, J: 7.2 Hz, 2H), 5.01 (m, 1H), 7.06 (m, 1H), 7.49 (d, J: 7.6 Hz, 1H), 8.35 (d, J: 5.2 Hz, 1H).

To a solution of Compound 9E (170 mg, 0.76 mmol) in EtOH (5 mL) was added LiOH (96 mg, 2.29 mmol) in water (5 mL). The mixture was stirred at rt ght and concentrated to remove EtOH. After adjusted pH to 7 with diluted aq HCl, a lyophilization of the solution led to Compound 9F (148 mg, crude), which was used for the next step t further puriﬁcation. LC-MS (m/z): 196 [M+1]+.

A mixture of Compound 9F (100 mg, 0.51 mmol), EDCI (148 mg, 0.77 mmol), HOBt (105 mg, 0.77 mmol), DIPEA (198 mg, 1.54 mmol), Intermediate A (142 mg, 0.51 mmol) in THF (20 mL) was stirred at rt overnight. After addition of aq sat.NaHC03, the mixture was extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give nd 9 (39 mg, yield 18%) as a white solid. LC-MS (m/z): 456 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.73 (s, 4H), 2.86 (m, 11H), 4.16 (m, 5H), 4.76 (s, 0.5H), 4.87 (m, 1H), 4.98 (s, 0.5H), 6.75 (m, 4H), 6.95 , 7.35 (m, 1H), 8.24 (m, 1H).

Example 10 CI No2 CI No2 CI NH2 CI N CI U _. U —»U _. U>—»CE\CI N 0 N/ N/ N N o H H \ \ O ) 10A 103 10C 10D ::N OH 0' N F CI N F \ F O _’ \ —> _. F F N OEt N OH N NH j \ O \ \ O N o 10E 10F GAG\ 10 A solution of 1, 4-dichloronitrobenzene (5 g, 26 mmol) in 30% methylamine alcohol solution (50 mL) was d at 50 °C for 4 h. The mixture was ed with water (50 mL) and extracted with ethyl acetate (80 mL x 3). The organic layer was washed with brine (150 mL x 2) and then evaporated to give Compound 10A (4 g, yield 84%) as a red solid. LC-MS (m/z): 187 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.95 (d, J: 4.8 Hz, 3H), 7.04 (d, J: 9.2 Hz, 1H), 7.59 (d, J: 9.2 Hz, 1H), 8.05 (s, 1H), 8.24 (s, 1H).

To a solution of Compound 10A (3 g, 16 mmol) in ethanol (100 mL) was added 10 N aq HCl (2 mL) and Fe (9 g, 0.16 mmol). The e was d at 80 °C overnight. After ﬁltration, the ﬁltrate was washed with 3 N aq NaOH (50 mL), extracted with ethyl acetate (100 mL x 2), and dried over Na2S04. Filtration and t evaporation led to crude Compound 10B (2.7 g, crude) as a red solid, which was used to next step without puriﬁed. LC-MS (m/z): 157 [M+1]f To a solution of Compound 10B (2.5 g, 16 mmol) in methanol (50 mL) was added triethoxymethane (2.8 g, 19 mmol) and sulfamic acid (155 mg, 1.6 mmol). The mixture was stirred at rt for 5 h. After removal of solvents, the mixture was diluted with water (30 mL) and extracted with ethyl e (50 mL x 3). The organic layer was dried over Na2S04. Filtration and evaporation of solvents gave a crude product Compound 10C (2.3 g, crude) as a red solid, which was used to next step without puriﬁcation. LC-MS (m/z): 167 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.84 (s, 3H), 7.30 (d, J: 8.4 Hz, 1H), 7.61 (d, J: 8.8 Hz, 1H), 7.70 (s, 1H), 8.25 (s, 1H).

Ethyl oxalyl chloride (2.7 g, 20 mmol) was added dropwise over 20 mins to a stirred solution of Compound 10C (2.5 g, 15 mmol) in dichloromethane (60 mL) at -20 °C.

Then DIPEA (3.9 g, 30 mmol) was added and the mixture was warmed to rt and kept stirring ght. The mixture was quenched with water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic layer was dried over Na2S04 before ﬁltered and concentrated, giving a crude t. The crude product was puriﬁed by column cMmmmgmmwon$MmgdGﬂwhwdﬁempambmndmm30%vN)mgNeCmmmmm 10D (3.3 g, yield 83%) as yellow solid.LC-MS (In/Z): 267 [M+l]+.

To a solution of Compound 10D (1.5 g, 5.6 mmol) in dichloromethane (30 mL) was added DAST (2.7 g, 17 mmol). The mixture was stirred at rt overnight, quenched with water (30 mL), and extracted with dichloromethane (50 mL x 2). After dried over Na2S04, the organic layer was ﬁltered and concentrated to give the crude t Compound 10E (0.9 g, crude) as a colorless oil, which was used for the next step without puriﬁcation.

LC-MS (m/z); 289 [M+l]f To a solution of Compound 10E (1 g, 3.5 mmol) in methanol (20 mL) and H20 (10 mL) was added LiOH-HZO (294 mg, 7 mmol). The mixture was stirred at rt for 5 h, quenched with water (30 mL), and extracted with ethyl acetate (50 mL x 2). The organic layer was dried over Na2S04. Filtration and l of solvents led to the crude product Compound 10F (0.4 g, crude) as a colorless oil, which was used for the next step without puriﬁcation. LC-MS (m/z): 261 [M+l]+; 1H-NMR (CDClg, 400 MHZ) 5 (ppm) 3.97(s, 3H), 7.47 (d, J: 10.4 Hz, 1H), 7.78 (d, J: 8.8 Hz, 1H), 7.86 (s, 1H).

To a solution of Intermediate A (0.16 g, 0.58 mmol) in dichloromethane (15 mL) was added Compound 10F (150 mg, 0.58 mmol), EDCI (167 mg, 0.87 mmol), HOBt (116 mg, 0.87 mmol). The mixture was stirred at rt overnight, quenched with water (20 mL), extracted with dichloromethane (20 mL x 2), washed with brine (50 mL x 2), and ated.

The crude product was d by prep-HPLC to afford Compound 10 (29 mg, yield 9.6%) as a white solid. LC-MS : 521 [M+1]+;1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.95 (m, 4H), 3.47 (m, 6H), 3.89 (s, 3H), 4.16 (s, 4H), 4.42 (s, 11D,469(&11D,591(&11D,657(d"1=88lﬂz11D,679(dﬂl=10443L11D,681(& 1H), 7.50 (d, J: 11.2 Hz, 1H), 7.80 (d, J: 10.8 Hz, 2H), 8.96 (d, J: 9.2 Hz, 1H), 9.37 (s, 111) Example 11 OH CI 0 —> | —. / CI o _. (3| 0 O 11A 11B 110 N 9H CI F CI F o \ F \ F F F NH j o O O OH \ O o 0 CI 0 o 11D 11E 11 A mixture of rophenol (10 g, 78 mmol), 2-bromo-1,1- dimethoxyethane(13.l g, 78 mmol), K2C03 (14 g, 101 mmol), KI (100 mg) in DMF (50 mL) was stirred at reﬂux for 3 h. The mixture was cooled to rt and ﬁltered. The ﬁltrate was added water (200 mL), extracted with ethyl acetate (100 mL x 2), washed with water (100 mL x 3), brine (100 mL x 1), dried over Na2S04, concentrated, and puriﬁed by column tography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to yield Compound 11A (15 g, yield 89 %) as a colorless liquid. 1H-NMR (CDC13, 400 MHz) major teristic peaks: 5 (ppm) 3.45 (s, 6H), 3.96 (d, J: 5.2 Hz, 2H), 4.70 (t, J: 5.6 Hz, 1H), 6.85 (d, J: 8.8 Hz, 2H), 7.21 (d, J: 8.8 Hz, 2H).

A solution of polyphosphoric acid (90 g) in toluene was heated to 90 °C. To this solution was added Compound 11A (15.4 g, 71 mmol) in toluene (20 mL), followed by stirring at 90 °C for 3 h. The e was poured into ice and stirred for 30 min. It was extracted with ethyl acetate (2 x 100 mL), washed with brine (100 mL x 1), dried over Na2S04, concentrated and puriﬁed by column chromatography on silica gel (petroleum ether, 100% V/V) to yield Compound 11B (4.5 g, yield 50%) as a red liquid. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 6.72 (m, 1H), 7.24 (dd, (115.12 = 8.8, 2.4 Hz, 1H), 7.42 (d, J: 8.8 Hz, 1H), 7.56 (d, J: 2.0 Hz, 1H), 7.63 (d, J: 2.4 Hz, 1H).

To a solution of Compound 11B (4.5 g, 30 mmol) in THF (20 mL) was added n-BuLi (14 mL) at -78 °C under N2. d for 30 min, to the e was added diethyl oxalate (10.8 g, 74 mmol). The mixture was stirred at -78 °C for 1 h before the addition of aq sat. NH4Cl. It was extracted with ethyl acetate (50 mL x 2), washed with sat.NaHC03 (50 mL x 2), brine (50 mL x 1), dried over Na2S04, trated and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 20% V/V) to give Compound 11C (3.5 g, yield 47%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.37 (t, J: 6.8 Hz, 3H), 4.41 (q, J: 6.8 Hz, 2H), 7.64 (m, 1H), 7.82 (d, J: 8.8 Hz, 1H), 8.03 (d, J: 2.4 Hz, 1H), 8.19 (s, 1H).

To a solution of Compound 11C (1 g, 3.95 mmol) in DCM (50 mL) was added DA$X3mg1&mmDMOTJMnmmmmmmwmwmdMﬁmmmﬂtmemmm was quenched by addition of ice-water and sat. aq NaHC03 (20 mL). It was then extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and evaporated to remove ts. The crude product was d by silica gel column chromatography (ethyl acetate in eum ether, 10% v/v) to yield Compound 11D (700 mg, yield 65%) as a yellow liquid. 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 1.37 (t, J = 6.8 Hz, 3H), 4.41 (q, J: 6.8 Hz, 2H), 7.10 (s, 1H), 7.36 (m, 1H), 7.47 (d, J: 8.8 Hz, 1H), 7.62 (d, J: 2.0 Hz, 1H).

To a solution of Compound 11D (120 mg, 0.44 mmol) in EtOH (5 mL) was added LiOH (46 mg, 1.09 mmol) in water (5 mL). The e was stirred at rt overnight, followed by removal of EtOH. It was adjusted to pH 7 with diluted HCl and freeze-dried to give Compound 11E (100 mg, crude) which was used for the next step without further puriﬁcation. LC-MS (m/z): 245 [M-1]'.

A mixture of Compound 11E (100 mg, 0.41 mmol), EDCI (117 mg, 0.61 mmol), HOBt (83 mg, 0.61 mmol), Intermediate A (115 mg, 0.41 mmol) in DCM (20 mL) was stirred at rt overnight. The reaction was quenched by addition of sat.NaHCOg. The resulting mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and evaporated to dryness. The crude product was puriﬁed by prep-HPLC to give nd 11 (49 mg, yield 24%) as a white solid. LC-MS (m/z): 507 [M+1]+; 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (s, 4H), 2.91 (m, 2H), 3.48 (s, 2H), 3.84 (s, 2H), 4.15 (m, 4H), 4.46 (m, 1H), 5.13(s, 1H), 6.77 (s, 3H), 6.84 (s,1H), 7.35 (m, 1H), 7.42 (d, J: 8.8 Hz, 1H), 7.58 (d, J: 2.0 Hz, 1H), 7.43 (d, J: 7.6 Hz, 1H), 11.68 (s, Example 12 O Q0. w N OH H207 O] AWN—IF O B 12A To a mixture of Intermediate B (300 mg, 1 mmol) in DCM (15 mL) was added EDCI (400 mg, 2 mmol), HOBt (264 mg 2 mmol) and Compound 1H (300 mg, 1.5 mmol) and stirred at rt overnight. The reaction mixture was poured into water (50 mL), extracted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep-HPLC to afford a crude product 12A (100 mg, yield 20%) as a white solid. The chiral resolution on nd 12A was achieved using -prep-HPLC to give Compound 12B (70 mg) and 12 (1.2 mg). For Compound 12B, LCMS: 491 [M+1]+; 1H-NMR (CDCl3, 400 MHz) major teristic peaks: 5 (ppm) 1.82 (m, 4H), 2.82 (m, 7H), 3.04 (m, 3H), 3.19 (m, 1H), 4.16 (m, 1H), 4.26 (m, 4H), 5.05 (m, 1H), 6.56 (d, J: 10.8 Hz, 1H), 6.69 (m, 1H), 7.06 (d, J: 7.2 Hz, 1H), 7.16 (m, 4H). For Compound 12, LCMS: 491 [M+1]+; 1H-NMR (CDCl3, 400 MHz) major characteristic peaks: 5 (ppm) 2.23 (m, 4H), 2.67 (m, 1H), 2.82 (m, 1H), 2.97 (m, 2H), 3.12 (m, 2H), 3.65 (m, 1H), 3.81 (m, 1H), 3.89 (m, 1H), 4.03 (m, 1H), 4.12 (m, 1H), 4.18 (m, 1H), 4.47 (m, 1H), 5.43 (m, 1H), 6.60 (d, J: 11.2 Hz, 1H), 7.08 (d, J: 7.2 Hz, 1H), 7.16 (m, 5H).

Example 13 6m" 61:?) N —> —>("1234" —>61233:"—> 13A 13B 13C 13D ) [MAMarmfagaj LN 13 To a solution of Compound 13A (2.00 g, 10 mmol) in DCM (50 mL) was added DMP (7.44 g, 18 mmol). The mixture was stirred at rt for 2 h and ﬁltered. The ﬁltrate was washed with sat. aq NaHCOg (50 mL x 2), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, concentrated, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 10% v/v) to get Compound 133 (1.2 g, yield 56%) as a white solid. LC-MS (m/z): 199 [M+1]+.

Compound 13B (1.13 g, 5 mmol) was added to a solution of sodium metabisulfate (1.55 g, 8.2 mmol) in water (35 mL). The mixture was vigorously stirred for 2 h at rt, before the addition ofNaCN (800 mg, 16 mmol). After stirred ght, the reaction mixture was poured to a mixture of water (30 mL) and THF(10 mL). It was then extracted with ethyl acetate (100 mL x 2), washed with brine (00 mL), dried over Na2S04, and concentrated to give Compound 13C (1.15 g, 81%) as a white solid. LC-MS (m/z): 226 [M+1]+.

To a solution of Compound 13C (1.15 g, 5 mmol) in EtOH (20 mL) was bubbled with a gentle stream of HCl (gas) (dried over con.H2SO4) at 0 DC for 5 h. Water (20 mL) was added to the mixture and d at rt for 2 h. It was ed to pH = 7 with diluted NaOH (2M), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, concentrated, and puriﬁed by silica gel column tography (ethyl acetate in petroleum ether, 50% v/v) to get Compound 13D (1 g, yield 69%) as a colorless oil. LC-MS (m/z): 273 [M+1]+.

To a solution of Compound 13D (2.72 g, 10 mmol) in DCM (50 mL) was added DMP (7.44 g, 18 mmol). The mixture was stirred at rt for 2 h and ﬁltered. The ﬁltrate was washed with sat. aq NaHCOg (50 mL x 2), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, concentrated, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to get nd 13E (1.2 g, yield 56%) as a white solid. LC-MS : 271 .

To a solution of Compound 13E (540 mg, 2 mmol) in DCM (20 mL) was zmwdDAﬂXflg67%mmmaﬂﬂzmmﬂwmmmmwwsmmdmmowmQMKme on mixture was quenched by pouring into ice-water. After neutralized with sat.NaHC03 hemmnnewwennwmdwﬁhDCNH2x50mL)waﬂwdwﬁhhﬂw(lx50mL) dried over Na2S04, and evaporated to dryness. The crude product was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 50% v/v) to yield Compound 13F (170 mg, yield 34%) as a colorless oil. LC-MS (m/z): 293 [M+1]+.

To a solution of Compound 13F (293 mg, 1 mmol) in EtOH (5 mL) was added LiOH (96 mg, 2.29 mmol) in water (5 mL). The mixture was stirred at rt overnight, concentrated to remove EtOH, and adjusted to pH 7 with diluted HCl. It was then lyophilized to give Compound 13G (148 mg, crude), which was used for the next step without further ation. LC-MS (m/z): 265 [M+1]+.

A mixture of Compound 13G (132 mg, 0.51 mmol), EDCI (148 mg, 0.77 mmol), HOBt (105 mg, 0.77 mmol), DIPEA (198 mg, 1.54 mmol), Intermediate A (142 mg, 0.51 mmol) in THF (20 mL) was d at rt overnight. After the addition of sat. aq NaHCOgs the mixture was extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and evaporated to dryness. The crude product was puriﬁed by prep-HPLC to give nd 13 (39 mg, yield 18%) as a white solid. LC-MS (m/z): 525 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.84 (m, 4H), 2.75 (m, 4H), 3.03 (m, 6H), 4.22 (m, 6H), 5.11 (m, 1H), 6.90 (m, 4H), 7.85 (s, 2H), 8.76 (s, 2H). e 14 CI CI Wrﬁ0 ()3 —» <15N \ H \ \ 0 14A 14B 14C QC§)H ‘ o \ o \ CI O 0 N\ 14D 14E 14 To a solution of Compound 14A (1.21 g, 8 mmol) in THF (20 mL) was added NaH (480 mg, 12 mmol ) under N2 atmosphere. The mixture was stirred at 0 °C for 1 h. CH3I (0.47 mL,l6 mmol) was added . The mixture was stirred at 25 °C for additional 2h. It was diluted with NH4Cl (30 mL) and extracted with EtOAc (30 mL x 3). The ed c layers were washed with brine (60 mL), dried over Na2S04, and concentrated to give a crude product, which was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum 10% v/v) to yield Compound 14B (1.2 g, yield 90%) as a red oil. LCMS (m/z): 166 [M+1]+. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.76 (s, 3H), 6.40 (d, J: 3.2 Hz, 1H), 7.05 (d, J: 3.2 Hz, 1H), 7.16 (dd, J: 1.6, 8.4 Hz, 1H), 7.20 (d, J: 8.4 , 7.57 (d, J: 1.6 Hz, 1H).

To a solution of Compound 14B (1.04 g, 6 mmol) in THF (20 mL) was added n-BuLi (3 ml, 8 mmol) at — 78 °C under the protection of nitrogen. Then it was allowed to warm up to rt over one hour. At this point, diethyl oxalate (2.1 mL 16 mmol) was added to —104— the mixture at — 78 °C and then it was allowed to warm up to rt over one hour. The mixture was quenched with sat. aq NH4Cl. The c phase was washed with brine, dried over anhydrous Na2S04, and puriﬁed by silica gel column tography (ethyl acetate in petroleum 3% to 10 % v/v) to afford Compound 14C (1.38 g, yield 86%) as a yellow solid.

LCMS (m/z): 266 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 145GVJ=72Ikg3HL4JB(&3HL445QLJ=72}h,HD,733@LJ=84}h,HD,739 (dd, J: 1.6, 8.4 Hz, 1H), 7.53 (s, 1H), 7.69 (d, J: 1.6 Hz, 1H).

To a solution of Compound 14C (530 mg, 2 mmol) in DCM (20 mL) was added DAST (1.6 mL, 12 mmol) at 0 °C under N2 and stirred at 25 °C overnight. It was poured into 50 mL of ice-water and extracted with DCM (20 mL x 3). The combined c phase was washed with brine, and dried over anhydrous Na2S04, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum, 10% v/v) to yield Compound 14D (195 mg, yield 33%) as yellow oil. LCMS (m/z): 288[M+l]+; 1H-NMR(CDC13, 400 MHz) major Qmwsd@mm137@J=88HLHDJ86GJHL4MH%J=88Hzﬂﬁ, 6.73 (s, 1H), 7.28 (s, 2H), 7.60 (s, 1H).

To a solution of Compound 14D (195 mg, 0.68 mmol) in THF/MeOH/water (6 mL, 1:1:1, v/v/) was added LiOH'HzO (34 mg, 0.8lmmol). The mixture was stirred at 25 °C for 1 h. After removal of the solvents, it was adjust pH to 6 with 1N HCl. The mixture was dissolved ethyl acetate (100 mL), washed with water, brine, and dried over anhydrous Na2S04. Removal of solvent by evaporation led to a crude product Compound 14E (140 mg, yield 80%) was got as a yellow solid, which was used for the next step without puriﬁcation.

LCMS (m/z): 260 [M+l]+.

To a mixture of Compound 14E (70 mg, 0.27 mmol) in DCM (20 mL) was added EDCI (78 mg, 0.40 mmol), HOBt (54 mg 0.40 mmol) and Intermediate A (66 mg, 0.27 mmol) and stirred at 25 °C for overnight. The on was quenched with addition of water (10 mL). The mixture was ted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by PLC to give a triﬂuoroacetic acid salt of Compound 14 (80 mg, yield 56%) as a colorless solid. LCMS (m/z): 529 [M+l]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (m, 4H), .91 (m, 2H), 3.06-3.43 (s, 2H), 3.73 (s, 3H), 3.86 (s, 2H), 4.00-4.09 (m, lH),4.09-4.2l (m, 2H), 4.49 (s, 1H), 5.17 (s, 1H), 6.09 (s, 1H), 6.76-6.80 (m, 2H), 6.83 (s, 1H), 7.23-7.24 (m, 2H), 7.54 (s, 2H). e 15 OH CI 0 —> —> —> O 0 CI O CI CI CI CI CI 0 15A 153 15C 150 ::N 9H C' F CI F F F F _ \ \ F NH j —. /— —> —> \ o o o o OH CI 0 0 o 0 CI CI 15E 15F CI 15 A mixture of Compound 15A (12.64 g, 78 mmol), 2-bromo-1,1- dimethoxyethane(13.6 g, 79 mmol), K2C03 (14 g, 101 mmol), KI (100 mg) in DMF (50 mL) was stirred at reﬂux for 3 h, and then cooled to rt, and ﬁltered. The ﬁltrate was diluted with water (200 mL), extracted with ethyl acetate (100 mL x 2), washed with water (100 mL x 3), brine (100 mL x 1), dried over Na2S04, concentrated, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 10% V/V) to yield Compound ISB (17.2 g, yield 88%) as a red liquid. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 3.49 (s, 6H), 4.02 (d, J: 5.2 Hz, 2H), 4.73 (t, J: 5.6 Hz, 1H), 6.86 (d, J: 8.8 Hz, 1H), 7.15- 7.18 (dd, J: 2.8, 8.8 Hz, 1H) 7.36 (d, J: 2.8 Hz,1H).

A solution of polyphosphoric acid (90 g) in toluene was stirred to 90°C, then to the solution was added Compound 15B (15 g, 60 mmol) in toluene (20 mL). The mixture was stirred at 90 °C for 3 h before it was poured into ice and stirred for 30 min. It was then extracted with ethyl e (100 mL x 2), washed with brine (100 mL x 1), dried over Na2S04, concentrated, and puriﬁed by silica gel column tography (petroleum ether, 100% V/V) to give Compound 15C (2.6 g, yield 23%) as a white solid. 1H-NMR(CDC13, 400 MHz) major teristic peaks: 5 (ppm) 6.76 (d, J: 2.4 Hz, 1H), 7.30 (d, J: 2.0 Hz, 1H), 7.46 (d, J: 2.0 Hz, 1H), 7.69 (d, J: 2.4 Hz, 1H).

To a solution of Compound 15C (1.6 g, 8.6 mmol) in THF (10 mL) was added n-BuLi (4.2 mL) at -78 °C under N2. After stirred for 30 min, to the mixture was added diethyl e (10.8 g, 74 mmol). It was stirred at -78 °C for 1 h before it was ed by addition of aq sat. NH4Cl. The mixture was sequentially extracted with ethyl acetate (50 mL x 2), washed with sat.NaHC03 (50 mL x 2), brine (50 mL x 1), dried over Na2S04, concentrated, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 20% V/V) to yield Compound 15D (1.64 g, yield 67%) as a yellow solid. 1H-NMR WO 42397 , 400 MHz) major characteristic peaks: 5 (ppm) 1.46 (t, J = 7.2 Hz, 3H), 4.48 (q, J = 7.2 Hz, 2H), 7.54 (m, 1H), 7.66 (d, J: 1.6 Hz, 1H), 8.04 (s, 1H).

To a solution of Compound ISD (500 mg, 1.75 mmol) in DCM (15 mL) was added DAST (1.15 g, 8.74 mmol) at 0 °C. The mixture was stirred at rt overnight before it was poured into ice-water, and followed by addition of aq sat. aq NaHC03 (20 mL). The ed mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated to give a crude product, which was puriﬁed by silica gel column chromatography (ethyl e in petroleum ether, 10% v/v) to afford Compound 15E (269 mg, yield 50%) as a red liquid. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: (ppm) 1.37 (t, J: 6.8 Hz, 3H), 4.44 (q, J: 7.2 Hz, 2H), 7.14 (s, 1H), 7.41 (m, 1H), 7.54 (m, To a solution of Compound 15E (260 mg, 0.88 mmol) in EtOH (0.5 mL) was added LiOH (46 mg, 1.09 mmol) in water (0.5 mL). The mixture was stirred at rt overnight, ewmmmmdmrmmweEKHLamhmMmhmdwﬁhmmwdHClThmammmmsdmmnwas lyophilized to yield a crude Compound 15F (193 mg), which was used for the next step t further puriﬁcation. LC-MS (m/z): 279 .

A mixture of Compound 15F (70 mg, 0.25 mmol), EDCI'HCl (71 mg, 0.37 mmol), HOBt (50 mg, 0.37 mmol), Intermediate A (61 mg, 0.25 mmol) in DCM (10 mL) was stirred at 28 °C overnight. The reaction was quenched by addition of aq sat. NaHCOg. The mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated to give a crude product, which was puriﬁed by prep-HPLC to afford Compound 15 (46.3 mg, yield 23%) as a white solid. LC-MS (m/z): 541 [M+1]+; 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.12-2.17 (m, 4H), 2.93-2.99 (m, 2H), 3.45-3.55 (m, 2H), 3.82-3.92 (m, 3H), 4.10-4.16 (m, 4H), 4.52 (s, 1H), 5.05 (s,1H), 6.70-6.83 (m, 4H), 7.40 (s, 1H), 7.49 (s, 1H), 7.94-7.96 (d, J: 8.0 Hz, 1H), 11.53 (s, 1H).

Example 16 \ \ \ CN | | | N/ OH —> N/ —’ \o —> N/ OH 16A 16B 160 \ OH I \ O \ —> I —> I F F N/ O\ N/ o\ N/ O\ o O 16D 16E 0 16F N C=)H \ = I F F O / F F . 014—. | N \ NH j N o 16G 16 The mixture of Compound 16A (4.10 g, 19.25 mmol) in DCM (100 mL) was added DMP (9.79 g, 23.09 mol) at rt. After stirred at rt for l h the e was diluted with ethyl e (200 mL), ﬁltered to remove solid, washed with water and brine, and puriﬁed by silica gel chromatography (ethyl acetate in petroleum ether, 20% v/v) to give Compound 163 (3.10 g, yield 76%) as a colorless oil. LCMS (m/z): 212 [M+l]+, 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.90 (t, J: 9. 2 Hz, 2H), 3. 06 (t, J: 9.2 Hz, 2H), 7.25- 7.32 (m, 2H), 7.43 (t, J: 12.8 Hz, 1H), 7.78-7.93 (m, 4H), 8.74 (s, 1H), 9.86 (s, 1H).

A mixture of Compound 16B (3.00 g, 14.22 mmol) and 2Na05S2 (2.70 g, 14.22 mmol) in HzO/dioxane (50/10 mL) was stirred at rt for 2 h. After the on ofNaCN (l .39 g, 28.43 mmol), the mixture was stirred at rt overnight. It was diluted with ethyl e (200 mL), washed with water and brine, and d by silica gel column tography (ethyl acetate in petroleum ether, 50% v/v) to yield Compound 16C (2.00 g, yield 59%) as a colorless oil. LCMS (m/z): 239 [M+l]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.05-2.26 (m, 2H), 2.83-2.96 (m, 2H), 4. 36 (t, J: 6. 8 Hz, 1H), 4.97 (s, 1H), 7. 22-7. 31 (m, 2H), 7.41 (t, J: 7.6 Hz, 1H), 7.69-7.82 (m, 4H), 8.68 (s, 1H).

A solution of Compound 16C (2.00 g, 8.40 mmol) in MeOH (50 mL) was stirred at rt for 6 h with HCl gas bubbling. The reaction was quenched with H20 (10 mL) and stirred at rt for l h. It was diluted with ethyl acetate (150 mL), washed with water and brine, dried with anhydrous NaSO4, and evaporated to give Compound 16D (1.90 g, yield 83%) as colorless oil. LCMS (m/z): 272 [M+l]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.96-2.06 (m, 1H), 2.14-2.23 (m, 1H), 2.83-2.90 (m, 2H), 3.75 (s, 3H), 4.21- 4.24 (m, 1H), 7.21-7.29 (m, 1H), 7.40 (t, J: 7.6 Hz, 1H), 7.22-7.80 (m, 3H), 7.87 (s, 1H), 870(slfD.

To a solution of Compound 16D (800 mg, 2.95 mmol) in DCM (20 mL) was added DMP (1.50 g, 3.54 mmol). The mixture was stirred at rt for 2 h. It was then diluted with ethyl acetate (150 mL), ﬁltered to remove solid, washed with water and brine, dried with anhydrous Na2S04, and d by silica gel column chromatography (ethyl acetate in PE, % v/v) to yield Compound 16E (300 mg, yield 38%) as a colorless oil. LCMS (m/z): 270 [M+1]+, 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.07 (t, J = 7.2 Hz, 2H), 3.28 (t, J: 7.2 Hz, 2H), 3.86 (m, 3H), 7.25-7.35 (m, 2H), 7.43 (t, J: 7.2 Hz, 1H), 7.78- 793(nL4PD,874(&11D.

To a on of Compound 16E (400 mg, 1.48 mmol) in DCM (15 mL) was 2ﬂ®dDASTU23g743mmdﬂﬁmThmmmmewwstdMﬁowmQMlhwsmm diluted with ethyl acetate (150 mL), washed with ted NaHCOg, waster and brine, puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 40% v/v) to afford Compound 16F (120 mg, yield 28%) as a white solid. LCMS (m/z): 292 [M+1]+.

A mixture of nd 16F (120 mg, 0.41 mmol) and LiOH-HZO (52 mg, 124mmdﬁdHﬁﬂkOHHﬂKﬂy2mmwmwmmdmmﬁn2hhwwammmdmpH6 with 1 M HCl and puriﬁed by prep-HPLC to give Compound 16G (80 mg, yield 70%) as white solid. LCMS (m/z): 278 [M+1]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 2.40-2.53 (m, 2H), 2.89-2.93 (m, 2H), 7.26-7.37 (m, 2H), 7.42 (t, J: 7.2 Hz, 1H), 7.73-7.88 (m, 4H), 8.72 (s, 1H).

A solution of ediate A (80 mg, 0.29 mmol), Compound 16G (80 mg, 0.29 mmol), EDCI (83 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol) in DCM (5 mL) was stirred at rt overnight. It was then diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by prep-HPLC to afford Compound 16 (50 mg, yield 32%) as a white solid. LCMS (m/z): 538 [M+1]+; 1H-NMR (CDCl3, 400 MHz) major characteristic peaks: 5 (ppm) 1.58 (br s, 2H), 1.86 (s, 4H), 2.21-2.42 (m, 3H), 2.56-2.64 (m, 1H), 2.75-2.85 (m, 3H), 3.02 (s, 2H), 3.88-4.06 (m, 4H), 4.21 (s, 1H), 5.12 (s, 1H), 6.78-6.87 (m, 4H), 7.14 (d, J: 7.6, 1H), 7.39 (t, J: 7.6 Hz, 1H), 7.72-7.82(m, 4H), 8.69 (s, 1H). 2014/056555 Example 17 OH o s‘;\o o \o 0/\_. _. , o" F F 17A 17B 17C 0 O N 9" o/\ OH F F F F F F NH I 17D 17E 17 3] To a solution of Compound 17A (3.12 g, 20 mmol) in ous tetrahydrofuran (80 mL) was added zinc (2.1 g, 26 mmol). The mixture was heated at 75 °C under N2 atmosphere and ethyl 2-bromo-2,2-diﬂuoroacetate (3.2 mL, 29 mmol) was slowly added. The mixture was heated under the same conditions for 2 h. After cooling, it was ﬁltered. The ﬁltrate was concentrated to give a crude product which was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum 5% to 20% v/v) to yield Compound 17B (3.9 g, yield 70%) as a white solid. LCMS (m/z): 281 [M+1]+. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.26 (t, J = 7.2 Hz, 3H), 4.30 (q, J = 7.2 Hz, 2H), .34 (q, J: 8 Hz, 1H), 7.50-7.56 (m, 3H), 7.83-7.88 (m, 3 3H), 7.91 (s, 1H) To a solution of Compound 17B (280 mg, 1 mmol) in DCM (20 mL) was added dropwise N,N’-thiocarbonyldiimidazole (25.0 g, 126 mmol) in DCM (10 mL) at 72 °C.

After stirring for 3 h, the reaction e was cooled to rt and concentrated in vacuum to give a crude product. It was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum 5% to 20% v/v) to afford Compound 17C (310 mg, yield 79%) as a yellow oil.

LCMS (m/z): 391 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.24 (t, J: 7.2 Hz, 3H), 4.30 (q, J: 7.2 Hz, 2H), 6.98 (m, 1H), 7.10 (s, 1H), 7.53-7.55 (m, 3H), 7.70 (s, 1H), 7.84-7.90 (m, 3H), 7.94 (s, 1H) ,8.43 (s, 1H).

To a solution of 11-13113an (922 mg, 1.59 mmol) and AIBN (2 mg, cat.) in reﬂuxing toluene (10 ml) was added dropwise the Compound 17C (310 mg, 0.79 mmol) in e (10 ml). After stirred for 3 h at 110 °C, the reaction mixture was cooled to rt and concentrated in vacuum to give a crude product Compound 17D (500 mg, crude) as a yellow oil. It was used for the next step without puriﬁcation. LCMS (m/z): 265 [M+1]+.

To a on of Compound 17D (500 mg, 0.79 mmol) in THF/MeOH/water (3 mL, 1:1:1, v/v/) was added LiOH'HzO (60 mg, 1.5 mmol). The e was stirred at 25 °C WO 42397 for 1 h. After the addition of water (20 mL), the mixture was extracted with ethyl acetate (20 mL x 2). The water phrase was adjusted pH to 6 with 1 N HCl and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to give a crude product nd 17E (169 mg, yield 80%) as a white solid. LCMS (m/z): 235 ; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 3.59 (t, J: 17.2 Hz, 2H), 7.42 (d, J: 8 Hz, 1H), 7.52 (d, J: 8 Hz, 1H), 7.82 (s, 1H), 7.90 (t, J: 8 Hz, 3H), 14.75 (s, 1H).

To a mixture of Compound 17E (67 mg, 0.25 mmol) in DCM (10 mL) was added EDCI (72 mg, 0.38 mmol), HOBt (51 mg 0.38 mmol) and Intermediate A (61 mg, 0.25 mmol) and d at 25 °C overnight. After the addition of water (10 mL), the mixture was extracted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep- HPLC to afford triﬂuoroacetic acid salt of Compound 17 (47 mg, yield 27%) as a white solid.

LCMS (m/z): 496 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.62-2.03 (m, 4H), 2.53 (s, 1H), 2.95 (s, 1H), 3.33-3.56 (m, 4H), 3.94 (s, 2H), 4.19 (s, 4H), 4.25 (s, 1H),4.89 (s, 1H), 6.60 (d, J: 8 Hz, 1H), 6. 71 (d, J: 8 Hz, 1H), 6.78 (s, 1H), 7.34 (t, J: 8 Hz, 2H), 7.48 (d, J: 8 Hz, 2H), 7.70 (s, 1H), 7.77-7.83 (m, 3H), 11.31 (s, 1H).

Example 18 0/ Cl 0' 0" CI o\)\o/ CI CI —> m I + \ CI CI 0 0 18A 183 130 18C.

CI 0 CI \ 0 C' O _. /— \ \ 0 O /_ /_ CI o 0 CI 0 O O O 18D 18D' 180 ::N oH CI F CI F \ F F —, \ /_ I I F F CI 0 0 CI 0 OH NH 1 \ O o 0 CI 0 O 18E 18F A mixture of Compound 18A (30 g, 184 mmol), 2-bromo-1,1- dimethoxyethane(37 g, 221 mmol), K2C03 (38 g, 276 mmol), KI (600 mg) in DMF (150 mL) was stirred at reﬂux overnight. Cooling to rt, it was filtered. The te was diluted with water (500 mL), extracted with ethyl acetate (250 mL x 2), washed with water (250 mL x 3) and brine (250 mL), dried over Na2S04, and evaporated to dryness to yield a crude Compound 18B (46 g, yield 100%), which was used for the next step without further puriﬁcation.

A solution of polyphosphoric acid (75 g) in toluene was stirred to 90 °C, then tMMMmmmwwwkdammmﬂBBM6QmmmmﬁmanMMmmmwmmmw at90°Clbr4lnthm1pomedinu)km,andsﬁnedfor30nnn.CoohngtorLthennxunewms extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL), dried over Na2S04, concentrated, and d by silica gel column chromatography (petroleum ether, 100% V/V) to yield a mixture of Compound 18C and nd 18C9 (7 g, yield 21%) as a white solid. 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 6.69 (d, J = 1.6 Hz, 1H), 6.84 (d, J: 1.6 Hz, 1H), 7.34 (s, 2H), 7.61 (s, 1H), 7.62 (d, J: 2.0 Hz, 1H), 7.65 (s, 1H).

To a solution of nd 18C and 18C’ (8 g, 42.8 mmol) in THF (60 mL) was added n-BuLi (20 mL) at -78 °C under N2. After stirred for 30 min, diethyl oxalate (6 g, 51 mmol) was added to the mixture and it was stirred at -78 °C for 1 h, followed by the on of aq sat. NH4Cl. The resulting mixture was extracted with ethyl acetate (100 mL x 2), washed with aq sat. NaHC03 (100 mL x 2), brine (100 mL), dried over Na2S04, concentrated, and puriﬁed by silica gel column tography (ethyl acetate in petroleum ether, 20% V/V) to give Compound 18D (2.5 g, yield 19%) and Compound 18D9 (250 mg, yield 1.9%) as a yellow solid. Compound 18D: LC-MS (m/z): 287 [M1]; 1H-NMR (DMSO- d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.45 (t, J: 6.8 Hz, 3H), 4.45 (q, J: 6.8 Hz, 2H), 6.79 (d, J: 2.4 Hz, 1H), 7.70 (d, J: 2.4 Hz, 1H), 7.83 (s, 1H). Compound 18D’: LC-MS (m/z): 287 [M +1]; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.47 (t, J: 6.8 Hz, 3H), 4.50 (q, J: 8.8 Hz, 2H), 7.47 (d, J: 2.4 Hz, 1H), 7.58 (d, J: 8.8 Hz, 1H), 8.12 (s, 1H).

To a solution of Compound 18D (750 mg, 2.6 mmol) in DCM (50 mL) was added DAST (2.5 g, 15.7 mmol) at 0 °C and the mixture was stirred at rt overnight. It was poured into ice-water, followed by addition of aq sat. aq NaHCOg (20 mL). The resulted mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and concentrated. The crude product was d by silica gel column chromatography (ethyl acetate in petroleum ether, 10% V/V) to render Compound 18E (350 mg, yield 51%) as a yellow liquid. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.26 (t, J: 6.8 Hz, 3H), 4.31 (q, J: 6.8 Hz, 2H), 6.71 (d, J: 1.6 Hz, 1H), 7.66 (d, J: 1.6 Hz, 1H), 7.76 (s, 1H).

To a solution of Compound 18E (150 mg, 0.5 mmol) in THF (20 mL) was added LiOH (24 mg, 0.6 mmol) in water (5 mL) and the mixture was stirred at rt 3 h. It was concentrated by removal of EtOH and adjusted to pH 7 with diluted HCl. Lyophilization of the solution led to Compound 18F (124 mg, , which was used for the next step without further puriﬁcation. LC-MS (m/z): 280 [M-l]'; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 7.17 (s, 1H), 8.24 (s, 1H), 8.26 (s, 1H).

A mixture of Compound 18F (124 mg, 0.44 mmol), EDCI (117 mg, 0.61 mmol), HOBt (83 mg, 0.61 mmol), Intermediate A (115 mg, 0.41 mmol) in DCM (20 mL) was stirred at rt overnight. To the mixture was added dropwise aq sat. NaHCOg. It was then ted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 18 (78 mg, yield 26%) as a white solid. LC-MS (m/z): 541 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (s, 4H), 2.89 (m, 2H), 3.09 (brs, 1H), 3.37 (brs, 1H), 3.62 (brs, 1H), 3.87 (brs, 2H), 4.25 (s, 4H), 4.36 (m, 1H), , 1H), 6.75 (s, 1H), 6.83 (s, 2H), 6.89 (s, 1H), 7.62 (d, J: 2 Hz,, 1H), 7.68 (d, J: 2 Hz,, 1H), 7.80 (s, 1H), 11.41 (s, 1H).

Example 19 CI I 3 CI F O N 9H CI 0 CI F 1 \ > \ F > / o F F o o —> o —> —> CI NH o j \ o O 0 CI CI 0 0 18D' 19A 19B 19 To a solution of Compound 18D’ (240 mg, 0.84 mmol) in DCM (11 mL) was added DAST (740 mg, 4.59 mmol) at 0 °C and the mixture was stirred at rt ght. The reaction was quenched by pouring the mixture into ice-water, and followed with on of sat. aq NaHCOg (20 mL). It was ted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 10% v/v) to render Compound 19A (245 mg, yield 94.8%) as a yellow liquid. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.35-1.40 (m, 3H), 4.35-4.44 (m, 2H), 7.23 (s, 1H), 7.40-7.42 (d, J: 8.8 Hz, 1H), 7.46-7.48 (d, J: 8.8 Hz, 1H).

To a solution of Compound 19A (245 mg, 0.795 mmol) in THF (10 mL) was added LiOH (63 mg, 1.49 mmol) in water (5 mL) and the mixture was stirred at rt for 4 h.

The mixture was concentrated by removal of solvent and then adjusted pH to 6 with diluted HCl. lization of the solution gave rise to Compound 19B (210 mg, crude), which was used for the next step without r puriﬁcation. LC-MS (m/z): 279 [M-l]'. -ll3- A mixture of Compound 19B (135 mg, 0.48 mmol), EDCI (135 mg, 0.70 mmol), HOBt (94 mg, 0.69 mmol), Intermediate A (130 mg, 0.47 mmol) in DCM (20 mL) was stirred at rt overnight. The mixture was diluted with aq sat. NaHC03, extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give 19 (83 mg, yield 32%) as a white solid.

LC-MS (m/z): 541.2 [M+1]+; 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.11 (s, 4H), 2.91-2.99 (m, 2H), 3.41-3.42 (m, 1H), 3.56-3.62 (m, 1H), 3.78 (s, 1H), 3.94-3.80 (m, 2H), 4.11-4.15 (m, 4H) 4.48(s, 1H), 5.03 (s, 1H), 6.69-6.77 (m, 2H), 6.80 (s, 1H), 7.35-7.38 (d, J: 9.2 Hz, 1H), 7.44-7.46 (d, J: 8.8 Hz, 1H), .04 (d, J: 8.8 Hz, 1H), 11.70 (s, 1H).

Example 20 F F 0\ HO o\/ N\ —> N\ —> | | / / 20A 203 F F F F 0V OH 0 o N N —> \ \ | | N / / \ | 20 200 20E To a solution of Compound 20A (2.2 g, 12 mmol) in anhydrous tetrahydrofuran (80 mL) was added zinc (1.01 g, 15.6 mmol). The mixture was heated at 75 °C under N2 atmosphere and ethyl o-2, 2-diﬁuoroacetate (1.9 mL, 15 mmol) was slowly added. The mixture was heated under the same conditions for 2 h. After cooling, it was d. The e was concentrated to give a crude product, which was d by silica gel column chromatography (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 20B (1.9 g, yield 58%) as a colorless oil. LCMS (m/z): 309 [M+1]+.

To a solution of Compound 20B (500 mg, 1.63 mmol) in DCM (20 mL) was added dropwise N,N’-thiocarbonyldiimidazole (349 mg, 1.95 mmol) in DCM (10 mL) at 72 °C. After 3 h, the reaction mixture was cooled to rt and concentrated in vacuum to give a crude product. It was puriﬁed by silica gel column chromatography (ethyl e in petroleum ether, 20% v/v) to render Compound 20C (590 mg, yield 87%) as a colorless oil. —114— LCMS (m/z): 418 [M+1]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 1.26 (t, J: 6.8 Hz, 3H), 4.31 (q, J: 6.8 Hz, 2H), 6.92 (m, 1H), 7.09 (s, 1H), 7.28 (m, 1H), 7.60 (m, 2H), 7.70-7.81 (m, 3H), 8.07 (d, J: 7.2 Hz, 1H), 8.13 (s, 1H), 8.41 (s, 1H), 8.70 (d, J=441h,HD.

To a solution of n-Bu3SnH (821 mg, 2.8 mmol) and AIBN (2 mg, cat.) in reﬂuxing toluene (10 ml) was added dropwise the Compound 20C (590 mg, 1.4 mmol) in toluene (10 ml). After stirred for 3 h at 110 °C, the reaction mixture was cooled to rt and concentrated in vacuum to puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 20D (200 mg, yield 50%) as a colorless oil.

LCMS (m/z): 392 .

To a solution of Compound 20D (100 mg, 0.34 mmol) in THF/MeOH/water (3 nwwmmwlﬂﬂﬂﬁOG6mg15mmd)ﬂwmmmmw%stdm25T for 1 h. After the completion of the reaction, water (20 mL) was added. It was extracted with ethyl acetate (20 mL x 2). The aqueous phrase was adjusted pH to 6 with 1 N HCl and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to give crude t Compound 20E (90 mg, crude) as a yellow solid. LCMS (m/z): 264 [M+1]+.

To a mixture of Compound 20E (80 mg, 0.3 mmol) in DCM (10 mL) was added EDCI (88 mg, 0.45 mmol), HOBt (62 mg 0.45 mmol) and Intermediate A (85 mg, 0.3mmol) and stirred at 25 °C overnight. After the addition of water (10 mL), the mixture was ennwmdwﬁhDCNH20mLx3LdnahwmamndmusNQSO%pmﬁhdbymepHPLCK) render Compound 20 (35 mg, yield 22%) as a white solid. LCMS (m/z): 524 [M+1]+; 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.99 (s, 4H), 2.72 (m, 2H), 3.19 (s, 1H), .66 (m, 6H), 4.20 (s, 4H), 4.40 (s, 1H), 4.77 (s, 1H), 4.89 (s, 1H), 6.68 (m, 1H), 6.76(nL2PD,745J154(nL2PD,770(nLlfD,777J185(nL3PD,799(d"I=8I)Hz,1H) 8.28 (t, J: 7.6 Hz, 1H), 8.90 (s, lH),11.43 (s, 1H).

Example 21 Br COOEt COOH Br COOEt COOH F F F F 21A 21B 21C 21D OH /O 4 4m4 —» F F F 21E 21F 21G OH OH 0 4 om 4 4 F CN F COOMe F COOMe 21H 21I Fmoom NH F COOH 0 21L 21 To a solution of nd 21A (2.5 g, 20 mmol) in CCl4 (100 mL) was added NBS (7.12 g, 40 mmol), BPO (100 mg) and it was stirred at reﬂux overnight. The mixture was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to render Compound 21B (2.34 g, yield 41%) as a colorless oil. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 4.60 (s, 2H), 4.62 (s, 2H), 6.98 (m, 1H), 7.08 (m, 1H), 7.33 (m, 1H).

To a solution of diethyl malonate (1.52 mL, 10 mmol) in THF (100 mL) was added NaH (60%, 400 mg, 10 mmol) at 0 °C and stirred at 0°C for 15 min. To the e was added Compound 21B (2.8 g, 10 mmol) at 0°C and stirred for 15 min and then followed by on ofNaH (60%, 400 mg, 10 mmol) at 0°C. The mixture was stirred at rt for 2 h and was ﬁltered to remove the salt. The ﬁltrate was concentrated and puriﬁed by ﬂash column (ethyl acetate in petroleum ether, 10% v/v) to give Compound 21C (2.2 g, yield 79%) as a colorless oil. LC-MS (m/z): 281 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.26 (t, J: 7.0 Hz, 6H), 3.53 (s, 2H), 3.56 (s, 2H), 4.20 (m, 4H), 6.87(m, 2H), 7.12 (m, 1H).

To a on of Compound 21B (2.2 g, 7.9 mmol) in ethanol (30 mL) was added a solution of LiOH (1.26 g, 31.4 mmol) in water (30 mL) and stirred at rt ght.

The mixture was concentrated to remove ethanol, acidiﬁed with conc. aqueous HCl solution, extracted with ethyl acetate (100 mL x 3) and concentrated to render Compound 21D (1 g, yield 62%) as a yellow solid. LC-MS (m/z): 247 [M+23]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 3.38 (s, 2H), 3.42 (s, 2H), 6.93 (m, 1H), 7.05 (m, 1H), 7.21 (m, 1H), 12.93 (s, 2H).

To a solution of Compound 21D (1 g, 4.5 mmol) in DMSO (15 mL) was added NaCl (1 g). The mixture was stirred at 130 °C for 6 h. After the on of ethyl acetate (100 mL), the mixture was washed with water (200 mL x 3) and brine (200 mL x 1), dried over anhydrous Na2S04, and concentrated to yield Compound 21E (0.6 g, yield 74%) as a brown solid. 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 3.08 (m, 4H), 3.29 (m, 1H), 6.92 (m, 1H), 7.03 (m, 1H), 7.21 (m, 1H), 12.37 (s, 1H).

To a solution of Compound 21E (0.6 g, 3.3 mmol) in DCM (10 mL) was added B2H6 in THF solution (1M, 4 mL, 4 mmol) at -78 °C under N2 and stirred at rt for 1 h.

MeOH (2 mL) was added to the mixture and it was stirred at the same temperature overnight.

After removal of the solvents, the residues were puriﬁed with ﬂash column chromatography (ethyl acetate in petroleum ether, 35% v/v) to give Compound 21F (250 mg, yield 46%) as a yellow oil. 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 2.70 (m, 3H), 3.04 (m, 2H), 3.65 (d, J: 6.4 Hz, 2H), 6.80 (m, 1H), 6.87 (m, 1H), 7.11 (m, 1H).

To a solution of Compound 21F (6.3 g, 38 mmol) in DCM (300 mL) was added DMP (19 g, 45.5 mmol) at 0 °C and it was stirred at rt for 3 h. The mixture was concentrated and d by ﬂash column chromatography (ethyl acetate in eum ether, % v/v) to give Compound 21G (6 g, yield 96%) as a yellow oil. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.23 (m, 5H), 6.88 (m, 2H), 7.15 (m, 1H), 9.77 (d, J: 0.8 Hz,1H).

To a solution ofNa2S205 (3.6 g, 73.2 mmol) in water (100 mL) was added Compound 21G (6 g, 36.6 mmol) and it was d at rt for 2 h and ed by the on ofNaCN (3.6 g, 73.2 mmol). The mixture was stirred at rt overnight. It was extracted with ethyl acetate (100 mL x 3), dried over anhydrous Na2S04, puriﬁed by ﬂash column chromatography (ethyl acetate in petroleum, 30% v/v) to give Compound 21H (3.3 g, 47%) as a colorless oil. 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 2.96 (m, 3H), 3.16 (m, 2H), 4.45 (m, 1H), 6.86 (m, 2H), 7.14 (m, 1H).

To a solution of Compound 21H (3.3 g, 17.3 mmol) in MeOH (100 mL) was bubbled with a gentle stream of HCl gas (dried over conc. H2S04) for 6 h and was allowed to stand overnight at 4 °C. To the mixture was added water (50 mL) and it was stirred at rt for 3 h. Saturated aqueous NaHCOg solution was added to adjust pH > 7, the mixture was then extracted with ethyl acetate (100 mL x 3), washed with brine (100 mL x 1), dried over anhydrous Na2S04, and puriﬁed by ﬂash column chromatography (ethyl acetate in petroleum 2014/056555 ether, 25% v/v) to give Compound 211 (1.9 g, yield 49%) as a yellow oil. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.90 (m, 5H), 3.77 (d, J = 2.4 Hz, 3H), 4.27 (d, J=36Ph,HD,681mL2HL707Gm1H) To a solution of Compound 211 (1.9 g, 8.5 mmol) in DCM (100 mL) was added DMP (5.4 g, 12.7 mmol) at 0 °C and it was stirred at rt for 3 h. After removal of the solvent, the residues were puriﬁed by ﬂash column chromatography (ethyl acetate in petroleum ether, 10% v/v) to give Compound 21J (1.7 g, yield 90%) as a colorless oil. 1H- NMR , 400 MHz) major characteristic peaks: 5 (ppm) 3.19 (m, 4H), 3.91 (s, 3H), 4.07 (nnlfD,683(nn2}D,710(nL11D.

To a solution of Compound 21J (444 mg, 2 mmol) in DCM (10 mL) was added DAST (1 mL, 8 mmol) and it was stirred at 25 °C overnight. The e was puriﬁed by ﬂash column tography (ethyl acetate in petroleum ether, 2% v/v) to give 21K (300 mg, 61%) as a yellow oil. LC-MS (m/z): 225 [M-l9]+. 2] To a solution of Compound 21K (300 mg, 1.23 mmol) in MeOH (5 mL) was added a solution of LiOH (100 mg, 2.46 mmol) in water (5 mL) and it was stirred at rt ght. The mixture was acidiﬁed using 1M aqueous HCl solution, extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2S04, and concentrated to give Compound 21L (200 mg, yield 35%) as a colorless oil. LC-MS (m/z): 229 [M-1]'.

To a solution of Compound 21L (230 mg, 0.87 mmol) in DCM (10 mL) was added EDCI (250 mg, 1.3 mmol), HOBt (175 mg, 1.3 mmol), Intermediate A (240 mg, 0.87 mmol) and it was stirred at rt overnight. The mixture was diluted with DCM (20 mL), washed with water (50 mL x 2) and brine (50 mL x 1), dried over anhydrous Na2S04, concentrated, and puriﬁed by prep-HPLC to give Compound 21 (20 mg, yield 5%) as a white solid. LC-MS (m/z): 491 [M+l]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.15 (br, 4H), 2.61 (m, 2H), 2.91 (m, 5H), 3.38 (br, 1H), 3.54 (br, 1H), 3.88(s, 2H),4.20 (m, 4H), 4.44 (s, 1H), 5.20 (s, 1H), 6.83 (m, 4H), 6.90 (m, 1H), 7.05 (m, 1H), 7.39 (m, 1H), 11.42 (s, 1H). -ll8- Example 22 We~ooj"Mm 22A O22D ~~M~MW ~W~Qﬁr2H NOH N9H —> F F : I F F NH NH 1 CO O CO O O 0 22K 22 To a solution of ethyl 2-(diethoxyphosphoryl)acetate (7.2 g, 32 mmol) in THF (150 mL) was added NaH (1.3 g, 32 mmol) at 0 °C under N2 and it was stirred at this temperature for 30 min, followed by the addition of Compound 22A (5 g, 32 mmol) in THF (15 mL). Stirred at 40 °C for 1 h, the mixture was ﬁrst cooled down to rt, and then added water, extracted with ethyl e (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, concentrated, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 20% V/V) to give Compound 22B (7 g, yield 97%). LC-MS (m/z): 227 [M+1]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 1.36 (t, J = 6.8 Hz, 3H), 4.28 (q, J: 7.2 Hz, 2H), 6.54 (d, J: 16 Hz, 1H), 7.5 (m, 2H), 7.65 (d, J: 10 Hz, 1H), 7.82 (m, 4H), 7.91 (s, 1H).

To a solution of Compound 22B (7 g, 31 mmol) in methanol (50 mL) and THF (30 mL) was added Pd/C (700 mg) and it was stirred at 25 °C for 4 h under H2. The mixture was ﬁltered, and the ﬁltrate was concentrated to render nd 22C (7 g, crude), which was used for the next step without ﬁthher puriﬁcation. LC-MS (m/z): 229 .

To a on of AlLiH4 (1.16 g, 31 mmol) in THF (100 mL) was added Compound 22C (7 g, 31 mmol) in THF (20 mL) at -60 °C under N2 and the mixture was stirred for 2 h, and then allowed the temperature raised to rt. Sodium sulfate was added to the mixture. After ﬁltration, the ﬁltrate was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 20% V/V) to yield the Compound 22D (5.6 g, yield 98%) as a white solid. LC-MS (m/z): 169 [M-18]+; (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.06 (s, 1H), 1.97 (m, 2H), 2.87 (d, J: 7.6 Hz, 2H), 3.70 (d, J: 6.4 Hz, 2H), 7.33 (d, J: 8.4 Hz, 1H), 7.43 (m, 2H), 7.63 (s, 1H), 7.78 (m, 3H).

To a solution of Compound 22D (3 g, 16 mmol) in DCM (100 mL) was added DMP (8.2 g, 19 mmol) and the mixture was stirred at rt for 2 h, and then ﬁltered. The ﬁltrate was washed with aq sat. NaHCOg (2 x 50 mL), extracted with DCM (2 x 50 mL), washed with brine (1 x 50 mL), dried over Na2S04, concentrated, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 20% V/V) to afford Compound 22E (2.6 g, yield 88%) as a colorless oil. (CDC13, 400 MHz) major teristic peaks: 5 (ppm) 2.87 (d, J: 7.2 Hz, 2H), 3.12 (d, J: 7.6 Hz, 2H), 7.33 (d, J: 8.4 Hz, 1H), 7.44 (m, 3(&11D,779(nL3PD,986(s,H{) Compound 22E (2.6 g, 14 mmol) was added to a solution of sodium metabisulfate (2.7 g, 14 mmol) in water (100 mL). The mixture was Vigorously d for 2 h at rt, and after the addition ofNaCN (1.4 mg, 28 mmol) it was stirred overnight. The mixture was added water (30 mL) and THF(10 mL), extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL x 1), dried over Na2S04, concentrated to yield Compound 22F (2 g, 66% yield). LC-MS (m/z): 212 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 2.25 (m, 2H), 2.99 (m, 2H), 4.43 (t, J: 6.8 Hz, 1H), 7.33 (d, J: 8.8 Hz, 1H), 7.44 (m, 2H), 7.65 (s, 1H), 7.81 (m, 3H).

To a solution of Compound 22F (2.0 g, 9.5 mmol) in EtOH (30 mL) at 0 °C was bubbled with a gentle stream of HCl (gas) (dried over con.H2SO4) for 5 h. The mixture was added water (20 mL), stirred at rt for 2 h, and ed pH to 7 with diluted NaOH (2 M).

It was extracted with DCM (100 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, concentrated, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 33% V/V) to render Compound 22G (1.56 g, yield 64%) as a yellow oil. LC-MS (m/z): 259 ; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.27 (t, J = 7.6 Hz, 1H), 2.03 (m, 1H), 2.22 (m, 1H), 2.92 (m, 2H), 4.20 (m, 3H), 7.35 (d, J: 9.2 Hz, 1H), 7.44 (m, 2H), 7.65 (s, 1H), 7.79 (m, 3H). 0] To a solution of Compound 22G (500 mg, 1.94 mmol) in DCM (20 mL) was added DMP (986 mg, 2.3 mmol) and the mixture was stirred at rt for 2 h and then ﬁltered.

The ﬁltrate was washed with aq sat. NaHCOg (50 mL x 2) and aq sat. Na2S203 (50 mL x 2), extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated to yield Compound 22H (450 mg, yield 91%) as a yellow oil. LC-MS (m/z): 239 [M-18]+.

To a solution of Compound 22H (450 mg, 1.76 mmol) in DCM (20 mL) was added DAST (l .4 g, 8.8 mmol) at 0 °C and the mixture was stirred at rt overnight. The reaction mixture was poured into ice-water, extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 20% v/v) to yield nd 221 (450 mg, yield 92%) as a colorless oil. LC-MS (m/z): 279 [M+1]+; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 1.31 (t, J = 7.2 Hz, 1H), 2.47 (m, 2H), 2.98 (m, 2H), 4.27 (q, J: 7.2 Hz, 2H), 7.31 (d, J: 8.4 Hz, 1H), 7.45 (m, 2H), 7.63 (s, 1H), 7.77 (m, 3H).

To a solution of Compound 22] (450 mg, 1.6 mmol) in EtOH (5 mL) was added LiOH (136 mg, 3.2 mmol) in water (5 mL) and the mixture was stirred at rt overnight.

After concentration by evaporation, the mixture was adjusted to pH 2 with diluted HCl, extracted with DCM (20 mL x 2), washed with brine (20 mL x 1), dried over Na2S04, and concentrated to give Compound 22J (250 mg, yield 62%), which was used for the next step without further ation. LC-MS (m/z): 251 .

A mixture of Compound 22J (100 mg, 0.4 mmol), EDCI (115 mg, 0.6 mmol), HOBt (82 mg, 0.6 mmol), Intermediate A (110 mg, 0.4 mmol) in DCM (20 mL) was stirred at rt overnight. The reaction mixture was diluted with water, extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and trated. The crude product was puriﬁed ﬁrst by prep-HPLC, ed by chiral-prep-HPLC to give Compound 22K (24 mg, yield 12%) as a white solid and Compound 22 (22 mg, yield 11%) as a white solid. For Compound 22K: LC-MS (m/z): 511 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.81 (s, 4H), 2.46 (m, 3H), 2.70 (m, 5H), 2.98 (d, J: 3.6 Hz, 2PD,394(nL4PD,420(g11D,507(&11D,682(nL4PD,722(nL11D,745(nL2PD,754 (s, 1H), 7.77 (m, 3H). For Compound 22: LC-MS (m/z): 511 [M+1]+; (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.89 (s, 4H), 2.36 (m, 2H), 2.88 (m, 4H), 2.99 (m, 3H), 3.19 (s, 1H), 4.04 (m, 4H), 4.25 (s, 1H), 4.77 (d, J: 5.6 Hz, 1H), 6.86 (m, 3H), 7.28 (m, 11D,744(nL2PD,759(&llD,778(nn3H) -l2l- Example 23 co4 o \ F O O o o o o \— O ) 23A 233 ::N 9H F O —— \ F F —» I 0 OH \ o o o o 230 23 To a solution of Compound 23A (2.36 g, 20.0 mmol) in tetrahydrofuran (30 mL) stirring at -70° C (C02, acetone bath) was added n-BuLi (8.0 mL, 20.0 mmol, 1.6 M in s). The on was stirred for 30 min (yellow color) and added se via a ted needle into a solution of diethyl oxalate (2.92 g, 20.0 mmol) in tetrahydrofuran (20 mL) stirring at -70 °C. The reaction mixture was d for 1 h and then quenched with saturated aqueous ammonium chloride solution. The mixture was warmed to rt, diluted with dichloromethane, and washed with 0.1 N HCl. The organic layer was separated, dried over anhydrous magnesium sulfate, ﬁltered, and ated under reduced pressure. The residue was puriﬁed by chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to provide Compound 23B (1.10 g, yield 25%). (CDC13, 400 MHz) major teristic peaks: 5 (ppm) 1.46 (t, J=7.2 Hz, 3H), 4.87 (q, J=7.2 Hz, 2H), 7.35-7.37 (m, 1H), 7.55-7.57 (m, 1H), 7.61-7.64 (m, 1H), 7.77-7.78 (m, 1H), 8.09-8.10 (m, 1H).

To a solution of Compound 23B (800 mg, 3.67 mmol) in CH2C12 (10 mL) was added DAST (1.77 g, 11.01 mmol). The reaction mixture was stirred for 10 h and then poured into ice-water, extracted with CHzClz. The combined organic layers were dried over Na2SO4, ﬁltered, evaporated to give desired product Compound 23C (860 mg, yield 97%). 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.35-1.40 (m, 3H), 4.33-4.43 (m, 2H), 7.14-7.15 (m, 1H), 7.31-7.33 (m, 1H), 7.38-7.42 (m, 1H), 7.54-7.56 (m, 1H), 7.64-7.66 (m, 1H).

To a solution of Compound 23C (480 mg, 2 mmol) in THF (2 mL) was added LiOH-HZO (3 mmol, 126 mg), H20 (2 mL) and MeOH (2 mL). The reaction mixture was stirred for 3 h at 25 °C, neutralized with l N HCl, and evaporated to dryness. The residue was dissolved in H20 and extracted with ethyl acetate. The c layer was dried over Na2S04, ﬁltered, evaporated to give Compound 23D (290 mg, yield 68%). LCMS (m/z): 213 [M+l] +.

To a solution of Compound 23D (88 mg, 0.41 mmol) in DCM (10 mL) was added Intermediate A (114 mg, 0.41 mmol), HOBt (82 mg, 0.61 mmol) and EDCI (116 mg, 0.61mmol). The mixture was stirred for 3 h at 25 °C, washed with brine, dried over Na2S04, ﬁltered, evaporated, and puriﬁed by prep-HPLC to give Compound 23 (30 mg, yield 15%) as a white solid. LC-MS (m/z): 473 ; 1H-NMR(MeOD-d4, 400 MHz) major characteristic peaks: 5 (ppm) 1.77-1.78 (m, 4H), 2.55-2.64 (m, 4H), 2.74-2.75 (m, 2H), 4.08- 4.14 (m, 4H), 4.35-4.36 (m, 1H), 4.79 (d, J=4.0 Hz, 1H), 6.66-6.68 (m, 1H), 6.76-6.78 (m, 1H), 6.83-6.84 (m, 1H), 7.00 (s, 1H), 7.30-7.34 (m, 1H), 7.41-7.45 (m, 1H), 7.55-7.57 (m, 1H), 7.66-7.68 (m, 1H), 7.81-7.83 (m, 1H).

Example 24 O —. @‘Mo/OH F F F 0 24A 24B 240 F o F F F F \ \ F \ F /— a /_ o o o o 0 OH O o O 24D /\—/\ 24E 24F N 9H F F NH j \ 0 F o o A mixture of Compound 24A (10 g, 89 mmol), 2-bromo-1,1- dimethoxyethane(15 g, 89 mmol), K2C03 (18.4 g, 134 mmol), KI (100 mg) in DMF (100 mL) was d at reﬂux for 3 h, then cooled to rt, and d. The ﬁltrate was added water (200 mL), extracted with ethyl acetate (100 mL x 2), washed with water (100 mL x 3), brine (100 mL x 1), dried over Na2S04, concentrated, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 10% V/V) to render Compound 24B (15 g, yield 85%) as a colorless liquid. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.46 (s, 6H), 3.96 (d, J: 5.2 Hz, 2H), 4.71 (t, J: 5.6 Hz, 1H), 6.90 (m, 2H), 7.26 (m, 2H).

A solution of polyphosphoric acid (90 g) in toluene was d to 90 °C, then to the on was added Compound 24B (15 g, 75 mmol) in e (20 mL) and the mixture was stirred at 90 °C for 3 h, then poured into ice, and stirred for 30 min. It was extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL x 1), dried over Na2S04, concentrated, and puriﬁed by column chromatography on silica gel leum ether, 100% V/V) to yield Compound 24C (4.5 g, yield 44%) as a red liquid. 1H-NMR (CDClg, 400 MHZ) major characteristic peaks: 5 (ppm) 6.742-6.746 (m, 1H), 6.994-7.035 (m, 1H), 7.24- 7.26 (m, 1H), 7.41-7.44 (m, lH),7.651-7.655 (d, J: 1.6 Hz, 1H). 0] To a on of Compound 24C (4.5 g, 33 mmol) in THF (20 mL) was added n-BuLi (15 mL) at -78 °C under N2 and the mixture was d for 30 min, before the addition of diethyl e (10.8 g, 74 mmol). The mixture was stirred at -78 °C for l h, and ed with addition of aq sat. NH4Cl. It was extracted with ethyl acetate (2 x 50 mL), washed with sat.NaHC03 (50 mL x 2), brine (50 mL), dried over Na2S04, concentrated, and puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to give Compound 24D (2.5 g, yield 32%) as a yellow solid.

To a solution of Compound 24D (1 g, 4.2 mmol) in DCM (50 mL) was added DAST (3.18 g, 18 mmol) at 0 °C and the mixture was stirred at rt overnight, poured into ice- water, and added sat. aq NaHCOg (20 mL). The mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by silica gel column tography (ethyl acetate in petroleum ether, 10% v/v) to yield Compound 24E (600 mg, yield 55%) as a yellow liquid.

To a solution of Compound 24E (120 mg, 0.46 mmol) in EtOH (5 mL) was added LiOH (46 mg, 1.09 mmol) in water (5 mL) and the mixture was stirred at rt overnight, concentrated to remove EtOH, and adjusted to pH 7 with diluted HCl. Lyophilization of the solution provided Compound 24F (60 mg, crude), which was used for the next step without further puriﬁcation. LC-MS (m/z): 229 [M-l]'. 3] A mixture of Compound 24F (60 mg, 0.26 mmol), EDCI (75 mg, 0.39 mmol), HOBt (53 mg, 0.39 mmol), Intermediate A (72 mg, 0.41 mmol) in DCM (10 mL) was stirred at rt overnight. After quenched with sat.NaHC03, the mixture was extracted with DCM (2 x 50 mL), washed with brine (l x 50 mL), dried over Na2S04, concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 24 (2 mg, yield 2%) as a white solid. LC-MS (m/Z): 491 [M+l]+; 1H-NMR (CDClg, 400 MHZ) major characteristic peaks: 5 (ppm) 1.85 (m, 4H), 3.07 (m, 2H), 3.43 (m, 4H), 4.15 (s, 4H), 4.45 (s, 1H), 4.70 (s, 1H), 5.90(s, 1H), 6.67 (m, 2H), 6.79 (s,lH), 7.02 (s, 1H), 7.36 (s, 1H), 7.56 (s, 1H), 7.73 (s, 1H), 8.85 (s, 1H), 9.49 (s, 1H). —124— Example 25 Compound 25A (5.64 g, 40 mmol) and 2-oxopropanoic acid (3.52 g, 40 mmol) were dissolved in MeOH (4 mL). To this solution, KOH (3.95 g, 60 mmol) in MeOH (10 mL) was added. The mixture was stirred at rt for 5 h. The precipitate was isolated by ﬁltration. Compound 25B (8.5g, yield 85%) was obtained as a yellow solid. LCMS (m/z): 211 [M+1]+.

Acetyl chloride (3.84 mL) was added dropwise to MeOH (23 mL) at 0 °C.

Then Compound 25B (3.98 mg, 16 mmol) was added to the mixture. The e was heated to reﬂux overnight. After evaporation, the mixture was diluted with water, extracted by ethyl acetate and dried over anhydrous Na2S04. After ation to dryness, the residue was recrystallized from EtOH. nd 25C (1 .34 g, yield 37%) was obtained as a yellow solid. LCMS (m/z): 247 [M+l]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.94 (s, 3H), 7.36 (d, J: 16 Hz, 1H), 7.40 (d, J: 8.4 Hz, 2H), 7.57 (d, J: 8.4 Hz, 2H), 7.82 (d, J: 16.4 Hz, 1H).

To the solution of Compound 25C (225 mg, 1 mmol) in CHzClz (5 mL) was added DAST (483.6 mg, 3 mmol) at 0 °C. The mixture was stirred at rt overnight. After evaporation, the residue was purified by silica gel column chromatography (ethyl acetate in petroleum, 5% v/v). Compound 25D was obtained as a yellow solid (150 mg, 60%). LCMS (m/z): 227 [M-19]+.

To the on of compound 25D (86 mg, 0.35 mmol) in MeOH (5 mL) and H20 (1 .5 mL) was added LiOH-HZO (74 mg, 1.75 mmol) at 0 °C. The mixture was stirred for an hour at rt. After evaporation of the t, the residue was diluted with water and the mixture was ed to pH 4 with l M HCl. The resulted mixture was extracted with ethyl acetate and dried over anhydrous Na2S04. After evaporation, nd 25E was obtained as a yellow solid (63 mg, yield 77%). LCMS (m/z): 231 [M-l]'; 1H-NMR(CDC13, 400 MHz) -l25- major characteristic peaks: 5 (ppm) 6.27-6.31 (m, 1H), 7.08 (d, J: 16.4 Hz, 1H), 7.34-7.40 (m, 4H).

To the solution of Compound 25E (63 mg, 0.27 mmol), Intermediate A (75 mg, 0.27 mmol) in DCM (4 mL) was added EDCI (52 mg, 0.27 mmol). The mixture was stirred at rt overnight. After evaporation, the crude was puriﬁed by prep-HPLC to give nd 25 (11 mg, yield 6.7%) as a white solid. LCMS (m/z): 493 [M+l]+; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 2.02 (m, 4H), 2.71-2.85 (m, 2H), 3.09 (m, 2H), 3.60-3.89 (m, 3H), 4.15 (s, 4H), 4.34 (s, 1H), 4.91 (s, 1H), 6.19-6.23 (m, 1H), 6.78- 7.00 (m, 4H), .35 (m, 4H), 8.72 (s, 1H), 11.7 (s, 1H).

Example 26 H H 7 BOG-NV N QTBS N QTBS = E O] O - CI F F g "HZ j —> 0 WW 0 O lntermedlate E.

BOO—NV HZNV N QH N QH WC E CI F F 1 CI F F NH 1 O o O o 263 26 A solution of Compound 11E (100 mg, 0.41 mmol), Intermediate C (222 mg, 0.41 mmol), EDCI (118 mg, 0.62 mmol) and HOBt (84 mg, 0.62 mmol) in DCM (20 mL) was stirred at rt overnight. The mixture was diluted with ethyl acetate (150 mL), washed with water and brine, dried over anhydrous Na2S04, and evaporated to render Compound 26A (200 mg, yield 63%) as a yellow oil, which was used for next step directly. LCMS (m/z): 776 [M+1]+.

A mixture of Compound 26A (200 mg, 0.23 mmol) and Bu4NF (20 mg) in THF (10 mL) was stirred at 25 °C overnight. It was then diluted with ethyl acetate (150 mL), washed with water and brine, dried with anhydrous , evaporated, and puriﬁed by prep-HPLC to yield Compound 26B (103 mg, yield 68%) as colorless oil. LCMS (m/z): 662 A solution of Compound 26B (103 mg, 0.16 mmol) and TFA (0.5 mL) in DCM (5 mL) was stirred at rt for 2 h. The reaction was quenched with saturated aqueous NaHCOg, diluted with ethyl acetate (150 mL), washed with water and brine, dried with anhydrous Na2S04, evaporated, and puriﬁed by prep-HPLC to afford Compound 26 (30 mg, yield 33%) as a white solid. LCMS (m/z): 562 [M+1]+; 1H-NMR(DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.92-2.16 (m, 7H), 3.26-3.60 (m, 6H), .20 (m, 5H), 4.51 (s, 1H), 6.00-6.13 (m, 1H), 6.68-6.84 (m, 3H), 7.51-7.54 (m, 1 H), 7.72 (t, J: 8.4 Hz, 1H), 7.80 (d, J: 17.6 Hz, 1H), 8.15 (br s, 2H).

Example 27 o /— o o ,— CI 0 CI 0/ CI 0 \ _, \ \ o o o OH O F 11c 27A 273 N 9H 0' NH \ 0 ﬂ WW —> o F CI 0 O 27c 27 To a solution of Compound 11C (5 64 mg, 2.24 mmol) in dichloromethane, under an atmosphere of en at —76 °C was added diisobutylaluminium hydride (2.95 ml, 2.95 mmol). The solution was stirred at —76 °C for 45 min, and then allowed to warm to rt. A e of methanol (10 mL, 1/ 1 v/v) was added dropwise. The two layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried, evaporated and puriﬁed on silica gel column (ethyl acetate/PE) to give Compound 27A (153 mg, yield 27%) as a yellow solid. 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.25-1.29 (m, 3H), 4.27-4.35 (m, 2H), 5.29 (s, 1H), 6.72 (s, 1H), 7.248 (d, J: 2.4 Hz, 1H), 7.261-7.269 (d, J: 3.2 Hz, 1H), 7.38-7.40 (d, J: 8.4 Hz, 1H). 7.534-7.538 (d, J: 2.4 Hz, 1H).

To a solution of Compound 27A (184 mg, 0.72 mmol) in DCM (8 mL) was added DAST (380 mg, 2.36 mmol) at 0 °C and the mixture was stirred at rt overnight. It was poured into ice-water, extracted with DCM (2 x 50 mL), washed with brine (1 x 50 mL), dried over Na2S04, and concentrated. The crude product was puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 27B (70 mg, yield 37.9%) as a yellow liquid. 1H-NMR (CDC13, 400 MHz) major characteristic peaks: (ppm) .34 (m, 3H), 4.33-4.37 (m, 2H), 5.85-5.97 (d, J: 47.6 Hz, 1H), 6.89-6.90 (d, J = 4.0 Hz, 1H), 7.30-7.33 (d, J: 8.8 Hz, 1H), 7.43-7.45 (d, J: 8.8 Hz, 1H), 7.583-7.588 (d, J = 2.0 Hz, 1H).

To a solution of Compound 27B (70 mg, 0.273 mmol) in THF (5 mL) was added LiOH (22 mg, 0.52 mmol) in water (2.5 mL) and the mixture was stirred at rt for 4 h. It was trated and adjusted to pH 6 with diluted HCl. Lyophilization of the solution led to Compound 27C (210 mg, crude), which was used for the next step without ﬁarther puriﬁcation. LC-MS (m/z): 227 [M-1]'.

A mixture of Compound 27C (66 mg, 0.29 mmol), EDCI (80.8 mg, 0.42 mmol), HOBt (56 mg, 0.42 mmol), Intermediate A (77.8 mg, 0.28 mmol) in DCM (12 mL) was d at rt overnight. It was d with sat. aq , extracted with DCM (2 x 50 mL), washed with brine (1 x 50 mL), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 27 (15 mg, yield 10.6%) as a white solid. LC- MS (m/z): 489.1 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.03-2.08 (m, 4H), 2.48 (s, 6H), 2.73-3.50 (m, 3H), 3.83-3.90 (m, 2H), 4.16-4.22 (m, 3H), 4.45-4.64 (m, 1H), 4.88-5.08 (m, 1H), 5.72-5.96 (m, 1H), 6.76-6.95 (m, 3H), 7.28-7.38 (m, 1H), 7.49-7.56 (m, 1H),7.75-8.70 (m, 1H), 11.80 (m, 1H).

Example 28 F F o {w H \ —> 4Co a _ —> 28A 28B 28C 28D 2 F F F F 9H W eW e . "or; s s OH o o) 0 FWNH o 28E 28F 28 To 4-ﬂuorothiophenol 28A (1.28 g, 10 mmol) in anhydrous acetone (40 mL), under nitrogen at rt was added potassium carbonate (1.38 g, 10 mmol). To the mixture was slowly added cetaldehyde diethyl acetal (1.69 g, 10 mmol). The reaction mixture was stirred at rt ght. The potassium carbonate was ﬁltered off and washed thoroughly with acetone. The e was then concentrated and the oily residue diluted with H20 and extracted with ethyl acetate. The ethyl acetate extracts were washed with 0.5 M KOH, H20 and brine, dried over anhydrous magnesium sulfate, ﬁltered and concentrated. Puriﬁcation by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) afforded Compound 28B (1.54 g, yield 71%). 1H-NMR (CDClg, 400 MHz) major characteristic peaks: W0 2015/042397 (ppm) 3.05 (d, J: 6.4 Hz, 2H), 3.32 (s, 6H), 4.49 (t, J: 6.4 Hz, 1H), 6.97-7.01 (m, 2H), 7.38-7.42 (m, 2H).

To a 3-neck 100 mL ﬂask was introduced polyphosphoric acid (5 g) and anhydrous chlorobenzene (30 ml). The mixture was stirred under en at reﬂux.

Compound 28B (1.54 g, 7.1 mmol) was then added over 5 min period in 2 mL of chlorobenzene. Within 30 min the reaction mixture turned relatively dark and it was kept under reﬂux for 3 h. The e was cooled down to rt and the chlorobenzene layer decanted. The black tar was suspended in H20 (50 mL) and stirred for about 30 min. The aqueous layer was extracted with CH2C12. The organic extracts were pooled with the chlorobenzene layer, treated with brine, dried over anhydrous magnesium sulfate, ﬁltered and concentrated. Puriﬁcation by column chromatography on silica gel (petroleum ether, 100% v/v) afforded Compound 28C (470 mg, yield 43%). 1H-NMR (MeOD-d4, 400 MHz) major characteristic peaks: 5 (ppm) 7.11-7.16 (m, 1H), 7.34-7.35 (m, 1H), 7.53-7.56 (m, 1H), 7.66- 7.67 (m, 1H), 7.86-7.89 (m, 1H).

Compound 28C (470 mg, 3.1 mmol) was added to THF (10 mL) followed by on of n-BuLi (1.24 mL, 3.1 mmol) at rt. The reaction mixture was d at rt for 60 min. Diethyl oxalate (905 mg, 6.2 mmol) was added to THF (30 mL) -78 CC. To this solution, -ﬂuorobenzo[b]thiophene anion on was added dropwise and the reaction was stirred at -78 0C for 20 min. It was quenched with saturated aqueous NH4C1 (30 mL) and ted with ethyl e (30 mL x 3). The organic extracts were concentrated in vacuum and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give the nd 28D (450 mg, yield 57%) as an orange oil. 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.36 (t, J: 7.2 Hz, 3H), 4.36 (q, J: 7.2 Hz, 2H), 7.25-7.30 (m, 1H), 7.65-7.68 (m, 1H), 7.87-7.91 (m, 1H), 7.77-7.78 (m, 1H), 8.35 (s, 1H).

To a solution of Compound 28D (450 mg, 1.78 mmol) in CH2C12 (10 mL) was added DAST (2.86 g, 17.8 mmol). The reaction mixture was stirred for 10 h before poured into ice-water and extracted with CH2C12 (50 mL x 2). The combined organic layers were dried over Na2S04, ed, and evaporated to give Compound 28E (88 mg, yield 18%). 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.34 (t, J = 7.2 Hz, 3H), 4.40 (q, .1: 7.2 Hz, 2H), 7.26-7.31 (m, 1H), 7.64-7.67 (m, 1H), 7.72 (s, 1H), 7.94-7.98 (m, 1H).

To a solution of Compound 28E (88 mg, 0.32 mmol) in THF (2 mL) was added LiOH-HZO (20 mg, 0.48 mmol), H20 (2 mL) and MeOH (2 mL). The reaction mixture was stirred for 3 hours at 25 °C, and then neutralized with 1 N HCl, It was evaporated to dryness, the resulted residue was ved in H20 and extracted with ethyl acetate. The WO 42397 organic layer was dried over Na2S04, ﬁltered, and ated to give Compound 28F (80 mg, yield 100%). LCMS (m/z): 245 [M-1]'.

To a solution of Compound 28F (80 mg, 0.32 mmol) in DCM (10 mL) was added Intermediate A (88 mg, 0.32 mmol), HOBt (65 mg, 0.48 mmol) and EDCI (92 mg, 0.48mmol). The mixture was stirred overnight at 25 °C, then washed with brine, dried over Na2S04, ﬁltered, evaporated, and puriﬁed by prep-HPLC to give nd 28 (31 mg, yield 19%) as a white solid. LC-MS (m/z): 507 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.11-2.17 (m, 4H), 2.89-3.01 (m, 2H), 3.494-3.51 (m, 2H), 3.79-3.81 (m, 2H), .13 (m, 4H), 4.45-4.47 (m, 1H), 5.08 (s, 1H), 6.72-6.74 (m, 1H), 6.82 (s, 1H), 7.17-7.19 (m, 2H), 7.43-7.46 (m, 1H), 7.73-7.77 (m, 1H), 7.85-7.87 (m, 1H), 7.66-7.68 (m, 1H), 11.94 (br, 1H).

Example 29 V V OMS 9H E J [N] N QH N OH E j _> _> = .

Cbz 0 Cbz’NH j NH2 ] o 0 293 29c . "(II \ 0 CI 0 O To a on of Compound A8 (406 mg, 0.93 mmol) in CH3CN (15 mL) was added 1-cyclopropylpiperazine (350 mg, 2.80 mmol), K2C03 (387 mg, 2.80 mmol) and NaI (100 mg). The mixture was heated at 82 °C for 2 h. It was cooled to rt and ﬁltered. The ﬁltrate was concentrated in vacuum to give a crude product Compound 29B (450 mg, crude) as a yellow oil. LCMS (m/z): 468 [M+1]+.

To a solution of Compound 29B (450 mg, 0.96 mmol) in EtOH/water (10 mL, 9:1, v/v) was added LiOH-HZO (126 mg, 2.88 mmol). After reﬁuxed overnight, water (20 mL) was added to the mixture. It was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to give a crude product nd 29C (350 mg, crude) as a yellow oil. LCMS (m/z): 334 [M+1]+.

To a mixture of Compound 29C (100 mg, 0.30 mmol) in DCM (10 mL) was added EDCI (86 mg, 0.45 mmol), HOBt (61 mg 0.45 mmol) and Intermediate A (88 mg, 0.30 mmol) and stirred at 25 °C for 2 h. Water (10 mL) was added to the mixture, which was then ted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep- HPLC to yield a triﬂuoroacetic acid salt of nd 29 (33 mg, yield 20%) as a white solid. LCMS (m/z): 562 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 0.87 (d, J: 8 Hz, 2H), l.l7(s, 2H), 2.45(s, 1H), 3.28 (d, J: 16 Hz, 1H), .63 (m, 10H), .16(m, 4H), 4.54 (s, 1H), 4.84 (s, 1H), 6.78-6.86 (m, 4H), 7.35(d, J: 8 Hz, 1H), 7.44 (d, J: 8 Hz, 1H), 7.59 (s, 1H), 8.23 (d, J: 8 Hz, 1H).

Example 30 | | F30 F C3 O O a r; I ~OH F3C o 0 \ \ 0 r~ 30A 303 30c 300 W0—» OH o \— F30@NH0 o 30E 30F 30 A mixture of Compound 30A (10 g, 62 mmol), 2-bromo-1,1- dimethoxyethane(l8.2 g, 108 mmol), Cs2C03 (28 g, 86 mmol), NaI (100 mg) in DMF (10 mL) was stirred at 65 °C overnight. It was then cooled to rt and ﬁltered. The e was added water (200 mL), and extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with water (100 mL x 3), brine (100 mL x 1), and dried over Na2S04. Filtration and concentration of the mixture gave rise to Compound 30B (10 g, yield 67%) as a yellow liquid. 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.46 (s, 6H), 4.03- 4.05 (d, J: 5.2 Hz, 2H), 4.72-4.74 (t, J: 4.8 Hz, 1H), 6.98-6.99 (d, J: 8.8 Hz, 2H), 7.53- 7.55 (d, J: 8.8 Hz, 2H).

A solution of polyphosphoric acid (8.1 g, 24 mmol) in toluene (10 mL) was added compound 30B (5 g, 20 mmol) in toluene (10 mL) and the mixture was stirred at 80 °C for 2 h. It was then poured into ice, stirred for 30 min, and extracted with DCM (50 mL x 3).

The combined extracts were washed with brine (50 mL x 1), dried over Na2S04, concentrated, and puriﬁed by column chromatography on silica gel (petroleum, 100% V/V) to afford Compound 30C (690 mg, yield 19%) as a yellow on in petroleum. 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 6.79 (s, 1H), 7.54 (m, 2H), 7.67 (s, 1H), 7.87 @,1H) To a solution of Compound 30C (690 mg, 3.71 mmol) in petroleum ether from last step and anhydrous THF (10 mL) was added n-BuLi (2.5 M in hexane, 1.78 mL) at -78 °C under N2. After stirred for 30 min, to the mixture was added diethyl oxalate (2.7 g, 18.5 mmmﬁmmdeVCmﬂhﬂvmqmmkdmmwtmNHﬂLmMmeﬂmmdml acetate (50 mL x 2). The combined extracts were washed with brine (50 mL x 1), dried over Na2S04, concentrated and recrystallized from MeOH (3 mL) to afford Compound 30D (500 g, yield 47%) as a yellow solid. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.35-1.38 (t, J: 7.2 Hz, 3H), 4.37-4.43 (q, J: 7.6 Hz, 2H), 7.93-8.03 (m, 2H), 8.34 (s, 11D,842-844(nn1}D.

To a solution of Compound 30D (500 mg, 1.75 mmol) in DCM (10 mL) was added DAST (1.41 g, 8.76 mmol) at 0 °C and the mixture was stirred at rt for 1 h. It was poured into ice-water, added sat.NaHC03 (20 mL), and extracted with DCM (50 mL x 2).

The combined extracts were washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was d by column chromatography on silica gel (ethyl acetate in petroleum, 4% v/v) to render Compound 30E (200 mg, yield 62%) as a yellow liquid. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.36-1.39 (t, J = 7.2 Hz, 3H), 4.39-4.45 (q, J: 7.2 Hz, 2H), 7.23 (s, 1H), 7.63-7.68 (m, 2H), 7.96 (s, 1H). 9] To a solution of Compound 30E (170 mg, 0.55 mmol) in EtOH (2 mL) was added LiOH'HzO (28 mg, 0.66 mmol) in water (0.5 mL) and the mixture was stirred at rt mwmgmthwﬂmnmmmmdmﬂm46"ﬂh1NlKlemmemmdwﬁhdMAdedﬂ) mL x 3). The combined extracts were washed with brine (20 mL), dried over Na2S04, and concentrated to give Compound 30F (150 mg, yield 100%) as a yellow solid. LC-MS (m/z): 279 [M-1]'. 0] A e of Compound 30F (60 mg, 0.21 mmol), EDCI (61 mg, 0.31 mmol), HOBt (48 mg, 0.31 mmol), Intermediate A (59 mg, 0.21 mmol) in DCM (5 mL) was stirred at 28 °C overnight before ed with sat. aq NaHCOg. The e was extracted with DCM (50 mL x 2). The combined extracts were washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude t was puriﬁed by PLC to give Compound (5 mg, yield 4%) as a white solid. LC-MS (m/z): 541 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (m, 4H), 2.70-3.02 (m, 2H), 3.49-3.54 (m, 2H), 3.83 (m, 2H), .18 (m, 4H), 4.50 (m, 1H), 5.10 (s,1H), 6.75-6.84 (m, 4H), 7.60- 7.67 (m, 2H), 7.88-7.92 (m, 2H), 11.96 (s, 1H).

Example 3 1 Br Br \0 \0 Br 0 Br OH \ 9 m O/Y0.4 OH o 0 CN 31 A 313 /0 31¢ 31D Br OH Br 0 \ \ / / o o o o W/FO 0 0 O 31E 31F 316 ::N 9H Br F Va 3o \ F O NH 0 OH 0 o F Br 0 A mixture of Compound 31A (3.00 g, 14.93 mmol), 2-bromo-1,1- dimethoxyethane (2.77 g, 16.42 mmol) and K2C03 (4.12 g, 29.86 mmol) in DMF (26 mL) was stirred at 150 °C for 2 h. It was evaporated to remove DMF. The residue was diluted with ethyl acetate (200 mL), washed with water and brine, dried with anhydrous Na2S04, and evaporated to render Compound 31B (3.80 g, yield 88%) as a white solid. 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 4.10 (d, J: 5.2 Hz, 2H), 4.75 (t, J: 5.2 Hz, 1H), 6.89 (d, J: 9.2 Hz, 1H), 7.61-7.64 (m, 1H), 7.93 (s, 1H), 10.42 (s, 1H).

A mixture of nd 31B (2.00 g, 6.90 mmol) in Acetic acid (50 mL) was stirred at 120 °C overnight. The mixture was evaporated to remove Acetic acid, diluted with ethyl acetate (200 mL), washed with water and brine, dried with anhydrous Na2SO4, and evaporated to yield Compound 31C (1.26 g, yield 81%) as a white solid. 1H-NMR(CDC13, 400 MHz) major teristic peaks : 5 (ppm) 7.49-7.52 (m, 2H), 7.60-7.64 (m, 1H), 7.90 (s, 1H), 9.89 (s, 1H).

To a solution of Compound 31C (2.00 g, 8.93 mmol) and NaCN (1.31 g, 26.78 mmol) in MeOH (100 mL) was added Acetic acid (1.61 g, 26.78 mmol). The mixture was stirred at rt overnight. It was then quenched with sat. aq NaHCOg solution diluted with ethyl acetate (200 mL), washed with water and brine, and d by silica gel column chromatography (ethyl acetate in petroleum, 30 % v/v) to e Compound 31D (1.60 g, yield 71 %) as a colorless oil. LCMS: 252 ; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks : 5 (ppm) 6.10 (d, J: 6.8 Hz, 1H), 7.06 (s, 1H), 7.48-7.54 (m, 2H), 7.65 (d, J: 8.8 Hz, 1H), 7.93 (s, 1H).

A solution of Compound 31D (1.00 g, 3.98 mmol) in MeOH (20 mL) was stirred at rt overnight with bubbling of HCl gas. The reaction was quenched with H20 (100 mL) and d at rt for 2 h. It was evaporated to remove MeOH, d with ethyl acetate -l33- (150 mL), washed with water and brine, dried with anhydrous Na2S04, and evaporated to render Compound 31E (900 mg, yield 82%) as a white solid. LCMS: 285 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 3.69 (s, 3H), 5.41 (d, J = 6.4 Hz, 1H), 6.52 (t, J: 6.4 Hz, 1H), 6.90 (s, 1H), 7.43-7.47 (m, 1H), 7.55-7.58 (m, 1H), 7.86 (s, 1H).

A suspension of nd 31E (400 mg, 1.40 mmol) and DMP (712 mg, 1.68 mmol) in DCM (20 mL) was stirred at rt overnight. It was quenched with saturated aq NaZSZOg, diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by silica gel column chromatography eluted with ethyl acetate in petroleum (from 10% to 20%, v/v) to give Compound 31F (180 mg, yield 46%) as a white solid. LCMS: 283 [M+1]+; 1H- NMR (DMSO-d6, 400 MHz) major characteristic peaks : 5 (ppm) 3.92 (s, 3H), 7.77 (m, 2H), 8.19 (d, J: 7.6 Hz, 2H).

To a solution of Compound 31F (500 mg, 1.77 mmol) in DCM (5 mL) was added DAST (1.42 g, 8.85 mmol). The mixture was stirred at rt overnight. The mixture was puriﬁed by column chromatography on silica gel eluted with ethyl acetate in petroleum (10%, v/v) to yield Compound 31G (300 mg, yield 55%) as a white solid. 1H-NMR d6, 400 MHz) major characteristic peaks: 5 (ppm) 3.95 (s, 3H), 7.55 (s, 1H), 7.65 (d, J: 9.2 Hz, 1H), 7.74 (d, J: 9.6 Hz, 1H), 8.01 (s, 1H).

A mixture of Compound 31G (300 mg, 0.98 mmol) and LiOH-HZO (123 mg, 2.94 mmol) in MeOH/HZO (10 mL/2 mL) was stirred at rt for 2 h. The mixture was evaporated to remove MeOH. The residue was adjusted to pH 3 with 1 N HCl and d to afford nd 31H (200 mg, yield 70%) as a white solid. LCMS: 289 [M-l]'.

A solution of Intermediate A (95 mg, 0.34 mmol), Compound 31H (100 mg, 0.34 mmol), EDCI (98 mg, 0.5lmmol) and HOBt (67 mg, 0.51 mmol) in DCM (5 mL) was d at rt overnight. The mixture was diluted with ethyl acetate (150 mL), washed with water and brine, dried with anhydrous Na2S04, and puriﬁed by prep-HPLC to afford nd 31 (100 mg, yield 53%) as a white solid. LCMS: 551 ; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.12 (br s, 4H), 2.89-3.02 (m, 2H), 3.48 (s, 2H), 3.81 (br s, 3H), 4.07-4.19 (m, 4H), 4.45-4.52 (m, 1H), 5.09 (s, 1H), 6.73-6.76 (m, 3H), 6.83 (s, 1H), 7.38 (d, J: 8.8 Hz, 1H), 7.39-7.50 (m, 1H), 7.74 (s, 1H), 7.83 (s, 1H). —134— Example 32 OH (14> N OH 0 0 M80 O , . = _ j _ HKL ] NHz j Cbz o Cbz/NH 0 A8 32A 323 N OH (I? C_)H o O F F F F —> NH 1 + RH \ O \ 0 CI 0 0 CI 0 o 320 320 To a solution of Compound A8 (437 mg, lmmol) in ACN (20 mL) was added azetidine (171 mg, 3 mmol), K2C03 (414 mg, 3 mmol) and NaI (449 mg,3 mmol). The e was heated at 82°C overnight. It was cooled to rt and ﬁltered. The ﬁltration was concentrated in vacuum to give crude product Compound 32A (330 mg, crude) as a yellow oil. LCMS (m/z): 399 [M+1]+.

To a on of Compound 32A (330 mg, 0.83 mmol) in EtOH/water (10 mL, 9:1, v/v) was added LiOH-HZO (104 mg, 2.48 mmol). The mixture was reﬂuxed ght.

After reaction, water (20 mL) was added. It was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and trated in vacuum to give a crude t Compound 32B (170 mg, crude) as a yellow oil. LCMS (m/z): 265 [M+1]+.

To a mixture of Compound 32B (150 mg, 0.57 mmol) in DCM (20 mL) was added EDCI (164 mg, 0.85 mmol), HOBt (115 mg, 0.85 mmol) and Compound 11E (140 mg, 0.57 mmol) and stirred at 25 °C overnight. It was added water (10 mL), extracted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep-HPLC and followed by prep-chiral-HPLC to render triﬂuoroacetic acid salts of Compound 32C (10 mg, yield 3.6%) as a white solid and Compound 32D (5 mg, yield 1.8%) as a white solid. For Compound 32C, LCMS (m/z): 493 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks : 5 (ppm) 2.42 (s, 1H), 2.66(s, 2H), 3.50-3.6l(m, 2H), 4.06-4.14 (m, 6H), 4.23-4.30 (m, 3H), 4.12-4.16 (m, 4H), 4.63 (d, J: 8 Hz ,1H), 6.56 (s, 1H), 6.73 (d, J: 8 Hz, 1H), .85 (m, 3H), 7.37 (d, J: 8 Hz, 1H), 7.45 (d, J: 8 Hz, 1H), 7.61 (s, 1H); For Compound 32D, LCMS (m/z): 493 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.40 (s, 1H), 2.70 (s, 1H), 3.38 (s, 1H), 3.47 (d, J: 8 Hz ,2H), 4.10-4.17 (m, 5H), 4.20-4.30 (m, 3H), 4.89- 4.90 (d, J: 4 Hz ,1H), 6.75 (s, 3H), 6.82 (s, 1H), 7.36 (d, J: 8 Hz, 1H), 7.45 (d, J: 8 Hz, 1H), 7.60 (s, 1H). e 33 N OH Q V160 + Fm:F 0 H2Nwe: # O elm 0 mmF F 33A 33 To a solution of Intermediate B (300 mg, 1 mmol) in DCM (15 mL) was added EDCI (288 mg, 1.5 mmol), HOBt (200 mg, 1.5 mmol), and Compound 11E (247 mg, 1 mmol). It was stirred at rt overnight. The mixture was added DCM (20 mL), washed with water (50 mL x 2), brine (50 mL x 1), and dried over anhydrous Na2S04. The residue was puriﬁed by prep-HPLC, followed by prep-chiral-HPLC to give nd 33A (70 mg, yield 13%) as a white foam and Compound 33 (65 mg, yield 12%) as a white foam. For Compound 33A, LC-MS (m/z): 525 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.09 (s, 4H), 2.87 (d, J: 39.6 Hz, 2H), 3.34 (s, 1H), 3.81 (s, 3H), 4.11 (m, 4H), 4.60 (s, 1H), 5.12 (s, 1H), 6.45 (d,.]= 10.8 Hz, 1H), 6.91 (m, 2H), 7.32 (m, 1H), 7.41 (d,.]= 8.8 Hz, 1H), 7.57 (d, J: 2.4 Hz, 1H), 8.49 (d, J: 6.8 Hz, 1H), 10.65 (s, 1H). For Compound 33, LC-MS (m/z): 525 ; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.09 (s, 4H), 2.84 (d, J: 44 Hz, 2H), 3.29 (d, J: 10.8 Hz, 1H), 3.73 (m, 3H), 4.12 (m, 4H), 4.58 (s, 1H), 5.14 (d, J: 5.2 Hz, 1H), 6.47 (d, J: 10.8 Hz, 1H), 6.94 (m, 2H), 7.32 (m, 1H), 7.42 (d, J: 8.8 Hz, 1H), 7.58 (d, J: 1.6 Hz, 1H), 8.60 (d, J: 8 Hz, 1H), 11.06 (s, 1H).

Example 34 O OH TBSO¢N’O\| _,TBso _,TBso \ 4 _, KJHCbz CszN§ CbZHN A4 34B HO \ /\/§\©\/j : \ Cb HN / Z Cb HNZ N CszN N/ 340 34E /\—/\ OH ::N 9H N OH \ \ m F F : + F F \ N/ \ N/ NH2 N/ CI 0 0 CI 0 o 34F 34G 34 To a solution of 6-bromoquinoline (7.9 g, 38 mmol) in THF (200 mL) was added n-BuLi (15 mL) at -60 °C under N2 and after stirred for 0.5 h, nd A4 (5 g, 13 mmol) in THF (10 mL) was added slowly. The reaction mixture was maintained at this temperature with stirring for 1 h, and then added saturate aq NH4Cl, extracted with ethyl e (100 mL x 2), brine (100 mL), and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl e in petroleum, 10% V/V) to give nd 34A (4.4 g, yield 75%) as a colorless liquid. LC-MS (m/z): 465 [M+1]+; 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) , 3H), 0.04 (s, 3H), 0.89 (s, 9H), 4.22 (m, 2H), 5.33 (s, 2H), 5.40 (s, 1H), 7.55 (m, 5H), 8.37 (m, 4H), 8.66 (s, 1H), 9.20 (m, Compound 34A (4.4 g, 9.5 mmol) was dissolved in THF (60 mL) and cooled down -80 °C under nitrogen atmosphere. L-Selectride (20 mL of 1M solution in THF, 18.9 mmol) was added dropwise while keeping the temperature at -80 °C. After an hour, the reaction was quenched with saturate aq NH4Cl solution and the mixture was extracted with ethyl acetate (50mL x 2), washed with brine (100 mL), and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, % v/v) to render Compound 34B (3 g, yield 68%) as a colorless liquid. LC-MS (m/z): 466 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 .03 (m, 6H), 0.92(m, 9H), 4.10 (m, 3H), 4.96(m, 1H), 5.12 (s, 1H), 7.20 (s, 1H), 7.35 (m, 2H), 7.41 (m, 1H), 7.62 (m, 1H), 7.88 (m, 1H), 8.18 (m, 2H), 8.91 (s, 1H).

Compound 34B (3 g, 6.4 mmol) was dissolved in THF (50 mL) at 0 °C, to this solution was added TBAF (839 mg, 3.2 mmol) at 0 °C. The mixture was stirred at rt overnight. It was condensed by evaporation of solvent, added water (50 mL), and extracted with ethyl e (50 mL x 2), washed with brine (100 mL), dried over Na2S04, and concentrated. The residue was suspended in a mixture of ethyl acetate in petroleum (10% V/V). Filtration gave Compound 34C (1.7 g, yield 75%) as a white solid. LC-MS (m/z): 466 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm)3.72 (m, 3H), 4.89 (m, 4H), 5.63 (m, 1H), 6.80 (m, 1H), 7.15 (m, 5H), 7.52 (m, 1H),7.74 (m, 1H), 7.89 (s, 1H), 793(nL11D,832(nn1}D,887(s,H{) Compound 34C (1 g, 2.8 mmol) was ved in THF (20 mL), to the mixture was added TEA (860 mg, 8.5 mmol). The mixture was cooled to -15 °C, to the mixture was lG60nggilmmmDsbwb;$hmdaHMsmmpmmmeﬁn30mnnmemnhne was diluted with water, extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL), WO 42397 dried over Na2S04, and concentrated to yield Compound 34D (1.2 g, crude) which was used for the next step without further puriﬁcation. LC-MS (m/z): 431 .

To a solution of Compound 34D (1.2 g, 2.8 mmol) in THF (20 mL) was added pyrrolidine (2 g, 28mmol). The reaction mixture was allowed to warm up to rt and then hwmdmﬂVCowmQMJhmmhmmmawwpmmmﬂwammmCMmeg@MMm silica gel (methanol in dichloromethane, 5% v/v) to give 34E (1 g, yield 91%). LC-MS (m/z): 406 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.88 (m, 4H), 2770;2PD,286(nL4PD,363(nu11D,415(nn11D,494(&11D,504(&11D,715(& 11D,724(nn4}D,739(nL11D,768(nn11D,785(nn11D,808(nL2PD,890(nL11D.

To a solution of nd 34E (1 g, 2.5 mmol) in methanol (20 mL) was added Pd(OH)2 (100 mg) and the mixture was stirred at rt under H2 overnight. Filtration and evaporation of the mixture gave Compound 34F (400 mg, yield 60%). LC-MS (m/z): 272 [M+1]+.

A mixture of Compound 11E (182 mg, 0.74 mmol), EDCI (212 mg, 1.1 mmol), HOBt (150 mg, 1.1 mmol), Compound 34F (200 mg, 0.74 mmol) in DCM (20 mL) was stirred at rt overnight. After added water, the mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC and followed by chiral-prep-HPLC to give Compound 34G (46 mg, yield 13%) as a white solid and Compound 34 (58 mg, yield 16%) as a white solid. For Compound 34G, LC-MS (m/z): 500 [M+1]+. 1H-NMR(CDC13, 400 MHz) major teristic peaks: 5 (ppm) 2.08 (s, 4H), 2.90 (m, 2H), 3.52 (m, 1H), 3.64 (m, 2H), 3.94 (t, J: 16.8 Hz, 1H), 4.71 (m, 2H), 5.14 (d, J: 7.2 Hz, 1H), 6.79 (s, 1H), 7.20 (m, 1H), 7.23 (s, 1H), 7.38 (s, 1H), 7.66 (m, 1H), 8.06 (m, 2H), 8.22 (d, J: 8.8 Hz, 1H), 8.52 (d, J: 8.4 Hz, 1H), 8.88 (d, J: 4.0 Hz, 1H), 9.43 (d, J: 8.4 Hz, 1H),11.56(s, 1H); For nd 34, LC- MS (m/z): 500 [M+1]+. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.16 (s, 2H), 3.05 (s, 2H), 3.74 (s, 3H), 4.32 (s, 4H), 4.81 (s, 1H), 5.43 (s, 1H), 6.70 (s, 1H), 7.17 (m, 1H), 7.24 (m, 1H), 7.34 (m, 1H), 7.66 (m, 1H), 7.90 (d, J: 8.8 Hz, 1H), 8.05 (s, 1H), 8.23 (m, 1H), 8.45 (d, J: 8.4 Hz, 1H), 8.96 (d, J: 4.4 Hz, 1H), 11.80 (s, 1H).

Example 35 F F F F OH Br: OH Br: OH M8U11 U m: UHN‘Cbz o Cbz’NH 0 U101KW 0 A8 35A 353 FF FF Br: OH is 9H 0 o NH NH —. \ 0 \ 0 CI 0 0 CI 0 o 350 35 0] To a solution of Compound A8 (847 mg, 2 mmol) in ACN (20 mL) was added 4,4-diﬂuoropiperidine (628 mg, 4 mmol), K2C03 (414 mg, 3 mmol) and NaI (449 mg,3 mmol). The mixture was heated at 82 °C overnight. It was cooled to rt, d and added ethyl acetate (30 mL). It was washed with brine, dried over ous Na2S04 and concentrated in vacuum to give a crude product Compound 35A (900 mg, crude) as a colorless solid. LCMS (m/z): 463 [M+l]+.

To a solution of Compound 35A (100 mg, 0.22 mmol) in EtOH/water (10 mL, 9:1, v/v) was added LiOH-HZO (28 mg, 0.66 mmol). The mixture was reﬂuxed ght, cooled down to rt, and added water (20 mL). It was extracted with ethyl acetate (20 mL x 3).

The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to give crude t Compound 35B (70 mg, crude) as a yellow oil. LCMS (m/z): 329 [M+1]+.

To a mixture of Compound 35B (70 mg, 0.20 mmol) in DCM (10 mL) was added EDCI (57 mg, 0.30 mmol), HOBt (40 mg, 0.30 mmol) and Compound 11E (49 mg, 0.2 mmol) and stirred at 25 °C overnight. It was diluted with water (10 mL), extracted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by chiral-prep-HPLC to give Compound 35C (6.5 mg, yield 4.5%) as a white solid and Compound 35 (16.5 mg, yield 11.5%) as a white solid. For Compound 35C, LCMS (m/z): 557 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks : 5 (ppm) 2.32 (s, 4H), 3.16 (dd, J = 4,12 Hz, 2H), 3.81 (t, J: 12 Hz, 1H), 4.14-4.20 (m, 5H), 4.55 (s, 1H), 4.89 (d, J: 4 Hz ,1H), 6.77-6.84 (m, 2H), 6.89 (d, J: 8 Hz, 2H), 7.32-7.37 (m,1H), 7.42 (d, J: 8 Hz, 1H), 7.60 (s, 1H), 8.93 (d, J: 8 Hz, 1H); For Compound 35, LCMS (m/z): 557 [M+1] +; 1H NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.38 (s, 4H), 3.33 (dd, J: 4, 12 Hz, 2H), 3.52-3.58 (m, 2H), 4.07-4.21 (m, 5H), 4.56 (s, 1H), 4.98 (s, 1H), 6.75 (s, 2H), 6.82 (s, 2H), 7.35 (d, J: 8 Hz, 1H),7.43 (d, J: 8 Hz, 1H), 7.59 (s, 1H),7.94 (d, J: 8 Hz, 1H).

%)Example 36 moms/Dig: :xm3wet/0:1I To a solution of 3,3-dimethylpyrrolidine (645 mg, 4.79 mmol) in THF (15 mL) was added Compound A8 (520 mg, 1.19 mmol) and TEA (1 mL). The reaction mixture was stirred at 85 °C overnight. The solvents were removed and the residue was puriﬁed by PLC to afford the Compound 36A (110 mg, yield 21%). LCMS: 441 [M+1]+.

To a solution of Compound 36A (110 mg, 0.25 mmol) in MeOH (5 mL) was added Pd(OH)2 (15 mg). The reaction mixture was stirred at rt overnight, then ﬁltered and evaporated to give Compound 36B (80 mg, yield 100 %). LCMS: 307 [M+1]+.

] A on of Compound 36B (80 mg, 0.26 mmol), Compound 11E (64.5 mg, 0.26 mmol), HOBT (53 mg, 0.39 mmol), EDCI (75 mg, 0.39 mmol) in DCM (10 mL) was stirred at rt overnight. After added water (50 mL), the mixture was extracted with DCM (50 mL x 2). The ed organic phases were dried over Na2S04, f11tered, evaporated, and puriﬁed by chiral-prep-HPLC to give nd 36C (13.8 mg, yield 10%) as a white solid and Compound 36D (10.4 mg, yield 7.5%) as a white solid. For Compound 36C, LCMS (m/z): 535 ; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.09- 1.31 (m, 6H), 1.84-1.94 (d, J: 20 Hz, 2H), 2.46-2.52 (m, 1H), 2.90-3.01 (m, 1H), 3.13-3.27 (m, 2H), 3.55-3.96 (m, 2H), 4.16-4.19 (m, 4H), 4.43 (s, 1H), 4.90 (s, 1H), 6.76-6.78 (m, 1H), 6.82-6.91 (m, 3H), 7.31-7.34 (m, 1H), 7.42-7.44 (m, 1H), 7.58-7.59 (m, 1H), 9.07-9.38 (m, 1H), 11.85 (s, 1H); For Compound 36D, LCMS (m/z): 535 [M+1]+; 1H NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.19-1.24 (m, 6H), 1.90-2.00 (d, J = 20 Hz, 2H), —140— 2.65-2.83 (m, 1H), 3.07—3.09 (m, 1H), 3.42 (s, 1H), 3.54 (s, 2H), 3.88 (s, 1H), .20 (m, 4H), 4.44 (s, 08-5.12(m, 1H), 6.72-6.75 (m, 3H), 6.83 (s, 1H), 7.32—7.35 (m, 1H), 7.40—7.43 (m, 1H), 7.57-7.58 (m, 1H), 7.70-7.988 (m, 1H), 11.78-12.01 (m, 1H).

Example 37 OH OH OCF3—> NCbz CszN OCF3 OCF3 37A 37B 37c OH ::N OH N OH CszN = — 00F3 Cb HNZ HN2 OCF3 OCF3 37E 37F ::N OH N 9H ZII H NH \ OCF3 \ 00F3 CI 0 0 CI 0 O 376 37 To a solution of Compound 37A (2 g, 8.3 mmol) in THF (30 mL) was added n-BuLi (4 mL, 2.5 M) under N2 at -60 °C. The mixture was stirred for l h, Compound 8C (2.2 g, 8.3 mmol) in THF (10 mL) was added. Stirred at rt for 15 min, the mixture was diluted with aq NH4Cl (40 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (100 mL x 2), and evaporated to dryness. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to give Compound 37B (1.4 g, yield 40%) as ess oil. LC-MS (m/z): 426 [M+l]+.

A solution of Compound 37B (1 g, 2.4 mmol) in THF (10 mL) and l N aq HCl (5 mL) was stirred at rt for 5 h. The mixture was quenched with water (10 mL), extracted with ethyl acetate (20 mL x 2), washed with brine (30 mL x 2), and evaporated to dryness.

The crude t was puriﬁed by column chromatography silica gel (ethyl acetate in petroleum ether, 50% v/v) to afford nd 37C (693 mg, yield 75%) as colorless oil.

LC-MS (m/z): 386 [M+1]+.

To a solution of Compound 37C (0.5 g, 1.3 mmol) in THF (10 mL) was added triethylamine (0.26 g, 2.6 mmol) and MsCl (164 mg, 1.4 mmol) under N2 at -40 °C. The mixture was stirred at this temperature for 3 h, quenched with water (20 mL), ted with ethyl acetate (30 mL x 2), washed with brine (50 mL x 2), and evaporated to dryness. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in —141— petroleum ether, 50% v/v) to yield Compound 37D (0.42 g, yield 70%) as colorless oil. LC- MS (m/z): 464 [M-17]+.

To a solution of Compound 37D (0.4 g, 0.86 mmol) in THF (10 mL) was added pyrrolidine (0.61 g, 8.6 mmol). The e was d at 60 °C overnight, quenched with water (20 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (100 mL x 2), and evaporated to dryness. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to give Compound 37E (0.2 g, yield 53%) as a colorless oil. LC-MS (m/z): 439 [M+l]+.

A solution of Compound 37E (0.2 g, 0.46 mmol) and LiOH-HZO (57 mg, 1.4 mmol) in ethanol (10 mL) was heated to reﬂux overnight. The mixture was quenched with water (10 mL), ted with ethyl acetate (20 mL x 3), washed with brine (50 mL x 2), and evaporated to dryness to give Compound 37F (126 mg, yield 90%) as a colorless oil. LC-MS (m/z): 305 [M+1]+.

To a solution of Compound 37F (01 g, 0.33 mmol) in dichloromethane (10 mL) was added Compound 11E (81 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol). The mixture was stirred at rt overnight, quenched with water (20 mL), ted with dichloromethane (20 mL x 2), washed with brine (50 mL x 2), and evaporated to dryness. The crude product was puriﬁed by prep-HPLC and followed Chiral-HPLC to give two isomers Compound 37G (ll mg) as a white solid and Compound 37 (6 mg) as a white solid. For nd 37G, LC-MS (m/z): 533 [M+l]+; 1H-NMR (DMSO-dg, 400 MHz) major characteristic peaks: 5 (ppm) 1.88 (m, 4H), 3.11 (m, 2H), 3.52 (m, 4H), 4.31 (m, 1H), 4.60 (m, 1H), 6.22 (s, 1H), 6.84 (s, 1H), 7.12 (m, 2H), 7.38 (m, 2H),7.52 (m, 1H), 7.67 (m, 1H), 7.78 (m, 1H), 9.28 (m, 1H), 9.82 (s, 1H). For Compound 37, LC-MS (m/z): 533 [M+l]+; 1H-NMR (DMSO-dg, 400 MHz) major teristic peaks: 5 (ppm) 1.87 (m, 4H), 3.10 (m, 2H), 3.50 (m, 4H), 4.51 (m, 1H), 4.89 (m, 1H), 6.11 (s, 1H), 7.05 (m, 3H), 7.39 (m, 2H), 7.54 (m, 73 (m, 1H), 7.82 (m, 1H), 8.94 (m, 1H), 9.63 (s, 1H).

Example 38 F F F CszNII-w b 21 U .....OH N 9H N 9H N 9H E = - O O O 1—. j —> F F —> 5 E EIH j NHCbz o NH2 0 \ o O 0 CI 0 0 A8 38A 383 38 —142— To a solution of ﬂuoropyrrolidine (650 mg, 5.2 mmol) in CH3CN (50 mL) was added N32C03 (717 mg, 5.2 mmol) and it was stirred at rt for 30 min. Compound A6 (756 mg, 1.73 mmol) was added and the reaction e was heated to reﬂux overnight.

It was poured into ice-water, extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL x 1), dried over Na2S04, and evaporated to dryness. The crude product was puriﬁed by prep-HPLC to afford the Compound 38A (270 mg, yield 36%) as a yellow liquid. LCMS: 431 [M+1]+.

To a solution of Compound 38A (170 mg, 0.55 mmol) in EtOH (2 mL) was added LiOH-HZO (79 mg, 1.89 mmol) in water (1 mL) and the mixture was stirred at reﬂux overnight. It was ed with H20 (50 mL), extracted by ethyl acetate (50 mL x 3), washed with brine (20 mL), dried over Na2S04, and ated to dryness to give Compound 38B (200 mg, 100%) as a yellow oil. LC-MS (m/z): 297 [M+1]'.

A mixture of Compound 11E (165 mg, 0.67 mmol), EDCI'HCl (192 mg, 0.99 mmol), HOBt (135 mg, 0.99 mmol), Compound 38B (200 mg, 0.67 mmol) in DCM (10 mL) was stirred at 28 °C overnight. The reaction was quenched with sat. aq NaHCOg (100 mL).

The mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over , and evaporated to dryness. The crude product was puriﬁed by prep-HPLC to give Compound 38 (100 mg, yield 28%) as a white solid. LC-MS (m/z): 525 [M+1]+; 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.04-2.49 (m, 2H), 3.21-3.97 (m, 6H), 4.06-4.20 (m, 4H), 4.52 (s, 1H), 5.04 (s, 1H), 5.32-5.45 (d, J: 52.4 Hz, 1H), 6.70- 6.83 (m, 4H), 7.33-7.44 (m, 2H), 7.58 (s, 1H), 7.74-7.76 (d, J: 7.6 Hz, 1H).

Example 39 OMS OH mjﬁ W114 Mg To a solution of nd A8 (514 mg, 1.16 mmol) in THF (15 mL) was added (R)methylpyrrolidine (400 mg, 4.7 mmol) and Eth (0.5 mL). The reaction mixture —143— WO 42397 was stirred at 85 °C overnight. After the removal of solvents, the residue was puriﬁed by prep-HPLC to afford the Compound 39A (150 mg, yield 30%) as a white solid. LCMS: 427 To a solution of Compound 39A (150 mg, 0.35 mmol) in MeOH (5 mL) was added Pd(OH)2 (15 mg). The reaction mixture was stirred in the presence of H2 at rt overnight. Filtration and evaporation of the on led to Compound 39B (102 mg, yield 100%) as the ess oil. LCMS: 293 [M+l]+.

A solution of Compound 39B (102 mg, 0.35 mmol), Compound 11E (86.3 mg, 0.35 mmol), HOBt (71.4 mg, 0.52 mmol), EDCI (100 mg, 0.52 mmol) in DCM (10 mL) was stirred at rt overnight. It was added water (50 mL), extracted with DCM (50 mL x 2), dried over Na2S04, ﬁltered, and evaporated to dryness. The residue was puriﬁed by prep- HPLC to give d product Compound 39 (8.7 mg, yield 5%) as the colorless oil. LCMS (m/z): 521 [M+l]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.25- 1.49 (m, 3H), 1.97-2.11 (m, 2H), .26 (m, 2H), 2.96-3.19 (m, 3H), .80 (m, 1H), 4.01 (s, 1H), 4.04-4.19 (m, 4H), 4.46 (s, 1H), 5.23 (s, 1H), 6.64 (s, lH),6.69-6.79 (m, 2H), 6.84 (s, 1H), 7.31-7.35 (m, 1H), 7.40-7.43 (m, 1H), 7.53-7.57 (m, 2H), 11.48 (s, 1H).

Example 40 OMS OH leu- m3* "(1] _. m: To a solution of (S)methylpyrrolidine hydrochloride (540 mg, 4.4 mmol) in CH3CN (10 mL) was added N32C03 (600 mg, 4.4 mmol). Stirred at rt for 30 min, Compound A8 (437 mg, 1 mmol) was added. The reaction mixture was stirred at reﬂux overnight. It was poured into ice-water, extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL x 1), dried over Na2S04, and concentrated to afford the mixture of Compound 40A (300 mg) as a yellow oil. LCMS: 427 [M+l]+. —144— To a on of Compound 40A (300 mg) in EtOH (10 mL) was added LiOH-HZO (197 mg, 4.7 mmol) in water (5 mL) and the mixture was stirred reﬂux overnight.

It was quenched in H20 (50 mL) and the mixture was extracted by ethyl acetate (50 mL x 3), washed with brine (20 mL), dried over Na2S04, and concentrated to render Compound 40B (326 mg, yield 100%) as a yellow oil. LC-MS (m/z): 293 [M+1]+.

A mixture of Compound 40B (326 mg, 1.12 mmol), EDCI-HCl (233 mg, 1.66 mmol), HOBt (164 mg, 1.66 mmol), Compound 11E (200 mg, 1.12 mmol) in DCM (10 mL) was d at 28 °C overnight. After quenched with sat. aq NaHCOg (100 mL), the mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 40 (126 mg, yield 18%) as a white solid. LC-MS (m/z): 525 [M+1]+; 1H-NMR d6, 400 MHz) major charactertic peaks: 5 (ppm) 1.31-1.33 (d, J: 6.4 Hz, 3H), 1.59-1.65 (m, 1H), 1.90-2.00 (m, 2H), 2.16-2.2l(m, 1H), 3.21-3.26 (m, 1H), 3.42-3.61 (m, 4H), 4.06-4.16 (m, 4H), 4.45- 4.47 (m, 1H), 4.66-4.67 (m, 1H), 5.91 (s, 1H), 6.62-6.77 (m, 3H), 7.01 (s, 1H), 7.52-7.55 (m, 1H), 7.75-7.77 (d, J: 8.8 Hz, 1H), 7.83-7.85 (m, 1H), 8.92-8.99 (m, 2H).

Example 41 F F F, F OMS 9H N 9H N 9H = ' 0 o 0 CszN 3 CszN ] H2N j o o 0 A8 41A F F To a solution of ﬂuoropyrrolidine (384 mg, 3mmol) in CH3CN (20 mL) was added Compound A8 (437 mg, 1 mmol), K2C03 (414 mg, 3 mmol) and NaI (449 mg, 3 mmol). The mixture was heated at 82 °C overnight. It was cooled to rt, ﬁltered and concentrated in vacuum to give a crude t Compound 41A (250 mg, crude) as a yellow oil. LCMS (m/z): 449 [M+1]+.

To a solution of Compound 41A (200 mg, 0.45 mmol) in EtOH/water (10 mL, 9:1, v/v) was added LiOH-HZO (93.6 mg, 2.23 mmol). The mixture was d overnight. —145— The mixture was diluted with water (20 mL) and then ted with ethyl acetate (20 mL x 3), dried over anhydrous Na2S04, and concentrated in vacuum to give a crude Compound 4113 (170 mg, crude) as a yellow oil. LCMS (m/z): 315 [M+1]+.

To a mixture of Compound 41B (150 mg, 0.47 mmol) in DCM (20 mL) was added EDCI (164 mg, 0.85 mmol), HOBt (115 mg 0.85 mmol) and Compound 11E (140 mg, 0.57 mmol) and stirred at 25 °C overnight. After the addition of water (10 mL), the mixture was ted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep-HPLC to afford nd 41 (40 mg) as a white solid. LCMS (m/z): 543 [M+1]+; 1H- NMR (CDClg, 400 MHz) major characteristic peaks : 5 (ppm) 2.59 (s, 2H), 3.44(s, 1H), 3.60- , 4H), 4.07-4.15 (m, 4H), 4.46 (s, 1H), 4.99 (s, 1H), 6.73-6.80 (m, 4H), 7.32-7.35 (m, 1H), 7.40-7.43 (d, 1H), 7.57 (d, 1H), 7.78 (s, 1H).

Example 42 TBSO TBSO _. 50bZHN‘ ] CbZHN NHCbz O NHCbz UASO 42A " :1PU:{@9311 Compound A5 (4.64 g, 9.85 mmol) was dissolved in anhydrous THF (100 mL) and cooled down -30 °C under nitrogen atmosphere. CHgMgBr (9.85 mL, 3M solution in ether, 29.55 mmol) was added dropwise while keeping the ature at -30 °C. Then the reaction was warmed to rt and stirred for 3 hrs. The reaction was quenched with saturate aq NH4Cl solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed water, brine, and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl e in petroleum, 10% v/v) to give Compound 42A (3.76g, yield 78%) as a white solid. LC-MS (m/z): 193 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) -0.09 (s, 3H), -0.05 (s, 3H), 0.84 (s, 9H), 1.42 (s, 3H), 3.51 (dd, J: 2.0, 10.4 Hz, 1H), 3.53 (dd, J: 2.0, 10.4 Hz, 1H), 3.91 (d, J: 7.2 Hz, 1H), 3.71 (m, 1H), 4.26 (s, 4H), 4.45 (m, 1H), 5.16 (s, 2H), 5.72 (d, J: 7.2 Hz, 1H), 6.85 (m, 2H), 6.95 (s, 1H), 7.38 (m, 5H).

To a solution of Compound 42A (5.9 g, 12.11 mmol) in THF (120 mL) was added a solution of TBAF (1.58 g, 6.06 mmol) in THF (10 mL) at 0 °C and the mixture was WO 42397 d at 25 °C overnight. The mixture was condensed by removal of solvent and added water (50 mL). It was ted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 1), dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (methanol in dichloromethane, 3% v/v) to give Compound 42B (3.2 g, yield 71%) as a yellow oil. LC-MS (m/z): 356 [M-17]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.49 (s, 3H), 3.34 (s, 1H), 3.58 (m, 2H), 3.91 (d, J: 8.8 Hz, 1H), 4.25 (s, 4H), 5.15 (s, 2H), 5.79 (d, J: 8.8 Hz, 1H), 6.85 (m, 2H), 6.96 (s, 1H), 7.38 (m, 5H).

To a solution of Compound 42B (3.2 g, 8.58 mmol) in THF (80 mL) was added Eth (2.6 g, 25.7 mmol) and the mixture was cooled to -40 °C, MsCl (0.7 mL, 9.01 mmol ) was added slowly and kept with stirring at -40 °C about 0.5 h. Pyrrolidine (5.48 g, 77.2 mmol) was added to -40 °C. The reaction e was allowed to warm up to rt and then heated to 50 °C overnight. The mixture was added water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 1), and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (methanol in dichloromethane, 3% v/v) to give Compound 42C (2.52 g, yield 77%) as a white syrup. LC-MS (m/z): 356 [M-17]+; 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.40 (s, 3H), 1.69 (m, 4H), 2.35 (m, 1H), 2.57 (m, 1H), 4.16 (m, 1H), 4.27 (s, 4H), 5.15 (s, 2H), 5.59 (d, J: 10.2 Hz, 1H), 6.86 (m, 2H), 6.98 (s, 1H), 7.38 (m, 5H).

To a solution of Compound 42C (2.52 g, 5.92 mmol) in methanol (60 mL) was added Pd(OH)2 (250 mg) and then the mixture was stirred at 25 °C under H2 overnight. It was ﬁltered and evaporated to render Compound 42D (1.82 g, crude). LC-MS (m/z): 356 [M- 171+. 8] To a solution of compound 42D (200 mg, 0.68 mmol) and Compound 11E (168 mg, 0.68 mmol) in DCM (210 mL) was added EDCI (197 mg, 1.03 mmol) and HOBt (139 mg, 1.03 mmol) under N2. The e was stirred at 25 °C overnight. When TLC showed the starting material was consumed, water was added to the mixture. It was then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give a crude product. The crude product was puriﬁed by prep-HPLC to give Compound 42 (145 mg, yield 41%) as a white solid. LC-MS (m/z): 521 (M+1)+; 1H-NMR(CDC13, 400 MHz) major teristic peaks: 5 (ppm) 1.52 (s, 3H), 1.99-2.06 (m, 4H), 2.60-2.74 (m, 4H), 3.60-3.69 (m, 2H), 3.88 (t, J: 7.2 Hz, 1H), 4.03 (m, 2H), 4.27 (s, 4H), 4.61 (t, J: 7.2 Hz, 1H), 6.86 (d, J: 8.4 Hz, 1H), 6.93 (d, J: 8.4 Hz, 1H), 7.03 (s, 1H), 7.15 (s, 1H), 7.34 (d, J: 8.4 Hz, 1H), 7.44 (d, J: 8.4 Hz, 1H), 7.62 (s, 1H), 9.19 (d, J: 8.4 Hz, 1H), 11.20 (s, 1H). —147— Example 43 NH Qo To a stirred solution of Compound 43A (100 mg, 0.2 mmol), NaHC03 (33 mg, 0.4 mmol) and NMP (126 mg, 0.3 mmol) in DCM (5 mL) was stirred at rt for 2h. The re was diluted with saturation aq NaH803 (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with saturate aq NaH803(15 mL), brine (15 mL), dried over NaZSO4, and concentrated to give a crude product. The crude product was puriﬁed by prep-HPLC to afford Compound 43 (17 mg, yield 14%) as a white solid. LC-MS (m/z): 505 [M+1]+; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (s, 4H), 2.95-2.96 (m, 2H), 3.58-3.61 (m, 2H), 3.89-3.99 (m, 2H), 4.06-4.23 (m, 4H), 5.47 (s, 1H), 6.70-6.72 (d, J: 9 Hz, 2H), 6.86 (s, 1H), 7.30-7.33 (m, 4H), 7.54 (s, 1H), 9.66-9.68 (d, J = 8 Hz, 1H). e 44 U0 _. TBSO —> CszKi o/A _. CszN o/A 44A 44B 44C OH OH QOH CI _. CI CI _ _.

HO MsO Cszﬁ 0A Cszrxig 0A S.

CszN 0A 44D 44E 44F 0 QOH Q9H N OH + CI F F F F _ : 3H A \ mO/A \ moﬁ CI 0 0 CI CI 0 0 CI 44G 44H 44 To a solution of Compound 44A (3.73 g, 15.1 mmol) in THF (200 mL) was added n-BuLi (6.1 mL) at -60 °C under N2 and it was stirred for 0.5 h, and then added slowly Compound A4 (2 g, 5.06 mmol) in THF (10 mL). The mixture was stirred at -60 °C for 1 h.

After the addition of saturate aq NH4Cl solution, the e was extracted with ethyl acetate 2014/056555 (100 mL x 2), brine (100 mL), and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to yield Compound 44B (1.2 g, yield 47%) as a colorless oil. LC-MS (m/z): 504.2 [M+1]+. 1] Compound 44B (714 mg, 1.42 mmol) was dissolved in THF (9 mL) and cooled down -80 °C under en here. L-Selectride (3 mL of 1M solution in THF, 18.9 mmol) was added dropwise while keeping the temperature at -80 °C. After an hour, the reaction was quenched with saturate aq NH4C1 on and extracted with ethyl acetate (50mL x 2), washed with brine (100 mL), and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (10% ethyl acetate in petroleum) to give Compound 44C (350 g, yield 49%) as a colorless oil. LC-MS (m/z): 488.2 [M-17]+.

A solution of Compound 44C (2.08 g, 4.11 mmol) in THF (40 mL) was added TBAF (537 mg, 2.06 mol) at 0 °C and the mixture was stirred at rt overnight. The mixture was condensed and then added water (50 mL). It was extracted with ethyl acetate (50 mL x 2), washed with brine (100 mL), dried over Na2S04, and concentrated. The residue was suspended in a mixture solution of ethyl acetate in petroleum (10% v/v). Filtration gave Compound 44D (1 g, yield 65%) as a white solid. LC-MS (m/z): 374.1 [M+1]+.

A solution of Compound 44D (0.9 g, 2.3 mmol) in THF (60 mL) was added Eth (700 mg, 6.9 mmol) and the mixture was cooled to -15 °C, to the mixture was added MsCl (467 mg, 4.1 mmol) slowly. The mixture was stirred at -15 °C about half an hour, and then diluted water. It was extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL), dried over , and concentrated to give Compound 44E (1 . 12 g, crude), which was used for the next step without ﬁarther puriﬁcation. LC-MS (m/z): 452.1 .

To a solution of Compound 44E (1.12 g, 2.83mmol) in THF (60 mL) was added pyrrolidine (2 g, ). The reaction mixture was allowed to warm up to rt and then heated at 50 °C overnight. The crude product was puriﬁed by column chromatography on silica gel (methanol in dichloromethane, 5% v/v) to render Compound 44F (0.5 g, yield 50%). LC-MS (m/z): 445 [M+1]+.

To a solution of Compound 44F (520 mg, 1.17 mmol) in ethanol (12 mL) and water (2 mL) was added LiOHHZO (197 mg, 4.68 mmol). The e was stirred at 80 °C overnight, diluted water, extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and concentrated to give Compound 44G (360 mg, , which was used for the next step without further puriﬁcation. LC-MS (m/z): 311.1 [M+1]+.

A mixture of nd 11E (149 mg, 0.60mmol), EDCI (175 mg, 0.9 mmol), HOBt (150 mg, 1.1 mmol), Compound 44G (188 mg, 0.60 mmol) in DCM (10 mL) —149— was stirred at rt overnight. The mixture was added water, ted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC and followed by chiral-prep-HPLC to give Compound 44H (23 mg, yield 7%) as a white solid and Compound 44 (22 mg, yield 7%) as a white solid. For Compound 44H, LC-MS (m/z): 539.1 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 0.72-0.79 (m, 4H), 2.06 (s, 4H), 2.78-3.20 (m, 6H), 3.60-3.93 (m, 4H), 4.50 (s, 1H), 4.93-4.95 (d, J: 5.6 Hz, 1H), 6.83 (s, 1H), .12 (d, J: 8.4 Hz, 1H), 7.20-7.22 (d, J: 8.0 Hz, 1H), .33 (dd, J: 2.0, 8.8 Hz, 1H), 7.40-7.42 (m, 2H), 7.56-7.57 (d, J: 2.0 Hz, 1H), 9.07-9.09 (d, J: 8.0 Hz, 1H). For Compound 44, LC-MS (m/z): 539.1 [M+1]+; 1H NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 0.72- 0.77 (m, 4H), 2.08-2.14 (d, J: 24.4 Hz, 4H), .02 (d, J: 34.4 Hz, 5H ), 3.53-3.58 (m, 3H), 3.81-3.82 (d, J: 2.4 Hz, 2H), 4.48-4.50 (d, J: 9.6 Hz, 1H), 5.14 (s, 1H), 6.71(s,1H), 7.04-7.06 (d, J: 8.4 Hz, 1H), 7.12-7.14 (d, J: 8.4 Hz, 1H), 7.32-7.41 (m, 3H), 7.56 (s, 1H),7.88-7.90 (d, J: 7.2 Hz, 1H).

Example45 N OH ::N CI 0 o FF 14 m \ NH 0 J# \ 0 CI 0 0 CI 0 0 43A 45A N 0\ F F NH 1 \ 0 CI 0 O 7] To a solution of Compound 43A (100 mg, 0.2 mmol) in DCM (10 mL) was added SOC12 (0.1 mL). The mixture was stirred at 25 °C for 3 h, and concentrated to afford the Compound 45A (105 mg) as a yellow liquid. LCMS (m/z): 525 [M+1]+.

A solution ofNH20CH3 in MeOH (30%, m/v, 1 mL) was added to the Compound 45A (105 mg, 0.2 mmol). The mixture was stirred at 25 °C for 3 h. After reaction, the mixture was concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 45 (15 mg, yield 15%) as a white solid. LC-MS (m/z): 536 [M+1]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 1.82 (m, 4H), 2.72 (m, 5H), .96 (m, 1H), 3.76 (s, 3H), 4.06-4.07 (m, 1H), 4.23-4.27 (m, 4H), 4.94 (d, J: 2.4 Hz, 1H), 5.26- .28 (d, .1: 10.8 Hz, 1H), 6.72 (s, 1H), 6.75-6.81 (m, 2H), 6.86 (s, 1H), 7.31—7.34 (m, 1H), 7.43—7.45 (m, 1H), .56 (m, 1H).

Example 46 OMs OH 1 3 i N OH N OH _ o _ NHCbZ O ﬁHCbz o ﬁHZ 0 A8 45A N 9H \ 0 CI 0 O To a solution of (R)ﬂuoropyrrolidine (174 mg, 1.38 mmol) in CH3CN (10 mL) was added K2C03 (190 mg, 1.38 mmol). Stirred at rt for 30 min, nd A8 (200 mg, 0.46 mmol) was added. The on mixture was stirred at reﬂux overnight. It was poured into ice-water, extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL x 1), dried over Na2S04, and concentrated to give a crude Compound 46A (200 mg, 100 %), which was used for the next step without ﬁthher puriﬁcation. LC-MS (m/z): 431 [M+1]+.

To a solution of Compound 46A (200 mg, 0.62 mmol) in EtOH (10 mL) was added LiOH-HZO (130 mg, 3.1 mmol) in water (10 mL) and the mixture was stirred at reﬂux overnight. It was poured into H20 (50 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (20 mL), dried over Na2S04, and concentrated to yield a crude Compound 46B (170 mg, yield 100%) as a yellow oil. LC-MS (m/z): 297 [M+1]+.

A mixture of Compound 11E (140 mg, 0.57 mmol), EDCI (160 mg, 0.84 mmol), HOBt (113 mg, 0.84 mmol) and Compound 46B (170 mg, 0.57 mmol) in DCM (20 mL) was stirred at 28 °C overnight. The mixture was added sat.NaHC03 (100 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 46 (60 mg, %) as a white solid. LC-MS (m/z): 525 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.08-2.39 (m, 2H), .86 (m, 6H), .14 (m, 4H), 4.49 (s, 1H), 4.71 (s, 1H), 5.38-5.54 (d, J: 48.4 Hz, 1H), 5.91 (s, 1H), 6.64-6.72 (m, 3H), 6.96- 6.99 (m, 1H), 7.52-7.55 (m, 1H), .83 (m, 2H), 8.82-8.89 (m, 1H), 10.33 (s, 1H). -l5l- e 47 Br CI TBSO _>TBSO O —> CbZHN CbZHN W CI CbZHN CszN CszN FO/CO To a solution of Compound 47A (12.6 g, 45.5 mmol) in THF (300 mL) was added n-BuLi (18.3 mL) at -60 °C under N2 and it was stirred for 0.5 h, and then slowly added A4 (6 g, 15.2 mmol) in THF (40 mL). The mixture was stirred at -60 °C for 1 h, and ed by the addition of saturate aq NH4C1 solution. It was extracted with ethyl acetate (300 mL x 2), brine (200 mL), dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 10 v/v) to give Compound 47B (4 g, yield 50%) as a ess oil. LC-MS (m/z): 534.2 [M+1]+.

Compound 47B (4.05 g, 7.6 mmol) was dissolved in THF (48 mL) and cooled down to -80 °C under nitrogen atmosphere. L-Selectride (16 mL of 1M solution in THF, 15 mmol) was added dropwise while keeping the temperature at -80 °C. After an hour, the reaction was quenched with saturate aq NH4C1 on and then extracted with ethyl acetate (200mL x 2), washed with brine (200 mL), and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to give Compound 47C (3.2 g, 79%) as a colorless oil. LC-MS (m/z): 518.2 [M-17]+.

A solution of nd 47C (3.2 g, 5.98 mmol) in THF (40 mL) was added TBAF (780 mg, 3 mmol) at 0 °C. The mixture was stirred at rt overnight, sed by removal of solvents, and added water (150 mL). It was extracted with ethyl acetate (250 mL x 2), washed with brine (100 mL), dried over Na2S04, trated. The residue was suspended in a solution of ethyl acetate in petroleum (10% v/v). ﬁltration of the suspension gave Compound 47D (2.25 g, yield 89%) as a white solid. LC-MS (m/z): 422.1 [M+1]+.

A solution of Compound 47D (2.25 g, 5.34 mmol) in THF (120 mL) was added Eth (1.63 g, 16 mmol) and MsCl (1.08 g, 9.43 mmol) slowly at -15 °C. The mixture was stirred about half an hour, and then diluted water, extracted with ethyl acetate (200 mL x 2), washed with brine (150 mL), dried over Na2S04, and concentrated to render Compound 47E (2.3 g, crude), which was used for the next step without ﬁarther puriﬁcation. LC-MS (m/z): 482 [M-17]+.

To a solution of Compound 47E (2.3 g, 4.61 mmol) in THF (60 mL) was mmwpwmmmw65gA9mmd)Hmmmmmmmmmwwdbwwunwmummﬁmm then heated at 50 °C overnight. The crude t was puriﬁed by column chromatography on silica gel nol in dichloromethane, 5% v/v) to give Compound 47F (0.52 g, yield 23.8%). LC-MS (m/z): 475 [M+1]+.

To a solution of Compound 47F (520 mg, 1.1 mmol) in ethanol (12 mL) and water (2 mL ) was added LiOHHZO (197 mg, 4.68 mmol). The mixture was stirred at 80 °C overnight, and then diluted water, extracted with DCM (150 mL x 2), washed with brine (150 mL), dried over Na2S04, and concentrated to afford Compound 47G (360 mg, crude), which was used for the next step without r puriﬁcation. LC-MS (m/z): 341.2 [M+1]+.

A mixture of Compound 11E (149 mg, 0.60 mmol), EDCI (175 mg, 0.9 nnnoD,}H)Bt(1501ng,1.1nnnoD,Cknnpound47(}(206rng,01K)nnnoDinl)Ch4(101nL) was stirred at rt overnight. The e was added water, extracted with DCM (150 mL x 2), washed with brine (100 mL), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC and followed by chiral-prep-HPLC to give Compound 47H (13 mg, yield 4%) as a white solid and Compound 47 (31 mg, 10.5%) as a white solid. For Compound 47H, LC-MS (m/z): 569.2 [M+1]+; 1H NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.05-2.81 (m, 6H), 2.78-2.89 (m, 5H), 3.21-3.22 (d, J: 4.0 Hz, 1H), 3.62 (s, 1H), 3.75 (S, 1H), 3.90-4.02 (m, 5H), 4.50 (s, 1H), 4.77 (s, 1H), 4.90 (s, 1H), .66 (dd, J; = 5.2 Hz, .12 = 8.0 Hz, 1H), 6.80-6.81 (d, J: 4.8 Hz, 1H), 7.17-7.19 (d, J: 8.0 Hz, 1H), 7.30-7.32 (m, 1H), 7.38-7.41 (dd, J; = 3.2 Hz, J; = 8.0 Hz, 1H), 7.44-7.46 (d, J: 6.4 Hz, 1H), 7.55- 7.56 (m, 1H), 9.14 (s, 1H), 11.57 (s, 1H). For Compound 47, LC-MS (m/z): 569.2 ; 1H NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) .11 (m, 6H), 2.97- 302(nn2PD,350(s11D,369412(nn9PD,456(nL11D,471(s11D,510(s11D,655- 6.57 (d, J: 8.0 Hz, 1H), .65 (d, J: 7.6 Hz, 1H), 7.09-7.11 (d, J: 7.2 Hz, 1H), 7.31- 7.40 (m, 3H), 7.55 (1s, 1H), 8.06 (s, 1H), 11.48 (s, 1H).

WO 42397 Example 48 3 $5 Mzamjammjamj To a solution of piro [3.3] heptane (100 mg, 1.0 mmol) in CH3CN (10 mL) was added K2C03 (414 mg, 3.0 mmol) and Compound A6 (437 mg, 1.0 mmol). The reaction mixture was stirred at reﬂux overnight. It was poured into ice-water, extracted with ethyl acetate (20 mL x 2), washed with brine (20 mL x 1), dried over Na2S04, and concentrated to afford the Compound 48A (180 mg, yield 40%) as a yellow liquid. LC-MS (m/z): 439 [M+1]+.

To a solution of Compound 48A (180 mg, 0.4 mmol) in EtOH (3 mL) was added LiOH-HZO (84 mg, 2.0 mmol) in water (1 mL) and the mixture was stirred at reﬂux overnight. The mixture was diluted with H20 (30 mL), extracted by ethyl acetate (30 mL x 3), washed with brine (20 mL), dried by Na2S04, and concentrated to render nd 48B (100 mg, yield 80%) as a yellow oil. LC-MS (m/z): 305 [M+1]+.

A mixture of Compound 11E (81 mg, 0.3 mmol), EDCI (76 mg, 0.4 mmol), HOBt (54 mg, 0.4 mmol), Compound 48B (100 mg, 0.3 mmol) in DCM (5 mL) was stirred at 28 °C ght. After the addition of sat. aq NaHCOg (100 mL), the mixture was extracted with DCM (30 mL x 2), washed with brine (30 mL x 1), dried over Na2S04, and concentrated. The crude product was purified by prep-HPLC to give Compound 48 (14 mg, yield 8%) as a white solid. LC-MS (m/z); 533 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.83-1.88 (m, 2H), 2.15 (s, 2H), 2.34 (s, 2H), 3.34 (s, 2H), 3.78- 3.84 (m, 2H), 4.06-4.19 (m, 4H), .38 (m, 3H), 5.01 (s, 1H), .81 (m, 4H), 7.34- 7.736 (m, 1H), 7.42-7.44 (m, 1H), 7.58-7.58 (m, 1H), 7.84-7.86 (m, 1H), 12.29-12.30 (m, 1H). —154— Example 49 o OH OVLH O HO _ N 5: \N NCbz VNCbZ N\ CszN N’ 80 49A 493 OH 1 5 N OH I g. \N , _ CszN N, ‘ \N \ CszN N' 490 \ O 49D O N N OH OH ch F F \N + F \ : _ \N N —> , NH _ NH NI NH2 N’ \ \ \ \ N\ CI 0 0 CI 0 0 49E 49F 49 To a solution of 5-bromomethyl-1H-indazole (3.2 g, 15 mmol) in THF (50 mL) was added n-BuLi (7.2 mL, 2.5 M) under N2 at -60 °C. The mixture was stirred for 1 h, Compound 8C (1.3 g, 5 mmol) in THF (10 mL) was added. After stirred at rt for 3 h, the mixture was diluted with aq NH4Cl (40 mL) solution, extracted with ethyl acetate (50 mL x 2), washed with brine (100 mL x 2), and evaporated. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to give Compound 49A (1.0 g, yield 51%) as a colorless oil. LC-MS (m/z): 396 [M+1]+.

A solution of nd 49A (0.5 g, 1.3 mmol) in THF (20 mL) and 1 N aq HCl (4 mL) was stirred at rt for 5 h. The mixture was quenched with water (10 mL), extracted with ethyl acetate (20 mL x 2), washed with brine (30 mL x 2), and evaporated to remove the solvents. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to give Compound 49B (374 mg, yield 81%) as a colorless oil. LC-MS (m/z): 356 [M+1]+.

To a on of Compound 49B (1 g, 2.8 mmol) in THF (25 mL) was added triethylamine (0.44 g, 4.4 mmol) and MsCl (0.4 g, 3.5 mmol) under N2 at -40 °C. The mixture was stirred at this temperature for 3 h, quenched with water (40 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 2), NS ated to dryness. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to give Compound 49C (0.87 g, yield 72%) as a ess oil. LC-MS (m/z): 416 +.

To a solution of Compound 49C (0.8 g, 1.8 mmol) in THF (25 mL) was added pyrrolidine (1.3 g, 18 mmol). The mixture was d at 60 °C overnight, quenched with water (40 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 2), and evaporated to dryness. The crude product was puriﬁed by column chromatography on mhwgd(demaMempambmnde50%vh)mgNeCmmmmm4ﬂ)m»4gymm 5596)ascoknle&soﬂ.LC)h4S(nﬂz):409[h4+1]h A solution of Compound 49D (0.4 g, 1 mmol) and LiOH-HZO (157 mg, 3.6 mmol) in ethanol (20 mL) was heated to reﬂux overnight. After the addition of water (40 mL), the mixture was extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL x 2), evaporated to give Compound 49E (247 mg, yield 90%) as a ess oil. LC-MS (m/z): 275 [M+1]f 7] To a solution of Compound 49E (0.2 g, 0.73 mmol) in dichloromethane (15 mL) was added nd 11E (222 mg, 0.9 mmol), EDCI (216 mg, 1.13 mmol), HOBt (152 mg, 1.13 mmol). The mixture was stirred at rt overnight, quenched with water (20 mL), extracted with dichloromethane (20 mL x 2), washed with brine (50 mL x 2), and evaporated to dryness. The crude product was puriﬁed by prep-HPLC and and followed by prepl- HPLC to give two s Compound 49F (5 mg) as white solid and Compound 49 (5 mg) as white solid. For Compound 49F, LC-MS (m/z): 503 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.88 (m, 4H), 3.14 (m, 2H), 3.58 (m, 2H), 3.68 (m, 1H), 3.92 (s, 3H), 4.44 (m, 1H), 4.66 (m, 1H), 6.12 (s, 2H), 7.47 (m, 5H), 7.63 (s, 1H), 7.92 (s, 1H), 9.27 (s, 1H), 9.70 (s, 1H); For Compound 49, LC-MS (m/z): 503 [M+1]+;1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 2.0 (m, 6H), 3.17 (m, 3H), 3.50 (nL3PD,3980n,4H)¢160(&11D,496(&11D,605(&11D,669(s11D,757(nL9PD,788 (s,1IT),8.92 (s,1I{),9.65 (s,1I{) Example 50 m—»OH /©:>_/—» —» Br 6 —N _ \ / 50A SOB soc \ /N 500 OH OH o 0 ﬂ —> # —> N N _N \ / \ / \ / 50E 50F 506 ::N 9H F F F F O 0V OH F NH 1 o o # —> —N —N — \ / \ / 50H 50| \ /N 50 To a stirred solution of nd 50A (500 mg, 2.21 mmol) in dioxane (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (618 mg, 2.43 mmol), KOAc (694 mg, 7.08 mmol) and Pd(PPh3)2Cl2 (90 mg, 0.11 mmol) under N2. The mixture was stirred at 90 °C overnight. The reaction mixture was evaporated to remove the solvent. The residue was diluted with ethyl e (100 mL), washed with water, brine, and dried over anhydrous Na2S04. Filtration and evaporation of the solvents gave Compound 50B (606 mg, yield 100%) as a brown oil which was used for the next step without puriﬁcation.

LCMS: (m/z) 275 [M+1]+; To a stirred solution of nd 50B (606 mg, 2.21 mmol) in dioxane (10 mL) was added Pd(PPh3)4 (127 mg, 0.11 mmol), 2-bromopyridine (384 mg, 2.43 mmol) and 3 mL of 30% aq NaOH under N2. The mixture was stirred at 90 °C overnight. The mixture was ated to remove the solvents. The residue was diluted with ethyl acetate (100 mL), washed with water, brine, and dried over ous Na2S04. The crude was puriﬁed by column chromatography on silica gel (methanol in DCM, 5% v/v) to render Compound 50C (230 mg, yield 46%, two steps) as a yellow oil. LCMS: (m/z) 226 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.58 (brs, 1H), 2.76-2.85 (m, 3H), 3.10-3.18 (m, 2H), 3.69 (d, J: 6.0 Hz, 2H), 7.20 (m, 1H), 7.30 (d, J: 8.0 Hz, 1H), 7.71-7.75 (m, 3H), 7.86 (s, 1H), 8.67 (d, J: 4.8 Hz, 1H).

To a d on of Compound 50C (230 mg, 1.02 mmol) in DCM (10 mL) was added DMP (520 mg, 1.23 mmol). The mixture was stirred at rt for 3 h. The reaction mixture was quenched with sat. aq Na2S03 solution. The aqueous phase was extracted with DCM (50 mL x 3). The ed c phase was washed with water, brine, and dried over anhydrous Na2S04. The crude was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 34% v/v) to give Compound 50D (200 mg, yield 88%) as colorless oil. LCMS: (m/z) 224 [M+l]+.

To a stirred solution of Compound 50D (200 mg, 0.90 mmol) in H20 (10 mL) was added NaSzOs (170 mg, 0.90 mmol). The mixture was stirred at rt for 3 h, and NaCN (88 mg, 1.79 mmol) was added to the mixture. After stirred at rt overnight, the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with water, brine, and dried over anhydrous Na2S04. Filtration and evaporation of the solvents gave Compound 50E (180 mg, yield 80%) as a white solid. LCMS: (m/z) 251 [M+l]+; 1H- NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.86-3.03 (m, 3H), 3.15-3.18 (m, 3H), 4.28 (d, J: 4.2 Hz, 1H), 7.30 (m, 2H), 7.65-7.69 (m, 2H), 7.77-7.80 (m, 2H), 8.70 (d, J: 2.8 Hz, 1H).

A solution of Compound 50E (1 .88 g, 7.52 mmol) in ethanol (80 mL) was bubbled with a gentle stream of HCl gas (dried over conc H2S04) for 6 h and left to stand overnight at 4 °C. The e was added water (30 mL) and d at 80 °C for 2 h. After cooled down to rt, the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with water, brine, and dried over anhydrous Na2S04, and puriﬁed by column chromatography on silica gel (methanol in dichloromethane, 3% v/v) to yield Compound 50F (1.17 g, yield 52%) as a yellow solid. LCMS: (m/z) 298 [M+l]+. 3] To a stirred solution of Compound 50F (210 mg, ol) in DCM (11 mL) was added NaHC03 (1 19 mg, 1.41 mmol), and DMP (360 mg, 0.85 mol) at 0 °C. The mixture was stirred at 0 °C for one hour. The reaction mixture was quenched with sat. aq Na2S03 solution. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic phase was washed with water, brine, and dried over anhydrous Na2S04. The crude was ed by column chromatography on silica gel nol in dichloromethane, 3% v/v) to afford Compound 50G (180 mg, yield 86%) as yellow oil. LCMS: (m/z) 224 [M+l]+.

To a stirred solution of Compound 50G (233 mg, 0.79 mmol) in DCM (10 mL) was added DAST (720 mg, 4.47 mmol). The mixture was stirred at rt overnight. After cooled down to rt, the mixture was poured into water and then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with water, brine, and dried over anhydrous , puriﬁed by column chromatography on silica gel nol in dichloromethane, 5% v/v) to give Compound 50H (140 mg, yield 56%) as a yellow oil.

LCMS: (m/z) 318 [M+l]+.

To a stirred solution of Compound 50H (140 mg, 0.44 mmol) in THF (10 mL) was added LiOH-HZO (37 mg, 0.88 mmol) and water (2 mL). The mixture was stirred at rt for 3 h. The mixture was acidiﬁed to pH 1 with 1M HCl and evaporated. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined c phase was washed with water, brine, and dried over anhydrous Na2S04, concentrated to give Compound 50] (110 mg, yield 86%) as a yellow oil. LCMS: (m/z) 290 [M+l]+.

To a solution of Compound 50] (110 mg, 0.38 mmol) in DCM (10 mL) was added EDCI (110 mg, 0.57 mmol), HOBt (77 mg, 0.57 mmol), Intermediate A (106 mg, 0.38 mmol). Then it was stirred at rt overnight. The mixture was added DCM (20 mL), washed with water (50 mL x 2) and brine (50 mL x 1), dried over anhydrous Na2S04, concentrated, and puriﬁed by prep-HPLC twice to give Compound 50 (1.6 mg, yield 1%) as a colorless oil.

LC-MS (m/z): 550 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.95 (m, 4H), 2.68-2.96 (m, 5H), .38 (m, 2H), 3.76 (s, 2H), 4.11 (s, 4H), 4.37(s, 1H), .08 (m, 1H), 5.28 (s, 1H), 6.79-6.85 (m, 3H), 7.30 (s, 1H), 7.47 (m, 1H), 7.65 (m, 3H), 7.92 (m, 1H), 8.24 (m, 1H), 8.96 (m, 1H), 11.79 (s, 1H).

Example 51 OMs OH yo E j = N HN 9H ‘ o f or 1—»., o J—» 1,, 0 CszN 0 QN o NH2 1 A8 51A 51B ENi 9H _, F F NH j \ 0 CI 0 0 To a solution of 2-azabicyclo [2.2.1] e (132 mg, 1 mmol) in MeCN (10 mL) was added K2C03 (69 mg, 0.5 mmol) and Compound A8 (219 mg, 0.5 mmol). The e was stirred at 70 °C for 48 h. After evaporation to remove solvents, the residue was dissolved in H20, extracted with ethyl acetate; the combined organic layers were dried over anhydrous Na2S04. After ﬁltration and evaporation, a crude Compound 51A (210 mg) was ed as an oil, which was used for the next step directly. LCMS (m/z): 331 [M+1]+.

To a solution of Compound 51A (210 mg, 0.64 mmol) in EtOH (9 mL) and H20 (9 mL) was added LiOH-HZO (267 mg, 6.4 mmol). The on e was reﬂuxed for 24 h. After removal of the solvents, the residue was dissolved in H20, extracted with ethyl acetate, and dried over Na2S04 to give Compound 51B (190 mg), which was used for the next step without puriﬁcation. LCMS (m/z): 305 [M+l]+.

To a solution of Compound 51B (91 mg, 0.3 mmol) in DCM (12 mL) was added Compound 11E (111 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) and EDCI (86 mg, 0.45 mmol). The mixture was stirred for 12 h at 25 °C. The mixture was washed with brine and dried over anhydrous Na2S04. After ﬁltration and evaporation, the residue was puriﬁed by prep-HPLC to give Compound 51 (38 mg, yield 19%) as a white solid. LC-MS (m/z): 507 [M+l]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 1.52-1.90 (m, 4H), 2.04-2.24 (m, 1H), 2.57-2.98 (m, 2H), 3.30-3.72 (m, 3H), 4.07-4.50 (m, 8H), 5.01-5.16 (m, 1H), 6.68-6.83 (m, 4H), 7.33-7.35 (m, 1H), 7.42-7.44 (m, 1H), 7.57 (d, J: 1.2 Hz, 1H), 8.02- 8.17 (m, 1H), 10.21-10.33 (m, 1H).

Example 52 wawiawiaya 0.".0"W403" awFZLW"MEI To a solution of ethyl 2-(diethoxyphosphoryl) acetate (10.77 g, 48.08 mmol) in THF (50 mL) was added t—BuOK (5.38 g, 48.08 mmol) at room temperature. After stirred for 30 min, Compound 52A (5.00 g, 32.05 mmol) was added. The mixture was stirred at room temperature overnight. It was diluted with ethyl acetate (200 mL), washed with water and brine, and d with silica gel column chromatography (ethyl acetate in petroleum ether, 10% v/v) to render Compound 52B (6.60 g, yield 91%) as a colorless oil. LC-MS (m/z): 227 ; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 1.36 (t, -l60- J: 7.2 Hz, 3H), 426-4.32 (m, 2H), 6.55 (d, J: 15.6 Hz, 1H), 75-753 (m, 2H), 7.65-7.69 (m, 1H), 7.83-7.87 (m, 4H).

A suspension of Pd/C (1.00 g, 10%) and Compound 52B (7.30 g, 32.0 mmol) in MeOH (100 mL) was stirred at room ature overnight under H2. The mixture was ﬁltered to remove Pd/C. The ﬁltrate was evaporated to yield Compound 52C (7.30 g, yield 100%) as a colorless oil. LC-MS (m/z): 229 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.23 (t, J: 7.2 Hz, 3H), 2.71 (t, J: 7.6 Hz, 2H), 3.12 (t, J: 8.4, 2H), 4.10-4.16 (m, 2H), 7.34 (d, J: 7.6 Hz, 1H), 7.40-7.47 (m, 2H), 7.64 (s, 1H), .81 (m, 3H). 2] To a solution of Compound 52C (7.30 g, 32.02 mmol) in dry THF (80 mL) was added LiAlH4 (1.20 g, 32.0 mmol) at 0 °C. Then it was warmed to room temperature and stirred for 2 h. It was added with Na2S04.10H20 and ﬁltered to remove the solid. The ﬁltrate was ated to give Compound 52D (6.10 g, yield 100 %) as a colorless oil. LC-MS (m/z): 187 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.95- 2.02 (m, 2H), 2.88 (t, J: 8.0 Hz, 2H), 3.72 (t, J: 6.8 Hz, 2H), 7.33 (d, J: 7.2 Hz, 1H), 7.39- 7.47 (m, 2H), 7.63 (s, 1H), 7.76-7.81 (m, 3H). 3] A mixture of Compound 52D (16 g, 86 mmol) in DCM (300 mL) was added DMP (43 g, 103 mmol) at room temperature. Then it was stirred at room temperature for 1 h.

The mixture was diluted with EA (400 mL), ﬁltered to remove solid, washed with water and brine, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, % v/v) to afford Compound 52E (14 g, yield 88%) as a colorless oil. LC-MS (m/z): 185 [M+1]+. [0005241 A mixture of Compound 52E (8.00 g, 43.4 mmol) and 2Na05S2 (8.3 g, 43.4 mmol) in water/dioxane (100/20 mL) was stirred at room temperature for 2 h. Then NaCN (4 g, 86.95 mmol) was added. The e was stirred at room temperature overnight. It was diluted with ethyl acetate (200 mL), washed with water and brine, and d by silica gel column chromatography (ethyl acetate in petroleum ether, 50% v/v) to give Compound 52F (6.6 g, yield 72%) as a colorless oil. LC-MS (m/z): 212 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 2.07-2.13 (m, 2H), 2.87-2.91 (m, 2H), 4.50-4.55 (m, 1H), 6.48-6.49 (d, J: 4 Hz, 1H), 7.40-7.51 (m, 3H), 7.73 (s, 1H), 7.85-7.89 (m, 3H).

A solution of Compound 52F (6.6 g, 31.27 mmol) in MeOH (150 mL) was d with a gentle stream of HCl gas at room temperature for 6 h. Then it was quenched with H20 (30 mL) and stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (300 mL), washed with water and brine, dried with ous Na2S04, and evaporated to give nd 52G (6.7 g, yield 87%) as colorless oil. LC-MS (m/z): 245 [M+l]+; 1H- NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.91-2.03 (m, 2H), 2.81- 2.85 (t, J: 8 Hz, 2H), 3.64 (s, 3H), 5.54-5.55 (m, 1H), 7.37-7.39 (m, 1H), 7.42-7.50 (m, 2H), 7.69 (s, 1H), 7.83-7.87 (t, J: 8 Hz, 3H).

To a solution of Compound 52G (6.7 g, 27.46 mmol) in DCM (50 mL) was added DMP (14 g, 33 mmol). The mixture was stirred at room temperature for 2 h. Then it was diluted with ethyl e (150 mL), ﬁltered to remove the solid, washed with water and brine, dried over anhydrous , and puriﬁed by silica gel column chromatography (ethyl e in petroleum ether, 30% v/v) to yield Compound 52H (5 g, yield 75%) as a colorless oil. LC-MS (m/z): 243 [M+l]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) .02 (t, J: 8 Hz, 2H), 3.24-3.28 (t, J: 8 Hz, 2H), 3.77 (s, 3H), 7.39-7.48 (m, 3H), 7.71 (s, 1H), 7.82-7.87 (m, 3H).

To a solution of Compound 52H (2.0 g, 8.26 mmol) in DCM (50 mL) was wwdmwTGmLM3mmﬂﬁmmﬁmpmmmTMmMmmmemmnmm temperature overnight. Then it was diluted with ethyl acetate (150 mL), washed with saturated NaHCOg, water and brine, and puriﬁed by silica gel column chromatography (ethyl mdﬁempambmnamm40%vw)maﬁMdemmmﬂSﬂ120gykM9P%ﬂmame solid. LC-MS (m/z):265 [M+l]+.

A mixutre of nd 52] (2.5 g, 4.47 mmol) and LiOH.H20 (1.2 g, 28.4 nmmDmTHWMdHM£O(Nﬂw4mmwmwmmdemnmmmmmmﬁn2hTMnﬁww adjusted to pH 6 with l M HCl aq solution. The mixture was diluted with ethyl acetate (150 mL), washed with water and brine, dried with anhydrous Na2S04, and puriﬁed by silica gel column chromatography (ethyl acetate in petroleum ether, 30% v/v) to give Compound 52J (1.8 g, yield 75%) as a white solid. LC-MS (m/z): 251 [M+l]+; 1H-NMR d6, 400 MHz) major characteristic peaks: 5 (ppm) 2.45-2.49 (m, 2H), 2.88-2.92 (m, 2H), 7.42-7.50 (m, 3H), 7.76 (s, 1H), 7.84-7.88 (m, 3H).

A solution of Compound 11E (200 mg, 0.64 mmol), nd 52J (241 mg, 0.96 mmol), EDCI (183 mg, 0.96 mmol) and HOBt (130 mg, 0.96 mmol) in DCM (15 mL) was stirred at room temperature overnight. Then it was diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by prep-HPLC to afford nd 52 (108 mg, yield 30%) as a white solid. LC-MS (m/z): 543 [M+l]+; 1H-NMR(DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 0.41-0.44 (m, 2H), 0.54-0.59 (m, 2H), 1.87-1.88 (m, 2H), 2.01 (s, 2H), 2.16-2.27 (m, 2H), 2.49-2.71 (m, 2H), 3.10-3.15 (m, 2H), 3.46-3.61 (m, 5H), -l62- 4.47-4.48 (m, 1H), 4.82 (s, 1H), 6.01-6.02 (m, 1H), 7.24—7.34 (m, 3H), 7.38 (s, 1H), 7.45— 7.51 (m, 2H), 7.65 (s, 1H), 7.83-7.89 (m, 3H), 8.41-8.44 (m, 1H), 9.52 (s, 1H).

Example 53 OH E:N’ E:N’ 9H 9H 0 5 O 0 ~ 1 I E. ] _ HN Ha NH2 j ‘CbZ 0 0 A3 53A 53B E:N’ 9H F F —> NH j \ 0 CI 0 O To a solution of Compound A8 (500 mg, 1.1 mmol) in THF (20 mL) was added 7-azabicyclo [2.2.1] heptane (1.1 g, 11 mmol) and stirred at 50 °C for 16 h. The mixture was added water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with water (50 mL x 3), brine (50 mL x 1), dried over anhydrous Na2S04, and concentrated to give Compound 53A (600 mg, crude) as a colorless oil. LCMS: 439 [M+1]+.

A mixture of Compound 53A (660 mg, crude), LiOH-HZO (150 mg) in EtOH (30 mL) and H20 (5 mL) was stirred at 100 °C for 16 h. The mixture was concentrated and added water (50 mL), and then extracted with DCM (30 mL x 3), dried over anhydrous Na2S04, and concentrated to give Compound 53B (400 mg, crude) as a colorless oil. LCMS: 305 [M+1]+.

To a solution of nd 11E (250 mg), EDCI (290 mg), HOBt (200 mg, 0.75 mmol) in DCM (10 mL) was added Compound 53B (400 mg, . The mixture was stirred at 25 °C for 24 h, added water (50 mL), extracted with DCM (30 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep-HPLC to give nd 53 (15 mg, yield 2%) as a colorless oil. LCMS: 533 ; (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.69 (m, 4H), 2.14 (m, 4H), 3.35 (br, 1H), 3.47 (br, 1H), 4.11 (m, 5H), 4.49 (br, 2H), .06 (s, 1H), 6.78 (m, 4H), 7.33 (m, 1H), 7.41 (m, 1H), 7.58 (m, 1H), 8.10 (br, 1H), 10.58 (br, 1H).

Example 54 OH OH / / / Br N N\ O HO N\ ‘N —> N —> N—> / N\ / HN\ / Cbz Cbz 54A 54B 54C 0H N / OH N OH / / HN\Cbz / HN‘Cbz / NHZ / 54E 54F O U N OH N OH / : / N‘ N‘ F F F F —’ N N NH / NH / \ \ CI 0 0 CI 0 O 546 54 To a solution of Compound 54A (14.1 g, 19.4 mmol) in THF (15 mL) was added n-BuLi (8.1 mL, 19.4 mmol) carefully at -68 °C. The mixture was stirred at -68 °C for min, and then Compound 8C (1.70 g, 6.48 mmol) in THF (10 mL) was added. The mixture was stirred at -68 °C for 15 min before quenched with saturated aq NH4Cl. It was diluted with ethyl e (100 mL), washed with water and brine, dried with anhydrous , and evaporated to give Compound 54B (1.90 g, yield 79%) as a light yellow oil. LC- MS (m/z): 396 .

A mixture of Compound 54B (1.90 g, 4.81 mmol) in THF (5 mL) and hydrochloric acid (6 M, 5 mL) was stirred at 20 °C overnight. It was diluted with ethyl acetate (200 mL), washed with water and brine, d by silica gel chromatography eluted with MeOH in DCM (from 0% to 5%, v/v) to render Compound 54C (500 mg, yield 48%) as a colorless oil. LC-MS (m/z): 356 [M+1]+.

To a solution of Compound 54C (520 mg, 1.46 mmol) in THF (50 mL) was added se MsCl (184 mg, 161 mmol) at -40 °C. The mixture was stirred at -30 °C for 2 h. It was quenched with ice-water, diluted with ethyl acetate (200 mL), washed with water and brine, dried with anhydrous , and evaporated to give Compound 54D (500 mg, yield 79%) as a colorless oil. LC-MS (m/z): 434 [M+1]+.

A mixture of Compound 54D (500 mg, 1.15 mmol) and pyrrolidine (3 mL) in THF (20 mL) was stirred at 50 °C overnight. It was evaporated to remove THF. The residue was diluted with ethyl acetate (150 mL), washed with water and brine, puriﬁed by silica gel chromatography (methanol in dichloromethane, from 0% to 8% v/v) to yield Compound 54E (120 mg) as a colorless oil. LC-MS (m/z): 409 [M+l]+. 7] A mixture of Compound 54E (120 mg, 0.29 mmol) in EtOH/HZO (10/2 mL) was stirred at 85 °C overnight. It was diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by silica gel chromatography (methanol in dichloromethane, from 0% to 10% v/v) to give Compound 54F (90 mg, yield 100%) as a colorless oil. LC-MS (m/z): 275 [M+1]+.

The mixture of Compound 54F (90 mg, 0.33 mmol), EDCI (95 mg, 0.50 mmol), HOBt (68 mg, 0.50 mmol) and Compound 11E (81 mg, 0.33 mmol) in DCM (5 mL) was stirred at 20 °C overnight. It was diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by prep-HPLC to afford Compound 54G (20 mg) as a white solid and Compound 54 (15 mg) as a white solid. For Compound 54G, LC-MS (m/z): 503 ; 1H- NMR (MeOD, 400 MHz) major characteristic peaks: 5 (ppm) 2.07 (s, 2H), 2.21 (s, 2H), 3.13- 3.26 (m, 2H), 3.52-3.58 (m, 1H), .89 (m, 3H), 3.91 (s, 3H), 4.61-4.67 (m, 1H), 4.82 (d, J: 5.2 Hz, 1H), 6.34 (s, 1H), 7.21-7.27 (m, 2H), .38 (m, 2H), 7.47 (s, 2H), 7.58 (d, J: 8.8 Hz, 1H), 7.87 (s, 1H). For Compound 54, LC-MS (m/z): 503 [M+1]+; 1H-NMR (MeOD, 400 MHz) major characteristic peaks: 5 (ppm) 2.05 (s, 2H), 2.20 (s, 2H), 3.17-3.26 (m, 2H), 3.64-3.82 (m, 4H), 3.85 (s, 3H), 4.80 (d, J: 5.2 Hz, 1H), 5.16 (s, 1H), 6.34 (s, 1H), 7.18-7.21 (m, 1H), .34 (m, 1H), 7.38-7.40 (m, 2H), 7.55-7.60 (m, 2H), 7.91 (s, 1H).

Example 55 A on of Compound 55A (100 mg, 0.2 mmol), hydroxylamine hydrochloride (41 mg, 0.6 mmol) in MeOH (5 mL) was d at 25 °C for 16 h. The mixiture was diluted with saturation aq NaHCOg (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2S04, and concentrated to give a crude product. The crude product was puriﬁed by prep-HPLC to give a triﬂuoroacetic acid salt of Compound 55 (1.6 mg, yield 1.3%) as a white solid. LC-MS (m/z): 520 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.82 (s, 4H), 2.00-2.22 (m, 2H), 2.65-2.75 (m, 3H), 2.92-2.97 (m, 1H), .24 (m, 4H), 5.33-5.47 (m, 2H), 6.82-6.84 (m, 1H), 6.95 (s, 1H), .14 (m, 2H), 7.33—7.34 (m, 1H), 7.40—7.43 (m, 1H), 7.54—7.55 (m, 1H). e 56 o 9H TBSOYLN/ TBSO \N TBSO \N _.

Cszli I / CbZH'i / / CszN 0\ 0 0 A4 56A 563 pH 9H ::N 9H HOW —> MSO - \N —> CszN I / I 0/ CszN / o/ cum] / o/ 560 56D 57F N 9H N F F \N oH | E NH _. / _, \ O/ _ \N 56F 56 0] To a solution of 5-bromomethoxypyridine (10 g, 53.2 mmol) in THF (200 mL) was added n-BuLi (2.5 M, 22 mL) at -60 °C under N2. It was stirred for 0.5 h, and then a solution of Compound A4 (7.02 g, 17.7 mmol) in THF (50 mL) was added. The reaction e was stirred at -60 °C for an additional 1 h, before quenched with saturate aq NH4C1 on. It was extracted with ethyl acetate (100 mL x 2), brine (100 mL), and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to give Compound 56A (7.5 g, yield 95%) as a colorless liquid. LC-MS (m/z): 445[M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) -0.13 (s, 3H), -0.11 (s, 3H), 0.75 (s, 9H), 3.88-3.92 (m, 1H), 3.99-4.00 (m, 1H), 4.02 (s, 3H), 5.14 (s, 2H), 5.29 (t, J: 3.6 Hz, 1H), 5.93 (d, J: 6.8 Hz, 1H), 6.81 (d, J: 8.8 Hz, 1H), 7.37-7.38 (m, 5H), 8.13 (dd, J: 2.0, 8.8 Hz, 1H), 8.80 (d, J: 2.0 Hz, 1H). nd 56A (7.5 g, 16.9 mmol) was dissolved in anhydrous THF (500 mL) and cooled down -80 °C under nitrogen atmosphere. L-Selectride (33.8 mL, 1M solution in THF, 33.8 mmol) was added dropwise to the solution while keeping the temperature at -80 °C. The reaction was stirred at -80 °C for 0.5 h before quenched with saturate aq NH4C1 solution. It was ted with ethyl acetate (100 mL x 3). The combined organic phases were washed water and brine, and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 20% v/v) to give Compound 56B (5.1g, yield 68%) as a colorless oil. LC-MS (m/z): 447 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) -0.08 (s, 6H), 0.92 (s, 9H), 3.68 (m, 1H), 3.84 (m, 3H), 3.94 (s, 3H), 5.05 (m, 3H), 5.46 (d, J: 7.6 Hz, 1H), 6.71 (d, J: 8.4 Hz, 1H), 7.32-7.34 (m, 5HL759GLJ=84HL1HL814@,HD.

To a solution of Compound 56B (5.1 g, 11.4 mmol) in THF (120 mL) was added a solution of TBAF (1.49 g, 5.7 mmol) in THF (10 mL) at 0 °C. The mixture was mnmdm25ThwanQMgmdﬂmnmaynﬁahommmemevdmnqawhdwmmrQOmLL extracted with ethyl acetate (100 mL x 3), washed with brine, and dried over Na2S04. The crude product was d by column chromatography on silica gel (methanol in dichloromethane, 5% v/v) to give Compound 56C (3.42 g, yield 52 %) as a colorless oil. LC- MS (m/z): 333 [M+1]+.

To a solution of nd 56C (3.42 g, 8.58 mmol) in THF (100 mL) was added Eth (3.12 g, 30.9 mmol). The mixture was cooled to -40 °C, and then MsCl (1.30 g, 11.3 mmol ) was added slowly. It was stirred at -40 °C about half an hour before added idine (3.78 g, 53.2 mmol). The reaction e was allowed to warm up to rt and then heated to 50 °C. Stirred overnight, the mixture was added water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with brine (100 mL), and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (methanol in dichloromethane, 3% v/v) and ﬂash column (reverse-phase, 0.05 %NH4OH/MeOH, v/v) to give nd 56D (800 mg, yield 39%) as white syrup. LC-MS (m/z): 386 [M+1]+.

To a solution of Compound 56D (400 mg, 1.04 mmol) in ol (10 mL) wwaﬂthﬂOHhMOng)Tmnmmmewwsmmdm25ThmmxHﬁwmmgmhwms ﬁltered and evaporated to give Compound 56E (260 mg, crude). LC-MS (m/z): 252 [M+1]+.

To a solution of Compound 56E (260 mg, 1.04 mmol) and Compound 11E (255 mg, 1.04 mmol) in DCM (10 mL) was added EDCI (298 mg, 1.55 mmol) and HOBt (210 mg, 1.55 mmol) under N2. The mixture was stirred at 25 °C overnight. TLC showed the starting material was consumed completely; water was added to the mixture and then extracted with DCM (50 mL x 3). The combined c layers were washed with brine, dried over sodium sulfate, and concentrated to give a crude product. The crude product was d by prep-HPLC to give Compound 56 (98.6 mg, yield 19%) as a white solid. LC-MS (m/z): 480 [M+1]+; 1H-NMR (CDCl3, 400 MHz) major characteristic peaks 5 (ppm): 2.10 (s, 4H), 3.03 (s, 2H), 3.58-3.72 (m, 4H), 3.86 (s, 3H), 4.26 (s, 1H), 5.24 (m, 1H), 6.71 (s, 1H), 6.84 (s, 1H), 7.33 (d, J: 8.4 Hz, 1H), 7.40 (d, J: 8.4 Hz, 1H), 7.55 (s, 1H), 7.86 (s, 1H), 838(nL2PD,1L43(s1}D.

W0 2015/042397 Example 57 C j N o N Ho 0 O F F —> F F NH j NH \ j _, o \ 0 0 0 0 CI 0 55A 573 Hg D N HO 0 o F F and F F NH j NH j \ 0 \ o 0 0 0 0 Cl CI 57 57c To a solution of Compound 55A was dissolved in CD301) (5 mL) was added NaBD4 (13 mg, 0.32 mmol) at -30 °C under nitrogen atmosphere. The reaction was warmed to 0 °C and kept ng for 1 h. After quenched with 2% CD3COOD in D20, the mixture was extracted with dichloromethane (50 mL x 3) and washed with D20. The crude product was puriﬁed by prep-HPLC to give Compound 57 (20 mg, yield 25%) as a white solid. LC-MS (m/z): 508 ; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (s, 4H), 3.01 (s, 2H), 3.49 (s, 2H), 3.81 (s, 2H), 4.12-4.17 (m, 4H), 4.47-4.49 (m, 1H), 6.76 (m, 2H), 6.84 (s, 1H), 7.35 (dd, J: 2.0, 8.8 Hz, 1H), 7.44 (d, J: 8.8 Hz, 1H), 7.45 (s, 1H), 7.90 (d, J: 2.0 Hz, 1H), 11.95 (s, 1H).

Example 58 F F F F NH 1 j _. \ o \ 0 CI 0 0 CI 0 0 45A 58A N NH2 F F _> : NH j \ 0 CI 0 O A solution of Compound 45A (62 mg, 0.12 mmol) in DMF (2 mL) was added NaNg (24 mg, 0.36 mmol) and the mixture was stirred at 50 °C for 3 h. The mixture was added H20 (mL) and extracted with ethyl e (50 mL x 3). The combined organic layer was washed with brine, and concentrated to give nd 58A (40 mg, yield 63%) as a white solid. LC-MS (m/z): 532 [M+1]+.

To a solution of Compound 58A (40 mg, 0.075 mmol) in THF (1 mL) was added PPh3 (21 mg, 0.08 mmol), the mixture was stirred at 20 °C for 18 h. It was added H20 (mL) and stirred for 2 h and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 58 (5 mg, yield 13%) as a white solid. LC-MS (m/z): 506 [M+1]+; 1H-NMR (CDClg, 400 MHz) major teristic peaks: 5 (ppm) 1.79-1.81 (m, 4H), 2.40-2.45 (m, 1H), 2.56-2.64 (m, 6H), 3.34-3.38 (m, 1H), 4.14-4.34 (m, 5H), 4.90-4.91 (m, 2H), 6.75-6.84 (m, 3H), 7.07 (s, 1H), 7.32-7.35 (m, 1H), 7.45-7.58 (m, 1H), 7.59 (s, 1H), 9.66-9.67 (m, 1H).

Example 59 CHF2 oror(1;:er NTBDMSO NHCbz CHF2 CHF2 CHI:2 HO HO I O\ —> O\ —> O\ TBDMSO NHCbZ HO 3NHCbZ CB NHCbZ 59E 59F 596 CHF2 _.Ofoo Mk/KCZCHFZ Mk/ﬁma To a solution of Compound 59A (10 g, 50 mmol) and K2C03 (20.7 g, 150 mmol) in DMF (30 mL) was added Mel (21.3 g, 150 mmol), and the mixture was stirred for h at 25 °C. After the TLC showed complete disappearance of the starting material, the reaction was quenched by adding water. It was extracted with ethyl acetate. The extracts were evaporated to dryness to give Compound 59B (10.6 g, yield 98%) as a yellow solid. LC- MS (m/z): 215 ; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 3.92 (s, 3H), 6.90 (d, J: 8.8 Hz, 1H), 7.63 (dd, J: 8.8, 2.0 Hz, 1H), 7.91 (d, J: 2.0 Hz, 1H), .39 (s, 1H).

To a on of Compound 59B (9 g, 42 mmol) in DCM (90 mL) was added DAST (33.7 g, 209 mmol), and the mixture was stirred for 18 h at 25 °C. The mixture was adjusted to pH 8 with saturated NaHCOg, ted with DCM, and dried over anhydrous Na2S04. After evaporation, the crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum ether, 3% v/v) to get nd 59C (5.14 g, yield 52%) as a colorless oil. 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 3.85 (s, 3H), 6.82 (d, J: 9.2 Hz, 1H), 6.89 (t, JF_H= 552 Hz, 1H), 7.52 (dt, J: 8.8, 1.2 Hz, 1H), 7.66 (t, J: 1.2 Hz, 1H).

To a solution of Compound 59C (5 g, 21 mmol) in THF (100 mL) was added n-BuLi (2.4 M, 8.75 mL) at -60 °C under N2. After stirred for 0.5 h, a solution of nd A4 (2.77 g, 7 mmol) in THF (50 mL) was added . The mixture was stirred at -60 °C for 1 h, before quenched with saturated aq NH4Cl solution. It was extracted with ethyl acetate, washed with brine (100 mL) and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 20% v/v) to give nd 59D (2.65 g, yield 76%) as a yellow oil. LC-MS (m/z): 494 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) -0.15 (s, 3H), -0.12 (s, 3H), 0.74 (s, 9H), 3.85-3.92 (m, 2H), 3.96 (s, 3H), 5.13 (s, 2H), 5.33-5.38 (m, 1H), 5.93 (d, J: 7.6 Hz, 1H), 6.79-7.06 (m, 2H), .37 (m, 5H), 8.10 (d, J: 8.4 Hz, 1H), 8.18 (s, 1H). 2] Compound 59D (2.65 g, 5.36 mmol) was dissolved in THF (100 mL) and cooled to -70 °C under nitrogen atmosphere. L-Selectride (1M solution in THF, 10.7 mL) was added se while keeping the temperature at -70 °C. After an hour, the reaction was quenched with saturated aq NH4Cl on and the mixture was extracted with ethyl acetate, and dried over Na2S04. The crude product was purified by column chromatography on silica gel (ethyl acetate in petroleum, 20% v/v) to give Compound 59E (2.1 g, yield 79%) as a colorless oil. LC-MS (ESI) m/z: 478 [M-17]+.

To a solution of Compound 59E (2.1 g, 4.23 mmol) in THF (50 mL) was added a on of TBAF (555 mg, 2.12 mmol) in THF (5 mL) at 0 °C. The mixture was stirred at rt for 18 h, condensed, added water, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2S04. The crude product was purified by ﬂash column chromatography on silica gel (MeOH in H20, 40% v/v) to give Compound 59F (760 mg, yield 47%) as a colorless oil. LC-MS (m/z): 364 [M-17]+.

To a solution of Compound 59F (0.76 g, 2 mmol) in THF (50 mL) was added Eth (0.6 g, 6 mmol) at -40 °C. MsCl (241 mg, 2.09 mmol) was added slowly and the mixture was stirred at -20 °C for 7 h. Pyrrolidine (1.13 g, 16 mmol) were added and the reaction mixture was allowed to warm up to rt and then heated to 50 °C for 15 h. The crude product was puriﬁed by column chromatography silica gel (methanol in dichloromethane, 5% v/v) to give Compound 59G (270 mg, yield 31%) as colorless oil. LC-MS (m/z): 435 [M+1]+.

To a solution of Compound 59G (270 mg, 0.62 mmol) in methanol (20 mL) was added Pd(OH)2 (27 mg) and the mixture was stirred at 25 °C under H2 for 24 h. The mixture was ﬁltered and evaporated to render Compound 59H (260 mg, yield 98%) as a white solid. LC-MS (m/z): 301 . 6] The mixture of Compound 59H (180 mg, 0.6 mmol), EDCI (173 mg, 0.9 mmol), HOBt (122 mg, 0.9 mmol) and Compound 11E (178 mg, 0.72 mmol) in DCM (15 mL) was stirred for 16 h at 25 °C. The mixture was washed with saturated aq NaHCOg and brine. After evaporation, the residues were puriﬁed by prep-HPLC to afford nd 59] (64 mg, yield 11%) as the white solid and Compound 59 (59 mg, yield 10%) as the white solid. For Compound 59], LC-MS (m/z): 529 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.07-2.19 (m, 4H), 2.77-2.91 (m, 2H), 3.21-3.24 (m, 1H), 3.63- 3.64 (m, 1H), 3.76 (s, 3H), 3.80-3.82 (m, 1H), 3.88-3.90 (m, 1H), 4.52 (s, 1H), 5.02 (s, 1H), 6.72-7.00 (m, 3H), .34 (m, 1H), 7.40-7.42 (m, 2H), 7.52-7.62 (m, 2H), 9.15 (d, J: 4.8 Hz, 1H), 11.78 (s, 1H). For Compound 59, LC-MS (m/z): 529 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (s, 4H), .04 (m, 2H), 3.53-3.63 (m, 2H), 3.71 (s, 3H), 3.74-3.81 (m, 2H), 4.60 (s, 1H), 5.19 (s, 1H), 6.65-6.98 (m, 3H), 7.32-7.39 (m, 3H), 7.51-7.53 (m, 2H), 7.95 (d, J: 6.4 Hz, 1H), 11.69 (s, 1H).

Example 60 0 o 0 CI OH CI OH CI CI 0 0 DD 0 DD 60A 60B 60C N 9H D "U 1 _> mm 0 A solution of Compound 60A (21 mg, 0.1 mmol) and K2C03 (55 mg, 0.4 mmol) in D20 (3 mL) was stirred at 110 °C for 16 h under N2. The mixture was acidified by the addition of 1M HCl solution, extracted with DCM (20 mL x 2), dried over anhydrous Na2S04, and concentrated to yield Compound 60B (15 mg, yield 71%) as a white solid. LC- MS (m/z): 167 [M-45]'; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 6.63 (s, 1H), 7.21 (m, 1H), 7.35 (d, J: 8.8 Hz, 1H), 7.50 (d, J: 2.0 Hz, 1H). -l7l- 2014/056555 A mixture of Compound 60B (100 mg, 0.47 mmol) in SOClz (3 mL) was stirred at 25 °C for 2 h. The mixture was concentrated to give Compound 60C (100 mg, crude) as a yellow oil which was used for the next step without further puriﬁcation.

Intermediate A was dissolved in CD30D and the t evaporated. To a solution of ediate A (100 mg, 0.36 mmol) in DCM (3 mL) was added Compound 60C solution (100 mg, 0.43 mmol). The mixture was stirred at 25 °C for 0.5 h. The mixture was added water (30 mL), extracted with DCM (30 mL x 3), dried over anhydrous Na2S04, and d by prep-HPLC to give Compound 60 (19 mg, yield 9%) as a white foam. LC-MS (m/z): 473 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.03 (m, 4H), 2.82 (m, 2H), 3.16 (m, 1H), 3.48 (m, 1H), 3.73 (br, 2H), 4.14 (m, 4H), 4.45 (m, 1H), 4.84 (d, J: 2.4 Hz, 1H), 6.41 (s, 1H), 6.64 (s, 2H), 6.76 (s, 1H), 7.18 (m, 1H), 7.32(d, J: 8.4 Hz, 1H), 7.45 (d, J: 2.0 Hz, 1H), 7.53 (d, J: 8.8 Hz, 1H), 11.42 (br, 1H).

Example 61 OH oH 0M3 9H "a;"mom 0 o NH 14 o Cbz’NEr 1 61B 610 N 9H N9H N 9" V131 I e "11 1aE E ' o 0 Cbz’NEr 0 NE'? 0 \"m1Er 0 CI 0 O 61D 61E 61 0] To a solution of Compound A6 (1 g, 2 mmol) in CH3CN (15 mL) was added NBS (564 mg, 3.2 mmol) and the mixture was stirred at 50 °C for 1.5 h. It was cooled to rt, diluted with DCM (50 mL), washed with water (100 mL x 3) and brine (100 mL), dried over Na2S04, and concentrated to give Compound 61A (1.2 g, crude) as a yellow solid. LC-MS (m/z): 534 [M-18]+.

To a on of Compound 61A (1 g, 2.1 mmol) in THF (20 mL) was added TBAF (275 mg, 1.05 mol) at 0 °C. The mixture was stirred at rt overnight, evaporated to remove solvent, and added water (50 mL). It was extracted with ethyl acetate (50 mL x 2), washed with brine (100 mL), dried over Na2S04, concentrated and, puriﬁed by column chromatography on silica gel (33% ethyl acetate in petroleum) to give Compound 61B (720 mg, yield 80%) as a white solid. LC-MS (m/z): 420 [M-18]+. 2] To a solution of Compound 61B (720 mg, 1.6 mmol) in THF (20 mL) was added Eth (500 mg, 4.94 mmol). The mixture was cooled to -15 °C, added MsCl (207 mg, -l72- 1.8 mmol) slowly, and stirred at -15 °C for half an hour. It was diluted with water, extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and concentrated to render Compound 61C (700 mg, yield 83%), which was used for the next step without further puriﬁcation. LC-MS (m/z): 498 [M-18]+.

To a solution of Compound 61C (700 mg, 1.36 mmol) in THF (20 mL) was added and idine (1 g, 13.6 mmol). The reaction mixture was allowed to warm up to rt and then heated at 50 °C overnight. After cooled to rt and added water (20 mL), the mixture was extracted with ethyl acetate (50 mL x 2), washed with water (50 ml x 3) and brine (50 mL), dried over Na2S04, and concentrated to give Compound 61D (600 mg, . LC-MS (m/z): 491 [M+1]+.

To a solution of nd 61D (600 mg, 1.22 mmol) in EtOH (20 mL) and H20 (2 mL) was added LiOH (154 mg, 3.67 mmol) and then the mixture was stirred at 100 °C overnight. After cooled to rt and added water (50 mL), the e was extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over , and concentrated to yield Compound 61E (200 mg, yield 50%) as a yellow liquid. LC-MS (m/z): 357 [M+1]+.

A mixture of Compound 11E (166 mg, 0.67 mmol), EDCI (216 mg, 1.12 mmol), HOBt (216 mg, 1.12 mmol), and Compound 61E (200 mg, 0.56 mmol) in DCM (20 nmhwmmmdMﬁmmmﬂtmemmmwwmmwMMMﬁmmmdmmDCM60mLx 2), washed with brine (50 mL), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 61 (130 mg, yield 40%) as a white solid. LC-MS (m/z): 585 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.15 (s, 4PD,295(&11D,310(&11D,257(nL2PD,387(nL2PD,394(nL2PD,404(nL11D,413 (nL11D,468(dwﬂ=72lﬂz11D,531(&11D,679(&11D,701(g11D,708(&11D,733 (m, 1H), 7.44 (d, J: 8.8 Hz, 1H), 7.56 (d, J: 1.6 Hz, 1H), 7.67 (d, J: 8.4 Hz, 1H), 11.79 (s, 111) Example 62 OH X X : N OH N OH MGMCU ~ "of w "(>0HN 0 § § 2 E ‘Cb 0 j ‘ z Cbz’NH NH2 j O 0 A8 62A 623 N H —> NH j \ 0 CI 0 0 To a solution of Compound A8 (437 mg, 1mmol) in CH3CN (20 mL) was added 3,3-dimethylazetidine (363 mg, 3 mmol), K2C03 (414 mg, 3 mmol), and NaI (449 mg,3 mmol). The mixture was heated at 82 °C overnight. It was cooled to rt, ﬁltered and concentrated in vacuum to give a crude Compound 62A (426 mg, crude) as a yellow oil. LC- MS (m/z): 427 [M+1]+. 7] To a solution of Compound 62A (426 mg, 1 mmol) in EtOH/water (20 mL, 9:1, v/v) was added LiOH-HZO (420 mg, 10 mmol). The mixture was reﬂuxed for 36 h. It was added water (20 mL) and ted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to yield Compound 62B (300 mg, crude) as a yellow oil. LC-MS (m/z): 293 [M+1]+.

To a e of Compound 62B (292 mg, 1 mmol) in DCM (20 mL) was added EDCI (288mg, 1.5 mmol), HOBt (202 mg, 1.5 mmol) and Compound 11E (246 mg, 1 mmol). It was stirred at 25 °C overnight, added water (10 mL), extracted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep-HPLC to afford a triﬂuoroacetic acid salt of Compound 62 (139 mg, yield 27%) as a white solid. LC-MS (m/z): 521 [M+1]+; 1H- NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.30 (s, 3H), 1.43 (s, 3H), 3.50 (s, 2H), 3.64 (t, J: 12 Hz, 2H), 4.05-4.19 (m, 6H), 4.30 (s, 1H), 5.01(s, 1H), 6.73 (s, 3H), 6.8 (s, 1H), 7.34 (d, J: 8 Hz, 1H), 7.42 (d, J: 8 Hz, 1H), 7.58 (s, 1H), 7.89 (d, J: 8 Hz, 1H), 12.23 (s, 1H). —174— Example 63 CI OH CI 0 CI F --—-—> ———____. F O o 0 63A 63C ::N 9H F FK/U 1 0' F F _, 0 CI O 63D 63 To a solution of nd 63A (3.00 g, 12.50 mmol) in DCM (100 mL) was added DMP (6.36 g, 15.00 mmol) carefully. The mixture was stirred at 25 °C overnight. The mixture was quenched with aq NaZSZOg solution, diluted with ethyl acetate (200 mL), washed with water and brine, and puriﬁed with silica gel column chromatography (ethyl acetate in petroleum ether, from 0% to 20% v/v) to render Compound 63B (2.10 g, yield 70%) as a white solid. LC-MS (m/z): 239 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 3.06-3.11 (m, 3H), 3.15-3.30 (m, 1H), 3.84 (s, 3H), .93 (m, 0.5H), 4.06- 4.10 (m, 0.5H), 7.10-7.20 (m, 3H).

To a solution of Compound 63B (200 mg, 1.26 mmol), in DCM (5 mL) was added DAST (1.01 g, 6.30 mmol) dropwise at 20 °C. The mixture was stirred at 20 °C overnight. The mixture was diluted with ethyl acetate (100 mL), washed with water and brine, and puriﬁed by silica gel column tography (dichloromethane in petroleum ether, from 0% to 8% v/v) to yield Compound 63C (280 mg, yield 85%) as a colorless oil.

LC-MS (m/z): 261 [M+1]+; 1H-NMR (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 3.06-3.11 (m, 3H), 3.15-3.30 (m, 1H), 3.84 (s, 3H), 3.90-3.93 (m, 0.5H), 4.06-4.10 (m, 0.5H), 7.10-7.20 (m, 3H).

A mixture of Compound 63C (280 mg, 1.08 mmol) and ZO (136 mg, 3.24 mmol) in THF/MeOH/H20 (10/10/5 mL) was stirred at 20 °C overnight. The mixture was acidiﬁed to pH 2 with dilute HCl and extracted with DCM. Then organic phase washed with water and brine, dried over anhydrous , and evaporated to give Compound 63D (230 mg, yield 86%) as white solid. LC-MS (m/z): 465 [M-1]'.

A e of Compound 63D (89 mg, 0.36 mmol), Compound 11E (100 mg, 0.36 mmol), EDCI (104 mg, 0.54 mmol) and HOBt (73 mg, 0.54 mmol) in DCM (10 mL) was stirred at 25 °C overnight. The mixture was d with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by prep-HPLC to afford Compound 63 (100 mg, yield 55%) as a white solid. LC-MS (m/z): 507 ; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.88 (br s, 2H), 2.01 (br s, 2H), 2.50-2.83 (m, 4H), 3.00-3.16 (m, 3H), 3.50-3.55 (m, 5H), 4.13-4.20 (m, 4H), 4.42-4.50 (m, 1H), 4.74 (br s, 1H), 5.88 (s, 1H), 6.78-6.84 (m, 3H), 7.20-7.26 (m, 3H), 8.40 (d, J: 8.8 Hz, 1H), 9.50 (s, 1H).

Example 64 U N 9H N IIO I —’ F F ' j NH : Oj O KlHZ CI 0 O F c 64 3] To a solution of ediate C (292 mg, 1 mmol) in DCM (20 mL) was added EDCI (288 mg, 1.5 mmol), HOBt (202 mg, 1.5 mmol) and Compound 11E (246 mg, 1 mmol) and it was stirred at 25 °C overnight. The mixture was added water (10 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep- HPLC to afford a triﬂuoroacetic acid salt of Compound 64 (120 mg, yield 19%) as a white solid. LC-MS (m/z): 525 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.14 (s, 4H), 2.91-3.03 (m, 2H), 3.50 (d, J: 4 Hz, 2H), 3.82 (s, 2H), 4.11-4.19 (m, 4H), 4.44 (d, J: 4Hz, 1H), 5.07 (s, 1H), 6.61 (s, 1H), 6.70 (d, J: 12 Hz, 1H), 6.86 (s, 1H), 7.34 (d, J: 12 Hz, 1H), 7.43 (d, J: 12 Hz, 1H), 7.58 (s, 1H), 7.80 (d, J=8 Hz, 1H), 11.76 (s, 1H).

Example 65 To a solution of Intermediate D (250 mg, 0.8 mmol) in dichloromethane (20 mL) was added EDCI (230 mg, 1.2 mmol), HOBt (162 mg, 1.2 mmol) and Compound 11E (196 mg, 0.8 mmol). The mixture was stirred at 25 °C overnight, added water (10 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous Na2S04, and d by prep-HPLC to afford a triﬂuoroacetic acid salt of Compound 65 (75 mg, yield 14%) as a white solid. LC-MS (m/z): 1]+; 1H-NMR (CDClg, 400 MHz) major characteristic WO 42397 peaks: 5 (ppm) 2.13 (s, 4H), 3.01 (s, 2H), 3.51 (s, 2H), 3.80 (s, 2H), 4.06 (s, 2H), 4.20 (s, 2H), 4.47(d, J: 4 Hz, 1H), 5.06 (s, 1H), 6.74 (s, 1H), 6.80 (s, 1H), 6.94 (s, 1H), 7.34 (d, J: 12 Hz, 1H), 7.43 (d, J: 12 Hz, 1H), 7.58 (s, 1H), 7.80 (d, J: 8 Hz, 1H), 11.76 (s, 1H). e 66 Cbzm1~mmj~OMS OH "(11 To a solution of nd A8 (437 mg, 1mmol) in CH3CN (20 mL) was added 3-methylazetidine hydrochloride (321 mg, 3 mmol), K2C03 (414 mg, 3 mmol) and Nal (449 mg, 3 mmol). The mixture was heated at 82 °C overnight. It was cooled to rt, ﬁltered, and concentrated in vacuum to give crude Compound 66A (426 mg, crude) as a yellow oil.

LC-MS (m/z): 413 [M+1]+.

To a solution of Compound 66A (412 mg, 1 mmol) in EtOH/water (20 mL, 9:1, v/v) was added LiOH-HZO (420 mg, 10 mmol). The mixture was reﬂuxed for 24 h and water (20 mL) was added. It was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to give crude Compound 66B (280 mg, crude) as a yellow oil. LC-MS (m/z): 278 [M+1]+.

To a mixture of Compound 66B (140 mg, 0.5 mmol) in DCM (10 mL) was added EDCI (144 mg, 0.75 mmol), HOBt (100 mg, 0.75 mmol), and Compound 11E (123 mg, 0.5 mmol) and d at 30 °C overnight. It was added water (10 mL), extracted with DCM (20 mL x 3), dried over anhydrous Na2S04, and puriﬁed by prep-HPLC to give a triﬂuoroacetic acid salt of Compound 66 (20 mg, yield 6%) as a white solid. LC-MS (m/z): 507 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.23-1.38 (m, 3H), 2.92 (s, 1H), 3.15 (s, 1H), 3.49 (s, 3H), .15 (m, 5H), 4.30 (s, 1H), 4.43 (s, 1H), .00 (s, 1H), 6.73(s, 3H), 6.80 (s, 1H), 7.34 (d, J: 8 Hz, 1H), 7.42 (d, J: 8 Hz, 1H), 7.58 (s, 1H), 7.85 (s, 1H), 12.34 (s, 1H).

WO 42397 Example 67 N 9H I 5 N 9H 1 E NH CI —» o/A 0H2 o/A 0' O 44G 67 A mixture of Compound 11E (100 mg, 0.41 mmol), EDCI.HC1 (118 mg, 0.62 mmol), HOBt (81 mg, 0.62 mmol), Compound 44G (126 mg, 0.41 mmol) in DCM (5 mL) was stirred at 28 °C overnight. The mixture was added dropwise sat. aq NaHC03, and then extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 67 (62 mg, yield 28%) as a white solid. LC-MS: 539 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major teristic peaks: 5 (ppm) 0.62 (m, 2H), 081 (m, 2H), 1.88 (m, 2H), 2.03 (m, 2H), 2.60- 2.65 (m, 2H), 2.76-2.80 (m, 2H), 3.06-3.20 (m, 3H), 3.41-3.54 (m, 4H), 3.88 (s, 1H), 5.53 (s, 1H), 8.84 (s, 1H), 6.00 (s, 1H), 7.15-7.21 (m, 3H), 7.27-7.31 (m, 1H), 7.36-7.40 (m, 2H), 8.45 (d, J: 9.2 Hz, 1H). e 68 ‘ / .

TBSO NHCbZ G / _> [le 0 FIH 0 g \ CI \ CI 68F 686 68 To a solution of Compound 11B (4.59 g, 30 mmol) in THF (125 mL) was added n-BuLi (2.4 M, 12.5 mL) at -60 °C under N2 and stirred for 0.5 h and then a on of Compound A4 (3.97 g, 10 mmol) in THF (50 mL) was added slowly. The mixture was stirred at -60 °C for 1 h, before quenched by addition of saturate aq NH4C1 solution The mixture was extracted with ethyl acetate, brine, and dried over Na2S04. The crude product was puriﬁed by column chromatography on silica gel (ethyl acetate in petroleum, 5% v/v) to give Compound 68A (3.48 g, yield 71%) as a yellow oil. LC-MS (m/z): 488 [M+1]+; 1H-NMR(CDC13, 400 MHz) major teristic peaks: 5 (ppm) -0.11 (s, 3H), -0.08 (s, 3H), 0.75 (s, 9H), 4.99 (dd, J: 4.4, 10.0 Hz, 1H), 4.19 (dd, J: 3.6, 10.0 Hz, 1H), 5.14 (s, 2H), 5.26-5.30 (m, 1H), 5.87 (d, J: 7.6 Hz, 1H), 7.32-7.38 (m, 5H), 7.45-7.57 (m, 3H), 7.70 (d, J: 2.0 Hz, 1H).

A solution of Compound 68A (3.48 g, 7.14 mmol) in THF (200 mL) was added L-selectride (1M solution in THF, 14.3 mL) dropwise at -70 °C under nitrogen atmosphere. After d for one hour, the reaction was quenched with saturated aq NH4Cl solution and the mixture was extracted with ethyl acetate and dried over Na2S04. The crude product was d by column chromatography on silica gel (ethyl acetate in petroleum, % v/v) to give Compound 68B (3.41 g, yield 97%) as a colorless oil. LC-MS (m/z): 472 To a solution of Compound 68B (3.41 g, 6.95 mmol) in THF (100 mL) was added a solution of TBAF (0.91 mg, 3.48 mmol) in THF (10 mL) at 0 °C. After stirred at rt for 18 h, the mixture was evaporated to remove solvent. The residue was taken up with water, extracted with ethyl acetate, washed with brine, and dried over Na2S04. The crude was d by ﬂash column tography on silica gel (MeOH in DCM, 5% v/v) to render Compound 69C (2.01 g, yield 76%) as a white solid. LC-MS (m/z): 358 [M-17]+.

To a solution of nd 68C (2.01 g, 5.35 mmol) in THF (100 mL) was added Eth (1.62 g, 16.01 mmol) at -40 °C. MsCl (646 mg, 5.62 mmol) was added slowly amHmnmmmewwsmmdMHﬂVCﬁw4hAﬁmewmmmmmCmmmmﬂ6$)@28g yield 100%) was obtained as yellow oil, which was used for the next step without puriﬁcation.

To a solution of Compound 68D (2.28 g, 5.35 mmol) in THF (100 mL) was added pyrrolidine (3.03 g, 42.8 mmol). The reaction mixture was heated at 50 °C for 15 h.

After evaporation, the crude product was puriﬁed by column chromatography on silica gel (methanol in dichloromethane, 5% v/v) to give Compound 68E (940 mg) as a colorless oil.

LC-MS (m/z): 429 [M+H]+.

To a solution of Compound 68E (310 mg, 0.72 mmol) in l (10 mL) and H20 (10 mL) was added LiOH (152 mg, 3.61 mmol). The mixture was reﬂuxed for 4 h. After evaporation, the mixture was extracted by DCM, and washed by brine, and dried over anhydrous Na2S04. After ﬁltration and evaporation, Compound 69F (210 mg, yield 98%) was obtained as a yellow oil. LC-MS (m/z): 295 [M+1]+.

A mixture of Compound 68F (210 mg, 0.71 mmol), EDCI (204 mg, 1.07 mmol), HOBt (145 mg, 1.07 mmol) and Compound 11E (210 mg, 0.85 mmol) in DCM (10 mL) was stirred at 25 °C for 16 h. The mixture was washed by saturated NaHCOg and brine.

After evaporation, the crude was d by prep-HPLC and followed by chiral-prep-HPLC to afford Compound 68G (77 mg, yield 17%) as a white solid and Compund 68 (82 mg, yield 18%) as a white solid. For Compound 68G, LCMS (m/z): 523 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.07 (s, 4H), .91 (m, 2H), .29 (m, 1H), 3.70-3.95 (m, 3H), 4.82 (s, 1H), 5.02 (d, J: 4.0 Hz, 1H), 6.68 (s, 1H), 6.91 (s, 19-7.21 (m, 1H), 7.28-7.33 (m, 3H), 7.35 (d, J: 2.0 Hz, 1H), 7.50 (d, J = 1.2 Hz, 1H), 9.18 (d, J: 7.2 Hz, 1H), 11.70 (s, 1H). For Compound 68, LC-MS (m/z): 523 [M+1]+; 1H-NMR , 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (s, 4H), 2.94-3.06 (m, 2H), 3.61 (s, 2H), 3.85 (s, 2H), 4.81 (d, J: 6.0 Hz, 1H), 5.33 (s, 1H), 6.64 (s, 2H), 7.06-7.09 (m, 1H), 7.14-7.15 (m, 1H), .21 (m, 1H), 7.28-7.31 (m, 2H), 7.39-7.40 (m, 1H), 7.96 (d, J: 7.2 Hz, 1H), 11.78 (s, 1H).

Example 69 M95MW A mixture of Compound 33F (150 mg, 0.54 mmol), EDCI.HC1 (154 mg, 0.81 mmol), HOBt (109 mg, 0.81 mmol), nd 44G (166 mg, 0.54 mmol) in DCM (5 mL) was stirred at 28 °C overnight. The reaction was quenched with addition of sat. aq NaHCOg and the mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 70 (42 mg, yield 14.1%) as a white solid and Compound 69A (42 mg, yield 14.1%) as a white solid. For Compound 69, LC-MS (m/z): 573 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 0.52-0.61 (m, 2H), 0.73-0.76 (m, 2H), 1.89 (br s, 2H), 2.02 (br s, 2H), 3.08-3.21 (m, 2H), 3.50 (s, 4H), 3.67-3.72 (m, 1H), 4.53 (s, 1H), 4.82 (s, 1H), 6.04 (s, 1H), 7.02 (s, 1H), 7.13 (d, J: 8.8 Hz, 1H), 7.21 (d, J: 8.8 Hz, 1H), 7.32 (s, 1H), 7.86 (s, 1H), 7.93 (d, J: 8.8 Hz, 1H), 8.16 (s, 1H), 8.93 (d, J: 9.2 Hz, 1H), 9.66 (s, 1H). For Compound 69A, LC-MS (m/z): 573 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 0.46-0.54 (m, 2H), 0.70-0.74 (m, 2H), 1.89 (br s, 2H), 2.04 (br s, 2H), 3.15 (s, 2H), 3.38-3.48 (m, 4H), 3.60-3.65 (m, 1H), 4.13-4.37 (s, 1H), 4.52 (s, 1H), 6.09 (s, 1H), 6.73 (s, 1H), 7.14 (d, J: 8.8 Hz, 1H), 7.23 (d, J: 8.8 Hz, 1H), 7.82-7.90 (m, 2H), 8.09 (s, 1H), 9.27 (d, J: 9.2 Hz, 1H), 9.62 (s, 1H).

Example 70 6341:; 6;»?ng UOTBS :1 _.Cgtﬁﬁ:1 To a stirred on of Compound 1E (500 mg, 2.27 mmol) in THF (8 mL) was added LiOH.H2O (99 mg, 2.27 mmol) and water (2 mL). The mixture was stirred at room temperature for 3 h. After reaction, the e was adjusted pH to 1 with 1 M HCl and concentrated by evaporation. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, and trated to render Compound 70A (403 mg, yield 92%) as a yellow solid.

LCMS: (m/z) 193 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.97 (m, 3H), 3.07-3.09 (m, 2H), 4.39 (d, J: 4.4 Hz, 1H), 7.15 — 7.19 (m, 4H).

To a solution of (1R,2R)((tert-butyldimethylsilyl)oxy)(2,3- dihydrobenzo[b][1,4]dioxinyl)(pyrrolidinyl)propanamine (392 mg, 1.0 mmol) in DCM (20 mL) was added EDCI (288 mg, 1.5 mmol), HOBt (202 mg, 1.5 mmol) and Compound 70A (192 mg, 1.0 mmol). The mixture was stirred at room temperature overnight and diluted with DCM (20 mL). It was washed with water (50 mL x 2), brine (50 mL x 1), dried over anhydrous Na2S04, concentrated, and puriﬁed by silica gel column chromatography (methanol in dichloromathane, 5% v/v) to give Compound 70B (360 mg, yield 64%) as a yellow oil. LC-MS (m/z): 567 [M+1]+.

To a stirred solution of Compound 70B (360 mg, 0.64 mmol) in DCM (20 mL) was added DMP (324 mg, 0.76 mmol). The mixture was stirred at room temperature overnight. It was quenched with sat. aq Na2S03 solution and then concentrate by evaporation.

The s phase was extracted with DCM (50 mL x 3). The combined organic phase was washed with water, brine, and dried over anhydrous Na2S04. Filtration and evaporation to dryness gave Compound 70C (210 mg, yield 60%) as a yellow oil. LCMS: (m/z) 565 [M+1]+.

To a solution of Compound 70C (210 mg, 0.37 mmol) in THF (20 mL) was added TBAF (195 mg, 0.74 mmol). The mixture was stirred at room temperature overnight, quenched with sat. aq NH4Cl solution, and trated by evaporation. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic phase was washed with water, brine, and dried over ous Na2S04. Removal of solvent led to a crude product, which was puriﬁed by prep-HPLC to give Compound 70 (12 mg, yield 7%) as a yellow solid. LC- MS (m/z): 451 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.07 (s, 4H), 2.87 (m, 3H), 3.21 (m, 4H), 3.82 (m, 3H), 4.08 (m, 1H), , 4H), 4.45 (m, 2H), 4.96 (m, 1H), 6.76-6.82 (m, 3H), 7.14 (m, 4H), 7.86 (s, 1H), 11.11 (s, 1H).

Example71 N 9H = o Wr W —» NH \ o O O O OH CI 0 O o 0 11C 71A 71 To a solution of Compound 11C (300 mg, 1.19 mmol) in EtOH (5 mL) was added LiOH (43 mg, 1.78 mmol) in water (5 mL). The e was stirred at room temperature overnight. After removal of EtOH by evaporation, the mixture was adjusted to pH 7 with diluted HCl. lyophilization of the solution gave Compound 71A (200 mg, crude), which was used for the next step without ﬁlrther puriﬁcation. LC-MS (m/z): 223 [M-1]'.

A mixture of Compound 71A (100 mg, 0.45 mmol), EDCI (130 mg, 0.68 mmol), HOBt (91 mg, 0.68 mmol), ediate A (125 mg, 0.45 mmol) in DCM (10 mL) was stirred at room temperature ght. After addition of sat. aq NaHCOg, the mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and trated. The crude product was puriﬁed by prep-HPLC to give Compound 71 (68 mg, yield 31%) as a white solid. LC-MS (m/z): 485 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.84 (m, 4H), 3.13 (m, 2H), 3.51 (m, 4H), 4.18 (s, 4H), 4.42 (s, 1H), 4.70 (s, 1H), 5.92 (s, 1H), 6.80 (m, 3H), 7.65 (m,1H), 7.81 (m, 1H), 8.05 (s, 1H), 8.19 (m, 1H), 8.59 (s, 1H), 9.18 (s, 1H).

Example 72 Q Q QH Q" o vac] Ho\IN :oj NH —» NH \ 0 0 C|4< £0 0 CI4< >/:0 0 A mixture of Compound 71 (20 mg, 0.042 mmol) and saturated hydroxylamine solution in methanol (5 mL) was stirred at 70 °C for 5 h. After addition of sat. aq NH4Cl (10 mL), the mixture was extracted with DCM (10 mL x 2), washed with brine (30 mL), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 72 (3 mg, yield 14%) as a white solid. LC-MS (m/z): 500 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5 (ppm) 1.92 (m, 4H), 3.11 (m, 2H), 3.55 (m, 4H), 4.21 (s, 4H), 4.58 (s, 1H), 4.80 (s, 1H), 5.95(s, 1H), 6.46 (s, 1H), 6.87 (m, 3H), 7.40 (m,1H), 7.64 (m, 2H), 8.84 (m, 1H), 10.07 (s, 1H), 12.42 (s, 1H).

Example 73 ::N QTBS OH 5 OH O 0 .

\/ OH HH —> —> O \ N — / \ /N \ N 50F 73A / 733 N 9TBS N 9H 0 O] o NH = NH O] 0 0 \ /N 730 \ /N 73 To a stirred solution of Compound 50F (250 mg, 0.84 mmol) in THF (10 mL) was added LiOH.H20 (71 mg, 1.68 mmol) and water (2 mL). The e was stirred at room temperature for 3 h. After adjusted pH to 1 with 1 M HCl, the mixture was concentrated by evaporation. The aqueous phase was ted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water, brine, and dried over anhydrous , and concentrated to give Compound 73A (160 mg, yield 71%) as a yellow solid. LCMS: (m/z) 270 [M+1]+.

To a solution of (1R,2R)((tert—butyldimethylsilyl)oxy)(2,3- dihydrobenzo[b][1,4]dioxinyl)(pyrrolidinyl)propanamine (233 mg, 0.59 mmol) in DCM (10 mL) was added EDCI (171 mg, 0.89 mmol), HOBt (120 mg, 0.89 mmol) and Compound 73A (160 mg, 0.59 mmol). The mixture was stirred at 25 °C overnight. After diluted with DCM (20 mL), it was washed with water (50 mL x 2), brine (50 mL x 1), dried over anhydrous Na2S04, trated, and puriﬁed by column chromatography on silica gel (methanol in dichloromethane, 5% v/v) to give Compound 73B (120 mg, yield 31%) as a yellow oil. LC-MS (m/z): 644 [M+1]+.

To a stirred solution of Compound 73B (120 mg, 0.19 mmol) in DCM (10 mL) was added DMP (97 mg, 0.23 mmol) and NaHC03 (31 mg, 0.37 mmol). The mixture was stirred at 25 °C overnight. After addition with sat. aq Na2S03 solution, the e was concentrated by evaporation. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic phase was washed with water, brine, and dried over anhydrous Na2S04.

Filtration and ation of the solution to dryness gave Compound 73C (110 mg, yield 92%) as a colorless oil. LCMS (m/z): 642 [M+1]+.

To a solution of Compound 73C (110 mg, 0.17 mmol) in THF (10 mL) was added TBAF (22 mg, 0.09 mmol). The mixture was stirred at 25 °C overnight and followed by quenched with sat. aq NH4C1 on. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic phase was washed with water, brine, and dried over ous Na2S04. After removal of the solvents, the crude product was puriﬁed by prep- HPLC twice to give Compound 73 (5.9 mg, yield 7%) as a white solid. LC-MS (m/z): 528 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.72 (m, 2H), 1.85 (m, 3H), 1.94-1.97 (m, 1H), 2.31 (s, 1H), 2.53 (s, 1H), 2.77 (m, 3H), 2.92-3.12 (m, 3H), 3.26- 3.28 (m, 3H), 4.23-4.24 (m, 5H), 4.62 (d, J: 4.8 HZ, 0.36 H), 5.03 (m, 0.64H), 6.62-6.72 (m, 1H), .85 (m, 2H), 7.21 (m, 1H), 7.29-7.34 (m, 1H), 7.70-7.72 (m, 3H), 7.83-7.86 (m, 1H), 8.66 (m, 1H).

WO 42397 2014/056555 Example 74 ::N QTBs Cl OH CI OH o _. _. 1 0 OH 0 o \ 0 CI 0 63A 74A 743 ::N OTBS i 3 —> E CI 0 74C 74 A e of Compound 63A (1.10 g, 4.58 mmol) and LiOH.H20 (577 mg, 13.75 mmol) in THF/MeOH/HZO (20/20/10 mL) was stirred at 25 °C for 3 h. It was diluted with ice-water (150 mL) and adjusted to pH 1 with cone. HCl. Filtration to collect the solid gave Compound 74A (900 mg, yield 87%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) major characteristic peaks: 5(ppm) 2.75-2.91 (m, 5H), 3.96 (s, 1H), 7.12-7.24 (m, 3H).

A mixture of Compound 74A (100 mg, 0.44 mmol), EDCI (127 mg, 0.66 mmol), HOBt (89 mg, 0.66 mmol) and (1R,2R)(tert—butyldimethylsilyloxy)(2,3- dihydrobenzo[b][1,4]dioxinyl)(pyrrolidinyl)propanamine (173 mg, 0.44 mmol) in DCM (10 mL) was stirred at 25 °C ght. It was diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by silica gel column chromatography (methanol in dichloromethane, from 0% to 8% v/v) to give Compound 74B (230 mg, yield 87%) as a white solid. LC-MS (m/z): 601 [M+1]+.

A mixture of Compound 74B (200 mg, 0.33 mmol) and DMP (212 mg, 0.50 mmol) in DCM (10 mL) was stirred at 25 °C overnight. The mixture was diluted with ethyl e (150 mL), washed with water and brine, and puriﬁed by silica gel column chromatography (methanol in dichloromethane, from 0% to 8% v/v) to afford Compound 74C (160 mg, yield 80%) as a colorless oil. LC-MS (m/z): 599 [M+1]+.

A mixture of Compound 74C (160 mg, 0.27 mmol) and Bu4NF (50 mg) in THF (20 mL) was stirred at 25 °C overnight. The mixture was diluted with ethyl acetate (150 mL), washed with water and brine, and d by prep-HPLC to yield Compound 74 (60 mg, yield 46%) as a white solid. LC-MS (m/z): 485 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.72 (br s, 4H), 1.87-1.96 (m, 2H), 2.30 (br s, 1H), 2.54- 2.65 (m, 2H), 2.95-3.03 (m, 3H), 3.12-3.25 (m, 3H), 3.49-3.56 (m, 1H), 4.59 (s, 5H), 4.60 (d, J: 8.0 Hz, 1H), 5.09 (s, 1H), 6.57-6.63 (m, 1H), 6.77-6.85 (m, 2H), 7.10-7.17 (m, 4H).

Example 75 N OTBS 1:... _, %:N._, 9m _.

N9TBs N Q 933 Q 2H A mixture of 75A (1.00 g, 9.09 mmol) and Pd/C (1.00 g, 10%) in MeOH (20 mL) was stirred at 25 °C overnight in the presence of H2. Then mixture was ﬁltered to remove Pd/C. The ﬁltrate was evaporated to render Compound 75B (1 .OOg, yield 100%) as a white solid. LC-MS (m/z): 89 [M-1]'. 3] A mixture of Compound 75B (57 mg, 0.51 mmol), (1R,2R)(tert- butyldimethylsilyloxy)(2,3-dihydrobenzo [b] [1 ,4]dioxinyl)-3 -(pyrrolidinyl)propan amine (200 mg, 0.51 mmol), EDCI (147 mg, 0.76 mmol) and HOBt (103 mg, 0.76 mmol) in DMSO (5 mL) was stirred at 20 °C overnight. It was diluted with ethyl acetate (200 mL), washed with water and brine, and puriﬁed by silica gel column tography (methanol in dichloromethane, from 0% to 8% v/v) to yield Compound 75C (180 mg, yield 76%) as colorless oil. LC-MS (m/z): 465 .

To a solution of Compound 75C (470 mg, 1.01 mmol) in DCM (10 mL) was added DMP (478 mg, 1.11 mmol) at 20 °C. The mixture was d at 20 °C overnight. The mixture was quenched with Na2S203 aqueous solution, diluted with ethyla acetate (200 mL), washed with water and brine, dried with ous Na2S04, and puriﬁed by silica gel column chromatography (methanol in dichloromethane, from 0% to 8% v/v) to afford Compound 75D (320 mg, yield 68%) as colorless oil. LC-MS (m/z): 463 [M+1]+.

A mixture of Compound 75D (150 mg, 0.32 mmol), sodium acetate (53 mg, 0.64 mmol) and ylhydroxylamine hydrochloride (91 mg, 0.64 mmol) in EtOH (10 mL) was stirred at 85 0C for 3 h. Puriﬁcation by prep-HPLC gave Compound 75E (100 mg, yield 56%) as a colorless oil. LC-MS (m/z): 554 [M+1]+.

A e of Compound 75E (100 mg, 0.23 mmol) and Bu4NF (10 mg) in THF (10 mL) was stirred at 20 °C overnight. The mixture was diluted with ethyl acetate (150 mL), washed with water and brine, and puriﬁed by prep-HPLC to give Compound 75 (22 mg, yield 22%) as a white solid. LC-MS (m/z): 440 [M+1]+; 1H-NMR (MeOD, 400 MHz) major characteristic peaks: 5 (ppm) 1.99-2.06 (m, 2H), 2.17 (s, 5H), 3.14-3.23 (m, 2H), 3.43-3.49 (m, 1H), 3.59-3.68 (m, 2H), 3.80-3.87 (m, 1H), 4.21 (s, 4H), 4.50-4.55 (m, 1H), 4.83 (s, 1H), 6.80 (d, J: 8.0 Hz, 1H), 6.87-6.90 (m, 1H), 6.96 (s, 1H), .16 (m, 1H), 7.30-7.33 (m, 2H), 7.38-7.42 (m, 2H). e 76 A mixture of nd 71 (30 mg, 0.062 mmol), O-methylhydroxylamine (29 mg, 0.62 mmol) in methanol (5 mL) was stirred at 60 °C for 5 h. After addition of sat. aq NH4Cl (10 mL), the mixture was ted with DCM (10 mL x 2), washed with brine (30 mL x 1), dried over Na2S04, and concentrated. The crude product was puriﬁed by prep-HPLC to give Compound 76 (10 mg, yield: 31%) as a white solid. LC-MS (m/z): 514 [M+1]+; 1H- NMR (DMSO-dg, 400 MHz) major teristic peaks: 5 (ppm) 1.88 (m, 4H), 3.10 (m, 2H), 3.61 (m, 4H), 3.96 (m, 3H), 4.20 (m, 4H), 4.48 (m, 1H), 4.83 (m, 1H), 5.98(s, 1H), 6.44 (s, 1H), 6.91 (m, 3H), 7.61 (m,1H), 8.40 (m, 1H), 9.61 (m, 1H).

Example 77 CEO—(10HCCNJ’L/_,03;0/03" mcgﬁ035;QWWJ A mixture ofNaH (60%, 20 g, 500 mmol), THF (3 L), EtOH (2.5 mL) was cooled to 0 0C, ethyl formate (55.5 g, 750 mmol) and Compound 77A (49 g, 500 mmol) were added. The mixture was stirred for 6 hrs, and stood for 24 hrs. After the addition of EtOH (10 mL), the mixture was stirred for 1 hr, added water (1L) and EA (1L), washed with water (500 mL x 2). The aqueous layer was acidiﬁed with 6 N HCl, extracted with EA (300 mL x 2), washed with brine (300 mL x 1), dried over anhydrous Na2S04, and puriﬁed by column chromatography on silica (ethyl e in eum ether, 10% v/v) to give Compound 77B. 9] To a solution of Compound 77B (23 g, 183 mmol) in MeOH (300 mL) was added 2-aminoacetate hydrochloride (23 g, 183 mmol) and NEt3 (18.4 g, 183 mmol). The mixture was stirred at 25 0C for 16 hrs. The mixture was concentrated and added water (100 mL), extracted with DCM (100 mL x 3), washed with brine (100 mL x 1), dried over anhydrous Na2S04, concentrated to give Compound 77C.

To a solution ofNaOMe (6.86 g, 127 mmol) in MeOH (200 mL) was added Conmmund77C(25g,127nnnoD.Thennxunewmssﬁnedat90°C1br3lnszhennxune was poured into water (500 mL), extracted with EA (100 mL x 3), washed with water (50 mL x 1), dried over anhydrous Na2S04, puriﬁed by column tography (dichloromethane, 100% v/v) to give Compound 77D.

A mixture of Compound 77D (1 g, 5.6 mmol) and KOH (0.6 g, 11.2 mmol) in ethane-1,2-diol (20 mL) was stirred at 200 0C for 3 hrs. The mixture was cooled down, added DCM (50 mL), washed with water (50 mL x 3), brine (50 mL x 1), dried over anhydrous N®SohmnmmeFCC(dbdmdﬁempdmbmnde020%vw)mgNeCmmmmm 77E.

To a solution of Compound 77E (200 mg, 1.7 mmol) and NEtg (550 mg, 5.1 mmol) in DCM (20 mL) was added ethyl 2-chlorooxoacetate (455 mg, 3.4 mmol) and stirred at 25 0C for 3 hrs. The mixture was added DCM (50 mL), washed with water (50 mL x 3), brine (50 mL x 1), dried over anhydrous Na2S04, puriﬁed by FCC (ethyl acetate in petroleum ether, 0-20% v/v) to give Compound 77F.

To a on of Compound 77F (350 mg, 1.58 mmol) in EtOH (30 mL) and H20 (3 mL) was added LiOH.HzO (133 mg, 3.17 mmol) and d at 25 0C for 10 min, concentrated and added water (30 mL), extracted with DCM (20 mL x 2). The aqueous layer was acidiﬁed via the addition of 1 N HCl, extracted with DCM (20 mL x 3), dried over anhydrous Na2S04, concentrated to give Compound 77G.

To a solution of Compound 77G (100 mg, 0.5 mmol), EDCI (144 mg, 0.75 mmol), HOBt (100 mg, 0.75 mmol) in DCM (10 mL) was added Intermediate A (140 mg, 0.5 mmol). The mixture was d at 25°C for 24 hrs, added water (50 mL), extracted with DCM (30 mL x 3), dried over anhydrous Na2S04, puriﬁed by prep-HPLC to give Compound 77. LCMS: 454 [M+H] +; 1H NMR(CDC13, 400 MHz) 5 (ppm) 1.73 (m, 4H), 2.10 (m, 5H), 2.51 (m, 2H), 2.84 (m, 2H), 2.97 (br, 1H), 3.40 (m, 2H), 3.92 (m, 2H), 4.21 (s, 4H), 4.44 (s, 1H), 5.10 (s, 1H), 6.80 (m, 3H), 6.88 (s, 1H), 8.20 (br, 1H), 11.02 (br, 1H), 11.49 (br, 1H).

Example 78 Q 9H CI O 0 W : NH 1 \ O O OH 0 CI 0 0 73A 78 A mixture of Compound 73A (200 mg, 0.75 mmol), EDCI (218 mg, 1.13 mmol), HOBt (154 mg, 1.13 mmol), Intermediate F (168 mg, 0.75 mmol) in DCM (20 mL) was stirred at room temperature overnight. Then added water, extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, concentrated. The crude product was puriﬁed by pre-HPLC to give Compound 78. LC-MS (ESI) m/z: 471 [M+H]+; 1H NMR (CDC13, 400 MHz) 5 (ppm) 2.43 (m, 2H), 3.14 (s, 3H), 3.58 (m, 2H), 4.13 (s, 4H), 4.41 (m, 2H), 4.99 (s, 1H), 6.83 (m, 3H), 7.44 (s, 2H), 7.67 (s, 1H), 8.01 (s, 1H), 8.19(s, 1H), 10.96 (s, 1H).

Example 79 A mixture of Compound 73A (254 mg, 1.13 mmol), EDCI.HC1 (325 mg, 1.69 mmol), HOBt (230 mg, 1.69 mmol) and Intermediate I (350 mg, 1.13 mmol) in DCM (25 mL) was stirred at room ature overnight. Then the mixture was d with water, extracted with DCM (150 mL x 2), washed with brine (100 mL x 1), dried over Na2S04 and concentrated. The crude product was d with Prep-HPLC to provide Compound 79. LC- MS (ESI) m/z: 517.0 [M+H]+; 1H NMR (CDC13, 400 MHz) 5 (ppm) 0.74-0.76 (d, J: 5.2 Hz, 4H), 2.15 (s, 4H), 2.98-2.99 (m, 3H), 3.66 (s, 1H), .77 (m, 2H), 3.91 (s, 2H), 4.53 (s, 1H), 5.14 (s, 1H), 7.17-7.22 (m, 2H), 7.35 (s, 1H), 7.43-7.49 (m, 2H), 7.685-7.688 (d, J: 1.2 Hz, 1H), 8.11-8.18 (m, 2H), 11.77 (s, 1H). e 80 f \ ::N QH N OH \ F Fm k CI F \ N F / I + \ — \ O HN2 / o o OH CI 0 0 K 11E 80 To a solution of Intermediate K (200 mg, 0.72 mmol) and Compound 11E (176 mg, 0.72 mmol) in DCM (10 mL) was added EDCI.HC1 (207 mg, 1.08 mmol) and HOBt (146 mg, 1.08 mmol) under N2. The mixture was stirred at 30 0C overnight. TLC and LC-MS showed the starting material was consumed completely, then water (3 mL) was added to the mixture and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over anhydrous Na2S04, and concentrated to provide the crude product. The crude product was puriﬁed with Prep-HPLC to provide a racemic mixture (45 mg, Yield: 12%) as a white solid, which was further d by chiral HPLC (AD-H, 0.1% DEA in methanol) to furnish Compound 80. LC-MS (ESI) m/z: 508 [M+H]+; 1H NMR (MeOD, 400 MHz) 5 (ppm) 1.29 (m, 6H), 1.83 (s, 4H), 2.69-2.73 (m, 4H), 2.91 (d, J: 6.8 Hz, 2H), 4.41 (m, 1H), 4.93 (d, J: 3.6 Hz, 1H), 5.08 (m, 1H), 6.56 (d, J: 8.4 Hz, 1H), 7.07 (s, 1H), 7.45 (dd, J: 2.4, 8.8 Hz, 1H), 7.59 (d, J: 8.8 Hz, 1H), 7.63 (dd, J: 2.4, 8.8 Hz, 1H), 7.71 (d, J: 2.0 Hz, 1H), 8.09 (d, J: 2.8 Hz, 1H).

Example 82 11.84 4 4 4 4 4.1; 0°"4.1t5i‘;4.10t5i0" N QH F F _ .WNH A A e of Compound 82A (20 g, 89 mmol), methyl acrylate (23 g, 268 mmol), Pd(PPh3)2C12 (3 g, 45 mmol) and K2C03 (30 g, 223 mmol) in DMF (100 mL) was stirred at 100 0C for 12 h, then cooled to room temperature, then ﬁltered. The ﬁltrate was treated with water, extracted with DCM (100 mL x 2), washed with water (100 mL x 3), brine (100 mL), dried over Na2S04, and concentrated to furnish the solid, then the solid was washed with PE, ﬁltered to furnish the crude Compound 82B.

To a solution of Compound 82B (17 g, 74 mmol) in MeOH (200 mL) and THF (80 mL) was added Pd/C (2 g), then the mixture was stirred at room temperature for 12 h under H2, then ﬁltered. The ﬁltrate was concentrated to furnish the crude nd 82C.

To a solution of LiAlH4 (3 g, 73 mmol) in THE (100 mL) was added dropwise Compound 82C (17 g, 73 mmol) in THF (50 mL) at -78 0C under N2, then the mixture was stirred at -78 0C for 30 min, then quenched with Na2S04.10H20 and ﬁltered. The ﬁltrate was concentrated to furnish the crude Compound 82D. 2] To a on of Compound 82D (13 g, 64 mmol) in DCM (100 mL) was added DMP (32 g, 76 mmol) at 0 0C, then the e was stirred at room temperature for 2 h, then d. The ﬁltrate was concentrated and the residue was puriﬁed with column chromatography (ethyl acetate in petroleum, 10% V/V) to furnish Compound 82E.

Compound 82E (25 g, 0.12 mol) was added to a solution ofNa2S205 (24 g, 0.12 mol) in water (300 mL), then the mixture was stirred for 2 h at room temperature. And after the addition ofNaCN (12 g, 0.24 mol) for 15 h, the mixture was diluted with EA (50 mL), extracted with EA (100 mL x 2), washed with sat. NaHCOg (100 mL x 2), brine (100 mL), dried over Na2S04, and concentrated to h the crude product Compound 82F. 4] To a solution of Compound 82F (5 g, 22 mmol) in EtOH (50 mL) was bubbled a gentle stream of HCl gas (dried over con. H2S04) at 0 0C for 5 h. Then the mixture was treated with water slowly at 0 0C, stirred at room temperature for 2 h, then extracted with DCM (100 mL x 2), washed with brine (100 mL), dried over Na2S04, concentrated and puriﬁed with column chromatography (ethyl acetate in petroleum, 10% V/V) to ﬁlmish Compound 82G.

To a solution of nd 82G (4 g, 14.5 mmol) in DCM (100 mL) was added DMP (7.4 g, 17.4 mmol), then the mixture was stirred at room temperature for 1 h, then d. The ﬁltrate was concentrated and the residue was puriﬁed with column chromatography (10% ethyl acetate in petroleum) to ﬁlmish Compound 82H.

To a solution of Compound 82H (2 g, 7.3 mmol) in DCM (50 mL) was added DAST (5.9 g, 36 mmol), then the mixture was stirred at room temperature for 12 h, poured into ice water, extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04, trated and puriﬁed with column chromatography (10% ethyl acetate in petroleum) to furnish Compound 82].

To a solution of Compound 821 (1.8 g, 6.07 mmol) in THF (30 mL) was added LiOH (383 mg, 9.1 mmol) in water (2 mL), then the mixture was stirred at room temperature for 2 h, then evaporated to remove solvent. The mixture was treated with water, adjusted PH to 2 with diluted HCl, then extracted with EA (50 mL x 2), washed with brine (50 mL), dried over Na2S04, and concentrated to furnish the Compound 82J.

To a solution of Compound 82J (173 mg, 0.64 mmol) in DCM (50 mL) was added EDCI.HCl (186 mg, 0.97 mmol), HOBt (132 mg, 0.97 mmol), and )amino-l- (3 -chlorocyclopropoxyphenyl)(pyrrolidin- l -yl)propan01 (200 mg, 0.97 mmol), then the mixture was d at room ature overnight. The mixture was treated with water (50 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04 and concentrated. The crude product was d with Prep-HPLC to provide Compound 82.

LC-MS (ESI) m/z: 561 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 0.56 (m, 4H), 2.13 (m, 4H), 2.41 (m, 2H), 2.60 (m, 2H), 2.90 (m, 2H), 3.43 (s, 3H), 3.81 (s, 2H), 4.47 (s, 1H), 5.16 (s, 1H), 7.16 (m, 3H), 7.40 (m, 2H), 7.49 (s, 1H), 7.56 (s, 1H), 7.68 (s, 1H), 7.75 (m, 1H), 7.79 (m, 1H), 11.99 (s, 1H).

Example 83 a (14> 9H N 9H ' o F F . . o] —> \ m1O 0 CI 0 o F H 83 To a mixture of Compound 11E (106 mg, 0.3 mmol) in dichloromethane (20 mL) was added Cl (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) and Intermediate H (74 mg, 0.3 mmol). It was stirred at 30 0C for 5 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous Na2S04, evaporated and d with Prep-HPLC to furnish triﬂuoroacetic acid salt of Compound 83. LC-MS (ESI) m/z: 493 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 2.42 (s, 1H), 2.60 (s, 1H), 3.55-3.58 (m, 2H), 4.05—4.13 (m, 4H), 4.24 (s, 1H), 4.41(t, .1: 8 Hz,1H), 4.80 (s, 1H), 6.64 (s, 1H), 6.72 (d, .1: 12 Hz, 1H), 6.90 (s, 1H), 7.43 (d, J: 8 Hz, 1H), 7.46 (d, J: 8 Hz, 1H), 7.70 (s, 1H).

Example 84 Q (3H ?H 0 F FN mil#Mm]: A mixture of Intermediate A (100 mg, 0.36 mmol), Compound 82J (96 mg, 0.36 mmol), EDCI.HC1 (104 mg, 0.54 mmol) and HOBt (73 mg, 0.54 mmol) in DCM (20 mL) was stirred at room temperature overnight. The mixture was treated with water (50 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2S04 and concentrated. The crude t was puriﬁed with Prep-HPLC to provide Compound 84. LC- MS (ESI) m/z: 529 [M+H]+; 1H NMR (CDC13, 400 MHz) 5 (ppm) 2.09 (s, 4H), 2.22 (m, 2H), 2.49 (m, 1H), 2.65 (m, 1H), 3.45 (m, 4H), 3.89 (m, 4H), 4.48 (s, 1H), 5.05 (s, 1H), 6.80 (s, 2H), 6.90 (s, 1H), 7.24 (m, 2H), 7.41 (m, 1H), 7.52 (s, 1H), 7.79 (m, 2H), 7.76 (m, 1H), 11.76 (s, 1H).

Example 85 \N NH / I \ _> OACF3 NHZ / o/\CF3 CI 0 o L 85 To a solution of Intermediate L (200 mg, 0.63 mmol) and 11E (185 mg, 0.75 mmol) in DCM (10 mL) was added C1 (181 mg, 0.94 mmol) and HOBt (127 mg, 0.94 mmol) under N2. The mixture was stirred at 30 0C overnight. TLC and LC-MS showed the starting material was consumed completely, and sat. NaHCOg (3 mL) was added to the mixture and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried over anhydrous Na2S04, and concentrated to e the crude product. The crude product was puriﬁed with Prep-HPLC to e Compound 85.

LC-MS (ESI) m/z: 548 [M+H]+;1H NMR (MeOD, 400 MHz) 5 (ppm) 2.08-2.22 (m, 4H), 3.25 (m, 2H), 3.65-3.77 (m, 4H), .57 (m, 1H), 4.67-4.72 (m, 2H), 6.71 (d, J: 2.8 Hz, 1H), 6.62 (d, J: 8.4 Hz, 1H), 7.02 (s, 1H), 7.48 (dd, J: 2.0, 8.8 Hz, 1H), 7.59 (d, J: 9.2 Hz, 1H), 7.71 (dd, J: 2.4, 8.4, 1H), 7.75 (d, J: 2.0, Hz, 1H), 8.15 (d, J: 2.4 Hz, 1H).

Example 86 <> N 9H F F N OH 0 F F OH 0 a 1 F 0 CO 0 F 82J H F 86 To a mixture of Compound 82J (99 mg, 0.35 mmol) in dichloromethane (10 mL) was added C1 (99 mg, 0.52 mmol), HOBt (71 mg, 0.52 mmol) and Intermediate H (94 mg, 0.35 mmol). It was stirred at 30 0C for 2 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous Na2S04, evaporated and puriﬁed with Prep-HPLC to furnish roacetic acid salt of Compound 86. LC-MS (ESI) m/z: 533 [M+H]+; 1H NMR(CDC13, 400 MHz) of Compound 5 (ppm) 2.18-2.68 (m, 6H), .59 (m, 2H), 3.72-3.95 (m, 4H), 4.25-4.45 (m, 4H), 4.46 (m, 1H), 4.85-4.86 (d, J: 2.8 Hz, 1H), 6.75-6.82 (m, 2H), 7.28-7.34 (m, 2H), 7.49-7.52 (m, 1H), 7.63 (s, 1H), 7.79-7.90 (m, 2H).

Example 87 Z 5 N QH F N 9H 0 CO ' N" E J —> O F NH2 0 CO 0 F 82J F c 87 To a mixture of Compound 82J (80 mg, 0.3 mmol) in dichloromethane (10 mL) was added EDCI.HC1 (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) and ediate C (118 mg, 0.4 mmol) and the resultant e was stirred at 30 0C for 15 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous Na2S04, evaporated and puriﬁed with Prep-HPLC to furnish triﬂuoroacetic acid salt of Compound 87. LC-MS (ESI) m/z: 557 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 2.12-2.31 (m, 3H), .52 (m, 1H), 2.62-2.70 (m, 1H), 2.90 (s, 1H), 3.01-3.ll(m,5H), 3.46 (m, 2H), 3.79-3.98 (m, 6H), 4.45 (s, 1H), 5.50 (s, lH),6.68-6.74 (m, 2H), 7.22-7.24 (m, 1H), 7.39 (d, J: 12 Hz, 1H), 7.53-7.58 (m, 2H), 7.70 (d, J: 12 Hz, 1H), 7.76 (t, J: 8 Hz, 1H), 11.62 (s, 1H).

Example 88 U 9H F F N OH F FW: OH — I so "H / 0% + m 4 F H2N / OACFZ, g 0 82J L as —194— 2014/056555 To a solution of Intermediate L (238 mg, 0.75 mmol) and Compound 82J (200 mg, 0.75 mmol) in DCM (10 mL) was added EDCI.HCl (216 mg, 1.12 mmol) and HOBt (152 mg, 1.12 mmol) under N2. The e was stirred at 30 0C overnight. TLC and LC-MS showed the starting material was consumed completely, then sat. NaHC03 (5 mL) was added to the mixture and then extracted with DCM (50 mL x 3). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over anhydrous sodium te, and concentrated to offer crude product. The crude product was puriﬁed with Prep-HPLC to offer Compound 88. LC-MS (ESI) m/z: 548 [M+H]+; 1H NMR (MeOD, 400 MHz) 8 (ppm) 2.06 (m, 2H), 2.17-2.26 (m, 4H), 2.49-2.56 (m, 1H), 2.67-2.75 (m, 1H), 3.20-3.26 (m, 2H), 3.57- 3.61 (m, 1H), .73 (m, 3H), 4.29-4.34 (m, 1H), 4.58-4.67 (m, 2H), 5.02 (d, J: 2.8 Hz, 1H), 6.86 (d, J: 8.4 Hz, 1H), 7.27-7.33 (m, 2H), 7.49 (dd, J: 2.4, 10.0 Hz, 1H), 7.64 (s, 1H), 7.79-7.88 (m, 3H), 8.25 (d, J: 2.4 Hz, 1H).

Example89 a 9.

N 9H 0 We] NH2 Cl 0 o F 0 0H 0 0 F 73A H 89 To a solution of Compound 73A (114 mg, 0.5 mmol), HATU (285 mg, 0.75 mmol) in DCM (5 mL) was added Intermediate H (141 mg, 0.5 mmol). Then the reaction was stirred at room temperature for 1.5 h. Then the mixture was treated with water, extracted with DCM (25 mL x 2), washed with brine (50 mL), dried over sodium sulphate and trated. The crude product was puriﬁed with puriﬁed with Prep-HPLC and chiral HPLC (OJ-H, ethanol-DEA), ed by Prep-HPLC to furnish triﬂuoroacetic acid salt of Compound 89. LC-MS (ESI) m/z: 489 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 2.41 (m, 2H), 3.31-3.50 (m, 1H), 4.13-4.23 (m, 10H), 4.79-4.80 (d, J: 2.8 Hz, 1H), 6.63-6.68 (m, 2H), 7.42-7.48 (m, 2H), 7.65-7.66 (s, 1H), 8.10-8.11 (s, 1H).

Example 90 N 9H 0 T O O O\/ _ CO OH : —* CD —> o 0 0 F F O 82H 90A 90 To a on of Compound 82H (1.1 g, 4.0 mmol) in THF (50 mL) was added LiOH (252 mg, 6.0 mmol) in water (5 mL) at -10 0C, then the mixture was stirred at -10 0C for 30 min, then added ice water, ed pH 2 with diluted HCl, extracted with EtOAc (50 mL x 2). The organic layer was trated to form a solid, washed with PE, ﬁltered to furnish Compound 90A.

A e of Compound 90A (177 mg, 0.72 mmol), Intermediate A (200 mg, 0.72 mmol), EDCI.HCl (207 mg, 1.08 mmol), HOBt (147 mg, 1.08 mmol) in DMF (20 mL) was stirred at room temperature overnight, then puriﬁed with Prep-HPLC to offer Compound 90. LC-MS (ESI) m/z: 507 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 2.05 (s, 4H), 2.85 (m, 6H), 3.22 (s, 2H), 3.65 (s, 1H), 3.83 (s, 1H), 4.18 (s, 4H), 4.40 (s, 1H), 4.92 (s, 1H), 6.77 (s, 2H), 6.84 (s, 1H), 7.30 (m, 1H), 7.38 (m, 2H), 7.59 (s, 1H), 7.73 (m, 3H), 11.58 (s, 1H).

Example 91 7 \ N oH N 9" F \N CF3 F F | + \N / J F I CF3 O NH J —> OH 2 / 0 CI 0 63D L 91 The solution of Compound 63D (60 mg, 0.24 mmol), Intermediate L (77 mg, 0.24 mmol), EDCI.HCl (68 mg, 0.36 mmol) and HOBt (49 mg, 0.36 mmol) in DCM (5 mL) was stirred at 25 0C for 16 h. Then it was diluted with EA (150 mL), washed with water (50 mL x 3) and brine (50 x 2 mL), dried over sulphate, evaporated and puriﬁed with Prep-HPLC to furnish Compound 91. LC-MS (ESI) m/z: 548 [M+H]+; 1H NMR (MeOD, 400 MHz) 5 2.06 (br s, 2H), 2.19 (br s, 2H), 2.68-2.76 (m, 3H), .92 (m, 2H), 2.97-3.07 (m, 2H), .69 (m, 3H), 3.75 (br s, 1H), 4.65-4.72 (m, 2H), 4.74-4.83 (m, 1H), 5.02 (s, 1H), 6.91 (d, J: 8.8 Hz, 1H), 7.10-7.15 (m, 3H), 7.83 (d, J: 8.8 Hz, 1H), 8.24 (s, 1H).

Example 92 a N am N oH T CIWF = F F o 5 + NH g j 0H2 NH2 j—> 0 CI 0 F H 92 To a mixture of Compound 63D (59 mg, 0.24 mmol) and Intermediate H (59 mg, 0.2 mmol) in dichloromethane (9 mL) was added EDCI.HCl (58 mg, 0.3 mmol), HOBt (41 mg, 0.3 mmol). It was stirred at 30 0C for 2 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulphate, evaporated and puriﬁed with PLC to furnish triﬂuoroacetic acid salt of Compound 92.

LC-MS (ESI) m/z: 511 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 2.38-3.07 (m, 7H), 3.48 (s, 2H), 3.96-4.39 (m, 9H), 5.00 (s, 1H), 6.65-6.73 (m, 2H), 7.03-7.12 (m, 3H), 7.50- 7.52 (d, J: 4 Hz, 1H), 12.33 (br, 1H).

Example 93 Z 5 N QH N 9H 7 Cl F = o F Fi F 1 OH NH2 CI 0 F 63D F c 93 To a mixture of nd 63D (118 mg, 0.48 mmol) in dichloromethane (10 mL) was added EDCI.HC1 (115 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol) and Intermediate C (118 mg, 0.4 mmol). It was stirred at 30 0C for 2 h. Then it was treated with water (20 mL), ted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulphate, evaporated and puriﬁed with Prep-HPLC to furnish triﬂuoroacetic acid salt of Compound 93.

LC-MS (ESI) m/z: 525 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 2.12 (s, 4H), 2.57-2.66 (m, 2H), 2.80-2.93 (m, 5H), 3.47 (s, 2H), 3.77 (s, 2H), 4.16-4.24 (m, 4H), 4.44 (s, 1H), 5.06 (s, 1H), 6.68-6.75 (m, 2H), 7.03-7.11 (m, 3H), 7.58 (s, 1H), 11.69 (s, 1H). e 94 0 oH CI F N OH F Fm \ F + _> 0* O OH m; \o o O C, M 94 A mixture of Intermediate M (150 mg, 0.48 mmol), EDCI.HC1 (138 mg, 0.72 mmol), HOBt (97 mg, 0.72 mmol) and Compound 11E (142 mg, 0.58 mmol) in DCM (15 mL) was stirred for 18 h at 25 0C. Then the mixture was washed with saturated NaHCOg (15 mL) and brine (15 mL), dried over anhydrous sodium sulphate. After evaporation, the crude compound was puriﬁed with Prep-HPLC to ﬁlI'I‘llSh Compound 94. LC-MS (ESI) m/z: 541 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) .34 (m, 6H), 2.11 (m, 4H), .01 (m, 4H), 3.52-3.55 (m, 1H), 3.79 (m, 1H), 4.37-4.43 (m, 1H), 4.52 (m, 1H), 5.13 (s, 1H), 6.67 (s, 1H), 6.71 (d, J: 4.4 Hz, 1H), 7.10 (d, J: 8.4 Hz, 1H), 7.32-7.43 (m, 3H), 7.94 (d, J: 6.4 Hz, 1H), 11.80 (s, 1H).

WO 42397 Example 95 0 Q9H CI 9H O W0 0 ; + : j —> NH O] OH 1le 2 0 CI 0 o F 73A F c 95 To a mixture of Compound 73A (180 mg, 0.8 mmol) in dichloromethane (20 mL) was added HATU (456 mg, 1.2 mmol), DMF (0.1 mL) and Intermediate C (237 mg, 0.8 mmol). It was stirred at 30 0C for 2 h. Then it was d with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulphate, evaporated and puriﬁed with Prep-HPLC to furnish the mixture. Then the mixture was ﬁlrther puriﬁed with chiral separation, Prep-HPLC to furnish triﬂuoroacetic acid salt of Compound 95. LC-MS (ESI) m/z: 503 ;1H NMR (CDC13, 400 MHz) 5 (ppm) 2.18 (s, 4H), 2.95-3.08 (m, 2H), 3.52 (s, 2H), 3.93 (s, 2H), 4.23 (s, 4H), 4.47 (s, 1H), 5.13 (s, 1H), 6.73 (d, J: 12 Hz, 2H), 7.46- 7.53(m, 2H), 7.70 (s, 1H), 7.99 (s, 1H), 8.25 (s, 1H), 11.86 (s, 1H).

Example 96 F F N QH ?H = —> NH O NH2 O F 0 82J 66B F A mixture of Compound 82J (80 mg, 0.3 mmol), C1 (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol) and Compound 66B (83 mg, 0.3 mmol) in DCM (10 mL) was stirred at room temperature for 5 h. Then the reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over sodium sulphate and concentrated under vacuum. The residue was puriﬁed with Prep-HPLC to offer Compound 96. LC-MS (ESI) m/z: 529 [M+H]+; 1H NMR (CDC13, 400 MHz) 5 (ppm) 1.21- 1.35 (m, 3H), 2.21 (s, 2H), 2.47 (s, 1H), 2.61 (s, 1H), 3.10 (s, 2H), 3.39-3.49 (m, 3H), 3.81- 3.96 (m, 5H), 4.30-4.38 (m, 2H), 4.98 (s, 1H), 6.78-6.86 (m, 3H), , J: 8 Hz, 1H), 7.51 (s, 1H), 7.68-7.77 (m, 3H), 12.13 (s, 1H).

Example 97 Z \ N OH F F ? OH+ N OH F F i |\N O ; _ |\N O NH2 / k 82J o WNHto 0 K 97 A mixture of Intermediate K (200 mg, 0.72 mmol), 82J (192 mg, 0.72 mmol), EDCI.HC1 (206 mg, 1.07 mmol), HOBt (146 mg, 1.07 mmol) in DCM (20 mL) was stirred at 0C for 4 h, added water, ted with DCM (50 mL x 2), washed with brine (50 mL), dried over sodium sulphate, concentrated, and puriﬁed with Prep-HPLC to offer Compound 97. LC-MS (ESI) m/z: 529 [M+H]+.1H NMR(CDC13, 400 MHz) 5 (ppm) 1.20-1.23 (m, 6H), 2.07 (s, 4H), 2.23-2.28 (m, 2H), 2.64-2.69 (m, 2H), 3.00 (s, 2H), 3.62-3.82 (m, 4H), 4.63 (s, 1H), 4.94 (s, 1H), 5.26 (s, 1H), 6.85 (s, 1H), 7.19-7.23 (m, 2H), 7.36-7.39 (m, 1H), 7.52 (s, 1H), 7.65-7.74 (m, 2H), 8.04 (s, 2H), 8.41 (s, 1H), 11.54 (s, 1H). e 98 <3 9H Q 9H NH —> NH \ o \ 0 CI 0 0 CI 0 O 89 98 To a solution of 89 (12 mg, 0.025 mmol) in MeOH (6 mL) was added hydroxylamine hydrochloride (34 mg, 0.5 mmol) at 30 0C, then the reaction was stirred at 55 0C for 4 h. Then it was d with Prep-HPLC to ﬁll'lllSh Compound 98. LC-MS (ESI) m/z: 504 [M+H]+; 1H NMR (MeOD, 400 MHz) 5 (ppm) 2.21-2.61 (m, 2H), 3.37-3.41 (m, 2H), 4.12-4.18 (m, 9H), 4.74-4.79 (m, 1H), 6.36 (s, 1H), 6.63-6.71 (m, 2H), 7.26-7.27 (m, 1H), 7.28-7.54 (m, 3H). e 99 U \ CI F N OH FF N W 5 F | NH / O/A + —' \ ' \N O OH : I 0 O / A CI o NH2 11E o N 99 7] To a solution of Intermediate N (110 mg, 0.397 mmol) in CHzClz (5 mL) was added Compound 11E (97 mg, 0.397 mmol), EDCI.HCl (113 mg, 0.595 mmol) and HOBt (80 mg, 0.595 mmol). The reaction mixture was stirred for 10 hours at 30 0C. The solvent was removed under reduced pressure, and the residue was puriﬁed sively by prep. TLC (MeOH in , 10% v/v) and chiral HPLC (co-solvent MeOH (0.1% DEA), column, AD- H 4.6 * 250mm, 5 um) to offer desired product Compound 99. LC-MS (ESI) m/z: 506 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 0.73-0.79 (m, 4H), 1.78-1.82 (m, 4H), 2.64- 2.67 (m, 2H), 2.74-2.76 (m, 2H), 2.97-3.07 (m, 2H), 4.07-4.10 (m, 1H), 4.23 (br, 1H), 5.17 (s, 1H), 6.68 (d, J: 8.4 Hz, 1H), 6.87 (s, 1H), 7.32-7.35 (m, 1H), 7.41-7.44 (m, 1H), 7.53-7.58 (m ,2H), 8.21 (d, J: 2.0 Hz, 1H).

Example 100 - 0 N O m] CI 0 9H 0 OH _ NH2 CI 0 0 O 0 73A 663 100 A mixture of Compound 73A (145 mg, 0.65 mmol), HATU (370 mg, 0.97 mmol), and nd 66B (180 mg, 0.65 mmol) in DCM (20 mL) and DMF (2 mL) was stirred at room temperature for 2 h. Then the reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over sodium te and concentrated. The crude product was puriﬁed with Prep-HPLC to offer Compound 100. LC-MS (ESI) m/z: 485 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 1.25- 1.37 (m, 3H), 2.31-2.45 (m, 1H), 3.01-3.15 (m, 1H), 3.47-3.59 (m, 3H), 4.08-4.16 (m, 5H), 4.33 (s, 1H), 4.51 (s, 1H), 5.01 (s, 1H), 6.78-6.85 (m, 3H), .49 (m, 2H), 7.69 (s, 1H), 7.95 (s, 1H), 8.24 (s, 1H), 11.32 (s, 1H).

Example 101 Z S N QH F F N OH = OH \ F F ; + I |\ —> NH / A O i N O F NH2 / A N O o 82J N F A mixture of Intermediate N (100 mg, 0.36 mmol), Compound 82J (96 mg, 0.36 mmol), EDCI.HCl (104 mg, 0.54 mmol), HOBt (74 mg, 0.54 mmol) in DCM (20 mL) was stirred at 25 0C ght, added water, extracted with DCM (50 mL x 2), Brine (50 mL), dried over sodium sulphate, concentrated and puriﬁed with Prep-HPLC to offer Compound 101. LC-MS (ESI) m/z: 528 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 0.67-0.72 (m, 4H), 2.06 (s, 4H), 2.17-2.27 (m, 2H), 2.57-2.71 (m, 2H), 3.04 (s, 2H), 3.53-3.67 (m, 3H), 3.88 (s, 2H), 4.67 (s, 1H), 5.23 (s, 1H), 6.01 (s, 1H), 7.10 (s, 1H), 7.19-7.24 (m, 2H), 7.37-7.39 (m, 1H), 7.51 (s, 1H), 7.66-7.68 (m, 1H), 7.70-7.74 (m, 1H), 8.10 (s, 2H), 8.50 (s, 1H), 11.31 (s, 1H).

Example 102 (NR 9H 2'? 9H ‘ O O ' 0 HO\N 2 ; 1 my— WWI); CI 0 0 CI 0 O 100 102 1] A mixture of 100 (12 mg, 0.025 mmol) and hydroxylamine hydrochloride (17 mg, 0.25 mmol) in MeOH (3 mL) was stirred at room temperature for 4 h. Then it was puriﬁed with PLC directly to offer Compound 102. LC-MS (ESI) m/z: 500 [M+H]+; 1H NMR (MeOD, 400 MHz) 5 (ppm) 1.26-1.35 (m, 3H), 3.12 (s, 1H), 3.45-3.52 (m, 2H), 3.78-4.14 (m, 4H), 4.38-4.52 (m, 5H), 4.86-4.93 (m, 1H), 6.23 (s, 1H), 6.80-6.94 (m, 3H), 7.29 (s, J: 8 Hz, 1H), 7.34-7.41 (m, 1H), 7.44-7.62 (m, 2H).

Example 103 0 OH Br F Br \ \ CY TBSO \ CY TBSO \ or I I : : I /N /N CszN I /N CszN /N 103A 103B 103C 103D 0" OH N OH 0 o \ \ . _ —> HgszN I I \ CY / N Y—Jﬂsgb HN \l/ —> N Z / CszN | 1035 1an 103G N 9H U ' o N OH F F | —' NH —’ /N \ OT \ NH2 /N CI 0 O 103H 103 60% NaH (1.04 g, 26 mmol) was added in two portions to isopropyl alcohol (30 mL) at room temperature (about 30 0C) under N2. The mixture was stirred at 60 0C for 30 min. Compound 103A (2 g, 11.36 mmol) was added in two portions and the mixture was stirred at reﬂux 4 h and at 80 0C overnight. The solution was concentrated in vacuo. Water (100 mL) and ethyl e (200 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl e (50 mL x 3). The combined organic layers were washed with water (10 mL x 2), brine (10 mL x 2) and dried over anhydrous sodium sulphate.

After ﬁltration the solvent was removed in vacuo. The crude product was subjected to ﬂash chromatography (silica, ethyl acetate in petroleum, 0~lO% v/v) to offer Compound 103B. 4] To a solution of Compound 103B (13 g, 60 mmol) in THF (300 mL) was added n-BuLi (2.4 M, 25 mL) at -60 0C under N2 and the resultant e was stirred for 0.5 h, then a solution of Compound A4 (8 g, 20 mmol) in THF (50 mL) was added, then the mixture was stirred at -60 0C for l h. After reaction monitored by LC-MS and TLC, added saturated NH4Cl solution (50 mL), extracted with ethyl acetate (100 mL x 3), washed with brine (100 mL x 2), and dried over anhydrous sodium sulphate. The crude product was puriﬁed with column chromatography (ethyl acetate in petroleum, 0-20% v/v) to offer Cknnpound,103(L Compound 103C (472 mg, 1 mmol) was dissolved in anhydrous THF (10 mL) and cooled down to -70 0C under en atmosphere. ctride (2 mL, lM solution in THF, 2 mmol) was added dropwise while keeping the temperature at -70 0C. Then the reaction was stirred for 0.5 h at -70 0C. After reaction was monitored by TLC, the reaction was quenched with saturated NH4Cl on (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed water (30 mL), brine (30 mL x 2), and dried over ous sodium sulphate. The crude product was puriﬁed with column chromatography (ethyl acetate in petroleum, 0-20% v/v) to offer nd 103D.

To a solution of Compound 103D (2.1 g, 4.4 mmol) in THF (40 mL) was added a solution of TBAF (0.58 g, 2.2 mmol) in THF (10 mL) at 0 0C, then the mixture was stirred at 30 0C overnight. After the reaction was monitored by TLC and LC-MS. THF was evaporated. Then the e was d with water (50 mL) and extracted with ethyl acetate (50 mL x 3), washed with brine (50 mL), and dried over anhydrous sodium sulphate. The crude product was puriﬁed with ﬂash column (silica, methanol in dichloromethane, 0-lO% v/v) to offer Compound 103E.

To a solution of Compound 103E (1.2 g, 3.3 mmol) in dry DCM (20 mL) was added Eth (1 mL) under N2, then the e was cooled to -40 0C, MsCl (0.31 mL, 4 mmol) was added . Then the mixture was stirred at -40 0C about an hour. After reaction was monitored by TLC, the mixture was treated with water (10 mL) and extracted with DCM (50 mL x 3), washed with brine (50 mL), dried over anhydrous sodium sulphate.

The crude product was puriﬁed with ﬂash column (silica, methanol in dichloromethane, 0- 3096V#v)u)oﬂeernnpound103Fi To a solution of Compound 103F (l g, 2.3 mmol) in THF (40 mL) was added pyrrolidine (2 mL) under N2, then the mixture was stirred at 50 0C for 16 h. After reaction monitored by LC-MS, the mixture was treated with water (50 mL) and ted with EA (50 mL x 3), washed with brine (50 mL x 2), dried over anhydrous sodium sulphate. The crude product was puriﬁed with column chromatography (methanol in dichloromethane, 0-10% V/V) to offer Compound 103G.

To a solution of Compound 103G (400 mg, 0.97 mmol) in EtOH (20 mL) and water (5 mL) was added LiOH.HzO (163 mg, 3.87 mmol). The mixture was stirred at 90 0C overnight, concentrated and added water (50 mL), extracted with DCM (30 mL x 3), dried over anhydrous sodium sulphate, and concentrated to ﬁamish the product nd 103H.

To a solution of Compound 103H (140 mg, 0.5 mmol) and Compound 11E (123 mg, 0.5 mmol) in DMF (5 mL) was added EDCI.HCl (144 mg, 0.75 mmol) and HOBt (101 mg, 0.75 mmol) under N2. The mixture was stirred at 30 0C overnight. TLC and LC-MS showed the starting al was consumed completely, EA (50 mL) was added to the mixture and then washed with water (50 mL x 3), brine (50 mL x 1), dried over anhydrous sodium sulphate, and concentrated to offer crude t. The crude product was puriﬁed with Prep-HPLC to offer a mixture (50 mg, 20%) as a white solid, then the mixture was separated by Chiral-HPLC (Co-solvent EtOH (0.1% DEA), column OJ-H 250 * 4.6 mm 5 um) to offer Compound 103.

Example 104 QoH QQ" :10"a CI 0 0 CI 501"@5010 0 95 104 1] A mixture of 95 (18 mg, 0.036 mmol) and hydroxylamine hydrochloride (25 mg, 0.36 mmol) in MeOH (3 mL) was stirred at room temperature for 8 h. Then it was puriﬁed with Prep-HPLC directly to offer Compound 104. LC-MS (ESI) m/z: 518 [M+H]+; 1H NMR (MeOD, 400 MHz) 5 (ppm) 2.06-2.18 (m, 4H), 3.24 (s, 2H), 3.48-3.83 (m, 4H), .34 (m, 4H), 4.59-4.77 (m, 1H), 4.91 (d, J: 4 Hz, 1H), 6.39 (s, 1H), .89 (m, 2H), 7.35-7.60 (m, 3H), 7.67-7.71 (m, 1H).

Example 105 ::N QH ' CI 0 OH 2 0 O o NH2 CI 0 105 The mixture of Intermediate 0 (120 mg, 0.34 mmol), EDCI.HCl (98 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol) and nd 11E (101 mg, 0.41 mmol) in DCM (15 mL) was stirred for 18 h at 25 0C. Then the mixture was washed with saturated NaHCOg (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate. After ation, the crude compound was puriﬁed with Prep-HPLC to ﬁamish Compound 105. LC-MS (ESI) m/z: 583 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm)1.75-1.84 (m, 2H), 1.96-2.14 (m, 6H), 2.77- 2.87 (m, 2H), 3.17-3.20 (m, 1H), 3.55-3.60 (m, 3H), 3.76 (m, 1H), .02 (m, 3H), 4.41- 4.48 (m, 2H), 4.95 (d, J: 4.8 Hz, 1H), 6.79 (d, J: 8.4 Hz, 1H), 6.87 (s, 1H), 7.19 (dd, J: 8.4, 1.6 Hz, 1H), 7.32 (dd, J: 8.8, 2.0 Hz, 1H), 7.42 (d, J: 9.2 Hz, 1H), 7.46 (d, J: 1.6 Hz, 1H), 7.58 (d, J: 2.0 Hz, 1H), 9.23 (d, J: 8.0 Hz, 1H), 11.87 (s, 1H).

Example 106 O HO\N CO 0v —> CO o WOVﬂO F F 82H 106A HO\N N QH | HO\ O CO |N ; —> NH 1 O 0 F CO O 1063 106 To a solution of Compound 82H (310 mg, 1.13 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (102 mg, 1.47 mmol) and K2C03 (203 mg, 1.47 mmol), then the mixture was stirred at 25 0C for 12 h and ﬁltered. The ﬁltrate was concentrated to furnish the Compound 106A. LC-MS (ESI) m/z: 290 [M+H]+; 1H NMR (CDC13, 400 MHz) 5 (ppm) 1.25 (t, J: 6.8 Hz, 3H), 2.98 (s, 4H), 4.17-4.23 (m, 2H), 7.18-7.26 (m, 1H), 7.37-7.41 (m, 2H), 7.63 (s, 1H), 7.70-7.73 (m,2H).

To a solution of Compound 106A (1500 mg, 0.52 mmol) in THF (15 mL) was added LiOH (65 mg, 1.55 mmol) in water (2 mL), then the mixture was stirred at 25 0C for 12 h, then added water, diluted with EA (20 mL), adjusted to PH = 2 with d HCl, ted with EA (5OmL x 2), brine (50 mL), dried over sodium te, and concentrated to furnish crude Compound 106B.

A mixture of Compound 106B (135 mg, 0.52 mmol), Intermediate A, Cl (149 mg, 0.77 mmol), HOBt (106 mg, 0.77 mmol) in DMF (8 mL) was stirred at 0C overnight, puriﬁed with Prep-HPLC to offer Compound 106. LC-MS (ESI) m/z: 522 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 1.97 (s, 4H), 2.83-2.87 (m, 6H), 3.09 (s, 1H), —204— 2014/056555 3.49 (s, 1H), 3.72 (s, 2H), 4.14 (s, 4H), 4.48 (s, 1H), 4.84 (s, 1H), 6.74-6.79 (m, 2H), 6.87 (s, 1H), 7.16-7.23 (m,1H), 7.36-7.40 (m, 2H), 7.61 (s, 1H), 7.65-7.67 (m, 1H), 7.71-7.75 (m, 1H), 11.17 (s, 1H).

Example 107 f E N QH F F + \ NH / 2 / O ZZJ K 107 To a solution of Intermediate K (167 mg, 0.60 mmol) and Compound 22J (150 mg, 0.60 mmol) in DMF (10 mL) was added EDCI.HCl (173 mg, 0.90 mmol) and HOBt (122 mg, 0.90 mmol) under N2. The mixture was stirred at 25 0C overnight. TLC and LC-MS showed the starting material was consumed completely, sat. NaHCOg (5 mL) was added to the e and then extracted with EA (50 mL x 3). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulphate, and concentrated to offer crude product. The crude product was puriﬁed with Prep-HPLC to offer Compound 107. LC-MS (ESI) m/z: 512 [M+H]+;1H NMR (MeOD, 400 MHz) 5 (ppm) 0.97 (d, J: 6.0 Hz, 3H), 1.06 (d, J: 6.4 Hz, 3H), 1.98-2.01 (m, 2H), .25 (m, 4H), 2.49-2.57 (m, 1H), 2.65-2.73 (m, 1H), 3.13-3.21 (m, 2H), .56 (m, 1H), 3.61-3.67 (m, 3H), 4.61 (d, J: 10.0 Hz, 1H), .85 (m, 1H), 4.97 (d, J: 2.4 Hz, 1H), 6.79-6.81 (m, 1H), 7.24 (dd, J: 8.4, 1.6 Hz, 1H), 7.38-7.44 (m, 2H), 7.57 (s, 1H), 7.75-7.79 (m, 3H), 7.82-7.85 (m, 1H), 8.17 (s, 1H).

Example 108 Z l N 9H F F W0" N OH : VTEL F F i + \ '\ O 5 I NH N/ OACF NH 3 2 N/ OACF3 ZZJ L 108 The on of Intermediate L (230 mg, 0.72 mmol), Compound 22J (150 mg, 0.60 mmol), EDCI.HCl (172 mg, 0.90 mmol) and HOBt (122 mg, 0.90 mmol) in DCM (10 mL) was stirred at room temperature overnight. Then it was diluted with EA (150 mL), washed with water (50 mL x 3) and brine (50 x 2 mL), dried over sulphate, evaporated and puriﬁed with Prep-HPLC to offer Compound 108. LC-MS (ESI) m/z: 552 [M+H]+; 1H NMR (CDClg, 400 MHz) 5 (ppm) 2.02-2.16 (m, 4H), 2.09-2.36 (m, 2H), 2.53-2.60 (m, 2H), 2.77- 2.99 (m, 2H), .40 (m, 2H), 3.67-3.77 (m, 2H), 4.42-4.47 (m, 2H), 4.54-4.60 (m, 1H), .18 (s, 1H), 6.80-6.82 (m, 1H), 7.19-7.21 (m, 1H), 7.43-7.46 (m, 2H), 7.53 (s, 1H), 7.61- 7.63 (m, 2H), 7.75-7.80 (m, 3H), 8.14 (s, 1H), 11.88 (s, 1H).

Example 109 WW* mo] —'WWO] o co . . 10.9 A mixture of Compound 22J (100 mg, 0.40 mmol), EDCI.HC1 (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in Dichloromethane (20 mL) was d at 30 0C for min. Intermediate C (148 mg, 0.50 mmol) was added. The reaction was stirred at 30 0C for h. It was treated with water (20 mL), extracted with dichloromethane (20 mL x 3). The organic layer was washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulphate, evaporated and puriﬁed with PLC to mmish Compound 109. LC- MS (ESI) m/z: 529 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 2.10 (m, 4H), 2.27 (s, 1H), 2.45-2.54 (m, 1H), 2.63-2.71 (m,1H), 2.84 (s, 1H), 2.98 (s, 1H), 3.42 (s, 2H), 3.77-3.95 (m, 6H), 4.43 (s, 1H), 5.04 (s, 1H),6.68-6.73 (m, 2H), .24 (m, 1H), 7.41-7.47 (m, 2H), 7.54 (s, 2H), 7.75-7.80 (m, 3H), 11.59(s, 1H).

Example 110 Z 3 N C_)H F F ' N OH CI 0" O CI F F a . o —> NH 0 "H o 2 o o 22.1 o The e of Intermediate 0 (120 mg, 0.34 mmol), EDCI.HC1 (98 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol) and Compound 22J (103 mg, 0.41 mmol) in DCM (15 mL) was stirred for 3 h at 25 0C. Then the mixture was washed with saturated NaHCOg (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate. After evaporation, the crude compound was d with Prep-HPLC to mmish Compound 110. LC-MS (ESI) m/z: 587 [M+H]+; 1H NMR(CDC13, 400 MHz) 5 (ppm) 1.57 (m, 2H), 1.71 (m, 2H), 2.10 (m, 4H), .33 (m, 2H), 2.44-2.68 (m, 2H), 2.81-2.95 (m, 2H), 3.32-3.42 (m, 4H), 3.77-3.79 (m, 4H), 4.21 (m, 1H), 4.45 (m, 1H), 5.12 (s, 1H), 6.82 (d, J: 8.0 Hz, 1H), 7.14-7.22 (m, 2H), 7.41-7.48 (m, 3H), 7.59 (s, 1H), 7.63 (s, 1H), 7.74-7.80 (m, 3H), 11.7 (s, 1H).

Example 1 1 1 o N N QH 9" O NH2 0 F 0 90A 0 F c F 111 A e of Compound 90A (160 mg 0.65 mmol), HATU (370 mg, 0.97 mmol) and DMF (0.5 mL) in Dichloromethane (20 mL) was stirred at 30 0C for 15 min.

Intermediate C (192 mg, 0.65 mmol) was added. The reaction was d at 30 0C for 4 h.

Then water (20 mL) was added to reaction mixture. The resulting mixture was extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulphate, evaporated and puriﬁed with Prep-HPLC to furnish triﬂuoroacetic acid salt of Compound 111. LC-MS (ESI) m/z: 525 [M+H]+; 1H NMR (CDC13 & MeOD, 400 MHz) 5 (ppm) .05 (m, 4H), 2.93-2.97 (m, 3H), 3.12-3.16 (m, 3H), 3.09-3.33 (m, 1H), 3.47 (t, J: 12 Hz, 1H), 3.62 (s, 1H), 3.76 (s, 1H), 4.14-4.18 (m, 4H), 4.23-4.27(m, 1H), 4.74 (s, 1H),6.60-6.65 (m, 2H), 7.16 (t, J: 8 Hz, 1H), 7.27(d, J: 8 Hz, 1H), 7.34 (d, J: 12 Hz, 1H), 7.56 (s, 1H), 7.61-7.71 (m, 2H).

Example 112 2] A mixture of Compound 106B (150 mg, 0.57 mmol), Intermediate G (178 mg, 0.57 mmol), EDCI.HCl (165 mg, 0.86 mmol), HOBt (117 mg, 0.86 mmol) in DMF (5 mL) was stirred at 25 0C for 12 h, puriﬁed with Prep-HPLC to offer Compound 112. LC-MS (ESI) m/z: 529 .1H NMR(CDC13, 400 MHz) 5 (ppm) 0.72 (s, 4H), 1.97 (s, 4H), 2.77-2.82 (m, 7H), 3.66 (s, 4H), 4.52 (s, 1H), 4.92 (s, 1H), 7.16-7.21 (m, 3H), 7.34-7.38 (m, 3H), 7.57 (s, 1H), 7.63-7.65 (m, 1H), 7.68-7.72 (m, 2H), 8.15 (s, 1H), 10.90 (s, 1H).

Example 113 WONJ—ijZIIII To a solution of Compound 22J (100 mg, 0.40 mmol) in Dichloromethane (20 mL) was added EDCI.HCl (115 mg, 0.60 mmol), HOBt (81 mg, 0.60 mmol), and the resultant mixture was stirred at 30 0C for 15 min. then Intermediate H (140 mg, 0.50 mmol) was added. The reaction was stirred at 30 0C for 15 h. It was poured into ice water (20 mL), extracted with romethane (20 mL x 3). The organic layer was washed with water (50 mL x 2) and brine (30 mL), dried over anhydrous sodium sulphate, ated and puriﬁed with Prep-HPLC to h Compound 113. LC-MS (ESI) m/z: 515 [M+H]+; 1H NMR (CDClg, 400 MHz) 5 (ppm) .66 (m, 6H), 3.43 (s, 2H), 3.82-3.95 (m, 6H), 4.18-4.45 (m, 3H), 4.98 (s, 1H), 6.66-6.72 (m, 2H), 7.21-7.25 (m, 1H), 7.43-7.54 (m, 4H), 7.75-7.81 (m, 3H), 12.25 (s, 1H).

Example 114 WW Q0H F FmOY 00 * VH0 r—;0 mm 114 To a solution of Intermediate 103H (140 mg, 0.5 mmol) and Compound 82J (134 mg, 0.5 mmol) in DCM (5 mL) was added EDCI.HCl (144 mg, 0.75 mmol) and HOBt (101 mg, 0.75 mmol) under N2. The mixture was stirred at 30 0C overnight. TLC and LC-MS showed the starting material was consumed completely, EA (50 mL) was added to the mixture and then washed with water (50 mL x 3), brine (50 mL x 1), dried over anhydrous sodium sulphate, and concentrated to offer crude product. The crude product was puriﬁed with Prep-HPLC to offer a mixture (50 mg, Yield: 57%) as a white solid, then the mixture * 4.6 was separated by Chiral-HPLC (Co-solvent EtOH (0.1% DEA), column OZ-H 250 mm um) to offer Compound 114. LC-MS (ESI) m/z: 530 [M+H]+; 1H NMR , 400 MHz) (ppm) 1.12 (d, J: 6.0 Hz, 3H), 1.20 (d, J: 6.4 Hz, 3H), 2.00 (m, 4H), 2.26 (m, 2H), 2.50 (m, 1H), 2.67 (m, 1H), 3.14 (m, 4H), 3.30 (m, 1H), 3.47 (m, 1H), 4.47 (m, 1H), 5.11 (m, 2H), 6.73 (s, 1H), 6.82 (m, 1H), 7.21 (m, 2H), 7.41 (m, 1H), 7.51 (m, 2H), 7.68 (d, J: 8.4 Hz, 1H), 7.74 (m, 1H), 8.05 (d, J: 5.2 Hz, 1H). Co-solvent: EtOH (0.1% DEA), column: OZ-H 250 * 4.6 mm 5 um, Rt: 3.56 min.

Example 115 HO\ ( 3 N OH IN N 9H 5 = HO 0 CO o ‘N . + : 3 —> 0 F NH2 O O "NHI O F 1063 F F C 115 A mixture of Intermediate C (200 mg, 0.67 mmol), Compound 106B (176 mg, 0.67 mmol), EDCI.HC1 (194 mg, 1.01 mmol), HOBt (137 mg, 1.01 mmol) in DMF (5 mL) was stirred at 25 0C for 12 h, puriﬁed with PLC to offer Compound 115. LC-MS (ESI) m/z: 540 , 1H NMR(CDC13, 400 MHz) 5 (ppm) 1.99 (s, 4H), 2.84 (s, 6H), 3.14 (s, 1H), 3.45 (s, 1H), 3.74 (s, 2H), 4.19 (s, 4H), 4.45 (s, 1H), 4.87 (s, 1H), 6.66-6.69 (m, 2H), 7.18-7.23 (m, 1H), 7.35-7.40 (m, 2H), 7.59-7.71 (m, 3H), 7.73-7.75 (m, 1H), 11.19 (s, 1H).

Example 116 "(33%; 0" F ijm . CI o 116 The mixture of Compound 63D (150 mg, 0.42 mmol), EDCI.HC1 (121 mg, 0.63 mmol), HOBt (85 mg, 0.63 mmol) and Intermediate 0 (152 mg, 0.62 mmol) in DCM (15 mL) was d for 16 h at 25 0C. Then the mixture was washed with saturated NaHCOg (10 mL) and brine (10 mL), dried over anhydrous sodium te. After ation, the crude nd was puriﬁed with Prep-HPLC to furnish Compound 116. LC-MS (ESI) m/z: 583 [M+H]+; 1H NMR (CDC13, 400 MHz) 5 (ppm) 1.84 (m, 2H), 1.99 (m, 2H), 2.16 (m, 4H), 2.45 (d, J: 8.8 Hz, 1H), 7.55 (d, J: 8.8 Hz, 1H), 2.83-3.04 (m, 5H), 3.43-3.58 (m, 4H), 3.82 (m, 2H), 4.01 (m, 2H), 4.48-4.54 (m, 2H), 5.18 (s, 1H), 6.91-6.93 (m, 1H), 7.04-7.11 (m, 3H), 7.18-7.19 (m, 1H), 7.43 (s, 1H), 7.50 (s, 1H), 11.75 (s, 1H).

Example 117 F F 9H N OH so F F ; + —» 0 O O O 22.] P 117 A mixture of Compound 22J (188 mg, 0.618 mmol), Intermediate P (155 mg, 0.618 mmol), EDCI.HC1 (176 mg, 0.927 mmol) and HOBt (125 mg, 0.927 mmol) in DCM (10 mL) was stirred at 25 0C for 16 h. Then it was diluted with ethyl acetate (100 mL), washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to ﬁll‘IlISh Compound 117. LC-MS (ESI) m/z: 537 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) 5 (ppm) 1.03 (s, 3H), 1.05 (s, 3H), 1.47-1.52 (m, 2H), 1.83-1.82 (m, 2H), 1.98-2.02 (m, 2H), 2.27-2.29 (m, 2H), 2.53-2.60 (m, 2H), 2.63- 2.76 (m, 2H), 3.06-3.40 (m, 2H), 3.43-3.48 (m, 4H), 4.52 (s, 1H), 4.72 (s, 1H), 5.82 (s, 4H), WO 42397 6.63 (d, J: 8.8 Hz, 1H), 7.00-7.12 (m, 2H), 7.35 (d, J: 8.8 Hz, 1H), 7.45-7.52 (m, 2H), 7.68 (s, 1H), 7.84-7.90 (m, 3H), 8.35 (d, J: 8.8 Hz, 1H), 9.49 (s, 1H).

Example 118 O F 106B H F F 118 A mixture of Intermediate H (200 mg, 0.71mol), EDCI.HC1 (204, 1.06 mmol), HOBt (145, 1.01 mmol) and Compound 106B (185mg, 0.71mol) in DMF (5 mL) was stirred at room temperature overnight. Then the reaction mixture was puriﬁed with prep-HPLC to give Compound 118. LC-MS (ESI) m/z: 526 [M+H]+; 1H-NMR (CDC13, 400 MHz) 5 (ppm) 2.15 (s, 1H), 2.50 (m, 1H), 2.81-2.90 (m, 4H), 3.27-3.37 (m, 2H), 3.76 (s, 3H), 4.15-4.17 (m, 5H), 4.29 (s, 1H), 4.82 (s, 1H), .64 (m, 2H), 7.18-7.22 (m, 1H), 7.34-7.39 (m, 2H), , 1H), 7.59 (s, 1H), 7.65-7.67 (m, 1H), 7.71-7.74 (m, 1H), 11.37 (s, 1H).

Example 119 /\—/\ N QH 0 N OH CI F F OH i \ NH F a \ 0 0 F NH2 CI 0 o 11E P A mixture of Intermediate P (150 mg, 0.490 mmol), Compound 11E (121 mg, 0.490 mmol), EDCI.HC1 (140 mg, 0.740 mmol) and HOBt (100 mg, 0.740 mmol) in DCM/Eth (10/0.5 mL) was stirred at 25 0C for 16 h. Then it was diluted with ethyl acetate (100 mL), washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with PLC to h Compound 119. LC- MS (ESI) m/z: 533 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) 5 (ppm) 1.24 (s, 6H), 1.62-1.67 (m, 2H), .90 (m, 2H), 2.00 (s, 2H), 2.57-2.60 (m, 2H), 3.06-3.18 (m, 2H), 3.41-3.47 (m, 4H), 4.46-4.51 (m, 1H), 4.72 (s, 1H), 5.82 (s, 1H), 5.58 (d, J: 8.4 Hz, 1H), 6.82 (s, 1H), 6.95-7.00 (m, 2H), 7.53 (d, J: 6.8 Hz, 1H), 7.74 (d, J: 8.4 Hz, 1H), 7.82 (s, 1H), 8.86 (d, J = 9.2 Hz, 1H), 9.48 (s, 1H).

Example 120 U N QH F F N OH F "T1 A CD NH + 5 |\ 1: CO N/ o 0 MHz N/ O 0 22.1 N 120 To a solution of Intermediate N (130 mg, 0.52 mmol) in dichloromethane (5 mL) was added Compound 22J (120 mg, 0.433 mmol), EDCI.HCl (149 mg, 0.7794 mmol), and HOBt (107 mg, 0.7794 mmol). The mixture was stirred at 30 0C for 2h. The mixture was evaporated in vacuo to ﬁlI'IllSh the crude compound. The crude compound was puriﬁed with PLC to furnish a white solid (83 mg, yield 37 %), which was separated by chiral HPLC (co-solvent IPA (0.5% DEA), column AD-H 250 * 4.6 mm 5 um) to give Compound 120. LC-MS (ESI) m/z: 510 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 0.46-0.61 (m, 4H), .80 (m, 4H), .30 (m, 2H), .63 (m, 5H), 2.73-2.81 (m, 3H), 3.76- 3.79(m, 1H), 4.36 (brs, 1H), 4.96 (d, J: 2.8 Hz, 1H), 6.88-6.89 (m, 1H), 7.27-7.29 (m, 1H), 7.41-7.45 (m, 2H), 7.59 (s, 1H), 7.75-7.81 (m, 4H), 8.16 (s, 1H). Co-solvent: IPA (0.5% DEA), column: AD-H 250 * 4.6 mm 5 um, Rt: 3.51 min.

Example 121 f 5 N QH F F N OH OH F s N’ + N o o O 0 0 CI Q CI 121 A mixture of Intermediate Q (150 mg, 0.41 mmol), EDCI.HCl (1 18 mg, 0.62 mmol), HOBt (84 mg, 0.62 mmol) and Compound 22J (103 mg, 0.41 mmol) in DCM (5 mL) was stirred for 18 h at 25 0C. Then the mixture was washed with water (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. After evaporation, the crude product was d with prep-HPLC to furnish Compound 121. LC-MS (ESI) m/z: 600 [M+H]+; 1H- NMR (MEOD, 400 MHz) 5 (ppm) 1.65-2.11 (m, 11H), 2.49-3.20 (m, 10H), 3.54-3.66 (m, 4H), 4.31 (s, 1H), 4.58-4.61 (d, J: 10 Hz, 1H), 4.91 (s, 1H), 6.93-6.95 (m, 1H), 7.19-7.30 (m, 2H), 7.39-7.52 (m, 4H), 7.74-7.76 (m, 3H). -2ll- 2014/056555 Example 122 N 9H 0 - CI CI N W+0 9H ? - N. a ﬁ \ 0A 0 OH a CI 0 O O NHZ 11E O I 122 A mixture of Intermediate I (117 mg, 0.4 mmol), EDCI.HCl (114 mg, 0.59 mmol), HOBt (78 mg, 0.59 mmol) and nd 11E (88.5 mg, 0.4 mmol) in DCM (15 mL) was d at room temperature overnight. Then the reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 122. LC-MS (ESI) m/z: 503 [M+H]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 0.67-0.75 (m, 4H), 2.35-2.36 (m, 1H), 2.64 (s, 1H), 3.48 (s, 1H), 3.59-3.69 (m, 2H), 4.0 (s, 2H), 4.35-4.63 (m, 5H), 4.99 (s, 1H), 7.09-7.11 (m, 1H), 7.30 (s, 1H), 7.35-7.40 (m, 2H), 7.60 (s, 1H), 8.04-8.06 (d, J: 8.0 Hz, 1H), 8.21 (s, 1H), 11.38 (s, 1H).

Example 123 ( 3 QH HO N OH F F 5 o NH O DEMO O ' I F NH2 0 CI CI F 0O/ﬁ 11E Q 0' CI 123 A mixture of Intermediate Q (150 mg, 0.41 mmol), EDCI.HCl (118 mg, 0.62 mmol), HOBt (84 mg, 0.62 mmol) and Compound 11E (101 mg, 0.41 mmol) in DCM (5 mL) was stirred for 18 h at 25 0C. Then the mixture was washed with water (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude t was purified with prep-HPLC to furnish Compound 123. LC-MS (ESI) m/z: 596 [M+H]+; 1H- NMR (MeOD, 400 MHz) 5 (ppm) 2.06-2.28 (m, 8H), 2.92 (s, 3H), 3.13-3.32 (m, 4H), 3.42- 3.76 (m, 6H), 4.60-4.68 (m, 2H), 4.96 (s, 1H), 6.69-6.78 (m, 1H), 6.87-6.95 (m, 1H), 7.27- 7.29 (m, 1H), 7.28 (s, 2H), 7.57-7.59 (m, 1H), 7.74 (m, 1H).

Example 124 N OH N QH F F = OH F so F 5 —» NH o N N .I 0. so 0 CI @ W0 2015/042397 A mixture of Intermediate R (180 mg, 0.530 mmol), Compound 22J (132 mg, 0.530 mmol), EDCI.HCl (153 mg, 0.800 mmol) and HOBt (108 mg, 0.800 mmol) in DCM (10 mL) was stirred at 25 0C for 16 h. Then it was diluted with ethyl acetate (100 mL), washed with water (200 mL) and brine (200 mL), dried over ous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to ﬁlmish Compound 124. LC-MS (ESI) m/z: 572 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz) 5 (ppm) .90 (m, 2H), 2.00-2.19 (m, 4H), 2.50-2.68 (m, 6H), 3.07-3.20 (m, 2H), 3.34-3.40 (m, 4H), 3.42-3.49 (m, 4H), 4.47-4.53 (m, 1H), 4.83 (s, 2H), 6.03 (s, 1H), 6.98 (d J: 8.4 Hz, 1H), 7.25-7.34 (m, 2H), 7.38 (s, 1H), 7.45- 7.53 (m, 2H), 7.66 (s, 1H), .90 (m, 3H), 8.42 (d, J: 8.4 Hz, 1H).

Example 125 FF N QH 9H 00 F F - o .Awww 0A 22" 0 F s F A mixture of Intermediate S (140 mg, 0.48 mmol), EDCI.HCl (137 mg, 0.72 mmol), HOBt (97 mg, 0.72 mmol) and nd 22J (120 mg, 0.48 mmol) in DCM (5 mL) was stirred for 18 h at 25 0C. Then the mixture was washed with H20 (50 mL) and brine (50 mL), and dried over ous sodium sulfate. After evaporation, the crude product was purified with prep-HPLC to furnish Compound 125. LC-MS (ESI) m/z: 527 [M+H]+; 1H- NMR(CDC13, 400 MHz) 5 (ppm) 0.51-0.52 (m, 4H), 2.08 (s, 4H), 2.22-2.47 (m, 2H), 2.49- 2.53 (m, 1H), 2.62-2.69 (m, 1H), 2.81-2.95 (m, 2H), 3.41-3.42 (m, 3H), 3.76 (s, 2H), 4.46- 4.47 (m, 1H), 5.12 (s, 1H), 7.05-7.22 (m, 4H), 7.41-7.47 (m, 2H), 7.52 (s, 1H), .61 (d, J = 8.0 Hz, 1H), 7.74-7.79 (m, 3H), 11.7 (s, 1H).

Example 126 Z 5 ::N 9H 0 N 9H 0 OH i + A—* \ 1"" 0A CI F 2 o C. o o F 11E 3 F 7] A mixture of Intermediate S (140 mg, 0.48 mmol), EDCI.HCl (137 mg, 0.72 mmol), HOBt (97 mg, 0.72 mmol) and Compound 11E (119 mg, 0.48 mmol) in DCM (5 mL) was stirred for 18 h at 25 0C. Then the mixture was washed with H20 (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was purified with prep-HPLC to furnish Compound 126. LC-MS (ESI) m/z: 523 [M+H]+; 1H- NMR(CDC13, 400 MHz) 5 (ppm) 0.66-0.74 (m, 4H), 2.11 (s, 4H), 2.95-3.02 (m, 2H), 3.41- 3.65 (m, 5H), 4.47 (s, 1H), 5.10 (s, 1H), 6.74 (s, 1H), 6.68-7.15 (m, 3H), 7.32-7.35 (m, 1H), 7.39-7.41 (d, J: 8.8 Hz, 1H), 7.55 (d, J: 1.6 Hz, 1H), 7.99 (d, J: 6.0 Hz, 1H), 11.45 (s, 1H).

Example 127 0 Q0. 0 ; Cl OH F F : \ + a —» NH F NH2 \ O F N K/O CI O 11E R CI K/O A mixture of Intermediate R (150 mg, 0.442 mmol), Compound 11E (109 mg, 0.442 mmol), EDCI.HCl (127 mg, 0.663 mmol) and HOBt (90 mg, 0.663 mmol) in DCM/Eth (10/0.3 mL) was stirred at 25 0C for 16 h. Then it was diluted with ethyl acetate (100 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to furnish nd 127. LC-MS (ESI) m/z: 568 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.06 (s, 2H), 2.20 (s, 2H), 2.75-2.88 (m, 4H), 3.17-3.22 (m, 2H), 3.58-3.70 (m, 4H), 3.75-3.83 (m, 4H), 4.65-4.69 (m, 1H), 4.93 (s, 1H), 6.68 (s, 1H), 6.82 (d, J: 8.0 Hz, 1H), 7.24 (d, J: 8.0 Hz, 1H), 7.42-7.48 (m, 2H), 7.59 (d, J: 8.0 Hz, 1H), 7.79 (s, 1H).

Example 128 7 \ N C_)H N OH F F Cl F 5 \ F NH ,3 + ; \ CNN 0 OH NH2 o/\/NI: —> Cl 0 o C. 11E T Cl 128 To a solution of Intermediate T (100 mg, 0.28 mmol) and nd 11E (69 mg, 0.28 mmol) in DMF (10 mL) was added EDCI.HCl (82 mg, 0.42 mmol) and HOBt (58 mg, 0.42 mmol) under nitrogen. The e was stirred at 25 0C overnight. TLC and LC-MS showed the starting material was consumed completely, sat. sodium bicarbonate (3 mL) was added to the mixture and then extracted with EA (50 mL x 3). The ed organic layers were washed with water (5 mL x 3) and brine (5 mL), dried over ous sodium sulfate, and concentrated to offer the crude product. The crude product was puriﬁed with prep-HPLC to offer Compound 128. LC-MS (ESI) m/z: 582 [M+H]+. 1H-NMR(CDC13, 400 MHz) 5 (ppm) 2.16-2.17 (m, 4H), 2.39-2.44 (m, 1H), 2.75-2.83 (m, 1H), 2.92-3.01 (m, 2H), 3.45-3.54 (m, 4H), 3.76 (s, 2H), 4.14-4.16 (m, 4H), 4.44-4.53 (m, 3H), 5.08 (d, J: 2.8 Hz, 1H), 6.62 (d, J: 8.4 Hz, 1H), 6.81 (s, 1H), 7.12 (dd, J: 2.0, 8.8 Hz, 1H), 7.34-7.38 (m, 2H), 7.43 (d, J: 8.8 Hz, 1H), 7.58 (d, J: 2.0, 1H), 8.08 (d, J: 8.8 Hz, 1H), 11.95 (brs, 1H), 13.25 (brs, 1H). —214— Example 129 N 9H F F OH OH F F o _ i + WW"KACECI0L 22.] u C' A mixture of Intermediate U (108 mg, 0.33 mmol), EDCI.HCl (96 mg, 0.50 mmol), HOBt (67 mg, 0.50 mmol) and Compound 22J (84 mg, 0.33 mmol) in DCM (15 mL) was stirred at room ature for 4 hours. Then the reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to furnish Compound 129. LC-MS (ESI) m/z: 559 [M+H]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 2.04- 2.40 (m, 7H), 2.52-2.59 (m, 1H), 2.85-2.97 (m, 2H), 3.34-3.77 (m, 4H), 4.46-4.60 (m, 6H), .11 (s, 1H), 6.24-6.26 (d, J: 8.0 Hz, 1H), 7.14-7.20 (m, 2H), 7.42-7.48 (m, 4H), 7.60-7.63 (m, 1H), .81 (m, 3H).

Example 130 Z S N QH N OH CI F F F : F _ \ + NH L0 i L0 _ , \ K/UCI O OH NH2 0 CI 0 O 11E U CI 130 A mixture of ediate U (108 mg, 0.33 mmol), Cl (96 mg, 0.50 mmol), HOBt (67 mg, 0.50 mmol) and Compound 11E (82 mg, 0.33 mmol) in DCM (15 mL) was stirred at room temperature for 4 hours. Then the reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to furnish Compound 130. LC-MS (ESI) m/z: 555 [M+H]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 2.13 (s, 4H), 2.96-3.09 (m, 2H), .88 (m, 4H), 4.52 (s, 1H), 4.67-4.74 (m, 2H), 4.91-4.96 (m, 3H), 5.12 (s, 1H), 6.18-6.20 (d, J: 8.4 Hz, 1H), 6.72 (s, 1H), 7.06-7.08 (m, 1H), 7.33-7.42 (m, 3H), 7.58 (s, 1H), 7.96 (m, 1H), 11.65 (s, 1H).

Example 131 F F N OH 9" F F ; + WONGa —» KAQONNH NU 0 CI T CI 131 -2l5- 2] To a solution of Intermediate T (100 mg, 0.28 mmol) and nd 22J (71 mg, 0.28 mmol) in DCM (10 mL) was added EDCI.HCl (81 mg, 0.42 mmol) and HOBt (57 mg, 0.42 mmol) under en. The mixture was stirred at 25 0C overnight. TLC and LC-MS showed the starting material was consumed completely, then sat. sodium bicarbonate (5 mL) was added to the e and then extracted with EA (50 mL x 3). The ed organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to offer the crude product. The crude product was puriﬁed with prep-HPLC to offer Compound 131. LC-MS (ESI) m/z: 586 [M+H]+. 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.03-2.22 (m, 8H), 2.34-2.42 (m, 1H), 2.51-2.59 (m, 1H), 2.90-3.01 (m, 2H), 3.15-3.17 (m, 1H), 3.23-3.24 (m, 1H), 3.54-3.58 (m, 1H), 3.63-3.68 (m, 3H), 3.74-3.78 (m, 2H), 3.82-3.93 (m, 2H), 4.01-4.04 (m, 2H), 4.64 (d, J: 10.4 Hz, 1H), 4.96 (d, J: 2.4 Hz, 1H), 6.89 (d, J: 8.4 Hz, 1H), 7.24 (dd, J: 2.0, 8.4 Hz, 1H), 7.34 (dd, J: 2.0, 8.4 Hz, 1H), 7.46-7.52 (m, 3H), 7.57 (s, 1H), 7.81-7.88 (m, 3H).

Example 132 O F F O" 0" 0 0 CI Cl CI 132A 1323 132C N QH F F = OH F F CO a _. NH j 0 O 1320 132 To a suspension of aluminum trichloride (1.61 g, 12 mmol) and ethyl chloroacetate (1.63 g, 12 mmol) in dichloromethane (60 mL) was added Compound 132A (1.62 g, 10 mmol) in dichloromethane (15 mL) dropwise at room ature overnight.

After 24 h a solution of ice water (100 mL) and saturated sodium bicarbonate solution (100 mL) was added dropwise. The aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organics were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 2% v/v) to give the Compound 132B. 4] To a solution of Compound 132B (2.62 g, 10 mmol) in dichloromethane (350 mL) was added DAST (4 mL) at room temperature. The reaction mixture was stirred at room temperature. After 14 h, the mixture was poured into ice water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organics were washed with brine (200 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. Puriﬁcation by silica gel chromatography (ethyl e in petroleum ether, 2% V/V) gave the Compound 132C.

To a solution of nd 132C (284 mg, 1 mmol) in ethanol/water (16 mL) was added LiOH'HzO (84 mg, 2 mmol). The mixture was stirred at room temperature overnight. After the completion of the reaction, the mixture was adjusted to pH 2 with aqueous HCl solution (3 N, 40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to furnish Compound 132D.

To a solution of 132D (256 mg, 1 mmol) in DCM (30 mL) was added Intermediate A (278 mg, 1 mmol), EDCI.HCl (286 mg, 1.5 mmol), HOBt (202 mg, 1.5 mmol), and DIPEA (1 mL). The mixture was stirred at room temperature overnight. The on mixture was diluted by DCM (30 mL), washed with brine (50 mL), dried over sodium e, and concentrated to furnish the crude t, which was purified with prep- HPLC to ﬁlmish Compound 132. LC-MS (ESI) m/z: 517 [M+H]+; 1H-NMR (CDClg, 400 MHz) 5 (ppm) 1.65-1.68 (m, 4H), 2.53-2.63 (m, 4H), 2.86-2.88 (m, 2H), 4.02-4.15 (m, 5H), 4.94-4.95 (m, 1H), .69 (m, 3H), 6.89-6.70 (m, 1H), 7.33-7.40 (m, 2H), .79 (m, 4H).

Example 133 O O\/ o4 mv2O 0 o 0 2 Br Br 133A 1333 1330 N QH O = O NH D —> o F 1330 O F 133 To a stirred suspension of AlC13 (8.5 g, 64 mmol) in romethane (40 mL) was added dropwise ethyl 2-chlorooxoacetate (8.7 g, 64 mmol) at -10 0C. The mixture was stirred at -10 0C for 15 minutes. nd 133A (5 g, 32 mmol) was added dropwise at -lO 0C. The resulting mixture was stirred at 20 0C for 15 hours. The mixture was poured into ice water (100 mL) to quench the reaction and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated sodium bicarbonate solution (200 mL) -2l7- and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (petroleum ether) to h Compound 133B. 8] A mixture of Compound 133B (3.7 g, 14.4 mmol), ophenylboronic acid (2.4 g, 17.3 mmol), Pd(PPh3)4 (497 mg, 0.4 mmol) and K3P04 in toluene (40 mL) was heated to reﬂux, stirred for 3 h, and ﬁltered. The ﬁltrate was concentrated to give a crude compound.

The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 133C.

To a solution of Compound 133C (1.1 g, 4 mmol) in THF/water (30 mL, 15:1, v/v) was added LiOH’HzO (250 mg, 6 mmol). The mixture was stirred at -10 0C for 3 h. After the reaction was completed, it was adjusted to pH 6 with 3 N HCl and extracted with ethyl acetate (20 mL x 3). The combined organic layers were concentrated in vacuo to give Compound 133D.

A mixture of Compound 133D (195 mg, 0.8 mmol), Intermediate C (237 mg, 0.8 mmol), HATU (456 mg, 1.2 mmol) and in dichloromethane (20 mL) was stirred at 30 0C for 15 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuum and puriﬁed with prep- HPLC to furnish nd 133. LC-MS (ESI) m/z: 524 [M+H]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 2.14 (s, 5H), 3.11 (s, 2H), 3.51 (s, 1H), 3.79 (s, 1H), 3.93 (s, 2H), 4.16-4.21 (m, 4H), 4.52 (s, 1H), 5.04 (s, 1H), 6.72 (t, J: 8 Hz, 2H), 7.14 (t, J: 8 Hz, 2H), .57 (m, 4H), 7.82 (d, J: 8 Hz, 1H), 8.08 (d, J: 8 Hz, 2H), 9.21 (s, 1H).

Example 134 F F N 9H 9H ’ CI 0" 0' F VIZ A + WA WW_ : 3 —> F o 82J ' F 134 A mixture of Intermediate I (100 mg, 0.33 mmol), EDCI.HCl (97 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol) and nd 82J (91 mg, 0.33 mmol) in DMF (5 mL) was stirred at room temperature ght. Then the reaction e was puriﬁed with prep- HPLC to offer Compound 134. LC-MS (ESI) m/z: 547 [M+H]+; 1H-NMR (CDClg, 400 MHz) (ppm) 0.47-0.55 (m, 4H), 2.22 (s, 2H), 2.40 (s, 2H), 2.56 (s, 2H), 3.40-3.50 (m, 3H), 3.96 (s, 2H), 4.34 (s, 3H), 5.05 (s, 1H), 7.15-7.22 (m, 4H), 7.37-7.42 (m, 2H), 7.48 (s, 1H), 7.61 (s, 1H), 7.68-7.71 (m, 1H), 7.75-7.79 (s, 1H), 12.13 (s, 1H).

Example 135 K 3 N QH F N OH o F F F o g j 00 = j N. _ O CI 0 CO 0 F 132D C F A mixture of Compound 132D (256 mg, 1 mmol), Intermediate C (296 mg, 1 mmol), EDCI.HCl (286 mg, 1.5 mmol) and HOBt (202 mg, 1.5 mmol) in DCM (30 mL) was stirred at 25 0C for 16 h. Then it was diluted with DCM (70 mL), washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous sodium sulfate, trated, and puriﬁed with prep-HPLC to ﬁJrnish Compound 135. LC-MS (ESI) m/z: 535 [M+H]+; lH-NMR (CDClg, 400 MHz) 5 (ppm) 2.10-2.11 (m, 4H), 2.86-3.01 (m, 4H), 3.49-3.51 (m, 2H), 4.05- 4.10 (m, 4H), 4.37-4.39 (m, 1H), 5.03 (s, 1H), 6.51 (s, 1H), 6.68 (d, J: 2 Hz, 1H), 7.42 (d, J = 4.4 Hz, 1H), 7.47-7.50 (m, 1H), 7.75 (d, J: 2 Hz, 1H), 7.74-7.84 (m, 3H), 7.90 (s, 1H), 11.84 (s, 1H).

Example 136 N QH N QH ' CI HO\ ' CI 0 . N . : | m NH NH \ O/A \ 0A CI 0 0 CI 0 O 79 136 A mixture of Compound 79 (38 mg, 0.74 mmol), hydroxylamine hydrochloride (138 mg, 2 mmol) and ol (9 mL) was stirred at 50 0C ght. Then the mixture was puriﬁed with prep-HPLC to offer Compound 136. LC-MS (ESI) m/z: 532.1 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 0.74-0.86 (m, 4H), 2.05-2.19 (m, 4H), 3.25- 3.30 (m, 1H), 3.52-3.58 (m, 1H), 3.72-3.76 (m, 1H), 3.84-3.89 (m, 3H), 4.81-4.85 (m, 1H), .02 (d, J: 2.4 Hz, 1H), 5.97 (s, 1H), 7.32-7.36 (m, 1H), 7.40 (s, 2H), .47 (d, J: 8.4 Hz, 2H), 7.54-7.56 (m, 2H).

Example 137 HO‘N O T HO\ CI I N OH N OH a 00 | + VI; H CA F 0A CO 0 1063 I 137 -2l9- A mixture of Intermediate I (100 mg, 0.33 mmol), EDCI.HC1 (97 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol) and Compound 106B (88 mg, 0.33 mmol) in DMF (5 mL) was stirred at room temperature overnight. Then the reaction e was puriﬁed with prep- HPLC to offer Compound 137. LC-MS (ESI) m/z: 540 [M+H]+; 1H-NMR (CDC13, 400 MHz) (ppm) 0.71-0.72 (m, 4H), 1.26 (s, 1H), 2.11 (s, 1H), 2.46 (s, 1H), 2.78-2.82 (m, 4H), 3.22 (s, 1H), 3.65 (s, 3H), 4.10-4.18 (m, 2H), 4.33 (s, 1H), 4.83 (s, 1H), .22 (m, 3H), 7.32- 7.38 (m, 3H), 7.58 (s, 1H), 7.62-7.65 (m, 1H), 7.71-7.75 (m, 1H), 11.02 (s, 1H).

Example 138 N oH O 1 HO\N I NH 01 O o o F 133 F 138 ] A mixture of Compound 133 (41 mg, 0.078 mmol) and hydroxylamine hydrochloride (109 mg, 1.56 mmol) in MeOH (10 mL) was stirred at room temperature for 4 h. Then it was puriﬁed with prep-HPLC directly to offer Compound 138. LC-MS (ESI) m/z: 538 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.02 (s, 2H), 2.20 (s, 2H), 3.12-3.28 (m, 2H), 3.45-3.87 (m, 4H), 4.26-4.60 (m, 5H), 4.78-4.82 (m, 1H), 6.82 (t, J: 12 Hz, 2H), 7.17- 7.42 (m, 4H), 7.53-7.68 (m, 4H).

Example 139 F O F N OH F F 2 * C' F CO 0 CI 0H2 0A 0 132D G 139 A mixture of Compound 132D (256 mg, 1 mmol), ediate G (296 mg, 1 mmol), EDCI.HC1 (286 mg, 1.5 mmol) and HOBt (202 mg, 1.5 mmol) in DCM (30 mL) was stirred at 25 0C for 16 h. Then it was diluted with DCM (70 mL), washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, and d with prep-HPLC to ﬁamish Compound 139. LC-MS (ESI) m/z: 549 [M+H]+; lH-NMR (CDC13, 400 MHz) 5 (ppm) 0.69-0.71 (m, 4H), 1.65-1.68 (m, 4H), 2.34-2.37 (m, 4H), 2.64- 2.68 (m, 2H), 3.51-3.52 (m, 1H), 4.15 (s, 1H), 5.09 (s, 1H), 6.91-6.92 (m, 1H), 7.12-7.13 (m, 2H), 7.35 (s, 1H), 6.94 (m, 1H), 7.50-7.52 (t, J: 4.8 Hz, 2H), 7.78-7.86 (m, 3H), 7.96 (s, 1H).

Example 140 133C 140A 1403 N QH ' o F F 5 —» NH j o F F 140 To a on of Compound 133C (1.78 g, 6.54 mmol) in dry dichloromethane (40 mL) was added DAST (2.2 mL, 16.36 mmol). Then the mixture was stirred at 25 0C for 14 h. After the reaction was completed, dichloromethane (25 mL) was added. The c layer was washed with water (50 mL), followed by aq. sodium bicarbonate (30 mL) and brine (50 mL), dried over sodium sulfate and concentrated to provide the crude product. The crude product was purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 20 % v/v) to provide Compound 140A.

To a solution of Compound 140A (2.3 g, 7.8 mmol) in THF/water/MeOH (30 mL, 1:1: 1, v/v) was added LiOH.HzO (493 mg, 11.7 mmol). The mixture was stirred at 28 0C for 1 h. After the reaction was completed, it was adjusted to pH to 6 with 2 N HCl and extracted with ethyl acetate (60 mL x 3). The combined organic layers were concentrated in vacuum to provide the crude t Compound 140B. 9] To a solution of Compound 140B (133 mg, 0.5 mmol), Intermediate C (156 mg, 0.53 mmol), and EDCI.HCl (144 mg, 0.75 mmol) in romethane (20 mL) was added HOBt (102 mg, 0.75 mmol) at 19 0C, then the reaction was stirred at 19 0C for 4 h.

Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, trated in vacuum and purified with prep-HPLC to furnish Compound 140. LC-MS (ESI) m/z: 545 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.12 (m, 4H), .10 (m, 2H), 3.45-3.48 (m, 2H), 3.75-3.85 (m, 2H), 4.11-4.12 (m, 4H), 4.15-4.22 (m, 1H), 4.90-4.91 (d, J: 2.8 Hz, 1H), 6.57-6.67 (m, 2H), 7.14-7.19 (m, 2H), 7.43-7.46 (m, 2H), 7.55-7.61 (m, 4H).

Example 141 OH O Va O\ —> O\ o O 22F 141A 1413 N C_)H Ho, HO\ HO\ O IN N N I I o\ OH NH DO —> —> 0 0 O o O o F 1410 141D 141 A solution of Compound 22F (6.6 g, 31.27 mmol) in methanol (150 mL) was stirred under HCl gas at room temperature for 6 h. It was quenched with water (30 mL) and stirred at room temperature for l h. After removal of solvent, the residue was dissolved in ethyl acetate (200 mL), washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give nd 141A.

A solution of Compound 141A (6.7 g, 27.46 mmol) and Dess-Martin periodinane (14 g, 33 mmol) in DCM (50 mL) was stirred at room temperature for 2 h. After removal of solvent, the residue was dissolved in ethyl acetate (200 mL), washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium e, and concentrated to give a residue. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 20% to 30% v/v) to afford Compound 141B.

A on of Compound 141B (2.0 g, 8.26 mmol) in EtOH (20 mL) was added potassium carbonate (1.48 g, 10.7 mmol) and hydroxylamine hydrochloride (0.74 g, .7 mmol) at room temperature, then stirred at room temperature overnight. Then it was filtered and trated to obtain Compound 141C.

A mixture of Compound 141C (2.0 g, 7.78 mmol) and LiOH.H20 (1.0 g, 23.3 mmol) in THF/MeOH/HZO (10/10/4 mL) was stirred at room temperature for 3 h. The solution was concentrated to remove organic solvent, then it was adjusted to PH 6 with 3 M HCl (5 mL), filtered and washed with PE (100 mL), dried to obtain Compound 141D.

To a solution of Compound 141D (72 mg, 0.3 mmol) and Intermediate H (90 mg, 0.3 mmol) in DMF was added EDCI.HCl (86 mg, 0.45 mmol), followed by HOBt (62 mg, 0.45 mmol). Then the reaction was d at room temperature for 15 hours. Then the reaction mixture was d with water (40 mL), extracted with DCM (100 mL x 2), washed with brine (50 mL), dried over sodium sulfate, and concentrated. The crude t was purified with prep-HPLC to furnish Compound 141. LC-MS (ESI) m/z: 508 ; 1H- NMR (MeOD, 400 MHz) 5 (ppm) 2.15-2.20 (m, 1H), 2.41-2.55 (m, 1H), 3.15-3.27 (m, 2H), 2014/056555 3.65-3.90 (m, 2H), 4.12-4.15 (m, 3H), 4.24 (s, 4H), 4.75-4.76 (d, J: 2.8 Hz, 1H), 6.65-6.71 (m, 2H), 7.36-7.46 (m, 3H), 7.64 (s, 1H), 7.75-7.82 (m, 3H).

Example 142 HO\N O Q9H | N OH 9H CO CI HO\|N moi + "(I 0 Aﬁwr 0A 0 CO 0 141D G 142 A mixture of Compound 141D (150 mg, 0.62 mmol), EDCI.HC1 (178 mg, 0.93 mmol), HOBt (126 mg, 0.92 mmol) and Intermediate G (230 mg, 0.7 mmol) in DMF (8 mL) was stirred at room temperature overnight. Then the reaction mixture was puriﬁed with PLC to e Compound 142. LC-MS (ESI) m/z: 536.2 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) .73 (m, 4H), 1.95-2.09 (m, 4H), 2.65-3.14 (m, 7H), 3.43-3.47 (m, 1H), 3.55-3.58 (m, 2H), 3.70-3.77 (m, 2H), 4.47-4.50 (m, 1H), 4.84-4.85 (d, J: 2.4 Hz, 1H), 7.25-7.32 (m, 3H), .45 (m, 3H), 7.74 (s, 1H), 7.76-7.80 (m, 3H).

Example 143 e — . 141B 143A 143 A mixture of Compound 141B (2.0 g, 8.26 mmol) and LiOH'HgO (1.0 g, 24.8 mmol) in THF/MeOH/HZO (10/10/4 mL) was stirred at room temperature for 5 h. The mixture was adjusted to pH 6 with aqueous HC1 solution (6 N, 1.0 mL). After removal of solvent the residue was dissolved in ethyl acetate (100 mL), washed with water (50 mL x 2) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue.

The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 30% v/v) to afford Compound 143A.

A mixture of Compound 143A (90 mg, 0.4 mmol), Intermediate C (118 mg, 0.4 mmol), and HATU (228 mg, 0.6 mmol) in dichloromethane (10 mL) was stirred at 30 0C for 15 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, trated in vacuum and ed with prep- HPLC to ﬁlrnish Compound 143. LC-MS (ESI) m/z: 506 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz) 5 (ppm) 1.77 (s, 2H), 1.93 (s, 2H), 2.87-2.96 (m, 2H), 3.00-3.10 (m, 4H), 3.21-3.27 (m, 4H), 4.18-4.30 (m, 5H), 4.61 (s, 1H), 5.95 (s, 1H), 6.67 (t, J: 12 Hz, 2H), 7.36 (d, J: 8 Hz, 2014/056555 1H), 7.40-7.47 (m, 2H), 7.67 (s, 1H), 7.78-7.84 (m, 3H), 8.14 (d, J: 12 Hz, 1H), 9.03 (s, 1H).

Example 144 N QH a - o F F N QH F F 0H+ = o NH j o 3 0 2 O 22.1 F 144 8] A mixture of Compound 22J (0.1 g, 0.4 mmol), ediate F (0.11 g, 0.4 mmol), DIPEA (0.10 g, 0.8 mmol), EDCI.HC1 (0.11 g, 0.6 mmol) and HOBt (0.08 g, 0.6 mmol) in DCM (2 mL) was stirred at 25 0C for 16 h. Then the mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over sodium sulfate, concentrated, and puriﬁed with prep-HPLC to furnish Compound 144. LC-MS (ESI) m/z: 497 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.15-2.22 (m, 2H), 2.41-2.71 (m, 4H), 3.54-3.63 (m, 3H), 3.77-3.89 (m, 3H), 4.20-4.23 (m, 4H), .42 (m, 1H), 4.85 (d, J = 3.2 Hz, 1H), 6.77-6.79 (m, 1H), 6.84-6.90 (m, 2H), 7.26-7.29 (m, 1H), 7.44-7.48 (m, 2H), 7.59 (s, 1H), 7.80-7.83 (m, 3H).

Example 145 <> N 9H N QH _‘ o O o OH 0 NH 1 + J —’ 00 V t 0 0 NH2 O F 143A H F 145 To a solution of Compound 143A (90 mg, 0.4 mmol) in dry dichloromethane (8 mL) and DMF (2 mL) was added HATU (228 mg, 0.6 mmol), followed by Intermediate H (90 mg, 0.3 mmol) in DMF. Then EDCI.HCl (86 mg, 0.45 mmol) and HOBt (62 mg, 0.45 mmol) was added. The on was stirred at room temperature for 15 hours, ﬁltered, and evaporated to furnish the crude product in DMF (3 mL). It was puriﬁed with prep-HPLC to furnish Compound 145. LC-MS (ESI) m/z: 493 [M+H]+; 1H-NMR (DMSO-dg, 400 MHZ) 5 (ppm) .35 (m, 2H), 2.90-3.00 (m, 2H), 3.12-3.35 (m, 4H), 3.80-4.20 (m, 5H), 4.25 (s, 4H), 4.62 (s, 1H), 5.96 (s, 1H), 6.65-6.74 (m, 2H), 7.38-7.51 (m, 3H), 7.71 (s, 1H), 7.82-7.88 (m, 3H), 8.09-8.12 (d, J: 9.6 Hz, 1H), 9.35 (br, 1H). —224— Example 146 < 3 N QH N OH F F = OH F F _ o 5 + ’ WW 0O ° CI o 0 CI 132D CI CI 0 146 A mixture of Intermediate 0 (120 mg, 0.34 mmol), C1 (98 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol) and Compound 132D (120 mg, 0.34 mmol) in DCM (10 mL) was d h at 25 0C for 12. Then the mixture was washed with ted sodium bicarbonate (15 mL) and brine (15 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to ﬁlI'IllSh Compound 146. LC- MS (ESI) m/z: 593 ; 1H-NMR (CDC13, 400 MHz) 5 (ppm) 1.63-1.70 (m, 2H), 1.78- 1.84 (m, 2H), 2.03 (m, 4H), 2.83 (m, 1H), 2.93 (m, 1H), 3.71-3.92 (m, 8H), 4.17-4.22 (m, 1H), 4.37 (m, 1H), 5.00 (s, 1H), 6.48 (d, J: 8.4 Hz, 1H), 6.91 (d, J: 8.4 Hz, 1H), 7.25 (s, 1H), 7.31 (d, J: 9.2 Hz, 1H), 7.41 (dd, J: 8.8, 2.0 Hz, 1H), 7.65 (d, J: 8.8 Hz, 1H), 7.72 (d, J: 8.8 Hz, 1H), 7.76 (m, 1H), 7.82-7.86 (m, 2H), 11.44 (s, 1H).

Example 147 0 Q OH 9" o ilk/giac' + "(102* m 0A 143A G 147 A mixture of Compound 143A (152 mg, 0.67 mmol), HATU (456 mg, 1.2 mmol), DCM (16 mL) and Intermediate G (248 mg, 0.8 mmol) in DMF (6 mL) was d at room temperature overnight. Then the reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to provide Compound 147. LC-MS (ESI) m/z: 521.3 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz) 5 (ppm) 0.63-0.78 (m, 4H), 1.82-1.98 (m, 4H), 2.94-3.12 (m, 5H), .24 (m, 1H), 3.46-3.49 (m, 3H), 3.83-3.86 (m, 2H), 4.31-4.36 (m, 1H), 4.74 (d, J: 2.8 Hz, 1H), 6.01 (s, 1H), 7.21-7.24 (m, 1H), 7.30-7.40 (m, 3H), 7.45-7.50 (m, 2H), 7.70 (s, 1H), 7.82-7.88 (m, 3H), 8.20 (d, J: 9.6 Hz, 1H), 9.38 (s, 1H).

Example 148 U Q9H HO\ ' N C:)H HO\N O N K/\©:Oj W0]"Hz .

CO 0 0 CO 0 F 143A c F 148 2] A mixture of Compound 143A (97 mg, 0.4 mmol), Intermediate C (118 mg, 0.4 mmol), HOBt (81 mg, 0.6 mmol), and EDCI.HCl (115 mg, 0.6 mmol) in DMF (10 mL) was stirred at 30 0C for 8 h. The mixture was puriﬁed with prep-HPLC directly to ﬁlrnish Compound 148. LC-MS (ESI) m/z: 522 ; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 1.93 (s, 2H), 2.09 (s, 2H), 2.68-2.95 (m, 4H), 3.04-3.17 (m, 2H), .44 (m, 1H), 3.54 (t, J: 12 Hz, 2H), 3.69 (s, 1H), 4.14-4.21 (m, 4H), 4.44-4.49 (m, 1H), 4.75 (s, 1H), 6.74 (d, J: 12 Hz, 2H), 7.33 (d, J: 8 Hz, 1H), 7.38-7.45 (m, 2H), 7.62 (s, 1H), 7.70 (d, J: 8 Hz, 0.5H), 7.70- 7.85 (m, 3H).

Example 149 o O 0 v0 OH 9H rim A O 0 o + mA—> CI O c: 0 O F CI 133D F 149 A mixture of Compound 133D (230 mg, 0.94 mmol), HATU (515 mg, 1.36 mmol), and Intermediate G (324 mg, 1.05 mmol) in DCM (25 mL) was stirred at room temperature overnight. Then the reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude t was puriﬁed with prep-HPLC to provide Compound 149. LC-MS (ESI) m/z: 537.2 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 0.69-0.83 (m, 4H), 1.82-1.98 (m, 4H), 2.94-3.12 (m, 5H), 3.21-3.24 (m, 1H), 3.46-3.49 (m, 3H), 2.04-2.08 (m, 3H), 2.19-2.22 (m, 2H), .33 (m, 1H), 3.58-3.75 (m, 4H), 3.82-3.86 (m, 2H), 4.70- 4.73 (m, 2H), 5.01 (s, 1H), 7.23-7.27 (m, 2H), 7.39 (d, J: 0.8 Hz, 1H), 7.64-7.70 (m, 4H), 7.73-7.76 (m, 2H).

Example 150 N QH o 6 0 OH 1 O ' 0 O + 5 ﬂ O O j 0 O F o 0 F 133D H F F 150 A mixture of Compound 133D (195 mg, 0.8 mmol), Intermediate H (225 mg, 0.8 mmol), and HATU (456 mg, 1.2 mmol) in dichloromethane (20 mL) was stirred at 30 0C for 8 h. Then it was d with water (20 mL), ted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, trated in vacuum and puriﬁed with prep-HPLC to h Compound 150. LC-MS (ESI) m/z: 509 ; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 2.47 (s, 2H), 3.46-3.65 (m, 2H), 4.12-4.34 (m, 9H), 4.89 (s, 1H), 6.69 (d, J: 12 Hz, 2H), 7.12 (t, J: 8 Hz, 2H), 7.55 (t, J: 8 Hz, 4H), 7.90 (d, J: 8 Hz, 2H).

Example 151 N QH O o o o _ 00 0V —’ OHﬁ "" 0 0 CI CI F 1323 151A 151 To a solution of Compound 132B (262 mg, 1 mmol) in ethanol/water (16 mL, /l V/V) was added LiOH'HgO (84 mg, 2 mmol). The mixture was stirred at room temperature overnight. After the completion of the reaction, the mixture was adjusted to pH 2 with aqueous HCl solution (3 N, 40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to yield the Compound 151A.

To a solution of Compound 151A (170 mg, 0.73 mmol) and Intermediate C (216 mg, 0.73 mmol) in dichloromethane (6 mL) was added HATU (414 mg, 1.09 mmol) at 0C. Then the on was stirred at 25 0C for 15 hours. Then the reaction mixture was treated with water (40 mL), extracted with DCM (10 mL x 2), washed with brine (10 mL), dried over sodium sulfate, and concentrated. The crude product was purified with prep-HPLC to furnish Compound 151. LC-MS (ESI) m/z: 513 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.05-2.07 (m, 2H), 2.22-2.25 (m, 1H), 3.20-3.22 (m, 2H), 3.58-3.95 (m, 4H), 4.05-4.24 (m, 4H), 4.56-4.59 (d, J: 10.4 Hz, 1H), 4.95-4.96 (d, J: 2.4 Hz, 1H), 6.75-6.81 (m, 2H), .55 (dd, J: 2.0 Hz, J: 8.4 Hz, 1H), 7.79-7.97 (m, 4H), 8.49 (s, 1H).

Example 152 O O 0 N OH OH 0H 00 133D A mixture of Compound 133D (82.5 mg, 0.34 mmol), HATU (193.8 mg, 0.51 mmol) and Intermediate O (120 mg, 0.34 mmol) in DCM (10 mL) was stirred for 12 h at 25 0C. Then the mixture was washed with water (15 mL) and brine (15 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to furnish nd 152. LC-MS (ESI) m/z: 581 [M+H]+; 1H-NMR (CDClg, 400 MHz) 5 (ppm) l.68-l.75 (s, 2H), 188-190 (S, 2H), 2.08-2.15 (m, 4H), 3.14-3.26 (m, 4H), .52 (m, 2H), 3.87-3.91 (m, 4H), 4.41-4.45 (m, 1H), 4.55-4.57 (m, 1H), 5.08 (s, 1H), 6.85 (d, J: 17.2 Hz, 1H), 7.10-7.14 (m, 2H), 7.20-7.22 (m, 1H), 7.40 (s, 1H), 7.50-7.54 (m, 4H), 7.90- 7.94 (m, 3H), 9.01 (s, 1H).

Example 153 U QQH O 0 0 0 CI I CI F 149 F 153 A mixture of 149 (36 mg, 0.07 mmol) and hydroxylamine hydrochloride (69 mg, 1.0 mmol) in methanol (6 mL) was d at 50 0C for 16 hours. Then the reaction mixture was puriﬁed with prep-HPLC to provide Compound 153. LC-MS (ESI) m/z: 552.1 ; 1H-NMR (MeOD, 400 MHz) 5 (ppm) .83 (m, 4H), 1.82-1.98 (m, 4H), 2.94- 312 (m, 5H), 3.21-3.24 (m, 1H), 3.46-3.49 (m, 3H), 2.04-2.08 (m, 3H), 2.04-2.21 (m, 4H), 3.20-3.33 (m, 2H), 3.59-3.89 (m, 5H), 4.83-4.87 (m, 1H), 5.03 (d, J: 2.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.38-7.42 (m, 2H), 7.48-7.52 (m, 3H), 7.66-7.69 (m, 2H).

Example 154 O O CI N OH 00 mgr"WA 90A | WO 42397 A mixture of Intermediate I (145 mg, 0.49 mmol), HATU (278 mg, 0.73 mmol), and Compound 90A (100 mg, 0.406 mmol) in DMF (3 mL) and DCM (6 mL) was stirred at 25 0C ght. Then the reaction mixture was concentrated to remove DCM. The residue was puriﬁed with prep-HPLC to provide Compound 154. LC-MS (ESI) m/z: 525 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz) 5 (ppm) 0.61-0.65 (m, 2H), 0.76-0.81 (m, 2H), .25 (m, 1H), 2.31-2.39 (m, 1H), 2.93-2.98 (m, 2H), 3.05-3.14 (m, 1H), 3.20-3.42 (m, 3H), 3.84-3.88 (m, 1H), 3.92-3.99 (m, 2H), .18 (m, 3H), 4.69 (s, 1H), 5.97 (s, 1H), 7.21 (d, J: 8.8 Hz, 1H), 7.31-7.33 (m, 2H), 7.39-7.45 (m, 2H), 7.66 (d, J: 12.8 Hz, 1H), 7.75 (s, 1H), 7.84 (d, J: 8.8 Hz, 1H), 7.91-7.94 (m, 1H), 8.13 (d, J: 9.6 Hz, 1H), 9.34 (s, 1H).

Example 155 N oH : oj HO\|N ; NH NH oj 0 o o F o F O O F 150 F 155 0] A mixture of 150 (90 mg, 0.18 mmol) and hydroxy1amine hydrochloride (248 mg, 3.54 mmol) in MeOH (10 mL) was stirred at room temperature for 4 h. Then it was puriﬁed with prep-HPLC directly to provide Compound 155. LC-MS (ESI) m/z: 523 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.44 (s, 1H), 2.56-2.66 (m, 1H), 3.53-3.67 (m, 2H), 4.18-4.45 (m, 9H), 4.45 (s, 0.5H), 4.81 (s, 0.5H), 6.77-6.83 (m, 2H), 7.17-7.23 (m, 3H), 7.40-7.69 (m, 5H).

Example 156 N QH o O ' 0 "WC" o 6' °" 0o CI NH 3 —> —> 0 0 0o 0 o F 156A 156B 156 To a solution of Compound 156A (100 mg, 0.38 mmol) in THF/water (8 mL, :1, v/v) was added LiOH.HzO (25 mg, 0.58 mmol). The mixture was stirred at -10 0C for 1 h. After the reaction was completed, it was adjusted to pH to 6 with 3 N HC1 and extracted with ethyl acetate (15 mL x 3). The combined organic layers were concentrated in vacuum without dryness to provide the d product Compound 156B.

To a solution of Compound 156B (85 mg, 0.36 mmol) and Intermediate C (108 mg, 0.36 mmol) in romethane (3 mL) was added HATU (207 mg, 0.54 mmol) at 0C. Then the reaction was stirred at 25 0C for 15 hours. Then the on mixture was 2014/056555 treated with water (20 mL), extracted with DCM (10 mL x 2), washed with brine (10 mL), dried over sodium sulfate, and concentrated. The crude product was d with prep-HPLC to h Compound 156. LC-MS (ESI) m/z: 513 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.05-2.17 (m, 4H), 3.11-4.12 (m, 6H), 4.17-4.31 (m, 4H), 4.55-4.57 (m, 1H), 4.95 (d, J = 2.0 Hz, 1H), 6.75-6.83 (m, 2H), 7.48-7.56 (m, 2H), 7.75-7.98 (m, 4H), 8.55 (d, J: 9.2 Hz, 1H).

Example 157 F F N OH O 0 O ; NH j —> O 2 0 O F 1403 H F F 157 To a solution of Compound 140B (67 mg, 0.25 mmol), Intermediate H (78 mg, 0.26 mmol), and EDCI.HCl (72 mg, 0.375 mmol) in dichloromethane (10 mL) was added HOBt (51 mg, 0.375 mmol) at 19 0C, then the reaction was stirred at 19 0C for 4 h.

Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over ous sodium sulfate, concentrated in vacuum and puriﬁed with prep-HPLC to furnish Compound 157. LC-MS (ESI) m/z: 531 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.29-2.38 (m, 2H), 2.72 (br, 1H), 4.08-4.37 (m, 10H), 4.91 (s, 1H), 6.54-6.66 (m, 2H), .17 (m, 2H), 7.41 (d, J: 8.4 Hz, 2H), 7.53-7.58 (m, 4H).

Example 158 Q9H QQ, 0 111°] m "£11 O F O F 151 C' To a solution of 151 (40 mg, 0.064 mmol) in MeOH (15 mL) was added hydroxylamine hloride (90 mg, 1.28 mmol) at 30 0C, then the reaction was stirred at 55 0C for 4 h. Then it was puriﬁed with prep-HPLC to furnish Compound 158. LC-MS (ESI) m/z: 528 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.03-2.23 (m, 4H), 3.28-3.34 (m, 1H), 3.50-3.92 (m, 4H), 4.13-4.32 (m, 4H), 4.84-4.93 (m, 1H), 6.81-6.90 (m, 2H), 7.50-7.53 (m, 2H), 7.72-7.92 (m, 4H).

Example 159 N OH F F K 3 F F ; 0 N QH NH 0A + C' —’ o o _ D 0 NH. A 0 F 1403 0 G F 159 A mixture of Compound 140B (172 mg, 0.64 mmol), EDCI.HCl (186 mg, 0.97 mmol), HOBt (132 mg, 0.97 mmol) and ediate G (200 mg, 0.64 mmol) in DCM (15 mL) was stirred at room temperature ght. Then the reaction mixture was treated with water (20 mL), ted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to provide Compound 159. LC-MS (ESI) m/z: 559.2 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 0.49-0.61 (m, 4H), 2.03-2.04 (m, 4H), 3.15-3.30 (m, 2H), 3.53-3.81 (m, 5H), 4.63 (d, J = 10.4 Hz, 1H), 7.04 (d, J: 8.4 Hz, 1H), 7.11-7.13 (m, 1H), 7.21-7.25 (m, 2H), 7.34-7.36 (m, 3H), 7.63 (d, J: 8.0 Hz, 2H), .75 (m, 2H).

Example 160 ' o * m]ﬂ ° F 1403 A F 160 A mixture of Compound 140B (0.10 g, 0.4 mmol), ediate A (0.10 g, 0.4 mmol), DIPEA (0.1 g, 0.8 mmol), EDCI.HCl (0.10 g, 0.6 mmol) and HOBt (0.08 g, 0.6 mmol) in DCM (2 mL) was stirred at 25 0C for 16 h. Then the mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over sodium sulfate, concentrated, and puriﬁed with prep-HPLC to furnish Compound 160. LC-MS (ESI) m/z: 527 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.01-2.25 (m, 4H), 3.15-3.22 (m, 2H), 3.52-3.66 (m, 3H), 3.77-3.79 (m, 1H), 4.07 (s, 4H), 4.56-4.58 (m, 1H), 4.83 (d, J: 3.2 Hz, 1H), 6.63-6.65 (m, 1H), 6.72-6.77 (m, 2H), 7.20-7.25 (m, 2H), 7.43-7.45 (m, 2H), 7.65- 7.73 (m, 4H).

Example 161 a" * my,"161 A mixture of Compound 140B (0.10 g, 0.4 mmol), Intermediate F (0.10 g, 0.4 mmol), DIPEA (0.1 g, 0.8 mmol), EDCI.HC1 (0.10 g, 0.6 mmol) and HOBt (0.08 g, 0.6 mmol) in DCM (2 mL) was stirred at 25 0C for 16 h. Then the e was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over sodium sulfate, concentrated, and puriﬁed with prep-HPLC to furnish Compound 161. LC-MS (ESI) m/z: 513 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 2.38-2.62 (m, 2H), 3.53-3.56 (m, 2H), 4.08 (s, 4H), 4.19-4.26 (m, 4H), 4.36-4.38 (m, 1H), 4.80 (d, J: 3.2 Hz, 1H), 6.64-6.77 (m, 3H), 7.21-7.25 (m, 2H), 7.41-7.43 (m, 2H), 7.65-7.73 (m, 4H).

Example 162 N OH F F F F ; OH (11> NH 0A 0 QH o + a —» o A O O F 1403 I F 162 A mixture of Compound 140B (172 mg, 0.64 mmol), EDCI.HC1 (186 mg, 0.97 mmol), HOBt (132 mg, 0.97 mmol) and Intermediate I (191 mg, 0.64 mmol) in DCM (15 mL) was stirred at room temperature overnight. Then the reaction e was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was d with prep-HPLC to provide Compound 162. LC-MS (ESI) m/z: 545.1 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 0.49-0.64 (m, 4H), 2.43-2.61 (m, 2H), 3.54-3.62 (m, 3H), 4.21-4.47 (m, 6H), 7.06 (d, J = 8.4 Hz, 1H), .13 (m, 1H), 7.21-7.25 (m, 2H), .36 (m, 3H), .64 (m, 3H), 7.71-7.74 (m, 2H).

Example 163 FFOH QOH FFﬁH? 00 1403 2014/056555 A mixture of Intermediate 0 (120 mg, 0.34 mmol), Cl (98 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol) and Compound 140B (90 mg, 0.34 mmol) in DCM (10 mL) was d for 12 h at 25 0C. Then the e was washed with saturated sodium bicarbonate (15 mL) and brine (15 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to furnish Compound 163. LC- MS (ESI) m/z: 603 [M+H]+; 1H-NMR (CDC13, 400 MHz) 5 (ppm) 1.65-1.75 (m, 2H), 1.85- 1.89 (m, 2H), 2.13 (m, 4H), 2.91-3.03 (m, 2H), 3.49-3.54 (m, 4H), 3.76-3.94 (m, 4H), 4.40 (m, 2H), 5.16 (s, 1H), 6.78 (d, J: 8.8 Hz, 1H), 7.07-7.15 (m, 3H), 7.31-7.37 (m, 3H), 7.50- 7.57 (m, 4H), 7.69 (d, J: 4.8 Hz, 1H), 11.80 (s, 1H).

Example 164 N OH ,OH O ? NI CI N 9H HO~N .

OH + CI —> I Km 4 O NH2 0/4 o 141D | 164 A solution of Compound 141D (150 mg, 0.60 mmol), ediate I (182 mg, 0.6 mmol), EDCI.HCl (171 mg, 0.9 mmol), HOBt (121 mg, 0.9 mmol), and DIPEA (0.2 mL, 2.40 mmol) in DCM (10 mL) and DMF (10 mL) was stirred at room temperature overnight under nitrogen. Then it was evaporated and puriﬁed with prep-HPLC to ﬁlmish Compound 164. LC-MS (ESI) m/z: 522 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 0.64-0.75 (m, 4H), 2.21-2.48 (m, 2H), 2.64-2.80 (m, 2H), 2.82-2.98 (m, 2H), 3.38-3.55 (m, 2H), 3.73-3.80 (m, 1H), 3.80-3.89 (m, 2H), 4.06-4.19 (m, 2H), 4.21-4.32 (m, 1H), 4.80-4.83 (m, 1H), 7.22- 7.27 (m, 1H), 7.30-7.34 (m, 2H), 7.38-7.47 (m, 3H), 7.58-7.62 (m, 1H), 7.74-7.83 (m, 3H).

Example 165 To a cooled solution of Compound 165A (10 g, 67 mmol), 2,6- dimethylpyridine (10.8 g, 101 mmol), and DMAP (1.65 mmol, 13 mmol) in DCM (100 mL) was added dropwise szO (30.5 g, 108 mmol) at 0 0C. The resulting mixture was stirred at room temperature ght, diluted with DCM, and washed with diluted HCl. The mixture was extracted with DCM (50 mL x 2), washed with sat. sodium bicarbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and d with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, 5% V/V) to afford Compound 165B. 2] A mixture of Compound 165B (18 g, 64 mmol), methyl acrylate (16.6 g, 193 mmol), Pd(PPh3)2Clz (2.26 g, 3.2 mmol), and K2C03 (22 g, 161 mmol) in DMF (100 mL) was stirred at 100 0C for 12 h. The mixture was cooled to room temperature, and ﬁltered. The filtrate was treated with water (50 mL), extracted with DCM (100 mL x 2), washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% V/V) to afford Compound 165C.

To a solution of Compound 165C (11 g, 51 mmol) in methanol (150 mL) was added Pd/C (1.1 g). The resulting mixture was stirred at room temperature for 12 h under H2 and filtered. The filtrate was concentrated to give a crude Compound 165D.

To a solution of AlLiH4 (1.2 g, 31 mmol) in THF (25 mL) was added Compound 165D (6.76 g, 31 mmol) in THF (20 mL) dropwise under nitrogen at -78 0C. The e was d at -78 0C for 2 h and quenched with .10H20. The filtrate was concentrated to afford the crude Compound 165E. —234— To a solution of Compound 165E (5.2 g, 27 mmol) in DCM (100 mL) was added Dess-Martin periodinane (13.9 g, 33 mmol) at 0 0C. The resulting mixture was stirred at room temperature for 2 h and ﬁltered. The ﬁltrate was concentrated and the resulting residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 165F. nd 165F (4 g, 22 mmol) was added to a on ofNa2S205 (4.11 g, 22 mmol) in water (150 mL). The resultant mixture was stirred for 2 h at room temperature, and NaCN (2.1 g, 43 mmol) was added. After stirring for 15 h, the mixture was diluted with ethyl e (50 mL), extracted with ethyl acetate (100 mL x 2), washed with sat. sodium bicarbonate (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 165G.

To a solution of Compound 165G (4.4 g, 20 mmol) in ethanol (50 mL) at 0 0C was d a gentle stream of HCl gas (dried over con. H2S04) for 5 h. The mixture was treated with water slowly at 0 0C and d at room temperature for 2 h. The mixture was extracted with DCM (100 mL x 2), washed with brine (100 mL), dried over anhydrous sodium sulfate, trated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, 10% v/v) to afford Compound 165H.

To a solution of Compound 165H (2 g, 7.6 mmol) in DCM (20 mL) was added Dess-Martin periodinane (3.88 g, 9.1 mmol). The mixture was d at room temperature for 2 h and ﬁltered. The ﬁltrate was concentrated and the resulting residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, % v/v) to afford Compound 1651.

To a solution of Compound 1651 (1.7 g, 6.5 mmol) in DCM (20 mL) was added DAST (5.3 g, 33 mmol). The mixture was stirred at room temperature for 12 h and poured into ice water. The mixture was extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 165J.

To a solution of Compound 165J (1.7 g, 6.0 mmol) in THF (50 mL) was added LiOH'HzO (758 mg, 18 mmol) in water (5 mL). The resulting mixture was stirred at room temperature for 2 h and evaporated to remove solvent. The mixture was d with water (50 mL), adjusted to pH 2 with diluted HCl, extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford the nd 165K.

A mixture of Compound 165K (164 mg, 0.65 mmol), Intermediate A (150 mg, 0.54 mmol), EDCI.HCl (155 mg, 0.81 mmol), and HOBt (110 mg, 0.81 mmol) in DCM (10 mL) was stirred at 25 0C ght. Then the reaction mixture was concentrated to remove DCM. The e was purified with prep-HPLC to e Compound 165. LC-MS (ESI) m/z: 515 [M+H]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 1.77 (s, 4H), 2.11-2.13 (m, 5H), 2.20-2.29 (m, 1H), 2.72 (s, 4H), 2.87 (s, 3H), 3.03 (s, 1H), 3.44-3.46 (m, 2H), 3.83 (s, 2H), 3.98-4.05 (m, 4H), 4.42-4.44 (m, 1H), 5.08 (s, 1H), 6.78-6.82 (m, 4H), 6.87 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 7.48 (d, J: 8.0 Hz, 1H), 11.76 (s, 1H).

Example 166 N QH Z l ' CI F F WN OH F F ; OH - + ' 0' mm" of o a NH2 0A 0 165K G 166 A mixture of Intermediate G (200 mg, 0.64 mmol), Compound 165K (164 mg, 0.64 mmol), EDCI.HCl (188 mg, 0.97 mmol), and HOBt (131 mg, 0.97 mmol) in DCM (10 mL) was stirred at 25 0C overnight. Then the reaction mixture was concentrated to remove DCM. The e was ed with prep-HPLC to provide Compound 165. LC-MS (ESI) m/z: 547 [M+H]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 0.63-0.69 (m, 4H), 1.77 (s, 4H), 2.14-2.16 (m, 5H), 2.33-2.40 (m, 1H), 2.71 (s, 4H), 2.91-2.93 (m, 1H), 3.04 (s, 1H), 3.50 (s, 5H), 3.82 (s, 2H), 4.47-4.48 (m, 1H), 5.13 (s, 1H), 6.75-6.78 (m, 2H), 6.95 (d, J: 7.6 Hz, 1H), .21 (m, 2H), 7.36 (s, 1H), 7.53 (d, J: 8.0 Hz, 1H), 11.60 (s, 1H).

Example 167 A mixture of Intermediate C (200 mg, 0.67 mmol), Compound 165K (172 mg, 0.67 mmol), EDCI.HCl (197 mg, 1.01 mmol), and HOBt (136 mg, 1.01 mmol) in DCM (10 mL) was stirred at 25 0C overnight. Then the reaction mixture was concentrated to remove DCM. The residue was purified with prep-HPLC to provide Compound 167. LC-MS (ESI) m/z: 533 [M+H]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) .78 (m, 4H), 2.15-2.21 (m, 6H), 2.38-2.44 (m, 1H), 2.71 (s, 4H), 2.91 (s, 1H), 3.05-3.13 (m, 3H), 3.48 (s, 2H), 3.83 (s, 2H), 4.00-4.06 (m, 3H), 4.44-4.45 (m, 1H), 5.07 (s, 1H), 6.67-6.72 (m, 2H), 6.78-6.82 (m, 2H), 6.96 (d, J: 8.0 Hz, 1H), 7.45 (d, J: 8.4 Hz, 1H), 11.70 (s, 1H).

Example 168 Z 5 N QH CI F F : \ F NH . \ o/K o NH2 OHZ 0 CI 0 O OH 0 CI OH 11E v 168 To a solution of Intermediate V (100 mg, 0.29 mmol) and Compound 11E (72 mg, 0.29 mmol) in DMF (10 mL) was added EDCI.HCl (84 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol) under nitrogen. The mixture was stirred at 25 0C overnight. TLC and LC-MS showed the starting material was ed completely, sat. sodium bicarbonate (5 mL) was added to the mixture and then extracted with EA (50 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (5 mL), and dried over anhydrous sodium sulfate, and concentrated to provide the crude product. The crude product was puriﬁed with prep-HPLC to provide nd 168. LC-MS (ESI) m/z: 571 ;1H-NMR(MeOD, 400 MHz) 5 (ppm) 1.31 (s, 6H), 1.98-2.00 (m, 2H), .15 (m, 2H), 3.15-3.23 (m, 2H), .67 (m, 5H), 3.72-3.75 (m, 1H), 4.60-4.62 (m, 1H), 4.90 (d, J: 2.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 7.19 (d, J: 8.4 Hz, 1H), 7.39-7.41 (m, 2H), 7.53 (d, J: 9.2, 1H), 7.68 (d, J: 2.0 Hz, 1H).

Example 169 QH N QH CI HO\ WC" 0 .

. N : 0A _. I : NH NH \ \ 0A 0 0 CI 0 O 122 169 A mixture of 122 (40.8 mg, 0.08 mmol), hydroxylamine hydrochloride (76 mg, 1.1 mmol) and methanol (9 mL) was stirred at 50 0C for overnight. Then the mixture was puriﬁed with prep-HPLC to provide Compound 169. LC-MS (ESI) m/z: 518.1 [M+H]+; 1H- NMR (MeOD, 400 MHz) 5 (ppm) 0.75-0.85 (m, 4H), .29 (m, 2H), 3.58-3.69 (m, 2H), 3.83-3.86 (m, 1H), 4.25-4.42 (m, 4H), 4.65-4.67 (m, 1H), 4.99 (d, J: 2.0 Hz, 1H), 5.86 (s, 1H), 7.32-7.35 (m, 1H), 7.38 (s, 2H), 7.44-7.46 (d, J: 8.8 Hz, 1H), 7.52-7.54 (m, 2H).

Example 170 (:DH a ' CI W0" " + 0' %me 0 WA O 0 143A I 170 A solution of Compound 143A (114 mg, 0.5 mmol), Intermediate I (148 mg, 0.5 mmol), and HATU (684 mg, 0.9 mmol) in DCM (16 mL) and DMF (6 mL) was stirred at room temperature ght under en. Then it was evaporated and puriﬁed with prep- HPLC to ﬁlrnish Compound 170. LC-MS (ESI) m/z: 507 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 0.10-0.90 (m, 4H), 1.77-2.05 (m, 2H), 2.05-2.43 (m, 3H), 2.85-3.21 (m, 2H), 3.45-3.76 (m, 2H), 4.08-4.41 (m, 5H), 4.88 (m, 1H), 7.12-7.14 (m, 2H), 7.21-7.51 (m, 4H), 7.65-7.87 (m, 4H).

Example 171 a 9H F F CI W0" "Cr #N 9" F Fm.»; o CA 00 o 22J l 171 A solution of Intermediate I (150 mg, 0.60 mmol), Compound 22J (148 mg, 0.5 mmol), EDCI.HCl (143 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), and DIPEA (0.1 mL, 1.20 mmol) in DCM (20 mL) was stirred at room temperature overnight under en.

Then it was evaporated, and puriﬁed with prep-HPLC to h a mixture (100 mg, yield 38%) as a white solid, then the mixture was further separated with chiral HPLC (co-solvent: MeOH (0.5% DEA), column OZ-H (250 * 4.6 mm 5 um)) and prep-HPLC to provide Compound 171. LC-MS (ESI) m/z: 529 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 0.29- 0.44 (m, 4H), 2.11-2.17 (m, 2H), 2.37-2.41 (m, 2H), 2.57-2.65 (m, 2H), 3.26-3.27 (m, 1H), 3.57-3.60 (m, 2H), 4.19-4.32 (m, 4H), 4.45-4.47 (m, 1H), 4.92-4.93 (m, 1H), .19 (m, 1H), 7.23-7.25 (m, 1H), 7.29-7.32 (m, 1H), 7.43-7.49 (m, 3H), 7.55 (s, 1H), 7.79-7.83 (m, 3H).

Example 172 g Q9H 0 N OH CI OH CI + ; ,iJH A o Aw so CI 0 0 151A G 172 A mixture of nd 151A (137 mg, 0.59 mmol), HATU (445 mg, 1.17 mmol), DMF (4 mL), and Intermediate G (218 mg, 0.70 mmol) in DCM (16 mL) was stirred at room temperature overnight. The reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to afford Compound 172. LC-MS (ESI) m/z: 527 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.54-0.79 (m, 4H), 2.04-2.22 (m, 5H), 3.23-3.26 (m, 1H), 3.58-3.82 (m, 6H), 4.70-4.73 (m, 1H), 4.99 (d, J: 2.8 Hz, 1H), 7.30 (d, J: 8.4 Hz, 1H), .41 (m, 1H), 7.50 (d, J: 2.0 Hz, 1H), 7.57-7.59 (m, 1H), 7.88-7.93 (m, 3H), 7.99 (d, J: 1.2 Hz, 1H), 8.29 (s, 1H). e 173 N QH ' CI HO\ 0 WA — I" 0A a" o CO 0 172 173 A mixture of 172 (40.8 mg, 0.08 mmol), hydroxylamine hloride (76 mg, 1.1 mmol) and methanol (9 mL) was stirred at 50 0C overnight. Then the mixture was purified with prep-HPLC to provide Compound 173. LC-MS (ESI) m/z: 542.1 [M+H]+; 1H- NMR (MeOD, 400 MHz) 5 (ppm) 0.69-0.84 (m, 4H), 2.02-2.22 (m, 4H), 3.21-3.29 (m, 1H), 3.62-3.80 (m, 5H), 4.70-4.73 (m, 1H), 5.01 (d, J: 2.8 Hz, 1H), 7.32-7.34 (m, 1H), 7.39-7.43 (m, 1H), 7.45-7.49 (m, 1H), 7.51-7.53 (m, 1H), 7.63-7.85 (m, 3H), 7.88-7.90 (m, 1H). 2014/056555 Example 174 B(OH)2 I \ O O I \ + E\>—Br —> S —> S O —> F s F F 174A 1743 174C 174D 0 = S —> O \s o 174E F 174 To a stirred solution of Compound 174A (2.0 g, 15.4 mmol) in dioxane (60 mL) and water (20 mL) was added Pd(PPh3)2C12 (1.08 g, 1.54 mmol), Compound 174B (3.0 g, 18.5 mmol) and N32C03 (6.53 g, 61.6 mmol) under nitrogen. The mixture was stirred at 80 ° C overnight. After the reaction was completed, it was evaporated to remove the solvent. The e was diluted with EA (200 mL), washed with water (5 mL) and brine (5 mL), and dried over anhydrous sodium sulfate. The crude product was puriﬁed with ﬂash column chromatography on silica gel leum in ethyl acetate, 3% v/v) to ﬁlrnish Compound 174C.

To a solution of Compound 174C (890 mg, 5.0 mmol) in dry THF (50 mL) was added dropwise LDA (2.0 M, 3.0 mL, 6.0 mmol) under nitrogen at -70 0C. After stirring for 30 min., diethyl oxalate (2.19 g, 15.0 mmol) was added as soon as possible. Then the mixture was stirred at -70 0C for about 1 h. Then the mixture was quenched with sat. NH4Cl (10 mL), extracted with ethyl acetate (50 mL x 3), washed with water (5 mL) and brine (5 mL), and dried over sodium sulfate. The crude product was purified with ﬂash column chromatography on silica gel (petroleum in ethyl acetate, 10% v/v) to ﬁlrnish Compound 174D.

To a solution of Compound 174D (500 mg, 1.8 mmol) in THF (6 mL) was added se a solution of zO (83 mg, 1.98 mmol) in water (1.5 mL) slowly at -30 0C. Then the mixture was d at -30 0C about 0.5 h. It was adjusted to pH 3 with HCl (1 N), and extracted with DCM (100 mL x 3). The organic phase was dried over sodium sulfate, ﬁltered and concentrated to ﬁlrnish the Compound 174E.

To a on of Compound 174E (360 mg, 1.44 mmol) in DMF (15 mL) was added HATU (821 mg, 2.16 mmol). After stirring for two hours at 25 0C, Intermediate A (400 mg, 1.44 mmol) was added and the resultant mixture was stirred overnight at 25 0C. —240— TLC and LC-MS showed the starting material was consumed completely, and sat. sodium bicarbonate (5 mL) was added to the mixture and then extracted with EA (50 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (5 mL), and dried over ous sodium sulfate, and concentrated to provide the crude product. The crude product was puriﬁed with prep-HPLC to provide Compound 174. LC-MS (ESI) m/z: 511 [M+H]+; 1H-NMR (MeOD, 400 MHz) 5 (ppm) 1.97-2.02 (m, 2H), .17 (m, 2H), 3.16- 3.23 (m, 2H), 3.40-3.44 (m, 1H), .70 (m, 2H), 3.76-3.82 (m, 1H), 4.11-4.18 (m, 4H), .51 (m, 1H), 4.82 (d, J: 3.6 Hz, 1H), 6.77 (d, J: 8.0 Hz, 1H), 6.85 (dd, J: 2.0, 8.4 Hz, 1H), 6.89 (d, J: 1.6 Hz, 1H), 7.21 (t, J: 8.8 Hz, 2H), 7.49 (d, J: 4.4 Hz, 1H), 7.78-7.82 (m, 2H), 8.15 (d, J: 4.4 Hz, 1H).

Example 175 o 0 O\/ N Br O\/ —> O + —> O 0‘3 I N O B l r F O l 175A 175B 175C 175D N (:DH 0 O OH mO/A N O —’ N 0 CI \ \ | I / / F F 175E 175 To a solution of Compound 175A (5.12 g, 20 mmol) in dioxane (75 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (6.10 g, 24 mmol), f)Clz (902 mg, 1 mmol) and KOAc (5.9 g, 60 mmol). The reaction mixture was heated to 90 0C for 2.5 h, then the solution was cooled to r.t and ﬁltered. The ﬁltrate was concentrated to offer the crude product. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% V/V) to offer Compound 175B.

A mixture of Compound 175B (730 mg, 2.4 mmol), Compound 175C (350 mg, 2 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol) and K3P04 (1.27 g, 6 mmol) in toluene (20 mL) was heated to reﬂux, stirred for 3 h and ﬁltered. The ﬁltrate was concentrated to offer the crude t. The crude t was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% V/V) to offer Compound 175D.

To a solution of Compound 175D (119 mg, 0.44 mmol) in THF/water (11 mL, : 1, V/V) was added LiOH.H20 (28 mg, 0.66 mmol). The mixture was stirred at -10 0C for —241— l h. After the reaction, it was adjusted to pH 6 with 3 N HCl and extracted with ethyl acetate (20 mL x 3). The combined organic layers were concentrated in vacuum without dryness to offer the crude product Compound 175E.

A mixture of Compound 175E (100 mg, 0.408 mmol), Intermediate G (124 mg, 0.408 mmol) and HATU (233 mg, 0.612 mmol) in romethane (2 mL) and DMF (2 mL) was stirred at 25 0C for 15 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, trated in vacuum and puriﬁed with prep-HPLC to obtain Compound 175. LC-MS (m/z): 538 [M+l]+; 1H-NMR (CD301), 400 MHz) 5 (ppm) 0.79-0.84 (m, 4H), 2.11-2.14 (m, 4H), 3.01-3.19 (m, 2H), 3.42- 3.90 (m, 5H), 4.55-4.57 (m, 1H), 4.79 (m, 1H), 7.28-7.32 (m, 2H), 7.41-7.62 (m, 2H), 7.82- 7.86 (m, 1H), 7.95-8.01 (m, 4H), 8.57 (d, J: 3.2 Hz, 1H).

Example 176 N QH ' 0 O N 0 9H a OH - NH O j N\ O O | / F / F F 175E C 176 A mixture of Compound 175E (98 mg, 0.4 mmol), ediate C (118 mg, 0.4 mmol), and HATU (228 mg, 0.6 mmol) in DMF (10 mL) was stirred at 30 0C for 8 h.

Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over ous sodium sulfate, concentrated in vacuum and purified with prep-HPLC to obtain Compound 176. LC-MS (m/z): 524 [M+l]+; 1H-NMR (CDgOD, 400 MHz) 5 (ppm) 2.04 (s, 2H), 2.19 (s, 2H), 3.18-3.30 (m, 2H), 3.48-3.57 (m, 1H), 3.65-3.74 (m, 2H), 3.78- 3.84 (m, 1H), 4.19-4.34 (m, 5H), 4.65 (d, J: 8 Hz, 1H), 6.81 (d, J: 12 Hz, 1H), 7.69-7.76 (m, 1H), 7.90 (d, J: 8 Hz, 2H), 8.02-8.05 (m, 1H), 8.11 (d, J: 8 Hz, 2H), 8.60 (s, 1H).

Example 177 :N: QH N QH NH —» NH 0 o O O D O F 152 F 177 A mixture of 152 (30 mg, 0.04 mmol) and NHZOHHCl (27.6 mg, 0.4 mmol) in MeOH (3 mL) was d for 4 h at 55 0C. After tion, the filtrate was purified with —242— prep-HPLC to furnish Compound 177. LC-MS (m/z): 596 [M+1]+; 1H-NMR (CD301), 400 MHz) major characteristic peaks: 5 (ppm) 172-1.81 (m, 2H), 1.98-2.08 (m, 2H), 3.30 (m, 1H), 3.51-3.74 (m, 4H), 3.88-3.99 (m, 4H), .70 (m, 1H), 5.03 (s, 1H), 7.09-7.11 (m, 2H), 7.15-7.23 (m, 3H), 7.35 (dd, J: 8.4, 2.0 Hz, 1H), 7.49 (d, J: 8.4 Hz, 2H), 7.55 (d, J: 2.0 Hz, 1H), 7.66-7.70 (m, 2H). e 178 F F O F F O\/ O\/ O\/ —> O\ O —> o O XV'.3 Br Br 178A 178B 178C ALION 178D To a solution of Compound 178A (2.56 g, 10 mmol) in dry dichloromethane (50 mL) was added DAST (3.30 mL, 25 mmol). Then the e was stirred at 25 0C for 14 h. After the reaction, dichloromethane (25 mL) was added, then the organic layer was washed with water (50 mL), followed by addition of aq. sodium bicarbonate (30 mL) and brine (50 mL), dried over sodium sulfate and concentrated to offer the crude product. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% V/V) to offer Compound 178B.

To a solution of Compound 178B (2.58 g, 9.3 mmol) in dioxane (45 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.82 g, 11.1 mmol), Pd(dppf)C12 (409 mg, 0.5 mmol) and KOAc (2.72 g, 27.8 mmol). The reaction mixture was heated to 90 0C for 2.5 h, then the solution was cooled to r.t and ﬁltered. The ﬁltrate was concentrated to offer the crude product. The crude product was d with ﬂash column chromatography on silica gel (ethyl e in petroleum ether, 10% V/V) to offer Compound 178C.

To a solution of Compound 178C (717 mg, 2.2 mmol), 2-bromo ﬂuoropyridine (350 mg, 2 mmol), and K3C03 (828 mg, 6 mmol) in dioxane (20 mL) and water (2 mL) was added f)C12 (82 mg, 0.1 mmol) at 25 0C under nitrogen. Then the mixture was heated to reﬂux, stirred for 3 h and ﬁltered. The ﬁltrate was concentrated to offer the crude product. Water (10 mL) was added, and the mixture was extracted with ethyl —243— WO 42397 2014/056555 acetate (100 mL). Then 2 N HCl was added to the aqueous layer, adjusted to pH = 6~7, then extracted with THF in ethyl acetate (20% v/v, 35 mL x 3). The organic layers were dried over anhydrous sodium sulfate, ﬁltered, and ated to obtain Compound 178D.

A mixture of Compound 178D (88 mg, 0.33 mmol), Intermediate G (105 mg, 0.34 mmol), EDCI.HCl (96 mg, 0.49 mmol), and HOBt (67 mg, 0.49 mmol) in dichloromethane (2 mL) and DMF (2 mL) was stirred at 25 0C for 5 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuum and puriﬁed with prep-HPLC to obtain Compound 178. LC-MS (m/z): 560 [M+l]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 0.63-0.69 (m, 4H), 2.13 (br, 2H), 3.03-3.05 (br, 2H), 3.36-3.61 (m, 5H), 4.51 (d, J: 8.0 Hz, 1H), 4.95 (d, J: 3.2 Hz, 1H), 7.08 (s, 2H), 7.34 (s, 1H), 7.41-7.44 (m, 2H), 7.58-7.62 (m, 1H), 7.83-7.95 (m, 3H), 8.54 (d, J: 3.2 Hz, 1H).

Example 179 N QH ' O F F o . Fm] OH N QH NH N O o / F F 178D A 179 A mixture of Compound 178D (88 mg, 0.33 mmol), Intermediate A (100 mg, 0.35 mmol), EDCI.HCl (96 mg, 0.49 mmol), and HOBt (67 mg, 0.49 mmol) in dichloromethane (15 mL) and DMF (2 mL) was stirred at 25 0C for 15 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuum and purified with prep-HPLC to obtain Compound 179. LC-MS (m/z): 528 ; 1H-NMR (CDgOD, 400 MHz) 5 (ppm) .14 (m, 4H), 2.81-2.84 (m, 2H), 3.41-3.45 (m, 2H), 3.72-3.88 (m, 2H), 4.15 (s, 4H), 4.41 (m, 1H), 5.06 (d, J: 2.0 Hz, 1H), 6.73-6.80 (m, 3H), 7.43-7.52 (m, 3H), 7.72-7.76 (m, 2H), 7.92 (d, J: 8.4 Hz, 2H), 8.56 (d, J: 2.8 Hz, 1H), ll.79 (brs, lH). —244— 2014/056555 Example 180 o/— o/— o O O OH F F 80 SF SF F F F 174D 180A 180B N (2H F "01 —> NH \ 0 S O To a solution of Compound 174D (290 mg, 1.07 mmol) in DCM (5 mL) was added DAST (1 mL, excess) at room temperature and the resultant mixture was stirred at 30 0C overnight. Poured into ice-water (100 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with water (5 mL) and brine (5 mL), and dried over ous sodium e. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to obtain nd 180A.

To a on of Compound 180A (130 mg, 0.43 mmol) in THF/water (6 mL, 4:1, V/V) was added LiOH.HzO (73 mg, 1.73 mmol). The mixture was d at 25 0C for 2 h.

After the reaction, it was adjusted to pH 3 with HCl (1 N) and separated. The organic phase was dried over sodium sulfate. Filtered and concentrated to mmish the Compound 180C.

To a mixture of Compound 180C (98 mg, 0.36 mmol) in DMF (10 mL) was added EDCI.HC1 (104 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol) and Compound (A) (100 mg, 0.36 mmol) under nitrogen. The mixture was stirred at 25 0C overnight. TLC and LC-MS showed the starting material was consumed completely. Then sat. sodium bicarbonate (5 mL) was added to the mixture which was extracted with EA (50 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (5 mL), dried over anhydrous sodium sulfate, and trated to offer the crude product. The crude product was puriﬁed with prep-HPLC to offer Compound 180. LC-MS (m/z): 533 [M+1]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 1.96-2.00 (m, 2H), 2.11-2.14 (m, 2H), 3.11-3.20 (m, 2H), 3.46-3.50 (m, 1H), 3.56-3.62 (m, 2H), 3.71-3.77 (m, 1H), 4.01 (s, 4H), 4.50-4.53 (m, 1H), 4.79 (d, J: 3.2 Hz, 1H), 6.59 (d, J: 8.4 Hz, 1H), 6.70 (dd, J: 2.0, 8.4 Hz, 1H), 6.74 (d, J: 2.4 Hz, 1H), 7.04 (d, J: 3.6 Hz, 1H), 7.15 (t, J: 8.4 Hz, 2H), 7.23 (d, J: 4.0 Hz, 1H), 7.63-7.67 (m, 2H). —245— WO 42397 Example 181 N 9H N 9H 0 EACEOJ HO\|N l\:/\©:Oj NH NH \ o \ O \ S O \ S O F 174 F 131 3] To a solution of 174 (50 mg, 0.08 mmol) in MeOH (10 mL) was added hydroxylamine hydrochloride (1 12 mg, 1.6 mmol). The mixture was stirred overnight at 25 0C. LC-MS showed the starting al was consumed completely, and the t was evaporated. The crude product was puriﬁed with prep-HPLC to offer Compound 181. LC-MS (m/z): 526 [M+l]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 1.97- 2.00 (m, 2H), 2.13-2.15 (m, 2H), 3.14-3.23 (m, 2H), 3.42-3.46 (m, 1H), 3.57-3.63 (m, 2H), 3.74-3.81 (m, 1H), 4.15-4.20 (m, 4H), 4.57-4.69 (m, 1H), 4.70 (d, J: 2.8 Hz, 1H), 6.74-6.86 (m, 2H), 6.90-6.94 (m, 1H), 7.10-7.15 (m, 2H), 7.27 (d, J: 4.0 Hz, 1H), 7.51 (d, J: 4.0 Hz, 1H), 7.61-7.69 (m, 2H). e 182 N QH W\/ F F o F F : O —> —> mo/A B N O N 0 CI 17sc 182A 182 A mixture of Compound 178C (1.3 g, 4 mmol), 2-bromopyridine (628 mg, 4 mmol), Pd(dppl)2C12 (160 mg, 0.2 mmol), and N32C03 (1.27 g, 12 mmol) in dioxane (30 mL) and water (4 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was ﬁltered and the ﬁltrate was treated with water (50 mL), extracted with ethyl acetate (50 mL x 2), then the water layer was adjusted to pH 3 by aqueous HCl solution (3 N), and extracted with ethyl acetate (50 mL x 2). The ethyl acetate layer was washed with water (50 mL x 2), dried over sodium sulfate, ﬁltered, and trated to ﬁlrnish the Compound 182A.

A mixture of Compound 182A (90 mg, 0.36 mmol), EDCI.HCl (103 mg, 0.54 mmol), HOBT (73 mg, 0.54 mmol), and Intermediate G (1 ll mg, 0.36 mmol) in DCM (5 mL) was stirred at 10 0C for 18 h. Then the mixture was d by ethyl acetate (50 mL), 2014/056555 washed with sat. sodium onate solution (50 mL x 2) and brine (50 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to furnish Compound 182. LC-MS (m/z): 542 [M+l]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 0.48-0.59 (m, 4H), 2.03-2.24 (m, 4H), 3.17-3.26 (m, 2H), 3.54- 3.81 (m, 5H), 4.62 (d, J: 9.2 Hz, 1H), 4.94-4.96 (m, 1H), 7.00-7.03 (m, 1H), 7.09-7.11 (m, 1H), 7.34-7.36 (m, 1H), 7.47-7.59 (m, 3H), 8.02-8.14 (m, 4H), 8.71-8.74 (m, 1H).

Example 183 N QH F F I 5 F F a OH N QH NH 1 ' 0 + o N\ o 5 j —’ N\ o F l/ NH2 0 I/ F F F 178D c 183 A mixture of Compound 178D (88 mg, 0.33 mmol), Intermediate C (105 mg, 0.34 mmol), EDCI.HCl (96 mg, 0.49 mmol), and HOBt (67 mg, 0.49 mmol) in dichloromethane (15 mL) was stirred at 25 0C for 15 h. Then it was treated with water (20 mL), extracted with romethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuum and purified with prep-HPLC to obtain Compound 183. LC-MS (m/z): 546 ; 1H-NMR (CDgOD, 400 MHz) 5 (ppm) 2.02-2.19 (m, 4H), 3.15-3.31 (m, 2H), 3.52-3.56 (m, 3H), 3.79-3.80 (m, 1H), .08 (m, 4H), 4.56 (d, J: 10.4 Hz, 1H), 4.81 (d, J: 2.8 Hz, 1H), 6.57-6.68 (m, 2H), 7.48 (d, J: 8.4 Hz, 2H), 7.71-7.76 (m, 1H), .07 (m, 3H), 8.59 (d, J: 3.2 Hz, 1H).

Example 184 N QH N QH o HO,N lilH O/A I lilH O/A N 0 CI N 0 CI \ ‘ | | / / F F 178 184 To a solution of nd 178 (56 mg, 0.086 mmol) in MeOH (20 mL) was added hydroxylamine hydrochloride (120 mg, 1.72 mmol) at 25 0C, then the reaction was stirred at 55 0C for 14 h. Then it was purified with prep-HPLC to obtain Compound 184. LC- MS (m/z): 553 [M+l]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 0.77-0.85 (m, 4H), 2.03-2.06 (m, 2H), 2.20-2.22 (m, 2H), 3.19-3.26 (m, 1H), 3.62-3.92 (m, —247— 2014/056555 5H), 4.60-4.89 (m, 2H), 5.02 (d, J: 2.8 Hz, 1H), 7.16-7.51 (m, 5H), 7.51-7.74 (m, 1H), 7.86- 7.98 (m, 3H), 8.51-8.54 (m, 1H).

Example 185 T880 0 (TH/ FIG] Bill/‘10] Cb HNZM]/ N OH N/ o N/ 0 N 0 185A 1853 185C 185D QH OH QH 0M3 (:DH : T ' O o o TBSO / / / ; _. _. - | _. - | _. | _.

CszN \ CszN \ CszN \ N o N o N o 185E 185F 185G ( 3 Z 5 N QH N (:DH N QH : Wiﬁw moj_: \ : \W") CbzHN / N O N o N/ 0 CI 0 o 185H 185I 135 A mixture of Compound 185A (22.2 g, 200 mmol), 1,2-dibromoethane (55.8 g, 300 mmol), and K2C03 (55.2 g, 600 mmol) in DMSO (270 mL) was stirred at 100 0C for h under nitrogen protection. Then it was cooled to room temperature and extracted with ethyl acetate (100 mL x 3). The ethyl acetate layers were combined and washed with water (50 mL x 3) and brine (50 mL), dried over sodium sulfate, and concentrated to offer the title Compound 185B.

A mixture of Compound 185B (1.37 g, 10 mmol) and Brz (1.6 g, 10 mmol) in DCM (27 mL) was stirred at 25 0C for 24 h, cooled to room temperature, quenched by NH4C1 (20 mL), and extracted with DCM (100 mL x 3). The DCM layers were combined and washed with water (50 mL x 3) and brine (50 mL), dried over sodium sulfate, concentrated and tallized from methanol to offer the title Compound 185C.

To a mixture of Compound 185C (3.23 g, 15 mmol) in THF (27 mL) at -65 0C was added by n-BuLi solution (6.45 mL), and the mixture was stirred at -65 0C for 1 h. Then a solution of Compound A4 (1.98 g, 5 mmol) in THF (10 mL) was added. The ant e was d for 1 h, quenched by NH4Cl (20 mL), and extracted with EA (100 mL x 3). The EA layers were combined and washed with water (50 mL x 3) and brine (50 mL), dried over sodium sulfate, concentrated, and purified with ﬂash column chromatography on silica gel with EA in PE (1/20 to 1/5 V/V) to offer the title Compound 185D.

To a mixture of Compound 185D (1.4 g, 3 mmol) in THF (17 mL) at -90 0C was added L-Selectride (1 M in THF, 6 mL), then it was stirred at -90 0C for 0.5 h, quenched by NH4Cl (20 mL), and extracted with EA (100 mL x 3). The EA layers were combined and washed with water (50 mL x 3) and brine (50 mL), dried over sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel with EA in PE (1/2 v/v) to offer the title Compound 185E.

A mixture of nd 185E (1.4 g, 3 mmol) and TBAF.3H20 (945 mg, 3 mmol) in THF (17 mL) at 20 0C was stirred for 15 h. Then it was diluted by EA (50 mL), washed with water (10 mL x 3) and brine (10 mL), dried over sodium e, concentrated, and puriﬁed with ﬂash column chromatography on silica gel with ol in DCM (l/100 to 1/20 v/v) to offer the title Compound 185F.

To a mixture of Compound 185F (800 mg, 2.2 mmol) and TEA (404 mg, 4.4 mmol) in DCM (8 mL) at 20 0C was added MsCl (1.77 mL, 2.2 mmol). The mixture was stirred for 30 min, quenched by water (5 mL), and extracted with DCM (10 mL x 3). The combined DCM layers were washed with water (10 mL x 3) and brine (10 mL), dried over sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel with methanol in DCM (1/100 to 1/50 V/V) to offer the title Compound 185G.

A mixture of Compound 185G (390 mg, 0.9 mmol) and pyrrolidine (632 mg, 9 mmol) in THF (8 mL) at 50 0C was stirred for 13 h then concentrated. The residue was dissolved into EA (50 mL), washed with water (10 mL x 3) and brine (10 mL), dried over sodium sulfate, and concentrated to offer the title Compound 185H.

] A mixture of Compound 185H (380 mg, 0.9 mmol) and LiOH.H20 (77 mg, 1.8 mmol) in EtOH (4 mL) was stirred at 100 0C for 13 h then concentrated. The residue was ved into DCM (50 mL), washed with water (10 mL x 3) and brine (10 mL), dried over sodium sulfate, and concentrated to offer the title Compound 1851.

A mixture of Compound 1851 (180 mg, 0.644 mmol), Compound 11E (159 mg, 0.644 mmol), HATU (294 mg, 0.773 mmol) and DIPEA (125 mg, 0.966 mmol) in DCM (4 mL) was stirred at r.t. overnight then concentrated. The residue was dissolved into DCM (50 mL), washed with water (10 mL x 3) and brine (10 mL), dried over sodium sulfate, concentrated, and puriﬁed with chiral HPLC to offer Compound 185. LC-MS (m/z): 508 [M+1]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 1.75 (m, 4H), 2.61- 2.69 (m, 4H), 2.77-2.81 (m, 1H), 2.92-2.97 (m, 1H), 4.03-4.10 (m, 1H), 4.18-4.36 (m, 4H), .19 (d, J: 7.6 Hz, 1H), 5.27-5.29 (m, 1H), 6.91 (s, 1H), 7.12 (d, J: 5.2 Hz, 1H), .30 (m, 1H), 7.37-7.39 (m, 1H), 7.40-7.42 (m, 1H), 7.51 (d, J: 1.6 Hz, 1H), 7.83 (d, J: 5.2 Hz, 1H). —249— Example 186 N QH ' O F F Z 3 F F OH NH N I QH O + ’ N O K/\©:O N O \ \ I : NH2 j I / 0 / 182A A 186 A mixture of Compound 182A (90 mg, 0.36 mmol), Cl (103 mg, 0.54 mmol), HOBT (73 mg, 0.54 mmol), and ediate A (100 mg, 0.36 mmol) in DCM (5 mL) was stirred for 18 h at 10 0C. Then the mixture was diluted by ethyl acetate (50 mL), washed with sat. sodium bicarbonate solution (50 mL x 2) and brine (50 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to furnish Compound 186. LC-MS (m/z): 510 [M+l]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 2.02-2.04 (m, 4H), 3.13-3.20 (m, 2H), 3.49-3.67 (m, 4H), 4.06- 4.09 (m, 4H), 4.55-4.57 (m, 1H), 4.81 (d, J: 3.2 Hz, 1H), 6.61 (d, J: 8.0 Hz, 1H), 6.73 (dd, J: 8.4, 2.0 Hz, 1H), 6.77 (d, J: 2.0 Hz, 1H), 7.62 (d, J: 8.8 Hz, 2H), 7.75 (t, J: 6.4 Hz, 1H), 8.04 (d, J: 8.4 Hz, 2H), 8.18 (d, J: 8.4 Hz, 1H), 8.30-8.32 (m, 1H), 8.80 (d, J: 5.2 Hz, 1H).

Example 187 182A 187 A e of nd 182A (90 mg, 0.36 mmol), EDCI.HCl (103 mg, 0.54 mmol), HOBT (73 mg, 0.54 mmol), and Intermediate C (107 mg, 0.36 mmol) in DCM (5 mL) was stirred for 18 h at 10 0C. Then the mixture was diluted by ethyl acetate (50 mL), washed with sat. sodium bicarbonate solution (50 mL x 2) and brine (50 mL), and dried over anhydrous sodium e. After evaporation, the crude product was purified with prep-HPLC to furnish Compound 187. LC-MS (m/z): 528 [M+l]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 2.04-2.16 (m, 4H), 3.31-3.32 (m, 2H), 3.52-3.19 (m, 4H), 4.05- 4.11 (m, 4H), 4.56-4.59 (m, 1H), 4.81 (d, J: 3.2 Hz, 1H), 6.58 (s, 1H), 6.64 (dd, J: 11.2, 2.0 Hz, 1H), 7.59 (d, J: 8.4 Hz, 2H), 7.64-7.67 (m, 1H), 8.04 (d, J: 8.0 Hz, 2H), 8.14 (d, J: 8.0 Hz, 1H), 8.20-8.23 (m, 1H), 8.76 (d, J: 9.0 Hz, 1H).

Example 188 O N 9H 0 : N QH O JL O ' ' ,OH W0 DC a 1 —* 5 NH 1 o NH 0 CI 0 F CI 151A H 188 9] To a solution of Compound 151A) (85 mg, 0.37 mmol) and Intermediate H (104 mg, 0.37 mmol) in dichloromethane (6 mL) and DMF (2 mL) was added HATU (208 mg, 0.55 mmol) at 25 0C. Then the reaction was stirred at 28 0C for 15 hours. Then the reaction mixture was treated with water (40 mL), extracted with DCM (20 mL x 2), washed with brine (10 mL), dried over sodium sulfate, and trated. The crude product was puriﬁed with prep-HPLC to obtain nd 188. LC-MS (m/z): 499 [M+1]+; 1H-NMR (DMSO-d6, 400 MHz) 5 (ppm) 2.08-2.40 (m, 2H), 2.70-3.35 (m, 2H), 3.50-4.10 (m, 3H), 4.24-4.29 (m, 6H), 4.78 (s, 1H), 6.76-6.85 (m, 2H), 7.67-7.70 (m, 1H), 7.87 (d, J: 1.6 Hz, 1H), 8.02 (d, J: 8.8 Hz, 1H), 8.10 (d, J: 8.8 Hz, 1H), 8.20 (d, J: 2.0 Hz, 1H), 8.48 (s, 1H), 8.76 (br, 1H).

Example 189 N QH OH 0N 0W5NH 9H 0 N o K/UO —> N o | i j \ NH2 | F O / 175E A 189 0] A mixture of Compound 175E (100 mg, 0.408 mmol) and Intermediate A (114 mg, 0.408 mmol) and HATU (155 mg, 0.612 mmol) in dichloromethane (4 mL) and DMF (2 mL) was stirred at 25 0C for 15 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuum and puriﬁed with prep-HPLC to obtain Compound 189. LC-MS (m/z): 506 ; 1H-NMR (CD30D, 400 MHz) 5 (ppm) 2.03-2.24 (m, 6H), 3.12-3.25 (m, 3H), 3.60-3.71 (m, 2H), 3.82- 3.95 (m, 1H), 4.19-4.28 (m, 2H), 4.55-4.58 (m, 1H), 4.93 (d, J: 2.8 Hz, 1H), 6.85-6.92 (m, 3H), 7.61-7.90 (m, 2H), 8.00 (s, 4H), 8.59 (d, J: 2.8 Hz, 1H).

Example 190 N C_)H N 9H 2 HO, 2 o v@101 ' r vc0 NH NH 0 o o N o | | / / 189 190 To a on of 189 (40 mg, 0.065 mmol) in MeOH (18 mL) was added ylamine hydrochloride (90 mg, 1.29 mmol) at 25 0C, then the reaction was stirred at 55 0C for 14 h. Then it was puriﬁed with prep-HPLC to obtain Compound 190. LC-MS (m/z): 521 [M+1]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 1.91- 2.10 (m, 4H), 2.56-3.17 (m, 1H), 3.17-3.77 (m, 4H), 4.12-4.19 (m, 4H), 4.46-4.71 (m, 2H), 4.83-4.84 (m, 1H), 6.70-6.90 (m, 3H), 7.19-7.34 (m, 2H), .63 (m, 1H), .85 (m, 3H), 8.47-8.50 (m, 1H).

Example 191 6 <5 NOH NOH : ? O HO‘ 2 1 |N ; NH ' —> 01 O F 0 F CI CI 188 191 To a solution of 188 (30 mg, 0.049 mmol) in MeOH (15 mL) was added hydroxylamine hydrochloride (80 mg, 0.98 mmol) at 30 0C, then the reaction was stirred at 55 0C for 4 h. Then it was puriﬁed with prep-HPLC to obtain Compound 191. LC-MS (m/z): 514 [M+1]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 2.40-2.71 (m, 2H), 3.55-3.64 (m, 2H), 4.02-4.50 (m, 9H), 4.63-4.83 (m, 1H), 6.78-6.85 (m, 2H), 7.47-7.51 (m, 2H), 7.68-7.90 (m, 4H).

Example 192 N 9H N OH = CI F . 0 CI 63D V 192 To a on of Intermediate V (100 mg, 0.29 mmol) and Compound 63D (72 mg, 0.29 mmol) in DMF (10 mL) was added EDCI.HCl (84 mg, 0.44 mmol), and HOBt (59 mg, 0.44 mmol) under nitrogen. The mixture was stirred at 25 0C overnight. TLC and LC-MS showed the starting material was consumed completely, sat. sodium bicarbonate (5 mL) was added to the mixture and then extracted with EA (50 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to offer the crude product. The crude product was d with prep-HPLC to offer Compound 192. LC—MS (m/z): 571 [M+1]+;1H-NMR(CD30D, 400 MHz) major characteristic peaks: 5 (ppm) 1.31-1.34 (m, 6H), 2.00-2.03 (m, 3H), 2.14-2.17 (m, 2H), 2.55- 2.61 (m, 2H), 2.64-2.72 (m, 1H), 2.78-2.98 (m, 2H), 3.15-3.25 (m, 2H), 3.51-3.55 (m, 1H), 3.60-3.66 (m, 2H), 3.74-3.79 (m, 3H), 4.62-4.65 (m, 1H), 4.92 (d, J: 2.8 Hz, 1H), 7.02 (dd, J = 1.2, 8.8 Hz, 1H), 7.08-7.15 (m, 3H), 7.29 (dd, J: 1.6, 8.4 Hz, 1H), 7.48 (d, J: 2.4 Hz, 1H).

Example 193 O 0 (U —>(WC/éW0 —>W"\ Br / N N N N H H 193A 1933 1930 1930 —> —> '1 h" "H Cbz 193E Cbz 193F Cbz 1936 0H 0 F F O\/ 0% 0V —> —> —> 0 O O N N N Cbz 193H Cbz 193| Cbz 193,] F F F F F F O\/ O\/ OH —> —> —> O O O M N 'I" 193K I 193L 193M N OH 4] A mixture of Compound 193A (13 g, 62 mmol), methyl acrylate (16.0 g, 187 mmol), Pd(PPh3)2Clz (2.0 g, 3.0 mmol), and K2C03 (22 g, 156 mmol) in DMF (100 mL) was stirred at 100 0C for 12 h, then cooled to room temperature and ﬁltered. The e was d with water (50 mL), extracted with DCM (100 mL x 2), washed with water (100 mL x 3) and brine (100 mL), dried over sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (20% ethyl acetate in petroleum) to lSh Compound 193B.

] To a solution of Compound 193B (11.5 g, 54 mmol) in MeOH (100 mL) was added Pd/C (l .l g), then the mixture was stirred at room temperature for 12 h under H2, then ﬁltered. The ﬁltrate was concentrated to furnish the crude Compound 193C.

To a solution of AlLiH4 (1.56 g, 41 mmol) in THE (100 mL) was added Compound 193C (9.0 g, 41 mmol) in THF (20 mL) dropwise at -78 0C under nitrogen, then the mixture was stirred at -78 0C for 2 h and quenched with Na2S04.10H20. Silica gel was added and the resultant mixture was ﬁltered. The ﬁltrate was trated to ﬁlmish the crude Compound 193D.

To a solution of Compound 193D (8 g, 42 mmol) in THF (80 mL) was added K2C03 (5.8 g, 42 mmol), water (25 mL), and Cszl (7.1 mL) under ice-cooling, and the resulting mixture was stirred at 25 0C for 12 h. EA (200 mL) was added. The organic layer was separated, dried over sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (20% ethyl acetate in eum) to furnish Compound 193E.

To a solution of Compound 193E (12.2 g, 37.5 mmol) in DCM (100 mL) was added DMP (16.0 g, 37.5 mmol) at 0 0C, then the mixture was d at room ature for 2 h, then d. The ﬁltrate was concentrated and the resulting residue was puriﬁed with ﬂash column chromatography on silica gel (20% ethyl acetate in petroleum) to ﬁlmish Compound 193F. 9] Compound 193F (9.8 g, 30 mmol) was added to a solution ofNa2S205 (5.8 g, mmol) in water (150 mL), then the mixture was stirred for 2 h at room temperature. And after the addition ofNaCN (3 g, 61 mmol) the mixture was stirred for 15 h, diluted with EA (50 mL), extracted with EA (100 mL x 2), washed with sat. sodium bicarbonate (100 mL x 2) and brine (100 mL), dried over sodium sulfate, concentrated, and d with ﬂash column chromatography on silica gel (20% ethyl acetate in petroleum) to furnish nd 193G.

To a solution of Compound 193G (10 g, 28 mmol) in EtOH (150 mL) cooled to 0 0C was bubbled a gentle stream of HCl gas (dried over con. H2S04) for 5 h. Then the mixture was treated with water slowly at 0 0C, stirred at room temperature for 2 h, then extracted with DCM (100 mL x 2), washed with brine (100 mL), dried over sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (20% ethyl acetate in petroleum) to furnish Compound 193H.

To a on of Compound 193H (845 mg, 2.13 mmol) in DCM (20 mL) was added DMP (1.1 g, 2.55 mmol) at 0 0C, then the e was stirred at room temperature for 2 h, then ﬁltered. The ﬁltrate was concentrated and the resulting residue was puriﬁed with —254— ﬂash column chromatography on silica gel (20% ethyl acetate in petroleum) to ﬁlmish Compound 1931. 2] To a solution of Compound 1931 (730 mg, 1.84 mmol) in DCM (20 mL) was added DAST (1.5 g, 9.24 mmol), then the mixture was d at room ature for 12 h, poured into ice water, extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (20% ethyl acetate in petroleum) to ﬁamish Compound 193J.

Compound 193J (730 mg, 1.75 mmol) was dissolved in ethanol (20 mL), then Pd(OH)2 (100 mg) was added, then the mixture was stirred at room temperature under H2 overnight, then ﬁltered and evaporated to furnish the product Compound 193K.

To a solution of Compound 193K (350 mg, 1.24 mmol) in CH3CN (5 mL) was added CH31 (526 mg, 3.71 mmol), then the mixture was stirred at 70 0C for 2 h, then cooled to room temperature, evaporated and puriﬁed with ﬂash column chromatography on silica gel (20% ethyl acetate in petroleum) to furnish Compound 193L.

To a solution of Compound 193L (200 mg, 0.67 mmol) in THF (10 mL) was added LiOH (85 mg, 2.02 mmol) in water (2 mL), then the mixture was stirred at room temperature for 2 h, then evaporated to remove solvent. The mixture was treated with water ﬁu$mﬁopH2VmﬂumudeCLﬂwnemnwmdwﬁhEA(ﬂhan2Lwaﬂwd with brine (50 mL), dried over sodium sulfate, and concentrated to furnish the Compound 19301 A mixture of Compound 193M (96 mg, 0.36 mmol), Intermediate G (111 mg, 0.36 mmol), EDCI.HCl (103 mg, 0.54 mmol), and HOBt (73 mg, 0.54 mmol) in DCM (10 mL) was stirred at room temperature ght. The mixture was d with water (50 mL), extracted with DCM (50 mL x 2), washed with water (50 mL x 2) and brine (50 mL), dried over sodium sulfate, concentrated, and puriﬁed with prep-HPLC to offer Compound 193. LC- MS (m/z): 562 ; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) .75 (m, 4H), 2.13 (s, 8H), 2.24-2.31 (m, 1H), 2.41-2.49 (m, 1H), 2.87-2.90 (m, 4H), 3.13 (s, 3H), 3.39-3.64 (m, 5H), 3.76 (s, 2H), 4.50 (s, 1H), 5.05 (s, 1H), 6.90 (s, 1H), 6.99 (d, J: 8.0 Hz, 1H), 7.19 (s, 2H), 7.27 (s, 1H), 7.29 (s, 1H), 7.69 (d, J: 8.8 Hz, 1H), 11.62 (s, Example 194 N OH OH NH + O/K o i —’ 0 OH O OXOH 0 F CI F 1330 v 194 7] To a solution of Intermediate V (100 mg, 0.29 mmol) in DMF (10 mL) was added HATU (167 mg, 0.44 mmol). After stirring for two hours at 25 0C, Compound 133D (71 mg, 0.29 mmol) was added and the resultant mixture was stirred overnight at 25 0C. TLC and LC-MS showed the starting material was consumed completely, and sat. sodium bicarbonate (5 mL) was added to the mixture which was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to offer the crude product. The crude product was d with prep-HPLC to offer nd 194. LC-MS (m/z): 569 [M+l]+; 1H-NMR (CDgOD, 400 MHz) major teristic peaks: 5 (ppm) 1.27-1.31 (m, 6H), 2.02- 2.07 (m, 2H), 2.20-2.23 (m, 2H), 3.19-3.24 (m, 1H), 3.46-3.56 (m, 1H), 3.60-3.83 (m, 5H), 4.56-4.57 (m, 1H), 4.69-4.72 (m, 1H), 4.98 (d, J: 2.4 Hz, 1H), 7.06 (d, J: 8.4 Hz, 1H), 7.22 (t, J: 8.4 Hz, 2H), 7.35 (dd, J: 2.0, 8.4 Hz, 1H), 7.50 (d, J: 2.0 Hz, 1H), 7.64-7.67 (m, 3H), 7.71-7.74 (m, 3H).

Example 195 1753 195A 195 A mixture of Compound 175B (608 mg, 2 mmol), 2-bromopyridine (314 mg, 2 mmol), Pd(dppl)Clz (82 mg, 0.1 mmol), and N32C03 (636 mg, 6 mmol) in dioxane (15 mL) and water (2 mL) was stirred at 100 0C for 3 h and concentrated. The mixture was treated with water (50 mL) and extracted with DCM (50 mL x 3). The aqueous layer was acidiﬁed with 1 M HCl and extracted with DCM (50 mL x 3). The aqueous layer was d with prep-HPLC to offer Compound 195A.

A solution of Compound 195A (100 mg, 0.44 mmol), Intermediate A (122 mg, 0.44 mmol), and HATU (335 mg, 0.88 mmol) in DMF (10 mL) was stirred at 25 0C for 16 h.

Then it was treated with EA (50 mL), washed with water (20 mL x 3) and brine (20 mL x l), dried over anhydrous sodium sulfate, concentrated, and d with prep-HPLC to obtain Compound 195. LC-MS (m/z): 488 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.75 (s, 4H), 2.64 (m, 4H), 2.81-2.94 (m, 2H), 4.15 (s, 4H), 4.27 (s, 1H), 4.99 (s, 1H), 6.77 (m, 3H), 7.31 (m, 1H), 7.72 (s, 2H), 8.00 (m, 2H), 8.26 (m, 2H), 8.66 (m, 1H).

Example 196 QNH,QW:—*QWOH—QWr#QWZZ 196A 1963 196C 196D 196E o o _./N/\)—2LO\—_./N\ O\__./N\FF _.

\ \N OH \ \N \ o \N 0/— 196F 196G 196H A mixture of Compound 196A (10 g, 106 mmol) and ethyl 3-bromo oxopropanoate (22.8 g, 117 mmol) in THF (300 mL) was stirred at r.t. for l h, then heated to 80 0C overnight, cooled to room temperature, diluted with water (50 mL), adjusted to pH > 9 with , and extracted with ethyl acetate (100 mL x 3). The ethyl acetate layers were combined and washed with brine (100 mL), dried over sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 33% V/V) to offer Compound 196B. 1] To a suspension of AlLiH4 (4.2 g, 111.3 mmol) in THF (200 mL) was added Compound 196B (10.7 g, 55.6 mmol) in THF (50 mL) dropwise at 0 0C under en. Then the mixture was stirred at 0 0C for 30 min, quenched with Na2S04.10H20 and ﬁltered. The ﬁltrate was concentrated to furnish the crude Compound 196C.

To a solution of Compound 196C (6.9 g, 46.6 mmol) in DCM (140 mL) was added DMP (23.7 g, 55.9 mmol) at 0 0C, then the mixture was stirred at room temperature for 2 h, then ﬁltered. The ﬁltrate was concentrated and the resulting residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, 33% V/V) to h Compound 196D.

Compound 196D (2.5 g, 17.1 mmol) was added to a solution ofNa2S205 (3.25 g, 17.1 mol) in water (300 mL), then the mixture was stirred for 2 h at room temperature. And after the addition ofNaCN (1.68 g, 34.2 mol), it was d again for 15 h, diluted with water (50 mL), stirred for 30 min, and ﬁltered. The solid was collected, washed with water (50 nﬂ),anddnedtooﬁeronmound196E.

To a solution of Compound 196E (2.8 g, 16.2 mmol) in EtOH (80 mL) at 0 0C was bubbled a gentle stream of HCl gas (dried over con. H2S04) for 5 h. Then the mixture wwﬁwEdeﬂvamﬂmﬂyMOTLmmﬂMKmmmmmmmmﬁx2maﬁmmdmpH > 7 with sodium bicarbonate, extracted with DCM (100 mL x 2), washed with brine (100 mL), dried over sodium e, and concentrated to furnish Compound 196F.

To a solution of Compound 196F (1.7 g, 7.72 mmol) in DCM (30 mL) was added DMP (3.93 g, 9.26 mmol), then the e was stirred at 0 0C for 2 h, then ﬁltered.

The ﬁltrate was trated and the resulting residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to ﬁlmish Compound 196G.

To a solution of Compound 196G (1.68 g, 7.72 mmol) in DCM (60 mL) was added DAST (6.22 g, 38.6 mmol), then the mixture was stirred at room temperature overnight, poured into ice water, extracted with DCM (100 mL x 2), washed with brine (50 mL), dried over sodium sulfate, concentrated, and puriﬁed with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, 33% v/v) to ﬁlmish Compound 196H. uﬁonof(knnpound196ll(9601ng,4()nnnoDin111F(201nL)and water (2 mL) was added LiOH (252 mg, 6.0 mmol), then the mixture was stirred at room temperature overnight, then evaporated to remove solvent. The mixture was treated with water (50 mL), adjusted to pH 2 with diluted HCl, and puriﬁed with PLC to ﬁlmish the(knnpound1961 A mixture of Compound 1961 (100 mg, 0.471 mmol), Intermediate C (140 mg, 0.471 mmol), and HATU (215 mg, 0.565 mmol) in DCM (2 mL) was stirred at room temperature overnight and concentrated. The residue was dissolved into DCM (50 mL), washed with water (50 mL) and brine (10 mL), dried over sodium sulfate, concentrated, and puriﬁed with chiral HPLC to offer Compound 196. LC-MS (m/z): 490 [M+1]+; 1H-NMR (DMSO-dg, 400 MHz) major characteristic peaks: 5 (ppm) 1.82-2.01 (m, 4H), 3.05-3.11 (m, 2H), 3.31-3.38 (m, 1H), 3.44-3.52 (m, 3H), 4.19-4.23 (m, 4H), 4.35-4.41 (m, 1H), 4.66-4.67 (m, 1H), 6.62 (s, 1H), .73 (m, 1H), 7.03-7.07 (m, 1H), 7.39-7.43 (m, 1H), 7.59-7.61 (m, 1H), 8.26 (s, 1H), 8.59 (d, J: 6.8 Hz, 1H), 8.68-8.70 (m, 1H), 9.41 (brs, 1H).

Example 197 F F F 197A 1973 197C 0 o OO\©)kCOOH o o rim 1 —> o F Om 197D 197 An aqueous solution ofKOH (4.9 g, 87.5 mmol) in water (10 mL) was added to a stirred solution of 4-ﬂuorophenol 197A (8.4 g, 75 mmol) in methanol (25 mL). When the addition was complete, the mixture was evaporated in vacuum and the residual solid was dissolved in l-methylpyrrolidinone (30 mL) and 3-ﬂuorobromobenzene (13 g, 75 mmol) was added and the mixture was reﬂuxed for 24 hours, then cooled to room temperature, poured into water (150 mL) and ted with ether (30 mL x 2). The combined extracts were dried over sodium sulfate and trated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 50% v/v) to furnish Compound 197B.

To a solution of Compound 197B (2.66 g, 10 mmol) in THF (30 mL) was added dropwise n-BuLi solution (2.5 M, 4 mL, 10 mmol) at -78 0C under nitrogen. The mixture was d at -78 0C for 0.5 h, and then the mixture was added to a solution of diethyl oxalate (3 g, 20 mmol) in THF (20 mL) at -78 0C. The mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl solution (40 mL). The reaction mixture was extracted with EA (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The residue was puriﬁed with ﬂash column tography on silica gel (ethyl e in petroleum ether, from 10% to 50% v/v) to furnish Compound 197C. 1] Lithium hydroxide (420 mg, 10 mmol) was added to a solution of Compound 197C (1 .44 mg, 5 mmol) in EtOH (20 mL) and water (5 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was added 1 N HCl to adjust to pH 7 and concentrated in . The residue was extracted with EA (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to ﬁlI'IllSh Compound 197D.

A mixture of Compound 197D (262 mg, 1 mmol), ediate A (278 mg, 1 mmol), and HATU (760 mg, 2 mmol) in DMF (20 mL) was stirred at 25 0C for 16 h. Then it was diluted with DCM (70 mL), washed with water (50 mL x 3) and brine (50 x 2 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to obtain Compound 197. LC-MS (m/z): 521 [M+l]+; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) .81 (m, 4H), 2.70-2.75 (m, 4H), 2.83-3.02 (m, 2H), 4.22 (s, 4H), .27 (m, 1H), 5.04 (s, 1H), 6.81-6.86 (m, 3H), 6.87-6.98 (m, 4H), 6.98-7.05 (m, 1H), 7.27 (m, 1H), 7.35-7.42 (t, J: 4.8 Hz, 1H), 7.77 (s, 1H), 7.95-7.97 (d, J: 4.2 Hz, 1H).

Example 198 <9 QH F F 0 WW . 0 "WI;NH 0 O ; N NH2 j o | 0 T 193M A 198 A mixture of Compound 193M (80 mg, 0.3 mmol), Intermediate A (83 mg, 0.3 mmol), EDCI.HCl (86 mg, 0.45 mmol), and HOBt (61 mg, 0.45 mmol) in DCM (10 mL) was stirred at 25 0C overnight. Then the reaction mixture was concentrated to remove DCM.

The residue was puriﬁed with prep-HPLC to offer Compound 198. LC-MS (m/z): 530 ; 1H-NMR (CDClg, 400 MHz) major characteristic peaks: 5 (ppm) 2.13 (s, 8H), 2.30- 2.37 (m, 1H), 2.45-2.53 (m, 1H), .88 (m, 3H), 2.91 (s, 1H), 3.10 (s, 3H), 3.43-3.46 (m, 2H), 3.79 (s, 2H), 4.00-4.09 (m, 5H), 4.26 (s, 1H), .48 (m, 1H), 5.01 (s, 1H), 6.80 (s, 2H), 6.86-6.90 (m, 1H), 6.98-7.01 (m, 1H), 7.21-7.24 (m, 1H), 7.61 (t,J= 8.0 Hz, 1H), 11.89 (s, 1H).

Example 199 O Q9H N QH CI O\ F F . + —> WA \ \N \ OH ﬁH A O o 0 F 196| G Cf"— 199 A mixture of Compound 1961 (100 mg, 0.471 mmol), Intermediate G (146 mg, 0.471 mmol), and HATU (215 mg, 0.565 mmol) in DCM (2 mL) was stirred at room temperature overnight and concentrated. The residue was dissolved into DCM (50 mL), washed with water (50 mL) and brine (10 mL), dried over sodium sulfate, concentrated, and puriﬁed with chiral HPLC to offer nd 199. LC-MS (m/z): 505 [M+l]+; 1H-NMR (DMSO-dg, 400 MHz) major characteristic peaks: 5 (ppm) 0.61-0.65 (m, 2H), 0.77-0.82 (m, 2H), .00 (m, 4H), 3.06-3.14 (m, 2H), 3.35-3.42 (m, 1H), 3.49-3.53 (m, 3H), 3.79-3.84 (m, 1H), 4.38-4.45 (m, 1H), 4.75-4.76 (m, 1H), 7.04-7.08 (m, 1H),7.15-7.21 (m, 2H), 7.30 (d, .1: 1.6 Hz, 1H), .44 (m, 1H), 7.62-7.64 (m, 1H), 8.23 (s, 1H), 8.59 (d, .1: 7.2 Hz, 1H), .71 (m, 1H), 9.52 (brs, 1H).

Example 200 0 K 01—> OrB —> W0 O O N 0 200A 2003 200C 200D 200 ] Compound 200A (1.72 g, 10.0 mmol), 1,5-dibromopentane (2.52 g, 11.0 mmol), and K2C03 (1.51 g, 11.0 11111101) were taken in water (5 mL) and heated at 100 0C for min. in a microwave oven. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL x 2). The combined organic extracts were dried over sodium sulfate, evaporated, and puriﬁed with ﬂash column chromatography on silica gel (petroleum ether in ethyl acetate, 10% v/v) to offer Compound 200B.

To a solution of Compound 200B (240 mg, 1.0 mmol) in THF (25 mL) was added dropwise n-BuLi (2.5 M in hexane, 0.48 mL) at -60 0C under nitrogen atmosphere. The reaction e was stirred for 30 min. at the same temperature. The resulting e was added to the solution of diethyl oxalate (292 mg, 2.0 mmol) in THF (25 mL) at -60 0C. The reaction mixture was stirred for 2 hours at -60 0C, quenched with sat NH4Cl, and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, evaporated, and puriﬁed with prep-TLC (petroleum ether in ethyl acetate, 20% v/v) to yield Compound 200C.

To a solution of Compound 200C (97 mg, 0.37 mmol) in MeOH (5 mL) was added LiOH-HZO (18 mg, 0.42 mmol) and water (0.5 mL). The reaction mixture was stirred overnight at 15 °C, neutralized with 1 N HCl, and ated. The residue was dissolved in water (5 mL), ted with ethyl acetate (10 mL x 2), dried over sodium sulfate, filtered, and evaporated to offer Compound 200D. 2014/056555 To a solution of nd 200D (58 mg, 0.25 mmol) in CHzClz (5 mL) was added Intermediate C (74 mg, 0.25 mmol) and HATU (142 mg, 0.375 mmol). The reaction mixture was stirred overnight at 15 0C, evaporated and puriﬁed with prep-HPLC to offer Compound 200. LC-MS: (m/z) 512 [M+1]+; 1H-NMR(CD30D, 400 MHz) major characteristic peaks: 5 (ppm) 1.71 (br, 6 H), 1.95-2.07 (m, 4H), 2.18-2.21 (m, 2H), 3.52-3.53 (m, 4H), .71 (m, 4H), .30 (m, 5H), 4.88-4.89 (m, 2H), 6.76-6.82 (m, 2H), 6.91- 6.93 (m, 2H), 7.57-7.63 (m, 2H).

Example 201 o F O O FQOWOV—» gomov—» F 197C 201A N QH ‘ O mom 0WO NH F F 201B 201 To a solution of Compound 197C (2.89 g, 10 mmol) in DCM (120 mL) was added se DAST (4 mL) at room temperature. The mixture was stirred at room temperature overnight. Then it was quenched with ice, extracted with DCM (30 mL x 3), washed with water (50 mL x 3) and brine (50 x 2 mL), dried over anhydrous sodium sulfate, and evaporated to obtain Compound 201A.

Lithium hydroxide (420 mg, 10 mmol) was added to a solution of Compound 201A (1.55 g, 5 mmol) in EtOH (20 mL) and water (5 mL). The on mixture was stirred at room temperature for 2 h. The on mixture was added 1 N HCl to adjust to pH 7 and concentrated in vacuum. The residue was extracted with EA (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to ﬁamish Compound 201B.

A mixture of Compound 201B (141 mg, 0.5 mmol), Intermediate A (139 mg, 0.5 mmol), HATU (380 mg, 1 mmol) in DMF (5 mL) was stirred at 25 0C for 16 h. Then it was diluted with DCM (70 mL), washed with water (50 mL x 3) and brine (50 x 2 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC to obtain Compound 201. LC-MS (m/z): 543 [M+1]+; (CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 1.71-1.80 (m, 4H), 2.64-2.69 (m, 4H), 2.94 (d, J: 4.4 Hz, 2H), 4.14 (m, 1H), 4.22 (m, 4H), 5.02 (s, 1H), 6.71-6.73 (m, 1H), 6.78-6.82 (m, 3H), 6.98-7.07 (m, 7H), 7.30-7.32 (m, 1H).

Example 202 Br Br Br / \ N N N/ H / 202A 2023 202C / 202 To a solution of 5-bromo-1H-indazole, 202A, (4.92 g, 25.0 mmol) in THF (300 mL) at 0 0C was added NaH (1.10 g, 27.5 mmol). The reaction solution was stirred at this ature for 1 hour before methyl iodide (5.32 g, 37.5 mmol) was added at 0 0C. The reaction was allowed to warm to room temperature slowly, stirred for 2 hours, and quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with dichloromethane (80 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to give nd 202B and Compound 202C.

A mixture of Compound 178C (153 mg, 0.47 mmol), 202B (100 mg, 0.47 mmol), Pd(dppf)2C12 (20 mg, 0.02 mmol), and K2C03 (195 mg, 1.41 mmol) in dioxane (3 mL) and water (3 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate (50 mL). The mixture was ﬁltered through celite, then the ﬁltrate was treated with water (40 mL), extracted with ethyl acetate (50 mL x 2). The water layer was puriﬁed with ﬂash chromatography to furnish the Compound 202D.

A mixture of nd 202D (90 mg, 0.30 mmol), EDCI.HCl (86 mg, 0.45 mmol), HOBt (61 mg, 0.45 mmol), and ediate G (93 mg, 0.30 mmol) in DCM (5 mL) was d for 18 h at 10 0C. Then the mixture was diluted by ethyl acetate (50 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over ous sodium sulfate. After evaporation, the crude t was puriﬁed with prep-HPLC to furnish Compound 202. LC- MS (m/z): 595 [M+1]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 0.49-0.51 (m, 4H), 2.03-2.17 (m, 4H), 3.16-3.31 (m, 2H), 3.51-3.74 (m, 5H), 4.11 (s, 3H), 4.64 (d, J: 10.4 Hz, 1H), 7.03 (d, J: 8.8 Hz, 1H), 7.12 (dd, J: 8.8, 1.2 Hz, 1H), 7.36-7.38 (m, 3H), 7.65-7.71 (m, 3H), 7.79 (dd, J: 8.8, 1.6 Hz, 1H), 8.08-8.09 (m, 2H).

Example 203 0 Q9H N OH = o ? o OW)" o a + ]—~ 0] CW 0 NH2 F O O F 197D c F ] A mixture of Compound 197D (131 mg, 0.5 mmol), Intermediate C (154 mg, 0.5 mmol), HATU (380 mg, 1 mmol) in DMF (5 mL) was stirred at 25 0C for 16 h. Then it was diluted with DCM (20 mL), washed with water (50 mL x 3) and brine (50 x 2 mL), dried over ous sodium sulfate, concentrated, and purified with prep-HPLC to obtain Compound 203. LC-MS (m/z): 539 [M+1]+; 1H-NMR(CDC13, 400 MHz) major characteristic peaks: 5 (ppm) 2.08-2.19 (m, 4H), 2.87-3.04 (m, 4H), 3.45-3.56 (m, 2H), 3.87 (m, 1H) 4.20-4.28 (m, 4H), 4.47 (m, 1H), 5.05 (s, 1H), 6.71-6.76 (m, 2H), 6.87-6.98 (m, 4H), 6.98-7.05 (m, 1H), 7.27 (m, 1H), 7.35-7.42 (m, 1H), 7.65 (s, 1H), 7.90-7.93 (m, 1H), 11.77 s, 1H).

Example204 F F I) OH Z l 9H O F N 9H F F O ; o + "U m of F NHZ 0A 0 o 1403 s O F 204 A mixture of ediate S (88 mg, 0.30 mmol), Compound 140B (78 mg, 0.30 mmol), EDCI.HCl (86 mg, 0.45 mmol), and HOBt (60 mg, 0.45 mmol) in dichloromethane (10 mL) was stirred at 10 0C for 15 h. Then it was treated with water (20 mL), ted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuum, and purified with prep-HPLC to obtain Compound 204. LC-MS (m/z): 543 [M+1]+; 1H-NMR(CDC13, 400 MHz) 5 (ppm) 0.49-0.62 (m, 4H), 2.04 (s, 2H), 2.18 (s, 2H), 3.17 (s, 1H), 3.27 (s, 1H), 3.54-3.71 (m, 4H), 3.78 (s, 1H), 4.58 (d, J: 12 Hz, 1H), 4.89 (s, 1H), 6.95 (d, .1: 8 Hz, 1H), 7.04 (t, .1: 8 Hz, 2H), 7.22 (t, .1: 8 Hz, 2H), 7.39 (d, .1: 8 Hz, 2H), 7.63 (d, .1: 8 Hz, 2H), 7.72 (t, .1: 8 Hz, 2H).

Example 205 0 OH 0\/ O UCVBr O + 0 ﬂ N l N O ’ Ax ’ 2023 175B 205 / 205 A mixture of Compound 175B (288 mg, 0.95 mmol), 202B (200 mg, 0.95 mmol), Pd(dppf)C12 (40 mg, 0.05 mmol), and K2C03 (393 mg, 2.85 mmol) in dioxane (5 mL) and water (5 mL) was stirred under en at 90 0C for 3 h. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate (50 mL). The mixture was ﬁltered through celite, then the ﬁltrate was treated with water (40 mL), extracted with ethyl acetate (50 mL x 2). The water layer was adjusted to pH 3 by s HCl solution (3 N), extracted with ethyl acetate (50 mL x 2) and the ethyl e layer was washed with water (50 mL x 2), dried over sodium sulfate, ﬁltered, and concentrated to h the Compound 205A.

A mixture of Compound 205A (120 mg, 0.43 mmol), HATU (247 mg, 0.65 mmol), and Intermediate G (133 mg, 0.43 mmol) in DMF (5 mL) was stirred for 18 h at 10 0C. Then the mixture was puriﬁed with prep-HPLC to furnish nd 205. LC-MS (m/z): 573 [M+1]+; 1H-NMR (CDgOD, 400 MHz) major characteristic peaks: 5 (ppm) 0.71-0.83 (m, 4H), 2.05-2.23 (m, 4H), 3.24-3.34 (m, 2H), 3.59-3.88 (m, 5H), 4.12 (s, 3H), 4.72-4.75 (m, 1H), 5.02 (d, J: 2.4 Hz, 1H), 7.40 (s, 2H), 7.50 (s, 1H), 7.67-7.75 (m, 5H), 7.81 (dd, J: 8.8, 1.2 Hz, 1H), 8.12-8.13 (m, 2H).

WO 42397 Example 206 Q Q OH 9" OO©/ Example 207 OH Q m]. o _> 205A A 207 A mixture of nd 205A (144 mg, 0.51 mmol), HATU (293 mg, 0.77 mmol), and Intermediate A (142 mg, 0.51 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, evaporated, and d with prep- HPLC to yield Compound 207. LC-MS (ESI) m/z: 541 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 2.01-2.24 (m, 4H), 3.19-3.31 (m, 2H), .56 (m, 1H), .72 (m, 2H), 3.81-3.88 (m, 1H), 4.10-4.21 (m, 7H), 4.65-4.69 (m, 1H), 4.87 (s, 1H), 6.85 (d, J: 8.4 Hz, 1H), 6.91-6.94 (m, 1H), 6.97 (d, J: 2.0 Hz, 1H), 7.69 (d, J: 8.8 Hz, 1H), 7.79-7.83 (m, 3H), 7.87-7.89 (m, 2H), 8.12-8.13 (m, 2H). e 208 QOH mg F00 0 + [5% :AﬁFOO o 1330 s 203 A mixture of Intermediate S (118 mg, 0.40 mmol), Compound 133D (97 mg, 0.40 mmol), and HATU (228 mg, 0.60 mmol) in dichloromethane (10 mL) was stirred at 30 0C for 15 h. Then it was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, trated in vacuum, and puriﬁed with prep- HPLC to obtain Compound 208. LC-MS (m/z): 521 ; 1H-NMR (CDgOD, 400 MHz) 5 (ppm) 0.67-0.82 (m, 4H), 2.05 (s, 2H), 2.21 (s, 2H), 3.10-3.27 (m, 2H), 3.56-3.60 (m, 1H), 3.68-3.74 (m, 2H), 3.80-3.88 (m, 2H), 4.70 (d, J: 8 Hz, 1H), 4.98 (s, 1H), 7.19-7.27 (m, 4H), 7.37 (t, J: 8 Hz, 1H), 7.68 (d, J: 8 Hz, 2H), 7.72-7.78 (m, 4H).

Example 209 0 o "(OH 0 VI; Br O\/ 00 [3H A 209A 2093 209C 209 A mixture of Compound 209A (1.0 g, 4.85 mmol), magnesium chips (0.17 g, 7.0 mmol) and THF (15 mL) was stirred at 50 0C for 1 h, and diethyl oxalate (3 mL) was added. The mixture was stirred at 60 0C for 3 h, and saturated NH4C1 solution (10 mL) was added. It was extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed ﬂash with column tography on silica gel (10% ethyl acetate in eum ether) to afford Compound 209B. 4] To a solution of Compound 209B (1.4 g, 6.1 mmol) in THF (15 mL) was added LiOH (390 mg, 9.0 mmol) in water (15 mL) at -10 0C, and the mixture was stirred at this temperature for 5 h. The reaction mixture was treated with ice water (20 mL) and extracted with ethyl acetate (50 mL). The water layer was adjusted to pH 2 with 1 M HCl and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting solid was washed with eum ether and ﬁltered to mmish the crude Compound 209C.

] A mixture of Compound 209C (160 mg, 0.8 mmol), HATU (608 mg, 1.6 mmol), DMF (6.5 mL), and Intermediate G (298 mg, 0.96 mmol) in DCM (8 mL) was d at room temperature overnight. The reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude t was puriﬁed with prep-HPLC to afford Compound 209. LC-MS (ESI) m/z: 493 ; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.5- 0.75 (m, 4H), 2.06-2.21 (m, 4H), 3.26-3.30 (m, 1H), 3.58-3.82 (m, 6H), 4.73 (d, J: 8.0 Hz, 1H), 5.0 (s, 1H), 7.30 (d, J: 8.8 Hz, 1H), 7.40 (d, J: 8.8 Hz, 1H), 7.51 (s, 1H), 7.57-7.71 (m, 2H), 7.84-7.95 (m, 4H), 8.26 (s, 1H).

Example 210 F ::N OH 9H F ? o O O F F : COOH _ ; _, F O o F F F 201B c 210 A mixture of Compound 201B (141 mg, 0.5 mmol), Intermediate C (148 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) in DMF (5 mL) was stirred at 25 0C for 16 h. The mixture was diluted with DCM (70 mL), and washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified with prep- HPLC to yield Compound 210. LC-MS (ESI) m/z: 561 [M+H]+; 1H-NMR (CD301), 400 MHz): 5 (ppm) 2.00-2.15 (m, 4H), 3.14-3.26 (m, 2H), 3.50-3.64 (m, 3H), 3.75 (m, 1H), 4.21- 4.23 (m, 4H), 4.54 (m, 1H), 4.79 (s, 1H), 6.60-6.63 (m, 2H), 7.05-7.09 (m, 5H), 7.15-7.17 (m, 2H), 7.34 (t, J: 8.0 Hz, 1H).

WO 42397 Example 211 Br~ To a solution of Compound 211B (2.00 g, 7.97 mmol) in THF (50 mL) was added LiAlH4 (303 mg, 7.97 mmol) carefully. The mixture was stirred at 25 0C for 16 h. The reaction mixture was quenched slowly with ice water (4 mL), ﬁltered, and trated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50% V/V) to afford Compound 211C.

To a solution of Compound 211C (4.30 g, 20.57 mmol) in DCM (100 mL) was added Dess-Martin periodinane (9.60 g, 22.63 mmol) carefully. The mixture was stirred at 25 0C for 16 h. The e was d to remove the solid and trated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 20% V/V) to afford Compound 211D.

To a solution of Compound 211D (1.80 g, 3.69 mmol) and NaCN (352 mg, 1739 mmol) in methanol (20 mL) was added AcOH (222 mg, 3.69 mmol) carefully. The mixture was stirred at 25 0C for 16 h, quenched with ice water to form a solid, ﬁltered, and dried to afford Compound 211E.

A e of Compound 211E (1.20 g, 5.13 mmol) in methanol (20 mL) under HCl gas was d at 20 0C for 16 h. The reaction mixture was quenched with ice water and extracted with dichloromethane (50 mL x 3). The ed organic phases were washed with water (150 mL) and brine (150 mL), dried over anhydrous sodium sulfate, and evaporated to ﬁnnmh(knnpound211F.

To a solution of Compound leF (1.20 g, 4.49 mmol) in DCM (20 mL) was added Dess-Martin periodinane (1.91 g, 4.49 mmol) careﬁllly. The mixture was stirred at 25 0C for 16 h. The mixture was ﬁltered to remove the solid. The ﬁltrate was trated and puriﬁed with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, from 0% to 30% V/V) to yield Compound 211G.

To a on of Compound 211G (1.00 g, 3.80 mmol) in DCM (10 mL) was added dropwise DAST (3.06 g, 19.00 mmol). The mixture was stirred at 25 0C for 16 h and concentrated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 15% V/V) to furnish Compound 211H.

A solution of Compound 211H (900 mg, 3.14 mmol) and aqueous ZO solution (1 N, 4.7 mL, 4.70 mmol) in THF (10 mL) was stirred at 25 0C for 2 h. The mixture was adjusted to pH 1 with aqueous HCl on (6 N, 5 mL), diluted with ice water (50 mL) to form a solid, ﬁltered, and dried to yield Compound 2111.

A mixture of Compound 2111 (100 mg, 0.37 mmol), Intermediate A (102 mg, 0.37 mmol), EDCI (106 mg, 0.56 mmol), and HOBt (76 mg, 0.56 mmol) in dichloromethane (5 mL) and triethylamine (0.2 mL) was stirred at 25 0C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over ous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to furnish Compound 211. LC-MS (ESI) m/z: 534 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 1.92-2.13 (m, 4H), 3.12-3.22 (m, 2H), 3.55-3.65 (m, 3H), 3.72-3.78 (m, 1H), 4.12 (s, 4H), 4.50-4.55 (m, 1H), 4.80 (s, 1H), 6.64 (d, J: 8.4 Hz, 1H), 6.75-6.81 (m, 2H), 7.26 (t, J: 8.8 Hz, 2H), 7.85 (s, 1H), 8.04-8.08 (m, 2H).

ExanqﬂeZlZ 202D A 212 A e of nd 202D (50 mg, 0.16 mmol), EDCI (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and Intermediate A (28 mg, 0.26 mmol) in DCM (5 mL) was stirred at 10 0C for 18 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to afford Compound 212. LC- MS (ESI) m/z: 563 [M+H]+; 1H-NMR , 400 MHz): 5 (ppm) 2.02-2.18 (m, 4H), 3.14- 3.24 (m, 2H), 3.53-3.65 (m, 3H), 3.77-3.84 (m, 1H), 4.06 (s, 4H), 4.12 (s, 3H), 4.55-4.57 (m, 1H), 4.82 (d, J: 3.2 Hz, 1H), 6.65 (d, J: 8.4 Hz, 1H), 6.74 (dd, J: 8.4, 2.0 Hz, 2H), 6.77 (d, J: 2.0 Hz, 1H), 7.45 (d, J: 8.8 Hz, 1H), 7.68 (d, J: 8.8 Hz, 1H), 7.75 (d, J: 8.4 Hz, 2H), 7.80 (dd, J: 8.8, 1.6 Hz, 1H), 8.08-8.09 (m, 1H), 8.10 (d, J: 1.2 Hz,1H).

Example 213 F F QOH N 9" F—< >_ FﬂNﬂNH NH2 o/A o/A CI 8 CI 211| G 213 A e of Compound 2111 (100 mg, 0.37 mmol), Intermediate G (115 mg, 0.37 mmol), HOBt (76 mg, 0.56 mmol), and EDCI (106 mg, 0.56 mmol) in dichloromethane (5 mL) and triethylamine (0.2 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (120 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep- HPLC to afford Compound 213. LC-MS (ESI) m/z: 566 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.62-0.75 (m, 4H), 1.96-2.14 (m, 4H), 3.13-3.26 (m, 2H), 3.60-3.67 (m, 4H), .78 (m, 1H), 4.54-4.58 (m, 1H), 4.88 (s, 1H), 7.14 (d, J: 8.4 Hz, 1H), 7.24-7.29 (m, 3H), 7.34 (s, 1H), 7.85 (s, 1H), 8.04-8.08 (m, 2H).

Example 214 N 9H 0 i > o .

N OH ; OH 3 mOA + 2 —> N o 0 CI | GA N\ / / / 195A G 214 A mixture of Compound 195A (150 mg, 0.66 mmol), Intermediate G (205 mg, 0.66 mmol), HATU (500 mg, 1.32 mmol), and DIPEA (0.2 mL) in DMF (20 mL) was stirred at 25 0C for 16 h. The reaction mixture was d with ethyl acetate (50 mL), washed with water (20 mL x 3) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC and chiral HPLC to ﬁlmish the desired product, which was further puriﬁed with prep-HPLC to yield Compound 214. LC-MS (ESI) m/z: 520 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.62-0.81 (m, 4H), 2.05-2.23 (m, 4H), 3.15-3.28 (m, 2H), 3.58- 3.85 (m, 5H), .72 (m, 1H), 4.99 (m, 1H), .06 (m, 10H), 8.72 (m, 1H).

Example 215 F O HO,Q.4 s 4F 8, 0v HO \ / N 0 215A 2153 2150 N QH S OH —>F —> 8 NH A \ I F o N 0 \ I N 0 CI 215D 215 A mixture of Compound 215A (2.05 g, 14.6 mmol), othiazole (2 g, 12.2 mmol), K2C03 (3.12 g, 24.4 mmol) and Pd(PPh3)2Clz (856 mg, 1.22 mmol) in e (40 mL) and water (4 mL) was stirred at 80 0C for 2 h. The mixture was cooled to room ature, diluted with water (50 mL), extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to afford Compound 215B.

To a solution of Compound 215B (14 g, 7.8 mmol) in THF (30 mL) was added n-BuLi (3.4 mL, 8.6 mmol) dropwise at -78 0C. The mixture was stirred for 15 min and diethyl oxalate (2.28 g, 15.6 mmol) was added at -78 0C. The mixture was stirred for l h. The reaction mixture was diluted with ethyl e (100 mL), washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford Compound 215C.

To a solution of Compound 215C (400 mg, 1.43 mmol) in THF (10 mL) and water (1 mL) was added LiOH (90 mg, 2.15 mmol). The mixture was stirred at room ature overnight, diluted with water (50 mL), and extracted with ethyl acetate (50 mL).

The aqueous layer was adjusted to pH 2 with l M HCl. The precipitate was collected with ﬁltration and dried to ﬁlmish Compound 215D.

To a e of Compound 215D (97 mg, 0.386 mmol) in DCM (2 mL) was added HATU (176 mg, 0.463 mmol) and Intermediate G (120 mg, 0.386 mmol). The mixture 2014/056555 was stirred at room temperature overnight. The mixture was treated with water (50 mL), extracted with DCM (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated.

The crude product was puriﬁed with prep-HPLC to afford Compound 215. LC-MS (ESI) m/z: 544 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.61-0.66 (m, 2H), 0.76-0.82 (m, 2H), 1.80-1.88 (m, 2H), 1.96-2.03 (m, 2H), .17 (m, 2H), .37 (m, 1H), 3.47-3.60 (m, 3H), 3.87-3.91 (m, 1H), 4.41-4.47 (m, 1H), 4.79-4.80 (m, 1H), 6.02-6.07 (m, 1H), 7.28- 7.45 (m, 5H), 8.14-8.18 (m, 2H), 8.63 (d, J: 9.2 Hz, 1H), 8.81 (s, 1H), 9.10-9.18 (m, 1H).

Example 216 O O OH B N‘53V W0" —>N\ —>N. 0 o N N N / / / 2023 216A 216B 0 "(In _,NWNH \N o / 216 To a solution of Compound 202B (400 mg, 1.89 mmol) in THF (10 mL) was added n-BuLi (2.5 N, 0.76 mL) under nitrogen at -78 0C, and the resultant mixture was stirred for 30 min. And then diethyl e (0.65 mL, 4.73 mmol) was added to above mixture, and the resultant mixture was stirred at -78 0C for l h. The mixture was quenched with saturated aqueous NH4Cl solution (10 mL), and extracted with ethyl acetate (50 mL x 2), washed with saturated aqueous sodium onate solution (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and trated to ﬁamish Compound 216A.

To a solution of Compound 216A (490 mg, 2.11 mmol) in methanol (5 mL) was added a solution of LiOH‘HZO (177 mg, 4.22 mmol) in water (5 mL), and the mixture was stirred at room ature overnight. The crude product was puriﬁed with reverse phase chromatography using eluent (methanol in water, from 0% to 7% v/v) to furnish Compound 216B.

A mixture of Compound 216B (100 mg, 0.49 mmol), HATU (279 mg, 0.74 mmol), and Intermediate A (136 mg, 0.49 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h. The mixture was purified with prep-HPLC to afford Compound 216. LC-MS (ESI) m/z: 465 [M+H]+; 1H-NMR (CD301), 400 MHz): 5 (ppm) 2.03-2.07 (m, 2H), 2.18-2.22 (m, 2H), 3.22—3.27 (m, 2H), 3.54-3.58 (m, 1H), 3.67-3.73 (m, 2H), 3.79-3.85 (m, 1H), 4.03—4.24 (m, 7H), 4.68-4.71 (m, 1H), 4.92 (s, 1H), 6.84 (d, .1: 8.0 Hz, 1H), 6.93 (dd, .1: 8.4, 2.0 Hz, 1H), 6.97 (d, .1: 1.6 Hz, 1H), 7.63 (d, .1: 9.2 Hz, 1H), 7.96 (dd, .1: 8.8, 1.6 Hz, 1H), 8.11 (s, 1H), 8.20 (s, 1H). e 217 216B A e of Compound 216B (100 mg, 0.49 mmol), HATU (279 mg, 0.74 mmol), and Intermediate C (138 mg, 0.49 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h. The mixture was puriﬁed with prep-HPLC to afford Compound 217. LC-MS (ESI) m/z: 483 [M+H]+; 1H-NMR , 400 MHz): 5 (ppm) 2.03-2.07 (m, 2H), 2.20-2.22 (m, 2H), 3.20-3.29 (m, 2H), 3.55-3.59 (m, 1H), 3.67-3.73 (m, 2H), 3.78-3.84 (m, 1H), 4.08-4.13 (m, 4H), 4.20-4.31 (m, 3H), 4.68-4.71 (m, 1H), 4.90 (d, J: 2.4 Hz, 1H), 6.82-6.86 (m, 2H), 7.63 (d, J: 8.8 Hz, 1H), 7.96 (dd, J: 8.8, 1.6 Hz, 1H), 8.17 (s, 1H), 8.19 (s, 1H).

Example 218 N (:DH F F 3 0 Z > \ mo/A OH 9" \s |\ 0 CI S + ; _.

F mOA F CI F 1803 G 218 To a solution of Compound 180B (88 mg, 0.32 mmol) in DMF (10 mL) was added EDCI (93 mg, 0.48 mmol), HOBt (65 mg, 0.48 mmol) and Intermediate G (100 mg, 0.32 mmol). The mixture was stirred at 25 0C overnight. The reaction mixture was ed with saturated sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ed, and concentrated. The crude product was puriﬁed with prep-HPLC to furnish Compound 218. LC-MS (ESI) m/z: 565 [M+H]+; 1H—NMR (CD301), 400 MHz): 5 (ppm) 0.54-0.56 (m, 2H), 0.63-0.64 (m, 2H), 2.03-2.05 (m, 2H), 2.16- 2.18 (m, 2H), 3.18-3.26 (m, 2H), 3.54-3.59 (m, 2H), 3.66-3.72 (m, 2H), 3.78-3.79 (m, 1H), —274— 4.61-4.64 (m, 1H), 4.91 (s, 1H), 7.05 (d, .1: 3.2 Hz, 1H), 7.10 (d, .1: 8.4 Hz, 1H),7.17-7.21 (m, 3H), 7.24 (d, .1: 3.6 Hz, 1H), 7.34 (d, .1: 1.2 Hz, 1H), 7.67-7.70 (m, 2H).

Example 219 F F 5 O U \ OH 9" \s ﬁve/40 I\ CI + ; —> S 0 mO/A F C' F 174E G 219 To a solution of Intermediate G (136 mg, 0.44 mmol) in DMF (10 mL) was added Compound 174E (l 10 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol), and DIPEA (114 mg, 0.88 mmol). The mixture was stirred at 25 0C ght. The reaction mixture was quenched with saturated sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over ous sodium sulfate, ﬁltered, and concentrated. The crude product was puriﬁed with prep-HPLC to afford Compound 219. LC-MS (ESI) m/z: 543 ; 1H-NMR (CD301), 400 MHz): 5 (ppm) 0.62-0.66 (m, 2H), 0.73-0.78 (m, 2H), 2.00-2.04 (m, 2H), 2.16- 2.19 (m, 2H), 3.19-3.28 (m, 2H), 3.48-3.52 (m, 1H), 3.65-3.79 (m, 4H), 4.52-4.54 (m, 1H), 4.91 (s, 1H), 7.22 (t, J: 8.8 Hz, 2H), 7.32 (s, 2H), 7.41 (s, 1H), 7.48 (t, J: 2.4 Hz, 1H), 7.78- 7.82 (m, 2H), 8.11 (d, J: 4.4 Hz, 1H).

Example 220 O o "(:61 N (2H NH + W0] —> 0 NM 0 c F l 205A 220 A e of Compound 205A (56 mg, 0.20 mmol), Intermediate C (59 mg, 0.20 mmol), and HATU (l 19 mg, 0.30 mmol) in DMF (10 mL) was d at 10 0C for 2 h.

The reaction mixture was treated with water (10 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and puriﬁed with prep- HPLC to yield Compound 220. LC-MS (ESI) m/z: 559 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.88 (s, 2H), 2.03 (s, 2H), 3.09-3.21 (m, 2H), 3.45 (d, J: 8 Hz, 2H), 3.56 (s, 2014/056555 2H), 4.09 (s, 3H), 4.28 (s, 4H), 4.51 (s, 1H), 4.78 (s, 1H), 6.81 (t, .1: 16 Hz, 2H), 7.80 (q, .1: 12 Hz, 2H), 7.91 (dd, .1: 12, 4 Hz, 4H), 8.17 (s, 2H), 8.74 (d, .1: 8 Hz, 1H).

Example221 F F N am Ffétfw + i O] F F F —> - NH O] F S O F 211| c A mixture of Compound 2111 (100 mg, 0.37 mmol), Intermediate C (110 mg, 0.37 mmol), HOBt (76 mg, 0.56 mmol), and EDCI (106 mg, 0.56 mmol) in dichloromethane (5 mL) and triethylamine (0.2 mL) was stirred at ambient temperature for 16 hours. The reaction e was diluted with ethyl acetate (120 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep- HPLC to afford Compound 221. LC-MS (ESI) m/z: 552 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) .14 (m, 4H), 3.14-3.31 (m, 2H), 3.58-3.64 (m, 3H), 3.72-3.78 (m, 1H), 4.17 (s, 4H), 4.52-4.56 (m, 1H), 4.82 (s, 1H), 6.85-6.70 (m, 2H), 7.24-7.29 (m, 2H), 7.91 (s, 1H), 8.05-8.09 (m, 2H).

Example 222 F\©\ To a solution of Compound 222A (1.04 g, 3.45 mmol) in THF (20 mL) and water (2 mL) was added LiOH (217 mg, 5.18 mmol). The mixture was stirred at room temperature overnight, diluted with water (50 mL), and adjusted to pH 2 with 1M HCl. The precipitate was collected with ﬁltration and dried to furnish Compound 2223.

To a mixture of Compound 222B (100 mg, 0.366 mmol) in DCM (2 mL) was added HATU (167 mg, 0.44 mmol) and Intermediate G (1 14 mg, 0.366 mmol). The mixture was stirred at room temperature overnight. The mixture was treated with water (50 mL), extracted with DCM (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated.

The crude t was d with prep-HPLC to afford Compound 222. LC-MS (ESI) m/z: 566 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) .53 (m, 2H), 0.66-0.67 (m, 2H), 1.85-1.90 (m, 2H), 1.98-2.02 (m, 2H), 3.10-3.21 (m, 2H), .53 (m, 4H), 3.63-3.67 (m, 1H), 4.45-4.51 (m, 1H), 4.80 (s, 1H), .01 (m, 1H), 7.14-7.18 (m, 2H), 7.26 (s, 1H), 7.39-7.43 (m, 2H), 7.94 (s, 1H), 8.02-8.05 (m, 2H), 8.89 (d, J: 9.2 Hz, 1H), 9.38-9.47 (m, 1H).

Example 223 N 9H ' o (5 O l j o Oj o F + ; / - éN o 0 /N H F 205A 223 A mixture of Compound 205A (56 mg, 0.20 mmol), Intermediate H (56 mg, 0.20 mmol), and HATU (1 19 mg, 0.30 mmol) in DMF (10 mL) was stirred at 10 0C for 2 h.

The on mixture was treated with water (10 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified with prep- HPLC to yield Compound 223. LC-MS (ESI) m/z: 545 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 2.26 (s, 1H), 2.42 (t, J: 8 Hz, 1H), 3.44-3.48 (m, 2H), 4.09 (s, 3H), 4.19-4.43 (m, 9H), 4.74 (s, 1H), 6.80 (t, J: 16 Hz, 2H), 7.81-7.87 (m, 6H), 8.17 (s, 2H), 8.74 (d, 2H), 9.63 (brs, 2H).

Example 224 o N QH o N + i —>N ‘N O NH2 CA \N 0 CI / / 2163 G 224 A mixture of Compound 216B (100 mg, 0.49 mmol), HATU (279 mg, 0.74 mmol), and Intermediate G (152 mg, 0.49 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h. The mixture was puriﬁed with prep-HPLC to afford Compound 224. LC-MS (ESI) m/z: 497 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.59-0.83 (m, 4H), 2.04-2.23 (m, 4H), 3.24-3.27 (m, 1H), 3.34-3.35 (m, 1H), 3.59-3.82 (m, 5H), 4.11 (s, 3H), 4.73-4.77 (m, 1H), .01 (s, 1H), 7.34 (d, J: 8.8 Hz, 1H), 7.40 (dd, J: 8.4, 1.6 Hz, 1H), 7.49 (d, J: 2.0 Hz, 1H), 7.59 (d, J: 8.8 Hz, 1H), 7.89 (d, J: 8.8 Hz, 1H), 7.99 (s, 1H), 8.15 (s, 1H). e 225 Br Br 8 8 225A 2253 HO : —> \ CI —> o / 225D To a mixture ofLDA (2 N, 8.3 mL, 16.5 mmol) in tetrahydrofuran (10 mL) under nitrogen was added Compound 225A (3.2 g, 15.0 mmol) in tetrahydrofuran (5 mL) slowly at -78 0C. It was stirred at -78 0C for 1 h, and the mixture was added to a solution of carbon tetrachloride (5.5 mL, 56.6 mmol) in tetrahydrofuran (15 mL) at -78 0C. The resultant mixture was stirred at -78 0C for 1.5 h, quenched with ammonium chloride solution (50 mL), warmed to room ature, and extracted with DCM (100 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and trated. The residue was purified with ﬂash column chromatography on silica gel (petroleum ether, 100% V/V) to h Compound 2253.

A solution of Compound 225B (1.2 g, 5 mmol) in THF (10 mL) under nitrogen was added n-BuLi (2.4 N, 2.5 mL, 6 mmol) at -78 0C. The mixture was stirred at -78 0C for 30 min. To the above mixture was added 1 oxalate (5 mL). The ant solution was stirred at -78 0C for 15 min, quenched with saturated aqueous NH4C1 solution (10 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over ous sodium sulfate, filtered, and concentrated. The residue was purified with ﬂash column chromatography on silica gel (petroleum ether, 100% V/V) to afford Compound 225C.

To a solution of Compound 225C (268 mg, 1 mmol) in MeOH (5 mL) was added a solution of LiOH'HzO (126 mg, 3 mmol) in water (2 mL). The e was d at room temperature overnight. The solution was concentrated to remove ol, adjusted to pH 2 with HCl (6 N, 2 mL), and extracted with ethyl acetate (50 mL x 2). The ed organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 20% v/v) to h Compound 225D.

A mixture of Compound 225D (125 mg, 0.5 mmol), HATU (342 mg, 0.9 mmol), and Intermediate G (162 mg, 0.5 mmol) in DMF (2 mL) and DCM (5 mL) was stirred at 25 0C overnight. The mixture was concentrated, and puriﬁed with prep-HPLC to yield Compound 225. LC-MS (ESI) m/z: 533 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.65-.090 (m, 4H), 1.97-2.23 (m, 4H), 3.12-3.27 (m, 1H), 3.58-3.62 (m, 1H), 3.69-3.85 (m, 5H), 4.60-4.63 (m, 1H), 5.01 (s, 1H), 7.37-7.52 (m, 4H), 7.52 (s, 1H), 7.68 (d, J: 8.0 Hz, 1H), 7.84 (d, J: 8.0 Hz, 1H).

Example 226 O o N (:JH O (~14er o F / —> F—©— _ o o 0] S S F ﬂﬂNH o 2116 226A 3 O F A solution of Compound 211G (500 mg, 1.89 mmol) and LiOH‘HZO (119 mg, 2.83 mmol) in THF (10 mL) and water (2 mL) was stirred at -10 0C for 1 h. It was diluted with ice water (20 mL) and adjusted to pH 1 with diluted hydrochloric acid (6 M) to form a solid. The mixture was ﬁltered and the resulting solid was dried to yield Compound 226A.

A mixture of Compound 226A (100 mg, 0.40 mmol), ediate C (118 mg, 0.40 mmol), and HATU (228 mg, 0.60 mmol) in DMF (3 mL) was d at room temperature for 16 h. It was diluted with ethyl acetate (120 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to afford Compound 226. LC-MS (ESI) m/z: 530 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.84 (brs, 2H), 1.99 (brs, 2H), 3.08-3.16 (m, 2H), .54 (m, 4H), 4.25 (s, 4H), 4.45 (t, J: 6.0 Hz, 1H), 4.76 (s, 1H), 6.14 (brs, 1H), 6.74 (s, 1H), 6.81 (d, J: 11.6 Hz, 1H), 7.40 (t, J: 8.8 Hz, 2H), 8.08-8.12 (m, 2H), 8.80 (d, J: 9.6 Hz, 1H), 8.96 (s, 1H), 9.37 (brs, 1H). e 227 2000 H 227 A mixture of nd 200D (46 mg, 0.20 mmol), Intermediate H (63 mg, 0.20 mmol), and HATU (119 mg, 0.30 mmol) in DMF (10 mL) was stirred at 10 0C for 3 h.

The reaction mixture was treated with water (10 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and puriﬁed with prep- HPLC to yield Compound 227. LC-MS (ESI) m/z: 498 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) 1.22 (s, 2H), 1.66 (s, 6H), 3.44-3.48 (m, 5H), 3.67 (d, J: 12 Hz, 1H), 4.15- 4.33 (m, 9H), 4.90 (s, 1H), 6.69 (d, J: 12 Hz, 2H), 6.76 (d, J: 8 Hz, 2H), 7.67 (d, J: 8 Hz, 2H).

Example 228 N QH Z 5 T O 0 N 9H OH ' NH 1 o o + ; —> N\ o NH2 1 N\ o F | 0 | / / 195A 0 228 A mixture of Compound 195A (100 mg, 0.44 mmol), Intermediate C (130 mg, 0.44 mmol), and HATU (335 mg, 0.88 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction e was d with ethyl acetate (50 mL), washed with water (20 mL x 3) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to yield Compound 228. LC-MS (ESI) m/z: 506 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.73-1.75 (m, 4H), 2.54-2.68 (m, 6H), 4.31-4.33 (m, 5H), 4.76-4.77 (s, 1H), 5.69 (s, 1H), 6.75 (s, 1H), 6.81 (d, J: 10.4 Hz, 1H), 7.45-7.46 (m, 1H), 7.83-7.98 (m, 3H), .08 (m, 1H), 8.19-8.20 (m, 2H), 8.63-8.64 (m, 1H), 8.74-8.75 (m, 1H).

Example 229 0 Q(:DH {HI/W. 9m.)T {NWMore:: _- 0 s 0 226A A 229 A mixture of Compound 226A (100 mg, 0.40 mmol), Intermediate A (111 mg, 0.40 mmol), and HATU (228 mg, 0.60 mmol) in DMF (3 mL) was stirred at room temperature for 16 h. It was diluted with ethyl acetate (120 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, trated, and puriﬁed with prep-HPLC to afford Compound 229. LC-MS (ESI) m/z: 512 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.83 (brs, 2H), 1.99 (brs, 2H), 3.06-3.17 (m, 2H), .53 (m, 4H), 4.18 (s, 4H), 4.43 (t, J: 11.2 Hz, 1H), 4.74 (s, 1H), 5.99 (brs, 1H), 6.77-6.87 (m, 3H), 7.40 (t, J: 8.8 Hz, 2H), 8.08-8.12 (m, 2H), 8.80 (d, J: 9.6 Hz, 1H), 8.95 (s, 1H), 9.24 (brs, 1H).

Example 230 174E F 230 6] To a solution of Compound 174E (62 mg, 0.25 mmol) in DMF (5 mL) was added Intermediate C (74 mg, 0.25 mmol) and HATU (141 mg, 0.37 mmol). The reaction mixture was stirred at 25 0C for 16 h. The mixture was purified with prep-HPLC to yield Compound 230. LC-MS (m/z) 529 [M+H]+; (CDC13, 400 MHz): 5 (ppm) 2.14-2.17 (m, 4H), 2.77-2.87 (m, 2H), 3.11-3.14 (m, 2H), 3.49-3.51 (m, 1H), 3.82-3.92 (m, 3H), 4.15- 4.19 (m, 3H), 4.89 (brs, 1H), 5.16 (s, 1H), 6.70-6.74 (m, 2H), 7.07-7.11 (m, 2H), 7.24-7.25 (m, 1H), 7.59-7.63 (m, 2H), 8.03-8.06 (m, 1H), 8.16-8.17 (m, 1H), 9.70 (brs, 1H).

Example 231 200D 231 To a solution of Compound 200D (100 mg, 0.43 mmol) in DMF (5 mL) was added Intermediate G (151 mg, 0.43 mmol) and HATU (151 mg, 0.43 mmol). The reaction e was stirred at 15 0C overnight. The mixture was puriﬁed with prep-HPLC to give Compound 231. LC-MS (m/z) 526 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) 0.77-0.79 (m, 4H), 1.66 (s, 6H), 2.04-2.08 (m, 4H), 3.34-3.51 (m, 10H), 3.72-3.74 (m, 1H), .51 (m, 1H), 5.15 (s, 1H), 6.70-6.73 (m, 2H), 7.20-7.24 (m, 1H), 7.36 (s, 1H), 7.75-7.77 (m, 1H), 7.89-7.91 (m, 2H).

Example 232 Br N Br N/ ﬁx)" m» Br /N + a)"— 232A 2323 2320 2323 + O\ . N O 178C 232D FF:WA To Compound 232A (10 g, 50.8 mmol) in THF (50 mL) was added sodium e (60% in mineral, 2.2 g, 55.8 mmol) with ice bath cooling. The mixture was stirred at room temperature for 30 min. Methyl iodide (4.74 mL, 76.1 mmol) was added at room temperature. The reaction mixture was d at room temperature for l h, quenched with saturated s ammonium chloride solution (30 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over 2014/056555 anhydrous sodium sulfate, and concentrated. Puriﬁcation with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% to 30% v/v) gave Compound 232B and Compound 232C.

A e of Compound 232B (600 mg, 2.84 mmol), Compound 178B (926 mg, 2.84 mmol), Pd(dppf)C12 (116 mg, 0.14 mmol), and K2C03 (1.18 g, 8.52 mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction mixture was cooled to room temperature and ﬁltered through celite. The ﬁltrate was diluted with water (50 mL) and ted with ethyl acetate (50 mL x 2), and then the organic layer was discarded off. The aqueous layer was acidiﬁed to pH 3 with aqueous HCl on (1 N) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 232D.

A mixture of Compound 232D (100 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), and ediate G (102 mg, 0.33 mmol) in dichloromethane (5 mL) was stirred at 10 0C for 18 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over ous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to furnish Compound 232. LC-MS (ESI) m/z: 595 [M+H]+; 1H-NMR(CD30D, 400 MHz): 5 (ppm) 0.33-0.41 (m, 4H), 1.95-2.08 (m, 4H), 3.08-3.17 (m, 2H), 3.38-3.64 (m, 4H), 3.70-3.72 (m, 1H), 4.05 (s, 3H), 4.54-4.56 (m, 1H), 4.82 (d, J: 2.4 Hz, 1H), 6.94 (d, J: 8.4 Hz, 1H), 7.02 (dd, J: 8.8, 1.6 Hz, 1H), 7.28-7.30 (m, 3H), 7.42 (d, J: 9.2 Hz, 1H), 7.66 (d, J: 7.6 Hz, 2H), 7.75-7.77 (m, 2H), 7.95 (s, 1H).

Example 233 O 0 no 4Gift "4 comS Br 0 OH O 0 s s 233A 2333 2330 To a solution of Compound 233A (1.0 g, 4.7 mmol) in THF (30 mL) was added ium chips (0.23 g, 9.4 mmol) at room temperature. The mixture was stirred at 50 0C for 2 h, and then diethyl oxalate (3 mL) was added in one portion. The mixture was stirred at 60 0C for 3 h. The solution was quenched with ted NH4Cl solution and extracted with ethyl acetate (50 mL x 2). The combined c phases were washed with water (15 mL) and brine (15 mL), dried over ous sodium sulfate, d, and trated. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 233B.

To a solution of Compound 233B (1.4 g, 6.1 mmol) in THF (15 mL) was added LiOH'HzO (390 mg, 9.0 mmol) in water (15 mL) at -10 0C, and the mixture was stirred at this ature for 5 hours. The reaction mixture was treated with ice water (20 mL) and extracted with ethyl acetate (50 mL). The water layer was adjusted to pH 2 with diluted HCl and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting solid was washed with petroleum ether and ﬁltered off to ﬁamish the crude Compound 233C.

A mixture of Compound 233C (160 mg, (0.8 mmol), HATU (608 mg, 1.6 mmol), DMF (6.5 mL) and Intermediate G (298 mg, 0.96 mmol) in DCM (8 mL) was stirred at room temperature overnight. The reaction mixture was treated with water (20 mL), extracted with DCM 50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 233. LC-MS (ESI) m/z: 499.1 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.61-0.79 (m, 4H), 2.01-2.23 (m, 4H), 3.21-3.30 (m, 1H), 3.58-3.86 (m, 6H), 4.73 (d, J: 10.8 Hz, 1H), 5.00 (s, 1H), 7.32 (d, J: 8.4 Hz, 1H), 7.39 (d, J: 8.8 Hz, 1H), 7.47 (d, J: 5.2 Hz, 1H), 7.50 (d, J: 1.2 Hz, 1H), 7.73-7.75 (m, 2H), 7.98 (d, J: 8.4 Hz, 1H), 8.15 (s, 1H).

Example234 0 O o N OH OH NH O] o 0 o o + o O 34 o a NH2 0 O F CI F 1330 D 234 A mixture of nd 133D (156 mg, 0.50 mmol), Intermediate D (100 mg, 0.45 mmol), and HATU (285 mg, 0.75 mmol) in dichloromethane (10 mL) was stirred at 10 0C for 15 h. And then it was treated with water (10 mL) and extracted with dichloromethane (10 mL x 3mL). The organic layers were washed with water (20 mL x 3), dried over ous sodium sulfate, concentrated in vacuo, and puriﬁed with PLC to furnish Compound 234. LC-MS (ESI) m/z: 539 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) 2.09 (s, 4H), 3.06 (s, 2H), 3.46 (s, 1H), 3.73 (t, J: 12 Hz, 1H), 3.89 (s, 2H), 4.10-4.19 (m, 4H), 4.43 (s, 1H), 4.99 (s, 1H), 6.76 (s, 1H), 6.92 (s, 1H), 7.08 (t, J: 8 Hz, 2H), 7.50 (t, J: 8 Hz, 4H), 7.67 (d, J: 8 Hz, 2H), 7.80 (d, J: 8 Hz, 2H), 8.50 (s, 1H).

Example 235 F Q = O] COOH 9H + O o] _> RJH2 N A mixture of Compound 232D (100 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), and ediate A (92 mg, 0.33 mmol) in dichloromethane (5 mL) was stirred at 10 0C for 18 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over ous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to furnish Compound 235. LC-MS (ESI) m/z: 563 [M+H]+; 1H-NMR (CD30D, 400 MHz): 5 (ppm) 2.03-2.17 (m, 4H), 3.15-3.24 (m, 2H), 3.53-3.67 (m, 3H), 3.80-3.82 (m, 1H), 4.07 (s, 4H), 4.15 (s, 3H), 4.56-4.58 (m, 1H), 4.83 (d, J: 3.2 Hz, 1H), 6.64 (d, J: 8.4 Hz, 1H), 6.72- 6.79 (m, 2H), 7.47-7.53 (m, 3H), 7.81 (d, J: 8.0 Hz, 2H), .88 (m, 2H), 8.05 (s, 1H).

Example 236 A mixture of Compound 232D (100 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), and Intermediate C (98 mg, 0.33 mmol) in dichloromethane (5 mL) was d at 10 0C for 18 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was purified with prep-HPLC to furnish Compound 236. LC-MS (ESI) m/z: 581 [M+H]+; 1H-NMR (CD30D, 400 MHz): 5 (ppm) 2.03-2.18 (m, 4H), 3.17-3.27 (m, 2H), 3.53-3.81 (m, 4H), 4.01-4.07 (m, 4H), 4.15 (s, 3H), 4.59-4.62 (m, 1H), 4.84 (d, J: 2.8 Hz, 1H), 6.59 (s, 1H), 6.68 (dd, J: 11.6, 2.0 Hz, 1H), 7.48 (d, .1: 8.0 Hz, 2H), 7.52 (d, .1: 8.8 Hz, 1H), 7.79 (d, .1: 8.4 Hz, 2H), 7.86-7.88 (m, 2H), 8.05 (s, 1H). e 237 A mixture of Compound 232C (200 mg, 0.95 mmol), Compound 178C (310 mg, 0.95 mmol), Pd(dppf)Clz (39 mg, 0.05 mmol), and K2C03 (393 mg, 2.85 mmol) in dioxane (3 mL) and water (3 mL) was stirred under nitrogen at 100 0C for 4 h. The reaction mixture was cooled to room temperature and ﬁltered through celite. The ﬁltrate was treated with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The aqueous layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give nd 237A.

A mixture of Compound 237A (100 mg, 0.33 mmol), EDCI (95 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), and Intermediate G (102 mg, 0.33 mmol) in dichloromethane (5 mL) was stirred at 10 0C for 18 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over anhydrous sodium sulfate. After ation, the crude product was puriﬁed with prep-HPLC to h Compound 237. LC-MS (ESI) m/z: 595 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.45-0.54 (m, 4H), 2.04-2.18 (m, 4H), 3.17-3.32 (m, 2H), 3.49-3.81 (m, 5H), 4.26 (s, 3H), 4.62-4.64 (m, 1H), 4.90 (s, 1H), 7.03 (d, J: 8.4 Hz, 1H), 7.11 (dd, J: 8.4, 1.6 Hz, 1H), 7.37-7.40 (m, 3H), 7.47 (d, J: 8.8 Hz, 1H), 7.74 (d, J: 8.0 Hz, 2H), 7.82 (d, J: 8.8 Hz, 1H), 7.90 (s, 1H), 8.25 (s, 1H).

Example 238 "NOE"_>G Br ON O o\/ 238A 2383 238C A mixture of Compound 238A (1.72 g, 10 mmol), 1,5-dibromopentane (2.75 g, 12 mmol), sodium dodecyl sulfate (SDS, cat. 40 mg), and sodium bicarbonate (1 g, 12 mmol) in water (20 mL) was heated at 100 CC for 1.5 hours. The reaction e was treated with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The extraction was washed with water (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 1% V/V) to give Compound 238B.

To a solution of Compound 238B (2.4 g, 10 mmol) in dry THF (50 mL) was added dropwise LDA (2.0 M, 5.0 mL, 12.0 mmol) under nitrogen at -70 0C. After stirring for min., diethyl oxalate (2.19 g, 15.0 mmol) was added quickly. The mixture was d at - 70 0C for about an hour. It was quenched with saturated ammonium chloride (10 mL) solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to give a residue. The crude product was puriﬁed with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% V/V) to afford Compound 238C.

To a on of Compound 238C (261 mg, 1 mmol) in methanol (5 mL) was added se lithium ide (1 N, 2 mL, 2 mmol). The reaction mixture was stirred at room temperature for 2 h. After the reaction e was concentrated, HCl (2 N, 1 mL) was added to adjust pH 7, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to mmish Compound 238D.

To a solution of Compound 238D (100 mg, 0.429 mmol) in dichloromethane (3 mL) was added Intermediate G (130 mg, 0.429 mmol) and HATU (196 mg, 0.515 mmol).

The mixture was stirred at room temperature for 2 h. It was concentrated and the resulting residue was puriﬁed with prep-HPLC to ﬁamish nd 238. LC-MS (ESI) m/z: 526 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) 0.79-0.83 (m, 4H), 1.57-1.61 (m, 2H), 1.67- 1.72 (m, 5H), 1.85-1.87 (m, 4H), 2.71-2.92 (m, 4H), 2.96-3.07 (m, 2H), .19 (m, 4H), 3.75-3.78 (m, 1H), 4.31-4.32 (m, 1H), 5.14 (d, J: 1.6 Hz, 1H), 7.16-7.23 (m, 2H), 7.24-7.37 (m, 3H), 7.58-7.60 (m, 1H), .78 (m, 1H).

Example 239 1803 F 239 To a solution of Compound 180B (68 mg, 0.25 mmol) in DMF (5 mL) was added Intermediate C (74 mg, 0.25 mmol) and HATU (142 mg, 0.37 mmol). The reaction e was stirred at 25 0C for 16 h. The mixture was puriﬁed with prep-HPLC to yield Compound 239. LC-MS (m/z) 551 [M+H]+; 1H-NMR (CDC13, 400 MHz): 5 (ppm) 2.15-2.18 (m, 4H), 2.94-2.97 (m, 1H), 3.06-3.10 (m, 1H), 3.50-3.53 (m, 2H), 3.82-3.88 (m, 2H), 4.08- 4.10 (m, 3H), 4.16-4.23 (m, 1H), 4.39-4.42 (m, 1H), 5.08 (brs, 1H), 6.59-6.67 (m, 2H), 7.08- 7.11 (m, 3H), .55 (m, 3H).

Example 240 To a solution of Compound 202C (158 mg, 0.75 mmol) in 1,4-dioxane (15 mL) was added ethyl 178C (250 mg, 0.825 mmol), Pd(dppf)C12 (30 mg, 0.0375 mmol), potassium carbonate (310 mg, 2.25 mmol) and water (1 mL) under nitrogen. The on mixture was stirred at 100 0C for 2 hours. The ing mixture was cooled to 25 0C. The precipitated solid was ﬁltered and dried to afford Compound 240A.

To a solution of nd 240A (68 mg, 0.24 mmol) in DMF (3 mL) was added Intermediate C (71 mg, 0.24 mmol) and HATU (137 mg, 0.36 mmol). The reaction mixture was stirred at 10 0C overnight. The mixture was puriﬁed with prep-HPLC to yield the product Compound 240. LC-MS (m/z) 559 [M+H]+; (CDC13, 400 MHz): 5 (ppm) 2.15-2.22 (m, 4H), 2.94-2.95 (m, 2H), 3.08-3.09 (m, 2H), 3.49-3.50 (m, 1H), 3.56-3.57 (m, 1H), 3.91-3.94 (m, 2H), 4.23-4.27 (m, 5H), 4.49-4.52 (m, 1H), 5.12-5.13 (m, 1H), 6.73-6.78 (m, 2H), 7.58-7.61 (m, 1H), 7.69-7.71 (m, 2H), 7.79-7.81 (m, 1H), 7.85-7.90 (m, 2H), 7.99 (s, 1H), 8.19-8.21 (m, 2H).

Example 241 F0 ~0ion 4 r1ryeF \o F OH 0 241A 2413 2410 o o\ o o\ 0 OH WODIﬁ (EDI #001F o O o 241D 241E 241F 0 . _, <10 moA 0 CI To a solution of Compound 241A (3.1 g, 27.6 mmol) and potassium ate (4.15 g, 30.0 mmol) in DMF (50 mL) was added 4-bromobenzaldehyde (5.0 g, 27.6 mmol).

The reaction mixture was stirred at 130 0C for 12 h. The reaction was quenched with water (50 mL) and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The remaining residue was purified with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, from 0% to 10% V/V) to furnish Compound 241B. 7] A mixture of Compound 241B (1.9 g, 8.8 mmol), and sodium metabisulfite (3.3 g, 17.6 mmol) in water (40 mL) was pre-stirred for 1 h, and then NaCN (431.2 mg, 8.8 mmol) was added into the above-mentioned mixture, and the whole reaction solution was stirred at room ature for 12 h. The reaction was treated with water (100 mL) and 2014/056555 extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium e, ﬁltered, and evaporated. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30% v/v) to give Compound 241C.

To a solution of Compound 241C (1.0 g, 27.6 mmol) in methanol (50 mL) was bubbled with HCl (gas), which was prepared with condensed H2S04 and NaCl. After 4 h later, the reaction was quenched with water (50 mL) and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, ﬁltered, and evaporated. The remaining residue was d with ﬂash column chromatography on silica gel (ethyl e in petroleum ether, from 0% to 30% v/v) to afford nd 241D.

To a solution of Compound 241D (170 mg, 0.62 mmol) in dichloromethane (15 mL) was added Dess-Martin periodinane (3 13 mg, 0.74 mmol). The reaction was stirred at 0 0C for 0.5 h. The reaction was d with water (50 mL) and extracted with dichloromethane (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, ﬁltered, and evaporated. The remaining residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 3% v/v) to ﬁamish nd 241E.

To a on of Compound 241E (160 mg, 0.58 mmol) in methanol (15 mL) was added LiOH on (1 N, 0.6 mL, 0.60 mmol). The reaction was stirred at 0 0C for 0.5 h. The reaction was quenched with water (50 mL) and neutralized to pH 1 with HCl (1 M).

The mixture was extracted with dichloromethane (150 mL x 3). The combined organic layers were washed with brine (l 50 mL), dried over anhydrous sodium sulfate, ﬁltered, and evaporated to afford nd 241F.

Tozlyﬂuﬁonof(knnpound241F(1001ng,038rnnuﬂ)n1annxuneof dichloromethane (14 mL) and DMF (2 mL) was added Intermediate G (1 19 mg, 0.38 mmol) and HATU (175 mg, 0.46 mmol). The mixture was d at room temperature for 12 h. The reaction was quenched with water (50 mL) and extracted with dichloromethane (150 mL x 3).

The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, ﬁltered, and evaporated. The remaining residue was puriﬁcation with prep- HPLC to give Compound 241. LC-MS (ESI) m/z: 553 [M+H]+; 1H-NMR (CDClg, 400 MHz): (ppm) 0.65-0.82 (m, 4H), 2.14 (s, 4H), 2.66-2.96 (m, 4H), 3.51-3.90 (m, 4H), 4.54 (s, 1H), .12 (s, 1H), 6.88 (d, J: 8.6 Hz, 2H), 7.00-7.12 (m, 4H), 7.16-7.26 (m, 2H), 7.34-7.37 (m, 1H), 7.97-8.03 (m, 3H), 11.60 (s, 1H).

Example 242 £1CH0 0 0 _. {>34 —» 034 CI F CI 8 O—\ CI 5 OH 242A 2423 242C CI 3 CI 8 2420 o A \ _, 0 CI S OH 242F CI 242 Compound 242A (2.44 g, 15.4 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were suspended in dry DMF (15 mL) and the resulting mixture was cooled to 0 0C.

Ethyl thioglycolate (1.7 mL, 15.5 mmol) was added in portions over 1 h and the reaction mixture was warmed slowly to room temperature and stirred at 25 0C for 16 h. The reaction was heated at 60 0C for 5.5 h before cooling and adding water (30 mL). The resulting mixture was stirred at room temperature for 30 min and ﬁltered. The e was washed with water (5 mL x 2) and dried to afford the Compound 242B.

Compound 242B (500 mg, 2.08 mmol) was dissolved in hot ethanol (12 mL) and a solution of potassium hydroxide (642 mg, 11.5 mmol) in water (12 mL) was added to the e. The suspension was heated at reﬂux for 1.5 h during which time it mostly dissolved. After cooling slightly aqueous HCl solution (6 N, 5 mL) was added dropwise.

Ethanol was evaporated in vacuo and the residual solid was ﬁltered. The ﬁltered cake was washed with water (20 mL) and dried to give Compound 242C.

Compound 242C (420 mg, 1.98 mmol) and copper powder (63 mg, 0.99 mmol) were suspended in quinoline (10 mL) and the resulting mixture was heated at 185 0C for 2 h. After cooling down to room temperature, ethyl acetate (25 mL) was added and the suspension was ﬁltered. The d cake was washed with ethyl acetate (5 mL x 2) and the combined organic layers were washed with aqueous HCl solution (2 N, 10 mL x 2). After drying over ous sodium sulfate, the solution was ﬁltered and evaporated in vacuo to give a e. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% V/V) to afford Compound 242D.

To a solution of Compound 242D (310 mg, 1.85 mmol) in dry THF (20 mL) was added dropwise n-BuLi (2.4 M solution in hexane, 1.2 mL, 2.78 mmol) under nitrogen at -78 0C. After stirring for 30 min, diethyl oxalate (808 mg, 5.54 mmol) was added quickly.

The mixture was stirred at -78 0C for about an hour. The resulting mixture was quenched with saturated aqueous NH4Cl solution (5 mL), extracted with ethyl acetate (50 mL x 3), washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ed, and concentrated to yield a crude compound. The crude product was purified with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to h Compound 242E. 6] To a solution of Compound 242E (150 mg, 0.56 mmol) in THF (10 mL) was ammddnmwmeayﬂmmnofLKHTHﬁ)Q5ng,062mmmDh1me125nﬂ)at60°Cwa mixture was stirred at -30 0C for half an hour. The reaction solution was ed to pH 3 with aqueous HCl solution (1 N, 2.5 mL) and separated. The organic layer was dried directly over ous sodium e, ﬁltered, and concentrated to afford nd 242F.

To a solution of Intermediate G (129 mg, 0.42 mmol) in DMF (10 mL) was added Compound 242F (100 mg, 0.42 mmol), HATU (237 mg, 0.62 mmol), and N, N- diisopropylethylamine (107 mg, 0.83 mmol) under nitrogen. The mixture was stirred at 25 0C overnight. The resulting mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined c phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude compound. The crude product was purified with prep-HPLC to furnish Compound 242. LC-MS (ESI) m/z: 533 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.58-0.70 (m, 2H), 0.73-0.79 (m, 2H), 2.01-2.04 (m, 2H), 2.16-2.21 (m, 2H), 3.20-3.26 (m, 2H), 3.49-3.53 (m, 1H), 3.70-3.76 (m, 4H), 4.58-4.60 (m, 1H), 4.91 (d, J = 2.8 Hz, 1H), 7.32-7.34 (m, 2H), 7.44 (d, J: 1.6 Hz, 1H), 7.47 (dd, J: 8.8, 2.0 Hz, 1H), 7.97 (d, J: 8.4 Hz, 1H), 8.04 (s, 1H), 8.38 (s, 1H).

Example 243 o o WOVBr N/ 0‘8 0 + \©://N —> ,N"cow 1753 232C 243A 0 moﬁ.

—’ \N O 0 CI O 243 A e of Compound 232C (600 mg, 2.84 mmol), Compound 175B (863 mg, 2.84 mmol), Pd(dppf)C12 (116 mg, 0.14 mmol), and K2C03 (1.18 g, 8.52 mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction mixture was cooled to room temperature and ﬁltered through celite. The ﬁltrate was treated with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The aqueous layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and ﬁltered. The cake was washed with water (20 mL) and dried in vacuo to give Compound 243A.

A mixture of Compound 243A (100 mg, 0.36 mmol), HATU (205 mg, 0.54 mmol), and Intermediate A (112 mg, 0.36 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h. The mixture was puriﬁed with prep-HPLC to furnish Compound 243. LC-MS (ESI) m/z: 573 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) .82 (m, 4H), 2.07-2.08 (m, 2H), 2.23-2.24 (m, 2H), 3.31-3.32 (m, 2H), 3.60-3.63 (m, 1H), 3.71-3.77 (m, 2H), .89 (m, 2H), 4.15-4.16 (m, 3H), .76 (m, 1H), 5.02 (s, 1H), 7.41 (s, 2H), 7.50 (s, 1H), 7.53-7.55 (m, 1H), 7.70-7.72 (m, 2H), 7.79-7.81 (m, 2H), 7.88-7.89 (m, 2H), 8.07 (s, 1H).

Example 244 O O N Br \N O\/ \N "Q OH N\ o N\ o 232C 244A 244B To a solution of Compound 232C (800 mg, 3.79 mmol) in dry THF (10 mL) was added n-BuLi (2.5 N solution in hexane, 1.53 mL) under nitrogen at -78 0C. The resulting solution was stirred at -78 0C for 30 min and transferred into a stirred solution of diethyl oxalate (1.39 g, 9.5 mmol) in dry THF (5 mL) at -78 0C. The solution was stirred at -78 0C for l h, quenched with addition of saturated NH4Cl solution (10 mL), poured into water (100 mL), and extracted with ethyl acetate (50 mL x 2). The ed organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a solid. This solid was triturated with methanol and ﬁltered. The ﬁltrate was concentrated to give the desired Compound 244A which was used for the next step t ﬁarther puriﬁcation.

To a solution of Compound 244A (500 mg, 2.16 mmol) in methanol (10 mL) was added a on of LiOH‘HZO (200 mg, 4.32 mmol) in water (5 mL). The mixture was d at room temperature ght and puriﬁed with reverse phase chromatography using eluent (methanol in water, from 0% to 7% v/v) to ﬁamish Compound 244B.

A mixture of Compound 244B (70 mg, 0.34 mmol), HATU (194 mg, 0.51 mmol), and Intermediate G (105 mg, 0.34 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h. The mixture was d with prep-HPLC to afford Compound 244. LC-MS (ESI) m/z: 497 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.62-0.82 (m, 4H), 1.88-1.91 (m, 2H), 2.03-2.05 (m, 2H), 3.13-3.20 (m, 2H), 3.47-3.59 (m, 4H), 3.89-3.90 (m, 1H), 4.14 (s, 3H), 4.54-4.56 (m, 1H), 4.86 (d, J: 2.8 Hz, 1H), .39 (m, 2H), 7.45-7.49 (m, 2H), 7.84 (d, J: 8.8 Hz, 1H), 8.21 (s, 1H), 8.27 (s, 1H), 8.83 (d, J: 9.2 Hz, 1H), 9.32 (brs, 1H).

Example 245 \ 2 \N OH O W NI + 1 _> N \ O \ O 244B 245 A mixture of Compound 244B (60 mg, 0.29 mmol), HATU (167 mg, 0.44 mmol), and Intermediate C (86 mg, 0.29 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h.

The mixture was puriﬁed with prep-HPLC to afford Compound 245. LC-MS (ESI) m/z: 483 ; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.87-2.04 (m, 4H), 3.08-3.21 (m, 2H), 3.43-3.46 (m, 2H), 3.54-3.57 (m, 2H), 4.12 (s, 3H), 4.22-4.32 (m, 4H), 4.48-4.55 (m, 1H), 4.77 (d, J: 2.8 Hz, 1H), 6.77 (s, 1H), 6.84 (dd, J: 11.6, 1.6 Hz, 1H), 7.51 (dd, J: 8.4, 0.8 —294— Hz, 1H), 7.86 (d, J: 8.8 Hz, 1H), 8.21 (s, 1H), 8.31 (s, 1H), 8.81 (d, J: 9.2 Hz, 1H), 9.31 (brs, 1H).

Example 246 N QH Z 5 o N 9H NH COOH = o o \ + F a N o NH2 j—> o N\ O 243A c 246 A mixture of Compound 243A (100 mg, 0.36 mmol), HATU (205 mg, 0.54 mmol), and Intermediate C (107 mg, 0.36 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h. The mixture was d with prep-HPLC to furnish Compound 246. LC-MS (ESI) m/z: 559 [M+H]+; 1H-NMR (DMSO-dg, 400 MHZ): 5 (ppm) 1.73-1.74 (m, 4H), 2.54-2.61 (m, 5H), 2.66-2.71 (m, 1H), 4.13 (s, 3H), 4.27-4.31 (m, 5H), 4.78 (d, J: 2.8 Hz, 1H), 6.76 (s, 1H), 6.83 (dd, J: 11.2, 1.2 Hz, 1H), 7.52 (dd, J: 8.4, 1.2 Hz, 1H), 7.79-7.92 (m, 5H), 8.05 (s, 1H), 8.11 (s, 1H), 8.66 (d, J: 9.6 Hz, 1H).

Example 247 247A 2473 247C 247D 247E A e of Compound 247A (14.2 g, 50 mmol), Compound (4- ﬂuorophenyl)boronic acid (7.7 g, 55 mmol), Pd(dppl)C12 (2.05 g, 2.5 mmol) and K2C03 (20.7 g, 150 mmol) in dioxane (600 mL) and water (80 mL) was heated to reﬂux for 2 h. Ethyl acetate (500 mL) was added. The organic layers were washed with water (50 mL), saturated sodium bicarbonate solution (100 mL) and brine (100 mL), dried over ous sodium sulfate, and trated to give a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 5% to 10% V/V) to mmish Compound 247B.

To a solution of Compound 247B (2.51 g, 10 mmol) in THF (20 mL) was added n-BuLi (4.4 mL, 2.4 M in hexane, 11 mmol) dropwise under nitrogen at -76 0C. The reaction mixture was d at -76 0C for 15 minutes. The reaction was added to a solution of diethyl oxalate (4.7 mL, 35 mmol) in THF (10 mL) under nitrogen at -60 0C for 30 minutes.

The reaction mixture was quenched with ted NH4Cl on (10 mL) and water (50 mL)mnemnwmdwﬁhemthdam(ﬂhan3)Theammnwdmgmncbyﬂswmewaﬂwd with brine (25 mL), dried over anhydrous sodium sulfate, ﬁltered, and ated to give a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 5% to 10% v/v) to furnish Compound 247C.

To a solution of Compound 247C (445 mg, 1.64 mmol) in dry dichloromethane (10 mL) was added DAST (0.55 mL, 4.09 mmol). The mixture was stirred at 25 0C for 14 hours. After the reaction was completed, romethane (35 mL) was added.

The organic layer was washed with water (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude nd. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl e in petroleum ether, from 10% to 20% v/v) to furnish Compound 247D. 9] To a solution of Compound 247D (458 mg, 1.57 mmol) in THF/water/MeOH (9 mL, 1:1:1, v/v) was added LiOH’HzO (98 mg, 2.35 mmol). The mixture was stirred at 28 0C for 1 h. After the reaction was completed, it was adjusted to pH 6 with 2 N HCl. The reaction mixture was concentrated in vacuo. The crude product was in lyophilization to ﬁnnmh(knnpound247E.

A mixture of Compound 247E (88 mg, 0.33 mmol), Intermediate G (128 mg, 0.41 mmol), EDCI.HCl (96 mg, 0.49 mmol), and HOBt (67 mg, 0.49 mmol) in dichloromethane (15 mL) and DMF (2 mL) was stirred at 25 0C for 5 h. It was treated with water (20 mL), extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and puriﬁed with prep-HPLC to furnish Compound 247. LC- MS (ESI) m/z: 560 [M+H]+; 1H-NMR (CD301), 400 MHz): 5 (ppm) 0.65-0.68 (m, 4H), 2.12- 2.15 (m, 4H), 3.00-3.02 (m, 2H), 3.38-3.45 (m, 2H), 3.53-3.62 (m, 2H), 3.75-3.82 (m, 2H), 450452ﬁm1HL49¢496mvﬁ=28HL1H)7070g2HL72OGﬂﬁ=88HL2HL732 7.34 (m, 1H), 7.65-7.71 (m, 2H), 8.00-8.04 (m, 2H), 8.68 (s, 1H).

Example 248 a Q 9H 0 N QH : o OH = oW o o 2 + 14 . j O O F NH2 0 0 o F 197D H 248 A mixture of Compound 197D (52 mg, 0.20 mmol), Intermediate H (63 mg, 0.20 mmol), and HATU (119 mg, 0.30 mmol) in DMF (5 mL) was stirred at 10 0C for 3 h.

The mixture was puriﬁed with prep-HPLC to ﬁlrnish Compound 248. LC-MS (ESI) m/z: 525 [M+H]+; 1H-NMR (CDC13, 400 MHz): 5 (ppm) 2.34-2.46 (m, 1H), 2.55-2.66 (m, 1H), 3.34 (s, 1H), 3.41-3.47 (m, 1H), 3.56 (dd, J: 8, 12 Hz, 1H), 4.07-4.15 (s, 5H), 4.22-4.29 (m, 3H), 4.85 (s, 1H), 6.62-6.63 (m, 2H), 6.66-7.02 (m, 4H), 7.13 (d, J: 8 Hz, 1H), 7.31 (t, J: 8 Hz, 1H), 7.52 (t, J: 8 Hz, 2H).

Example 249 O N OH o@000"O x4 197D G OOWWo To a mixture of Compound 197D (130 mg, 0.5 mmol) and intermediate G (148 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The on mixture was stirred at room temperature ght. The resulting solution was washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was d with reverse phase chromatography using e1uent (methanol in water, from 10% to 50% V/V) to furnish Compound 249. LC-MS (ESI) m/z: 553 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) .68 (m, 2H), 0.81-0.82 (m, 2H), 1.63-1.69 (m, 4H), 2.468 (m, 2H), 2.56-2.63 (m, 4H), 3.91-3.92 (m, 1H), 4.21-4.25 (m, 1H), 4.80 (s, 1H), 5.69 (s, 1H), 7.11-7.13 (m, 2H), 7.27-7.54 (m, 9H), 8.64-8.66 (d, J: 8.6 Hz, 1H).

Example 250 F F BrU02 CN O 2\O O OH 250A 2503 250C FVOHo O o\ F o o\ F 0 OH _. 0\.\.IO ﬂ 0 0 250D 250E 250F A e of Compound 250A (5.0 g, 27 mmol), 4-ﬂuorophenylboronic acid (4.92 g, 35.13 mmol), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.19 g, 1.62 mmol), potassium carbonate (11.2 g, 81.07 mmol), water (38 mL) and 1,4-dioxane (38 mL) was stirred under nitrogen atmosphere at 120 0C for 6 h. After cooling, water (20 mL) was added, and the e was ted with ethyl acetate (100 mL x 3). The combined organic layers were washed until neutral and dried over anhydrous sodium sulfate. After removal of the t in vacuo, the crude product was purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 5% to 10% V/V) to furnish Compound 250B.

To a solution of Compound 250B (3.0 g, 14.98 mmol) in water (40 mL) was added sodium metabisulfite (2.85 g, 14.98 mmol). The reaction mixture was stirred at room temperature for 1 h. After that, NaCN (1.47 g, 29.97 mmol) was added careﬁllly. The mixture was stirred for 12 h and treated with ethyl acetate (100 mL). The resulting biphasic mixture was transferred to a separatory funnel. The layers were ted and the organic phase was washed with water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 20% to 40% V/V)) to furnish Compound 250C.

] To a on of Compound 250C (2.5 g, 11 mmol) in methanol (25 mL) at 0 0C was bubbled a gentle stream of HCl (gas) (dried over con. H2S04) for 6 h. The reaction mixture was diluted with water (20 mL) and stirred at room temperature for 2 h. An aqueous WO 42397 solution ofNaOH (2 M) was added dropwise into the reaction mixture until the pH was adjusted to 7. The mixture was extracted with dichloromethane (50 mL x 3) and washed with water (50 mL) and brine (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, ﬁltered, and concentrated to give the crude product. The crude compound was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 15% to 20% V/V) to furnish Compound 250D.

To a solution of Compound 250D (2.3 g, 8.84 mmol) in dichloromethane (30 mL) was added l,2-benziodoxol-3(1H)-one (2.41 g, 9.72 mmol) at 0 0C. The mixture was stirred at this temperature for 4 h. After that, the reaction solution was quenched with saturated ammonium de solution (10 mL) and ted with ethyl acetate (30 mL x 3).

The organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to ﬁamish the crude product. The crude oil was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 5% to 10% V/V) to ﬁamish Compound 250E.

To a solution of Compound 250E (1.80 g, 6.97 mmol) in THF (20 mL) was added LiOH’HzO (335 mg, 7.98 mmol) in water (14 mL) at 0 0C. The e was stirred at room temperature for 1 h. The reaction mixture was treated with ice water (10 mL) and extracted with ethyl acetate (50 mL). The water layer was adjusted to pH 2 with diluted HCl and extracted with ethyl acetate (50 mL x 2). The combined c layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting solid was washed with petroleum ether and ﬁltered off to afford Compound 250F.

A e of nd 250F (110 mg, 0.45 mmol), Intermediate C (146 mg, 0.49 mmol), and HATU (205 mg, 0.54 mmol) in dichloromethane (3 mL) and DMF (3 mL) was stirred at 0 0C for 4 h. The mixture was concentrated in vacuo and the resulting residue was d with prep-HPLC to furnish the crude product as a white solid. The crude solid was further puriﬁed with prep-TLC on silica gel (ethyl acetate in petroleum ether, 30% V/V) to furnish nd 250. LC-MS (ESI) m/z: 523 [M+H]+; 1H-NMR (CDC13, 400 MHz): 5 (ppm) 1.82-1.85 (m, 4H), 2.72-2.78 (m, 4H), .03 (m, 2H), 4.23-4.31 (m, 5H), 5.05 (d, J = 2.1, 1H), 6.70 (s, 1H), 6.74 (dd, J: 11.3, 1.9 Hz, 1H), 7.15 (t, J: 8.7 Hz, 3H), 7.42-7.59 (m, 3H), 7.79 (d, J: 8.3, 1H), 8.20 (d, J: 6.7, 1H), 8.44 (s, 1H). Chiral separation condition: n-hexane (0.1% DEA) * 4.6 : EtOH (0.1% DEA) = 30 : 60, : OD-H (250 mm 5 um), retention time: 4.09 min.

Example 251 A mixture of Compound 250F (130 mg, 0.53 mmol), Intermediate G (182 mg, 0.58 mmol), and HATU (304 mg, 0.79 mmol) in dichloromethane (3 mL) and DMF (3 mL) was stirred at 0 0C for 4 h. The mixture was concentrated in vacuo and puriﬁed with prep- HPLC to mmish the crude product as a yellow solid. The crude solid was ﬁthher puriﬁed with LC on silica gel (ethyl acetate in petroleum ether, 30% V/V) to furnish nd 251. LC-MS (ESI) m/z: 537 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) 0.71 (dd, J: .7, 4.5 Hz, 4H), 1.89 (s, 1H), 2.08 (s, 4H), 3.12 (s, 2H), 3.48-3.71 (m, 2H), 3.83-3.94 (m, 3H), 4.55 (s, 1H), 5.07 (s, 1H), 7.08-7.12 (m, 2H), 7.15-7.23 (m, 2H), 7.35 (d, J: 1.8 Hz, 1H), 7.38-7.49 (m, 3H), 7.71 (d, J: 7.9 Hz, 1H), 7.81 (d, J: 7.8 Hz, 1H), 7.94 (d, J: 9.6 Hz, 1H), 8.12 (s, 1H).

Example 252 Nd o {Dmoo .0 _> .0 o 252C 252 0] To a mixture of Compound 252A (1.8 g, 0.01 mol) and ylamine (3 g, 0.03 mol) in dichloromethane (100 mL) was added ethyl rooxoacetate (2.1 g, 0.015 mol). The mixture was stirred at room temperature for about 2 h until it was complete by thin layer chromatography analysis. The resulting mixture was washed with brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 50% V/V) to furnish Compound 252B.

To a solution of Compound 252B (2.8 g, 0.01 mol) in ethanol/water (40 mL/lO mL) was added LiOH'HgO (840 mg, 0.02 mol). The mixture was stirred at room temperature for about 2 h until it was complete by thin layer chromatography analysis. The on mixture was acidiﬁed to pH 2 with aqueous HCl on (1 .0 N, 40 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, d, and trated to afford Compound 252C.

To a mixture of nd 252C (126 mg, 0.5 mmol) and Intermediate A (139 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solution was washed with brine (30 mL), dried over anhydrous sodium e, ﬁltered, and concentrated. The residue was puriﬁed with reverse phase chromatography using eluent nol in water, from 10% to 55% v/v) to furnish Compound 252. LC-MS (ESI) m/z: 5 l3 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 1.83-1.84 (m, 4H), 2.68-2.72 (m, 5H), 2.88-2.94 (m, 2H), 3.03-3.06 (m, 2H), 3.09-3.14 (m, 1H), 3.33-3.37 (m, 2H), 3.58-.366 (m, 1H), 3.75-3.81 (m, 1H), 4.20-4.21 (m, 4H), 4.37-4.39 (m, 1H), 4.84-4.85 (m, 1H), 6.79-6.81 (m, 1H), 6.86-6.88 (m, 1H), 6.96 (s, 1H), 7.01-7.04 (m, 4H); Example 253 N 9H 0 a o N ; O 9" o moﬁ + = —» O O moﬁ O C' F O 1330 I C' F 253 3] A mixture of Compound 133D (146 mg, 0.60 mmol), EDCI (193 mg, 0.90 mmol), HOBt (l 19 mg, 0.9 mmol) and Intermediate I (178 mg, 0.60 mmol) in DCM (20 mL) was stirred at room temperature overnight. The reaction mixture was treated with water (50 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 253. LC-MS (ESI) m/z: 523.1 [M+H]+, 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.71-0.84 (m, 4H), 2.45-2.66 (m, 2H), .67 (m, 2H), 3.84-3.86 (m, 1H), 4.21-4.36 (m, 5H), 4.55-4.57 (m, 1H), 4.98 (d, J: 2.4 Hz, 1H), 7.21-7.28 (m, 2H), 7.35-7.40 (m, 2H), 7.52 (s, 1H), 7.64-7.67 (m, 4H), 7.73-7.77 (m, 2H). -30l- Example 254 O O ‘ o (\NHOH o N ?H _ o 1 \2 o o + mo]2 (\NHim O F 252C c F FONd 254 To a mixture of Compound 252C (126 mg, 0.5 mmol) and Intermediate C (150 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was stirred at room temperature ght. The resulting solution was washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and trated. The resulting residue was puriﬁed with reverse phase chromatography using eluent (methanol in water, from 10% to 55% V/V) to h Compound 254. LC-MS (ESI) m/z: 531 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) .01 (m, 4H), 2.87-3.84 (m, 14H), 4.27 (s, 4H), 4.40- 4.43 (m, 1H), 4.47 (s, 1H), 6.73 (s, 1H), 6.80-6.81 (m, 1H), 6.83-6.85 (m, 2H), 7.06-7.18 (m, 2H), 8.68 (d, J: 9.6 Hz, 1H), 9.83 (brs, lH).

Example 255 O O\/ WOV~ 0 0 Br 0 255A 2553 2550 255 A mixture of Compound 255A (0.72 g, 2.8 mmol), K3P04 (1.78 g, 8.4 mmol), (4-(tert-butyl)phenyl)boronic acid (0.5 g, 2.8 mmol), and Pd(dppf)Clz (20 mg, 0.28 mmol) in e (10 mL) was stirred under nitrogen at 100 0C for 16 h. The mixture was cooled to 25 0C, diluted with ethyl acetate (50 mL), washed with water (20 mL x 2) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% V/V) to afford Compound 255B.

A e of nd 255B (0.45 g, 1.5 mmol) and LiOH-HZO (0.09 g, 2.2 mmol) in THF (5 mL) and water (2 mL) was stirred at 0 0C for 2 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with reverse phase chromatography using eluent (methanol in water, from 0% to 100% V/V) to afford nd 255C.

A mixture of Compound 255C (0.1 g, 0.35 mmol), HATU (0.2 g, 0.5 mmol), and Intermediate G in dichloromethane (5 mL) was stirred at 25 0C for 16 h. The mixture was diluted with ethyl e (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC to furnish Compound 255. LC-MS (ESI) m/z: 575 [M+H]+; 1H-NMR d6, 400 MHz): 5 (ppm) 0.67-0.68 (m, 2H), 0.82-0.83 (m, 2H), 1.33 (s, 9H), 1.88-1.90 (m, 2H), 2.04 (s, 2H), 3.13- 3.23 (m, 2H), 3.48-3.56 (m, 4H), 3.93 (s, 1H), 4.54-4.59 (m, 1H), 4.88 (s, 1H), 6.05 (s, 1H), 7.36-7.44 (m, 3H), 7.53-7.56 (m, 2H), 7.68-7.77 (m, 6H), .81 (m, 1H), 9.36 (s, 1H).

Example 256 To 6-bromoindazole (3.2 g, 16.2 mmol) in DMF (30 mL) was added sodium hydride (60% in mineral, 712 mg, 17.8 mmol) with ice bath cooling. The mixture was stirred at room temperature for 30 min. Compound 2-iodopropane (8.3 g 48.6 mmol) was added at room temperature. The reaction mixture was stirred at room ature for 1 h, quenched with saturated aqueous ammonium chloride solution (30 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. Puriﬁcation with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, from 0% to 1% v/v) gave Compound 256A and Compound 256B.

A e of Compound 256A (1.0 g, 4.2 mmol), Compound 175B (1.28 g, 4.2 mmol), Pd(dppf)C12 (171 mg, 0.21 mmol), and K2C03 (1.74 g, 12.6 mmol) in dioxane (20 mL) and water (20 mL) was stirred under nitrogen at 100 0C for 3.5 h. The reaction mixture was cooled to room temperature and ﬁltered through celite. The ﬁltrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The aqueous layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 256C.

A mixture of Compound 256C (100 mg, 0.32 mmol), HATU (182 mg, 0.48 mmol), and Intermediate G (99 mg, 0.32 mmol) in DMF (5 mL) was stirred for 18 h at 10 0C.

The mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to furnish Compound 256. LC-MS (ESI) m/z: 601 [M+H]+; 1H- NMR dg, 400 MHz): 5 (ppm) 0.63-0.85 (m, 4H), 1.52 (dd, J: 6.4, 1.6 Hz, 6H), 1.89-2.05 (m, 4H), 3.13-3.25 (m, 2H), 3.41-3.58 (m, 4H), .98 (m, 1H), 4.57-4.62 (m, 1H), 4.91 (s, 1H), .18 (m, 1H), 6.10 (s, 1H), 7.37 (dd, J: 8.4, 1.6 Hz, 1H), 7.43-7.48 (m, 2H), 7.52 (dd, J: 8.4, 1.2 Hz, 1H), 7.78 (d, J: 8.4 Hz, 2H), 7.89 (d, J: 8.8 Hz, 3H), 8.09 (s, 1H), 8.14 (s, 1H), 8.84 (d, J: 9.6 Hz, 1H), 9.59 (brs, 1H).

Example 257 BrnewN W"o 4 cs }' 2563 175B A mixture of nd 175B (500 mg, 2.1 mmol), Compound 256B (638 mg, 2.1 mmol), f)C12 (92 mg, 0.11 mmol), and K2C03 (869 mg, 6.3 mmol) in dioxane —304_ (10 mL) and water (10 mL) was stirred under nitrogen at 100 0C for 3.5 h. The reaction e was cooled to room temperature and ﬁltered through celite. The ﬁltrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The s layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 257A.

A mixture of nd 257A (100 mg, 0.32 mmol), HATU (182 mg, 0.48 mmol), and Intermediate G (99 mg, 0.32 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h.

The mixture was d with ethyl e (50 mL), washed with water (50 mL x 2) and brine (50 mL), and dried over anhydrous sodium sulfate. After evaporation, the crude product was puriﬁed with prep-HPLC to furnish Compound 257. LC-MS (ESI) m/z: 601 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.68-0.84 (m, 4H), 1.58 (d, J: 6.4 Hz, 6H), 1.89-2.04 (m, 4H), 3.09-3.22 (m, 2H), 3.43-3.58 (m, 4H), 3.93-3.97 (m, 1H), 4.56-4.61 (m, 1H), 4.84- 4.92 (m, 2H), 6.08-609 (m, 1H), 7.35-7.38 (m, 1H), 7.41-7.46 (m, 3H), 7.75-7.77 (m, 2H), 7.82-7.85 (m, 3H), 8.01 (s, 1H), 8.48 (s, 1H), 8.83 (d, J: 10.0 Hz, 1H), 9.65 (brs, 1H).

Example 258 K 258 3] To a solution of 5-bromo-1H-indazole (5.91 g, 30 mmol) in anhydrous DMF (100 mL) was added 2-bromopropane (8.67 g, 70.5 mmol) and cesium carbonate (29.2 g, 90 mmol) at room temperature. After stirring the reaction mixture at room temperature for 3 h, 2 N hloric acid was added until a neutral pH was reached. The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic ts were washed with brine (100 mL x 2) and dried over anhydrous sodium sulfate. After ﬁltration, the solvent was removed in vacuo and the residue was purified with ﬂash column chromatography on silica gel to give Compound 258A and Compound 258B.

To a solution of Compound 258A (180 mg, 0.75 mmol) in 1,4-dioxane (15 mL) was added Compound 175B (250 mg, 0.825 mmol), Pd(dppf)Clz (30 mg, 0.0375 mmol), potassium carbonate (310 mg, 2.25 mmol) and water (1 mL) under nitrogen. The reaction mixture was d at 100 0C for 2 hours. The resulting mixture was cooled to 25 0C. The precipitated solid was filtered and dried to afford Compound 258C.

] To a solution of Compound 258C (45 mg, 0.146 mmol) in DMF (3 mL) was added Intermediate G (45 mg, 0.146 mmol) and HATU (83 mg, 0.219 mmol). The reaction e was d at 20 0C for 10 h. The mixture was purified with prep-HPLC to yield the product Compound 258. LC-MS (m/z) 601 [M+H]+; 1H-NMR ne-d6, 400 MHz): 5 (ppm) 0.71-0.72 (m, 2H), 0.82-0.84 (m, 2H), 1.57 (s, 3H), 1.58 (s, 3H), 2.05-2.25 (m, 4H), 3.45-3.60 (m, 2H), 3.82-4.15 (m, 5H), 4.92-4.97 (m, 1H), 5.02-5.09 (m, 1H), 5.20-5.21 (m, 1H), 5.47-5.50 (m, 1H), 7.42-7.44 (m, 2H), 7.51-7.52 (m, 1H), 7.79-7.83 (m, 4H), 7.97-7.99 (m, 2H), 8.12-8.16 (m, 2H), 8.19-8.21 (m, 1H), 8.94 (brs, 1H).

Example 259 To a solution of Compound 258B (180 mg, 0.75 mmol) in 1,4-dioxane (15 mL) was added Compound 175B (250 mg, 0.825 mmol), Pd(dppf)Clz (30 mg, 0.0375 mmol), potassium carbonate (310 mg, 2.25 mmol) and water (1 mL) under nitrogen. The reaction mixture was stirred at 100 0C for 2 hours. The ing e was cooled to 25 0C. The itated solid was ﬁltered and dried to afford Compound 259A.

To a solution of Compound 259A (74 mg, 0.24 mmol) in DMF (3 mL) was added Intermediate G (74 mg, 0.24 mmol) and HATU (136 mg, 0.36 mmol). The reaction mixture was stirred at 20 0C for 10 h. The e was puriﬁed with prep-HPLC to yield the product Compound 259. LC-MS (m/z) 601 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 0.70-0.72 (m, 2H), 0.79-0.84 (m, 2H), 1.68 (s, 3H), 1.70 (s, 3H), 2.05-2.13 (m, 2H), 2.26-2.28 (m, 2H), 3.43-3.56 (m, 2H), .91 (m, 3H), 4.06-4.09 (m, 2H), 4.93-5.01 (m, 2H), 5.20-5.21 (m, 1H), 7.39-7.46 (m, 2H), 7.51-7.52 (m, 1H), 7.75-7.82 (m, 4H), 7.97-7.99 (m, 2H), 8.16-8.21 (m, 2H), 8.58-8.59 (m, 1H), 8.82 (brs, 1H). e 260 N QH F F ( > o N OH .

N OH - / 0 + 5 —» |N\ WA NH2 o/A / 0 CI F CI F 247E G 260 To a mixture of Compound 247E (100 mg, 0.3 mmol) in THF (10 mL) and DMF (2 mL) was added EDCI (106 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol) and Intermediate G (115 mg, 0.37 mmol). The mixture was stirred at 25 0C for 15 hours. It was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude compound. The crude product was puriﬁed with prep-HPLC to afford Compound 260. LC-MS (ESI) m/z: 538 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.61-0.75 (m, 4H), 2.06-2.20 (m, 4H), 3.22-3.28 (m, 2H), 3.56-3.80 (m, 5H), 4.61-4.64 (m, 1H), 4.94 (s, 1H), 7.21-7.31 (m, 4H), 7.41 (d, J: 1.6 Hz, 1H), 7.72 (d, J: 8.0 Hz, 1H), 7.77-7.80 (m, 2H), 8.19 (dd, J: 8.0, 2.0 Hz, 1H), 8.82 (s, 1H). 2014/056555 Example 261 o o o Br\©* ‘/OH o o —> —>BFWO\—> O \ o o 3(3)"0 261A 2613 261C 2610 ::N OH A suspension of Compound 261A (6.00 g, 30.15 mmol) and SeOz (5.02 g, 45.22 mmol) in pyridine (50 mL) was stirred at 100 0C for 16 h. It was ﬁltered to remove the resultant solid and the ﬁltrate was evaporated to remove pyridine. The residue was dissolved in aqueous NaOH solution (5% w/w, 200 mL) and extracted with diethyl ether (100 mL x 2).

The aqueous was adjusted to pH 1 with con. HCl to form a solid, which was ﬁltered and dried to afford Compound 261B.

A e of Compound 261B (3.00 g, 13.22 mmol) and concentrated H2S04 (1 mL) in methanol (50 mL) was stirred at 80 0C for 16. After evaporation, the residue was diluted with ethyl acetate (200 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to furnish Compound 261C.

A mixture of Compound 261C (1.58 g, 6.53 mmol), ,4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.82 g, 7.18 mmol), KOAc (1.92 g, 19.59 mmol), and PdC12(PPh3)2 (229 mg, 0.33 mmol) in dioxane (50 mL) was stirred under nitrogen at 90 0C for 16 h. It was d with ethyl acetate (150 mL), washed with water (200 mL) and brine (200 mL), dried over ous sodium sulfate, and ated to afford Compound 261D.

A mixture of Compound 261D (500 mg, 1.72 mmol), 6-bromomethyl-1H- indazole (364 mg, 1.72 mmol), K2C03 (475 mg, 3.44 mmol), and Pd(dppf)C12 (70 mg, 0.09 mmol) in dioxane (10 mL) and water (2 mL) was stirred under nitrogen at 85 0C for 16 h. The mixture was cooled down to room temperature and puriﬁed with reverse phase chromatography using eluent (methanol in water, from 0% to 100% v/v) to give Compound 261E.

A mixture of Compound 261E (100 mg, 0.36 mmol), Intermediate G (111 mg, 0.36 mmol), and HATU (207 mg, 0.54 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. It was diluted with ethyl acetate (120 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, trated, and puriﬁed with prep-HPLC to yield nd 261. LC-MS (ESI) m/z: 573 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.63-0.78 (m, 4H), 1.87-2.03 (m, 4H), 3.15 (brs, 2H), 3.49-3.84 (m, 4H), 4.12 (s, 4H), 4.54 (s, 1H), 4.86 (s, 1H), 6.09 (s, 1H), 7.34-7.68 (m, 6H), 7.86-8.31 (m, 5H), 8.81 (s, 1H), 9.42 (s, 1H).

Example 262 Nd + o EH42 0A—’ PO Nd 0 CI CI F0 252C G 262 To a mixture of Compound 252C (126 mg, 0.5 mmol) and Intermediate G (160 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with dichloromethane (50 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The resulting residue was puriﬁed with reverse phase chromatography using eluent (methanol in water, from 10% to 55% V/V) to furnish nd 262. LC-MS (ESI) m/z: 545 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.64-0.65 (m, 2H), .82 (m, 2H), 1.86-2.01 (m, 4H), 2.80-3.65 (m, 14H), 3.91-3.93 (m, 1H), 4.47-4.48 (m, 1H), 4.87-4.88 (m, 1H), 6.04 (br s, 1H), 6.94-6.96 (m, 2H), 7.13-7.18 (m, 2H), .84 (m, 3H), 8.69 (d, J: 9.6 Hz, 1H), 10.10 (hrs, 1H).

Example 263 0 o 0%Br W+ 0‘3 o —» Q o S 1 Cl / s lg 263A 1753 263B O CI 2014/056555 A mixture of Compound 263A (492 mg, 2 mmol), Compound 175B (669 mg, 2.2 mmol), K2C03 (828 mg, 6 mmol), and Pd(dppf)C12 (50 mg, 0.07 mmol) in dioxane (20 mL) and water (4 mL) was d under nitrogen at 100 0C overnight. The solution was cooled to room temperature and adjusted to pH 6 with aqueous hydrochloric acid solution (6 N, 1 mL). The solution was extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and evaporated to afford Compound 263B. 6] A mixture of Compound 263B (156 mg, 0.5 mmol), HATU (342 mg, 0.9 mmol), and Intermediate G (155 mg, 0.5 mmol) in romethane (10 mL) and DMF (4 mL) was stirred at 25 0C overnight. The solution was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The crude product was purified with prep-HPLC to afford Compound 263. LC-MS (ESI) m/z: 609 [M+H]+; 1H-NMR ), 400 MHz): 5 (ppm) 0.66-0.85 (m, 4H), 2.05-2.25 (m, 4H), 3.42- 3.90 (m, 7H), 4.71-4.74 (m, 1H), 5.00 (s, 1H), 7.38-7.39 (m, 2H), 7.42 (s, 1H), .52 (m, 1H), 7.73-7.76 (m, 5H), 7.93-7.95 (m, 1H), 8.08-8.09 (m, 1H).

Example 264 O O N\ o\/ N\ OH | | O ’ O ' / / 264A To a solution of Compound 247C (500 mg, 1.82 mmol) in methanol/water (10 mL, 1:1, v/v) was added LiOH'HzO (153 mg, 3.64 mmol). The reaction mixture was stirred at 0C for 18 h. After the on was completed, it was adjusted to pH 6 with aqueous HCl solution (3 N) and concentrated in vacuo to give a crude compound. The crude product was lyophilized to ﬁlmish Compound 264A.

To a mixture of Compound 264A (90 mg, 0.37 mmol) in dichloromethane (5 mL) was added HATU (213 mg, 0.55 mmol) and Intermediate G (115 mg, 0.37 mmol). The mixture was stirred at 15 0C for 18 h. It was treated with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude compound. The crude product was puriﬁed with prep-HPLC to afford Compound 264. LC-MS (ESI) m/z: 538 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.65-0.84 (m, 4H), 1.87-2.08 (m, 4H), .26 (m, 3H), .72 (m, 3H), 3.91-3.95 (m, 1H), 4.50-4.55 (m, 1H), 4.88 (d, J: 2.8 Hz, 1H), 6.09 (brs, 1H), 7.36-7.49 (m, 5H), 7.91-7.94 (m, 2H), 8.06 (d, J: 8.4 Hz, 1H), 8.33 (dd, J: 8.0, 2.0 Hz, 1H), 8.99 (d, J: 2.0 Hz, 1H), 9.13 (d, J: 9.2 Hz, 1H), 9.53 (brs, 1H).

Example 265 Br CF3 Br CF3 CF3 TBDMSO A ; CszN A OH 0 0 265A 2653 265C OH OH OH CF3 CF3 TBDMSO 5 CszN 0A CszN 0A 265D 265E OMS OH N OH N OH CF3 CF3 CF3 2 A—» a A_. 5 CszN CszN NH2 A o o o 265F 2656 265H To a solution of nd 265A (11.6 g, 48 mmol) in 1-methyl pyrrolidinone (150 mL) was added cesium carbonate (33 g, 87 mmol) and bromocyclopropane (16.5 mL, 1999 mmol). The mixture was d for 24 h while keeping inner temperature between 145 0C and 155 0C. After the reaction was cooled to ambient ature, the dark solution was diluted with water (400 mL) and extracted with a mixture of ethyl acetate in petroleum ether (15% V/V) (300 mL x 3). The combined organic phases were washed with brine (150 mL x 4), dried over anhydrous sodium sulfate, ﬁltered, and trated to afford the crude product as a brown oil. The crude product was puriﬁed with ﬂash column chromatography on silica gel (petroleum ether) to ﬁlrnish Compound 2653.

To a solution of Compound 265B (6.79 g, 8.1 mmol) in dry THF (200 mL) maintained at -70 0C was added n-BuLi (2.5 M in hexane, 9.76 mL) dropwise under nitrogen atmosphere over a period of 20 minutes. After the on was stirred at -70 0C for 40 minutes, Intermediate A4 (3.2 g, 8.1 mmol) dissolved in dry THF (20 mL) was added slowly to the cold solution at a rate that maintained the internal temperature between -70 0C and -50 0C. After the addition was complete, the solution was left to stir for l h. The reaction was quenched with saturated um chloride solution (400 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish the crude Compound 265C. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 5% to 10% v/v) to furnish Compound 265C. a on of Compound 265C (5.95 g, 110 mmol) in dry THF (70 mL) was added L-Selectride (l .0 M in THF, 23.7 mL) dropwise under nitrogen atmosphere while keeping the temperature at -90 0C. After the addition was complete, the solution was allowed to stir at this temperature for l h. The reaction was quenched with saturated um de solution (50 mL), ted with ethyl e (100 mL x 2), washed with water (100 mL) and brine (100 mL), dried over ous sodium sulfate, ﬁltered, and concentrated to furnish a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give nd 265D.

To a solution of Compound 265D (5.4 g, 10 mmol) in THF (100 mL) was added tetrabutylammonium ﬂuoride (1 .31 g, 5.0 mmol) at 0 0C. The mixture was stirred at room temperature for 12 h. After that, the reaction e was evaporated to remove tetrahydrofuran. The mixture was treated with water (50 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with water (150 mL) and brine (150 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to ﬁamish Compound 265E.

To a solution of Compound 265E (1.18 g, 2.78 mmol) dissolved in THF (50 mL) was added triethylamine (866 mg, 8.5 mmol). The e was cooled to -30 0C, and then methanesulfonyl chloride (389 mg, 3.41 mmol) was added dropwise over a period of 15 minutes. After the on was complete, the reaction was stirred at -30 0C for 1.5 h, diluted -3l2- WO 42397 with water (50 mL), and extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, ﬁltered, and trated to ﬁamish Compound 265F.

To a solution of Compound 265F (1.0 g, 1.98 mmol) in THF (30 mL) was added pyrrolidine (2.3 g, 32 mmol). The reaction mixture was d to heat to 50 0C for 16 h. The mixture was diluted with water (100 mL), extracted with ethyl acetate (150 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and trated to furnish a crude compound. The crude product was d with ﬂash column chromatography on silica gel (methanol in dichloromethane, 5% v/v) to give Compound 265(1 To a solution of Compound 265G (100 mg, 0.21 mmol) in ethanol (8 mL) and water (2 mL) was added LiOH‘HZO (56 mg, 1.33 mmol). The mixture was heated to 80 0C and stirred for 16 h. And then it was diluted with water (15 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish Compound 265H.

A mixture of Compound 265H (100 mg, (0.21 mmol), HATU (95 mg, 0.25 mmol), and Intermediate C (40.8 mg, 0.17 mmol) in DCM (15 mL) was stirred at room temperature overnight. The reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and trated. The crude product was puriﬁed with prep-HPLC to give Compound 265. LC- MS (ESI) m/z: 571.2 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.66-0.82 (m, 4H), 2.04-2.23 (m, 4H), 3.23-3.26 (m, 1H), 3.60-3.89 (m, 6H), 4.72-4.76 (m, 1H), 5.06 (d, J: 2.4 Hz, 1H), 7.22-7.26 (m, 2H), 7.47 (d, J: 8.8 Hz, 1H), 7.65 (s, 1H), 7.67-7.77 (m, 8 H).

Example 266 cried)Br Br 00 N /0 1 N A 3 266A 266C O o 0 CI K 266 To a on of Compound 266A (1.96 g, 10 mmol) in DMF (50 mL) was added sodium hydride (60% suspend in oil, 800 mg, 20 mmol) at 0 0C. The mixture was stirred at 0 0C for 0.5 h and 2-iodopropane (2.55 g, 15 mmol) was added at 0 0C. The ant e was stirred at room temperature overnight, d with ethyl acetate (100 mL), washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 266B.

A mixture of Compound 266B (500 mg, 2.1 mmol), Pd(dppf)C12 (86 mg, 0.1 mmol), 175B (638 mg, 2.1 mmol), and K2C03 (668 mg, 6.3 mmol) in dioxane (15 mL) and water (2 mL) was stirred under nitrogen at 100 0C overnight. The mixture was cooled down to room temperature, concentrated, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The aqueous layer was acidiﬁed to pH 2 with aqueous HCl solution (1 N) and extracted with dichloromethane (10 mL x 3). The dichloromethane layer was dried over anhydrous sodium sulfate and ﬁltered to afford Compound ichloromethane solution. A solution of Compound 266C in dichloromethane was directly used for the next step without further puriﬁcation.

To a solution of Compound 266C in romethane (15 mL, from previous step) was added Intermediate G (155 mg, 0.5 mmol) and HATU (380 mg, 1 mmol). The mixture was d at room temperature overnight. The mixture was puriﬁed with prep- —314— WO 42397 HPLC to ﬁlmish Compound 266. LC-MS (ESI) m/z: 600 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.67-0.71 (m, 2H), 0.81-0.86 (m, 2H), 1.48 (d, J: 6.4 Hz, 6H), 1.88-1.92 (m, 2H), 2.03-2.08 (m, 2H), 3.13-3.24 (m, 2H), 3.43-3.52 (m, 4H), .97 (m, 1H), .61 (m, 1H), 4.79-4.86 (m, 1H), 4.89-4.89 (m, 1H), 6.04 (brs, 1H), 6.56 (d, J: 3.6 Hz, 1H), 7.35- 7.37 (m, 1H), 7.42-7.46 (m, 2H), 7.52-7.55 (m, 1H), 7.59-7.59 (m, 1H), 7.66-7.68 (m, 1H), 7.72-7.74 (m, 2H), 7.78-7.80 (m, 2H), 7.69 (d, J: 1.6 Hz, 1H), 8.79 (d, J: 9.2 Hz, 1H), 9.34 (brs, 1H).

Example 267 —> O _> Br 0 175A 267A Cl 267B C Cl 267 To a mixture of Compound 175A (2.56 g, 0.01 mol), 4-chlorophenylboronic acid (2 g, 1.32 mol), and K3P04 (6.4 g, 0.03 mol) in toluene (80 mL) was added Pd(PPh3)4 (1.156 g, 0.001 mol). The reaction mixture was stirred under en at 100 0C overnight.

The resulting mixture was cooled down to room temperature, washed with brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 50% V/V) to furnish nd 267A.

To a solution of nd 267A (2.9 g, 0.01 mol) in ethanol/water (40 mL/10 mL) was added LiOH'HzO (840 mg, 0.02 mol). The mixture was stirred at room temperature for about 2 h until completion by thin layer chromatography analysis. The reaction mixture was acidiﬁed to pH 2 with aqueous HCl solution (1.0 N, 40 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford Compound 267B.

To a mixture of Compound 267B (130 mg, 0.5 mmol) and Intermediate A (139 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solution was washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with reverse phase tography using eluent (methanol in water, from 10% to 55% v/v) to furnish Compound 267. LC-MS (ESI) m/z: 521 [M+H]+; lH-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.66-1.74 (m, 4H), .70 (m, 6H), 4.21-4.22 (m, 5H), 4.75 (s, 1H), .57 (s, 1H), 6.82 (s, 2H), 6.87 (s, 1H), 7.58-7.60 (m, 2H), 7.78-7.83 (m, 6H), 8.61 (d, J: 9.6 Hz, 1H).

Example 268 F F o F OH F CEO)4BUG)wvﬁrj J—JBSOWO]Cb HN o z CszN o o 0 0 268A 2683 268C 268D OH OH F OMsOH F (N) OH F o o 4 Vii)4 Vii)4 ~ CszN CszN 0 0 Cszlfl O] 268E 268F 2686 N QH F N OH F ""601NH NH2 j o O 268H F 268 To a solution of Compound 268A (3.35 g, 21.73 mmol) in methanol (10 mL) was added se bromine (1.34 mL, 26.10 mmol) at -10 0C. The mixture was stirred room ature for 5 h. It was quenched with saturated aqueous Na2S203 solution (100 mL) and ﬁltered to remove the resultant solid. The ﬁltrate was evaporated and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 3% v/v) to afford nd 268B.

To a solution of nd 268B (12.00 g, 51.72 mmol) in THF (30 mL) was added dropwise n-BuLi (2.4 M in hexane, 22 mL, 51.72 mmol) under nitrogen at -78 0C. The mixture was stirred at -78 0C for 30 min. A solution of Intermediate A4 (6.77 g, 17.11 mmol) in THF (20 mL) was added dropwise under nitrogen at -78 0C. The e was stirred at -78 0C for 20 min and quenched with ted aqueous ammonium chloride solution (100 mL).

The mixture was diluted with ethyl acetate (300 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to ﬁnnmh(knnpound268C.

To a solution of Compound 268C (7.20 g, 14.72 mmol) in THF (200 mL) was added dropwise L-Selectride (1 M in THF, 29 mL, 29.00 mmol) under nitrogen at -90 0C. The mixture was stirred at -90 0C for 1 h and quenched with saturated aqueous ammonium chloride solution (100 mL). It was d with ethyl acetate (300 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, from 0% to 20% v/v) to afford Compound 268D.

A mixture of Compound 268D (2.00 g, 4.07 mmol) and Bu4NF (641 mg, 2.04 mmol) in THF (20 mL) was stirred at 20 0C for 16 h. It was diluted with ethyl acetate (200 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium e, and puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, from 0% to 5% v/v) to give Compound 268E. 7] To a solution of nd 268E (1.70 g, 4.50 mmol) and triethylamine (909 mg, 9.00 mmol) in THF (20 mL) was added dropwise methanesulfonyl chloride (565 mg, 4.96 mmol) at -15 0C. The mixture was stirred at -15 0C for 1 h. It was quenched with saturated ice water (50 mL), diluted with ethyl acetate (200 mL), washed with water (150 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 80% v/v) to afford Compound 268F.

A solution of Compound 268F (1.50 g, 3.30 mmol) and pyrrolidine (2.34 g, 32.92 mmol) in THF (10 mL) was d at 50 0C for 16 h. It was diluted with ethyl acetate (200 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and puriﬁed with reverse phase chromatography using eluent nol in water, from 0% to 100% v/v) to furnish Compound 268G.

A e of Compound 268G (900 mg, 2.09 mmol) and Pd(OH)2/C (20%, 500 mg) in methanol (10 mL) was stirred under en at 20 0C for 16 h. It was ﬁltered to remove Pd(OH)2/C and the ﬁltrate was evaporated to give Compound 268H. 00] A mixture of Compound 268H (100 mg, 0.34 mmol), Compound 133D (82 mg, 0.34 mmol), and HATU (194 mg, 0.51 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. It was diluted with ethyl acetate (120 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to yield Compound 268. LC-MS (ESI) m/z: 523 [M+H]+; lH-NMR (DMSO-d6, 400 MHz): (5 (ppm) 1.82-2.03 (m, 4H), 3.08-3.19 (m, 2H), 3.47-3.60 (m, 4H), 4.17—4.30 (m, 4H), 4.4-4.54 (m, 1H), 4.80 (d, .1: 8.0 Hz, 1H), 6.10 (s, 1H), 6.75 (d, .1: 7.6 Hz, 1H), 6.92 (t, .1: 8.0 Hz, 1H), 7.37 (t, .1: 8.8 Hz, 2H), 7.79—7.90 (m, 6H), 9.01 (d, .1: 8.8 Hz, 1H), 9.41 (s, 1H).

Example 269 W0" 9 o O + "$0 / O N NHZ N A O F K 266C 0 269 To a on of Compound 266C in dichloromethane (15 mL, from previous step) was added Intermediate C (150 mg, 0.5 mmol) and HATU (380 mg, 1 mmol). The mixture was stirred at room temperature overnight. The mixture was directly puriﬁed with prep-HPLC to afford Compound 269. LC-MS (ESI) m/z: 586 [M+H]+; 1H-NMR (DMSO-dg, 400 MHZ): 5 (ppm) 1.48 (d, J: 6.8 Hz, 6H), l.88-l.89(m, 2H), 2.03-2.03 (m, 2H), 3.12-3.20 (m, 2H), .55 (m, 4H), 4.28-4.30 (m, 4H), 4.51-4.54 (m, 1H), 4.79-4.83 (m, 2H), 6.04- 6.05 (m, 1H), 6.57-6.58 (m, 1H), 6.78 (s, 1H), 6.83-6.85 (m, 1H), 7.53-7.55 (m, 1H), 7.58- 7.59 (m, 1H), 7.65-7.67 (m, 1H), 7.83-7.89 (m, 4H), 7.96-7.97 (m, 1H), 8.73-8.76 (m, 1H), 9.36 (brs, 1H).

Example 270 0 o mox OH Q O ,1 + W" —’ 0 O 0 CI O M 0% 0 CI C, 266C G 270 To a mixture of nd 266C (130 mg, 0.5 mmol) and Intermediate G (151 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was d at room ature overnight. The resulting solution was washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was d with reverse phase chromatography using eluent (methanol in water, from 10% to 55% v/v) to furnish Compound 270. LC-MS (ESI) m/z: 553 [M+H]+; 1H-NMR (DMSO-dg, 400 MHZ): 5 (ppm) 0.66-0.83 (m, 4H), 1.88-2.04 (m, 4H), 3.15-3.20 (m, 2H), 3.49-3.56 (m, -3l8- 4H), 3.93 (s, 1H), 4.56 (s, 1H), 4.88 (s, 1H), 6.07 (s, 1H), 7.36-7.44 (m, 3H), 7.59-7.62 (m, 2H), 7.77-7.80 (m, 6H), 8.80-8.83 (d, .1: 10.0 Hz, 1H), 9.48 (s, 1H).

Example271 OZNUBr H2NUBr «DN Br F A /l\ 271A 2713 271C 271D 271E 271 To a solution of Compound 271A (6.6 g, 30 mmol) in dichloromethane (30 mL) was added propanamine (3.54 g, 60 mmol) at 0 0C. The mixture was stirred at 40 0C overnight and the mixture was dispersed between water (100 mL) and ethyl e (200 mL).

After separation, the organic phase was washed with water (10 mL x 3) and brine (10 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford the Compound 271B.

To a solution of nd 271B (2.0 g, 7.75 mmol) in ethanol (60 mL) was added stannic chloride (5.25 g, 23.3 mmol). The mixture was stirred at reﬂux for 4 h. After cooling down to room ature, s sodium ide solution (4 N, 5 mL) was added dropwise to the mixture and the resulting mixture was ﬁltered. After removal of solvent, the residue was ted with ethyl acetate (50 mL x 3), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 20% v/v) to furnish Compound 271C.

To a solution of Compound 271C (1.3 g, 5.70 mmol) in DMF (30 mL) was added triethoxymethane (4.74 mL, 28.5 mmol) and con. HCl (1 .5 mL). The mixture was stirred at 100 0C for 8 h. After g down to room temperature, the mixture was poured into water (150 mL) and adjusted to pH 8 with saturated aqueous sodium onate solution (3.5 mL). The mixture was extracted with ethyl acetate (50 mL x 3) and separated. The combined organic phases were washed with water (10 mL x 2) and brine (10 mL), dried over -3l9- WO 42397 ous sodium sulfate, ﬁltered, and concentrated. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50% v/v) to yield Compound 271D.

To a solution of Compound 271D (476 mg, 2.0 mmol) in dioxane (30 mL) and water (5 mL) was added K2C03 (828 mg, 6.0 mmol), Compound 175B (608 mg, 2.0 mmol), and Pd(dppf)C12 (146 mg, 0.2 mmol). The mixture was stirred under nitrogen at 100 0C for 2 h. After removal of solvent, the residue was dissolved in ethyl acetate (150 mL), washed with water (5 mL x 2) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to yield a crude compound. The crude product was puriﬁed with e phase tography using eluent (methanol in pure water, 50% v/v) to give Compound 271E.

To a solution of Intermediate G (121 mg, 0.39 mmol) in DMF (10 mL) was added Compound 271E (100 mg, 0.32 mmol), HATU (182 mg, 0.48 mmol), and MN- diisopropylethylamine (124 mg, 0.96 mmol). The mixture was stirred under nitrogen at 25 0C overnight. The resulting mixture was quenched with saturated s sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and trated to afford a crude compound. The crude product was puriﬁed with prep-HPLC to furnish Compound 271. LC-MS (ESI) m/z: 601 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.68-0.70 (m, 2H), 0.82-0.83 (m, 2H), 1.65 (d, J: 6.4 Hz, 6H), 1.90-1.93 (m, 2H), 2.02-2.05 (m, 2H), 3.14-3.24 (m, 2H), 3.50-3.59 (m, 4H), 3.93-3.97 (m, 1H), 4.57- 4.60 (m, 1H), 4.92 (d, J: 2.4 Hz, 1H), 5.02-5.09 (m, 1H), .46 (m, 3H), 7.81-7.88 (m, 4H), 7.92-7.95 (m, 1H), 8.16-8.19 (m, 2H), 9.54 (s, 1H), 9.84 (brs, 1H).

Example 272 0 Q 0 mo] OH : NH O ' o o o mJ—* F O 2 o 0 CI F CI 2673 C 272 To a mixture of Compound 267B (130 mg, 0.5 mmol) and Intermediate C (143 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was d at room temperature overnight. The ing solution was washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with reverse phase chromatography using eluent (methanol in water, from 10% to 55% v/v) to furnish Compound 272. LC-MS (ESI) m/z: 539 [M+H]+; 1H—NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.87-2.03 (m, 4H), 3.10-3.18 (m, 2H), 3.42—3.54 (m, 4H), 4.23-4.28 (m, 4H), 4.51 (s, 1H), 4.78 (s, 1H), 6.05 (s, 1H), 6.76 (s, 1H), 6.81 (d, .1: 11.6 Hz, 1H), 7.59 (m, 2H), 7.79-7.84 (m, 4H), 7.91-7.93(m, 2H), 8.75 (d, .1: 10.0 Hz, 1H), 9.37 (s, 1H).

Example 273 0 K C1 0 273A 2733 o O WW Wm 273C 273 09] A mixture of 4-bromoaniline (2 g, 11.7 mmol), C82C03 (11.4 g, 35.1 mmol), and l, 4-dibromobutane (3.7 g, 17.5 mmol) in DMF (40 mL) was d under nitrogen at 60 0C for 16 h. The e was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, from 0% to 10% V/V) to afford Compound 273A.

To a solution of Compound 273A (300 mg, 1.3 mmol) in dry THF (10 mL) was added n-BuLi (2.5 N in hexane, 0.6 mL, 1.5 mmol) under nitrogen at -78 0C. The resulting solution was stirred at -78 0C for 30 min and erred into a stirred solution of diethyl oxalate (0.97 g, 6.6 mmol) in dry THF (5 mL) at this temperature. The solution was d at -78 0C for l h, quenched with addition of saturated aqueous ammonium chloride solution (10 mL), poured into water (50 mL), and extracted with ethyl acetate (50 mL x 2).

The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium e, and concentrated in vacuo to give Compound 273B.

A mixture of Compound 273B (0.2 g, 0.8 mmol) and LiOH-HZO (68 mg, 1.6 mmol) in THF (5 mL) and water (2 mL) was stirred at 0 0C for 2 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over ous sodium sulfate, concentrated, and puriﬁed with reverse phase chromatography using eluent (methanol in water, from 0% to 100% v/v) to afford Compound 273C.

A mixture of Compound 273C (74 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol), and Intermediate C (100 mg, 0.3 mmol) in dichloromethane (5 mL) was stirred at 25 0C for 16 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with PLC to furnish nd 273. LC-MS (ESI) m/z: 498 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.85 (s, 2H), 1.98 (s, 6H), .17 (m, 2H), 3.41-3.53 (m, 4H), 3.98- 4.11 (m, 4H), 4.27 (m, 4H), 4.47 (s, 1H), 4.74 (s, 1H), 6.55 (d, J: 9.2 Hz, 2H), 6.72-6.81 (m, 2H), 7.75 (d, J: 8.8 Hz, 2H), 8.42 (d, J: 9.6 Hz, 1H), 9.28 (s, 1H).

Example 274 HO 0 9" O 5 WW 0 o "" A 0 CI 0 o Br O O 175A 274A F30 274 A mixture of (4-(triﬁuoromethyl)phenyl)boronic acid (500 mg, 2.63 mmol), Compound 175A (615 mg, 2.39 mmol), Pd(dppf)C12 (87.5 mg, 0.12 mmol), potassium carbonate (992 mg, 7.18 mmol), water (3 mL), and 1,4-dioxane (10 mL) was heated under en atmosphere at 90 0C for 2 h. After cooling, water (5 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed until neutralization and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 20% v/v) to furnish Compound 274A.

A mixture of Compound 274A (130 mg, 0.44 mmol), Intermediate G (164 mg, 0.53 mmol), and HATU (252 mg, 0.66 mmol) in dichloromethane (10 mL) was stirred under nitrogen atmosphere at 25 0C for 5 h. The mixture was quenched with water (5 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated in vacuo to afford a crude nd. The crude product was puriﬁed with prep-HPLC to h Compound 274. LC-MS (ESI) m/z: 587 [M+H]+; lH-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.64-0.68 (m, 2H), 0.79-0.84 (m, 2H), .91 (m, 2H), 1.99-2.04 (m, 2H), 3.14-3.19 (m, 2H), 3.47-3.49 (m, 3H), 3.87-3.95 (m, 1H), 4.55 (t, J: 4.0 Hz, 1H), 4.87 (s, 1H), 6.05 (d, J: 4.0 Hz, 1H), .44 (m, 3H), 7.85-7.89 (m, 4H), 7.91-7.99 (m, 4H), 8.82 (d, J: 9.7 Hz, 1H), 9.34 (brs, 1H).

Example 275 ] To a sion of 5-bromo-1H-indazole (600 mg, 3.1 mmol) in 1,2- dichloroethane (30 mL) was added cyclopropylboronic acid (532 mg, 6.2 mmol), copper acetate (562 mg, 6.2 mmol), sodium carbonate (658 mg, 6.2 mmol), 2,2'-bipyridine (967 mg, 6.2 mmol) and molecular sieve (2.0 g) at room temperature. The reaction mixture was stirred at room temperature for 48 h. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (50 mL x 2). The combined organic extracts were washed with brine (100 mL x 2) and dried over anhydrous sodium sulfate. After ﬁltration, the solvent was removed in vacuo and the residue was puriﬁed with prep-TLC (ethyl acetate in petroleum ether, 10% v/v) to give Compound 275A.

To a solution of Compound 275A (575 mg, 2.43 mmol) in oxane (15 mL) was added 175B (738 mg, 2.43 mmol), Pd(dppf)C12 (98 mg, 0.12 mmol), potassium carbonate (1.06 g, 7.29 mmol) and water (1 mL) under nitrogen. The reaction e was d at 110 0C for 3 hours. The resulting mixture was cooled to 25 0C. The precipitated solid was ﬁltered and dried to afford Compound 275B.

To a solution of nd 275B (60 mg, 0.196 mmol) in DMF (5 mL) was added Intermediate C (58 mg, 0.196 mmol) and HATU (111 mg, 0.294 mmol). The reaction mixture was stirred at 20 0C for 2 h. The mixture was puriﬁed with prep-HPLC to yield the t Compound 275. LC-MS (m/z) 585 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 1.27-1.29 (m, 4H), 2.06-2.13 (m, 2H), 2.28-2.30 (m, 2H), 3.50-3.63 (m, 2H), 4.04-4.11 (m, 5H), 4.23-4.31 (m, 5H), 4.90-4.91 (m, 1H), 5.10-5.11 (m, 1H), 6.82-6.88 (m, 2H), 7.87- 7.95 (m, 4H), .14 (m, 3H), 8.24-8.25 (m, 1H), 8.35 (s, 1H).

Example 276 CI 4 275B D 276 A mixture of Intermediate D (97 mg, 0.31 mmol), Compound 275B (80 mg, 0.26 mmol), and HATU (150 mg, 0.40 mmol) in DMF (5 mL) was stirred at 10 0C for 1.5 h.

And then it was puriﬁed with prep-HPLC to yield Compound 276. LC-MS (ESI) m/z: 601 [M+H]+; 1H-NMR 2CO, 400 MHz): 5 (ppm) 1.18-1.19 (m, 4H), 2.03-2.17 (m, 2H), 2.24 (s, 2H), 3.47 (m, 3H), 3.73-3.83 (m, 2H), 3.88-3.99 (m, 3H), 4.20-4.38 (m, 4H), 4.87 (s, 1H), 5.14 (d, J: 2.0 Hz, 1H), 6.96 (d, J: 2.0 Hz, 1H), 7.09 (d, J: 2.0 Hz, 1H), 7.83 (d, J: 8.4 Hz, 4H), 8.03 (d, J: 9.6 Hz, 3H), 8.15 (d, J: 10.4 Hz, 2H), 9.93 (brs, lH).

Example 277 NH A O o 0 CI A—> N\N O CI A 2753 G 277 To a solution of Compound 275B (60 mg, 0.196 mmol) in DMF (5 mL) was added ediate G (60 mg, 0.196 mmol) and HATU (111 mg, 0.294 mmol). The reaction mixture was stirred at 20 0C for 2 h. The mixture was d with prep-HPLC to yield Compound 277. LC-MS (m/z) 599 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 0.69- 0.7l(m, 2H), 0.79-0.84 (m, 2H), 1.18-1.20 (m, 4H), .09 (m, 1H), 2.25-2.27 (m, 2H), 3.46-3.55 (m, 2H), 3.77-3.78 (m, 1H), 3.88-3.92 (m, 2H), 3.96-4.08 (m, 4H), 4.90-4.94 (m, 1H), 5.20 (s, 1H), 7.36-7.46 (m, 2H), 7.51-7.52 (m, 1H), 7.80-7.82 (m, 4H), 7.98-8.00 (m, 2H), 8.05 (s, 1H), 8.14 (s, 1H), 8.17-8.20 (m, 1H), 914 (hrs, lH). —324— Example 278 N QH OH O NH 1 - o F o o + a NH2 j—»N. O/N F A 2753 H 278 To a solution of Compound 275B (60 mg, 0.196 mmol) in DMF (5 mL) was added Intermediate H (55 mg, 0.196 mmol) and HATU (1 11 mg, 0.294 mmol). The reaction e was d at 20 0C for 2 h. The mixture was puriﬁed with prep-HPLC to yield Compound 278. LC-MS (ESI) m/z: 571 [M+H]+; 1H—NMR (acetone-d6, 400 MHz): 5 (ppm) 1.33-1.37 (m, 4H), 2.60-2.62 (m, 1H), .74 (m, 1H), 3.92-3.95 (m, 3H), 4.27-4.31 (m, 4H), 4.61-4.64 (m, 4H), 4.73-4.74 (m, 1H), 5.10-5.11 (m, 1H), 6.82-6.88 (m, 2H), 7.88-7.90 (m, 2H), 7.98-8.10 (m, 4H), 8.31 (s, 1H), 8.56 (s, 1H).

Example 279 N ?H O . 0. <9 ; 0 mx0 + mOA CI CI IN 205A I 279 To a solution of Compound 205A (70 mg, 0.25 mmol) in DMF (3 mL) was added Intermediate I (74 mg, 0.25 mmol) and HATU (142 mg, 0.375 mmol). The on mixture was stirred at 15 0C overnight. The mixture was puriﬁed with prep-HPLC to yield Compound 279. LC-MS (m/z) 559 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 0.70- 0.73 (m, 2H), 0.80-0.84 (m, 2H), 2.56-2.57 (m, 1H), 2.71-2.74 (m, 1H), 3.86-3.96 (m, 4H), 4.13 (s, 3H), 4.47-4.60 (m, 4H), 4.77-4.78 (m, 1H), 5.20-5.21 (m, 1H), 7.39-7.45 (m, 2H), .51 (m, 1H), 7.71-7.74 (m, 1H), 7.79-7.8 2 (m, 3H), 7.93-7.95 (m, 2H), 8.09 (s, 1H), 8.13-8.15 (m, 2H), 9.51 (brs, lH).

WO 42397 Example 280 F Br F Br 0 Br \ HO’N\ 280A 2803 280C 280D 280 A mixture of Compound 280A (2 g, 10 mmol), hydroxylamine hydrochloride (830 mg, 12 mmol), and sodium acetate (656 mg, 8 mmol) in water (5 mL) and ethanol (20 mL) was stirred under nitrogen at 25 0C for 5 h. The solution was concentrated to dryness.

The crude product was washed with water (5 mL) and dried to afford Compound 280B.

To a solution of Compound 280B (717 mg, 3.3 mmol) in DMSO (10 mL) was added potassium carbonate (638 mg, 4.6 mmol) at 25 0C. The mixture was d at 120 OC overnight. The on was cooled to room temperature and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium e, ﬁltered, and evaporated to give Compound 280C.

A mixture of Compound 280C (197 mg, 1 mmol), Compound 175B (334 mg, 1.1 mmol), potassium carbonate (414 mg, 3 mmol), and Pd(dppf)C12 (20 mg, 0.04 mmol) in dioxane (10 mL) and water (2 mL) was stirred under nitrogen at 100 0C overnight. The solution was cooled to room temperature, adjusted to pH 4 with s hydrochloric acid solution (6 N, 2 mL), and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and evaporated to afford Compound 280D.

A mixture of Compound 280D (133.5 mg, 0.5 mmol), HATU (342 mg, 0.9 mmol), and Intermediate C (148 mg, 0.5 mmol) in dichloromethane (10 mL) and DMF (4 mL) was d at 25 0C overnight. The solution was extracted with ethyl acetate (50 mL x 2). The combined c phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to give a residue. The residue was purified with prep-HPLC to furnish Compound 280. LC-MS (ESI) m/z: 546 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): 5 (ppm) .03 (m, 4H), 3.09-3.20 (m, 2H), 3.45-3.53 (m, 4H), 4.22—4.32 (m, 4H), 4.47—4.50 (m, 1H), 4.77 (s, 1H), 6.04 (s, 1H), 6.76-6.84 (m, 2H), 7.29—7.32 (m, 2H), .79 (m, 3H), 7.92—7.94 (m, 2H), 8.76-8.79 (m, 1H), 9.24-9.26 (m, 1H), 11.41 (s, 1H).

Example 281 " Br [RDBr N Br ,N\ + N N [ / 281A 2813 Solvent 1,2-dichloroethane (30 mL) was added to a 500 mL of roundbottomed ﬂask containing 6-bromoindazole (3 g, 15.2 mmol), ropylboronic acid (2.6 g, .4 mmol), Cu(OAc)2 (5.5 g, 30.4 mmol), N32C03 (3.2 g, 30.4 mmol), bipyridine (1.7 g, .4 mmol), and 4 A molecular sieve (8 g). The ﬂask was equipped with a drying tube. The mixture was stirred at room temperature for 4 days and ﬁltered through . The ﬁltrate was diluted with water (200 mL) and extracted with ethyl e (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to give Compound 281A and Compound 281B.

A mixture of Compound 281A (600 mg, 2.53 mmol), Compound 175B (769 mg, 2.53 mmol), Pd(dppf)Clz (106 mg, 0.13 mmol), and K2C03 (1.05 g, 7.59 mmol) in e (10 mL) and water (10 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction mixture was cooled to room temperature and ﬁltered h celite. The ﬁltrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic layers were discarded off. The aqueous layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, and trated to give Compound 281C.

A mixture of Compound 281C (100 mg, 0.33 mmol), HATU (190 mg, 0.50 mmol), and Intermediate G (102 mg, 0.33 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h. The e was directly d with prep-HPLC to furnish Compound 281. LC-MS (ESI) m/z: 599 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.66-0.85 (m, 4H), 1.17- 1.19 (m, 4H), 1.88-2.08 (m, 4H), 3.12-3.25 (m, 2H), 3.48-3.59 (m, 4H), 3.83-3.88 (m, 1H), 3.93-3.98 (m, 1H), 4.56-4.63 (m, 1H), 4.90 (s, 1H), 6.17 (brs, 1H), 7.37 (dd, J: 8.8, 2.4 Hz, 1H), 7.43-7.47 (m, 2H), 7.55 (dd, J: 8.4, 1.2 Hz, 1H), 7.79 (d, J: 8.0 Hz, 2H), 7.88-7.92 (m, 3H), 8.03 (s, 1H), 8.09 (s, 1H), 8.86 (d, J: 10.0 Hz, 1H), 941 (hrs, lH).

Example 282 O ‘ o N QH 5 OH = o 1 q NH j— o 0 + = N O F o N' o 2810 c 282 A mixture of Compound 281C (100 mg, 0.33 mmol), HATU (190 mg, 0.50 mmol), and Intermediate C (98 mg, 0.33 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to furnish Compound 282. LC-MS (ESI) m/z: 585 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.17-1.19 (m, 4H), 1.88-2.08 (m, 4H), 3.1 l-3.22 (m, 2H), .56 (m, 4H), 3.84-3.89 (m, 1H), 4.29-4.31 (m, 4H), 4.52-4.54 (m, 1H), 4.80 (d, J: 2.4 Hz, 1H), 6.05 (brs, 1H), 6.79 (s, 1H), 6.84 (d, J: 12.0 Hz, 1H), 7.55 (d, J: 8.4 Hz, 1H), .94 (m, 5H), 8.04 (s, 1H), 8.09 (s, 1H), 8.79 (d, J: 9.2 Hz, 1H), 9.33 (brs, lH).

Example 283 N 9" a ' o N 9H 0 OH = NH 1 01 i O O + .

NH N 0 F o N' 0 H 283 A mixture of Compound 281C (100 mg, 0.33 mmol), HATU (190 mg, 0.50 mmol), and Intermediate H (93 mg, 0.33 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to furnish Compound 283. LC-MS (ESI) m/z: 571 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.16-1.18 (m, 4H), 2.26-2.30 (m, 1H), 2.40-2.48 (m, 1H), .39 (m, 1H), 3.49-3.54 (m, 1H), 3.84-3.89 (m, 1H), 4.05-4.40 (m, 9H), 4.76 (d, J: 3.2 Hz, 1H), 6.03 (brs, 1H), 6.78 (s, 1H), 6.83 (dd, J: 11.2, 1.6 Hz, 1H), 7.55 (dd, J: 8.4, 1.2 Hz, 1H), 7.85-7.94 (m, 5H), 8.03 (s, 1H), 8.09 (s, 1H), 8.79 (d, J: 9.6 Hz, 1H), 9.65 (brs, lH).

Example 284 A mixture of Compound 281B (100 mg, 0.42 mmol), Compound 175B (128 mg, 0.42 mmol), Pd(dppf)Clz (17 mg, 0.02 mmol), and K2C03 (174 mg, 1.26 mmol) in dioxane (5 mL) and water (5 mL) was d under nitrogen at 100 0C for 3 h. The reaction mixture was cooled to room temperature and ﬁltered through celite. The e was diluted with water (100 mL), extracted with ethyl e (100 mL x 2), and the c layer was discarded off. The aqueous layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 284A.

A mixture of Compound 284A (80 mg, 0.26 mmol), HATU (148 mg, 0.39 mmol), and Intermediate G (81 mg, 0.26 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h.

The e was directly puriﬁed with prep-HPLC to furnish Compound 284. LC-MS (ESI) m/z: 599 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.67-0.85 (m, 4H), .34 (m, 4H), 1.87-1.92 (m, 4H), 3.11-3.24 (m, 2H), 3.46-3.58 (m, 4H), 3.92-3.96 (m, 1H), 4.18-4.23 (m, 1H), 4.43-4.56 (m, 1H), 4.89 (d, J: 2.8 Hz, 1H), 6.05 (brs, 1H), 7.35-7.46 (m, 4H), 7.77 (d, J: 8.4 Hz, 2H), 7.81-7.85 (m, 3H), 7.97 (s, 1H), 8.55 (s, 1H), 8.83 (d, J: 10.0 Hz, 1H), 9.38 (brs, 1H).

Example 285 N QH OH NH O] {N} 0 o 0 CI 0 / + i :] , N\ "Iii CI 4 2810 w 285 A mixture of Intermediate W (89 mg, 0.30 mmol), Compound 281C (90 mg, 0.30 mmol), and HATU (148 mg, 0.39 mmol) in DMF (4 mL) was stirred at 10 0C for 1.5 h.

And then it was puriﬁed with prep-HPLC to yield Compound 285. LC-MS (ESI) m/z: 587 [M+H]+; 1H-NMR 2CO, 400 MHz): 5 (ppm) 1.21-1.23 (m, 4H), 2.56-2.65 (m, 1H), 2.69-2.81 (m, 1H), 3.77-3.82 (m, 1H), 3.91-4.05 (m, 2H), .39 (m, 4H), 4.50-4.68 (m, 4H), 4.72-4.78 (m, 1H), 5.11 (d, J: 2.8 Hz, 1H), 6.95 (d, J: 2.0 Hz, 1H), 7.08 (d, J: 2.0 Hz, 1H), 7.85 (d, J: 8.8 Hz, 4H), 8.02 (t, J: 8.4 Hz, 2H), 8.10 (d, J: 9.6 Hz, 1H), 8.14 (s, 1H), 8.18 (s, 1H), 8.86 (brs, 1H).

Example 286 CHO Br CHO Br OH o, q, r2, a, CF3 CF3 CF3 CF3 286A 2863 286C 286D O OH 0 Br 01 TBSO : Oj ; Cb HNZ CszN Oj 0 0 0 286E To a solution of Compound 286A (5 g, 31 mmol) in 2,2,2-triﬂuoroacetic acid (50 mL) was added hexamethylenetramine (4.7 g, 33.6 mmol). The on solution was heated at reﬂux overnight. After cooling, the mixture was treated with 50% H2S04 (20 mL) at room temperature for 4 h and extracted with ether (50 mL x 3). The ed ether phases were washed with aqueous HCl solution (5 M, 50 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 286B.

To a solution of Compound 286B (1 g, 5.3 mmol) in itrile (15 mL) was added NBS (0.88 g, 5.3 mmol) and ammonium formate (32 mg, 0.5 mmol) at 0 0C. The mixture was stirred at room temperature for 2 h. The solvent was removed to give yellow solid. The yellow solid was diluted with ethyl acetate (100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, and trated to yield Compound 286C.

To a solution of Compound 286C (1.3 g, 4.8 mmol) in THF (10 mL) was added dropwise s NaOH solution (0.05 N, 18 mL) at 0 0C, and 30% H202 (2.3 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. Other portion of % H202 (2.3 mL) was added dropwise. The mixture was stirred for 4 h. It was cooled to 0 0C and aq. NaOH solution (2 N, 2 mL) was added dropwise until pH 10~11. The mixture was stirred at 25 0C for 0.5 h, adjusted to pH 2~3 with concentrated HCl at 0 ° C, and extracted with dichloromethane (20 mL x 3). The organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give Compound 286D.

To a mixture of Compound 286D (1.2 g, 4.7 mol) and K2C03 (1.9 g, 14.1 mol) in DMF (12 mL) was added 1, omoethane (4.4 g, 23.5 mol). The mixture was stirred at 80 0C for 4 h. It was cooled down to room temperature and ﬁltered. The cake was washed with ethyl acetate (50 mL). The ﬁltrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The c layer was washed with water (50 mL x 5) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum, 5% v/v) to ﬁlmish Compound 286E.

To a solution of Compound 286E (0.9 g, 3.2 mmol) in dry THF (10 mL) was added n-BuLi solution (2.5 N in hexane, 1.3 mL) under nitrogen at -60 0C. The above e was d at -60 0C for 0.5 h. A solution of nd A4 (0.4 g, 1.1 mmol) in THF (4 mL) was added. The resulting mixture was d at -60 0C for 0.5 h, quenched with saturated aqueous um chloride solution (20 mL), extracted with ethyl acetate (30 mL x 2), washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to yield Compound 286F.

To a solution of Compound 286F (4.8 g, 8.9 mmol) in THF (25 mL) and water (25 mL) was added acetic acid (75 mL). The resulting mixture was stirred at 35 0C for 16 h, diluted with brine (150 mL), and adjusted to pH 8 with saturated aqueous sodium bicarbonate solution (75 mL). The mixture was extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column tography on silica gel (ethyl acetate in petroleum, 20% v/v) to afford Compound 286G.

To a solution of Compound 286G (2 g, 4.7 mmol) in dry THF (60 mL) was added se DIBAL-H (1 N in toluene, 9.4 mL, 9.4 mmol) under nitrogen at -80 0C. The resultant mixture was stirred at -80 0C for 30 min and onal DIBAL-H (1 N in toluene, 9.4 mL, 9.4 mmol) was added dropwise again. The mixture was d at -80 0C for 1 h and quenched with aqueous HCl solution (2 N, 28 mL) at -20 0C. The mixture was extracted with WO 42397 ethyl acetate (200 mL x 2), washed with water (200 mL) and brine (100 mL), dried over anhydrous sodium e, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum, 50% v/v) to ﬁamish Compound 286H. 42] To a solution of nd 286H (1.5 g, 3.5 mmol) in THF (50 mL) was added triethylamine (1.1 g, 10.5 mmol). The mixture was cooled to -20 0C and MsCl (0.44 g, 3.9 mmol) was added slowly. The mixture was stirred at -20 0C for about half an hour and pyrrolidine (2.1 g, 30 mmol) was added to the mixture. The ing e was stirred at - 60 0C for 16 h and cooled to 25 0C. The mixture was diluted with ethyl acetate (200 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, from 5% to 10% v/v) to give Compound 2861.

To a solution of Compound 2861 (0.5 g, 1.2 mmol) in methanol (10 mL) was added Pd(OH)2 (100 mg). The mixture was stirred under hydrogen at room temperature overnight. After removal of Pd(OH)2 by filtration, the filtrate was evaporated to ﬁll‘ﬂlSh Compound 286J.

A mixture of Compound 2861 (0.1 g, 0.28 mmol), HATU (0.16 g, 0.43 mmol), and Intermediate C (70 mg, 0.28 mmol) in DMF (3 mL) was stirred at 25 0C for 16 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC to yield Compound 286. LC-MS (ESI) m/z: 573 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) .89 (m, 2H), 2.03-2.04 (m, 2H), 3.14-3.20 (m, 2H), 3.52-3.55 (m, 4H), 4.29-4.35 (m, 4H), 4.53-4.56 (m, 1H), 4.87 (s, 1H), 6.10 (d, J: 4 Hz, 1H), 7.20-7.23 (m, 2H), 7.35-7.40 (m, 2H), 7.79-7.88 (m, 6H), 8.77-8.79 (m, 1H), 9.30 (s, 1H).

Example 287 N QH 4 \ ' CI 0 o .

N OH 2 OH NH / / o/A | + o/A ’ | \ O i \ O N NH2 N F C' F 264A G 287 A mixture of Compound 264A (100 mg, 0.40 mmol), Intermediate G (150 mg, 0.48 mmol), and HATU (233 mg, 0.60 mmol) in dichloromethane (2 mL) and DMF (2 mL) was stirred at 25 0C for 15 h. After the reaction was completed, it was poured into water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were 2014/056555 dried over anhydrous sodium sulfate, concentrated in vacuo, and puriﬁed with prep-HPLC to afford Compound 287. LC-MS (ESI) m/z: 538 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.68-0.81 (m, 4H), 1.88-2.04 (m, 5H), 3.01-3.20 (m, 3H), 3.41-3.55 (m, 4H), 4.51-4.53 (m, 1H), 4.86 (s, 1H), 7.32-7.44 (m, 5H), 8.12-8.31 (m, 4H), 8.76-8.81 (m, 1H), 9.01 (s, 1H).

Example 288 / 0% Br N N, / N O N , _.

H 0 do 288A 2883 O F 288C 288D 288E o o .

OH NH A N/ N/ o 288D —> ‘N O —» ‘N 0 CI 288F 288 A mixture of 5-bromoindazole (4 g, 20.3 mmol), 4-methylbenzenesulfonic acid (1.9 g, 10.1 mmol), and DHP (3.4 g, 40.6 mmol) in dichloromethane (50 mL) was stirred at room temperature for 18 hours. The reaction mixture was treated with ethyl acetate (500 mL), washed with sodium bicarbonate solution (500 mL x 3) and water (500 mL x 3), dried over anhydrous sodium sulfate, and trated. The crude product was purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 33% V/V) to furnish Compound 288A. 47] To a solution of Compound 288A (4.2 g, 14.8 mmol) in dry THF (50 mL) was added dropwise n-BuLi (2.0 M, 7.5 mL, 17.8 mmol) under nitrogen at -70 0C. After stirring for 30 min., l oxalate (6.5 g, 44.4 mmol) was added quickly. The mixture was stirred at -70 0C for one hour. It was ed with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium e, filtered, and concentrated to give a residue. The residue was purified with ﬂash column chromatography —334_ on silica gel (ethyl acetate in petroleum ether, from 0% to 20% V/V) to afford Compound 288B.

To a solution of Compound 288B (1.4 g, 4.6 mmol) in ethanol (10 mL) was added dropwise 2 N hydrogen chloride (10 mL, 18.5 mmol). The reaction mixture was stirred at room temperature for 8 h. Sodium bicarbonate solution was added to adjust pH 7, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to ﬁamish Compound 288C.

A mixture of nd 288C (500 mg, 2.29 mmol), 1-(bromomethyl) ﬂuorobenzene (647 mg, 3.44 mmol), and CS2C03 (897 mg, 2.75 mmol) in 1- methylpyrrolidinone (20 mL) was stirred at room temperature for 18 hours. The reaction mixture was treated with H20 (50 mL) and ethyl acetate (50 mL), washed with and water (500 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude t was purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 33% V/V) to furnish Compound 288D and Compound 288E. 50] To a solution of nd 288D (300 mg, 0.91 mmol) in THF (2 mL) was added dropwise 1 N lithium hydroxide (2 mL, 2 mmol). The reaction mixture was stirred at room temperature for 2 h. After the reaction mixture was concentrated, 2 N HCl (1 mL) was ammdma®u$pH7¢mdemmdmhmmedwhwaMeGOmLx3)Theammmmhngmm phases were washed with water (5 mL) and brine (5 mL), dried over ous sodium sulfate, filtered, and trated to ﬁamish Compound 288F.

To a solution of Compound 288F (50 mg, 0.167 mmol) in dichloromethane (3 mL) was added Intermediate G (62 mg, 0.201 mmol) and HATU (95 mg, 0.25 mmol). The mixture was stirred at room temperature for 2 h. It was concentrated and the resulting residue was purified with prep-HPLC to afford Compound 288. LC-MS (ESI) m/z: 591 [M+H]+; 1H- NMR(CDC13, 400 MHz): 5 (ppm) .91 (m, 4H), .15 (m, 4H), 2.97-3.05 (m, 2H), .50 (m, 1H), 3.65-3.68 (m, 1H), 3.70-3.85 (m, 1H), 3.87-3.91 (m, 2H), 4.53-4.57 (m, 1H), 5.01-5.06 (m, 1H), 5.56 (s, 2H), 6.96-7.00 (m, 2H), 7.13-7.19 (m, 3H), 7.20-7.23 (m, 1H), 7.28-7.31 (m, 1H), 7.38 (s, 1H), .95 (m, 1H), 8.11-8.13 (m, 2H), 8.58 (s, 1H), 11.48 (brs, 1H).

Example 289 288F c 289 To a solution of Compound 288F (50 mg, 0.167 mmol) in dichloromethane (3 mL) was added Intermediate C (59 mg, 0.201 mmol) and HATU (95 mg, 0.25 mmol). The mixture was stirred at room temperature for 2 hours. It was trated and the resulting e was puriﬁed with PLC to afford Compound 289. LC-MS (ESI) m/z: 577 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) 2.18-2.19 (m, 4H), 3.01-3.05 (m, 2H), 3.49- 3.51 (m, 1H), 3.71-3.79 (m, 2H), 3.96-4.02 (m, 2H), .22 (m, 4H), 4.45-4.47 (m, 1H), .10 (d, J: 3.2 Hz, 1H), 5.56 (s, 2H), 6.72-6.73 (m, 2H), 6.97-7.03 (m, 2H), 7.16-7.19 (m, 2H), 7.35-7.37 (m, 1H), 7.68-7.70 (m, 1H), 8.02-8.04 (m, 1H), 8.18 (s, 1H), 8.73 (s, 1H).

Example 290 290D A mixture of Compound 290A (2 g, 9.85 mmol) and aminooxysulfonic acid (1.67 g, 14.78 mmol) in ethanol (50 mL) was stirred at room temperature for 2 h. The mixture was diluted with DCM (200 mL), washed with water (200 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to afford Compound 290B.

To a solution of PPh3 (3.44 g, 13.12 mmol) in DCM (40 mL) was added DDQ (2.98 g, 13.12 mmol) in portions at room temperature and the resultant mixture was d for 5 min. Compound 290B (1.89 g, 8.75 mmol) was added. The reaction mixture was stirred for 5 min, diluted with DCM (100 mL), and filtered. The filtrate was washed with water (100 mL x 2) and brine (50 mL), dried over ous sodium sulfate, concentrated, and purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 290C.

A mixture of Compound 290C (198 mg, 1 mmol), Compound 175B (456 mg, 1.5 mmol), Pd(PPh3)2Clz (70 mg, 0.1 mmol), and K2C03 (256 mg, 2 mmol) in dioxane (5 mL) and water (0.5 mL) was d at 80 0C for 2 h. The mixture was cooled down and d. The precipitate was ved in water and ﬁltered. The ﬁltrate was puriﬁed with reverse phase chromatography using eluent (methanol in water, from 0% to 100% v/v) to yield Compound 290D.

A mixture of Compound 290D (100 mg, 0.374 mmol), Intermediate C (111 mg, 0.374 mmol), and HATU (171 mg, 0.449 mmol) in DCM (3 mL) was stirred at room temperature overnight. The mixture was diluted with DCM (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 290. LC-MS (ESI) m/z: 546 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 2.09-2.22 (m, 4H), 3.27-3.40 (m, 3H), .77 (m, 2H), 3.87-3.96 (m, 2H), 4.26-4.33 (m, 4H), 4.77-4.82 (m, 1H), 5.12-5.13 (m, 1H), 6.84-6.90 (m, 2H), 7.36 (dd, .11 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.44 (d, J: 1.6 Hz, 1H), 7.72-7.78 (m, 3H), 8.05 (d, J: 8.8 Hz, 2H), .20 (m, 1H).

Example 291 Br Br J< TBSO CszN F 0 J< CI CI CI 291A 2291 B 291C 0 OH OH OMS oH ; ; _> ; Cb HN J< _> Cb HN J< Z z CszN O 0 J< CI CI CI 291D 291E 291 F U O N 9H N 9H 0 = = NH J< - - —> : J< —> : J< —> Cb HN Cl Z NH o 0 0 o CI CI 0 2916 291H 291 To a solution of nd 291A (10.00 g, 47.85 mmol) in DMF (100 mL) was added t—BuOK (8.04 mL, 71.77 mmol) at room temperature. The mixture was stirred room temperature for 2 h and quenched with water (100 mL). The mixture was diluted with ethylacetate (300 mL), washed with water (200 mL) and brine (200 mL), dried over WO 42397 anhydrous sodium sulfate, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 5% v/v) to afford Compound 291B.

To a solution of Compound 291B (11.00 g, 0.042 mol) in THF (30 mL) was added dropwise n-BuLi solution (2.5 M in , 16.8 mL, 0.042 mol) under nitrogen at -68 0C. The mixture was stirred at -78 0C for 30 min and a solution of Compound A4 (5.50 g, 13.89 mmol) in THF (20 mL) was added dropwise under nitrogen at -78 0C. The mixture was d at -78 0C for 20 min and ed with ted aqueous ammonium chloride solution (100 mL). The mixture was diluted with ethyl acetate (300 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and puriﬁed with ﬂash column chromatography on silica gel (ethyl e in eum ether, from 0% to 10% v/v) to furnish Compound 291C.

A solution of Compound 291C (6.00 g, 11.56 mmol) in THF (40 mL), AcOH (120 mL), and water (40 mL) was stirred at 25 0C for 48 h. The mixture was evaporated to remove solvent, diluted with ethyl acetate (300 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium e, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50% v/v) to afford Compound 291D.

To a solution of Compound 291D (3.20 g, 7.90 mmol) in THF (20 mL) was added se DIBAL-H solution (1 M in toluene, 15.8 mL, 15.80 mmol) under nitrogen at -80 0C. After 30 min, additional DIBAL-H solution (1 M in toluene, 15.8 mL, 15.80 mmol) was added dropwise under nitrogen at -80 0C. The mixture was stirred under nitrogen at -80 0C for 2 h and quenched with saturated aqueous ammonium chloride solution (200 mL) at -20 0C. The mixture was diluted with ethyl acetate (200 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium e, and puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, from 0% to 5% v/v) to give Compound 291E.

To a solution of Compound 291E (1.10 g, 2.70 mmol) and triethylamine (818 mg, 8.10 mmol) in THF (10 mL) was added dropwise methanesulfonyl chloride (370 mg, 3.24 mmol) at -15 0C. The mixture was stirred at -15 0C for 1 h. It was quenched with saturated ice water (50 mL), diluted with ethyl e (200 mL), washed with water (150 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and evaporated to afford Compound 291F. The target compound was directly used for the next step without ﬁthher puriﬁcation.

A solution of Compound 291F (1.10 g, 2.27 mmol) and idine (1.68 g, 22.68 mmol) in THF (10 mL) was stirred at 50 0C for 16 h. The e was cooled down to room ature and diluted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, from 0% to 8% V/V) to furnish Compound 291G.

A mixture of Compound 291G (300 mg, 0.65 mmol) and LiOH’HzO (356 mg, 6.52 mmol) in methanol (10 mL) and water (2 mL) was stirred at 80 0C for 16 h. It was diluted with ethyl acetate (200 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and puriﬁed with reverse phase chromatography using eluent (methanol in water, from 0% to 100% V/V) to furnish Compound 291H.

A mixture of Compound 291H (110 mg, 0.34 mmol), Intermediate C (82 mg, 0.34 mmol), and HATU (190 mg, 0.51 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. It was diluted with ethyl acetate (120 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and ed with prep-HPLC to afford Compound 291. LC-MS (ESI) m/z: 553 [M+H]+; 1H-NMR (DMSO-dg, 400 MHZ): 5 (ppm) 1.33 (s, 9H), 1.84-1.93 (m, 2H), 2.00-2.06 (m, 2H), 3.11-3.24 (m, 2H), 3.49-3.53 (m, 4H), 4.52-4.57 (m, 1H), 4.91 (s, 1H), 6.08 (s, 1H), 7.21 (d, J: 8.4 Hz, 1H), 7.27-7.30 (m, 1H), 7.37 (t, J: 8.8 Hz, 2H), 7.47 (s, 1H), 7.78-7.85 (m, 6H), 8.79 (d, J: 9.2 Hz, 1H), 7.43 (s, 1H).

Example 292 F CI 242F S 292 To a solution of Compound S (118 mg, 0.40 mmol) in DMF (10 mL) was added nd 242F (80 mg, 0.33 mmol), HATU (190 mg, 0.50 mmol), and MN- diisopropylethylamine (129 mg, 1.0 mmol). The mixture was stirred under nitrogen at 25 0C overnight. The resulting mixture was quenched with ted aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The ed organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ed, and concentrated to afford a crude compound. The crude product was purified with prep-HPLC to furnish Compound 292. LC-MS (ESI) m/z: 517 ; 1H-NMR (DMSO-d6 400 MHz): 5 (ppm) 0.64-0.76 (m, 4H), 1.84-2.00 (m, 4H), 3.09-3.17 (m, 2H), 3.33-3.38 (m, 1H), 3.50-3.56 (m, 3H), 3.86-3.90 (m, 1H), 4.43-4.48 (m, 1H), 4.79 (s, 1H), 6.06 (s, 1H), .20 (m, 2H), 7.35 (t, J: 8.8 Hz, 1H), 7.55 (dd, J: 8.8, 2.0 Hz, 1H), 8.13 (d, J: 8.4 Hz, 1H), 8.30 (d, J: 2.0 Hz, 1H), 8.58 (s, 1H), 8.63 (d, J: 10.0 Hz, 1H), 9.06 (s, 1H).

Example 293 0 a o OH N KIH o] o C_)H o o o F O . o] o O 2550 H 293 A mixture of Compound 255C (50 mg, 0.18 mmol), HATU (100 mg, 0.27 mmol), and Intermediate H (50 mg, 0.18 mmol) in DMF (3 mL) was stirred at 25 0C for 16 h.

The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium e, concentrated, and puriﬁed with prep- HPLC to mmish Compound 293. LC-MS (ESI) m/z: 547 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.33 (s, 9H), 2.26-2.45 (m, 2H), 3.36-3.48 (m, 2H), 4.07-4.30 (m, 9H), 4.74 (s, 1H), 6.02 (s, 1H), 6.76-6.84 (m, 2H), 7.54-7.56 (m, 2H), 7.69-7.71 (m, 2H), 7.78-7.84 (m, 4H), 8.75 (d, J: 9.6 Hz, 1H), 9.67 (s, 1H).

Example 294 0 O OH Q lilH (2H O] O ' O o O O F 0 + 2 "Hz 01 O 255C c 294 A mixture of Compound 255C (50 mg, 0.18 mmol), HATU (100 mg, 0.27 mmol), and Intermediate C (53 mg, 0.18 mmol) in DMF (3 mL) was stirred at 25 0C for 16 h.

The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep- HPLC to ﬁlmish nd 294. LC-MS (ESI) m/z: 561 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.33 (s, 9H), 1.87-2.03 (m, 4H), 3.12-3.19 (m, 2H), 3.46-3.55 (m, 4H), 4.26- —340— 4.30 (m, 4H), 4.51-4.52 (m, 1H), 4.79 (s, 1H), 6.06 (s, 1H), 6.77-6.84 (m, 2H), 7.54-7.56 (m, 2H), 7.71-7.89 (m, 6H), 8.76 (d, J: 9.6 Hz, 1H), 9.44 (s, 1H).

Example 295 To a solution of Compound 295A (752 mg, 4 mmol) in 1,4-dioxane (32 mL) and water (4 mL) was added Compound 175B (1.4 g, 4.4 mmol), Pd(dppf)C12 (164 mg, 0.2 mmol), and potassium carbonate (1.66 g, 12 mmol) under en at 20 0C. The reaction mixture was stirred at 110 0C for 3 hours. The resulting mixture was cooled to 20 0C. It was adjusted to pH 5 with 2 N HCl and extracted with ethyl acetate (40 mL x 3). The combined organic layers were concentrated in vacuo without dryness to give the crude Compound 2953.

To a solution of Compound 295B (78 mg, 0.3 mmol) in DMF (3 mL) and romethane (4 mL) was added Intermediate G (112 mg, 0.36 mmol) and HATU (171 mg, 0.45 mmol). The reaction mixture was stirred at 25 0C for 3 hours. The mixture was puriﬁed with prep-HPLC to yield the product Compound 295. LC-MS (m/z) 551 [M+H]+; 1H-NMR dg, 400 MHz): 5 (ppm) 0.74-0.90 (m, 4H), 1.93-2.01 (m, 5H), 2.27 (s, 3H), 2.95-3.10 (m, 2H), 3.11-3.3.15 (m, 1H), 3.61-3.65 (m, 3H), 4.00-4.02 (m, 1H), 4.76-4.79 (m, 1H), 5.52 (d, J: 10.4 Hz, 1H), 7.13-7.17 (m, 1H), .24 (m, 1H), 7.28-7.32 (m, 1H), 7.48 (d, J: 8.8 Hz, 2H), 7.55 (s, 2H), 7.69 (s, 1H), 8.16 (d, J: 8.4 Hz, 2H), 9.73 (brs, 1H). —341— WO 42397 2014/056555 Example 296 we 1%" O\'B O —> O\'B O —> O 0 296A 296B 296 To a solution of Compound 175B (600 mg, 1.97 mmol) in THF (20 mL) was added LiOH'HzO (124 mg, 2.96 mmol) dissolved in water (3 mL) at 0 0C. The mixture was stirred at room temperature for 4 h. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (10 mL). The water layer was adjusted to pH 6 with diluted HCl and extracted with ethyl acetate (25 mL x 2). The ed organic layers were washed with brine (15 mL), dried over ous sodium e, and concentrated to afford Compound 296A, which was used for the next step without ﬁthher purification.

A mixture of Compound 296A (480 mg, 1.74 mmol), Intermediate G (594 mg, 1.91 mmol), and HATU (991 mg, 2.61 mmol) in dichloromethane (20 mL) was stirred at 25 0C for 10 h. The mixture was quenched with water (10 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a crude compound. The crude product was purified with prep-HPLC to furnish Compound 296B.

A mixture of 5-bromobenzo[d]thiazole (35 mg, 0.16 mmol), Compound 296B (104 mg, 0.22 mmol), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 8.2 umol), potassium carbonate (68 mg, 0.49 mmol), water (0.5 mL), and 1,4-dioxane (2 mL) was heated under nitrogen atmosphere at 100 0C for 1 h. After cooling, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a black oil. The oil was ed with prep-HPLC to mmish Compound 296. LC-MS (ESI) m/z: 576 [M+H]+; 1H-NMR 2CO, 400 MHz): 5 (ppm) 0.71-0.73 (m, 2H), 0.81-0.84 (m, 2H), .13 (m, 2H), 2.28 (s, 2H), 3.55 (s, 1H), 3.89-3.90 (m, 2H), 4.05-4.08 (m, 4H), 4.94 (s, —342— 1H), 5.21 (d, J: 2 Hz, 1H), 7.42-7.43 (m, 2H), 7.51 (d, J: 1.6 Hz, 1H), 7.91 (dd, J: 8.5, 3.0 Hz, 4H), 8.03 (d, J: 8.5 Hz, 2H), 8.21 (d, J: 9.7 Hz, 1H), 8.31 (d, J: 8.5 Hz, 1H), 8.45 (d, J: 1.5 Hz, 1H), 9.37 (s, 1H).

Example 297 0 CI 296B 297 A mixture of obenzo[d]thiazole (30 mg, 0.14 mmol), Compound 296B (90 mg, 0.18 mmol), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 8.2 umol), potassium carbonate (58 mg, 0.42 mmol), water (0.5 mL), and 1,4-dioxane (2 mL) was heated under nitrogen atmosphere at 100 0C for 1 h. After cooling, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL). The combined organic layers were dried over anhydrous sodium e, ﬁltered, and concentrated to afford the crude product as a black oil. The oil was purified with prep-HPLC to mmish nd 297. LC-MS (ESI) m/z: 576 [M+H]+; 1H-NMR 2CO, 400 MHz): 5 (ppm) 0.60-0.86 (m, 4H), 2.06-2.38 (m, 4H), 3.27 (s, 1H), 3.52-3.64 (m, 2H), 3.89-3.91 (m, 2H), 4.01 (d, J: 5.7 Hz, 1H), 4.06-4.16 (m, 2H), 4.92-4.97 (m, 1H), 5.20 (d, J: 2.1 Hz, 1H), 7.35-7.45 (m, 2H), 7.49 (d, J: 1.7 Hz, 1H), 7.83-7.90 (m, 2H), 7.95 (dd, J: 8.6, 1.8 Hz, 1H), 8.03 (d, J: 8.6 Hz, 2H), 8.19-8.23 (m, 2H), 8.55 (d, J: 1.6 Hz, 1H), 9.36 (s, 1H). —343— Example 298 Br 0 r 0\/ _. —» o I O O F F 298A 2983 2980 o 0; OH NH —> 00 #000 F F 298D 298 To a mixture of Compound 298A (2.96 g, 0.01 mol), 4-ﬁuorophenylboronic acid (2 g, 1.32 mol), and K3P04 (6.4 g, 0.03 mol) in l,2-dimethoxyethane (80 mL) was added Pd(dppf)Clz (733 mg, 1.0 mmol). The reaction mixture was stirred under nitrogen at room temperature overnight. The resulting mixture washed with brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl e in petroleum ether, from 10% to 50% v/v) to furnish Compound 298B.

To a solution of Compound 298B (2.64 g, 10 mmol) in THF (30 mL) was added se n-BuLi solution (2.5 M in , 4 mL, 10 mmol) under nitrogen at -78 0C.

The mixture was stirred at -78 0C for 0.5 h and the solution was added to a solution of diethyl oxalate (3 g, 20 mmol) in THF (20 mL) under nitrogen at -78 0C. The e was stirred at room temperature overnight and quenched with saturated aqueous ammonium chloride solution (40 mL). The reaction mixture was extracted with ethyl e (50 mL x 3), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 50% v/v) to give Compound 298C.

To a on of Compound 298C (2.8 g, 0.01 mol) in ethanol/water (40 mL/10 mL) was added LiOH'HgO (840 mg, 0.02 mol). The mixture was stirred at room temperature for about 2 h until completion by thin layer chromatography analysis. The on mixture was acidiﬁed to pH 2 with aqueous HCl solution (1 .0 N, 40 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with —344— brine (100 mL), dried over anhydrous sodium sulfate, d, and trated to afford Compound 298D.

To a mixture of Compound 298D (126 mg, 0.5 mmol) and Intermediate G (155 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was stirred at room ature overnight. The resulting solution was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with prep-HPLC to furnish Compound 298. LC-MS (ESI) m/z: 551 [M+H]+; 1H- NMR d6, 400 MHz): 5 (ppm) 0.62-0.87 (m, 4H), 1.88-2.04 (m, 4H), 2.26 (s, 3H), 3.13-3.21 (m, 2H), 3.50-3.56 (m, 4H), 3.88-3.89 (m, 1H), 4.54-4.56 (m, 1H), 4.87 (s, 1H), 6.05 (s, 1H), 7.27-7.45 (m, 8H), 7.53 (d, J: 6.8 Hz, 1H), 7.76 (s, 1H), 8.80 (d, J: 9.2 Hz, 1H), 9.40 (s, 1H).

Example 299 N 9H i > O 0 o OH 9H NH O ' ° O o i j —’ 0 o F O o O F F F 2930 c 299 To a mixture of Compound 298D (130 mg, 0.5 mmol) and Intermediate C (143 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solution was washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and trated. The residue was purified with prep-HPLC to furnish Compound 299. LC-MS (ESI) m/z: 537 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.86-2.04 (m, 4H), 2.27 (s, 3H), 3.11-3.18 (m, 2H), 3.42-3.54 (m, 4H), 4.23-4.28 (m, 4H), 4.49 (s, 1H), 4.77 (s, 1H), 6.04 (s, 1H), 6.75 (s, 1H), 6.81-6.84 (m, 1H), .35 (m, 3H), 7.42-7.46 (m, 2H), 7.65 (d, J: 7.6 Hz, 1H), 7.80 (s, 1H), 8.75 (d, J: 9.6 Hz, 1H), 9.30 (s, 1H).

Example 300 0 a O O _ N OH OH KIH j 0 ° j —’ 0 O 0 0 CI NH2 0 F Cl D 1330 w 300 —345— A mixture of Compound 133D (l 10 mg, 0.37 mmol), Intermediate W (90 mg, 0.37 mmol), and HATU (182 mg, 0.48 mmol) in romethane (10 mL) was stirred at 10 0C for 15 h. And then it was treated with water (10 mL) and extracted with dichloromethane (10 mL x 3 mL). The organic layers were washed with water (20 mL x 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and puriﬁed with prep-HPLC to yield Compound 300. LC-MS (ESI) m/z: 525 [M+H]+; 1H-NMR ((CD3)2CO, 400 MHz): 5 (ppm) 2.58 (s, 1H), 2.70-2.77 (m, 1H), 3.88-4.01 (m, 2H), 4.22-4.38 (m, 4H), 4.49-4.64 (m, 4H), 4.71-4.77 (m, 1H), 5.12 (s, 1H), 5.47 (s, 1H), 6.94 (d, J: 1.6 Hz, 1H), 7.07 (d, J: 2.0 Hz, 1H), 7.30 (t, J: 8.8 Hz, 2H), 7.77-7.84 (m, 4H), 7.99 (d, J: 8.4 Hz, 2H), 8.11 (d, J: 9.6 Hz, 1H), 9.19 (s, 1H).

Example 301 N 9H 0 o O ; OH - m0"—’ 0 0 D m"0 Cl NC 0 175A 301A 301 A mixture of Compound 175A (512 mg, 2 mmol), ophenylboronic acid (294 mg, 2 mmol), potassium carbonate (828 mg, 6 mmol), and Pd(dppf)Clz (40 mg, 0.08 mmol) in e (20 mL) and water (4 mL) was stirred under nitrogen at 100 0C overnight.

The solution was cooled down to room temperature, adjusted to pH 4 with aqueous hydrochloric acid solution (6 N, 2 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and evaporated to afford Compound 301A.

A mixture of Compound 301A (100 mg, 0.4 mmol), HATU (273 mg, 0.72 mmol), and Intermediate G (124 mg, 0.4 mmol) in dichloromethane (10 mL) and DMF (2 mL) was stirred at 25 0C overnight. The solution was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and trated to give a residue. The residue was purified with prep-HPLC to furnish Compound 301. LC-MS (ESI) m/z: 544 [M+H]+; 1H- NMR dg, 400 MHz): 5 (ppm) 0.66-0.82 (m, 4H), 1.88-2.02 (m, 4H), 3.12-3.21 (m, 2H), .64 (m, 4H), 3.88-3.93 (m, 1H), 4.53-4.61 (m, 1H), 4.87 (s, 1H), 6.05 (s, 1H), .43 (m, 3H), 7.85-7.86 (m, 3H), .03 (m, 5H), 8.81-8.83 (m, 1H), 9.39 (s, 1H).

Example302 0 O\/ Br Br Br —* ﬂ 0 O O O O 0 302A 3023 OH Br Br 0 .

* O O O —’ 302D 302 To a solution of Compound 302A (1 g, 0.59 mmol) in CHC13 (6 mL) was added bromine (0.68 mL, 1326 mmol) at 0 0C. The mixture was stirred at 25 0C for 48 h. It was poured into aq. Na2S203 (50 mL) and extracted with ethyl acetate (20 mL x 3). The ed organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to ﬁamish the crude product. It was recrystallized from methanol to give Compound 302B. 83] To a solution of Compound 302B (324 mg, 1 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 0.4 mL, 1.06 mmol) under nitrogen at -60 0C. It was stirred at -60 0C for 0.5 h. And then a solution of diethyl oxalate (0.4 mL, 3 mmol) in THF (5 mL) was added.

The e was stirred at -60 0C for 0.5 h, quenched with saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (20 mL x 3), washed with brine (20 mL), dried over anhydrous sodium sulfate, and puriﬁed with ﬂash column tography on silica gel (ethyl e in petroleum ether, 5% v/v) to furnish Compound 302C. 84] To a solution of Compound 302C (39 mg, 0.11 mmol) in THF/water (6 mL, :1, v/v) was added LiOH'HzO (52 mg, 0. 12 mmol). The mixture was stirred at 0 0C for l h.

After the reaction was completed, water (20 mL) was added. It was extracted with ethyl acetate (20 mL). The water was adjusted to pH 2. It was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude Compound 302D.

A mixture of Compound 302D (35 mg, 0.11 mmol), Intermediate G (43 mg, 0.14 mmol), and HATU (54 mg, 0. 14 mmol) in DMF (4 mL) was stirred at 10 0C for 3 h.

And then it was purified with prep-HPLC to give Compound 302. LC-MS (ESI) m/z: 611 [M+H]+; 1H-NMR 2CO, 400 MHz): 5 (ppm) 0.58-0.83 (m, 4H), 2.07-2.16 (m, 2H), —347— 2.24 (s, 2H), 3.45 (s, 2H), 3.80-3.85 (m, 2H), 3.96 (s, 3H), 4.90 (s, 1H), 5.20 (s, 1H), 7.36 (d, J=8.0Hz,1H),7.44(dd, J1: 8.4Hz, J2=16,Hz 1H), 7.53 (d, J: 2.0,Hz 1H), 7.6-97.77 (m, 3H), 8.17 (dd, .11 = 8.4 Hz, J2 = 1.6 Hz, 1H), 8.23 (d, J: 9.6 Hz, 1H), 8.43 (d, J: 2 Hz, 1H), 8.84 (d, J: 1.2 Hz, 1H), 10.19 (brs, 1H).

Example 303 303A 303BU 303C A mixture of nd 303A (191 mg, 0.83 mmol), K2C03 (456 mg, 3.3 mmol), and D20 (12 mL) was stirred at 110 0C overnight. The mixture was acidiﬁed with the addition of 1 M HC1, ted with DCM (20 mL x 2), dried over ous sodium sulfate, and concentrated to furnish Compound 303B.

A mixture of Compound 303B (145 mg, 0.63 mmol) in SOClz (4.5 mL) was stirred at 25 0C for 2 h. The mixture was concentrated to give Compound 303C (160 mg, yield 100%) as a yellow oil, which was directly used for the next step without further puriﬁcation.

A solution of Intermediate G (200 mg, 0.63 mmol) in CD30D was evaporated to dryness and the e was dissolved CDC13 (8 mL). The solution was added to Compound 303C (200 mg, 0.63 mmol). The mixture was stirred at 25 0C for 0.5 h. The reaction mixture was treated with water (20 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 303. LC-MS (ESI) m/z: 525.2 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.57-0.66 (m, 4H), 2.02-2.23 (m, 4H), 3.13- 3.30 (m, 2H), .68 (m, 4H), 3.80-3.88 (m, 1H), .54 (m, 1H), 4.87 (d, J: 2.4 Hz, 1H), 7.06-7.20 (m, 6H), 7.42-7.49 (m, 3H), 7.62-7.66 (m, 2H).

Example 304 O 0 CW"\N/ O ("WW\N/ O —> —> F F 2088E 304A NWNH\ O To a solution of Compound 288E (150 mg, 0.45 mmol) in THF (1 mL) was added dropwise l N lithium hydroxide (1 mL, 1 mmol). The reaction mixture was stirred at room temperature for 2 h. After the reaction mixture was trated, 2 N HCl (1 mL) added to adjust pH 7, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to mmish Compound 304A.

To a solution of Compound 304A (50 mg, 0.167 mmol) in dichloromethane (3 mL) was added Intermediate G (62 mg, 0.201 mmol) and HATU (95 mg, 0.25 mmol). The e was stirred at room temperature for 2 h. It was concentrated and the resulting residue was puriﬁed with PLC to afford Compound 304. LC-MS (ESI) m/z: 591 [M+H]+; 1H- NMR(CDC13, 400 MHz): 5 (ppm) 0.74-0.76 (m, 4H), .15 (m, 4H), 3.01-3.05 (m, 1H), 3.50-3.58 (m, 1H), 3.59-3.81 (m, 3H), 3.87-4.01 (m, 2H), 4.53-4.57 (m, 1H), .16 (m, 1H), 5.56 (s, 2H), 7.05-7.09 (m, 2H), 7.21-7.23 (m, 1H), 7.27-7.33 (m, 3H), 7.36-7.37 (m, 1H), 7.66-7.68 (s, 1H), 7.79-7.80 (m, 1H), 8.12 (s, 2H), 8.58 (s, 1H).

Example 305 N C_)H O U _ H O] \N/ o 2' 01 \N/ o F F F F 304A C 305 —349— To a solution of nd 304A (50 mg, 0.167 mmol) in dichloromethane (3 mL) was added Intermediate C (59 mg, 0.201 mmol) and HATU (95 mg, 0.25 mmol). The mixture was stirred at room temperature for 2 h. It was puriﬁed with prep-HPLC and prep- TLC to afford Compound 305. LC-MS (ESI) m/z: 577 [M+H]+; 1H-NMR (CDClg, 400 MHz): 5 (ppm) 1.82-1.85 (m, 4H), 2.75-2.84 (m, 4H), 3.01-3.04 (m, 2H), 4.16-4.33 (m, 5H), .03 (d, J: 1.6 Hz, 1H), 5.57 (s, 2H), 6.69-6.74 (m, 2H), 7.04-7.09 (m, 2H), 7.26-7.32 (m, 2H), 7.42-7.45 (m, 1H), 7.69 (d, J: 8.8 Hz, 1H), 7.92 (d, J: 8.8 Hz, 1H), 8.09 (s, 1H), 8.93 (s, 1H).

Example 306 \6 \6 O N\\:©/N Br N , O\C/’______, N\ 0 256A 306A \( o N OH \( N' ,N \ O N 3063 306 To a solution of Compound 256A (640 mg, 2.69 mmol) in dry THF (10 mL) was added dropwise n-BuLi solution (2.5 M in hexane, 1.1 mL, 2.72 mmol) under nitrogen at -78 0C. The mixture was d at -78 0C for 30 min and diethyl oxalate (0.91 mL, 6.73 mmol) was added y to the above mixture. The mixture was stirred at -78 0C for 30 min, quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (80 mL x 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was puriﬁed with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, from 0% to 5% V/V) to furnish Compound 306A. 93] To a solution of Compound 306A (490 mg, 2.11 mmol) in methanol (5 mL) was added LiOH'HzO (177 mg, 4.22 mmol) in water (5 mL) and the e was stirred at room temperature overnight. After completion of the reaction, the e was adjusted to pH 6 with aqueous HCl solution (3 N) and concentrated in vacuo. The residue was in lyophilization to afford Compound 306B.

A mixture of Compound 306B (70 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol), and Intermediate G (93 mg, 0.30 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to yield nd 306. LC-MS (ESI) m/z: 525 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.59-0.81 (m, 4H), 1.47 (d, J: 6.4 Hz, 3H), 1.52 (d, J: 6.8 Hz, 3H), 1.87-2.04 (m, 4H), 3.06-3.22 (m, 2H), 3.47-3.56 (m, 4H), 3.87-3.91 (m, 1H), 4.54-4.56 (m, 1H), 4.86 (d, J: 2.8 Hz, 1H), 5.01-5.05 (m, 1H), 6.07 (brs, 1H), 7.33-7.39 (m, 2H), 7.45-7.48 (m, 2H), 7.83 (d, J: 8.8 Hz, 1H), 8.23 (s, 1H), 8.35 (s, 1H), 8.81 (d, J: 9.6 Hz, 1H), 9.34 (brs, 1H).

Example 307 \( o \( o ,N j —> ,N 3063 307 A mixture of Compound 306B (70 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol), and Intermediate C (93 mg, 0.30 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to afford nd 307. LC-MS (ESI) m/z: 511 ; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.49 (d, J: 6.8 Hz, 3H), 1.52 (d, J: 6.8 Hz, 3H), .89 (m, 2H), 2.02-2.04 (m, 2H), 3.10-3.21 (m, 2H), 3.43-3.55 (m, 4H), 4.21-4.31 (m, 4H), 4.48-4.55 (m, 1H), 4.77 (d, J: 3.2 Hz, 1H), 5.02-5.08 (m, 1H), 6.77 (s, 1H), 6.84 (dd, J: 11.6, 1.6 Hz, 1H), 7.50 (dd, J: 8.4, 1.2 Hz, 1H), 7.86 (d, J: 8.8 Hz, 1H), 8.24 (s, 1H), 8.38 (s, 1H), 8.79 (d, J: 9.6 Hz, 1H), 9.30 (brs, 1H).

Example 308 242F 308 To a solution of Intermediate C (118 mg, 0.40 mmol) in DMF (10 mL) was added Compound 242F (80 mg, 0.33 mmol), HATU (190 mg, 0.50 mmol), and MN- diisopropylethylamine (129 mg, 1.0 mmol). The mixture was d under nitrogen at 25 0C overnight. The resulting mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and trated to afford a crude compound. The crude product was purified with prep-HPLC to furnish Compound 308. LC-MS (ESI) m/z: 519 [M+H]+; 1H-NMR (CD30D, 400 MHz): 5 (ppm) 2.00-2.04 (m, 2H), 2.15-2.18 (m, 2H), 3.19-3.29 (m, 2H), 3.46-3.50 (m, 1H), 3.67-3.81 (m, 3H), 4.11-4.23 (m, 4H), 4.29-4.35 (m, 2H), .57 (m, 1H), 4.85 (d, J = 3.2 Hz, 1H), 6.76-6.81 (m, 2H), 7.46 (dd, J: 8.8, 2.0 Hz, 1H), 7.98 (d, J: 8.8 Hz, 1H), 8.04 (d, J: 1.6 Hz, 1H), 8.48 (s, 1H).

Example 309 BrUCl Br CI CI —> Uo~ ; o —> CszN OH 0 0 309A 3093 309C OH 0 OH QH 0M3 QH CI ' T CI CI i i i CszN D D CszN CszN D 0 0 0 309D 309E 309F :N: QH N QH : ' CI CI CszN D—> NH2 134 0 0 309H To a solution of Compound 309A (31.7 g, 154 mmol) in yl pyrrolidinone (300 mL) was added cesium ate (100.4 g, 308 mmol) and bromocyclopentane (68.4 g, 462 mmol). The mixture was stirred for 24 h while keeping inner ature between 145 0C and 155 0C. After the reaction was cooled to ambient temperature, the dark solution was diluted with water (400 mL) and ted with a mixture of ethyl acetate in petroleum ether (15% V/V) (300 mL x 3). The combined organic phases were washed with brine (150 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a brown oil. The crude product was purified with ﬂash column chromatography on silica gel (petroleum ether) to ﬁamish Compound 309B.

To a solution of Compound 309B (32 g, 116.8 mmol) in dry THF (360 mL) maintained at -70 0C was added n-BuLi (2.5 M in hexane, 46.7 mL) dropwise under nitrogen atmosphere over a period of 20 minutes. After the reaction was stirred for 40 s at -70 0C, nd A4 (18.5 g, 46.7 mmol) dissolved in dry THF (50 mL) was added slowly to the cold solution at a rate that maintained the internal ature between-70 0C and-50 0C.

After the addition was complete, the solution was left to stir for l h. The on was ed with saturated ammonium chloride solution (400 mL), extracted with ethyl acetate (400 mL x 3), washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to ﬁamish the crude Compound Q). The crude product was puriﬁed with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, from 5% to 20% v/v) to ﬁamish Compound 309C.

A solution of Compound 309C (14.1 g, 26.5 mmol) in a mixture of tetrahydrofuran water and glacial acetic acid (450 mL, l/l/3, v/v/v) was stirred at 25 0C for h. After that, the on mixture was concentrated under reduced pressure to remove excess solvent. The reaction the residue was poured into ice water (20 g) and adjusted pH 7~8 with aqueous sodium hydroxide (1 N) and saturated aqueous sodium bicarbonate solution.

The solution was extracted with ethyl acetate (100 mL x 3). The ed organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude target nd, which was ﬁarther purified with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, from 30% to 50% v/v) to give Compound 309D.

To a solution of Compound 309D (10.0 g, 24.0 mmol) in dry THF (500 mL) maintained at -78 0C was added diisobutylaluminum hydride (1.0 M in toluene, 96 mL) dropwise under nitrogen atmosphere over a period of 15 minutes. After the reaction was d at -70 0C for l h, a solution of HCl (2 N, 100 mL) was added to the mixture slowly.

The reaction e was extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude target nd, which was further purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 50% to 150% v/v) to furnish Compound 309E.

To a solution of Compound 309E (9.25 g, 24.0 mmol) dissolved in tetrahydrofuran (300 mL) was added triethylamine (7.3 g, 72.0 mmol). The mixture was cooled to -30 0C, and then methanesulfonyl chloride (3 g, 26.4 mmol) was added dropwise over a period of 15 minutes. After the addition was complete, the reaction was stirred at -30 0C for 1.5 h, diluted with water (150 mL), and extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford crude nd 309F, which was directly used for the next step without further puriﬁcation.

To a solution of Compound 309F 11.2 g, purity 70%) in tetrahydrofuran (50 mL) was added pyrrolidine (13.5 g, 190 mmol). The reaction mixture was allowed to heat to 50 0C for 16 h. The mixture was diluted with water (100 mL), extracted with ethyl acetate (250 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to ﬁamish a crude nd. The crude product was puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, 5% V/V) to give Compound 309G.

To a solution of Compound 309G (800 mg, 1.69 mmol) in ethanol (12 mL) and water (2 mL) was added LiOH‘HZO (284 mg, 6.76 mmol). The mixture was heated to 80 0C and stirred for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish Compound 309H, which was directly used for the next step without further ation.

To a solution of Compound 309H (200 mg, 0. 6 mmol), Intermediate C (146 mg, 0.6 mmol), and HATU (456 mg, 1.2 mmol) in N,N—dimethylformamide (3 mL) was stirred at room ature for 1 h. The reaction on was d with prep-HPLC to furnish Compound 309. LC-MS (ESI) m/z: 565 [M+H]+; 1H-NMR dg, 400 MHz): 5 (ppm) 1.55-1.74 (m, 6H), 1.87-202 (m, 6H), .54 (m, 6H), 4.51-4.91 (m, 3H), 6.01 (d, J = 4.4 Hz, 1H), 7.12 (d, J: 8.8 Hz, 1H), 7.29 (dd, .1: 88,20 Hz, 1H), 7.33-7.42 (m, 3H), 7.70-7.81 (m, 6H), 8.81 (d, J: 10.0 Hz, 1H), 9.34 (s, 1H).

Example 310 Br N/ Bl’ / \ \ N\ —> N + >*N\ N N H 4 310A 3103 310c —354— A mixture of Compound 310A (2.11 g, 10 mmol), 2-bromopropane (2.46 g, 20 mmol), and K2C03 in DMF (40 mL) was stirred at 100 0C overnight. The mixture was diluted with ethyl acetate (200 mL), washed with water (200 mL x 4) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 33% v/v) to afford Compound 310B and Compound 310C.

A mixture of nd 310C (330 mg, 1.3 mmol), Compound 175B (594 mg, 1.96 mmol), Pd(PPh3)2Clz (91 mg, 0.13 mmol), and K2C03 (333 mg, 2.6 mmol) in dioxane (6 mL) and water (0.6 mL) was stirred at 80 0C for 2 h. The e was cooled down and filtered. The precipitate was dissolved in water and washed with ethyl acetate (50 mL). The aqueous layer was adjusted to pH 2 with concentrated HCl and extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium e and concentrated to yield Compound 310D. 08] A mixture of Compound 310D (100 mg, 0.31 mmol), Intermediate C (96 mg, 0.31 mmol), and HATU (177 mg, 0.465 mmol) in DCM (2 mL) was stirred at room temperature overnight. The mixture was diluted with DCM (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over ous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 310. LC-MS (ESI) m/z: 615 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.64-0.70 (m, 2H), 0.79-0.85 (m, 2H), 1.52 (d, J: 6.4 Hz, 6H), 1.86-1.92 (m, 2H), 2.01-2.06 (m, 2H), 2.71 (s, 3H), 3.09-3.24 (m, 2H), 3.46-3.59 (m, 4H), 3.93-3.98 (m, 1H), 4.56-4.60 (m, 1H), 4.86-4.91 (m, 2H), 6.04-6.08 (m, 1H), 7.35-7.46 (m, 3H), 7.60-7.62 (m, 1H), 7.67-7.69 (m, 1H), .76 (m, 2H), 7.81- 7.84 (m, 2H), 8.13 (s, 1H), 8.81 (d, J: 10.0 Hz, 1H), 9.43 (brs, 1H).

Example 311 \ \ O\/ N\ / N >¥N\ / O 2583 311A H \ a N >_N \\N/ 3113 311 To a solution of Compound 256B (717 mg, 3.0 mmol) in THF (20 mL) was added dropwise n-BuLi (1.2 mL, 2.5 M in hexane, 3.0 mmol) under nitrogen atmosphere at - 60 0C. The reaction mixture was d at the same temperature for 30 minutes. Compound diethyl oxalate (1.31 g, 9.0 mmol) was added. The resulting mixture was d at -60 0C for an additional 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and ted with ethyl acetate (40 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, ﬁltered, evaporated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl e in eum ether, 10% v/v) to give Compound 311A.

To a solution of Compound 311A (20 mg, 0.077 mmol) in MeOH (2 mL) was added LiOH-HZO (4 mg, 0.095 mmol) and water (1.0 mL). The reaction mixture was d at 15 0C for 4 h. The reaction mixture was neutralized with HCl (1 N). The resulting mixture was evaporated. The residue was dissolved in water (3 mL). The mixture was extracted with ethyl acetate (5 mL x 2), dried over anhydrous sodium sulfate, ﬁltered, and evaporated to give Compound 311B.

To a solution of Compound 311B (17 mg, 0.073 mmol) in DMF (3 mL) was added Intermediate G (22 mg, 0.073 mmol) and HATU (28 mg, 0.073 mmol). The on mixture was stirred at 20 0C for 2 h. The mixture was puriﬁed with prep-HPLC to yield Compound 311. LC-MS (m/z) 525 [M+H]+; 1H-NMR(DMSO-d(5, 400 MHz): 5 (ppm) 0.62- 0.66 (m, 2H), .81 (m, 2H), 1.57 (d, J: 10.8 Hz, 6H), 1.87-1.89 (m, 2H), 2.01-2.03 (m, 2H), 3.11-3.22 (m, 2H), 3.47-3.55 (m, 4H), 3.90-3.93 (m, 1H), 4.55-4.60 (m, 2H), .91 (m, 2H), 7.35-7.44 (m, 3H), 7.64-7.67 (m, 2H), 8.27 (s, 1H), 8.64 (s, 1H), 8.71-8.74 (m, 1H), 9.39 (brs, 1H).

Example 312 N\ OH y" / + : 3163 A mixture of Compound 316B (70 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol), and Intermediate C (93 mg, 0.30 mmol) in DMF (5 mL) was d at 10 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to afford Compound 312. LC-MS (ESI) m/z: 511 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.57 (d, J: 6.8 Hz, 6H), 1.88- 2.04 (m, 4H), 3.10—3.20 (m, 2H), 3.43-3.56 (m, 4H), .30 (m, 4H), 4.51—4.55 (m, 1H), 4.77 (d, .1: 2.4 Hz, 1H), 4.86—4.96 (m, 1H), 6.76 (s, 1H), 6.82 (dd, .1: 11.6, 2.0 Hz, 1H), 7.45 (dd, .1: 8.4, 1.2 Hz, 1H), 7.80 (d, .1: 8.8 Hz, 1H), 8.29 (m, 1H), 8.56 (s, 1H), 8.71 (d, .1 = 9.6 Hz, 1H), 9.29 (brs, 1H).

Example 313 BrU ~ U22—Cl Br CI CI CszN 2:~ OH 0 0 313A 3133 OH 0 OH QH OMS QH Cl ' 1 CI Cl Cszﬁ D i Cb Hﬁ D z CszN D o 0 0 313C 3130 313E To a on of 4-bromochlorophenol (5.0 g, 24 mmol) in l-methyl pyrrolidinone (70 mL) was added cesium carbonate (15.6 g, 48 mmol) and bromocyclobutane (9.7 g, 72 mmol). The mixture was stirred for 24 h while keeping inner temperature between 145 0C and 155 0C. After the reaction mixture was cooled to ambient ature, the dark solution was diluted with water (100 mL) and extracted with a mixture of ethyl acetate in petroleum ether (15% V/V) (100 mL x 3). The combined organic phases were washed with brine (150 mL x 4), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford the crude product as a brown oil. The crude product was puriﬁed with ﬂash column chromatography on silica gel leum ether) to ﬁlrnish Compound 313A.

To a solution of Compound 313A (15.6 g, 60 mmol) in dry THF (500 mL) maintained at -70 0C was added n-BuLi (60 mmol, 2.4 M in hexane, 25 mL) dropwise under nitrogen atmosphere over a period of 20 minutes. After the reaction mixture was stirred at -70 0C for 40 s, Compound A4 (7.9 g, 20 mmol) dissolved in dry THF (50 mL) was added slowly to the cold solution at a rate that maintained the internal temperature between -70 0C and -50 0C. After the addition was complete, the solution was left to stir for 1 h. The reaction mixture was quenched with ted ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to ﬁamish the crude Compound 313B. The crude product was purified with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, from 5% to 10% v/v) to ﬁamish Compound 313B.

A solution of Compound 313B (8.5 g, 16.4 mmol) in a mixture of tetrahydrofuran, water, and l acetic acid (250 mL, 1/1/3, v/v/v) was stirred at 25 0C for 72 h. The reaction mixture was concentrated under reduced pressure to remove excess solvent. The residue was poured into ice water (20 g) and adjusted to pH 7~8 with s sodium hydroxide (1 N) and saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100 mL x 3). The combined c phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude target compound, which was ﬁarther ed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 30% to 50% v/v) to give Compound 313C.

To a on of Compound 313C (1.2 g, 2.97 mmol) in dry THF (700 mL) maintained at -78 0C was added diisobutylaluminum hydride (1.0 M in toluene, 11.9 mL) dropwise under nitrogen atmosphere over a period of 15 s. After the reaction e was stirred at -70 0C for 1 h, a solution of HCl (2 N, 20 mL) was added to the mixture slowly.

The reaction mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, ed, and concentrated to afford the crude target compound, which was further purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 50% to 150% v/v) to furnish Compound 313D.

To a solution of Compound 313D (607 mg, 1.50 mmol) dissolved in THF (15 mL) was added triethylamine (454 mg, 4.50 mmol). The mixture was cooled to -30 0C, and then methanesulfonyl chloride (188 mg, 1.65 mmol) was added dropwise over a period of 15 minutes. After the addition was complete, the reaction mixture was stirred at -30 0C for 1.5 h, d with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, WO 42397 ﬁltered, and concentrated to afford Compound 313E, which was directly used for the next step without further puriﬁcation.

To a solution of Compound 313E (690 mg, 1.42 mmol) in THF (30 mL) was added pyrrolidine (1.0 g, 14.2 mmol). The reaction e was allowed to heat to 50 0C for 16 h. The mixture was diluted with water (15 mL), extracted with ethyl acetate (75 mL x 2), washed with brine (25 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, 5% V/V) to give Compound 313F.

To a on of Compound 313F (330 mg, 0.72 mmol) in ethanol (6 mL) and water (1 mL) was added LiOH‘HZO (121 mg, 2.88 mmol). The mixture was heated to 80 0C and stirred for 10 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish Compound 313G, which was directly used for the next step without further puriﬁcation.

To a solution of nd 313G (75 mg, 0.23 mmol) in romethane (5 mL) was added Intermediate C (56 mg, 0.23 mmol) and (dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid orophosphate (131 mg, 0.345 mmol). The reaction mixture was stirred at 20 0C for 5 h. The resulting mixture was washed with brine.

The organic phase was dried over anhydrous sodium sulfate, ﬁltered, and trated. The crude product was puriﬁed with prep-HPLC to yield Compound 313. LC-MS (ESI) m/z: 551 [M+H]+; 1H-NMR (DMSO-dg, 400 MHZ): 5 (ppm) 1.60-1.63 (m, 1H), 1.74-1.77 (m, 1H), 1.89-1.91 (m, 2H), 2.00-2.08 (m, 4H), 2.41-2.45 (m, 2H), 3.15-3.22 (m, 2H), 3.45-3.48 (m, 3H), 3.55-3.56 (m, 2H), 4.55-4.56 (m, 1H), 4.71-4.75 (m, 1H), 4.87 (s, 1H), 6.03 (s, 1H), .98 (m, 1H), 7.26-7.29 (m, 1H), 7.36-7.40 (m, 2H), 7.44-7.45 (m, 1H), 7.73-7.76 (m, 3H), 7.80-7.84 (m, 2H), 8.79-8.81 (m, 1H), 9.47 (brs, 1H).

Example 314 31GB 314A 314B 314 A mixture of Compound 310B (330 mg, 1.3 mmol), Compound 175B (594 mg, 1.96 mmol), 3)2Clz (91 mg, 0.13 mmol), and K2C03 (333 mg, 2.6 mmol) in dioxane (6 mL) and water (0.6 mL) was d at 80 0C for 2 h. The mixture was cooled down, diluted with ethyl acetate (200 mL), washed with water (200 mL x 4) and brine (100 mL), dried over ous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to yield Compound 314A. 22] A mixture of Compound 314A (240 mg, 0.68 mmol) and LiOH'HgO (43 mg, 1.03 mmol) in THF (5 mL) and water (0.5 mL) was stirred at room temperature overnight.

The mixture was diluted with water (50 mL), adjusted to pH 2 with concentrated HCl, and extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield Compound 314B.

A mixture of nd 314B (120 mg, 0.372 mmol), Intermediate G (l 15 mg, 0.372 mmol), and HATU (211 mg, 0.555 mmol) in dichloromethane (3 mL) was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was ed with prep-HPLC to give Compound 314. LC- MS (ESI) m/z: 615 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.63-0.70 (m, 2H), 0.79-0.86 (m, 2H), 1.48 (d, J: 6.4 Hz, 6H), 1.87-1.93 (m, 2H), 2.02-2.07 (m, 2H), 2.57 (s, 3H), 3l3-3.24 (m, 2H), 3.49-3.60 (m, 4H), 3.93-3.98 (m, 1H), 4.52-4.61 (m, 1H), 4.89-5.00 WO 42397 (m, 2H), 6.06-6.07 (m, 1H), 7.35-7.46 (m, 3H), 7.73-7.79 (m, 4H), 7.82-7.86 (m, 2H), 8.11 (d, J: 7.2 Hz, 1H), 8.81-8.83 (m, 1H), 9.43 (brs, 1H).

Example 315 2953 315 To a solution of Compound 295B (78 mg, 0.3 mmol) in DMF (1.5 mL) and dichloromethane (4 mL) was added Intermediate C (100 mg, 0.33 mmol) and HATU (171 mg, 0.45 mmol). The reaction mixture was stirred at 25 0C for 3 hours. The mixture was puriﬁed with prep-HPLC to yield Compound 315. LC-MS (m/z) 537 [M+H]+; 1H-NMR dg, 400 MHz): 5 (ppm) 1.80-1.87 (m, 4H), 2.25 (s, 3H), .15 (m, 2H), 3.44-3.53 (m, 3H), 4.25-4.27 (m, 5H), 4.47-4.52 (m, 1H), 4.76 (s, 1H), 6.05 (s, 1H), 6.76-6.80 (m, 2H), 7.17-7.26 (m, 2H), 7.49 (d, J: 8.4 Hz, 2H), 7.88 (d, J: 8.4 Hz, 2H), 8.76 (d, J: 10 Hz, 1H), 9.30 (brs, 1H).

Example 316 N\ Br N\ O\/ N —> >7N —> / / o 2563 316A N\ OH >7N / O /N\ 31GB To a solution of Compound 256B (640 mg, 2.69 mmol) in dry THF (10 mL) was added dropwise n-BuLi solution (2.5 M in hexane, 1.1 mL, 2.72 mmol) under nitrogen at -78 0C. The mixture was stirred at -78 0C for 30 min and diethyl oxalate (0.91 mL, 6.73 mmol) was added quickly to the above mixture. The mixture was stirred at -78 0C for 30 min, quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (80 mL x 2). The combined c extracts were dried over ous sodium sulfate, d, and concentrated in vacuo. The crude product was puriﬁed with ﬂash column WO 42397 chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 20% V/V) to h Compound 316A.

To a solution of Compound 316A (180 mg, 0.69 mmol) in methanol (3 mL) was added LiOH'HzO (44 mg, 1.04 mmol) in water (3 mL) and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was adjusted to pH 3 with s HCl solution (3 N) and concentrated in vacuo. The residue was in lyophilization to afford Compound 316B.

A mixture of Compound 316B (70 mg, 0.30 mmol), HATU (171 mg, 0.45 mmol), and Intermediate G (93 mg, 0.30 mmol) in DMF (5 mL) was stirred at 10 0C for 18 h.

The mixture was directly purified with PLC to yield Compound 316. LC-MS (ESI) m/z: 525 ; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.67-0.81 (m, 4H), 1.67 (d, J: 6.8 Hz, 6H), 2.04-2.22 (m, 4H), 3.22-3.28 (m, 2H), 3.55-3.61 (m, 1H), 3.68-3.89 (m, 4H), 4.66- 4.69 (m, 1H), 4.87-4.90 (m, 1H), 4.95 (d, J: 3.2 Hz, 1H), 7.37 (s, 2H), 7.44-7.47 (m, 2H), 7.75 (d, J: 8.8 Hz, 1H), 8.37 (s, 1H), 8.39 (s, 1H).

Example 317 Br 0 N\ —> N\ —> O N\ 4 4 N 31GB 307A 3173 To a solution of Compound 310B (245 mg, 0.97 mmol) in dry THF (12 mL) maintained at -70 0C was added n-BuLi (2.5 M in hexane, 0.4 mL) dropwise under nitrogen atmosphere over a period of 5 minutes. After the reaction mixture was stirred at -70 0C for 40 minutes, diethyl e (355 mg, 2.4 mmol) was added in one portion. The mixture was stirred at 60 0C for 2 hours. The solution was quenched with saturated um chloride solution and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to give Compound 317A. 2014/056555 To a solution of Compound 317A (260 mg, 0.96 mmol) in THF (9 mL) was added LiOH'HzO (70 mg, 1.66 mmol) in water (3 mL) at -5 0C, the mixture was stirred at this temperature for 5 hours. The reaction mixture was treated with ice water (20 mL) and extracted with ethyl acetate (50 mL). The water layer was adjusted to pH 2 with diluted HCl and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium e, and concentrated. The resulting solid was washed with petroleum ether and ﬁltered to afford the crude Compound 317B.

A mixture of Compound 317B (75 mg, (0.3 mmol), HATU (174 mg, 0.46 mmol), and Intermediate G (1 13 mg, 0.36 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was treated with water (20 mL), extracted with dichloromethane 50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium e, and concentrated. The crude product was purified with PLC to give Compound 317. LC-MS (ESI) m/z: 539.2 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.45-0.75 (m, 4H), 1.53-1.56 (m, 6H), 2.04-2.23 (m, 4H), 2.55 (d, J: 4.0 Hz, 3H), 3.21-3.32 (m, 2H), .60 (m, 1H), 3.70-3.77 (m, 4H), 4.67 (d, J: 10.8 Hz, 1H), 4.90 (s, 1H), 4.98 (d, J: 2.8 Hz, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.37 (dd, J: 2.0 Hz, 8.4 Hz, 1H), 7.46 (d, J: 2.0 Hz, 1H), 7.52 (d, J: 8.8 Hz, 1H), 7.76 (dd, J: 1.6 Hz, 9.2 Hz, 1H), 8.36 (d, J: 0.8 Hz, 1H).

Example 318 / \ / N\ —N\ / + N\ N N Br N Br H / 310A 318A 3183 3180 To Compound 310A (1.9 g, 9.05 mmol) in DMF (15 mL) was added sodium hydride (60% in l, 398 mg, 9.96 mmol) with ice bath cooling. The mixture was stirred for 30 min at room temperature and iodomethane (0.94 mL, 27.15 mmol) was added. The reaction mixture was stirred at room ature for 3 h, ed with ammonium chloride solution (30 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over ous sodium sulfate, trated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 90% v/v) to give Compound 318A and Compound 318B.

A mixture of Compound 318B (225 mg, 1 mmol), Compound 175B (477 mg, 1.57 mmol), Pd(PPh3)2Clz (70 mg, 0.1 mmol), and K2C03 (256 mg, 2 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 80 0C for 2 h. The mixture was cooled down and ﬁltered. The precipitate dissolved with water (10 mL) and puriﬁed with reverse phase chromatography using eluent nol in water, from 0% to 100% v/v) to yield Compound 318C.

A mixture of Compound 318C (70 mg, 0.238 mmol), Intermediate G (74 mg, 0.238 mmol), and HATU (136 mg, 0.357 mmol) in dichloromethane (2 mL) was stirred at room ature overnight. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 318. LC- MS (ESI) m/z: 587 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.66-0.70 (m, 2H), 0.80-0.85 (m, 2H), 1.87-1.92 (m, 2H), 2.02-2.07 (m, 2H), 2.55 (s, 3H), 3.11-3.24 (m, 2H), 3.49-3.58 (m, 4H), 3.93-3.98 (m, 1H), 4.00 (s, 3H), 4.55-4.62 (m, 1H), .90 (m, 1H), 6.06-6.07 (m, 1H), 7.35-7.46 (m, 3H), 7.70-7.86 (m, 6H), 8.13 (s, 1H), 8.82 (d, J: 9.6 Hz, 1H), 9.44 (brs, 1H).

Example 319 Br\(>:0j Br\©:0] TB8Omoj —> —> HN \ —> O O Cbz 0 319A 3193 OH OH OMS OH Wjﬁmjﬁmjﬁ 319C 319D 319E W1~Vajﬁomj319F 3196 A mixture of 6-bromo-2,3-dihydrobenzo[b][l,4]dioxane (1.07 g, 5 mmol), NBS (2.1 g, 12 mmol), and AIBN (20 mg) in CCl4 (60 mL) was reﬂuxed under nitrogen for 18 h. The e was cooled down to room temperature and d. The ﬁltrate was washed with water (50 mL x 2) and dried over anhydrous ium sulfate. After removal of the solvent, the residue was dissolved in acetone (50 mL) and reﬂuxed under nitrogen for 3 h with NaI (3.75 g, 25 mmol). The mixture was cooled down to room temperature and evaporated. The residue was diluted with water (100 mL) and ted with dichloromethane (50 mL x 3). The organic layer was washed with aqueous Nazszog solution (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (petroleum ether, 100% v/v) to yield Compound 319A.

To a solution of Compound A4 (5.7 g, 26.8 mmol) in THF (120 mL) was added n-BuLi (2.5 M in hexane, 14.4 mL, 36 mmol) under nitrogen at -78 0C. The mixture was stirred at -78 0C for 0.5 h and a solution of Compound 319A (3.6 g, 9 mmol) in THF (30 mL) was added. The mixture was stirred at -78 0C for 5 min, quenched with saturated aqueous ammonium chloride on (100 mL), and ted with ethyl acetate (200 mL x 3). The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 9% v/v) to ﬁlI'IllSh nd 319B.

A e of Compound 319B (100 mg) in AcOH (5 mL), THF (2 mL), and water (2 mL) was stirred at 40 OC overnight. The mixture was cooled down to room temperature, diluted with brine (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layer was adjusted to pH 8 with saturated aqueous sodium bicarbonate on (30 mL) and separated. The c layer was dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to afford Compound 319C.

To a solution of Compound 319C (1 .5 g, 4.2 mmol) in THF (30 mL) was added se DIBAL-H (l .5 N in toluene, 12 mL, 17 mmol) under nitrogen at -80 0C. The mixture was d under nitrogen at -70 0C for 0.5 h, quenched with aqueous en chloride solution (1 N, 50 mL), and extracted with ethyl acetate (50 mL x 3). The c layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 55% v/v) to give nd 319D.

To a solution of Compound 319D (1.48 g, 4 mmol) and triethylamine (1.2 g, 12 mmol) in THF (30 mL) was added dropwise MsCl (0.52 g, 4.6 mmol) under nitrogen at - 0C. The e was stirred under nitrogen at -15 0C for l h, quenched with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to ﬁamish Compound 319E.

To a solution of Compound 319E (l .74 g, 4 mmol) in THF (50 mL) was added pyrrolidine (2.8 g, 40 mmol). The mixture was d at 50 0C ght. The mixture was cooled down to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, 5% v/v) to afford Compound 319F. 40] To a solution of Compound 319F (550 mg, 1.34 mmol) in ethanol (20 mL) was added a solution of LiOH‘HZO (225 mg, 5.37 mmol) in water (5 mL). The mixture was stirred at 100 0C overnight. After removal of l, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to furnish Compound 319(1 A mixture of Compound 319G (100 mg, 0.36 mmol), Compound 133D (88 mg, 0.36 mmol), and HATU (275 mg, 0.72 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was directly puriﬁed with prep-HPLC to yield Compound 319. LC-MS (ESI) m/z: 503 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.86-1.93 (m, 2H), 2.02-2.03 (m, 2H), 3.10-3.22 (m, 2H), 3.44-3.47 (m, 2H), 3.53-3.56 (m, 2H)44%454@mlHL476(slHL599G,HD,619@LJ=40fh,HD,622@LJ=36 2014/056555 Hz, 1H), 6.72 (d, .1: 8.0 Hz, 1H), 6.74 (d, .1: 2.0 Hz, 1H), 6.89-6.92 (m, 1H), 7.35—7.40 (m, 2H), 7.82-7.90 (m, 6H), 8.79 (d, .1: 10.0 Hz, 1H), 9.34 (s, 1H).

Example 320 TBSO + —’ A—* A—> Cszlfl A SH 3 s 3 CI CI CI CI 320A 3203 320C OH 0 OH QH OMS QH CszN s/A CszN SA CszN s/A CI CI CI 32013 320E 320F N QH . m. A _ ; : Cb HN A "oS NH A CI CI 3206 3on 0 F 320 To a solution of 2-chlorobenzenethiol (7.2 g, 50 mmol) in DMSO (20 mL) was added potassium tert—butoxide (6.7 g, 60 mmol) in portions under nitrogen at 5 °C. The reaction mixture was stirred at 25 0C for 15 min. To the above on was added bromocyclopropane (12 g, 100 mmol) in DMSO (10 mL) dropwise. The reaction mixture was stirred under nitrogen at 80 0C. After the reaction mixture was cooled to ambient temperature, the dark solution was diluted with water (400 mL) and extracted with a mixture of ethyl acetate (60 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, ﬁltered, and trated to afford the crude t as a brown oil. The crude product was puriﬁed with ﬂash column chromatography on silica gel (petroleum ether) to furnish Compound 320A. 44] To a solution of Compound 320A (36 g, 195.6 mmol) in dry dichloromethane (600 mL) was added Brz (37.6 g, 235 mmol) at 5 0C dropwise. The reaction mixture was stirred at 25 0C for 22 hours. It was washed with water (200 mL), saturated sodium thiosulfate (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford the crude product as a brown oil. The crude product was puriﬁed with ﬂash column chromatography on silica gel leum ether) to ﬁlrnish Compound 3203.

To a solution of Compound 320B (23.6 g, 90 mmol) in dry THF (400 mL) maintained at -70 0C was added n-BuLi (2.5 M in hexane, 36.4 mL) dropwise under nitrogen atmosphere over a period of 20 minutes. After the on e was stirred at -70 0C for 40 minutes, Compound A4 (11.9 g, 30 mmol) dissolved in dry THF (20 mL) was added slowly to the cold solution at a rate that maintained the internal temperature between -70 0C and -50 0C. After the addition was complete, the solution was left to stir for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to ﬁamish the crude Compound 320C. The crude t was puriﬁed with ﬂash column tography on silica gel (ethyl e in petroleum ether, from 5% to 10% v/v) to ﬁlmish the pure Compound 320C.

A solution of Compound 320C (7.0 g, 13.5 mmol) in a mixture of tetrahydrofuran, water, and glacial acetic acid (145 mL, 1/ 1/3, v/v/v) was stirred at 25 0C for h. The reaction mixture was concentrated under reduced pressure to remove excess t. The residue was poured into ice water (20 g) and adjusted to pH 7~8 with aqueous sodium hydroxide (l N) and saturated aqueous sodium onate solution. The mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford the crude target compound, which was ﬁarther purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 30% to 50% v/v) to give Compound 320D.

To a solution of Compound 320D (2.4 g, 5.9 mmol) in dry THF (50 mL) maintained at -78 0C was added diisobutylaluminum hydride (1.5 M in toluene, 16 mL) dropwise under nitrogen atmosphere over a period of 15 minutes. After the reaction mixture was stirred at -70 0C for 1 h, a solution of HCl (2 N) was added to the mixture slowly. The on mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, ed, and concentrated to afford the crude target nd, which was further puriﬁed with ﬂash column chromatography on silica gel (ethyl e in eum ether, from 50% to 67% v/v) to furnish Compound 320E.

To a on of Compound 320E (1.69 g, 4.15 mmol) dissolved in THF (30 mL) was added triethylamine (1.26 g, 12.5 mmol). The e was cooled to -30 0C, and then methanesulfonyl chloride (526 mg, 4.57 mmol) was added dropwise over a period of 15 minutes. After the addition was complete, the reaction mixture was stirred at -30 0C for 1.5 h, d with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford Compound 320F, which was directly used for the next step without further purification.

To a solution of Compound 320F (910 mg, 1.88 mmol) in THF (60 mL) was added pyrrolidine (1.33 g, 18.8 mmol). The reaction mixture was allowed to heat to 50 0C for 16 h. The mixture was diluted with water (30 mL), extracted with ethyl acetate (60 mL x 2), washed with brine (20 mL), dried over ous sodium sulfate, ﬁltered, and concentrated to furnish a crude compound. The crude product was d with ﬂash column chromatography on silica gel (methanol in dichloromethane, 7% V/V) to give Compound 320(1 To a solution of Compound 320G (548 mg, 1.19 mmol) in ethanol (14 mL) and water (2 mL) was added LiOH‘HZO (200 mg, 4.77 mmol). The mixture was heated to 80 0C and stirred for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to ﬁamish Compound 320H, which was ly used for the next step without ﬁnﬂwrpuﬁﬁcaﬁon.

To a solution of nd 320H (100 mg, 0.3 mmol) in dichloromethane (10 mL) was added Compound 133D (56 mg, 0.23 mmol) and HATU (131 mg, 0.35 mmol). The reaction e was stirred at 25 0C for 3 hours. The mixture was puriﬁed with prep-HPLC to yield Compound 320. LC-MS (m/z) 553 [M+H]+; 1H-NMR(DMSO-d§, 400 MHz): 5 (ppm) 0.57 (s, 2H), 1.15 (d, J: 7.6 Hz, 2H), 1.88-1.90 (m, 2H), 2.04 (s, 2H), 2.24-2.26 (m, 1H), .23 (m, 2H), 3.42-3.56 (m, 4H), 4.59-4.61 (m, 1H), 4.92 (s, 1H), 6.12 (d, J: 4.0 Hz, 1H), 7.36-7.46 (m, 4H), 7.61 (d, J: 8.4 Hz, 1H), 7.71-7.81 (m, 6H), 8.85 (d, J: 10.0 Hz, 1H), 9.36 (s, 1H).

Example 321 O O Br O\/ OH N/ N/ N/ ‘N —> \N o —> ‘N o 258A 321A 321 B _, NH 53] To a on of Compound 258A (960 mg, 4.0 mmol) in THF (30 mL) was added se n-BuLi (1.6 mL, 2.5 M in hexane, 4.0 mmol) under nitrogen atmosphere at - 60 0C. The reaction mixture was stirred at the same temperature for 30 minutes. Compound diethyl oxalate (1.75 g, 12.0 mmol) was added. The resulting mixture was stirred at -60 0C for an additional 30 s. The reaction mixture was quenched with saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, ﬁltered, evaporated, and d with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 321A.

To a solution of Compound 321A (160 mg, 0.61 mmol) in MeOH (5 mL) was added LiOH-HZO (51 mg, 1.22 mmol) and water (1.0 mL). The reaction mixture was stirred at 15 0C for 4 h. The on mixture was neutralized with HCl (1 N). The resulting mixture was ated. The residue was dissolved in water (5 mL). The mixture was extracted with ethyl acetate (10 mL x 2), dried over ous sodium sulfate, ﬁltered, and evaporated to give Compound 321B.

To a solution of Compound 321B (70 mg, 0.30 mmol) in DMF (4 mL) was added Intermediate G (93 mg, 0.30 mmol) and HATU (81 mg, 0.45 mmol). The reaction mixture was stirred at 20 0C for 5 h. The mixture was puriﬁed with prep-HPLC to yield Compound 321. LC-MS (m/z) 525 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 0.57- 0.59 (m, 1H), 0.67-0.68 (m, 1H), 0.76-0.81 (m, 2H), 1.57 (d, J: 6.8 Hz, 6H), 2.09-2.11 (m, 2H), 2.27 (s, 2H), 3.47-3.51 (m, 2H), 3.82-3.86 (m, 2H), 3.99-4.02 (m, 3H), 4.91-4.92 (m, 1H), 5.04-5.07 (m, 1H), 5.19 (s, 1H), 1.27 (m, 1H), .43 (m, 1H), 7.50 (s, 1H), 7.69-7.71 (m, 1H), 7.93-7.96 (m, 1H), 8.12-8.14 (m, 1H), 8.21 (s, 1H), 8.55 (s, 1H), 9.01 (brs, 1H).

Example 322 N QH g 5 o OH N QH NH 1 : O:]______, "Iii O F NH2 N\ O F / 318C c 322 A mixture of Compound 318C (80 mg, 0.272 mmol), Intermediate C (81 mg, 0.272 mmol), and HATU (155 mg, 0.408 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over ous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 322. LC- MS (ESI) m/z: 573 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.84-1.93 (m, 2H), 1.99-2.08 (m, 2H), 2.55 (s, 3H), .21 (m, 2H), 3.43-3.56 (m, 4H), 4.00 (s, 3H), 4.25- 4.29 (m, 4H), 4.49-4.56 (m, 1H), .80 (m, 1H), 6.05-6.06 (m, 1H), 6.77 (s, 1H), 6.83 (d, J: 11.2 Hz, 1H), 7.69-7.72 (m, 1H), 7.79-7.82 (m, 1H), 8.02-8.04 (m, 4H), 8.17 (s, 1H), 8.74 (d, .1: 10.0 Hz, 1H), 9.40 (brs, 1H).

Example 323 COBr 01:40 VOO «N 4i A 266B 323A 323B 59] To a solution of Compound 266B (1.6 g, 6.7 mmol) in THF (70 mL) was added n-BuLi (2.5 M in hexane, 3.2 mL, 8 mmol) under nitrogen at -78 0C. The mixture was stirred at -78 0C for 0.5 h and diethyl oxalate (1.96 g, 13.4 mmol) was added at this temperature. The mixture was stirred at -78 0C for 0.5 h, quenched with saturated aqueous ammonium chloride solution (100 mL), and ted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (100 mL), dried over ous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to yield Compound 323A.

To a solution of Compound 323A (259 mg, 1 mmol) in THF (10 mL) was added a solution of LiOH'HzO (84 mg, 2 mmol) in water (3 mL). The mixture was stirred at room temperature overnight. After removal of THF, the mixture was acidiﬁed to pH 1 with aqueous HCl solution (1 N) and extracted with dichloromethane (20 mL). The organic layer was dried over anhydrous sodium sulfate and used directly for the next step as a dichloromethane on.

A mixture of Compound 323B in dichloromethane solution (115 mg, 0.5 mmol), Intermediate C (150 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) in dichloromethane (10 mL) and DMF (3 mL) was stirred at room temperature ght. The mixture was trated and the ing residue was puriﬁed with prep-HPLC to yield Compound 323. LC-MS (ESI) m/z: 510 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.47 (d, J: 6.8 Hz, 6H), 1.87-1.90 (m, 2H), 2.01-2.03 (m, 2H), 3.09-3.21 (m, 2H), 3.37-3.43 (m, 2H), 3.53-3.59 (m, 2H), 4.22-4.32 (m, 4H), 4.52-4.56 (m, 1H), 4.78-4.79 (m, 1H), 4.82- 4.87 (m, 1H), 6.00 (s, 1H), 6.65 (d, J: 2.8 Hz, 1H), 6.77 (s, 1H), 6.82 (d, J: 13.2 Hz, 1H), 7.60-7.69 (m, 3H), 8.10 (s, 1H), 8.67 (d, J: 9.6 Hz, 1H), 9.34 (s, 1H).

Example 324 323B 324 A mixture of Compound 323B in dichloromethane on (115 mg, 0.5 mmol), Intermediate G (155 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) in dichloromethane (10 mL) and DMF (3 mL) was stirred at room temperature overnight. The mixture was concentrated and the resulting residue was puriﬁed with prep-HPLC to yield Compound 324. LC-MS (ESI) m/z: 524 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.59-0.69 (m, 2H), 0.80-0.81 (m, 2H), 1.46 (d, J: 6.8 Hz, 6H), 1.87-1.89 (m, 2H), 2.03 (s, 2H), 3.12-3.20 (m, 2H), .57 (m, 4H), 3.89-3.90 (m, 1H), 4.57-4.62 (m, 1H), 4.80-4.83 (m, 1H), 4.88 (s, 1H), 6.01 (d, J: 4.0 Hz, 1H), 6.62 (d, J: 3.2 Hz, 1H), 7.34-7.40 (m, 2H), 7.45 (s, 1H), 7.58 (s, 2H), 7.68 (d, J: 3.6 Hz, 1H), 8.04 (s, 1H), 8.68 (d, J: 9.2 Hz, 1H), 9.38 (s, 1H).

Example 325 325C 325 To a solution of Compound 325A (1.63 g, 10.0 mmol) and ethyl 2-chloro oxoacetate (1.49 g, 11.0 mmol) in dichloromethane (50 mL) was added dropwise titanium chloride solution (1 M in dichloromethane, 20 mL, 20.0 mol) at -10° C. The mixture was stirred for 4 hours while keeping the ature at ~10° C. The mixture was poured into ice water, and then extracted with diethyl ether (50 mL x 3). The resulting product was concentrated under reduced pressure and puriﬁed with silica gel column chromatography (ethyl acetate in petroleum ether, 30% v/v) to give Compound 325B.

To a on of Compound 325B (263 mg, 1.00 mmol) in MeOH (5 mL) was added LiOH-HZO (63 mg, 1.50 mmol) and water (1.0 mL). The reaction mixture was stirred at 15 0C for 4 h. The reaction mixture was neutralized with HCl (1 N). The resulting mixture was evaporated. The residue was ved in water (5 mL). The mixture was extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, d, and ated to give Compound 325C.

To a solution of Compound 325C (71 mg, 0.31 mmol) in DMF (4 mL) was added Intermediate C (92 mg, 0.31 mmol) and HATU (81 mg, 0.45 mmol). The on mixture was stirred at 20 0C for 5 h. The mixture was puriﬁed with prep-HPLC to yield Compound 325. LC-MS (m/z) 514 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 2.06- 2.12 (m, 2H), 2.26-2.28 (m, 2H), 3.55-3.64 (m, 5H), .85 (m, 1H), 3.93-4.10 (m, 7H), 4.23-4.31 (m, 5H), 4.80-4.87 (m, 1H), 5.05-5.06 (m, 1H), 6.78-6.84 (m, 2H), 7.33-7.34 (m, 2H), 8.04-8.06 (m, 1H), 8.11-8.14 (m, 2H), 8.56 (brs, 1H).

Example 326 0A Cszlél 0A Cszlél 0A 326A 0' 326B Cl 66] To a solution of Compound G7 (3.8 g, 8.6 mmol) in dichloromethane (20 mL) was added dropwise SOClz (3.05 g, 25.7 mmol) under nitrogen at 0 0C. The resulting mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH 8 with sat. sodium bicarbonate solution, extracted with dichloromethane (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% V/V) to ﬁlrnish Compound 326A.

To a solution of Compound 326A (600 mg, 1.30 mmol) in methanol (20 mL) was added K2C03 (89 mg, 0.65 mmol) and Pt/C (60 mg). The resulting mixture was stirred under H2 at 25 0C for 12 h. The mixture was ﬁltered. The ﬁltrate was concentrated and the ing e was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, 50% V/V) to furnish Compound 326B.

To a solution of Compound 326B (288 mg, 0.67 mmol) in dichloromethane (15 mL) was added PdClz (30 mg). The resulting mixture was stirred under H2 at room temperature for 12 h. The mixture was ﬁltered. The ﬁltrate was treated with water (20 mL) and NHg’HgO (20 mL). The mixture was stirred at room temperature for 10 min, extracted with romethane (50 mL x 2), washed with brine (50 mL), dried over ous sodium sulfate, and concentrated to afford nd 326C.

A mixture of Compound 326C (90 mg, 0.3 mmol), Intermediate C (75 mg, 0.3 mmol), and HATU (170 mg, 0.47 mmol) in dichloromethane (20 mL) was stirred at room ature for 4 h. The mixture was treated with water (50 mL), extracted with dichloromethane (20 mL x 2), washed with water (20 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to furnish Compound —374— WO 42397 326. LC-MS (ESI) m/z: 521 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) .75 (m, 4H), 2.07 (s, 4H), 2.85-3.05 (m, 4H), 3.19-3.24 (m, 1H), 3.66-3.77 (m, 3H), 3.91 (s, 1H), 4.67 (s, 1H), 7.09-7.11 (m, 3H), 7.14-7.16 (m, 1H), 7.18-7.24 (m, 1H), 7.50-7.54 (m, 4H), 7.85 (d, J: 9.2 Hz, 1H), 7.95 (d, J: 8.4 Hz, 2H), 8.94 (s, 1H).

Example 327 Ct" 2730 327 A mixture of Compound 273C (90 mg, 0.41 mmol), HATU (234 mg, 0.62 mmol), and ediate I (121 mg, 0.41 mmol) in DMF (3 mL) was stirred at 25 0C for 16 h.

The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep- HPLC to ﬁlrnish Compound 327. LC-MS (ESI) m/z: 498 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.67-0.68 (m, 2H), 0.82-0.84 (m, 2H), 1.97-2.00 (m, 4H), 2.25-2.30 (m, 1H), 2.38-2.46 (m, 1H), 3.47-4.19 (m, 11H), 4.35-4.40 (m, 1H), 4.79 (s, 1H), 5.96 (s, 1H), 6.49 (d, J: 8.8 Hz, 2H), 7.28-7.31 (m, 1H), 7.38-7.40 (m, 2H), 7.56 (d, J: 8.8 Hz, 2H), 8.47 (d, J: 9.6 Hz, 1H), 9.62 (s, 1H).

Example 328 MOA "WOH Br"CI CI Cl 328A 3283 328C WC CH CI CO 328D 328E COOEt COOEt F F WOH—» ""04 CI Cl Cl 328F 3286 328H N QH F F = ""0004 F F ; .2 CI CO 0 Cl 328I C' To a mixture of nd 328A (2.4 g, 10 mmol), 3,3-diethoxyprop-l-ene (4 g, 30 mmol), and TBAC (2.7 g, 10 mmol) in DMF (80 mL) was added Pd(OAc)2 (224 mg, 1 mmol). The on mixture was stirred under nitrogen at 90 0C overnight. After the completion of reaction, the resulting e was cooled down to room temperature, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 50% v/v) to ﬁamish Compound 328B. 72] To a solution of Compound 328B (2.64 g, 10 mmol) in anhydrous THF (30 mL) was added lithium aluminum hydride (458 mg, 12 mmol) in portions under nitrogen at 0 0C. The mixture was stirred at room temperature for 0.5 h and ed with addition of water (2 mL). The resulting precipitation was ﬁltered. The ﬁltrate was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to afford Compound 328C. 73] To a solution of Compound 328C (2.2 g, 0.01 mol) in dichloromethane (40 mL) was artin periodinane (845 mg, 0.02 mol). After 4 hours, the reaction mixture was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to furnish a residue. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 50% v/v) to yield Compound 328D.

To a suspension of Compound 328D (218 mg, 1 mmol) and NaCN (74 mg, 1.5 mmol) in methanol (5 mL) was carefully added dropwise AcOH (1 mL). The reaction mixture was stirred at room temperature overnight. After removal of methanol, the e was dissolved in dichloromethane (40 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 50% v/v) to furnish Compound 328E.

A solution of Compound 328E (2.5 g, 10 mmol) in methanol (50 mL) was stirred under HCl gas at room ature for 6 h. The reaction e was quenched with water (30 mL) and stirred at room temperature for l h. After removal of solvent, the e was dissolved in ethyl acetate (200 mL), washed with brine (50 mL), dried over anhydrous sodium e, and concentrated to give Compound 328F.

A solution of Compound 328F (2.9 g, 10 mmol) and Dess-Martin inane (6.3 g, 15 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 h. After the completion of reaction, the reaction mixture was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 20% to 30% v/v) to afford Compound 328G.

To a solution of Compound 328G (2.9 g, 10 mmol) in dichloromethane (50 mmwwmmeAﬂXbmﬂM3mmdmnmmmmmmMeTMnmmmwwmmwm room temperature overnight. After the completion of the reaction, the reaction mixture was washed with water (50 mL x 3) and brine (50 mL), dried over ous sodium sulfate, and concentrated to afford a e. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 20% to 40% v/v) to give Compound 328H.

A mixture of nd 328H (3.1 g, 10 mmol) and LiOH'HzO (l .2 g, 28.4 mmol) in ethanol/water (40 mL/4 mL) was stirred at room temperature overnight. After the completion of the reaction, the reaction mixture was adjusted to pH 6 with s HCl solution (2 N, 1.5 mL). After removal of solvent, the residue was dissolved in ethyl acetate (200 mL), washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to ﬁamish Compound 3281.

To a mixture of Compound 3281 (142 mg, 0.5 mmol) and ediate G (232 mg, 0.75 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight and the resulting solution was diluted with ethyl acetate (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with reverse phase chromatography using eluent nol in water, from 10% to 55% v/v) to furnish Compound 328. LC-MS (ESI) m/z: 577 ; 1H-NMR , 400 MHz): 5 (ppm) 0.28-0.29 (m, 2H), 0.41-0.51 (m, 2H), 2.01-2.23 (m, 6H), 2.39-2.65 (m, 2H), 3.18-3.35 (m, 3H), 3.51-3.59 (m, 1H), 3.63-3.84 (m, 3H), 3.61-3.65 (m, 1H), 4.94 (s, 1H), 7.19-7.21 (m, 1H), 7.31-7.38 (m, 2H), 7.42-7.51 (m, 2H), 7.61 (s, 1H), 7.76-7.89 (m, 3H).

Example 329 O OH o BrUCI TBSO/\;)‘\©:CI CI ‘ ‘ Cb HNZ 0/: 0/—_ CbZHN 0/—_ 329A 3293 329C OH QH OMs QH N 9H RACECI K/‘UCI ‘ CI : : CszN 0/—_ CszN 0/— _ _ Cb2H151 0/— 329D 329E 329F N OH Z 5 = N QH 5 NH O; —» VII a _. o NH2 0 3296 O F 329 80] To a solution of Compound 329A (19.8 g, 85.4 mmol) in dry THF (600 mL) maintained at -70 0C was added n-BuLi (2.5 M in hexane, 34.5 mL) dropwise under en atmosphere over a period of 20 minutes. After the reaction mixture was stirred at -70 0C for 40 minutes, Compound A4 (12 g, 30.4 mmol) ved in dry THF (50 mL) was added slowly to the cold solution at a rate that maintained the internal temperature between -70 0C and -50 0C. After the addition was complete, the solution was left to stir for l h. The reaction mixture was quenched with saturated ammonium chloride solution (400 mL) and extracted with ethyl acetate (300 mL x 3). The organic phase was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to mmish the crude Compound 329B. The crude t was purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 5% to 10% v/v) to mmish Compound 329B.

A solution of Compound 329B (7.4 g, 15.1 mmol) in a mixture of tetrahydrofuran, water, and glacial acetic acid (153 mL, 1/ U3, v/v/v) was stirred at 25 0C for h. The reaction mixture was concentrated under d pressure to remove excess solvent. The residue was poured into ice water (20 g) and adjusted to pH 7~8 with aqueous sodium hydroxide (l N) and saturated aqueous sodium bicarbonate on. The mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the WO 42397 crude target compound, which was ﬁarther puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, from 30% to 50% v/v) to give Compound 329C.

To a on of Compound 329C (3.0 g, 8 mmol) in dry THF (140 mL) maintained at -78 0C was added diisobutylaluminum hydride (l .5 M in toluene, 25 mL) dropwise under nitrogen atmosphere over a period of 15 minutes. After the on mixture was stirred at -70 0C for l h, a solution of HCl (2 N, 40 mL) was added to the mixture slowly.

The reaction mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, ﬁltered, and trated to afford the crude target nd, which was further puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 50% to 150% v/v) to furnish nd 329D.

To a solution of Compound 329D (2.30 g, 6.10 mmol) dissolved in THF (100 rnL)wasaddeduimhybnnne(f90g,1881rmmoD.Thennxunewmscoobdto-30°C,and then methanesulfonyl chloride (0.80 g, 6.98 mmol) was added dropwise over a period of 15 minutes. After the addition was complete, the reaction mixture was stirred at -30 0C for 1.5 h, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford Compound 329E, which was directly used for the next step without further puriﬁcation.

To a solution of Compound 329E (3.81 g, 6.10 mmol) in THF (100 mL) was added pyrrolidine (ll g, 154 mmol). The reaction mixture was allowed to heat to 50 0C for 16 h. The mixture was diluted with water (100 mL), extracted with ethyl acetate (150 mL x 2), washed with brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, 5% v/v) to give Compound 329F.

To a solution of Compound 329F (1.33 g, 3.08 mmol) in ethanol (30 mL) and water (7 mL) was added zO (570 mg, 1351 mmol). The mixture was heated to 80 0C and stirred for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish Compound 329G, which was ly used for the next step without further ation.

A mixture of Intermediate C (80 mg, 0.32 mmol), Compound 329G (1 16 mg, 0.39 mmol), and HATU (187 mg, 0.49 mmol) in romethane (20 mL) was stirred at room temperature overnight. The mixture was d with dichloromethane (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 329. LC- MS (ESI) m/z: 523 [M+H]+; 1H-NMR (CD30D, 400 MHz): 5 (ppm) 2.05-2.23 (m, 4H), 3.20- 3.37 (m, 2H), 3.60-3.77 (m, 4H), 4.48-4.50 (m, 1H), 4.68-4.74 (m, 2H), 5.04 (s, 1H), 6.73- 6.78 (m, 1H), 7.15 (d, J: 8.4 Hz, 1H), 7.22-7.27 (m, 2H), 7.42 (dd, J: 8.4 Hz, 2.0 Hz, 1H), 7.58 (d, J: 1.6 Hz, 1H), .76 (m, 6H).

Example 330 330B ‘N/ 330 To a solution of 4-bromo-1H-pyrazole (2.92 g, 20.0 mmol) in anhydrous DMF (50 mL) was added 2-bromopropane (3.69 g, 30.0 mmol) and potassium carbonate (6.90 g, 50 mmol) at room temperature. The reaction mixture was stirred for 10 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The ed organic extracts were washed with brine (150 mL x 2) and dried over anhydrous sodium sulfate. After ﬁltration, the solvent was removed in vacuo and the residue was puriﬁed with ﬂash column chromatography on silica gel to give Compound 330A.

To a solution of Compound 330A (189 mg, 1.0 mmol) in 1,4-dioxane (10 mL) was added Intermediate 175B (304 mg, 1.0 mmol), Pd(dppf)C12 (35 mg, 0.05 mmol), sodium carbonate (318 mg, 3.0 mmol), and water (1 mL) under nitrogen. The reaction mixture was d at 110 0C for 2 hours. The resulting mixture was cooled to 25 0C. The itated solid was ﬁltered and dried to afford Compound 330B.

To a solution of nd 330B (25 mg, 0.10 mmol) in DMF (2 mL) was added Intermediate C (30 mg, 0.10 mmol) and HATU (57 mg, 0.15 mmol). The reaction mixture was stirred at 20 0C for 2 h. The mixture was purified with prep-HPLC to yield Compound 330. LC-MS (ESI) m/z: 537 ; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 1.61 (d, J: 6.4 Hz, 6H), 2.09-2.12 (m, 1H), 2.25-2.31 (m, 2H), 2.86 (s, 1H), 3.03 (s, 1H), 3.46-3.54 (m, 2H), 3.82-3.85 (m, 1H), 3.95-4.07 (m, 3H), 4.24-4.30 (m, 4H), 5.07-5.08 (m, 1H), 6.81-6.87 (m, 2H), 7.79-7.81 (m, 2H), 8.06-8.10 (m, 3H), 8.30 (s, 1H), 8.56 (s, 1H), 8.69 (brs, 1H).

Example 331 1 "N 5? w wBr B. 03 \ 0 331A 3313 \( N OH O t N OH \( o \ —> N NH \ o 331C 331 90] To a solution of 6-bromo-1H-indole (6 g, 30 mmol) in DMF (150 mL) was added sodium hydride (60% suspend in oil, 2.4 g, 60 mmol) at 0 0C. The mixture was stirred at 0 0C for 0.5 h and 2-iodopropane (7.6 g, 45 mmol) was added at 0 0C. The resultant mixture was stirred at room ature overnight and diluted with ethyl acetate (300 mL).

The c layer was washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 331A.

To a solution of Compound 331A (476 mg, 2 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 1 mL, 2.4 mmol) under nitrogen at -78 0C. The mixture was d at -78 0C for 0.5 h and diethyl oxalate (584 mg, 4 mmol) was added at -78 0C. The mixture was stirred at -78 0C for 0.5 h, quenched with saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The c layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to yield nd 331B.

To a solution of Compound 331B (368 mg, 1.42 mmol) in THF (10 mL) was added a solution of LiOH'HzO (120 mg, 2.84 mmol) in water (3 mL). The mixture was stirred at room temperature overnight. After l of THF, the mixture was acidiﬁed to pH 1 with aqueous HCl solution (1 N) and extracted with dichloromethane (20 mL). The organic layer WO 42397 was dried over anhydrous sodium sulfate and used directly for the next step as a dichloromethane solution.

A mixture of Compound 331C in romethane solution (115 mg, 0.5 mmol), Intermediate C (150 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) in dichloromethane (10 mL) and DMF (3 mL) was stirred at room temperature overnight. The mixture was concentrated and the resulting residue was puriﬁed with prep-HPLC to yield Compound 331. LC-MS (ESI) m/z: 510 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.46 (d, J: 6.8 Hz, 3H), 1.50 (d, J: 6.4 Hz, 3H), 1.85-1.88 (m, 2H), 2.02-2.03 (m, 2H), 3.09-3.20 (m, 2H), 3.41-3.44 (m, 2H), 3.52-3.56 (m, 2H), 4.23-4.25 (m, 4H), 4.50-4.55 (m, 1H), 4.76-4.81 (m, 2H), 6.02 (s, 1H), 6.60 (d, J: 3.2 Hz, 1H), 6.76 (s, 1H), 6.82-6.85 (m, 1H), 7.45-7.47 (m, 1H), 7.61 (d, J: 8.4 Hz, 1H), 7.85 (d, J: 3.2 Hz, 1H), 8.27 (s, 1H), 8.66 (d, J: 9.2 Hz, 1H), 9.33 (s, 1H).

Example 332 \ 0+ 0A —’ N 331C 332 A mixture of Compound 331C in romethane solution (115 mg, 0.5 mmol), Intermediate G (155 mg, 0.5 mmol), and HATU (380 mg, 1 mmol) in dichloromethane (10 mL) and DMF (3 mL) was stirred at room temperature overnight. The mixture was concentrated and the resulting residue was puriﬁed with prep-HPLC to yield Compound 332. LC-MS (ESI) m/z: 524 [M+H]+; 1H-NMR d6, 400 MHz): 5 (ppm) 0.62-0.65 (m, 2H), 0.79-0.81 (m, 2H), 1.45 (d, J: 6.8 Hz, 3H), 1.49 (d, J: 6.8 Hz, 3H), 1.86-1.88 (m, 2H), 2.00-2.03 (m, 2H), 3.12-3.20 (m, 2H), 3.45-3.47 (m, 4H), 3.87-3.90 (m, 1H), 4.54-4.58 (m, 1H), .80 (m, 1H), 4.85 (s, 1H), 6.05 (s, 1H), 6.59 (d, J: 3.2 Hz, 1H), 7.32-7.38 (m, 2H), 7.41-7.45 (m, 2H), 7.58 (d, J: 8.8 Hz, 1H), 7.84 (d, J: 3.2 Hz, 1H), 8.24 (s, 1H), 8.67 (d, J: 9.2 Hz, 1H), 9.39 (s, 1H).

Example 333 0 O 0" Q 9H mO/A; O + 0 K/\ Example 334 2014/056555 To a solution of 1-(4-bromoﬂuorophenyl)ethanone (1.0 g, 3.89 mmol) in 1,2-ethanediol (12 mL) was added 80% of hydrazine monohydrate (0.6 mL, 7.78 mmol) at room temperature. The reaction mixture was stirred at 200 0C in a microwave for 4.5 h, cooled down to room temperature, and quenched with water (50 mL). The solid precipitated was ﬁltered, washed with water (20 mL), and dried under vacuo to afford Compound 334A.

To Compound 334A (1.9 g, 9.05 mmol) in DMF (15 mL) was added sodium hydride (60% in mineral, 398 mg, 9.96 mmol) with ice bath cooling. The mixture was stirred at room temperature for 30 min and 2-iodopropane (2.7 mL, 27.15 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, quenched with ammonium chloride on (30 mL), and ted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and purified with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, from 0% to 20% V/V) to give Compound 334B and Compound 334C.

A mixture of Compound 334C (400 mg, 1.59 mmol), Compound 175B (483 mg, 1.59 mmol), Pd(dppf)C12 (65 mg, 0.08 mmol), and K2C03 (658 mg, 4.77 mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction e was cooled down to room ature and filtered through celite. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The aqueous layer was acidified to pH 3 with aqueous HCl solution (1 N) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to yield Compound 334D.

A mixture of Compound 334D (80 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol), and Intermediate G (78 mg, 0.25 mmol) in DMF (5 mL) was stirred at 20 0C for 18 h.

The mixture was directly purified with prep-HPLC to h nd 334. LC-MS (ESI) m/z: 615 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.65-0.85 (m, 4H), .51 (m, 6H), 1.89-2.08 (m, 4H), 2.53 (s, 3H), 3.14-3.25 (m, 2H), 3.45-3.49 (m, 4H), 3.94-3.97 (m, 1H), 4.57-4.62 (m, 1H), 4.92 (s, 1H), 5.03-5.09 (m, 1H), 6.10 (brs, 1H), 7.37-7.49 (m, 4H), 7.77 (d, J: 8.4 Hz, 2H), 7.81 (d, J: 5.6 Hz, 1H), 7.88 (d, J: 8.8 Hz, 2H), 8.01 (s, 1H), 8.86 (d, J: 10.0 Hz, 1H), 9.57 (brs, 1H).

Example 335 COOH N\ Br N\ A36a . woo ﬁw o IB / / 1753 3343 335A A mixture of Compound 334B (460 mg, 1.82 mmol), nd 175B (553 mg, 1.82 mmol), Pd(dppi)C12 (73 mg, 0.09 mmol), and K2C03 (753 mg, 5.46 mmol) in dioxane (5 mL) and water (5 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction e was cooled down to room temperature and ﬁltered through celite. The ﬁltrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The s layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and ted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated to give Compound 335A.

A mixture of Compound 335A (80 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol), and Intermediate C (74 mg, 0.25 mmol) in DMF (5 mL) was stirred at 20 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to furnish Compound 335. LC-MS (ESI) m/z: 601 ; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.52 (d, J: 6.4 Hz, 6H), 1.88- 2.05 (m, 4H), 2.67 (s, 3H), 3.10-3.22 (m, 2H), 3.43-3.55 (m, 4H), 4.24-4.29 (m, 4H), 4.49- 4.54 (m, 1H), 4.78 (d, J: 2.8 Hz, 1H), 4.86-4.92 (m, 1H), 5.99 (brs, 1H), 6.77 (s, 1H), 6.84 (dd, J: 11.6, 1.6 Hz, 1H), 7.36 (dd, J: 8.8, 1.2 Hz, 1H), 7.82 (d, J: 8.8 Hz, 1H), 7.88-8.01 (m, 5H), 8.75 (d, J: 9.6 Hz, 1H), 9.33 (brs, 1H).

Example 336 A mixture of Compound 335A (80 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol), and ediate G (78 mg, 0.25 mmol) in DMF (5 mL) was stirred at 20 0C for 18 h.

The mixture was directly d with prep-HPLC to furnish Compound 336. LC-MS (ESI) m/z: 615 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.69-0.85 (m, 4H), 1.52 (d, J: 6.8 Hz, 6H), 1.89-2.08 (m, 4H), 2.67 (s, 3H), 3.11-3.24 (m, 2H), .57 (m, 4H), 3.93-3.97 (m, 1H), 4.55-4.59 (m, 1H), 4.86-4.93 (m, 2H), 5.99 (brs, 1H), 7.36 (d, J: 8.8 Hz, 2H), 7.42- 7.46 (m, 2H), 7.77 (d, J: 8.8 Hz, 2H), 7.80-7.85 (m, 3H), 7.95 (s, 1H), 8.82 (d, J: 10.0 Hz, 1H), 9.34 (brs, 1H).

Example 337 0 O 0 mo] \g N 9H NH 0 COOH o _ o l \g 0 o F N'\ O NH2 0] N'\ O 334D c F 337 A mixture of Compound 334D (80 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol), and Intermediate C (74 mg, 0.25 mmol) in DMF (5 mL) was stirred at 20 0C for 18 h.

The mixture was directly d with prep-HPLC to furnish Compound 337. LC-MS (ESI) m/z: 601 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.48 (d, J: 6.4 Hz, 6H), 1.88- 2.08 (m, 4H), 2.53 (s, 3H), 3.11-3.22 (m, 2H), 3.39-3.55 (m, 4H), 4.20-4.29 (m, 4H), 4.51- 4.55 (m, 1H), 4.79 (d, J: 2.8 Hz, 1H), 5.03-5.09 (m, 1H), 6.03 (brs, 1H), 6.78 (s, 1H), 6.84 (d, J: 11.6 Hz, 1H), 7.48 (d, J: 8.8 Hz, 1H), 7.82 (d, J: 8.4 Hz, 1H), 7.92-7.97 (m, 4H), 8.02 (s, 1H), 8.77 (d, J: 9.6 Hz, 1H), 9.31 (brs, 1H).

Example 338 242F 338 To a solution of Intermediate I (172 mg, 0.58 mmol) in dichloromethane (10 mL) was added Compound 242F (140 mg, 0.58 mmol) and HATU (332 mg, 0.87 mmol). The mixture was stirred under nitrogen at room temperature overnight. The resulting mixture was ed with saturated aqueous sodium onate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford a crude compound. The crude product was puriﬁed with prep-HPLC to furnish Compound 338.

LC-MS (ESI) m/z: 519 ; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.62-0.64 (m, 2H), 0.78-0.79 (m, 2H), 2.22-2.28 (m, 1H), 2.33-2.42 (m, 1H), 3.30-3.31 (m, 1H), .90 (m, 1H), 4.02-4.30 (m, 6H), 4.78 (d, J: 2.4 Hz, 1H), 6.04 (s, 1H), 7.29 (dd, J: 8.8, 2.0 Hz, 1H), 7.37 (d, J: 8.4 Hz, 1H), 7.39 (d, J: 2.4 Hz, 1H), 7.55 (dd, J: 8.4, 2.0 Hz, 1H), 8.11 (d, J: 8.8 Hz, 1H), 8.30 (d, J: 1.6 Hz, 1H), 8.49 (s, 1H), 8.57 (d, J: 10.0 Hz, 1H), 9.49 (s, 1H). e 339 HO\ domjkm 2963 339 A mixture of 1-bromoisopropylbenzene (44 mg, 0.22 mmol), Compound 296B (110 mg, 0.22 mmol), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 8.2 umol), sodium carbonate (47 mg, 0.44 mmol), water (0.5 mL), and 1,4-dioxane (5 mL) was stirred under nitrogen atmosphere at 80 0C for 2 h. After cooling, the reaction mixture was treated with water (5 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford the crude product as a black oil. The oil was puriﬁed with prep-HPLC to furnish Compound 339.

LC-MS (ESI) m/z: 561 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.60-0.66 (m, 2H), .84 (m, 2H), 1.23 (d, J: 7.2 Hz, 6H), 1.82-1.92 (m, 2H), 1.97-2.07 (m, 2H), 2.91- 3.00 (m, 1H), 3.08-3.27 (m, 2H), 3.41-3.61 (m, 4H), .95 (m, 1H), 4.42-4,61 (m, 1H), 4.85-4.91 (m, 1H), 6.04 (d, J: 4.8 Hz, 1H), 7.33-7.44 (m, 5H), 7.64 (d, J: 12.4 Hz, 2H), 7.69-7.80 (m, 4H), 8.77 (d, .1: 10,0 Hz, 1H), 9.34 (s, 1H).

Example 340 Br Br / ,N\ ,N N\ —’ —N + N\ N Br 340A 3403 o o O\/ COOH 3403 + A3: 0 _. N 0 B I l N o \ 0 175B 340C To 6-bromomethyl-lH-indazole (1.9 g, 9.05 mmol) in DMF (15 mL) was added sodium hydride (60% in mineral, 398 mg, 9.96 mmol) with ice bath cooling. The mixture was stirred for 30 min at room temperature and iodomethane (0.94 mL, 27.15 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, quenched with ammonium de solution (30 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over ous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 90% V/V) to give Compound 340A and Compound 340B.

A mixture of Compound 340B (500 mg, 2.23 mmol), Compound 175B (678 mg, 2.23 mmol), Pd(dppf)Clz (90 mg, 0.11 mmol), and K2C03 (923 mg, 6.69 mmol) in dioxane (10 mL) and water (10 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction mixture was cooled to room temperature and ﬁltered h celite. The ﬁltrate was diluted with water (100 mL) and extracted with ethyl e (100 mL x 2). The s layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (50 mL), dried over ous sodium sulfate, and concentrated to give Compound 340C.

A mixture of Compound 340C (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), and Intermediate G (75 mg, 0.24 mmol) in DMF (5 mL) was stirred at 20 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to furnish Compound 340. LC-MS (ESI) m/z: 587 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) .87 (m, 4H), 1.85-2.04 (m, 4H), 2.53 (s, 3H), .24 (m, 2H), 3.44-3.58 (m, 4H), 3.93-3.98 (m, 1H), 4.04 (s, 3H), 4.55-4.59 (m, 1H), 4.89 (d, J: 2.0 Hz, 1H), 6.06 (brs, 1H), 7.36 (dd, J: 8.4, 2.0 Hz, 1H), 7.42-7.50 (m, 3H), .86 (m, 3H), 7.89 (d, J: 8.4 Hz, 2H), 7.96 (s, 1H), 8.83 (d, J: 9.6 Hz, 1H), 9.35 (brs, lH).

Example 341 N 9H 0 Z 5 o N 9H NH \ 0 COOH o o \ ,N + g j —> N O O F N NH2 N \ D 0 \ O 3400 c 341 A mixture of Compound 340C (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), and Intermediate C (71 mg, 0.24 mmol) in DMF (5 mL) was stirred at 20 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to furnish Compound 341. LC-MS (ESI) m/z: 573 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.88-2.08 (m, 4H), 2.50 (s, 3H), 3.13-3.19 (m, 2H), 3.50-3.51 (m, 4H), 4.04 (s, 3H), 4.26-4.29 (m, 4H), .53 (m, 1H), 4.79 (d, J: 2.4 Hz, 1H), 6.06 (brs, 1H), 6.78 (s, 1H), 6.84 (d, J: 10.8 Hz, 1H), 7.49 (d, J: 8.4 Hz, 1H), 7.84 (d, J: 8.4 Hz, 1H), 7.95-7.97 (m, 5H), 8.77 (d, J: 9.6 Hz, 1H), 9.31 (brs, lH). 2014/056555 Example 342 342A A mixture of Compound 340A (500 mg, 2.23 mmol), Compound 175B (678 mg, 2.23 mmol), Pd(dppf)Clz (90 mg, 0.11 mmol), and K2C03 (923 mg, 6.69 mmol) in dioxane (10 mL) and water (10 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction e was cooled down to room temperature and d through celite. The ﬁltrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The aqueous layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 342A.

A mixture of Compound 342A (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), and Intermediate C (71 mg, 0.24 mmol) in DMF (5 mL) was stirred at 20 0C for 18 h.

The mixture was directly puriﬁed with prep-HPLC to furnish Compound 342. LC-MS (ESI) m/z: 573 [M+H]+; 1H-NMR dg, 400 MHz): 5 (ppm) 1.88-2.03 (m, 4H), 2.65 (s, 3H), 3.13-3.21 (m, 2H), 3.41-3.55 (m, 4H), 4.09 (s, 3H), .29 (m, 4H), 4.48-4.53 (m, 1H), 4.78 (d, J: 2.0 Hz, 1H), 6.77 (s, 1H), 6.83 (d, J: 12.8 Hz, 1H), 7.39 (d, J: 8.8 Hz, 1H), 7.82-7.93 (m, 6H), 7.76 (d, J: 9.6 Hz, 1H), 9.29 (brs, lH).

Example 343 273C A mixture of nd 273C (90 mg, 0.41 mmol), HATU (234 mg, 0.62 mmol), and Intermediate G (127 mg, 0.41 mmol) in DMF (3 mL) was stirred at 25 0C for 16 h. The e was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep- HPLC to ﬁJrnish Compound 343. LC-MS (ESI) m/z: 512 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.65-0.67 (m, 2H), 0.82-0.83 (m, 2H), 1.85-1.87 (m, 2H), 1.97-2.01 (m, 6H), 3.09-3.20 (m, 2H), 3.48-3.54 (m, 8H), 3.89-3.94 (m, 1H), 4.50-4.55 (m, 1H), 4.84 (d, J: 2.4 Hz, 1H), .04 (m, 1H), 6.51 (d, J: 9.2 Hz, 2H), 7.30-7.32 (m, 1H), 7.37-7.41 (m, 2H), 7.64 (d, J: 9.2 Hz, 2H), 8.47 (d, J: 9.6 Hz, 1H), 9.32 (s, 1H).

Example 344 o I0 | Br Br Br OH Br 0 ﬂ xﬁ 1* ox OH 0 o F F F F 344A 344B 344C 0 | OH 0 I O O TBSO . —> 2 k—> ; k—> CszN CszN 0 o F F 344D 344E 344| 344 To a mixture of 5-bromoﬂuorohydroxybenzaldehyde (21.8 g, 100 mol) and K2C03 (110 g, 800 mol) in DMF (400 mL) was added 2-iodopropane (20 mL, 200 mol).

The mixture was stirred at 70 0C for 4 h. It was cooled to room temperature and ﬁltered. The cake was washed with ethyl e (50 mL). The ﬁltrate was diluted with water (900 mL) and extracted with ethyl acetate (400 mL x 3). The organic layer was washed with water (900 mL x 5) and brine (900 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel on silica (ethyl acetate in petroleum, 10% v/v) to afford Compound 344A.

A mixture of Compound 344A (4.3 g, 16.5 mol) and m-chloroperoxybenzoic acid (5.7 g, 33 mole) in methylene chloride (40 mL) was reﬂuxed under en overnight.

The cooled mixture was ﬁltered and the precipitate was washed with methylene chloride. The combined ﬁltrate and washing were washed with aq. sodium bicarbonate (40 mL x 3) and NaCl (40 mL) and concentrated to give a solid. The solid was dissolved in MeOH (27 mL). A on of 10% NaOH (9 mL) was added with cooling. After stirring for 45 min at room temperature, the mixture was concentrated and 5% NaOH (100 mL) was added. The solution was washed with ether (80 mL X 2). The basic solution was acidiﬁed with con. HC1 and extracted with ether (80 mL x 2). The ether extracts were washed with aq. sodium bicarbonate (100 mL x 3), dried over MgSO4, and concentrated to give the crude Compound 344B.

To a mixture of Compound 344B (4.2 g, 17 mol) and K2C03 (3.5 g, 26 mol) in DMF (60 mL) was added iodomethane (1.27 mL, 20 mol). The mixture was stirred at 25 0C overnight. It was ﬁltered. The cake was washed with ethyl e (10 mL). The ﬁltrate was diluted with water (120 mL) and ted with ethyl acetate (40 mL x 3). The organic layer was washed with water (100 mL x 5) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column tography on silica gel on silica (ethyl acetate in petroleum, 5% V/V) to afford Compound 344C.

To a solution of Compound 344C (6.37 g, 24 mmol) in THF (70 mL) was added n-BuLi (2.4 M, 10 mL, 24 mmol) under en at -60 0C. It was stirred at -60 0C for 0.5 h. And then it was added a solution of Compound A4 (3.21 g, 8 mmol) in THF (20 mL).

The e was stirred at -60 0C for 0.5 h, quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (60 mL x 3), washed with brine (100 mL), dried over anhydrous sodium sulfate, and d with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to furnish Compound 344D.

To a solution of Compound 344D (3.89 g, 7.5 mmol) in THF (30 mL) was added TBAF (1 M, 2.2 mL) which had been adjusted to pH 6-7 with CH3COOH. The mixture was stirred at 35 0C for 16 h. Water (50 mL) was added. It was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% V/V) to yield Compound 344E.

To a solution of Compound 344E (1.54 g, 3.70 mmol) in dry THF (35 mL) was added DIBAL-H (1.5 M, 5 mL, 7.5 mmol) slowly dropwise under en at -60 0C. It was stirred at -65 0C for 0.5 h. And then DIBAL-H (1.5 M, 5 mL, 7.5 mmol) was added to the reaction. It was stirred at -65 0C for another 0.5 h. A solution of HCl (2 M) was added to quench the reaction. It was extracted with ethyl e (50 mL), washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, and trated to yield a crude product. It was puriﬁed with ﬂash column chromatography on silica gel (methanol in romethane, 5% V/V) to yield Compound 344F.

To a on of Compound 344F (1.04 g, 2.56 mmol) and triethylamine (0.7 mL, 5.12 mmol) in dichloromethane (30 mL) was added MsCl (0.22 mL, 2.81 mmol) at -30 0C and the resultant mixture was stirred at -30 0C for 2 h. It was treated with water (20 mL).

The organic layer was washed with water (40 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to ﬁamish Compound 344G.

To a solution of Compound 344G (1.2 g, 2.5 mmol) in THF (20 mL) was added pyrrolidine (2.3 mL, 25 mmol). The e was stirred at 50 0C overnight. It was treated with water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (30 mL x 1), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude t. It was puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, 20% v/v) to yield Compound 344H.

To a solution of Compound 344H (840 mg, 1.8 mmol) in MeOH (30 mL) was added 10% Pd(OH)2 (150 mg). The solution was stirred under H2 atmosphere at 25 0C for 24 h. The solution was ﬁltered. The ﬁltrate was concentrated to yield the crude Compound 3441.

A mixture of Compound 3441 (72 mg, 0.22 mmol), Compound 133D (49 mg, 0.20 mmol), and HATU (91 mg, 0.24 mmol) in DMF (4 mL) was stirred at 20 0C for 15 h. It was puriﬁed with PLC to give nd 344. LC-MS (ESI) m/z: 553 [M+H]+; 1H- NMR ((CD3)2CO, 400 MHz): 5 (ppm) 1.22 (t, J: 6.4 Hz, 6H), 2.08-2.17 (m, 2H), 2.25 (s, 2H), 2.49 (s, 3H), 3.74 (s, 3H), 3.85 (s, 1H), 3.90-4.03 (m, 3H), .38 (m, 1H), 4.91 (s, 1H), 5.23 (s, 1H), 6.90 (dd, .11 = 11.2 Hz, .12 = 1.6 Hz, 1H), 7.01 (s, 1H), 7.29 (t, J: 8.8 Hz, 2H), 7.76 (d, J: 8.8 Hz, 2H), 7.80-7.84 (m, 2H), 7.98 (d, J: 8.4 Hz, 2H), 8.15 (d, J: 10 Hz, 1H), 9.52 (brs, 1H).

Example 345 —394_ A e of Compound 345A (500 mg, 2.1 mmol), Pd(dppf)C12 (86 mg, 0.1 mmol), ethyl 2-oxo(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)acetate 175B (638 mg, 2.1 mmol), and K2C03 (668 mg, 6.3 mmol) in oxane (15 mL) and water (2 mL) was stirred under nitrogen at 100 OC overnight. The mixture was cooled down to room temperature, concentrated, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The aqueous layer was acidiﬁed to pH 2 with aqueous HCl solution (1 N) and extracted with dichloromethane (10 mL x 3). The dichloromethane layer was dried over anhydrous sodium sulfate, ﬁltered to afford Compound 345B/dichloromethane solution. The solution of Compound 345B in dichloromethane was ly used for the next step without further purification.

To a solution of Compound 345B in dichloromethane (15 mL, from previous step) and DMF (3 mL) was added Intermediate C (155 mg, 0.5 mmol) and HATU (380 mg, 1 mmol). The mixture was d at room temperature overnight. The mixture was concentrated and the resulting residue was puriﬁed with prep-HPLC to h Compound 345. LC-MS (ESI) m/z: 586 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.49-1.51 (m, 6H), 1.88-1.89 (m, 2H), 2.02-2.03 (m, 2H), 3.12-3.21 (m, 2H), .62 (m, 4H), 4.25-4.29 (m, 4H), 4.50-4.54 (m, 1H), 4.79 (s, 1H), 4.90-4.97 (m, 1H), 6.04 (s, 1H), 6.52-6.52 (m, 1H), 6.78 (s, 1H), 6.82-6.85 (m, 1H), 7.43-7.45 (m, 1H), 7.61-7.62 (m, 1H), 7.66-7.68 (m, 1H), 7.88-7.94 (m, 5H), 8.74-8.76 (m, 1H), 9.32 (brs, 1H). e 346 4 00 °" Q + _ mAO \N O O mOA CI 3453 G 346 To a solution of Compound 346B in dichloromethane (15 mL, from the previous step) was added Intermediate G (155 mg, 0.5 mmol) and HATU (380 mg, 1 mmol).

The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting residue was purified with prep-HPLC to ﬁamish Compound 346. LC-MS (ESI) m/z: 600 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.68-0.70 (m, 2H), 0.82-0.83 (m, 2H), 1.49-1.52 (m, 6H), 1.89-1.90 (m, 2H), 2.03-2.04 (m, 2H), 3.13-3.22 (m, 2H), 3.55-3.59 (m, 4H), 3.94-3.98 (m, 1H), 4.57-4.62 (m, 1H), .95 (m, 2H), 6.06-6.07 (m, 1H), 6.52- 6.53 (m, 1H), .46 (m, 4H), 7.62-7.73 (m, 4H), 7.84-7.86 (m, 2H), 7.92 (s, 1H), 8.82- 8.84 (m, 1H), 9.52 (brs, 1H). e 347 A—> ,N CI 342A G A e of Compound 342A (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), DIPEA (0.04 mL, 0.24 mmol), and ediate G (75 mg, 0.24 mmol) in DMF (5 mL) was stirred at 25 0C for 2 h. The mixture was directly puriﬁed with prep-HPLC to furnish Compound 347. LC-MS (ESI) m/z: 587 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.68-0.85 (m, 4H), 1.89-2.04 (m, 4H), 2.65 (s, 3H), 3.11-3.24 (m, 2H), 3.47-3.57 (m, 4H), 3.92-3.97 (m, 1H), 4.09 (s, 3H), 4.56-4.60 (m, 1H), 4.88 (s, 1H), 7.35-7.39 (m, 2H), 7.42-7.46 (m, 2H), 7.75-7.84 (m, 5H), 7.89 (s, 1H), 8.82 (d, J: 9.6 Hz, 1H), 9.34 (brs, 1H).

Example 348 242F2 344. 348 A mixture of Compound 3441 (72 mg, 0.22 mmol), Compound 242F (48 mg, 0.20 mmol), and HATU (91 mg, 0.24 mmol) in DMF (4 mL) was stirred at 20 0C for 15 h. It was puriﬁed with prep-HPLC to give Compound 348. LC-MS (ESI) m/z: 549 [M+H]+; 1H- NMR ((CD3)2CO, 400 MHz): 5 (ppm) 1.34 (dd, J1 = 15.2 Hz, J2 = 10.4 Hz, 6H), 2.22 (s, 2H), 2.97 (s, 3H), 3.45 (s, 2H), 3.78-3.81 (m, 4H), 3.95 (s, 3H), 4.23-4.29 (m, 1H), 4.86 (s, 1H), .17 (s, 1H), 6.86 (dd, .11 = 10.8 Hz, .12 = 1.6 Hz, 1H), 6.98 (s, 1H), 7.51 (dd, .11 = 8.8 Hz, .12 = 2 Hz, 1H), 8.09-8.17 (m, 3H), 8.60 (s, 1H), 9.83 (brs, 1H). 2014/056555 Example 349 Br Br 0v _’ —’ N N ,N O HN’ \ D‘N \ D‘N /\ 349A 3493 N o b‘N’ \ ,N\ 349C / 349 A mixture of romophenyl)-1H-pyrazole (1.0 g, 4.5 mmol), cyclopropylboronic acid (0.8 g, 9 mmol), Cu(OAc)2 (1.6 g, 9 mmol), N32C03 (0.9 g, 9 mmol), bipyridine (1.4 g, 9 mmol), and 4 A molecular sieve powder (5 g) in 1,2- dichloroethane (20 mL) was stirred at 30 0C for 72 h. After ﬁltration, the mixture was diluted with dichloromethane (50 mL), washed with water (30 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to afford Compound 349A.

To a solution of nd 349A (342 mg, 1.3 mmol) in dry THF (10 mL) was added n-BuLi (2.5 N in hexane, 0.6 mL, 1.5 mmol) under nitrogen at -78 0C. The resulting solution was stirred at -78 0C for 30 min and transferred into a stirred solution of diethyl oxalate (0.97 g, 6.6 mmol) in dry THF (5 mL) at this temperature. The solution was stirred at -78 0C for 1 h, quenched with addition of saturated aqueous ammonium chloride solution (10 mL), poured into water (50 mL), and extracted with ethyl acetate (50 mL x 2).

The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give nd 349B, which was used for the next step without further puriﬁcation.

A mixture of Compound 349B (0.26 g, 0.9 mmol) and LiOH-HZO (77 mg, 1.8 mmol) in THF (5 mL) and water (2 mL) was stirred at 0 0C for 2 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over ous sodium sulfate, concentrated, and puriﬁed with reverse phase chromatography using eluent (methanol in water, from 0% to 100% v/v) to afford Compound 349C.

A mixture of Compound 349D (77 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol), and Intermediate G (93 mg, 0.3 mmol) in dichloromethane (5 mL) was stirred at 25 0C for 16 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to yield a crude compound. The crude product was puriﬁed with prep-HPLC to ﬁamish Compound 349. LC- MS (ESI) m/z: 549 ; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.69-0.71 (m, 2H), 0.83-0.84 (m, 2H), 1.01-1.03 (m, 2H), 1.11-1.12 (m, 2H), 1.88-1.89 (m, 2H), 2.02-2.04 (m, 2H), 3.12-3.21 (m, 2H), 3.48-3.55 (m, 4H), 3.77-3.84 (m, 1H), 3.92-3.97 (m, 1H), 4.57 (s, 1H), 4.87 (s, 1H), 6.01-6.10 (m, 1H), 6.82-6.83 (m, 1H), 7.35-7.45 (m, 3H), .74 (m, 2H), 7.87-7.91 (m, 3H), 8.77 (d, J: 10 Hz, 1H), 9.32 (s, 1H).

Example 350 1—) N QH O i N OH 0 _ OH ? = O NH O] N O + Km 1 —> b , \ NH 0 F N 2 O D‘N,N\ / 3490 C 35° A mixture of nd 349D (77 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol), and ediate C (89 mg, 0.3 mmol) in dichloromethane (5 mL) was stirred at 25 0C for 16 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to yield a crude compound. The crude product was puriﬁed with PLC to ﬁamish Compound 350. LC- MS (ESI) m/z: 535 ; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.01-1.03 (m, 2H), 1.10-1.11 (m, 2H), 1.87-1.88 (m, 2H), 2.02-2.03 (m, 2H), 3.10-3.20 (m, 2H), 3.43-3.45 (m, 2H), 3.53-3.56 (m, 2H), 3.78-3.83 (m, 1H), 4.27-4.30 (m, 4H), 4.51-4.53 (m, 1H), 4.77 (s, 1H), 6.76-6.85 (m, 3H), 7.83-7.85 (m, 2H), 7.90-7.93 (m, 3H), 8.73 (d, J: 9.6 Hz, 1H), 9.29 (s, 1H).

Example 351 Br O\/ ,N\ N O HN >‘N\j/©/Br >‘N N\ 351A 351 B N’ \ ,N\ 0 CI / N 351C / 351 To a solution of 3-(4-bromophenyl)—1H-pyrazole (1.0 g, 4.5 mmol) in DMF (20 mL) was added NaH (198 mg, 5 mmol). The mixture was stirred at 25 0C for 0.5 h and 2- iodopropane (1.53 g, 9 mmol) was added. The mixture was stirred at 25 0C for 2 h. The mixture was diluted with water (30 mL) and ted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to % v/v) to afford Compound 351A.

To a solution of Compound 351A (343 mg, 1.3 mmol) in dry THF (10 mL) was added n-BuLi (2.5 N in hexane, 0.6 mL, 1.5 mmol) under nitrogen at -78 0C. The resulting solution was stirred at -78 0C for 30 min and transferred into a stirred solution of diethyl oxalate (0.97 g, 6.6 mmol) in dry THF (5 mL) at this ature. The solution was stirred at -78 0C for 1 h, quenched with addition of saturated aqueous ammonium chloride on (10 mL), poured into water (50 mL), and extracted with ethyl acetate (50 mL x 2).

The ed organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give Compound 351B, which was used for the next step t further puriﬁcation.

A mixture of Compound 351B (0.27 g, 0.9 mmol) and LiOH-HZO (77 mg, 1.8 mmol) in THF (5 mL) and water (2 mL) was stirred at 0 0C for 2 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over ous sodium e, concentrated, and purified with reverse phase chromatography using eluent (methanol in water, from 0% to 100% v/v) to afford Compound 351C.

A mixture of nd 351C (77 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol), and Intermediate G (93 mg, 0.3 mmol) in dichloromethane (5 mL) was stirred at 25 0C for 16 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to yield a crude nd. The crude product was puriﬁed with prep-HPLC to ﬁamish Compound 351. LC- MS (ESI) m/z: 551 ; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.70-0.71 (m, 2H), 0.83-0.84 (m, 2H), 1.47 (s, 3H), 1.48 (s, 3H), 1.89-1.90 (m, 2H), 2.04-2.05 (m, 2H), 3.12- 3.21 (m, 2H), 3.48-3.51 (m, 4H), 3.94 (s, 1H), 4.56-4.58 (m, 2H), 4.88 (s, 1H), 6.05-6.07 (m, 1H), 6.82-6.83 (m, 1H), 7.35-7.45 (m, 3H), 7.71-7.73 (m, 2H), 7.88-7.90 (m, 3H), 8.78 (d, J = 9.2 Hz, 1H), 9.41 (s, 1H).

Example 352 NOH 0.

OH ; = 351 c F c 352 A mixture of Compound 351C (77 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol), and Intermediate C (89 mg, 0.3 mmol) in DMF (5 mL) was stirred at 25 0C for 16 h.

The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to yield a crude compound. The crude product was puriﬁed with prep-HPLC to ﬁamish Compound 352. LC- MS (ESI) m/z: 537 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.47 (s, 3H), 1.48 (s, 3H), 1.87-1.88 (m, 2H), 2.02-2.03 (m, 2H), .21 (m, 2H), 3.43-3.45 (m, 2H), .56 (m, 2H), 4.27-4.30 (m, 4H), .58 (m, 2H), 4.78 (s, 1H), 6.77-6.85 (m, 3H), 7.83-7.85 (m, 2H), 7.90-7.94 (m, 3H), 8.74 (d, J: 9.6 Hz, 1H), 9.29 (s, 1H). -400— Example 353 F 353C 353 A mixture of l-ﬂuoroiodobenzene (5 g, 23 mmol), 5-bromo-lH-indazole (4.4 g, 23 mmol), CuI (428 mg, 2.3 mmol), L-proline (518 mg, 4.5 mmol), and K3PO4 (9.55 g, 45 mmol) in l,4-dioxane (200 mL) was stirred under nitrogen at reﬂux for 24 h. The resulting mixture was cooled to room temperature. The mixture was treated with water (200 mL), extracted with ethyl acetate (100 mL x 2), washed with sat. sodium bicarbonate (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to furnish Compound 353A.

To a solution of Compound 353A (650 mg, 2.2 mmol) in THF (50 mL) was added dropwise n-BuLi (l .1 mL, 2.7 mmol) under nitrogen at -78 0C. The resulting e was stirred at -78 0C for 15 min. To the resulting mixture was added diethyl oxalate (1.6 g, 11.2 mmol) as a soon as a y. The mixture was stirred at -78 0C for l h, quenched with sat. ammonium chloride on, d with water (50 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, trated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, % V/V) to furnish Compound 353B.

To a solution of nd 353B (130 mg, 0.42 mmol) in THF (5 mL) was added dropwise LiOH’HzO (35 mg, 0.83 mmol) in water (2 mL) at -20 0C. The resulting mixture was stirred at -20 0C for l h. The mixture was adjusted pH to l with diluted HCl. The —401— resulting mixture was extracted with ethyl acetate (50 mL x 2), and then the organic layer was dried over anhydrous sodium sulfate and concentrated to ﬁamish Compound 353C.

A mixture of Compound 353C (100 mg, 0.35 mmol), Intermediate 353G (109 mg, 0.35 mmol), and HATU (210 mg, 0.53 mmol) in DMF (5 mL) was d at room temperature for 12 h. The mixture was treated with water (50 mL), extracted with dichloromethane (20 mL x 2), washed with water (20 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, trated, and puriﬁed with prep-HPLC to furnish Compound 353. LC-MS (ESI) m/z: 577 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.59-0.81 (m, 4H), 1.86-2.05 (m, 4H), 3.13-3.22 (m, 2H), 3.50-3.57 (m, 4H), 3.89-3.92 (m, 1H), 4.56-4.62 (m, 1H), 4.89 (s, 1H), 6.05-6.06 (m, 1H), 7.34-7.51 (m, 5H), 7.79-7.85 (m, 4H), 7.43 (s, 1H), 8.56 (s, 1H), 8.01 (d, J: 9.6 Hz, 1H), 9.39 (s, 1H).

Example 354 Z 5 ::N QH o T N C_)H OH _ A F <:> NH N : + o NH A F—Q—N \ O N 2 o N/ 0 CI 354A G CI A mixture of Compound 354A (100 mg, 0.35 mmol), Intermediate G (109 mg, 0.35 mmol), and HATU (210 mg, 0.53 mmol) in DMF (5 mL) was stirred at room temperature for 12 h. The mixture was treated with water (50 mL), extracted with dichloromethane (20 mL x 2), washed with water (20 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC to furnish Compound 354. LC-MS (ESI) m/z: 577 [M+H]+; 1H-NMR d6, 400 MHz): 5 (ppm) 0.61-0.79 (m, 4H), .02 (m, 4H), .18 (m, 2H), 3.45-3.53 (m, 4H), 3.85-3.89 (m, 1H), 4.45-4.50 (m, 1H), 4.81 (s, 1H), 6.01 (s, 1H), 6.93 (d, J: 9.2 Hz, 1H), 7.25-7.39 (m, 7H), 7.73-7.76 (m, 1H), 8.27-8.28 (d, J: 2.0 Hz, 1H), 8.63 (d, J: 9.6 Hz, 1H), 9.21 (s, 1H), 9.30 (s, 1H). —402— Example 355 Br_» Br Ho 0 355A 3553 A mixture of 1-(4-bromophenyl)ethanone (2.0 g, 10 mmol) in tetrahydrofuran (30 mL) was maintained at -70 0C, and methylmagnesium bromide (3 M, 6.7 mL) was added at -70 0C. The reaction e was d at -78 0C for 0.5 h. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium e, ﬁltered, and concentrated. The remaining residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 25% V/V) to furnish Compound 355A.

A e of nd 175B (616 mg, 2 mmol), Compound 355A (428 mg, 2 mmol), [1 s(diphenylphosphino)ferrocene]dichloropalladium(II) (168 mg, 0.2 mol), sodium carbonate (424 mg, 4 mmol), water (0.5 mL), and oxane (5 mL) was stirred under nitrogen atmosphere at 80 0C for 2 h. After cooling, the reaction mixture was treated with water (30 mL), washed with ethyl acetate (30 mL x 3), adjusted pH to 2.0 with hydrochloric acid (1 M), extracted with ethyl acetate (20 mL x 3), washed with brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish Compound 355B.

A mixture of Compound 355B (100 mg, 0.35 mmol), Intermediate G (108 mg, 0.35 mmol), and HATU (266 mg, 0.70 mmol) in DMF (3.5 mL) was d at 25 0C for 2 h.

The mixture was puriﬁed with prep-HPLC directly to furnish Compound 355. LC-MS (ESI) m/z: 559 [M+H]+; 1H-NMR (CDC13, 400 MHz): 5 (ppm) 0.68-0.76 (m, 2H), 0.77-0.88 (m, 2H), 1.68-1.92 (m, 1H), 2.07-2.21 (m, 2H), 2.22 (s, 3H), 2.23-2.28 (m, 1H), 3.33-3.50 (m, 2H), 3.76-3.97 (m, 6H), 4.84-4.90 (m, 1H), 5.18-5.26 (m, 2H), 5.53 (s, 1H), 7.28-7.43 (m, -403— WO 42397 2H), 7.45—7.57 (m, 1H), 7.67 (d, .1: 8.4 Hz, 2H), 7.75-7.81 (m, 4H), 7.92—8.01 (m, 2H), 8.21 (d, .1: 6.0 Hz, 1H), 10.84 (brs, 1H).

Example 356 296A 46] A mixture of nd 296A (150 mg, 0.54 mmol), Intermediate C (175 mg, 0.59 mmol), and HATU (308 mg, 0.81 mmol) in romethane (5 mL) was stirred at 25 0C ght. The mixture was quenched with water (10 mL), extracted with dichloromethane (5 mL x 2), washed with brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The crude t was puriﬁed with prep-HPLC to furnish Compound 356A.

A mixture of 2-(4-bromophenyl)propanol (34 mg, 0.15 mmol), Compound 356A (75 mg, 0.15 mmol), [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 8.2 umol), sodium carbonate (44 mg, 0.30 mmol), water (0.5 mL), and l,4-dioxane (5 mL) was stirred under nitrogen atmosphere at 80 0C for 2 h. After cooling, the reaction mixture was treated with water (5 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with prep-HPLC. The solution was adjusted to pH = 8.0 with sodium bicarbonate solution, extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to ﬁJrnish Compound 356. LC-MS (ESI) m/z: 563 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) 1.42-1.75 (m, 6H), 1.79-1.86 (m, 4H), 2.74-2.81 (m, 4H), 2.96-3.04 (m, 2H), .31 (m, 6H), 5.05 (d, J: 2.4 Hz, 1H), 6.70-6.76 (m, 2H), 7.39 (d, J: 8.8 Hz, 1H), 7.75-7.64 (m, 5H), 7.68 (d, J: 9.2 Hz, 2H), 8.31 (d, J: 8.8 Hz, 2H). —404— Example 357 356A 357 A mixture of l-bromoisopropylbenzene (30 mg, 0.15 mmol), Compound 356A (75 mg, 0.15 mmol), [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 8.2 umol), sodium carbonate (32 mg, 0.30 mmol), water (0.5 mL), and l,4-dioxane (5 mL) was stirred under nitrogen atmosphere at 80 0C for 2 h. After g, the reaction mixture was d with water (5 mL), extracted with ethyl e (10 mL x 3), washed with brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was d with prep-HPLC to furnish Compound 357. LC-MS (ESI) m/z: 547 [M+H]+; 1H- NMR ((CD3)2CO, 400 MHz): 5 (ppm) 1.64 (m, 6H), 2.08-2.11 (m, 3H), 2.17-2.23 (m, 1H), 2.96-3.043 (m, 4H), 3.17-3.82 (m, 4H), 4.21-4.33 (m, 3H), 4.37 (d, 1H), 4.69-5.75 (m, 2H), 6.85-7.07 (m, 2H), 7.35-7.43 (m, 2H), 7.46-7.79 (m, 3H), 7.81-7.87 (m, 1H), 7.89--7.98 (m, 1H), .14 (m, 1H).

Example 358 N QH ‘ CI 0 .

O —> Ho, 0 E? HO 296B 358 A mixture of 2-(4-bromophenyl)propanol (49 mg, 0.23 mmol), Compound 296B (l 10 mg, 0.23 mmol), [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.4 mg, 10 umol), potassium ate (49 mg, 0.46 mmol), water (1 mL), and l,4-dioxane (5 mL) was heated under nitrogen atmosphere at 100 0C for 2 h. After cooling, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a black —405— oil. The oil was puriﬁed with prep-HPLC. The solution was adjusted to pH = 8.0 with sodium bicarbonate solution, extracted with ethyl acetate (50 mL x 2), dried over ous sodium sulfate, ﬁltered, and concentrated to ﬁamish Compound 358. LC-MS (ESI) m/z: 577 [M+H]+; 1H-NMR(CDC13, 400 MHz): 5 (ppm) 0.76-0.88 (m, 4H), .30 (m, 1H), 1.63 (s, 6H), 1.83-1.88 (m, 4H), 2.01 (s, 1H), 2.73-2.81 (m, 5H), .03 (m, 2H), 3.74-3.79 (m, 1H), 4.33 (d, J: 4.4 Hz, 1H), 5.11 (d, J: 2.4 Hz, 1H), .28 (m, 1H), 7.35-7.51 (m, 3H), 7.57-7.63 (m, 4H), 7.68 (d, J: 7.2 Hz, 2H), 8.26 (d, J: 8.8 Hz, 1H).

Example359 WV O A329 359A N QH ' F NH A S 0 \ I To a stirred solution of Compound 175B (1.29 g, 4.24 mmol) in DMF (20 mL) and water (20 mL) was added Na2C03 (1.12 g, 10.6 mmol), Pd(PPh3)4 (247 mg, 0.21 mmol), and 2-bromochlorothiophene (838 mg, 4.24 mmol). The mixture was stirred under nitrogen at 90 0C for 16 h. The reaction mixture was cooled to room temperature and puriﬁed with reverse phase chromatography using eluent (methanol in water (include 0.05% of NH3.H20), from 0% to 40% V/V) to afford nd 359A.

To a solution of Intermediate S (55 mg, 0.22 mmol) in dichloromethane (10 mL) was added Compound 359A (50 mg, 0.18 mmol) and HATU (107 mg, 0.28 mmol). The mixture was stirred under nitrogen at room temperature overnight. The resulting mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL) and ted with ethyl acetate (50 mL x 3). The ed organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford a crude nd. The crude product was puriﬁed with prep-HPLC to furnish Compound 359.

LC-MS (ESI) m/z: 543 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.68-0.70 (m, 2H), 0.79-0.81 (m, 2H), 1.87-1.90 (m, 2H), 2.02-2.04 (m, 2H), 3.12-3.18 (m, 2H), 3.45-3.55 (m, 4H), 3.92-3.95 (m, 1H), 4.51-4.53 (m, 1H), 4.85 (d, J: 2.4 Hz, 1H), 6.05 (d, J: 4.4 Hz, 1H), 7.19 (t, J: 8.8 Hz, 2H), 7.28 (d, J: 4.0 Hz, 1H), 7.39 (t, J: 8.8 Hz, 1H), 7.63 (d, J: 4.0 Hz, 1H), 7.74 (d, J: 8.4 Hz, 2H), 7.83 (d, J: 8.4 Hz, 2H), 7.75 (d, J: 9.6 Hz, 1H), 9.31 (s, 1H).

Example 360 S O + C|\l 359A 360 53] To a solution of Intermediate C (100 mg, 0.34 mmol) in dichloromethane (10 mL) was added Compound 359A (75 mg, 0.28 mmol) and HATU (160 mg, 0.42 mmol). The mixture was stirred under nitrogen at room temperature overnight. The resulting mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined c phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford a crude nd. The crude product was puriﬁed with prep-HPLC to furnish Compound 360.

LC-MS (ESI) m/z: 545 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.86-1.88 (m, 2H), 2.01-2.04 (m, 2H), 3.11-3.18 (m, 2H), 3.52-3.54 (m, 4H), .29 (m, 4H), 4.48-4.50 (m, 1H), 4.76 (s, 1H), 6.03 (s, 1H), 6.75 (s, 1H), 6.81 (d, J: 11.6 Hz, 1H), 7.27 (d, J: 2.0 Hz, 1H), 7.65 (d, J: 3.6 Hz, 1H), 7.76 (d, J: 8.4 Hz, 2H), 7.87 (d, J: 8.4 Hz, 2H), 8.73 (d, J: 9.6 Hz, 1H), 9.28 (s, 1H). —407— Example 361 Br CH0 Br CHO Br OH Br or F F F F ' 361A 3613 3610 0 OH O OH QH TBSO ; CY ; .

CszN CszN CY oszN CY o o o F F | | 361D 361E 361F 361| 361 To a mixture of oﬂuorohydroxybenzaldehyde (21 g, 97 mol) and K2C03 (20 g, 145 mmol) in DMF (200 mL) was added iodomethane (16.3 g, 115 mmol). The mixture was stirred at room temperature overnight. The mixture was d with water (500 mL) and extracted with ethyl acetate (400 mL x 3). The organic layer was washed with water (500 mL x 3) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 361A.

A mixture of Compound 361A (15.6 g, 66.9 mmol) and m- chloroperoxybenzoic acid (23 g, 133.9 mmol) in methylene chloride (200 mL) was stirred at 40 0C overnight. The mixture was ﬁltered and the itate was washed with methylene chloride. The ed ﬁltrate and washing were washed with aq. sodium bicarbonate (100 mL x 3) and brine (100 mL) and concentrated to give a yellow oil. The crude nd was dissolved in MeOH (300 mL). A solution of 33% NaOH (30 mL) was added with cooling.

After stirring for 2 h at room temperature, the mixture was acidiﬁed with concentrated HCl and extracted with ethyl acetate (200 mL x 2). The extract was washed with aqueous sodium 2014/056555 bicarbonate (100 mL x 3), dried over anhydrous sodium sulfate, and trated to give the crude Compound 361B.

To a e of Compound 361B (10.3 g, 46.6 mmol) and K2C03 (12.9 g, 93.2 mmol) in DMF (100 mL) was added 2-bromopropane (11.5 g, 93.2 mmol). The mixture was stirred at 80 0C overnight. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL x 2). The organic layer was washed with water (300 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum, 5% v/v) to give Compound 361C.

To a solution of Compound 361C (8.43 g, 32 mmol) in THF (100 mL) was added n-BuLi (2.4 M, 13.2 mL, 33.1 mmol) under nitrogen at -78 0C. It was stirred at -78 0C for 10 min. A solution of Compound A4 (4.2 g, 10.68 mmol) in THF (10 mL) was added.

The e was stirred at -78 0C for 0.5 h, quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (200 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, and puriﬁed with ﬂash column chromatography on silica gel (ethyl e in petroleum ether, 10% v/v) to ﬁamish Compound 361D.

A solution of Compound 361D (5 g, 9.62 mmol) in THF (25 mL), water (25 mL), and acetic acid (75 mL) was stirred at 35 0C overnight. The solvent was d with evaporation under reduced pressure and the residue was diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The c layer was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over ous sodium sulfate, trated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 33% v/v) to yield Compound 361E.

To a solution of Compound 361E (1.6 g, 3.95 mmol) in dry THF (70 mL) was added DIBAL-H (1 M, 15.8 mL, 15.8 mmol) slowly dropwise under nitrogen at -78 0C. It was stirred at -78 0C for 1 h. A solution of HCl (2 M, 20 mL) was added to quench the reaction. It was extracted with ethyl acetate (50 mL), washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to yield a crude product. It was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to give Compound 361F.

To a solution of Compound 361F (1.44 g, 3.53 mmol) and triethylamine (1.07 g, 10.6 mmol) in dichloromethane (30 mL) was added MsCl (445 mg, 3.89 mmol) at -30 0C and the ant mixture was stirred at -30 0C for 1 h. It was treated with water (100 mL) and -409— dichloromethane (100 mL). The c layer was washed with water (40 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to ﬁamish Compound 361G.

To a solution of Compound 361G (1.71 g, 3.6 mmol) in THF (40 mL) was added pyrrolidine (2.61 g, 36 mmol). The mixture was stirred at 50 OC overnight. It was treated with water (100 mL), extracted with ethyl acetate (100 mL x 3), washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude t. It was puriﬁed with ﬂash column chromatography on silica gel nol in dichloromethane, 5% v/v) to give Compound 361H.

To a solution of Compound 361H (1.25 g, 2.71 mmol) in ethanol (24 mL) was added LiOH’HzO (456 mg, 10.86 mmol). The solution was stirred at 80 OC ght. The mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude Compound 3611.

A mixture of Compound 3611 (100 mg, 0.306 mmol), Intermediate C (69 mg, 0.306 mmol), and HATU (174 mg, 0.459 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with water (100 mL) and brine (50 mL), dried over ous sodium sulfate, concentrated, and purified with prep-HPLC to give Compound 361. LC-MS (ESI) m/z: 553 [M+H]+; 1H- NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.17 (d, J: 6.0 Hz, 3H), 1.26 (d, J: 6.0 Hz, 3H), 1.87-1.93 (m, 2H), 2.01-2.05 (m, 2H), 3.11-3.24 (m, 2H), 3.45-3.57 (m, 4H), 3.77 (s, 3H), 4.49-4.57 (m, 2H), 4.84-4.85 (m, 1H), 6.09 (d, J: 4.0 Hz, 1H), 6.85 (d, J: 11.6 Hz, 1H), 6.89 (s, 1H), 7.38 (t, J: 8.8 Hz, 2H), 7.78-7.87 (m, 6H), 8.77 (d, J: 10.0 Hz, 1H), 9.38 (brs, 1H). —410— Example 362 Br OH Br OH Br 0x Br 0 Br 0 OH FO/\"/ OH o o F F 362A 362A' 3523 3623' OH 0 OH QH TBSO FZJL FZJL 0 CszN CszN CszN 362C 362D 362E OMs OH WW:IRAE;1 VT?1 362F 3626 362H N QH 0 "(If _, o F 362 To a mixture of Compound C3 (31 g, 150 mol) and Li2C03 (22.4 g, 310 mol) in DMF (250 mL) was added 3-bromomethylprop-l-ene (31.9 mL, 310 mol). The mixture was stirred at 55 0C for 48 h, cooled down to room temperature, and ﬁltered. The cake was washed with ethyl acetate (100 mL). The e was diluted with water (500 mL) and extracted with ethyl acetate (200 mL x 3). The organic layer was washed with saturated aqueous LiCl solution (100 mL x 5), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The crude product was puriﬁed with ﬂash column tography on silica gel on silica gel (ethyl acetate in petroleum ether, 5% v/v) to give a mixture of Compound 362A and nd 362A".

A solution of Compound 362A and Compound 362A’ (23 g, 88.5 mmol) in formic acid (200 mL) was stirred and heated to reﬂux for 2 h. After removal of the solvent, the e was diluted with dichloromethane (200 mL). The mixture was carefully adjusted pH to 9 with ted aqueous sodium bicarbonate solution at 0 OC and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous sodium sulfate, ed, and concentrated to afford a crude compound. The crude product was purified with ﬂash column —411— chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish a mixture of Compound 362B and Compound 362B".

To a solution of Compound 362B and Compound 362B" (3.8 g, 14.6 mmol) in dry THF (80 mL) maintained at -60 0C was dropwise added n-BuLi (2.5 M in hexane, 6.0 mL, 15 .1 mmol) under nitrogen here over a period of 20 minutes. After the reaction mixture was stirred at -60 0C for 40 minutes, a solution of Compound A4 (1.93 g, 4.87 mmol) in dry THF (20 mL) was added slowly. After the completion of addition, the solution was left to stir for 0.5 h at -60 0C. The reaction mixture was quenched with ted aqueous ammonium chloride on (20 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with brine (20 mL), dried over ous sodium sulfate, ﬁltered, and concentrated to furnish a crude compound. The crude t was puriﬁed with ﬂash column chromatography on silica gel (ethyl e in petroleum ether, from 5% to 10% v/v) to yield Compound 362C.

A solution of Compound 362C (1.1 g, 2.13 mmol) in a mixture of tetrahydrofuran, water, and glacial acetic acid (25 mL, 1/1/3 v/v/v) was stirred at 35 0C for 16 h. The on mixture was trated under reduced pressure to remove excess solvent.

The residue was poured into ethyl acetate (50 mL) and water (20 mL). The mixture was adjusted to pH 7~8 with saturated s sodium bicarbonate solution and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford the crude target compound. The crude product was further d with ﬂash column tography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to give Compound 362D.

To a solution of Compound 362D (690 mg, 1.71 mmol) in dry THF (20 mL) maintained at -78 0C was added diisobutylaluminum hydride (1.0 M in toluene, 6.85 mL) dropwise under nitrogen atmosphere over a period of 15 minutes. After the reaction mixture was stirred at -70 0C for 1 h, saturated solution of ammonium chloride solution (10 mL) was added to the mixture slowly. The reaction mixture was extracted with ethyl acetate (50 mL x 3), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford the crude target compound. The crude product was further puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, from 50% to 87% v/v) to furnish Compound 362E.

To a solution of Compound 362E (600 mg, 1.48 mmol) ved in dry THF (15 mL) was added triethylamine (0.62 mL, 4.44 mmol). The mixture was cooled to -40 0C, and then methanesulfonyl chloride (0.17 mL, 2.22 mmol) was added dropwise. After the —412— addition was complete, the reaction mixture was stirred at -40 0C for 2 h, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium e, ﬁltered, and concentrated to afford a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to give Compound 362F. 71] To a solution of Compound 362F (320 mg, 0.66 mmol) in THF (10 mL) was added pyrrolidine (0.55 mL, 6.6 mmol). The reaction mixture was allowed to heat to 50 0C for 16 h. The e was diluted with water (10 mL), extracted with ethyl acetate (50 mL x 3), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to furnish a crude compound. The crude product was puriﬁed with ﬂash column chromatography on silica gel (methanol in dichloromethane, 8% v/v) to give Compound 362G.

Compound 362G (215 mg, 0.47 mmol) was dissolved in methanol (20 mL), and 20% 2 (45 mg) was added. The mixture was stirred under hydrogen at room temperature overnight. After ﬁltration, the ﬁltrate was evaporated to give the Compound 362H.

To a solution of Compound 362H (93 mg, 0.29 mmol) in dichloromethane (10 mL) was added Compound 133D (70 mg, 0.29 mmol) and HATU (164 mg, 0.43 mmol). The mixture was stirred under en at room temperature overnight. The ing mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium e, ﬁltered, and concentrated to afford a crude compound. The crude product was puriﬁed with prep-HPLC to furnish nd 362.

LC-MS (ESI) m/z: 551 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.23 (s, 3H), 1.28 (s, 3H), 1.88-2.02 (m, 4H), 3.10-3.17 (m, 2H), .54 (m, 4H), 3.98 (s, 2H), 4.50 (s, 1H), 4.77 (s, 1H), 6.01 (d, J: 2.8 Hz, 1H), 6.72 (s, 1H), 6.81 (d, J: 10.8 Hz, 1H), 7.37 (t, J: 8.4 Hz, 2H), 7.80-7.92 (m, 6H), 8.73 (d, J: 9.2 Hz, 1H), 9.31 (s, 1H). —413— Example 363 N 9H 0 .

Q O : N OH OH mOA - 0 CI 8 O + 3 (5— \ \ I 0 \ 3 CI CI 359A G 363 To a solution of ediate G (112 mg, 0.36 mmol) in dichloromethane (10 mL) was added Compound 359A (80 mg, 0.30 mmol) and HATU (171 mg, 0.45 mmol). The mixture was stirred under nitrogen at room temperature overnight. The resulting mixture was quenched with ted aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford a crude compound. The crude product was puriﬁed with prep-HPLC to h Compound 363.

LC-MS (ESI) m/z: 559 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) .70 (m, 2H), 0.82-0.84 (m, 2H), 1.87-1.91 (m, 2H), 2.02-2.04 (m, 2H), 3.11-3.20 (m, 2H), 3.47-3.55 (m, 4H), .96 (m, 1H), 4.53-4.57 (m, 1H), 4.88 (s, 1H), 6.06 (d, J: 3.2 Hz, 1H), 7.27 (d, J: 4.0 Hz, 1H), 7.34 (dd, J: 8.8, 1.6 Hz, 1H), 7.41 (d, J: 8.4 Hz, 1H), 7.43 (d, J: 1.6 Hz, 1H), 7.62 (d, J: 4.0 Hz, 1H), 7.70-7.76 (m, 4H), 8.78 (d, J: 9.6 Hz, 1H), 9.48 (s, 1H).

Example 364 242F 361| 364 A mixture of Compound 3611 (100 mg, 0.306 mmol), Compound 242F (74 mg, 0.306 mmol), and HATU (174 mg, 0.459 mmol) in dichloromethane (2 mL) was stirred at room ature overnight. The mixture was diluted with dichloromethane (50 mL), washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC to give Compound 364. LC-MS (ESI) m/z: 549 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.17 (d, J: 6.0 Hz, 3H), 1.25 (d, J: 6.0 Hz, 3H), 1.81-1.88 (m, 2H), 1.98-2.05 (m, 2H), 3.09-3.20 (m, 2H), 3.40-3.57 (m, 4H), 3.71 (s, 3H), 4.44-4.56 (m, 2H), 4.78-4.80 (m, 1H), 6.10 (d, J: 2.0 Hz, 1H), 6.80-6.86 (m, 2H), —414— 7.54 (dd, .11 = 1.6 Hz, .12 = 8.4 Hz, 1H), 8.13 (d, .1: 8.8 Hz, 1H), 8.29 (d, .1: 2.0 Hz, 1H), 8.55 (s, 1H), 8.60 (d, .1: 9.6 Hz, 1H), 9.19 (brs, 1H).

Example 365 360—» mmoﬁ mﬁ\ O CI OH CI 0 CI 0 CI 0 0\ 365A 3653 365C ::N C_)H o _ O 2 _. _. \ mo" Cl 0 OH 0 0 CI 365D CI 365 A mixture of 4-chlorohydroxybenzaldehyde (l .56 g, 0.01 mol), diethyl 2- bromomalonate (2.38 g, 0.01 mol), and K2C03 (1.38 g, 0.01 mol) in 2-butanone (80 mL) was reﬂuxed overnight. After completion of the reaction, the resulting mixture was cooled down to room ature, poured into water, acidiﬁed to pH 2 with dilute aqueous sulﬁJric acid solution (2 N), and extracted with ether (40 mL x 3). After removal of the organic t, the residue was dissolved in alcoholic potash (prepared from 20 mL of alcohol and 2 g of solid potassium ide) and reﬂuxed for 2 h. The solvent was concentrated and the residue was dissolved in water (20 mL). The aqueous layer was acidiﬁed to pH 2 with dilute s ic acid solution (2 N) and solid was precipitated. The formed solid were collected with ﬁltration, washed with water (20 mL), and dried to afford Compound 365A.

A solution of Compound 365A (1.98 g, 10 mmol) and copper powder (0.4 g) were reﬂuxed in quinoline (20 mL) for 2 h. After cooling down to room temperature, the mixture was diluted with ether (80 mL) and washed with diluted aqueous HCl solution (2 N, 40 mL x 3). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and carefully concentrated at 0 0C to give Compound 365B.

To a solution of Compound 365B (1.53 g, 10 mmol) in THF (30 mL) was added dropwise n-BuLi solution (2.5 M in hexane, 4 mL, 10 mmol) under nitrogen at -78 0C.

The mixture was stirred at -78 0C for 0.5 h and the above on was added to a solution of diethyl oxalate (3 g, 20 mmol) in THF (20 mL) under nitrogen at -78 0C. The mixture was slowly warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with saturated aqueous ammonium chloride solution (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined c layers were washed with water (100 mL) and brine (100 mL), dried over ous sodium sulfate, and concentrated. The residue —415— was puriﬁed with ﬂash column chromatography on silica gel (ethyl e in petroleum ether, from 10% to 50% V/V) to ﬁamish Compound 365C.

To a solution of Compound 365C (2.4 g, 10 mmol) in THF/HZO (40 mL/10 mL) was added LiOH‘HzO (840 mg, 20 mmol). The e was stirred at room temperature for about 2 h until completion by thin layer chromatography is. The reaction mixture was acidiﬁed to pH 2 with diluted aqueous HCl solution (1.0 N, 40 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to yield Compound 365D.

To a mixture of Compound 365D (112 mg, 0.5 mmol) and Intermediate G (155 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was d at room temperature overnight. The resulting solution was d with ethyl acetate (50 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with prep-HPLC to furnish Compound 365. LC-MS (ESI) m/z: 517 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.63-0.79 (m, 4H), 1.88-1.99 (m, 4H), 3.13-3.21 (m, 2H), 3.38-3.56 (m, 4H), 3.88-3.89 (m, 1H), 4.43-4.45 (m, 1H), 4.78-4.79 (m, 1H), 6.04 (s, 1H), 7.27-7.39 (m, 3H), 7.47-7.49 (m, 1H), 7.93 (d, J: 8.4 Hz, 1H), 8.01 (s, 1H), 8.20 (s, 1H), 8.62 (d, J: 10.0 Hz, 1H), 9.07 (brs, 1H).

Example 366 365D 366 To a e of Compound 365D (114 mg, 0.5 mmol) and Intermediate C (143 mg, 0.5 mmol) in DMF (5 mL) was added HATU (380 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with ethyl acetate (30 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed with prep-HPLC to h Compound 366. LC-MS (ESI) m/z: 503 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 1.84-2.01 (m, 4H), .13 (m, 2H), 3.31-3.54 (m, 4H), 4.23-4.27 (m, 4H), 4.40-4.43 (m, 1H), 4.71 (s, 1H), 6.04 (br s, 1H), 6.72 (s, 1H), 6.77-6.81 (m, 1H), 7.47 (d, J: 8.4 Hz, 1H), 7.98 (d, .1: 8.4 Hz, 1H), 8.02 (s, 1H), 8.26 (s, 1H), 8.60 (d, .1: 9.6 Hz, 1H), 9.04 (br s, 1H).

Example 367 273C 367 A mixture of Compound 273C (66 mg, 0.3 mmol), HATU (200 mg, 0.5 mmol), and Intermediate H (85 mg, 0.3 mmol) in DMF (5 mL) was stirred at 25 0C for 16 h.

The mixture was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to yield a crude compound. The crude product was puriﬁed with prep-HPLC to mmish Compound 367. LC- MS (ESI) m/z: 484 ; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.97-2.00 (m, 4H), 2.24-2.27 (m, 1H), 2.38-2.43 (m, 1H), 3.31-3.35 (m, 6H), 4.07-4.16 (m, 4H), 4.28-4.33 (m, 5H), 4.72 (s, 1H), 6.00 (s, 1H), 6.52-6.54 (m, 2H), .80 (m, 2H), 7.64-7.66 (m, 2H), 8.43 (d, J: 10 Hz, 1H), 9.84 (s, 1H).

Example 368 CI Ox} 368A G 368 84] A mixture of Intermediate G (177 mg, 0.57 mmol), nd 368A (1 17 mg, 0.52 mmol), and HATU (350 mg, 0.92 mmol) in DMF (5 mL) was stirred at room temperature ght. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 368. LC- MS (ESI) m/z: 528.2 [M+H]+; 1H-NMR (CD30D, 400 MHz): 5 (ppm) 0.72-0.86 (m, 4H), 2.03-2.23 (m, 4H), 3.21-3.31 (m, 2H), 3.40-3.43 (m, 4H), 3.55-3.58 (m, 1H), 3.68-3.74 (m, 2H), 3.79-3.89 (m, 6H), 4.70-4.73 (m, 1H), 4.98 (d, J: 2.8 Hz, 1H), 6.84 (d, J: 9.2 Hz, 2H), 7.38 (s, 2H), 7.44-7.47 (m, 3H). —417— Example 369 368A A mixture of Intermediate H (100 mg, 0.42 mmol), Compound 368A (141 mg, 0.50 mmol), and HATU (290 mg, 0.76 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 369. LC- MS (ESI) m/z: 500.2 [M+H]+; 1H-NMR , 400 MHz): 5 (ppm) 2.40-2.68 (m, 2H), 3.40-3.43 (m, 4H), 3.51-3.75 (m, 3H), 3.82-3.85 (m, 4H), .20 (m, 1H), 4.20-4.34 (m, 9H), 4.34-4.49 (m, 1H), 4.86 (d, J: 3.2 Hz, 1H), 6.77-6.80 (m, 2H), 6.93 (d, J: 9.2 Hz, 2H), 7.64 (d, J: 9.2 Hz, 2H).

Example 370 V 370 86] A e of Compound 175A (200 mg, 1.23 mmol), ethyl 2-(4- bromophenyl)oxoacetate (316 mg, 1.23 mmol), Pd(dppf)C12 (49 mg, 0.06 mmol), and K2C03 (509 mg, 3.69 mmol) in 1,4-dioxane (10 mL) and water (10 mL) was stirred under nitrogen at 100 0C for 3 h. The reaction mixture was cooled down to room temperature and ﬁltered through celite. The ﬁltrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The aqueous layer was acidiﬁed to pH 3 with aqueous HCl solution (1 N) and ted with dichloromethane (100 mL x 3). The combined dichloromethane layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 370A. 87] A mixture of nd 370A (65 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), and Intermediate G (74 mg, 0.24 mmol) in DMF (5 mL) was stirred at 25 0C overnight. The mixture was directly puriﬁed with prep-HPLC to furnish nd 370. LC- MS (ESI) m/z: 559 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.65-0.85 (m, 6H), 0.99-1.03 (m, 2H), 1.90-2.02 (m, 5H), 3.12-3.19 (m, 2H), 3.41-3.55 (m, 4H), 3.91-3.96 (m, 1H), 4.55-4.59 (m, 1H), 4.91 (s, 1H), 6.07 (s, 1H), 7.22 (d, J: 8.4 Hz, 2H), 7.35 (dd, J: 8.4, 1.6 Hz, 1H), 7.41 (d, J: 8.4 Hz, 1H), 7.45 (d, J: 1.6 Hz, 1H), 7.64 (d, J: 8.8 Hz, 2H), 7.71- 7.74 (m, 4H), 8.80 (d, J: 9.6 Hz, 1H), 9.67 (brs, 1H).

Example 371 0 o OH N 9H NH °j i 01— O O 0 O F V 370A 0 371 A mixture of Compound 370A (65 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), and Intermediate C (71 mg, 0.24 mmol) in DMF (5 mL) was stirred at 25 0C overnight. The mixture was directly puriﬁed with prep-HPLC to furnish Compound 371. LC- MS (ESI) m/z: 545 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.72-0.76 (m, 2H), .03 (m, 2H), 1.88-2.02 (m, 5H), 3.11-3.14 (m, 2H), 3.26-3.55 (m, 4H), 4.23-4.29 (m, 4H), 4.49-4.54 (m, 1H), 4.80 (s, 1H), 6.05 (d, J: 4.0 Hz, 1H), 6.77 (s, 1H), 6.83 (dd, J: 12.0, 1.6 Hz, 1H), 7.22 (d, J: 8.4 Hz, 2H), 7.65 (d, J: 8.4 Hz, 2H), 7.78 (d, J: 8.4 Hz, 2H), 7.87 (d, J: 8.4 Hz, 2H), 8.74 (d, J: 9.6 Hz, 1H), 9.51 (brs, 1H). —419— Example 372 372A 372B 372C ' OO/ﬁO/dgm 372D To a solution of tetrahydro-4H-pyranone (380 mg, 3.8 mmol) and 1-bromo- 4-iodobenzene (2.4 g, 8.5 mmol) in dry THF (50 mL) was added dropwise n-BuLi (2.5 M solution in hexane, 1.52 mL, 3.8 mmol) under nitrogen at -78 0C over a period of 15 min. The resulting solution was d to warm slowly to room temperature and stirred for 3.5 h. The resulting mixture was quenched with ted aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to yield a crude product. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate, 100% V/V) to lSh nd 372A.

To a solution of Compound 372A (620 mg, 2.42 mmol) in dry dichloromethane (10 mL) was added triethylsilane (0.43 mL, 2.71 mmol). Triﬂuoroacetic acid (1.83 mL, 24.2 mmol) was added se. After one hour at -78 0C, the e was warmed to room ature and stirred for 3 h. The resulting mixture was quenched with aqueous NaOH on (1 N, 5 mL) and extracted with dichloromethane (50 mL x 3). The organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a crude product. The crude product was purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 80% V/V) to afford Compound 372B.

To a solution of Compound 372B (295 mg, 1.23 mmol) in dry THF (20 mL) was added dropwise n-BuLi (2.5 M solution in hexane, 0.74 mL, 1.84 mmol) under nitrogen at -78 0C. After stirring for 30 min, diethyl oxalate (449 mg, 3.07 mmol) was added in one portion. The mixture was stirred at -78 0C for about an hour. The resulting e was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with —420— ethyl acetate (50 mL x 3). The organic layer was washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to yield a crude product. The crude product was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to ﬁamish Compound 372C.

To a solution of Compound 372C (155 mg, 0.59 mmol) in THF (10 mL) was added dropwise a solution of LiOH’HZO (50 mg, 1.18 mmol) in water (3 mL). The e was stirred at room temperature for 3 h. The reaction solution was adjusted to pH 3 with aqueous HCl on (1 N, 1.5 mL) and separated. The c layer was dried directly over anhydrous sodium sulfate, ﬁltered, and concentrated to afford nd 372D.

To a solution of Intermediate G (87 mg, 0.28 mmol) in dichloromethane (10 mL) was added Compound 372D (55 mg, 0.23 mmol) and HATU (134 mg, 0.35 mmol) under nitrogen. The mixture was stirred at room temperature overnight. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over ous sodium sulfate, ﬁltered, and concentrated to afford a crude product. The crude t was puriﬁed with prep-HPLC to furnish Compound 372.

LC-MS (ESI) m/z: 527 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 0.68-0.84 (m, 4H), .69 (m, 4H), 1.87-2.03 (m, 4H), 2.83-2.91 (m, 1H), 3.11-3.20 (m, 2H), .54 (m, 6H), 3.95-3.97 (m, 3H), 4.53-4.58 (m, 1H), 4.87 (s, 1H), 6.05 (d, J: 4.0 Hz, 1H), 7.34- 7.42 (m, 5H), 7.62 (d, J: 8.4 Hz, 2H), 8.76 (d, J: 9.6 Hz, 1H), 9.51 (s, 1H).

Example 373 372D 373 To a solution of Intermediate C (83 mg, 0.28 mmol) in dichloromethane (10 mL) was added Compound 372D (55 mg, 0.23 mmol) and HATU (134 mg, 0.35 mmol) under nitrogen. The mixture was stirred at room temperature overnight. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, ﬁltered, and trated to afford a crude product. The crude t was puriﬁed with prep-HPLC to h Compound 373. —421— LC—MS (ESI) m/z: 513 [M+H]+; 1H-NMR d6, 400 MHz): 5 (ppm) .71 (m, 4H), 1.87-2.02 (m, 4H), 2.85-2.91 (m, 1H), 3.10-3.16 (m, 2H), 3.48-3.54 (m, 6H), 3.95-3.98 (m, 2H), 4.26-4.29 (m, 4H), 4.47-4.52 (m, 1H), 4.77 (s, 1H), 6.03 (d, J: 2.4 Hz, 1H), 6.75 (s, 1H), 6.81 (dd, J: 11.2, 1.6 Hz, 1H), 7.40 (d, J: 8.4 Hz, 2H), 7.74 (d, J: 8.4 Hz, 2H), 8.70 (d, J: 9.6 Hz, 1H), 9.42 (s, 1H).

Example 374 (\N O + —> ; 0 od NHz 0A ofN 368A X 374 95] A mixture of Intermediate X (77 mg, 0.34 mmol), Compound 368A (55 mg, 0.24 mmol), and HATU (175 mg, 0.46 mmol) in DMF (5 mL) was stirred at room ature overnight. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was puriﬁed with prep-HPLC to give Compound 374. LC- MS (ESI) m/z: 494.2 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.68-0.69 (m, 2H), 0.77-0.81 (m, 2H), 2.05-2.22 (m, 5H), 3.20-3.30 (m, 2H), 3.40-3.42 (m, 4H), 3.53-3.60 (m, 1H), 3.66-3.72 (m, 2H), 3.76-3.85 (m, 7H), 4.66-4.69 (m, 1H), 4.97 (d, J: 2.8 Hz, 1H), 6.88 (d, J: 9.2 Hz, 2H), 7.04 (d, J: 8.4 Hz, 2H), 7.37 (d, J: 8.4 Hz, 2H), 7.60 (d, J: 9.2 Hz, 2H).

Example 375 (j Mm —» ©—»NH2 0\/ 375C 375 —422— 96] To a solution of e (9.3 g, 100 mmol) in DMF (350 mL) was added cesium carbonate (100 g, 306 mmol) and l, 3-dibromopropane (27 g, 135 mmol). The mixture was stirred for 24 h while keeping inner temperature between 60 0C and 65 0C. After the on mixture was cooled to ambient temperature, the dark solution was diluted with water (400 mL) and ted with ethyl acetate (300 mL x 3). The combined organic phases were washed with brine (150 mL x 4), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to afford the crude product as a brown oil. The crude product was puriﬁed with ﬂash column chromatography on silica gel (petroleum ether) to ﬁamish Compound 375A.

To a solution of compound 375A (900 mg, 6.8 mmol) and aluminum trichloride (5.0 g, 37.9 mmol) in dichloromethane (30 mL) was added dropwise ethyl 2- chlorooxoacetate (1.06 g, 8.0 mmol) at 0 oC. The mixture was stirred for 4 hours while g the temperature at 0 CC. The mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The resulting product was concentrated under reduced pressure, and the resultant residue was puriﬁed with silica gel column chromatography (ethyl acetate in petroleum ether, 30% v/v) to give Compound 375B.

To a solution of Compound 375B (333 mg, 1.00 mmol) in MeOH (10 mL) was added LiOH-HZO (90 mg, 2.14 mmol) and water (2 mL). The reaction mixture was d at 15 0C for 4 h. The reaction mixture was neutralized with HCl (1 N). The resulting mixture was evaporated. The e was dissolved in water (5 mL). The mixture was extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, d, and evaporated to give Compound 375C.

A mixture of Intermediate G (203 mg, 0.65 mmol), Compound 375C (110 mg, 0.53 mmol), and HATU (350 mg, 0.92 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with romethane (150 mL), washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was d with prep-HPLC to give Compound 375. LC- MS (ESI) m/z: 498.2 [M+H]+; 1H-NMR (CDgOD, 400 MHz): 5 (ppm) 0.69-0.87 (m, 4H), 1.90-2.26 (m, 4H), 3.01-3.27 (m, 2H), 3.43-3.68 (m, 4H), 3.70-3.95 (m, 2H), 4.19-4.42 (m, 2H), 4.77 (s, 1H), 4.98-5.17 (m, 2H), 5.53-5.92 (m, 1H), 6.96-7.31 (m, 5H), 7.36-7.57 (m, 3H). —423— Example 376 376A A mixture of l-(4-ﬂuorophenyl)ethan-l-one (5.00 g, 36.20 mmol) and SeOz (6.06 g, 54.30 mmol) in pyridine (20 mL) was stirred at 70 0C for 16 h. After ﬁltration to remove the resultant solid, the ﬁltrate was evaporated to give a residue. The crude product was dissolved in s sodium hydroxide solution (1 M, 20 mL) and water (50 mL) and ted with diethyl ether (160 mL) to remove by-product. The aqueous solution was adjusted to pH 1 with concentrated hydrochloride acid (4 mL) and extracted with dichloromethane (100 mL x 3). The organic layer was washed with brine (50 mL), dried over ous sodium sulfate, and evaporated to afford Compound 376A.

A mixture of Compound 376A (54 mg, 0.32 mmol), Intermediate G (100 mg, 0.32 mmol), and HATU (183 mg, 0.48 mmol) in dichloromethane (3 mL) was stirred at 20 0C for 16 h. The mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and ated to give a residue.

The crude t was purified with prep-HPLC to afford Compound 376. LC-MS (ESI) m/z: 461 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.66-0.83 (m, 4H), 1.86-2.02 (m, 4H), 3.12-3.18 (m, 2H), 3.46-3.53 (m, 4H), 3.89-3.95 (m, 1H), 4.48-4.55 (m, 1H), 4.85 (s, 1H), 6.08 (s, 1H), .42 (m, 5H), 7.89 (t, J: 8.8 Hz, 2H), 8.74 (d, J: 9.6 Hz, 1H), 9.57 (s, 1H).

Example 377 o o s s o s OH 0 0 377A 377B —424— To a solution of benzo[b]thiophene (1 g, 7.5 mmol) in THF (25 mL) was added se n-BuLi (3.6 mL, 8.9 mmol) under nitrogen at -78 0C. The resulting mixture was stirred at -78 0C for 15 min. To the resulting mixture was added diethyl oxalate (3.3 g, 8.9 mmol) quickly. The mixture was stirred for l h at -78 0C, quenched with sat. ammonium chloride solution, treated with water (50 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (petroleum ether) to h Compound 377A.

To a solution of Compound 377A (1.5 g, 6.4 mmol) in THF (50 mL) was added dropwise LiOH’HzO (538 mg, 12.8 mmol) in water (4 mL) at -20 0C. The resulting mixture was stirred at -20 0C for l h. The mixture was adjusted to pH 1 with d HCl. The ing mixture was extracted with ethyl acetate (50 mL x 2). The c layer was concentrated, treated with petroleum ether (50 mL), and stirred for 30 min. The yellow solid was formed and ﬁltered to furnish Compound 377B.

A mixture of Compound 377B (100 mg, 0.48 mmol), Intermediate G (150 mg, 0.48 mmol), and HATU (277 mg, 0.73 mmol) in DMF (5 mL) was stirred at room temperature for 12 h. The mixture was treated with water (10 mL), extracted with dichloromethane (20 mL x 2), washed with water (20 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with prep-HPLC to furnish Compound 377. LC-MS (ESI) m/z: 499 ; 1H-NMR ne-d6, 400 MHZ): 5 (ppm) .81 (m, 4H), 2.23 (s, 2H), 2.93 (s, 3H), 3.50 (s, 2H), 3.81-3.85 (m, 2H), 4.00-4.06 (m, 3H), 4.86 (t, J: 7.2 Hz, 1H), 5.15 (d, J: 2.8 Hz, 1H), 7.33-7.41 (m, 2H), 7.47-7.53 (m, 2H), 7.61 (t, J = 7.2 Hz, 1H), 8.04-8.09 (m, 2H), 8.14-8.19 (m, 1H), 8.64 (s, 1H), 9.52 (s, 1H). —425— Example 378 m o\/ O\/_> —’ Br / 175A 0 o OH NH 0 0 ¢ ¢ 378B 378 To a solution of compound 175A (2.57 g, 10.0 mmol), CuI (190 mg, 1.0 mmol), and Pd(PPh3)2C12 (210 mg, 0.3 mmol) in ylamine (80 mL) was added dropwise ethynyltrimethylsilane (1.17 g, 12.0 mmol) under nitrogen atmosphere at room temperature.

The reaction mixture was stirred at 90 0C for 30 s. Solids were collected with ion and washed with acetate ethyl (80 mL x 2). The ﬁltrate was concentrated under reduced pressure to give a residue, which was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in eum ether, 5% v/v) to yield compound 378A.

To a solution of Compound 378A (500 mg, 1.8 mmol) in THF (5 mL) was added LiOH'HzO (113 mg, 2.7 mmol) in water (2.0 mL). The resulting mixture was stirred at room temperature for 2 h, evaporated, treated with water (5 mL), and adjusted to pH 2 with diluted HCl. The e was extracted with ethyl acetate (10 mL x 3), washed with brine (10 mL), dried over anhydrous sodium sulfate, and trated to afford the Compound 378B.

To a solution of Compound 378B (34 mg, 0.2 mmol) in DMF (3 mL) was added Intermediate S (59 mg, 0.2 mmol) and HATU (1 14 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was puriﬁed with prep-HPLC to give Compound 378. LC-MS (ESI) m/z: 451 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 0.68-0.70 (m, 2H), 0.79-0.81 (m, 2H), 2.04-2.09 (m, 4H), 3.60-3.63 (m, 3H), 3.88-3.93 (m, 5H), 4.00 (s, 1H), 4.81-4.83 (m, 1H), 5.15 (d, J: 2.8 Hz, 1H), 7.23-7.25 (m, 2H), 7.33- 7.35 (m, 1H), 7.58 (d, J: 8.4 Hz, 2H), 7.98 (d, J: 8.4 Hz, 2H), 8.15-8.18 (m, 1H), 9.31 (brs, 1H). 2014/056555 Example 379 376A 08] A mixture of Compound 376A (54 mg, 0.32 mmol), Intermediate C (95 mg, 0.32 mmol), and HATU (183 mg, 0.48 mmol) in dichloromethane (3 mL) was stirred at 20 0C for 16 h. The mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and evaporated to give a residue.

The crude product was puriﬁed with prep-HPLC to afford Compound 379. LC-MS (ESI) m/z: 447 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 5 (ppm) 1.83-2.04 (m, 4H), 3.07-3.19 (m, 2H), 3.41-3.47 (m, 4H), 4.27 (s, 4H), 4.42-4.50 (m, 1H), 4.75 (s, 1H), 6.04 (s, 1H), 6.74 (s, 1H), 6.80 (d, J: 10.4 Hz, 1H), 7.36 (t, J: 8.8 Hz, 2H), 7.9398 (m, 2H), 8.70 (d, J: 9.6 Hz, 1H), 9.40 (s, 1H). —427— Example 380 O o/\ OH o/\ —> N —> O ON —> F F 380A 380B CN OH 380C 380D 380E O\/ OH N O —’ ON 0 —> 380G A mixture of ethyl piperidinecarboxylate (10 g, 64 mmol), l-ﬂuoro nzene (14 g, 64 mmol), K2C03 (17.6 g, 127 mmol), and L-proline (1.46 g, 12.7 mmol) in DMSO (50 mL) was stirred under nitrogen at 85 0C for 12 h. The ing mixture was added NHg'HzO (50 mL), extracted with ethyl acetate (100 mL x 2), washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% V/V) to furnish Compound 380A.

To a solution ofAlLiH4 (1.2 g, 31 mmol) in THF (100 mL) was added Compound 380A (7.9 g, 31 mmol) in THF (50 mL) dropwise under nitrogen at -78 0C. The resulting mixture was stirred at -78 0C for 1.5 h, quenched with Na2S04‘10H20. The mixture was d with silica gel and ﬁltered. The e was concentrated and the resulting residue was puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% V/V)to afford Compound 380B.

To a cooled -78 0C solution of oxalyl chloride (9.1 g, 72 mmol) in dichloromethane (150 mL) was added dropwise DMSO (7.5 g, 96 mmol), ining the internal temperature below -40 0C. After 30 min, Compound 380B (5 g, 24 mmol) in romethane (10 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at -78 0C for 45 min, triethylamine (12 g, 120 mmol) was added dropwise, and the mixture was warmed to room temperature stirred for 2 h. The mixture was treated with water (100 mL), extracted with dichloromethane (50 mL x 2), washed with water (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, and puriﬁed with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% V/V) to ﬁlrnish Compound 380C.

Compound 380C (3.3 g, 16 mol) was added to a on ofNa2S205 (3 g, 16 mol) in water (100 mL). The e was stirred for 2 h at room ature. After the addition ofNaCN (l .6 g, 32 mmol) the resulting mixture was stirred for 15 h, diluted with ethyl acetate (50 mL), extracted with ethyl acetate (100 mL x 2), washed with sat. sodium onate (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to afford the crude nd 380D.

To a solution of Compound 380D (3.7 g, 15.8 mmol) in ethanol (80 mL) cooled to 0°C was bubbled a gentle stream of HCl gas (dried over con. H2S04) for 5 h. The mixture was treated with water slowly at 0 0C, stirred at room temperature for 2 h, adjusted to pH 8 with NaOH (1 M), extracted with dichloromethane (50 mL x 2), washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give Compound 380E.

To a cooled -78 0C solution of oxalyl chloride (3.66 g, 28.8 mmol) in dichloromethane (50 mL) was added dropwise DMSO (3 g, 38.4 mmol), maintaining the al temperature below -40 0C. After 30 min, Compound 380E (2.7 g, 9.6 mmol) in dichloromethane (10 mL) was added dropwise to the reaction mixture. The reaction e was stirred at -78 0C for 45 min, triethylamine (4.85 g, 48 mmol) was added dropwise, and the mixture was warmed to room temperature stirred for 2 h. The mixture was treated with water (100 mL), extracted with dichloromethane (50 mL x 2), washed with water (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, and purified with ﬂash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% V/V) to ﬁlrnish Compound 380F.

To a solution of Compound 380F (878 mg, 3.14 mmol) in THF (20 mL) was added LiOH'HzO (264 mg, 6.29 mmol) in water (2 mL) at -30 0C. The resulting mixture was d at -30 0C for 2 h, evaporated, treated with water, adjusted to pH 2 with diluted HCl, —429— and lyophilized. The solid was puriﬁed with reverse phase chromatography using eluent (acetonitrile in water, from 1% to 100% v/v) to h Compound 380G.

A mixture of Compound 380G (300 mg, 1.19 mmol), Intermediate G (370 mg, 1.19 mmol), and HATU (681 mg, 0.73 mmol) in DMF (15 mL) was stirred at room temperature for 12 h. The mixture was treated with water (10 mL), extracted with dichloromethane (20 mL x 2), washed with water (20 mL x 3) and brine (50 mL), dried over anhydrous sodium e, concentrated, and puriﬁed with reverse phase chromatography eluting with (acetonitrile in water, from 1% to 100% v/v) to furnish Compound 380. LC-MS (ESI) m/z: 544 [M+H]+; 1H-NMR (acetone-d6, 400 MHz): 5 (ppm) 0.69-0.84 (m, 4H), 1.68 (s, 1H), 1.92-2.13 (m, 9H), 3.15-3.37 (m, 4H), 3.62-3.69 (m, 3H), .89 (m, 4H), 4.65- 4.68 (m, 1H), 5.09 (s, 1H), .19 (m, 1H), 7.34-7.40 (m, 5H), 7.79-7.81 (m, 1H), 8.21 (s, 1H), 11.31 (s, 1H).

Example 381 242F 381 A mixture of Intermediate Y (70 mg, 0.25 mmol), HATU (143 mg, 0.37 mmol), and Compound 242F (60 mg, 0.25 mmol) in DMF (5 mL) was stirred at 25 0C overnight. The e was directly puriﬁed with prep-HPLC to furnish Compound 381. LC- MS (ESI) m/z: 503 [M+H]+; 1H-NMR (DMSO-dg, 400 MHz): 5 (ppm) 0.61-0.79 (m, 4H), 2.24-2.42 (m, 2H), 3.33-3.49 (m, 2H), 3.82-3.91 (m, 1H), 4.02-4.33 (m, 5H), 4.77 (d, J: 4.0 Hz, 1H), 6.03 (brs, 1H), .20 (m, 2H), 7.36 (t, J: 8.4 Hz, 1H), 7.56 (dd, J: 8.4, 2.0 Hz, 1H), 8.12 (d, J: 8.0 Hz, 1H), 8.30 (d, J: 2.0 Hz, 1H), 8.52 (s, 1H), 8.56 (d, J: 10.0 Hz, 1H), 9.44 (brs, 1H).

Example 382 U 0 mO/A N 9H Q 9H g —> F CszN 0A moﬁ —’ 37 382A -430— 2014/056555 To a solution of AlLiH4 (76 mg, 2 mmol) in THF (15 mL) was added Intermediate S7 (430 mg, 1 mmol) in THF (5 mL) se under nitrogen atmosphere. The ing mixture was stirred at 60 0C for 3 h and quenched with aqueous Na2S04 solution.

The ﬁltrate was concentrated to afford a crude product, which was puriﬁed by PLC to give Compound 382A (240 mg, yield 78%). LC-MS (ESI) m/z: 309 [M+H]+; 1H-NMR (CDClg, 400 MHz): 5 (ppm) 0.75-0.85 (m, 4H), 1.76-1.79 (m, 4H), 2.34 (s, 3H), 2.43-2.59 (m, 6H), .91 (m, 1H), 3.77-3.82 (m, 1H), 4.63-4.69 (m, 1H), 7.02-7.l2(m, 2H), 7.22- 7.26 (m, 1H).

A mixture of Compound 382A (92 mg, 0.33 mmol), Compound 133D (73 mg, 0.30 mmol), and HATU (137 mg, 0.36 mmol) in DMF (4 mL) was d at 25 0C for 4 h.

Then it was puriﬁed by prep-HPLC to give Compound 382 (70 mg, yield 36%) as a white solid. LC-MS (ESI) m/z: 535 [M+H]+; 1H-NMR ((CD3)2CO, 400 MHz): 5 (ppm) 0.61-0.90 (m, 4H), 2.06-2.25 (m, 4H), 3.08-3.27 (m, 3H), 3.45 (s, 2H), 3.71-4.46 (m, 5H), 5.08-5.38 (m, 1H), 5.57-5.72 (m, 1H), 6.88-7.85 (m, 11H), 9.20-9.95 (m, 1H).

Example 383 \ N\ O Hﬁ\ OA 3 o F 382A 383 A mixture of Compound 382A (140 mg, 0.45 mmol), Compound 242F (98 mg, 0.40 mmol), and HATU (182 mg, 0.48 mmol) in DMF (3 mL) was stirred at 25 0C for 15 h. It was puriﬁed by prep-HPLC to give Compound 383 (88 mg, yield 34%) as a white solid. LC- MS (ESI) m/z: 531 ; 1H-NMR (DMSO-d, 400 MHz): 5 (ppm) 0.30-0.84 (m, 4H), 1.88-2.04 (m, 4H), 2.99-3.29 (m, 6H), 3.55-3.69 (m, 2H), 3.81-4.08 (m, 2H), 4.31-4.78 (m, 1H), 4.95-5.15 (m, 1H), 6.04-6.19 (m, 1H), 6.90-7.71 (s, 5H), 7.86-8.12 (m, 1H), 8.26-8.32 (m, 1H), 9.38-9.53 (m, 1H). —431— 2014/056555 BIOLOGICAL EXAMPLES The following describes ways in which the compounds described herein were tested to measure in vitro ty in enzymatic and cell-based assays. A person of ordinary skill in the art would know that variations in the assay conditions could be used to determine the activity of the compounds.

Assay 1: GCS Enzymatic Assay This assay was modiﬁed based on the study by Larsen et al. (JLz'pz'd Res. 2011, 53, 282). Madin-Darby canine kidney (MDCK) cell lysate was prepared using M-PER Mammalian n Extraction Reagent (Thermal Scientiﬁc) in the presence of a protease inhibitor cocktail (Roche). Protein concentration was determined using BCA assay kit (Pierce). Sixty rams ofMDCK cell lysate was incubated with various trations of a compound described herein from 0.001 uM -10 uM, respectively, in 100 mM Tris buffer (pH 7.5) containing 10 mM MgC12, 1 mM dithiothreitol, 1 mM EGTA, 2 mM NAD, 100 uM ucose, 10 uM -Ceramide (Matreya LLC, Pleasant Gap, PA), 35 uM dioleoylphosphatidylcholine and 5 uM ide (Sigma) in a ﬁnal reaction volume of 100 uL at 37 °C for 1 hour. 0.1% DMSO was used as mock treatment or control. The reaction was terminated by adding 100 uL acetonitrile solution and subjected to LC/MS analysis.

The quantitative analysis ofNBD-Ceramide and glucosylceramide was performed on a Shimadzu ultra-fast liquid chromatography (Shimadzu, Japan) d with API 4000 triple quadrupole mass spectrometer (Applied Biosystems, Concord, o, Canada). Sample separation was conducted on a Waters XbridgeTM BEH130 C18, 100 mm><4.6 mm id, 3.5 um (Milford, MA, USA). The mobile phase consisted of water and acetonitrile supplemented with 0.1% formic acid (v/v). The ﬂow rate was 1.0 mL/min. The initial mobile phase was 20% acetonitrile and was ramped in a linear fashion to 50% acetonitrile in 0.4 min. From 0.4 to 1.5 min, the nt was ramped to 98% acetonitrile, and then was held at 100% until 8.0 min. Acetonitrile was reset to 20% in 1.5 min, and maintained until 10.0 min. The total run time was 10.0 min. The MS/MS detection was performed in ESI positive mode. The mass transition of NBD-Ceramide was m/z 576.36—>558.40 under the collision energy of 15 V, and the mass transition of glucosylceramide was m/z 738.35—>558.40 under 21V collision energy. The cell lysate was diluted with equal volume of acetonitrile. Aliquots of 50 uL diluted samples were added to 1.5 mL tubes, and 100 uL of acetonitrile containing internal standard (100 ng/mL tolbutamide) were added for protein precipitation. The mixture were vortexed and then —432— centrifuged at 13000 rpm for 10 min. 70 uL of supernatant were mixed with 140 uL of H20 and the ﬁnal solution were injected for LC/MS/MS analysis and IC50’s and/or percent inhibitions calculated.

Assay 2: K562 Cell-based Assay This assay was modiﬁed based on the study by Gupta et al. (JLz'pz'd Res. 2010, 51, 866). K562 cells were seeded into 12-well plates at 3 X 105 cells/well/mL in RPMI-1640 medium with 5% FBS and incubated at 37 0C for 24 h. One uL of a compound bed herein at desired tration (10 mM, 1 mM, 0.1 mM, 0.01 mM, 0.001 mM and 0.0001 mM in DMSO) or DMSO was added into corresponding well and mixed. Cells were incubated at 37 CC for 4h. Then 100 uL of RPMI-1640 medium ning 110 uM ofNBD- Ceramide, 11% BSA, 5% FBS, and corresponding concentration of a compound described herein was added into each well and mixed. Cells were ted for additional 0.5 h at 37 oC, ed by washing the cells with ice-cold PBS (pH 7.4) twice with centriﬁagation and resuspended with 50 uL cold PBS+1% Triton X-100. The cell lysate was sonicated for 15 min before adding equal volume of methanol for LCMS analysis. A small aliquot of cell lysate was used to determine protein tration by BCA assay kit.

The HPLC equipment and methods used in Assay 1 were used in this assay as well and ICso’s were calculated.

Assay 3: NCI/ADR—Res Cell-based Assay NCI/ADR-RES cells were seeded into 12-well plates (4 X 105 cells/well) in RPMI-1640 medium with 10% FBS and incubated at 37 CC for 24 h. Before treatment with a compound described herein, cell culture media were removed and replaced with 1 mL per well RPMI-1640 medium containing 5% FBS and a compound as described herein at desired concentrations (10 uM, 1 uM, 0.1 uM, 0.01 uM, 0.001 uM, and 0.0001 uM), respectively, or 0.1% DMSO only. Cells were cultured for 4 hours at 37 oC followed by replacing the media with 640 containing 1% BSA and 10uM of C6-NBD-Ceramide in the present of a compound described herein, and incubated for additional 0.5 hour at 37 oC. Cells were then washed twice with ice-cold PBS (pH 7.4), scraped with 50 uL cold PBS+1% Trition X-100.

The cell lysate was sonicated for 15 min before adding equal volume of ol for LCMS analysis. A small aliquot of cell lysate was used to determine protein concentration by BCA assay kit. 27] The HPLC equipment and methods used in Assay 1 were used in this assay as well and IC50’s and % inhibition were calculated. -433— Using the above assays, the following compounds were tested. In the tables below, "nt" means that the compound was not tested in the assay. Either IC50 or % inhibition data are included in the tables. The % inhibition data is identiﬁed by an asterix ("*"). For IC50 data, "A" means the compound had an IC50 of greater than zero but less than or equal to about 50 nM and "B" means the compound had an IC50 is greater than about 50 but less than or equal to about 5000 nM. For % tion data, "A*" means the compound had a % inhibition of a percent tion of greater than or equal to about 50% and "B*" means the compound had a % inhibition of greater than or equal to about 3% but less than about 50%. —434— Table 1. The data provided is the ICso (nM) generated from Assay 1, except as otherwise noted by *, which is % inhibition, also generated from Assay 1.

Cmpd 2-(2,3 -dihydro-1H-indeny1)-N—((1R,2R)(2,3- dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 -(pyrrolidin 2-(2,3-dihydrobenzo [b] [1 ,4] dioxiny1)—N—(( 1 R,2R)(2,3 - obenzo [b] [1 ,4] dioxiny1)hydroxy-3 -(pyrrolidin 2—(5-chlorobenzo[b]thiopheny1)—N—((1R,2R)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 -(pyrrolidin 2-(5-chlorobenzo[b]thiopheny1)-2,2-diﬂuoro-N—((2R)— 1 -(3-ﬂuoro- 03 * 4-n1ethoxypheny1)— 1 -hydroxy-3 -(pyrrolidiny1)propan 1 acetamide 01 11> 2-(2,3 -dihydro- 1 H-indeny1)-2,2-diﬂuoro-N—((2R)— 1 -(3-ﬂuoro methoxypheny1)hydroxy-3 -(pyrrolidin- 1 opan 1 acetamide 2-(2,3 -dihydro-1H-indeny1)-2,2-diﬂuoro-N—((1 S ,2R)(3-ﬂuoro- 4-n1ethoxypheny1)— 1 -hydroxy-3 -(pyrrolidiny1)propan 1 acetamide 2-(2,3 ro- 1H-indeny1)-2,2-diﬂuoro-N—((1R,2R)— 1 -(3-ﬂuoro- 4-n1ethoxypheny1)— 1 xy-3 -(pyrrolidiny1)propan 1 acetamide 2—(5 -chlorobenzo[d]thiazoly1)—N—((1R,2R)— 1 -(2,3 - 03 * dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 -(pyrrolidin -2,2-diﬂuoroacetan1ide 2—(5 ,6-dichloro-2,3 -dihydro-1H-indeny1)-N—((1R,2R)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 -(pyrrolidin -2,2-diﬂuoroacetan1ide 2-(2,3-dihydro-1H-indeny1)-2,2-diﬂuoro-N—((1R,2R)(2-ﬂuoro- DJ * -n1ethoxypheny1)— 1 -hydroxy-3 -(pyrrolidiny1)propan 1 acetamide 00H 2-(2,3 -dihydro-1H-indeny1)-2,2-diﬂuoro-N—((1 S,2R)(2—ﬂuoro- 03 * -n1ethoxypheny1)— 1 -hydroxy-3 olidiny1)propan 1 acetamide )—A O 2-(5 -chloron1ethy1-1H-benzo[d]in1idazoly1)-N—((1R,2R)—1-(2,3 - 03 * dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 olidin p-A p-A 2—(5-chlorobenzofurany1)-N—((1R,2R)—1-(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 -(pyrrolidin 2-(2,3-dihydro-1H-indeny1)-2,2-diﬂuoro-N—((1S,2R)(7-ﬂuoro- 2,3-dihydrobenzo [b] [1 ,4]dioxiny1)—1-hydroxy-3 -(pyrrolidin 2-(7,8-dihydro-6H-cyclopenta[g]quinoxa1iny1)-N—(( 1 R,2R)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 -(pyrrolidin —435— y1)pr0pany1)-2,2-diﬂuor0acetamide )—A L 2-(5-ch10r0methy1-1H-indol-Z-y1)-N-((1R,2R)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xy-3 01idin )—A £11 2—(5 ,7-dich10robenz0ﬁJran-Z-y1)-N-((1R,2R)(2,3 - obenzo [b] [1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin )—A O\ N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)—2,2-diﬂuor0(3 -(pyridin j—A \] N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidin- 1 opany1)—2,2-diﬂuor0-3 -(naphthalen 2—(5 ,6-dich10robenz0ﬁJran-Z-y1)-N-((1R,2R)(2,3 - 03 * dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xy-3 01idin )—A C 2-(4,5 -dich10robenz0ﬁ1rany1)-N-(( 1 R,2R)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin NO N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)hydr0xy-3 - 03 * (pyrrolidiny1)pr0pany1)—2,2—diﬂu0r0-3 -(3 -(pyridin N)—A N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)- 1 xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 -ﬂu0r0-2,3 -dihydr0- 1H-inden 1 acetamide NN N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)—2,2-diﬂu0r0(naphthalen 1 butanarnide N—((1 S ,2R)(2,3-dihydr0benzo [b] [ 1 ,4] dioxiny1)— 1 -hydr0xy-3 - DJ * (pyrrolidin- 1 0pany1)—2,2-diﬂu0r0(naphthalen 1 butanarnide Nb.) 2-(benzofurany1)—N—((1R,2R)(2,3-dihydr0benzo [b] [ 1 ,4] dioxin- 6-y1)hydr0xy(pyrr01idiny1)pr0pany1)-2,2- diﬂuoroacetarnide N4; N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5-ﬂuor0benzoﬁ1ran-2— 1 ide U1 (E)(4-ch10r0pheny1)-N—((1R,2R)(2,3 - 03 * dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin -2,2-diﬂuorobut—3-enarnide 0 N—((1R,2R)—3 -(3-aminoazabicyclo[3.2.1]octany1)(2,3 - 03 * dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xypr0pany1)(5 - chlorobenzofuran-Z2,2-diﬂuor0acetamide N 00 N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 - ﬂuorobenzo[b]thio o hen-Z- 1 ide DJ 0 N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 - (triﬂuoromethyl)benzofurany1)acetam1de 2-(5-brornobenz0furany1)—N—((1R,2R)(2,3- d1hydrobenz0 [b] [1 ,4] d10x1ny1)hydroxy-3 011d1n 1ﬂuoroacetam1de N—((1 S ,2R)-3 -(azet1d1ny1)(2,3 -d1hydrobenz0[b][1,4]d10x1n 03 * y1)hydroxypropany1)(5 -chlorobenzofurany1)-2,2- d1ﬂuoroacetarn1de N—((1R,2R)—3-(azet1d1ny1)—1-(2,3-d1hydrobenz0 [b] [1 ,4]d10x1n y1)hydroxypropany1)(5 -chlorobenzofurany1)-2,2- d1ﬂuoroacetarn1de 2-(5-chlorobenzofurany1)-2,2-d1ﬂuoro-N-((1S,2R)(7-ﬂuoro- 03 ae 2,3-d1hydrobenz0 [b] [1 ,4]d10x1ny1)—1-hydroxy-3 011d1n o 10 o an 1 acetamide h1010benz0furany1)-2,2-d1ﬂuoro-N-((1R,2R)— 1 -(7-ﬂuoro- 03 * 2,3-d1hydrobenz0 [b] [1 ,4]d10x1ny1)—1-hydroxy-3 -(py11011d1n o 10 o an 1 acetamide 2-(5-chlorobenzofurany1)-2,2-d1ﬂuoro-N-(( 1 S,2R)hydroxy-3 - 03 * (pyrrolidiny1)(qu1no11ny1)propany1)acetam1de 2-(5-ch1010benz0furany1)-2,2-d1ﬂuoro-N-((1R,2R)—1-hydroxy-3 - * (pyrrolidiny1)(qu1no11ny1)propany1)acetam1de 2-(5 -chlorobenz0furany1)-N-((1S,2R)(2,3 - d1hydrobenzo [b] [1 ,4] d10x1ny1)-3 -(3 ,3 -d1methy1py11011d1ny1) -2,2-d1ﬂuoroacetam1de 2-(5-chlorobenzofurany1)-2,2-d1ﬂuoro-N-(( 1 S,2R)hydroxy-3 - 03 * lidiny1)(4-(t11ﬂuoromethoxy)pheny1)propan 2-(5-ch1010benz0furany1)-2,2-d1ﬂuoro-N-((1R,2R)—1-hydroxy-3 - 03 * (pyrrolidiny1)(4-(t11ﬂuoromethoxy)pheny1)propan 2-(5-ch1010benz0furany1)-N-((1R,2R)— 1 -(2,3 - 03 * d1hydrobenzo [b] [1 ,4]d10x1ny1)-3 -((S)-3 -ﬂuoropy11011d1ny1) -2,2-d1ﬂuoroacetam1de 2-(5-chlorobenzofurany1)-N-((1R,2R)- 1-(2,3- d1hydrobenzo[b][1,4]d10x1ny1)— 1 -h-ydroxy3-((R) oo-roan 1 -2 ,2-d1ﬂuoroacetarn1de 2-(5-chlorobenzofurany1)-N-((1R,2R)- 1-(2,3- d1hydrobenzo[b][1,4]d10x1ny1)— 1 -h-ydroxy3-((S) .10 oan- 1 -2 ,2-d1ﬂuoroacetarn1de h1010benzofurany1)-N-((1R,2R)—3-(3,3-d1ﬂuoropy11011d1n 03 * y1)(2,3-d1hydrobenzo [b] [ 1 x1ny1)hydroxypropany1)- ﬂuoroacetam1de N-((1S,2R)(3-ch1010cyc10prop0xypheny1)hydroxy 03 * (pyrrolidiny1)propany1)(5 -chlorobenzofurany1)-2,2- d1ﬂuoroacetarn1de N—((1R,2R)— 1 -(3-ch1010cyclopropoxypheny1)hydroxy-3 - (pyrrolidiny1)propany1)(5 -chlorobenzofurany1)-2,2- d1ﬂuoroacetarn1de —437— LO\ 2—(5-ch10r0benz0furany1)-N-((1R,2R)— 1 -(2,3 - dihydrobenzo [b] [1 ,4]dioxiny1)-3 -((R)-3 -ﬂuoropyrr01idiny1)— 1 - L\] N—((1R,2R)— 1 -(3 -ch10ro((tetrahydrofuran-3 -y1)0xy)pheny1)— 1 - hydroxy(pyrr01idiny1)pr0pany1)—2-(5 -ch10r0benz0furan L 00 2—(5-ch10r0benz0furany1)-N-((1R,2R)— 1 -(2,3 - 03 * dihydrobenzo [b] [1 ,4]di0xiny1)hydr0xy-3 -(2- -2,2-diﬂuoroacetamide J; 2-(5-ch10r0benz0furany1)-2,2-diﬂuor0-N-((1R,2R)— 1 -hydr0xy (1 -methyl- az01-5 -y1)-3 -(pyrr01idiny1)pr0pan 1 acetamide UI N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂuor0(5 -(pyridiny1)-2,3 - dih dro-1H-inden 1 ide 01 N—((1R,2R)—3-(2-azabicyc10[2.2. 1]heptany1)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xypr0pany1)(5 - benzofuran-Z- 1 iﬂuor0acetamide m N—((1R,2R)— 1 -(3-ch10r0cyclopropoxypheny1)hydroxy-3 - (pyrrolidiny1)pr0pany1)—2,2-diﬂu0r0(naphthalen 1 butanarnide m N—((1R,2R)—3-(7-azabicyc10[2.2. 1]heptany1)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xypr0pany1)(5 - chlorobenzofuran-Z2,2-diﬂuor0acetamide m 2-(5-ch10r0benz0furany1)-2,2-diﬂuor0-N-((1R,2R)— 1 xy (1 -methyl- 1H-indaz01y1)-3 -(pyrr01idiny1)pr0pan 1 acetamide 2-(5 -ch10robenzofuran-Z-y1)-2,2-diﬂuor0-N-((1 S,2R)hydr0xy 03 * (1 -methyl- 1H-indaz01y1)-3 01idiny1)pr0pan 1 ide 2-(5-ch10r0benz0furany1)-2,2-diﬂuor0-N-((1R,2R)— 1 -hydr0xy hoxypyridin-3 -y1)-3 -(pyrr01idiny1)propany1)acetamide N—[2-(2H,3H-benz0[e] 1 ,4-di0xany1)(1R)hydr0xy (pyrro1idiny1rnethy1)ethy1] (5 -ch10r0benz0[d]ﬁ1rany1)—2,2- diﬂuoroacetarnide 2—(5 -ch10r0benz0furany1)- N—((1R,2R)(2,3 - dihydrobenzo [b] [1 ,4]di0xiny1)—1-deuter0hydroxy-3 - o rrolidin 1 -2,2-diﬂuoroacetamide 2—(5 -ch10r0benz0furany1)- N—((1 S ,2R)—1-(2,3 - 03 * dihydrobenzo [b] [1 ,4]di0xiny1)—1-deuter0hydroxy-3 - o rrolidin 1 -2,2-diﬂuoroacetamide 2-(5-ch10r0benz0furany1)-N-((1R,2R)— 1 -(3-(diﬂu0r0rnethy1)—4- methoxypheny1)hydr0xy-3 -(pyrr01idiny1)pr0pany1)-2,2- diﬂuoroacetarnide 2-(5 -ch10robenzofuran-Z-y1)-N-(( 1 S ,2R)(3 -(diﬂuor0rnethy1) 03 * ypheny1)- 1 xy-3 -(pyrr01idiny1)pr0pany1)-2,2- diﬂuoroacetarnide 2—(5-ch10r0benz0furany1)-N-((1R,2R)— 1 -(2,3 - dih drobenzo [b] [1 ,4] dioxin 1 h drox -3 - o rrolidin C\ ._1 N—((1R,2R)—1-(7-br0rno-2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1) 03 * hydroxy(pyrr01idiny1)pr0pany1)—2-(5 -ch10r0benz0furan -2,2-diﬂuoroacetarnide oN 2—(5-ch10r0benz0furany1)-N-((1R,2R)— 1 -(2,3 - US * dihydrobenzo [b] [1 ,4] dioxiny1)-3 -(3 ,3 thy1azetidiny1) 0DJ 2—(5 -ch10r0-2,3 -dihydr0-1H-inden-Z-y1)-N-((1R,2R)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin O\J; 2-(5-ch10r0benz0furany1)-2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0- 2,3-dihydr0benz0 [b] [1 ,4]di0xiny1)—1-hydr0xy-3 01idin U1 N—((1R,2R)—1-(8-ch10r0-2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1) hydroxy(pyrr01idiny1)pr0pany1)—2-(5 -ch10r0benz0furan h10r0benz0furany1)-N-((1R,2R)— 1 -(2,3 - dihydrobenzo [b] [1 ,4]di0xiny1)— 1 -hydr0xy-3 -(3 -rnethy1azetidin O\ \1 2-(5 -ch10r0-2,3 -dihydr0-1H-inden-Z-y1)-N-((1R,2R)—1-(3 0 ropoxypheny1)hydroxy-3 -(pyrr01idiny1)propany1)—2,2- diﬂuoroacetarnide 2-(5-ch10r0benz0furany1)-N-((1R,2R)—1-(5-ch10r0benz0furan 03 * y1)hydr0xy(pyrr01idiny1)pr0pany1)—2,2-diﬂuor0acetamide 2-(5 0benz0furan-Z-y1)-N-((1 S,2R)(5-ch10r0benz0furan y1)hydr0xy(pyrr01idiny1)pr0pany1)—2,2-diﬂuor0acetamide ,2R)— 1 -(3-ch10r0cyclopropoxypheny1)hydroxy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 - N-((1S,2R)(3-ch10r0cyc10prop0xypheny1)hydr0xy (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 - 2-(2,3 -dihydro-1H-inden-Z-y1)-N-((1R,2R)(2,3- dihydrobenzo [b] [1 ,4] y1)hydr0xy-3 -(pyrr01idin 2—(5-ch10r0benz0furany1)-N-((1R,2R)— 1 -(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin (E)(5-ch10robenz0ﬁJran-Z-y1)-N-((1R,2R)-1 -(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [ 1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)0X0(5 -(pyridiny1)-2,3 -dihydro- 2—(5 -ch10r0-2,3 -dihydr0-1H-inden-Z-y1)-N-((1R,2R)(2,3 - dihydrobenzo [b] [1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin -439— Table 2. The data provided is the IC50 (nM) generated from Assay 1, except as otherwise noted by *, which is % inhibition, also generated from Assay 1.

N—((1R,2R)(2,3-dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 - 03 * (pyrrolidiny1)propan-2—yl)oxo(4,5 ,6,7-tetrahydro-2H- isoindol 1 acetamide N—((1R,2R)(azetidiny1)(2,3-dihydrobenzo [b] [ 1 ,4] y1)hydroxypropany1)(5-chlorobenzoﬁ1ranyl) tamide N—((1R,2R)(3-chlorocyclopropoxypheny1)-1 -hydroxy-3 - (pyrrolidiny1)propanyl)(5 -ch10robenzoﬁ1ranyl) oxoacetamide 2-(5 -chlorobenzoﬁ1ranyl)-2,2-diﬂuoro-N—((1 S,2R)hydroxy (6-isopropoxypyridin-3 -y1)-3 -(pyrrolidiny1)propany1)acetan1ide N—((1R,2R)(3-chlorocyclopropoxypheny1)-1 -hydroxy-3 - (pyrrolidin- 1 opanyl)-2,2-diﬂuoro(6-ﬂuoronaphtha1en 1 butanarnide N—((1R,2R)(azetidiny1)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]dioxiny1)— 1 -hydroxypropany1)(5 - chlorobenzofuran-Z2,2-diﬂuoroacetan1ide ,2R)(2,3-dihydrobenzo [b] [1 ,4] dioxiny1)- 1 xy-3 - (pyrrolidiny1)propanyl)-2,2-diﬂuoro(6-ﬂuoronaphtha1en 1 butanarnide hlorobenzoﬁ1ranyl)-2,2-diﬂuoro-N—((1R,2R)-1 -hydroxy-3 - lidiny1)(6-(2,2,2-triﬂuoroethoxy)pyridin-3 -y1)propan 1 acetamide N—((1R,2R)(azetidiny1)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]dioxiny1)—1-hydroxypropany1)-2,2- diﬂuoro 6-ﬂuorona o hthalen 1 butananiide ﬂuoro-N-((1R,2R)(8-ﬂuoro-2,3-dihydrobenzo [b] [ 1 ,4] dioxin- 6-y1)hydroxy-3 -(pyrrolidin-1 -y1)propany1)—4-(6- ﬂuorona ohthalen 1 butananiide 2,2-diﬂuoro(6-ﬂuoronaphtha1eny1)-N-((1R,2R)—1-hydroxy-3 - a: (pyrrolidiny1)(6-(2,2,2-triﬂuoroethoxy)pyridin-3 -y1)propan 1 butanarnide N—((1R,2R)(azetidiny1)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]dioxiny1)— 1 -hydroxypropany1)(5 - benzofuran-Z2-oxoacetan1ide N—((1R,2R)(2,3-dihydrobenzo [b] [1 ,4] dioxiny1)hydroxy-3 - (pyrrolidiny1)propanyl)(6-ﬂuoronaphtha1enyl) oxobutanarnide 2-(5 -chloro-2,3 -dihydro-1H-indeny1)-2,2-diﬂuoro-N-((1R,2R)— 1 - 03 * hydroxy(pyrrolidiny1)(6-(2,2,2-triﬂuoroethoxy)pyridin-3 - o ro o an 1 acetamide N—((1R,2R)(azetidiny1)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]dioxiny1)— 1 -hydroxypropany1)(5 - —440— ch10ro-2,3-dihydr0-1H-inden-Z-y1)-2,2-diﬂuoroacetamide 2-(5 -chlor0-2,3 -dihydro-1H-indenyl)-2,2-diﬂu0ro-N-((1R,2R)— 1 - (8-ﬂuoro-2,3-dihydrobenzo [b] [ 1 ,4] dioxiny1)hydroxy-3 - o rrolidin 1 0 r0 0 an 1 acetamide N—((1R,2R)(3-chloroisopr0poxypheny1)hydroxy-3 - (pyrrolidiny1)pr0panyl)(5 -ch10robenz0ﬁ1ranyl)-2,2- diﬂuoroacetarnide 2-(5-ch10r0benz0ﬁ1ranyl)-N-((1R,2R)— 1 -(8-ﬂu0r0-2,3 - dihydrobenzo [b] [ 1 xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an-Z2-oxoacetamide N—((1R,2R)—1-(2,3-dihydr0benz0 [b] [1 ,4]di0xiny1)— 1 -hydr0xy-3 -(3 - * methylazetidiny1)pr0pany1)-2,2-diﬂuor0(6-ﬂu0r0naphthalen- 2- 1 butanarnide 2,2-diﬂuoro(6-ﬂuor0naphthaleny1)-N-((1R,2R)—1-hydroxy * (6-isopropoxypyridin-3 -y1)-3 -(pyrrolidiny1)propan 1 butanarnide N—((1R,2R)(azetidiny1)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)— 1 -hydr0xypr0pany1)(5 - chlorobenzofuran-Z2- h drox imino acetamide 2-(5-ch10robenz0ﬁ1rany1)-N-((1R,2R)(6-cyclopr0poxypyridiny1)hydr0xy-3 -(pyrr01idiny1)pr0pany1)—2,2- diﬂuoroacetarnide h10r0benzoﬁJran-Z-yl)-N-((1R,2R)—1-(2,3- dihydrobenzo [b] [ 1 xiny1)—1-hydr0xy-3 -(3 -methylazetidin oro .an-Z- 1 acetamide N—((1R,2R)—1-(6-cyclopr0p0xypyridiny1)hydr0xy-3 -(pyrr01idiny1)pr0panyl)-2,2-diﬂu0r0(6-ﬂuor0naphthalen 1 butanarnide (E)—2-(5-ch10r0benzofuran-Z-yl)—N—((1R,2R)-1 -(2,3 - dihydrobenzo [b] [ 1 xiny1)—1-hydr0xy-3 -(3 -methylazetidin 0 r0 0 an 1 h drox imino acetamide 2-(5 -ch10robenz0ﬁ1ranyl)-2,2-diﬂuor0-N—((1 S,2R)hydr0xy 03 * (2-isopr0poxypyridiny1)-3 -(pyrr01idin- 1 0panyl)acetarnide (E)—2-(5-chlorobenzofuran-Z-yl)—N—((1R,2R)(8-ﬂu0r0-2,3 - obenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - 0 r0 0 an 1 h drox imino acetamide N—((1R,2R)— 1 -(3 -ch10r0((tetrahydro-2H-pyrany1)0xy)phenyl)-1 - hydroxy(pyrr01idiny1)pr0panyl)-2—(5 -ch10r0benz0furan 1 iﬂuoroacetamide (E)—N—((1R,2R)(2,3-dihydr0benz0 [b] [ 1 ,4] dioxiny1)hydr0xy(pyrr01idiny1)pr0pany1)—4-(6-ﬂu0r0naphthaleny1) h drox imino butanarnide 2,2-diﬂu0ro-N-((1R,2R)—1-hydr0xy(6-isopr0poxypyridin-3 -y1)-3 - (pyrrolidiny1)pr0panyl)(naphthaleny1)butanarnide 2,2-diﬂuoro-N—((1R,2R)—1-hydroxy(pyrr01idiny1)(6-(2,2,2- triﬂuoroethoxy)pyridiny1)pr0pany1)(naphthalen 1 butanarnide —441— 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydrobenzo [b] [ 1 ,4] dioxin- 6-y1)-1 -hydr0xy-3 -(pyrr01idiny1)pr0pany1)—4-(naphthalen 1 butanarnide N—((1R,2R)— 1 -(3 -ch10r0((tetrahydro-2H-pyrany1)0xy)phenyl)-1 - y(pyrr01idiny1)pr0panyl)-2,2-diﬂuor0(naphthalen- 2- 1 butanarnide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(6-ﬂu0r0naphthaleny1)- 2-oxobutanamide (E)-N-((1R,2R)(3-ch10rocyclopropoxyphenyl)hydroxy-3 - (pyrrolidiny1)pr0panyl)(6-ﬂu0r0naphthalenyl) h drox imino butanarnide N—((1 S ,2R)-3 -(azetidiny1)—1-(8-ﬂu0r0-2 ,3 - 03 * dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydroxypr0panyl)-2,2- diﬂuor0 na 0 hthalen 1 butanarnide 2,2-diﬂuor0(6-ﬂuor0naphthaleny1)-N-((1R,2R)—1-hydroxy * (2-isopr0poxypyridiny1)-3 -(pyrr01idiny1)pr0pan 1 butanarnide ((1R,2R)(8-ﬂuor0-2,3-dihydr0benzo[b][1,4]di0xiny1)—1- hydroxy(pyrr01idin- 1 0panyl)(6-ﬂu0r0naphthaleny1)- 2- h drox imino butanarnide 2-(5 0-2,3 -dihydr0-1H-inden-Z-yl)-N—((1R,2R)— 1 -(3 -ch10r0 ((tetrahydro-ZH-pyrany1)0xy)pheny1)hydr0xy-3 -(pyrr01idin oro .an-Z2,2-diﬂuor0acetamide N—((1 S,2R)(2,2-dimethylchromanyl)hydr0xy-3 -(pyrr01idiny1)pr0pany1)-2,2-diﬂuor0(naphthaleny1)butanarnide (E)-N-((1R,2R)(azetidiny1)(8-ﬂu0r0-2,3 - dihydrobenzo [b] [ 1 ,4] dioxinyl)— 1 xypr0pany1)(6- ﬂuorona o hthalen 1 h drox imino butanarnide 2-(5-ch10robenz0ﬁJran-Z-y1)-N-((1R,2R)-1 -(2,2-dirnethylchrornan * y1)hydr0xy-3 -(pyrr01idin-1 -y1)propany1)-2,2-diﬂu0roacetarnide N—((1R,2R)—1-(6-cyclopr0p0xypyridiny1)hydr0xy-3 -(pyrr01idin- * 1 -y1)pr0pany1)-2,2-diﬂuor0(naphthaleny1)butanarnide N—((1R,2R)(3-ch10r0((1-rnethy1piperidiny1)oxy)pheny1) 03 * y(pyrr01idin- 1 0panyl)-2,2-diﬂuor0(naphthalen- 2- 1 butanarnide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) * hydroxypropan-Z-yl)(5-ch10r0benzoﬁJran-Z-y1)oxoacetamide N—((1R,2R)(3-ch10r0((1-rnethy1piperidiny1)oxy)pheny1) * hydroxy(pyrr01idiny1)pr0panyl)-2—(5 -ch10r0benz0furan 1 -2,2-diﬂuoroacetamide N—((1 S ,2R)(3 -chlor0rn0rph01inophenyl)hydr0xy-3 - 03 * (pyrrolidiny1)pr0panyl)-2,2-diﬂuoro(naphthalen 1 butanarnide N—((1R,2R)(4-cyclopr0p0xyﬂu0ropheny1)hydr0xy (pyrrolidiny1)pr0panyl)-2,2-diﬂuoro(naphthalen 1 butanarnide 2-(5-ch10r0benz0ﬁ1ranyl)-N-((1R,2R)— 1 -(4-cyclopr0p0xy-3 - ﬂuorophenyl)— 1 -hydr0xy-3 -(pyrr01idin-1 -y1)pr0pany1)—2,2- —442— diﬂuoroacetarnide N—((1R,2R)(3-ch10r0rn0rpholinophenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(5 -ch10robenz0ﬁ1ranyl)-2,2- diﬂuoroacetarnide N-((1R,2R)—1-(4-(2-(azetidiny1)ethoxy)ch10r0phenyl) hydroxy(pyrr01idiny1)pr0panyl)-2—(5 -ch10r0benz0furan 1 -2,2-diﬂuoroacetamide N—((1R,2R)(3-ch10r0(0xetany10xy)phenyl)hydroxy-3 - (pyrrolidiny1)pr0panyl)-2,2-diﬂuoro(naphthalen 1 rnide N—((1R,2R)(3-ch10r0(0xetany10xy)phenyl)hydroxy-3 - (pyrrolidiny1)pr0panyl)(5 obenz0ﬁ1ranyl)-2,2- diﬂuoroacetarnide N-((1R,2R)—1-(4-(2-(azetidiny1)ethoxy)ch10r0phenyl) * hydroxy(pyrr01idiny1)pr0panyl)-2,2-diﬂuor0(naphthalen- 2- 1 butanarnide 2-(6-chloronaphthalen-Z-yl)-N-((1R,2R)(2,3- dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an-Z2,2-diﬂuor0acetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrrolidiny1)pr0pany1)(4'-ﬂu0r0-[1 ,1'-bipheny1]- 42-oxoacetamide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) hydroxypropan-Z-yl)-2,2-diﬂuoro(6-ﬂuoronaphthalen 1 butanarnide 2-(6-chloronaphthaleny1)-2,2-diﬂu0ro-N—((1R,2R)(8-ﬂuor0- 2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1)hydr0xy-3 -(pyrr01idin 0 r0 0 an 1 ide (E)-N-((1R,2R)(3-ch10rocyclopropoxyphenyl)hydroxy-3 - (pyrrolidiny1)pr0panyl)(5 -ch10robenz0ﬁ1ranyl) h drox imino acetamide (E)-N-((1R,2R)(azetidinyl)(3 -ch10r0 03 * cyclopropoxyphenyl)— 1 -hydr0xypropanyl)(6-ﬂu0ronaphthalen- 22- h drox imino butanarnide (E)—N—((1R,2R)(8-ﬂuor0-2,3-dihydr0benzo[b][1,4]di0xiny1)—1- hydroxy(pyrrolidiny1)pr0pany1)(4'-ﬂu0r0-[1 pheny1]- 42- h drox imino acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)-1 xy-3 - * (pyrrolidin-l-y1)pr0panyl)(6-ch10ronaphthalen-Z-y1)-2,2- diﬂuoroacetarnide 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydrobenzo [b] [ 1 ,4] dioxin- 6-y1)hydr0xy-3 -(pyrr01idiny1)pr0pany1)—2-(4'-ﬂuor0- [1 , 1'- bi o hen 1] 1 acetamide (E)-N-((1R,2R)(azetidiny1)(8-ﬂu0r0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydroxypr0panyl) h drox imino na 0 n 1 butanarnide (E)-N-((1R,2R)(3-ch10rocyclopropoxyphenyl)hydroxy-3 - lidiny1)pr0panyl)(hydroxyirnino)(naphthalen-Z- —443— y1)butanan1ide ,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(naphtha1eny1) oxobutanamide N—((1R,2R)(azetidiny1)(2,3-dihydr0benzo [b] [ 1 ,4] dioxin y1)hydr0xypr0panyl)-2,2-diﬂuoro(naphthalen 1 butanamide N—((1R,2R)(azetidin-1 -y1)-1 -(8-ﬂuor0-2,3 - * dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydroxypr0panyl) naohthalen-Z2-0X0butanan1ide N—((1R,2R)— 1 -(3 -chlor0((tetrahydro-2H-pyrany1)0xy)pheny1) hydroxy(pyrr01idiny1)pr0panyl)(6-ch10r0naphthalen 1 -2,2-diﬂuoroacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - * (pyrrolidiny1)pr0panyl)(naphtha1eny1)0X0butanan1ide (E)—N—((1R,2R)(8-ﬂuor0-2,3-dihydr0benzo[b][1,4]di0xiny1)—1- hydroxy(pyrr01idiny1)pr0panyl)(hydr0xyin1ino)—4- na en-Z- 1 butanamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1'-bipheny1]y1) oxoacetamide N—((1R,2R)(azetidiny1)(8-ﬂuor0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xypr0pany1)(4'- ﬂuoro-[1,1'-bio hen 1] 1 oxoacetan1ide 2-(6-ch10r0naphtha1eny1)-N-((1R,2R)(8-ﬂuor0-2,3 - obenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 01idin-1 - oro .an 1 oxoacetan1ide N—((1R,2R)— 1 -(3 -chlor0((tetrahydro-2H-pyrany1)0xy)pheny1) hydroxy(pyrrolidiny1)pr0pany1)(4'-ﬂu0r0-[1 ,1'-bipheny1]- 42-oxoacetan1ide (E)-N-((1R,2R)(3-ch10rocyclopropoxyphenyl)hydroxy-3 - (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1'-bipheny1]y1) h drox imino ide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) 03 * hydroxypropan-Z-yl)(6-ﬂuor0naphthaleny1)0xobutanan1ide ((1R,2R)(azetidiny1)(8-ﬂuor0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xypr0pany1)(4'- ﬂuoro-[1,1'-bio hen 1] 1 h drox imino acetamide 2-(7-ch10r0naphtha1eny1)-N-((1R,2R)(8-ﬂuor0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an 1 oxoacetan1ide N—((1R,2R)(azetidiny1)(8-ﬂuor0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydroxypr0panyl)-2,2- diﬂuoro-Z- 4'-ﬂu0ro-[1,1'-bio hen 1] 1 acetamide (6-ch10r0naphthaleny1)-N-((1R,2R)— 1 -(8-ﬂu0r0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - 0 r0 0 an 1 h drox imino acetamide —444— N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(4'-ﬂuor0-[ 1 ,1'- bi o hen 1] 1 acetamide N—((1R,2R)(2,3-dihydr0benz0[b] [1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(4'-ﬂuor0-[ 1 ,1'- bi o hen 1] 1 acetamide N—((1R,2R)(azetidiny1)(2,3-dihydr0benzo [b] [ 1 ,4] dioxin y1)hydr0xypr0pany1)-2,2-diﬂu0ro(4'-ﬂuoro-[1 ,1'-bipheny1]- 4- 1 acetamide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) * hydroxypropan-Z-yl)-2,2-diﬂuor0(4'-ﬂuoro-[ 1 , 1'-bipheny1] 1 acetamide N—((1R,2R)— 1 -(3 -chlor0((tetrahydro-2H-pyrany1)0xy)pheny1) y(pyrr01idiny1)propanyl)-2,2-diﬂuor0-2—(4'-ﬂuoro- [1 , 1'-bi o hen 1] 1 ide (E)-N-((1R,2R)(azetidinyl)(3 -ch10r0 * cyclopropoxyphenyl)— 1 -hydr0xypr0pany1)(hydr0xyin1in0) na ohthalen-Z- 1 butanamide N—((1R,2R)(2,3-dihydr0benz0[b] [1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 ,6,7, 8- tetrah drona o hthalen 1 butanamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 ,6,7, 8- tetrah drona o hthalen 1 butanamide ﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydr0benzo [b] [ 1 ,4] dioxin- 6-y1)hydr0xy-3 -(pyrr01idin-1 -y1)pr0pany1)—4-(5 ,6,7, 8- tetrah drona o hthalen 1 mide N—((1 S -(3 -ch10r0(2-hydr0xyn1ethy1pr0poxy)phenyl) 03 * hydroxy(pyrr01idiny1)pr0panyl)-2—(5 -ch10r0benz0furan 1 -2,2-diﬂuoroacetan1ide - (E)-N-((1R,2R)(azetidinyl)(3 0 * cyclopropoxyphenyl)— 1 -hydr0xypr0pany1)(5-ch10r0benz0ﬁ1ran- 22- h drox imino acetamide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) 03 * hydroxypropany1)(naphtha1eny1)0X0butanan1ide - N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) ypropan-Z-yl)-2,2-diﬂuoro(naphthaleny1)butanan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(6-ch10r0naphthaleny1)—2- oxoacetamide ((1R,2R)(3-ch10rocyclopropoxyphenyl)hydroxy-3 - (pyrrolidiny1)pr0panyl)(6-ch10r0naphthaleny1)—2- h drox imino acetamide N—((1R,2R)(2,3-dihydr0benz0[b] [1 ,4]di0xiny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(5 -(4-ﬂuorophenyl)thi0pheny1) oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4-(5 -ﬂuoropyridin-Z-y1)pheny1)—2- oxoacetamide —445— N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1) hydroxy(pyrr01idin- 1 0pany1)(4-(5 -ﬂuor0pyridin-2— o hen 1 oxoacetan1ide (E)-N-((1R,2R)(3 -ch10r0((tetrahydro-2H-pyran y1)0xy)pheny1)hydr0xy-3 -(pyrr01idin- 1 0pany1)(4'- ﬂuoro- [1 1 '-bi o hen 1 h drox imino ide , 1] N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 3: (pyrrolidiny1)pr0pany1)-2,2-diﬂu0r0(4-(5 -ﬂuor0pyridin-2— o hen 1 acetamide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - a: lidiny1)pr0pany1)-2,2-diﬂu0r0(4-(5 -ﬂuor0pyridin-2— o hen 1 acetamide ,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - 3: (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 -(4- ﬂuoro o hen 1 thio o hen 1 acetamide (Z)-N-((1R,2R)(2,3-dihydr0benz0 [b] [ 1 ,4] dioxiny1)hydr0xy(pyrr01idiny1)propany1)-2—(5 -(4-ﬂuor0pheny1)thi0pheny1)— 2- h drox imino ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂuoro(4-(pyridin o hen 1 acetamide 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydr0benzo [b] [ 1 ,4] dioxin- 1-hydr0xy(pyrr01idiny1)propany1)—2-(4-(5 - ﬂuoro o ridin-Z o hen 1 acetamide (E)-N-((1R,2R)(3-ch10rocyclopropoxypheny1)hydroxy-3 - (pyrrolidin- 1 0pany1)(4-(5 -ﬂuoropyridin-Z-y1)pheny1)—2- h drox imino acetamide 2-(5-ch10r0benz0ﬁ1rany1)-N-((1R,2R)— 1 -(2,3 -dihydro- 03 * [1 ,4]di0xino [2,3 -b]pyridiny1)hydr0xy-3 -(pyrr01idin oro .an 1 -2,2-diﬂuor0acetan1ide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - 3: (pyrrolidiny1)pr0pany1)-2,2-diﬂuoro(4-(pyridin o hen 1 acetamide 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydr0benzo [b] [ 1 ,4] dioxin- 6-y1)hydr0xy(pyrr01idiny1)pr0pany1)—2-(4-(pyridin o hen 1 acetamide N—((1R,2R)(azetidiny1)(8-ﬂuor0-2,3 - a: dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xypr0pany1)(6- chloronaohthalen-Z2-0X0acetan1ide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - a: (pyrrolidiny1)pr0pany1)(4-(5 -ﬂuoropyridin-Z-y1)pheny1)—2- oxoacetamide (E)—N—((1R,2R)(2,3-dihydr0benz0 [b] [ 1 ,4] dioxiny1)hydr0xy- 3: 3 -(pyrr01idiny1)pr0pany1)—2-(4-(5 -ﬂuoropyridiny1)pheny1) h drox imino acetamide (E)-N-((1R,2R)(azetidiny1)(8-ﬂuor0-2,3 - dihydrobenzo [b] [ 1 xiny1)—1-hydr0xypr0pany1)(6- chlorona o hthalen 1 h drox imino acetamide 2-(5 -ch10r0-2,3 -dihydr0-1H-indeny1)-N—((1R,2R)— 1 -(3 -ch10r0 a: (2-hydr0xyn1ethy1propoxy)pheny1)hydr0xy-3 -(pyrr01idin oro .an 1 -2,2-diﬂuor0acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - a: (pyrrolidin- 1 0pan-2—y1)-2,2-diﬂuor0( 1 -n1ethy1-1 ,2,3 ,4- tetrah dro c uinolin 1 butanamide N—(( 1 R,2R)-1 -(3 -ch10r0(2-hydr0xyn1ethy1prop0xy)pheny1) hydroxy(pyrr01idiny1)pr0pany1)(4'-ﬂu0r0-[1 ,1'-bipheny1]- 42-oxoacetan1ide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - a: (pyrrolidiny1)propany1)0X0(4-(pyridin o hen 1 acetamide 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydr0benzo [b] [ 1 ,4] dioxin- 03 * 6-y1)hydr0xy(pyrr01idiny1)pr0pany1)—2-(in1idazo[1 ,2- a] o Z- 1 acetamide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(3-(4-ﬂuorophenoxy)pheny1) oxoacetamide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - a: (pyrrolidiny1)pr0pan-2—y1)-2,2-diﬂuor0( 1 -n1ethy1-1 ,2,3 ,4- tetrah dro c uinolin 1 butanamide ,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 03 * (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(in1idazo [1 ,2-a]pyridin- 2- 1 acetamide N—((2R)(8-ﬂu0r0-2,3-dihydr0benzo [b] [ 1 ,4]dioxiny1)— 1 - hydroxy(pyrr01idiny1)pr0pany1)ox0(4-(piperidin o hen 1 acetamide ,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - 3: (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(3 -(4- N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂuor0(4-(1-n1ethy1-1H- N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1) hydroxy(pyrr01idiny1)pr0pany1)(3 -(4- ,2R)(4-cyclopr0p0xyﬂu0ropheny1)hydr0xy (pyrrolidiny1)pr0pany1)-2,2-diﬂuor0(4'-ﬂuoro-[1 ,1'- bi o hen 1] 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propany1)(4-(1-n1ethy1-1H-indaz01-5 - o hen 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 3: (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(3 -(4- o hen 1 acetamide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - lidiny1)propany1)(4-(1-n1ethy1-1H-indaz01-5 - o hen 1 oxoacetan1ide —447— WO 42397 N—((1R,2R)(4-cyclopr0p0xyﬂu0ropheny1)hydr0xy (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1'-bipheny1]y1) oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 0X0acetan1ide 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydr0benzo [b] [ 1 ,4] dioxin- 6-y1)hydr0xy-3 -(pyrr01idin-1 -y1)pr0pany1)—2-(3 -(4- N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxinyl)hydr0xy-3 - 03 * (pyrrolidiny1)pr0pany1)-2,2—diﬂu0r0(2-(4- ﬂuoro o hen 1 thiaz01 1 acetamide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxinyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)-2,2-diﬂuor0(4-(1-n1ethy1—1H- indazol-S - 1 o hen 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 03 ae (pyrrolidiny1)pr0pany1)-2,2—diﬂu0r0(2-(4- ﬂuoro o hen 1 1 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propany1)0X0(4-(pyridin o hen 1 ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 03 * (pyrrolidiny1)pr0pany1)(2-(4-ﬂuor0pheny1)thiazol-5 -y1) oxoacetamide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxinyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(1-n1ethy1—1H-indaz01—5-y1) oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0pany1)(1 -n1ethy1—1H-indaz01—5 2-oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 03 ae (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 -(4- ﬂuoro o hen 1 thio o hen 1 ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - * (pyrrolidin- 1 0panyl)(5 -(4-ﬂuorophenyl)thi0pheny1) oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(4-(1 -methyl- 1 H-indazol- o hen 1 0X0acetan1ide 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydr0benzo [b] [ 1 ,4] dioxin- * 6-y1)hydr0xy(pyrr01idiny1)pr0pany1)(2-(4- ﬂuoro o hen 1 thiaz01 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 03 * (pyrrolidiny1)pr0pany1)-2,2—diﬂu0r0(2-(4- ﬂuoro o hen 1 thiazol-S - 1 acetamide N—((1R,2R)(azetidin-1 -y1)-1 or0-2,3 - dihydrobenzo [b] [ 1 ,4]dioxinyl)—1-hydroxypr0pany1)(4-(1- meth 1- 1 H-indazol-S - 1 o hen 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 3: (pyrrolidiny1)pr0panyl)(1-n1ethy1—1H-indaz01—5-y1) 2014/056555 oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - * lidiny1)pr0pan-2—y1)(2-ch10r0benzo[b]thiophen-5 -y1)—2- oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1) 03 * hydroxy(pyrr01idiny1)pr0pany1)(2-(4- ﬂuoro o hen 1 thiaz01 1 0X0acetan1ide N—((1R,2R)(azetidiny1)(8-ﬂuor0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xypr0pany1)0X0(4- o i o eridin 1 o hen 1 acetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo [b] [ 1 xiny1) hydroxy(pyrr01idiny1)propan-2—y1)oxo(4-(pyridin o hen 1 acetamide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - 03 * (pyrrolidiny1)propany1)(2-(4-ﬂuoropheny1)thiazo1y1) tamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1) hydroxy(pyrr01idiny1)pr0pany1)(5 -(4- ﬂuoro o hen 1 thio o hen 1 0X0acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidin- 1 0pany1)0X0(4-(piperidin o hen 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂuor0(4-(1-n1ethy1-1H- indaz01 1 o hen 1 acetamide 2-(benz0[b]thi0pheny1)—N—((1R,2R)(3 -ch10r0 cyclopropoxypheny1)hydroxy-3 -(pyrr01idiny1)propany1) oxoacetamide ,2R)(8-ch10r0-2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)— 1 - hydroxy(pyrr01idiny1)pr0pany1)(4'-ﬂu0r0-[1 ,1'-bipheny1]- 42-oxoacetan1ide N—((1R,2R)(2,3-dihydr0benz0 [b] [1 ,4] dioxiny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂuor0(4-(1-n1ethy1-1H- indaz01 1 o hen 1 acetamide 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydr0benzo [b] [ 1 ,4] dioxin- 6-y1)hydr0xy(pyrr01idiny1)pr0pany1)—2-(4-(1-n1ethy1-1H- indaz01 1 o hen 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - lidiny1)pr0pany1)-2,2-diﬂuor0(4-(2-n1ethy1-2H- indaz01 1 o hen 1 acetamide N—((2R)(3-ch10rocyc10pr0p0xypheny1)—1-hydroxy-3 - 03 * (pyrrolidiny1)pr0pany1)ox0(3 -(piperidin o hen 1 acetamide 2,2-diﬂu0r0-N-((1R,2R)—1-(8-ﬂuor0-2,3-dihydr0benzo [b] [ 1 ,4] dioxin- 6-y1)hydr0xy(pyrr01idiny1)propany1)—2—(5 -(4- ﬂuoro o hen 1 thio o hen 1 acetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1) hydroxy(pyrr01idiny1)propany1)(4-(2-n1ethy1-2H-indaz01- —449— -y1)phenyl)0X0acetarnide - N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4-(4-ﬂu0r0phenoxy)phenyl) tamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(6-ch10r0benz0[b]thi0pheny1)—2- oxoacetamide ,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1-rnethy1—1H-indaz01—6- o hen 1 oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(1-rnethy1—1H-indaz01—6-yl) oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) * hydroxy(pyrr01idiny1)pr0panyl)(1-rnethy1—1H-indazol 1 oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(4-(1 -methyl- 1 H-indazol- ,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - * (pyrrolidiny1)pr0panyl)-2,2—diﬂu0r0(6-(4- N—((1R,2R)(azetidiny1)(8-ﬂuor0-2,3- dihydrobenzo [b] [ 1 ,4] dioxinyl)— 1 -hydr0xypr0pany1)(3 -(4- N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(3-(4-ﬂuorophenoxy)phenyl) oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrrolidiny1)pr0pany1)(4'-ﬂu0r0-[1 ,1'-bipheny1] 1 oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - lidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1'-bipheny1]-3 -y1) oxoacetamide N—((1R,2R)(2,3-dihydr0benzo[b] [1 ,4]di0xiny1)- 1 xy-3 - * (pyrrolidiny1)propany1)(4-(4-ﬂuorophenyl)piperazin oxoacetamide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) hydroxypropany1)(4'-ﬂuoro-[1 , 1 '-bipheny1] y1) oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) y(pyrr01idiny1)pr0pany1)(4-(4- ﬂuoro o hen 1 o i o erazin 1 oxoacetamide 2-(4'-(tert-butyl)-[1,1'-bipheny1]yl)-N—((1R,2R)(3 -ch10r0 cyclopropoxyphenyl)— 1 -hydroxy-3 -(pyrrolidiny1)propany1) oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1-isopr0py1—1H-indazol —450— y1)pheny1)oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4-(2-isopr0py1—2H-indazol o hen 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidin-l-y1)pr0pany1)(4-(1-isopr0pyl-1H-indazol-5 - o hen 1 acetan1ide ,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(2-isopr0pyl-2H-indazo1-5 - o hen 1 oxoacetan1ide ,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2-diﬂu0ro(5 -(4- ﬂuoro o hen 1 o ridin 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - * (pyrrolidiny1)pr0panyl)(3 -(1-n1ethy1—1H-indaz01—6- o hen 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - 03 * (pyrrolidiny1)propany1)(4-(4-ﬂuorophenyl)piperaziny1) oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propany1)(4-(2-ch10r0benz0 [b]thi0phen-5 - o hen 1 oxoacetan1ide ,2R)-1 -(3-ch10r0cyc10pr0poxypheny1)-1 -hydr0xy (pyrrolidiny1)pr0panyl)(5 -(4-ﬂuorophenyl)pyridiny1) oxoacetamide N—((1R,2R)(4-cyclopr0p0xy(triﬂuor0n1ethy1)phenyl) 03 * hydroxy(pyrrolidiny1)pr0pany1)(4'-ﬂu0r0-[1 ,1'-bipheny1]- 42-oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propanyl)(4-(1-isopropy1—1H-indol-5 - o hen 1 oxoacetan1ide 2-(4'-ch10ro-[1,1'-bipheny1]y1)—N—((1R,2R)(2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an 1 oxoacetan1ide N—((1R,2R)(5-ﬂuoro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrrolidiny1)pr0pany1)(4'-ﬂu0r0-[1 ,1'-bipheny1]- 42-oxoacetan1ide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrrolidiny1)pr0pany1)(4-(1-isopropyl-1H-indol- o hen 1 0X0acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4'-ch10r0-[1 ,1'-bipheny1]y1) oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1-isopr0py1—1H- d]in1idaz01—5 - 1 o hen 1 oxoacetan1ide 2-(4'-ch10r0-[1,1'-bipheny1]y1)—N—((1R,2R)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - —451— panyl)oxoacetamide N—((1R,2R)(8-ﬂu0r0-2,3-dihydr0benzo[b][1,4]di0xiny1)—1- hydroxy(pyrrolidiny1)propany1)0X0(4-(pyrr01idin o hen 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)0x0(4'-(triﬂuor0n1ethy1)—[1 ,1'- bi o hen 1] 1 acetamide 2-(4-(1-cyclopr0py1—lH-indazol-S-y1)pheny1)-N—((1R,2R)—1-(8- 2,3-dihydrobenzo [b] [1 ,4]dioxiny1)hydroxy-3 - o rrolidin 1 0 r0 0 an 1 0X0acetan1ide N—((1R,2R)(8-chlor0-2,3-dihydr0benz0 [b] [1 ,4] dioxinyl)— 1 - hydroxy(pyrr01idiny1)pr0panyl)(4-(1-cyclopr0py1—1H- N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propany1)(4-(1 -cyclopropy1—lH-indazol-S - N—((1R,2R)(azetidin-1 -y1)-1 -(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]dioxinyl)—1-hydroxypr0pany1)(4-(1- 0X0acetan1ide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) hydroxypropan-Z-y1)(4-(1-n1ethy1—1H-indaz01—5-y1)pheny1) oxoacetamide 2-(4-(benz0[d]isoxazoly1)pheny1)—N—((1R,2R)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an 1 acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1-cyclopropy1—1H-indaz01—6- o hen 1 oxoacetan1ide 2-(4-(1-cyclopr0pyl-1H-indaz01—6-y1)pheny1)-N—((1R,2R)—1-(8- ﬂuoro-2,3-dihydrobenzo [b] [1 xiny1)hydroxy-3 - o rrolidin 1 0 r0 0 an 1 acetan1ide N—((1R,2R)(azetidin-1 -y1)-1 -(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]dioxinyl)—1-hydroxypr0pany1)(4-(1- c 010 0 r0 0 1— 1H-indaz01—6- 1 acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(2-cyc10propy1—2H-indazol o hen 1 oxoacetan1ide N—((1R,2R)(azetidiny1)(8-ch10r0-2,3 - dihydrobenzo [b] [ 1 ,4]dioxinyl)—1-hydroxypr0pany1)(4-(1- c 010 0 r0 0 1— 1 H-indazol-S 2-0X0acetan1ide 2-(4'-ﬂuor0-[1,1'-bipheny1]y1)-N-((1R,2R)—1-hydr0xy-3 - (pyrrolidiny1)(8-(triﬂu0ron1ethyl)-2,3 - dih drobenzo [b] [ 1 ,4] dioxin 1 0 r0 0 an 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(6-(4-ﬂuor0phenyl)pyridin-3 -y1) oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pan-2—yl)(1-(4-ﬂu0r0benzy1)-lH-indazol-S - —452— y1)ox0acetan1ide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1) hydroxy(pyrr01idiny1)pr0pany1)(1 -(4-ﬂuor0benzy1)-1H- indazol-S 2-0X0acetan1ide 2-(4-(benz0[d]isoxaz01y1)pheny1)—N—((1R,2R)(8-ﬂuor0-2,3 - D> dihydrobenzo [b] [ 1 ,4] dioxiny1)— 1 -hydr0xy-3 01idin oro .an 1 acetan1ide N—((1R,2R)—1-(4-(tert-butoxy)—3-ch10r0pheny1)—1-hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1 '-bipheny1] y1) oxoacetamide 2-(6-ch10r0benz0[b]thi0pheny1)-N—((1R,2R)—1-(4-cyc10prop0xy-3 - ﬂuoropheny1)hydr0xy-3 -(pyrr01idiny1)pr0pany1)—2- oxoacetamide N—((1R,2R)(azetidiny1)(8-ﬂuor0-2,3 - dihydrobenzo [b] [ 1 ,4] dioxiny1)— 1 -hydr0xypropany1)(4'-(tert- bu 1 - [1 1 '-bi o hen , 1] 1 oxoacetan1ide 2-(4'-(tert-buty1)-[1,1'-bipheny1]y1)-N—((1R,2R)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4] dioxiny1)— 1 -hydr0xy-3 -(pyrr01idin oro .an 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propany1)(4'-ﬂuor0-2'-n1ethy1-[1 , 1 '-bipheny1] - 42-oxoacetan1ide 2-(4-(benz0[d]thiaz01y1)pheny1)-N—((1R,2R)(3-ch10r0 cyclopropoxypheny1)hydroxy-3 -(pyrr01idiny1)propany1) oxoacetamide 2-(4-(benz0[d]thiaz01y1)pheny1)-N-((1R,2R)—1-(3 -ch10r0 cyclopropoxypheny1)- 1 xy-3 01idiny1)propany1) oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidin- 1 0pany1)(4'-ﬂu0r0n1ethy1-[ 1 pheny1]- 42-oxoacetan1ide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1) hydroxy(pyrr01idiny1)pr0pany1)(4'-ﬂu0r0n1ethy1-[1 ,1'- bi o hen 1] 1 oxoacetan1ide N—((1R,2R)(azetidiny1)(8-ch10r0-2,3 - dihydrobenzo [b] [ 1 ,4] dioxiny1)— 1 -hydr0xypropany1)(4'- [1,1'-bio hen 1] 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4'-cyan0- [1 , 1 '-bipheny1] y1) tamide 2-(8-br0n10dibenzo[b,d]furany1)-N—((1R,2R)(3-ch10r0 cyclopropoxypheny1)hydroxy-3 -(pyrr01idiny1)propany1) oxoacetamide N-[(1R,2R)—2-(3-ch10r0cyc10pr0p0xypheny1)hydr0xy o rrolidin lmeth 1 eth 1] [4- 0 o hen 1 o hen 1] acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(2-(4-ﬂu0r0benzy1)-2H-indaz01-5 2-oxoacetan1ide —453— 2014/056555 N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(2-(4-ﬂuor0benzyl)-2H- indazol-S 2-0X0acetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(1-isopropy1—1H-indaz01—6-yl) oxoacetamide ,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(1-isopr0py1—1H-indazol- 6- 1 acetamide 2-(6-chlorobenzo[b]thiophen-2—yl)-N—((1R,2R)—1-(8-ﬂu0r0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an-Z2-oxoacetamide N—((1R,2R)(3-ch10r0(cyc10pentyloxy)phenyl)-1 -hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1 '-bipheny1] y1) oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4-(2-isopr0py1—3 -rnethy1—2H- indazol-S 2-0X0acetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(2-isopropy1—2H-indazol-5 -y1) oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0pany1)(2-isopr0py1—2H-indazo1- 62-oxoacetamide N—((1R,2R)(3-ch10r0cyclobutoxyphenyl)hydroxy (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1 '-bipheny1] oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1-isopr0py1—3 -rnethy1—1H- indazol-S 2-0X0acetamide 2-(4'-ﬂu0r0-2'-rnethy1—[1 pheny1]y1)-N-((1R,2R)—1-(8-ﬂuor0- 2,3-dihydr0benzo [b] [ 1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin oro .an-Z2-oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(2-isopropy1—2H-indazo1y1) oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(1-isopropy1—3 -rnethy1—1H-indazol-5 - 1 acetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1 ,3 thy1— 1 H-indazol-S - o hen 1 oxoacetamide N—((1R,2R)—1-(benz0[b][1,4]di0xiny1)hydroxy-3 -(pyrr01idin y1)propanyl)(4'-ﬂuor0-[ 1 ,1'-bipheny1]y1)0X0acetamide N—((1R,2R)(3-ch10r0(cyclopropylthio)phenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1 '-bipheny1] y1) oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(1-isopr0pyl-1H-indazol-5 -y1) —454— oxoacetamide 1,3 -dirnethy1— 1 H-indazol-S -y1)pheny1)-N—((1R,2R)(8-ﬂu0r0- 2,3-dihydr0benzo [b] [ 1 ,4] dioxiny1)hydr0xy-3 -(pyrr01idin oro .an-Z2-oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(1-isopr0py1—lH-indol-S 2-oxoacetamide ,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)propany1)(1-isopropy1—1H-indol-5 -y1) tamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)propany1)(4-m0rph01inophenyl)—2- oxoacetamide (1-(3-chlorocyclopropoxyphenyl)-3 -(pyrrolidin y1)propanyl)(4'-ﬂuor0-[ 1 ,1'-bipheny1]y1)0X0acetamide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) hydroxypropany1)0X0(4-(pyrr01idiny1)pheny1)acetarnide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidin-l-y1)pr0panyl)(6-ch10ronaphthalen-Z-y1)-2,2- diﬂuorobutanamide ,2R)(3-ch10r0(Vinyloxy)phenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1'-bipheny1]yl) oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(4-(1-isopr0py1—1H- o razol 1 o hen 1 0X0acetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0pan-2—yl)(1-isopr0pyl-1H-indol 1 oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(1-isopropy1—1H-indolyl)—2- oxoacetamide N—((1R,2R)(4-cyclopr0poxypheny1)hydroxy(pyrr01idin y1)propanyl)(4'-ﬂuor0-[ 1 ,1'-bipheny1]y1)0X0acetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1-isopr0py1—3 -rnethy1—1H- N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(4-(2-isopropyl-3 -rnethy1— N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4-(2-isopr0py1—3 -rnethy1—2H- N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(4-(1 -isopr0pyl-3 -rnethy1— 1H-indaz01—6- 1 o hen 1 oxoacetamide N—((1R,2R)(azetidiny1)(3-chlorocyclopr0p0xypheny1) hydroxypropan-Z-y1)(6-ch10r0benzo[b]thi0phenyl) —455— oxoacetamide - ,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - lidin-l-y1)pr0pany1)(4'-isopr0py1—[1 ,1'-bipheny1]y1)—2- oxoacetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1 ,3 -din1ethy1—1H-indazol o hen 1 oxoacetan1ide 2-(4-(1,3 -din1ethyl-1H-indazo1y1)pheny1)-N—((1R,2R)(8-ﬂuoro- 2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1)hydr0xy-3 -(pyrr01idin oro .an 1 oxoacetan1ide 2-(4-(2,3 -din1ethyl-2H-indazo1y1)pheny1)-N—((1R,2R)(8-ﬂuoro- 2,3-dihydr0benzo [b] [ 1 ,4]di0xiny1)hydr0xy-3 -(pyrr01idin oro .an 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)0X0(4-(pyrrolidin o hen 1 ide ,2R)(3-ﬂuor0isopr0poxyn1eth0xypheny1)hydr0xy(pyrr01idiny1)pr0pany1)—2-(4'-ﬂuor0- [1 , 1'-bipheny1]y1)—2- oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrrolidiny1)pr0pany1)(4-(1-isopropyl-1H-indol- o hen 1 0X0acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-(1-isopr0py1—1H-ind01—6- o hen 1 oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propanyl)(4-(2,3 -din1ethy1—2H-indazol o hen 1 oxoacetan1ide 2-(6-chlorobenz0[b]thi0pheny1)-N—((1R,2R)— 1 -(3-ﬂu0r0 isopropoxy-S-n1eth0xyphenyl)hydr0xy-3 -(pyrr01idin-1 -y1)pr0pan- 22-oxoacetan1ide - N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4-(1-cyclopr0pyl-1H-pyrazol-3 - o hen 1 oxoacetan1ide 2-(4-(1 -cyclopr0pyl-1H-pyraz01—3-y1)pheny1)-N—((1R,2R)(8- 2,3-dihydrobenzo [b] [1 ,4]dioxiny1)hydroxy-3 - o rrolidin 1 0 r0 0 an 1 0X0acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propanyl)(4-(1-isopropy1—1H-pyrazol-3 - o hen 1 oxoacetan1ide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) y(pyrr01idiny1)pr0panyl)(4-(1-isopr0py1—1H- o hen 1 0X0acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(1-(4-ﬂu0r0pheny1)-lH-indazol-S 2-oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(2-(4-ﬂuor0pheny1)-2H-indaz01—5 - y1)oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propany1)oxo(4'-(pr0peny1)-[1 ,1'- bi o hen 1] 1 acetamide ,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(4'-(2-hydr0xypr0pan 1 -[1,1'-bi. hen 1] 1 oxoacetan1ide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)propan-2—y1)(4'-isopr0py1— [1 , 1'- bi o hen 1] 1 acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propany1)(4'-(2-hydr0xypropany1)- [1 , 1'- bi o hen 1] 1 oxoacetan1ide 2-(4-(5 -ch10r0thi0pheny1)pheny1)-N—((1R,2R)-1 c10pr0poxyﬂu0r0pheny1)— 1 -hydr0xy-3 -(pyrr01idiny1)pr0panyl) oxoacetamide 2-(4-(5 -ch10r0thi0pheny1)pheny1)-N—((1R,2R)-1 -(8-ﬂu0r0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an 1 oxoacetan1ide N—((1R,2R)(3-ﬂuor0isopr0p0xyn1eth0xypheny1)hydr0xy(pyrr01idiny1)pr0pany1)—2-(4'-ﬂuor0- [1 , 1'-bipheny1]y1)—2- oxoacetamide N—((1R,2R)(8-ﬂuoro-3 ,3-din1ethy1—2,3- dihydrobenzo [b] [ 1 ,4]di0xiny1)— 1 -hydr0xy-3 -(pyrr01idin-1 - 0 r0 0 an 1 4'-ﬂu0r0-[1,1'-bio hen 1] 1 acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1)(4-(5 0thi0pheny1)pheny1) oxoacetamide 2-(6-chlorobenz0[b]thi0pheny1)-N—((1R,2R)— 1 -(3-ﬂuor0-5 - isopropoxyn1eth0xypheny1)— 1 -hydr0xy-3 -(pyrr01idin-1 -y1)pr0pan- 22-oxoacetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propanyl)(6-ch10robenz0ﬁ1rany1) tamide 2-(6-ch10r0benzoﬁ1ranyl)-N-((1R,2R)—1-(8-ﬂu0r0-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an 1 oxoacetan1ide N—((1R,2R)(azetidin-1 -y1)-1 -(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xypr0pany1)0X0(4- o rrolidin 1 o hen 1 acetamide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - (pyrrolidiny1)propany1)(4-n10rph01inophenyl) oxoacetamide N—((1R,2R)(azetidin-1 -y1)-1 oro-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)— 1 xypr0pany1)-2—(4- o holino o hen 1 0X0acetan1ide N—((1R,2R)(3-ch10r0cyc10pr0p0xypheny1)hydr0xy-3 - o rrolidin 1 oro o an 1 4'-c c10or0 o 1—[1,1'-bi. hen 1] 1 - —457— 2014/056555 2-(4'-cyclopr0py1—[1,1'-bipheny1]y1)—N—((1R,2R)(8-ﬂuoro-2,3 - dihydrobenzo [b] [ 1 ,4]di0xiny1)—1-hydr0xy-3 -(pyrr01idin-1 - oro .an-Z2-oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)0X0(4-(tetrahydro-2H-pyran ,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)propany1)oxo(4-(tetrahydr0-2H- N—((1R,2R)(4-cyclopr0poxypheny1)hydroxy(pyrr01idin yl)pr0pany1)(4-rn0rpholinophenyl)0X0acetamide 2-(4-(azetidiny1)pheny1)-N—((1R,2R)—1-(3 -ch10r0 cyclopropoxyphenyl)— 1 -hydroxy-3 -(pyrrolidiny1)propany1) oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(4-ﬂuor0pheny1)—2-0X0acetarnide 2-(benzo[b]thi0pheny1)—N—((1R,2R)(3 -ch10r0 ropoxyphenyl)— 1 -hydroxy-3 -(pyrrolidiny1)propany1) oxoacetamide N—((1R,2R)(4-cyclopr0p0xyﬂu0ropheny1)hydr0xy (pyrrolidiny1)pr0panyl)(4-ethynylpheny1)oxoacetamide N—((1R,2R)(8-ﬂu0ro-2,3-dihydr0benzo[b][1,4]di0xinyl) hydroxy(pyrr01idiny1)pr0panyl)(4-ﬂu0r0phenyl) oxoacetamide N—((1R,2R)(3-ch10r0cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl)(1 orophenyl)piperidinyl)—2- oxoacetamide N—((1R,2R)(azetidiny1)(4-cyclopropoxyﬂuor0phenyl) hydroxypropan-Z-y1)(6-ch10r0benzo[b]thi0phenyl) oxoacetamide N—((1R,2R)(4-cyclopr0p0xyﬂu0ropheny1)hydr0xy (pyrrolidiny1)pr0pany1)(4'-ﬂuor0-[1 , 1 '-bipheny1] y1)-N— meth 10X0acetarnide 2-(6-ch10r0benzo[b]thi0phenyl)-N—((1R,2R)—1-(4-cyc10prop0xy-3 - ﬂuoropheny1)-1 -hydr0xy-3 -(pyrr01idin-1 -y1)pr0pany1)—N—rnethy1— 2-0X0acetamide Table 3. The data provided is the IC50 (nM) generated from Assay 1, except as otherwise noted by *, which is % inhibition, also generated from Assay 1.

N—((1R,2R)(3 -chloro , cyclopropoxypheny1)hydroxy 3 84 , (pyrrolidiny1)propany1)(5 - chlorobenzo [b]thiophen-Z-y1) oxoacetamide 2-(4-(1H-1,2,3 -triazol- 1-y1)pheny1)-N— ((1R,2R)(3-chloro ropoxypheny1)hydroxy-3 - 3 85 (pyrrolidiny1)propanyl) oxoacetamide 2—(6-chlorobenzo ophen-Z-y1)-N- ((1R,2R)(4-chlorophenyl) 3 86 y(pyrrolidin— 1 -y1)propan yl)oxoacetamide N—((1R,2R)(azetidiny1)(4- ropoxy-3 -ﬂuoropheny1) hydroxypropany1)(5 - 3 87 chlorobenzo[b]thiophen-Z-y1) oxoacetamide 2-(benzo [b]thiophen-Z-yl)-N- ((1R,2R)(4-cyclopropoxyphenyl) 3 8 8 - hydroxy(pyrrolidin— 1 -y1)propan yl)oxoacetamide —459— N—((1R,2R)(4-ch10r0phenyl) hydroxy(pyrr01idin—1-y1)pr0pan 3 89 yl)(4'—ﬂu0r0-[1,1'-bipheny1]—4-yl) oxoacetamide N—((1R,2R)(4- cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2— diﬂu0r0(naphthalen anamide 2—(5-chlor0benz0 [b]thi0pheny1)-N— ((1R,2R)(4-cyclopr0p0xyphenyl) 3 9 1 hydroxy(pyrr01idin— 1 -y1)pr0pan yl)0x0acetamide 2-(4-(5-chlorothiophen-Z-y1)pheny1)- N—((1R,2R)(4- cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl) oxoacetamide 2-(4-(5-chlorothiophen-Z-y1)pheny1)- N—((1R,2R)(4- ropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2— diﬂuoroacetamide ,2R)(4- cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0pany1)-2,2— diﬂuoro-Z-(4'-ﬂu0r0-[1,1'-bipheny1]—4- yl)acetamide N—((1R,2R)(4-cyclopr0p0xy-3 - ﬂuorophenyl)hydr0xy-3 - 395 ' (pyrrolidin- 1-y1)pr0panyl)(4- cyclopropylphenyl)oxoacetamide N—((1R,2R)(3 -ch10r0 cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidin- 1-y1)pr0panyl)(4-(5- chlorothiophen-Z-y1)phenyl)-2,2- diﬂuoroacetamide 2-(4-(5-chlorothiophen-Z-y1)pheny1)- N—((1R,2R)(4-cyclopr0p0xy-3 - ' ﬂuorophenyl)hydr0xy-3 - 3 97 (pyrrolidin-l-y1)pr0pany1)-2,2- diﬂuoroacetamide -chlorothiophen-Z-y1)pheny1)- 2,2-diﬂu0r0-N—((1R,2R)(8-ﬂu0r0- hydr0benz0[b][1,4]di0xiny1)hydr0xy-3 -(pyrr01idiny1)pr0pan- 2-y1)acetamide 2—(6-chlor0benzo [b]thi0pheny1)-N— ((1R,2R)(4-cyclopr0p0xyphenyl) 399 y(pyrr01idin— 1 -y1)pr0pan yl)0x0acetamide 2-(4-(1H-pyrazoly1)pheny1)-N— ((1R,2R)(3-ch10r0 cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl) oxoacetamide N—((1R,2R)(4- 7 cyclopropoxyphenyl)hydr0xy-3 - 401 * (pyrrolidin- 1-y1)pr0panyl)(4- ethynylphenyl)0x0acetamide 4-(6-ch10r0naphthaleny1)-N- ((1R,2R)(4-cyclopr0p0xyphenyl) 402 hydroxy(pyrr01idin— 1 -y1)pr0pan yl)-2,2—diﬂu0r0butanamide 2-(4-(2H-1,2,3 -triazoly1)phenyl)-N- ((1R,2R)(3-ch10r0 ropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl) oxoacetamide N—((1R,2R)(4-cyclopr0p0xy-3 - henyl)hydr0xy-3 - , (pyrrolidin- 1-yl)pr0panyl)(4'- ﬂuoro-[l,1'—b1phenyl]y1)-N—methy1- 2-0x0acetamide 2—(6-chlor0benzo [b]thi0pheny1)-N— ((1R,2R)(4- - (diﬂuoromethoxy)phenyl)hydr0xy(pyrr01idiny1)pr0panyl) oxoacetamide (E)-N-((1R,2R)(3-ch10r0 cyclopropoxyphenyl)hydr0xy-3 - 406 (pyrrolidin- 1-y1)pr0panyl)(6- ﬂuoronaphthalen-Z-yl)-2— h drox imino butanamide N—((1R,2R)-3 -(azetidiny1)(4- 1 cyclopropoxyphenyl)- 1- hydroxypropan-Z-y1)(4'-ﬂu0r0- [ 1 , 1'- biphenyl]y1)0x0acetamide N—((1R,2R)(3-ch10r0 _ cyclopropoxyphenyl)hydr0xy-3 - 408 (isoxazolidin-Z-y1)pr0panyl)(4'- ﬂuoro-[1,1'-bipheny1]—4-y1) tamide N—((1R,2R)(3-ch10r0 . cyclopropoxyphenyl)hydr0xy-3 - 409 (is0xazolidiny1)pr0pan-2—y1)-2—(6- benzo [b]thi0pheny1) oxoacetamide 2—(6-chlorobenzo[b]thi0pheny1)-N— ((1R,2R)(4-cyclopr0p0xyphenyl) 4 1 0 hydroxy(pyrr01idin— 1 -y1)pr0pan yl)0x0acetamide 4-(6-ch10r0naphthaleny1)-N- R)(4-cyclopr0p0xyphenyl) 41 1 hydroxy(pyrr01idin— 1 -y1)pr0pan yl)-2,2—diﬂu0r0butanamide _ N—((1R,2R)(4- 412 _ cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidin- 1-y1)pr0panyl)(4- ethynylphenyl)0x0acetamide 2-(4-(2H-1,2,3 -triazoly1)phenyl)-N- R)(3-ch10r0 413 cyclopropoxyphenyl)hydr0xy (pyrrolidiny1)pr0panyl) oxoacetamide 2-(4-(1H-pyrazoly1)pheny1)-N— ((1R,2R)(3-ch10r0 414 cyclopropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl) oxoacetamide 2-(benzo 0phenyl)-N- ((1R,2R)(4-cyclopr0p0xyphenyl) 4 1 5 y(pyrr01idin— 1 -y1)pr0pan yl)0x0acetamide 2-(5'-ch10r0-[2,2'-bithi0phen]y1)-N— : ((1 R,2R)(4-cyc10pr0p0xy ; ﬂuoropheny1)hydr0xy (pyrrolidiny1)pr0pany1) oxoacetamide N-(( 1 R,2R)(3 -ch10r0 _ cyclopropoxyphenyl)hydr0xy-3 - 417 (pyrrolidiny1)propany1)(2',4'- diﬂuoro-[1,1'—biphenyl]yl) oxoacetamide 2-(3 -chloropyrrolo[1,2-b]pyridazin : yl)-N—((1R,2R)(2,3- 418 dihydrobenzo[b][1,4]dioxiny1) N hydroxy(pyrrolidin—1-y1)propan yl)-2,2-diﬂu0r0acetamide 2-(7-chloroimidazo[1,2-a]pyridin = yl)-N—((1R,2R)(2,3- 419 dihydrobenzo[b][1,4]dioxiny1) y(pyrrolidin— 1 -y1)propan yl)-2,2-diﬂu0r0acetamide ,2R)(2,3- dihydrobenzo [b] [1 ,4] dioxiny1)- 1- 420 hydroxy-ﬁ-(pyrrolidin— 1 -y1)propan y1)-2,2-d1ﬂu0r0(6- oromethyl)ﬁ1r0[3 ,2-c]pyridin y1)acetamide 2—(6-chlor0fur0[3,2-b]pyridiny1)-N— : ((1R,2R)(2,3- 421 dihydrobenz0[b][1,4]dioxiny1) hydroxy(pyrrolidin— 1 -y1)propan yl)-2,2-diﬂu0r0acetamide N—((1R,2R)(2,3- dihydrobenzo [b] [1 ,4] y1)- 1- hydroxy(pyrrolidin— 1 -y1)propan yl)-2,2-diﬂu0r0(2- (triﬂuoromethyl)furo[2,3 -d]pyrimidin- 6-y1)acetamide 2-(5-chlor0thien0[3,2—b]furanyl)-N— = ((1R,2R)(2,3- 423 5 dihydrobenzo [b] [1 ,4] dioxiny1)- 1- y(pyrrolidin— 1 -y1)propan yl)-2,2-diﬂu0r0acetamide 2-(5-ch10r0thien0 [2,3-d]0xazolyl)- = N—((1R,2R)(2,3- 424 5 dihydrobenzo [b] [1 ,4] dioxiny1)- 1- 5 hydroxy(pyrr01idin—1-y1)pr0pan 2-diﬂu0r0acetamide 2-(2-ch10r0fur0[2,3-d]thiazoly1)-N— : ((1R,2R)(2,3- 425 5 dihydrobenzo [b] [1 ,4] dioxiny1)- 1- 5 hydroxy(pyrr01idin— 1 -y1)pr0pan yl)-2,2-diﬂu0r0acetamide 3-(3-chlor0benzy1)-N—((1R,2R)(2,3- dihydrobenzo [b] [ 1 ,4] dioxiny1)- 1- hydroxy(pyrr01idin— 1 -y1)pr0pan 2-diﬂu0r0butenamide 2-(5-ch10r0benzofurany1)-N— ((1R,2R)(2,3- dihydrobenzo[b] [1,4]di0xiny1)- 1- hydroxy-3 -(2,2,5,5- tetradeuteropyrrolidiny1)pr0pan yl)-2,2-diﬂu0r0acetamide N—((1R,2R)(3 -ch10r0((4- hydroxytetrahydro-2H—pyran yl)meth0xy)phenyl)- 1-hydr0xy-3 - (pyrrolidiny1)pr0pany1)(5 - ch10r0benzoﬁ1ran—2-y1)-2,2- diﬂuoroacetamide 2-(5-ch10r0-2,3 -dihydr0- en yl)-N—((1R,2R)(3 -ch10r0((4- ytetrahydro-2H—pyran yl)meth0xy)phenyl)- 1-hydr0xy-3 - (pyrrolidin-l-y1)pr0pany1)-2,2- diﬂuoroacetamide 2-(5-ch10r0benz0ﬁ1rany1)-2,2- = diﬂuoro-N—((1R,2R)hydr0xy(4- 430 5 dr0xytetrahydr0-2H—pyran 5 yl)meth0xy)phenyl)-3 -(pyrr01idin yl)pr0pany1)acetamide N—((1R,2R)(4-ch10r0-3 -((4- hydroxytetrahydro-2H—pyran yl)meth0xy)phenyl)- 0xy-3 - 431 5 (pyrrolidiny1)pr0pany1)(5 - ch10r0benzoﬁ1ran—2-y1)-2,2- diﬂuoroacetamide 2-(5-ch10r0benz0ﬁ1rany1)-2,2- diﬂuoro-N—((lR,2R)hydr0xy(2— isopropoxypyridinyl)-3 01idinyl)pr0panyl)acetamide E h10r0benzofuran-Z-yl)-N— R)(6-cyclopr0p0xypyridin 433 5 y1)hydr0xy(pyrr01idin— 1- y1)pr0panyl)0x0acetamide (E)(5-ch10r0benzoﬁ1rany1)-N— - ((1R,2R)(6-cyclopr0p0xypyridin-3 - 434 a y1)hydr0xy(pyrr01idin— 1- yl)pr0pany1) (hydroxyimin0)acetamide 2-(5-ch10r0-2,3 -dihydr0- 1H-inden yl)-N—((1R,2R)(6- 435 = cyclopropoxypyridinyl)hydr0xy- 3 01idiny1)pr0pany1) oxoacetamide (E)(5-ch10r0-2,3 -dihydr0- 1H-inden- 2-y1)-N—((1R,2R)(6- 436 i cyclopropoxypyridinyl)hydr0xy(pyrr01idin- 1 0pany1) (hydroxyimin0)acetamide 2-(5-ch10r0benz0ﬁ1rany1)-2,2- = diﬂuoro-N—((lR,2R)hydr0xy(6- 437 * ((4-hydr0xytetrahydr0-2H—pyran yl)meth0xy)pyridin—3 -y1)-3 - (pyrrolidiny1)pr0pan—2—yl)acetamide N—((1R,2R)(6-cyclopr0p0xypyridin- E 3 -y1)hydr0xy-3 -(pyrr01idin 43 8 _ = 5 y1)pr0pany1)(6-ﬂuoronaphthalen- 2—y1)-2—0x0butanamide (E)-N—((1R,2R)(6- ; cyclopropoxypyridin-3 -y1)hydr0xy- 439 a 3-(pyrr01idiny1)pr0pany1)(6- 5 ﬂuoronaphthalen-Z-yl)-2— (hydroxyimin0)butanamide 2014/056555 N—((1R,2R)(3-ch10r0 ; cyclopropoxyphenyl)hydr0xy-3 - 440 a (pyrrolidin- 1-y1)pr0panyl)(6- 5 ﬂuoronaphthalen-Z-yl)-2— oxobutanamide N—((1R,2R)(6-cyclopr0p0xypyridin- = 3 -y1)- 0xy-3 -(pyrr01idin 442 i yl)pr0pany1)-2,2—diﬂuoro-Z-(S - 5 (triﬂuoromethyl)benzofuran-Z- yl)acetamide N—((1R,2R)(3 -ch10r0 cyclopropoxyphenyl)hydr0xy-3 - 443 i (pyrrolidiny1)pr0pany1)0x0 (5-(triﬂuoromethyl)benzofuran-Z- yl)acetamide (E)-N—((1R,2R)(3-ch10r0 cyclopropoxyphenyl)hydr0xy-3 - lidiny1)pr0panyl) (hydroxyimino)(5 - (triﬂuoromethyl)benzofuran-Z- yl)acetamide (E)-N—((1R,2R)(6- = cyclopropoxypyridin-3 -y1)hydr0xy(pyrr01idiny1)pr0panyl) 445 E (hydroxyimino)(5 - (triﬂuoromethyl)benzofuran-Z- yl)acetamide N—((1R,2R)(6-cyclopr0p0xypyridin- = 3 -y1)- 1-hydr0xy-3 01idin 446 5 yl)pr0pany1)0x0-2—(5- oromethyl)benzofuran-Z- yl)acetamide 2-(5-ch10r0benzofuran-Z-yl)-N— E ((1R,2R)(2,3- 447 a dihydrobenzo[b][1,4]di0xiny1) 5 formamid0-3 -(pyrr01idiny1)pr0pan- 2-y1)-2,2-diﬂu0r0acetamide (E)-N—((1R,2R)(azetidiny1)- 1- ‘ (2,3-dihydr0benzo [b] [ 1 ,4]di0xinyl)- 448 ‘ 1-hydr0xypr0panyl)(5- 5 ch10r0benzoﬁ1rany1) (hydroxyimin0)acetamide (E)-N—((1R,2R)(azetidiny1)(3- ch10r0cyc10pr0p0xypheny1) 449 ‘ hydroxypropan-Z-yl)-2—(5- 5 ch10r0benzoﬁ1rany1) (methoxyimin0)acetamide 2-(5-chlor0benzofuran-2—y1)-N— ((1R,2R)(3,5-dich10r0 450 i cyclopropoxyphenyl)hydr0xy-3 - 5 (pyrrolidin- 1 0pany1)-2,2— diﬂuoroacetamide N—((1R,2R)(azetidiny1)- 1-(3- ch10r0cyc10pr0p0xypheny1) hydroxypropan-Z-yl)-2,2-diﬂu0r0 (6-ﬂuoronaphthalen-Z-yl)butanamide (E)-N—((1R,2R)(8-ﬂu0r0-2,3- = dihydrobenzo [b] [ 1 ,4] dioxiny1)- 1- 452 a hydroxy(pyrr01idin— 1 -y1)pr0pan yl)(6-ﬂu0r0naphthaleny1) (methoxyimin0)butanamide N—((1R,2R)(3 0 cyclopropoxyphenyl)hydr0xy-3 - 453 2 (pyrrolidiny1)pr0pany1)0x0 (5-(triﬂuoromethyl)benzofuran yl)acetamide (E)-N-((1R,2R)(3-ch10r0 ropoxyphenyl)hydr0xy-3 - (pyrrolidiny1)pr0panyl) (hydroxyimino)(5 - (triﬂuoromethyl)benzofuran-Z- yl)acetamide N—((1R,2R)(3 0 = cyclopropoxyphenyl)hydr0xy 455 = (pyrrolidiny1)pr0pany1)(5 - 5 chlorobenzo [b]thi0pheny1)-2,2- diﬂuorobutanamide N—((1R,2R)(3 -ch10r0 ropoxyphenyl)hydr0xy-3 - 456 5 (pyrrolidiny1)pr0pany1)0x0 (3 -(pyridiny10xy)pheny1)acetamide 2014/056555 N—((1R,2R)(3-ch10r0 _ cyclopropoxyphenyl)hydr0xy-3 - 457 (pyrrolidin- r0pany1)(3 -((1- 5 methyl-1H-indazo1yl)0xy)pheny1)- 2-0x0acetamide N—((1R,2R)(8-ﬂuor0-2,3- _ dihydrobenzo[b] [1,4]di0xiny1)- 1- 45 8 hydroxy(pyrr01idin— 1 -y1)pr0pan 5 yl)-2—(3 -((1-methy1-1H-indazol yl)0xy)pheny1)0x0acetamide N—((1R,2R)(8-ﬂuor0-2,3- _ dihydrobenzo[b] [1,4]di0xiny1)- 1- ; y(pyrr01idin— 1 -y1)pr0pan ' y1)(1-(4-flu0r0phenyl)-1H- imidazolyl)0x0acetamide 2-(1-(6-ch10r0naphthaleny1)-1H- : 1yl)-N-((1R,2R)(8-ﬂu0r0- ; 2,3-dihydr0benz0[b] [1 ,4]di0xiny1)hydr0xy-3 -(pyrr01idiny1)pr0pan- 2-y1)0x0acetamide 2-(1-(6-ch10r0naphthaleny1)-1H- : pyraz01yl)-N-((1R,2R)(8-ﬂu0r0- 461 ; 2,3-dihydr0benz0[b][1,4]di0xiny1)hydr0xy-3 -(pyrr01idiny1)pr0pan- 2-y1)0x0acetamide N—((1R,2R)(8-ﬂuor0-2,3- _ dihydrobenzo[b] [1,4]di0xiny1)- 1- ; hydroxy(pyrr01idin—1-y1)pr0pan (1-(4-ﬂu0r0phenyl)-lH-pyrazol- 4-y1)0x0acetamide 2-(4-(6-ch10r0naphthalenyl) methyl-1H-imidazol-Z-yl)-N—((lR,2R)- 1-(8-ﬂu0r0-2,3- 463 5 dihydrobenzo[b] [1 ,4]di0xiny1)- 1- hydroxy(pyrr01idin— 1 -y1)pr0pan 1 0x0acetamide N—((1R,2R)(8-ﬂuor0-2,3- . dihydrobenz0[b] [1,4]di0xiny1)- 1- 464 ; hydroxy(pyrr01idin—1-y1)pr0pan 5 yl)(4-(4-flu0r0pheny1)methyl- 1H-imidazol-Z-yl)0x0acetamide —470— N—((1R,2R)(3 -ch10r0 cyclopropoxyphenyl)hydr0xy-3 - 465 (pyrrolidin- 1-y1)pr0pany1)(2-(4- ﬂuorophenoxy)pyridiny1) oxoacetamide N—((1R,2R)(3 -ch10r0 cyclopropoxyphenyl)hydr0xy-3 - 466 (pyrrolidin- 1 0pany1)-2,2— diﬂuoro-Z-(Z-(4- ﬂuorophenoxy)pyridiny1)acetamide N—((1R,2R,3S)(2,3- ; dihydrobenzo[b] [1,4]di0xiny1)- 1- 467 hydroxy-3 -(pyrr01idin— 1 -y1)butan yl)(4'—ﬂu0r0-[1,1'-bipheny1]—4-yl) oxoacetamide N—((1R,2R)(3 -ch10r0 . (diﬂuoromethoxy)phenyl)hydr0xy- 468 3-(pyrr01idiny1)pr0pany1)(6- chlorobenzo [b]thi0pheny1) tamide - 2—(6-chlorobenzo[b]thi0pheny1)-N— : R)(4'-ﬂu0r0-[1,1'-bipheny1]— 4-y1)- 1-hydr0xy-3 -(pyrr01idin yl)pr0panyl)0x0acetamide N—((1R,2R)(3-ch10r0 ; ropoxyphenyl)hydr0xy-3 -(2- 470 oxopyrrolidiny1)pr0pany1)(4'- ﬂuoro-[1,1'-bipheny1]—4-y1) oxoacetamide —471— N—((1R,2R)(2,3- ; dihydrobenzo[b] [1,4]di0xiny1)- 1- 471 hydroxy(2-0x0pyrr01idin yl)pr0pany1)(4'-ﬂu0r0-[1,1'- biphenyl]y1)0x0acetamide N—((1R,2R)(3 -ch10r0 cyclopropoxyphenyl)hydr0xy-3 - 472 (pyrrolidinyl)pr0panyl)(1-(4- ﬂuorophenyl)- 1 H-pyrazoly1)-2— oxoacetamide N—((1R,2R)(3-ch10r0 _ cyclopropoxyphenyl)hydr0xy-3 - 473 (pyrazolidin—1-y1)pr0panyl)(4'- ﬂuoro-[1,1'-bipheny1]—4-y1) oxoacetamide N—((1R,2R)(3 -ch10r0 . ropoxyphenyl)hydr0xy-3 - 474 (pyrazolidin—1-y1)pr0panyl)(6- chlorobenzo [b]thi0pheny1) oxoacetamide _ N—((1R,2R)(4-cyc10pr0p0xy 475 . henyl)- 1 xy-3 - (pyrrolidiny1)pr0pany1)0x0 (4-(pr0pyny1)phenyl)acetamide 2-(5'-ch10r0- [2,2'-bithi0phen]—5-y1)-N— : ((1 R,2R)(4-cyc10pr0p0xy ; ﬂuoropheny1)hydr0xy-3 - (pyrrolidiny1)pr0pany1) oxoacetamide —472— ,2R)(3 -ch10r0 ; cyclopropoxyphenyl)hydr0xy-3 - 477 (pyrrolidin- 1-y1)pr0panyl)(6-(5- chlorothiophen-Z-y1)pyridin-3 -y1) oxoacetamide 2-(6-(5-chlorothiophen-Z-y1)pyridin-3 - ; y1)-N-((1R,2R)(4-cycloprop0xy 478 ﬂuoropheny1)hydr0xy (pyrrolidiny1)pr0pany1) oxoacetamide —473— WO 42397 Sandhoff e Mouse Model The murine model of Sandhoff disease is a knock out (KO) of the HEXB gene, which codes for beta-hexosaminidase in mice, as it does in humans. This KO mouse displays a phenotype closely resembling that seen in humans, although at a more advanced age, compared to humans. At ~3 months of age, the animals develop tremor and increased limb tone, which is worse in the hind legs. These manifestations become progressively more severe until 4—5 months of age, when the animals become moribund and rapidly lose weight.

The motor phenotype has been quantiﬁed by activity monitor, bar-crossing, and inverted screen tests (Jayakumar M et al Blood 2001, 97, 327-329; Cachon-Gonzalez et al PNAS 2006, 103(27),1037-10378). Histologically, the mouse neurons appear to be distended by lysosomal storage material, and signs of neuroinﬂammation are t. Biochemically, levels of beta-hexosaminidase are absent, and accumulations of gangliosides GM2, GA2, as well as sialic acid, can be trated (Cachon-Gonzalez et al 2006; Arthur et al Neurochem Res 2013, DOI lO.lOO7/sl10640992-5).

To te the potential efﬁcacy of different BioMarin substrate reduction compounds in Sandhoff disease, homozygous male mice are mated with zygous females. All pups ximately 50% K0 and 50% het) in a litter are treated by daily IP or SC injection with the same test (or l) article for 14 days, beginning at 3 days old. The chosen route of administration is determined based on pharmacokinetic/pharmacodynamic properties of the compound to be tested. At the end of the dosing period, pups are deeply anesthetized using isoﬂurane through nose cones (4% for induction and 1.5% for maintenance), blood is collected by cardiac re method, then the mice are euthanized.

Brains and livers are ted and snap frozen. These tissues are used for analysis of experimental endpoints (GM2 and sialic acid in brain, GA2 and sialic acid in liver). An onal tissue sample (tail tip or toe) is collected and snap frozen, then sent for genotyping. 1(f) tested compounds are found which have a marked effect on the experimental nts, an additional experiment is performed looking at effects on activity, inverted screen, and bar crossing tests, as well as average survival time, compared to vehicle- treated mice.

Polycystic Kidney Disease Mouse Model To jck mice is administered a compound of the invention ad libitum in food (standard chow) from 26-64 days of age. Control jck mice are fed a control diet from 26-64 days of age. At 63 days of age, the animals are transferred to metabolic cages for 24 hour —474— WO 42397 urine collection. At 64 days of age, animals are sacriﬁced, weighed, and blood is collected by heart re for serum isolation. Kidneys are isolated, bisected, and weighed and half of each kidney is ﬁxed in 4% paraformaldehyde in PBS overnight for parafﬁn embedding and hematoxylin and eosin staining. Kidney weight to body weight ratio is used to determine activity of the compound. Cyst volume is measured by quantitating the percentage of cystic area in histological ns ofkidneys from the treated and control animals and lied by the /body weight ratio. Kidney function is assessed by ing blood urea nitrogen (BUN) levels in serum samples derived ﬁom animals at sacriﬁce. BUN levels are elevated in untreated controls while the treated animals demonstrated a signiﬁcant reduction ofBUN levels.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent ﬁom the following description. It should be understood, however, that the description and the speciﬁc examples, while indicating speciﬁc ments, are given by way of illustration only, since various changes and modiﬁcations within the spirit and scope of the present description will become apparent from this ed description.

All publications including patents, patent applications and published patent applications cited herein are hereby incorporated by reference for all purposes. —475—

Claims

WHAT WE CLAIM IS:

1. A compound of Formula I: R2 R3 N R5 R1 R12 Formula I; wherein R1 is –C(O)C(R6)(R6a)R1a or (R6)(R6a)-X1-R1a; X1 is alkylene, alkenylene, or cycloalkylene; R1a is alkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R7 ; R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring, ally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R8; R4 is aryl substituted with a halo and a cycloalkyloxy group; R5 is –OH, and R5a is hydrogen; R6 and R6a together with the carbon to which they are attached form C(=NOH) or C(O); each R7, when present, is independently nitro, cyano, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, arbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or aryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently ally substituted with 1, 2 or 3 R7a; each R7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and lkyl; each R8, when t, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl; or two R8 together with the carbon to which they are attached form C(O); R12 is hydrogen or C1-5 alkyl; and optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound of Formula I is according to Formula I(b): R2 R3 N R5 Formula I(b) optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and onally optionally as a pharmaceutically able salt thereof.

3. The compound of claim 1, wherein the compound of a I is according to Formula I(c): R2 R3 N R5 Formula I(c) ally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally ally as a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein R2 and R3 together with the nitrogen to which they are attached form a 4-5 ed clic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl; each of which is optionally substituted with 1 or 2 R8; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, wherein R2 and R3 together with the en to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring, optionally substituted with 1 or 2 R8; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein R4 is phenyl substituted with a halo and a cycloalkyloxy group; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally ally as a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, n R1 is –C(O)C(R6)(R6a)R1a; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a ceutically acceptable salt thereof.

8. The compound of any one of claims 1-6, wherein R1 is –C(O)C(R6)(R6a)-X1-R1a; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

9. The compound of claim 8, n X1 is C1-3 alkylene; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-9, n R1a is aryl optionally substituted with 1, 2, or 3 R7 groups; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically able salt

11. The compound of claim 10, wherein R1a is phenyl optionally substituted with 1 R7 group, wherein each R7, when present, is independently phenyl, heterocycloalkyl, or heteroaryl; where the phenyl and the heteroaryl are independently optionally substituted with 1 or 2 R7a; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt f.

12. The compound of any one of claims 1-9, wherein R1a is heteroaryl optionally substituted with 1, 2, or 3 R7 groups; optionally as a er, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, n R1a is heteroaryl optionally substituted with 1 or 2 R7 groups, n each R7, when present, is independently halo, alkyl, cycloalkyl, heterocycloalkyl, , phenylalkyl, or heteroaryl; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally tuted with 1 R7a; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein R6 and R6a together with the carbon to which they are attached form C(=NOH); optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 wherein: R1 is –C(O)C(R6)(R6a)R1a or –C(O)C(R6)(R6a)-X1-R1a; X1 is alkylene, alkenylene, or cycloalkylene; R1a is alkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R7 groups; R2 and R3 together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl; each of which is optionally substituted with 1 or 2 R8; R4 is aryl tuted with a halo and a cycloalkyloxy group; R5 is –OH, and R5a is hydrogen; R6 and R6a together with the carbon to which they are attached form C(=NOH) or C(O); each R7, when t, is independently nitro, cyano, halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, oxy, heteroaryl, heteroarylalkyl, or heteroaryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1, 2 or 3 R7a; each R7a, when present, is independently ed from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl; each R8, when present, is independently amino, alkylamino, dialkylamino, alkyl, halo, or lkyl; or two R8 together with the carbon to which they are attached form C(O); R12 is hydrogen or CH3; and ally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally ally a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 wherein: R1 is –C(O)C(R6)(R6a)R1a or –C(O)C(R6)(R6a)-X1-R1a; X1 is alkylene; R1a is heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R7 groups; R2 and R3 together with the nitrogen to which they are ed form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 ed bicyclic heterocycloalkyl; each of which is optionally substituted with 1 or 2 R8; R4 is aryl substituted with a halo and a cycloalkyloxy group; R5 is –OH, and R5a is en; R6 and R6a together with the carbon to which they are attached form C(=NOH); each R7, when t, is independently nitro, cyano, halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or aryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1, 2 or 3 R7a; each R7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl; each R8, when present, is independently amino, alkylamino, dialkylamino, alkyl, or halo; R12 is hydrogen or CH3; and optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein the compound is selected from the group consisting: N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(5-chlorobenzofuranyl)oxoacetamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin yl)propanyl)(6-fluoronaphthalenyl)(hydroxyimino)butanamide; N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl)hydroxypropan yl)(5-chlorobenzofuranyl)oxoacetamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin yl)propanyl)(5-chlorobenzofuranyl)(hydroxyimino)acetamide; (E)-N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl) hydroxypropanyl)(6-fluoronaphthalenyl)(hydroxyimino)butanamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin yl)propanyl)(hydroxyimino)(naphthalenyl)butanamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(naphthalenyl)oxobutanamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin yl)propanyl)(4'-fluoro-[1,1'-biphenyl]yl)(hydroxyimino)acetamide; ,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl)hydroxypropan yl)(6-fluoronaphthalenyl)oxobutanamide; (E)-N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl) ypropanyl)(hydroxyimino)(naphthalenyl)butanamide; (E)-N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl) hydroxypropanyl)(5-chlorobenzofuranyl)(hydroxyimino)acetamide; N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl)hydroxypropan yl)(naphthalenyl)oxobutanamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(6-chloronaphthalenyl)oxoacetamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin yl)propanyl)(6-chloronaphthalenyl)(hydroxyimino)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(5-fluoropyridinyl)phenyl)oxoacetamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin yl)propanyl)(4-(5-fluoropyridinyl)phenyl)(hydroxyimino)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-methyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(4-cyclopropoxyfluorophenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(naphthalenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(4-(pyridinyl)phenyl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(2-(4-fluorophenyl)thiazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-methyl-1H-indazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(2-chlorobenzo[b]thiophenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(4-(piperidinyl)phenyl)acetamide; 2-(benzo[b]thiophenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan yl)oxo(3-(piperidinyl)phenyl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-(4-(4-fluorophenoxy)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(6-chlorobenzo[b]thiophenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-methyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-methyl-1H-indazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(3-(4-fluorophenoxy)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl)hydroxypropan yl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; (tert-butyl)-[1,1'-biphenyl]yl)-N-((1R,2R)(3-chloro cyclopropoxyphenyl)hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-isopropyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(2-isopropyl-2H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-isopropyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(2-isopropyl-2H-indazolyl)phenyl)oxoacetamide; ,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)-2,2-difluoro(5-(4-fluorophenyl)pyridinyl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(3-(1-methyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(4-fluorophenyl)piperazinyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(2-chlorobenzo[b]thiophenyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(5-(4-fluorophenyl)pyridinyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-isopropyl-1H-indolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-chloro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-isopropyl-1H-benzo[d]imidazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(4'-(trifluoromethyl)-[1,1'-biphenyl]yl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-cyclopropyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl)hydroxypropan (4-(1-methyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-cyclopropyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(2-cyclopropyl-2H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(6-(4-fluorophenyl)pyridinyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-(4-fluorobenzyl)-1H-indazolyl)oxoacetamide; 2-(6-chlorobenzo[b]thiophenyl)-N-((1R,2R)(4-cyclopropoxyfluorophenyl) y(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-fluoro-2'-methyl-[1,1'-biphenyl]yl)oxoacetamide; 2-(4-(benzo[d]thiazolyl)phenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; 2-(4-(benzo[d]thiazolyl)phenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-fluoromethyl-[1,1'-biphenyl]yl)oxoacetamide; ,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-cyano-[1,1'-biphenyl]yl)oxoacetamide; 2-(8-bromodibenzo[b,d]furanyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)- 1-hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(2-(4-fluorobenzyl)-2H-indazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-isopropyl-1H-indazolyl)oxoacetamide; N-((1R,2R)(3-chloro(cyclopentyloxy)phenyl)hydroxy(pyrrolidin yl)propanyl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(2-isopropylmethyl-2H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(2-isopropyl-2H-indazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclobutoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-(4-(1-isopropylmethyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(2-isopropyl-2H-indazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-isopropylmethyl-1H-indazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1,3-dimethyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-isopropyl-1H-indazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-isopropyl-1H-indolyl)oxoacetamide; (S)-N-(1-(3-chlorocyclopropoxyphenyl)(pyrrolidinyl)propanyl)(4'- fluoro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl)hydroxypropan yl)oxo(4-(pyrrolidinyl)phenyl)acetamide; ,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-isopropyl-1H-indolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-isopropylmethyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(2-isopropylmethyl-2H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl)hydroxypropan yl)(6-chlorobenzo[b]thiophenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-isopropyl-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1,3-dimethyl-1H-indazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(4-(pyrrolidinyl)phenyl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-isopropyl-1H-indolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(2,3-dimethyl-2H-indazolyl)phenyl)oxoacetamide; ,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-cyclopropyl-1H-pyrazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(1-isopropyl-1H-pyrazolyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-(4-fluorophenyl)-1H-indazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(2-(4-fluorophenyl)-2H-indazolyl)oxoacetamide; ,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(4'-(propenyl)-[1,1'-biphenyl]yl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-(2-hydroxypropanyl)-[1,1'-biphenyl]yl)oxoacetamide; 2-(4-(5-chlorothiophenyl)phenyl)-N-((1R,2R)(4-cyclopropoxyfluorophenyl)- 1-hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-(5-chlorothiophenyl)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(6-chlorobenzofuranyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-(4-morpholinophenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-cyclopropyl-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(4-(tetrahydro-2H-pyranyl)phenyl)acetamide; 2-(4-(azetidinyl)phenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-fluorophenyl)oxoacetamide; 2-(benzo[b]thiophenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(4-cyclopropoxyfluorophenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-ethynylphenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-(4-fluorophenyl)piperidinyl)oxoacetamide; N-((1R,2R)(azetidinyl)(4-cyclopropoxyfluorophenyl)hydroxypropan yl)(6-chlorobenzo[b]thiophenyl)oxoacetamide; N-((1R,2R)(4-cyclopropoxyfluorophenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-fluoro-[1,1'-biphenyl]yl)-N-methyloxoacetamide; 2-(6-chlorobenzo[b]thiophenyl)-N-((1R,2R)(4-cyclopropoxyfluorophenyl) hydroxy(pyrrolidinyl)propanyl)-N-methyloxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(5-chlorobenzo[b]thiophenyl)oxoacetamide; 2-(4-(1H-1,2,3-triazolyl)phenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)- 1-hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(azetidinyl)(4-cyclopropoxyfluorophenyl)hydroxypropan yl)(5-chlorobenzo[b]thiophenyl)oxoacetamide; N-((1R,2R)(4-cyclopropoxyfluorophenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4-cyclopropylphenyl)oxoacetamide; 2-(4-(1H-pyrazolyl)phenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; 2-(4-(2H-1,2,3-triazolyl)phenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)- 1-hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(4-cyclopropoxyfluorophenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(4'-fluoro-[1,1'-biphenyl]yl)-N-methyloxoacetamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin yl)propanyl)(6-fluoronaphthalenyl)(hydroxyimino)butanamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(isoxazolidin yl)propanyl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; ,2R)(3-chlorocyclopropoxyphenyl)hydroxy(isoxazolidin yl)propanyl)(6-chlorobenzo[b]thiophenyl)oxoacetamide; 2-(4-(2H-1,2,3-triazolyl)phenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)- 1-hydroxy(pyrrolidinyl)propanyl)oxoacetamide; 2-(4-(1H-pyrazolyl)phenyl)-N-((1R,2R)(3-chlorocyclopropoxyphenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; 2-(5'-chloro-[2,2'-bithiophen]yl)-N-((1R,2R)(4-cyclopropoxyfluorophenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(2',4'-difluoro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(6-fluoronaphthalenyl)oxobutanamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(5-(trifluoromethyl)benzofuranyl)acetamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin panyl)(hydroxyimino)(5-(trifluoromethyl)benzofuranyl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(5-(trifluoromethyl)benzofuranyl)acetamide; (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidin yl)propanyl)(hydroxyimino)(5-(trifluoromethyl)benzofuranyl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(3-(pyridinyloxy)phenyl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-(3-((1-methyl-1H-indazolyl)oxy)phenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(2-(4-fluorophenoxy)pyridinyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(2-oxopyrrolidin yl)propanyl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(1-(4-fluorophenyl)-1H-pyrazolyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrazolidin yl)propanyl)(4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrazolidin yl)propanyl)(6-chlorobenzo[b]thiophenyl)oxoacetamide; N-((1R,2R)(4-cyclopropoxyfluorophenyl)hydroxy(pyrrolidinyl)propan- 2-yl)oxo(4-(propynyl)phenyl)acetamide; 2-(5'-chloro-[2,2'-bithiophen]yl)-N-((1R,2R)(4-cyclopropoxyfluorophenyl) hydroxy(pyrrolidinyl)propanyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan- 2-yl)(6-(5-chlorothiophenyl)pyridinyl)oxoacetamide; and 5-chlorothiophenyl)pyridinyl)-N-((1R,2R)(4-cyclopropoxy fluorophenyl)hydroxy(pyrrolidinyl)propanyl)oxoacetamide; optionally as a er, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is ed from the group consisting of: (E)-N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propan yl)(6-chloronaphthalenyl)(hydroxyimino)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propanyl) (6-chlorobenzo[b]thiophenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propanyl) (6-chloronaphthalenyl)oxoacetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propanyl) oxo(4-(pyridinyl)phenyl)acetamide; N-((1R,2R)(3-chlorocyclopropoxyphenyl)hydroxy(pyrrolidinyl)propanyl) (2-(4-fluorophenyl)thiazolyl)oxoacetamide; N-((1R,2R)(azetidinyl)(3-chlorocyclopropoxyphenyl)hydroxypropanyl) (4'-fluoro-[1,1'-biphenyl]yl)oxoacetamide; and optionally as a tautomer, a single stereoisomer or mixture of isomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition sing i) a compound of any one of claims 1-18 optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, and ii) a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier.

20. Use of a nd according to any one of claims 1-18 or the pharmaceutical composition of claim 19 in the manufacture of a medicament for treating a disease or disorder.

21. A method of treating a e or disorder in a non-human animal comprising administering a compound ing to any one of claims 1-18 or the pharmaceutical composition of claim 19.

22. The use of claim 20 or the method of claim 21, wherein the disease or disorder is a glycolipid storage disease; a disease associated with glycolipid accumulation; a disease that causes renal hypertrophy or hyperplasia; a e that causes hyperglycemia or hyperinsulinemia; a cancer in which glycolipid synthesis is abnormal; an ious disease caused by organisms which use cell surface glycolipids as receptors or in which synthesis of glucosylceramide is essential or ant; atherosclerosis; polycystic kidney disease; renal hypertrophy; diabetes mellitus; breast cancer; renal arcinoma; brain ; neuroblastoma; lung cancer; intestinal cancer; pancreatic cancer; prostate cancer; a neuronal disorder; a neuronal injury; an matory disease or disorder; or obesity.

23. The use of claim 20 or the method of claim 21, wherein the disease or disorder is ed from the group consisting of atherosclerosis; polycystic kidney disease; renal hypertrophy; diabetes mellitus; breast cancer; renal adenocarcinoma; brain cancer; neuroblastoma; lung cancer; intestinal cancer; pancreatic cancer; prostate cancer; a neuronal injury; obesity; Tay Sachs; Sandhoffs; GM1 gangliosidosis; Fabry diseases; and Gaucher

24. A compound according to claim 1 substantially as herein described or exemplified.

25. A compound according to claim 17 substantially as herein described or exemplified.

26. A compound according to claim 18 substantially as herein described or exemplified.

27. A pharmaceutical composition according to claim 19 substantially as herein described or ified.

28. A use according to claim 20 substantially as herein described or exemplified.