Triazolopyridinyl compounds as kinase inhibitors

Abstract

Formula (I) Compounds having the formula TIFF2023546166000290.tif38153, and enantiomers, diastereomers, stereoisomers, and pharmaceutically acceptable salts thereof, are useful as kinase modulators, such as for modulating RIPK1. All substituents are defined herein.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 093,463, filed October 19, 2020, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present invention relates to novel compounds that inhibit receptor-interacting protein kinases, and methods for making and using same. In particular, the present invention relates to triazolopyridinyl compounds as receptor-interacting protein kinase 1 (RIPK1) inhibitors. [Background technology]

[0002] Apoptosis and necrosis represent two distinct mechanisms of cell death. Apoptosis is a highly regulated process involving the caspase family of cysteine ​​proteases and is characterized by cell shrinkage, chromatin condensation, and DNA degradation. In contrast, necrosis is associated with swelling of cells and organelles and plasma membrane rupture, accompanied by release of intracellular contents and secondary inflammation (Kroemer et al., (2009) Cell Death Differ 16:3-11). Necrosis is considered a passive, uncontrolled form of cell death; however, recent evidence suggests that some necrosis can be induced by regulated signaling pathways, such as those mediated by receptor-interacting protein kinases (RIPKs), particularly in situations where caspases are inhibited or cannot be efficiently activated (Golstein P & Kroemer G (2007) Trends Biochem. Sci. 32:37-43; Festjens et al. (2006) Biochim. Biophys. Acta 1757:1371-1387). Stimulation of the Fas and TNFR families of death domain receptors (DRs) is known to mediate apoptosis in most cell types by activating the extrinsic caspase pathway. Furthermore, in some caspase-8-deficient cells or cells treated with the pan-caspase inhibitor Z-VAD, stimulation of death domain receptors (DRs) results in receptor-interacting protein kinase 1 (RIPK1)-dependent necrotic programmed cell death instead of apoptosis (Holler et al. (2000) Nat. Immunol. 1:489-495; Degterev et al. (2008) Nat. Chem. Biol. 4:313-321). This novel mechanism of cell death has been termed "programmed necrosis" or "necroptosis" (Degterev et al., (2005) Nat. Chem. Biol. 1:112-119).

[0003] Necroptosis can be triggered by many mechanisms, including TNF receptor activation, Toll-like receptor involvement, genotoxic stress, and viral infection. The signaling pathway that leads to necroptosis downstream of various stimuli is dependent on RIPK1 and RIPK3 kinase activity (He et al., (2009) Cell 137:1100-1111; Cho et al., (2009) Cell 137:1112-1123; Zhang et al., (2009) Science 325:332-336).

[0004] Dysregulation of the necroptosis signaling pathway is associated with macrophage necrosis in the development of atherosclerosis, virus-induced inflammation, inflammatory diseases such as systemic inflammatory response syndrome and ethanol-induced liver injury, neurodegeneration such as retinal detachment, ischemia, amyotrophic lateral sclerosis (ALS), Gaucher disease, and AAV (ANCA-associated vasculitis) (Trichonas et al., (2010) Proc. Natl. Acad. Sci. 107, 21695-21700; Lin et al., (2013) CellRep. 3, 200-210; Cho et al., (2009) Cell, 137, 1112-1123; Duprez et al., (2011) Immunity 35, 908-918; Roychowdhury et al., Hepatology 57, 1773-1783;Vendenabeele et al., (2010) Nature 10, 700-714;Vandenabeele et al., (2010) Sci. Signalling 3, 1-8; Zhang et al., (2010) Cellular & Mol. Immunology 7, 243-249; Moriwaki et al., (2013) Genes Dev. 27, 1640-1649; Ito et al., (2016) Science 353, 603-608;Vitner et al., (2014) Nature Med. 20, 204-208)(Schreiber et al., (2017) Proc. Natl. Acad. Sci. 114, E9618-E9625).

[0005] Potent and selective small-molecule inhibitors of RIPK1 activity could inhibit RIPK1-dependent proinflammatory signaling, thereby offering therapeutic benefit in inflammatory diseases characterized by elevated and / or dysregulated RIPK1 kinase activity. Summary of the Invention

[0006] The present invention provides novel triazolopyridinyl compounds, their stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts, or solvates, which are useful as inhibitors of RIPK1. Alternatively, the compounds of the present invention may be useful as prodrugs of inhibitors of RIPK1.

[0007] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0008] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention, or a stereoisomer, tautomer, isotope, prodrug, pharmaceutically acceptable salt, salt, or solvate thereof.

[0009] The compounds of the present invention can be used in the treatment and / or prevention of pathologies associated with abnormal activity of RIPK1. The compounds of the present invention may be used in therapy.

[0010] The compounds of the present invention can be used for the manufacture of a medicament for the treatment and / or prevention of pathologies associated with the abnormal activity of RIPK1.

[0011] In another aspect, the present invention relates to a method for treating diseases mediated at least in part by RIPK1, such as inflammatory diseases, ischemia, neurodegeneration, and Gaucher disease, which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.

[0012] The compounds of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two, other drugs.

[0013] These and other features of the present invention are set forth in the broader disclosure that follows. DETAILED DESCRIPTION OF THE INVENTION

[0014] In one aspect, the present invention provides, inter alia, compounds of formula (I) [ka] [In the formula, R 1 is H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Deuterated alkyl, C 1-3 is a deuterated alkoxy, halogen, or cyclopropyl; R 2 is H, or a halogen; R 3 is H, halogen, or C 1-3 Alkyl or C 1-3 is a deuterated alkyl; R 4 is H or F; R 5a and R 5b are independently H, deuterium, and C 1-3 Alkyl or C 1-3 Is it a haloalkyl? Alternatively, R 5a and R 5b together to form a cyclopropyl; R 6a and R 6b are independently H, deuterium, OH, F, and C. 1-3 alkyl, or C(O)-4-fluorophenyl; Alternatively, R 6a and R 6b is =O or together form cyclopropyl or oxetanyl; R 7a and R 7b are each independently H, deuterium, OH, OP(O)(OR)2, OC(O)NH2, NH2, F, C 1-3 Alkyl, C 1-3 Alkoxy, OCD3, or C 1-3 Is it a haloalkyl? Alternatively, R7a and R 7b is =O or together form cyclopropyl or oxetanyl; R is H or C 1-3 is alkyl; R 8 are H, F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkyl, or C 1-3 deuterated alkoxy; R 9 is H or CH3; Ring Z is phenyl, a 6-membered heteroaryl containing 1 to 2 nitrogen atoms, cyclohexyl, cyclopentyl, or cyclobutyl; Y is F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, CN, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Deuterated alkyl, C 1-3 deuterated alkoxy, C(O)OCH3, or C≡CH; n is 0, 1, 2, or 3. or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0015] Another embodiment is a compound of formula (II) [ka] [In the formula, R 1 is H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 is a deuterated alkyl, halogen, or cyclopropyl; R 2 is H, or a halogen; R 3 is H, halogen, or C 1-3 Alkyl or C 1-3is a deuterated alkyl; R 4 is H or F; R 5a and R 5b are independently H, deuterium, and C 1-3 Alkyl or C 1-3 is haloalkyl; R 6a and R 6b are each independently H, deuterium, OH, F, or C 1-3 Is it alkyl; Alternatively, R 6a and R 6b is =O or together form cyclopropyl or oxetanyl; R 7a and R 7b are each independently H, deuterium, OH, OP(O)(OR)2, F, C 1-3 Alkyl or C 1-3 Is it a haloalkyl? Alternatively, R 7a and R 7b is =O or together form cyclopropyl or oxetanyl; R is H or C 1-3 is alkyl; Ring Z is phenyl, a 6-membered heteroaryl containing 1 to 2 nitrogen atoms, cyclohexyl, or cyclopentyl; Y is F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, CN, or C 1-3 is haloalkyl; n is 0, 1, 2, or 3. or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0016] Another embodiment is a compound of formula (I): R 1 But H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3is a deuterated alkyl, halogen, or cyclopropyl; R 2 is H, or a halogen; R 3 is H, halogen, or C 1-3 Alkyl or C 1-3 is a deuterated alkyl; R 4 is H or F; R 5a and R 5b are independently H, deuterium, and C 1-3 Alkyl or C 1-3 is haloalkyl; R 6a and R 6b are each independently H, deuterium, OH, F, or C 1-3 is alkyl; R 7a and R 7b are independently H, deuterium, OH, F, and C. 1-3 Alkyl or C 1-3 Is it a haloalkyl? Alternatively, R 7a and R 7b is ═O or together form cyclopropyl or oxetanyl; Ring Z is phenyl, a 6-membered heteroaryl containing 1 to 2 nitrogen atoms, cyclohexyl, or cyclopentyl; Y is F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, CN, or C 1-3 is haloalkyl; n is 0, 1, or 2; Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0017] Another embodiment is a compound of formula (I): R 1 But H, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C1-3 Deuterated alkyl, C 1-3 is a deuterated alkoxy, halogen, or cyclopropyl; R 2 is H, or a halogen; R 3 is H, halogen, or C 1-3 Alkyl or C 1-3 is a deuterated alkyl; R 4 is H or F; R 5a and R 5b are independently H, deuterium, and C 1-3 Alkyl or C 1-3 is haloalkyl; R 6a and R 6b are each independently H, deuterium, OH, F, or C 1-3 is alkyl; R 7a and R 7b are independently H, deuterium, OH, F, and C. 1-3 Alkyl or C 1-3 Is it a haloalkyl? Alternatively, R 7a and R 7b is ═O or together form cyclopropyl or oxetanyl; Ring Z is phenyl, a 6-membered heteroaryl containing 1 to 2 nitrogen atoms, cyclohexyl, or cyclopentyl; Y is F, Cl, C 1-3 Alkyl, C 1-3 Alkoxy, CN, or C 1-3 is haloalkyl; n is 0, 1, or 2; Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0018] Another embodiment is a compound represented by the formula (I) or (II): R 1 But H, C 1-2 Alkyl, C1-2 is alkoxy, CD3, halogen, or cyclopropyl; R 2 is H, or a halogen; R 3 is H, halogen, or C 1-2 is alkyl; R 4 is H or F; R 5a and R 5b are independently H, deuterium, and C 1-2 Alkyl or C 1-2 is haloalkyl; R 6a and R 6b are each independently H, deuterium, F, or C 1-2 is alkyl; R 7a and R 7b are independently H, deuterium, OH, F, and C. 1-2 Alkyl or C 1-2 Is it a haloalkyl? Alternatively, R 7a and R 7b are ═O or together form a cyclopropyl: Y is F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy, CN, or C 1-2 is haloalkyl; n is 0, 1, or 2; Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0019] Another embodiment is a compound represented by the formula (I) or (II): R 1 But H, C 1-2 Alkyl, C 1-2 is alkoxy, CD3, halogen, or cyclopropyl; R 2 is H, or a halogen; R 3 is H, halogen, or C 1-2is alkyl; R 4 is H or F; R 5a and R 5b are independently H, deuterium, and C 1-2 Alkyl or C 1-2 is haloalkyl; R 6a and R 6b are each independently H, deuterium, F, or C 1-2 is alkyl; R 7a and R 7b are independently H, deuterium, OH, F, and C. 1-2 Alkyl, C 1-2 Deuterated alkyl, or C 1-2 Is it a haloalkyl? Alternatively, R 7a and R 7b are ═O or together form a cyclopropyl: Y is F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy, CN, or C 1-2 is haloalkyl; n is 0, 1, or 2; Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0020] Another embodiment provides a compound of formula (I) or (II) wherein ring Z is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0021] Another embodiment provides a compound of formula (I) or (II) wherein ring Z is cyclohexyl or cyclopentyl, or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0022] Another embodiment is a compound represented by the formula (I) or (II): R 1 But C 1-2 Alkyl, C 1-2 Deuterated alkyl, C 1-2 haloalkyl, or halogen; R 2 is H, or a halogen; R 3 is H, halogen, or C 1-2 is alkyl; R 4 is H or F; R 5a and R 5b are independently H, deuterium, and C 1-2 Alkyl or C 1-3 haloalkyl and R 6a and R 6b are each independently H, deuterium, F, or C 1-3 is alkyl; R 7a and R 7b are independently H, deuterium, OH, F, and C. 1-4 Alkyl or C 1-3 Is it a haloalkyl? Alternatively, R 7a and R 7b is ═O or together form cyclopropyl; Y is F, Cl, C 1-2 Alkyl, CN, or C 1-2 is haloalkyl; n is 0, 1, or 2; Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0023] Another embodiment is a compound represented by the formula (I) or (II): R 1 is Cl or CH3; R 2 is H or F; R 3 is H or F; R 4 But H; R 5a and R 5b are H, respectively; R 6a and R 6b are each independently H or F; R 7a and R 7b one of which is H and the other is OH; Y is F or Cl; n is 0, 1, or 2; Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0024] Another embodiment is a compound represented by the formula (I) or (II): R 1 is Cl or CH3; R 2 is H or F; R 3 is H or F; R 4 But H; R 5a and R 5b are H, respectively; R 6a and R 6b are each independently H or F; R 7a and R 7b one of which is H, CH3 or CD3 and the other is OH; Y is F or Cl; n is 0, 1, or 2 Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0025] Another embodiment is a compound represented by the formula (I) or (II): R 5a and R 5b are H, respectively; R6a and R 6b are each independently H or F; R 7a and R 7b one of which is H and the other is OH, Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0026] Another embodiment is a compound represented by the formula (I) or (II): R 5a and R 5b are H, respectively; R 6a and R 6b are each independently H or F; R 7a and R 7b one of which is H, CH3 or CD3 and the other is OH; Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0027] Another embodiment is a compound represented by the formula (I) or (II): R 7a and R 7b one of which is H and the other is OP(O)(OR); and R is H or C 1-3 is alkyl, Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0028] Another embodiment is a compound represented by the formula (I) or (II): Ring Z is [ka] and; X is CH, N, or CY; Provided are compounds, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0029] Another embodiment provides a compound of formula (I) or (II) wherein ring Z is pyridinyl, or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0030] Another embodiment provides a compound of formula (I) or (II) wherein ring Z is phenyl, or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0031] Another embodiment provides a compound of formula (I) or (II) wherein ring Z is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0032] Another embodiment is when the compound has formula (Ia): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0033] Another embodiment is when the compound has formula (Ib): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0034] Another embodiment is when the compound has formula (Ic): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0035] Another embodiment is where the compound has the formula (Id): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0036] Another embodiment is a compound of formula: R 8 is H; and R 9 is H, Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0037] Another embodiment is [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0038] Another embodiment is [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0039] Another embodiment is where the compound has the formula (In): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0040] Another embodiment is when the compound has the formula (Io): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0041] Another embodiment is where the compound has formula I(p): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0042] Another embodiment is when the compound has formula (Iq): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0043] Another embodiment is when the compound has formula (Ir): [ka] or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0044] In another embodiment, the compound is of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io)(Ip), (Iq), or (Ir), wherein ring Z is [ka] and Y is Cl or F; Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0045] Another embodiment is a compound of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io)(Ip), (Iq), or (Ir), wherein R 5a and R 5b is H or deuterium; R 6a is F and R 6b is H or F; R 7a is OH and R 7b is H, CH3, or CD3; Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0046] Another embodiment is a compound of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io)(Ip), (Iq), or (Ir), wherein R 5a and R 5b is H or deuterium; R 6a is F and R 6b is F; R 7a is OH and R 7b is H, or CH3, Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0047] Another embodiment is a compound of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io)(Ip), (Iq), or (Ir), wherein R 5a and R 5b is H; R 6a is F and R 6b is H; R 7a is OH and R 7b is H, CH3, or CD3; Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0048] Another embodiment is a compound of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io)(Ip), (Iq), or (Ir), wherein R 5a and R 5b is H; R 6a is F and R 6b But H; R 7a is OH and R 7b is H, CH3, or CD3; Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0049] Another embodiment is a compound of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io)(Ip), (Iq), or (Ir), wherein R 1 But CH3, CD 3、 CF3, or Cl; R2 is F; R 3 is H; R 4 is H, Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0050] Another embodiment is a compound of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io)(Ip), (Iq), or (Ir), wherein R 6a and R 6b But F; R 1 But CH3, CD 3、 CF3, or Cl; R 2 is F; R 3 is H; R 4 is H; and Y is Cl or F; Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0051] Another embodiment is a compound of formula (I), (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io)(Ip), (Iq), or (Ir), wherein R 6a is H and R 6b is F; R 1 But CH3, CD 3、 CF3, or Cl; R 2 is F; R 3 is H; R 4 is H; and Y is Cl or F; Provided are compounds of formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof:

[0052] Another embodiment provides a compound of Formula (I), or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof, selected from the examples.

[0053] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, useful for the treatment of diseases associated with kinase modulation, such as modulation of receptor-interacting protein kinases such as RIPK1.

[0054] The present invention further relates to a method for treating diseases associated with kinase modulation, such as modulation of receptor-interacting protein kinases, such as RIPK1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0055] The present invention also provides processes and intermediates for making the compounds of the present invention, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0056] The present invention also provides methods for the treatment of proliferative, allergic, autoimmune, and inflammatory diseases, and fibrotic diseases, comprising administering to a host in need thereof a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0057] The present invention also provides a method for treating a disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), wherein the disease is inflammatory bowel disease, Crohn's disease or ulcerative colitis, psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), transplant rejection, non-alcoholic steatohepatitis (NASH), or ischemia-reperfusion.

[0058] The present invention also provides a method for treating a condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), wherein the condition is selected from the group consisting of systemic lupus erythematosus (SLE), multiple sclerosis (MS), transplant rejection, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, intraocular neovascularization, and infantile hemangioma, B-cell lymphoma, systemic lupus erythematosus (SLE), psoriatic arthritis, polyangiitis, idiopathic hematopoietic leukemia, and idiopathic hematopoietic leukemia. Selected from thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), graft rejection, type I diabetes, membranous nephropathy, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathy, pemphigus vulgaris, and asthma, nonalcoholic steatohepatitis (NASH), or ischemia-reperfusion.

[0059] The present invention also provides a method for treating a medical condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), wherein the medical condition is selected from the progression of atherosclerosis, viral-induced inflammation, macrophage necrosis in systemic inflammatory response syndrome and ethanol-induced liver injury, retinal detachment, retinal degeneration, exudative and atrophic age-related macular degeneration (AMD), ischemia, amyotrophic lateral sclerosis (ALS), and neurodegenerative diseases such as Gaucher disease.

[0060] The present invention also provides a method for treating a condition, wherein the condition is selected from inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis (RA), heart failure, and non-alcoholic steatohepatitis (NASH), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).

[0061] The present invention also provides a method for treating a condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), wherein the condition is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis. In another embodiment, the condition is selected from inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0062] The present invention also provides a method for treating a condition, wherein the condition is selected from non-alcoholic steatohepatitis (NASH) and ischemia-reperfusion, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0063] The present invention also provides a method for treating rheumatoid arthritis, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0064] The present invention also provides a method for treating a disease, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent.

[0065] The present invention also provides the compounds of the present invention, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.

[0066] In another embodiment, a compound of formula (I) is selected from an exemplified example, or a combination of the exemplified examples, or other embodiments described herein.

[0067] The invention also provides the use of a compound of the invention, or a stereoisomer, tautomer, isotope, salt, pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a medicament for the treatment of cancer, an allergic disease, an autoimmune disease, or an inflammatory disease.

[0068] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention includes all combinations of the preferred aspects and / or embodiments of the present invention described herein. It is understood that any and all embodiments of the present invention may be combined with any other embodiment to describe additional embodiments. It is also understood that each individual element of an embodiment is itself an independent embodiment. Furthermore, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments.

[0069] The following are definitions of terms used in this specification and the appended claims: The first definition given for a group or term in this specification applies to that group or term throughout the specification and claims, unless otherwise stated, either individually or as part of another group.

[0070] Unless otherwise stated herein, words referred to in the singular may also include the plural. For example, "a" and "an" can refer to either "one" or "one or more."

[0071] Any variable part (e.g., R 3 When any group R occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. 3 When a group is shown as being substituted with at most two R 3 optionally substituted with R 3 are each independently, R 3Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0072] Unless otherwise specified, any carbon atom or heteroatom with unsatisfied valences is assumed to include enough hydrogen atoms to satisfy the valences.

[0073] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom through which it is bonded to the remainder of the compound of the depicted formula, such substituent may be bonded through any atom in the substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0074] When nitrogen atoms (e.g., amines) are present on the compounds of the invention, they can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxide) to yield other compounds of the invention. Thus, all shown and claimed nitrogen atoms are considered to include both the shown nitrogen and its N-oxide (N→O) derivative.

[0075] According to the practice used in the art, [ka] is used in structural formulas herein to represent the bond that is the site of attachment of a group or substituent to a core or backbone structure.

[0076] A dash "-" that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C or H2 is attached through the carbon atom.

[0077] The term "optionally substituted" with respect to a particular moiety in a compound of Formula (I) (e.g., an optionally substituted heteroaryl group) refers to a moiety having zero, one, two, or more substituents. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl," as defined below. It will be understood by those skilled in the art that with respect to any group that contains one or more substituents, it is not intended that such group introduce any substitution or substitution pattern that is sterically infeasible, synthetically infeasible, and / or inherently unstable.

[0078] As used herein, the terms "alkyl" or "alkylene" are intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1-10 "Alkyl" (or alkylene) is a group consisting of C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 It is intended to include alkyl groups. Further, for example, "C1-C6 alkyl" refers to an alkyl having from 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted such that one or more hydrogen atoms have been replaced with other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0079] When the term "alkyl" is used with other groups, such as in "arylalkyl," the connection is more specifically defined by at least one substituent, which includes a substituted alkyl. For example, "arylalkyl" refers to a substituted alkyl group, as defined above, where at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl (C 0-4)Alkyl includes substituted lower alkyl having at least one aryl substituent, and also includes aryls directly bonded to other groups, i.e., aryl(C0)alkyl. The term "heteroarylalkyl" refers to a substituted alkyl group, as defined above, where at least one of the substituents is a heteroaryl.

[0080] "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains in either a straight or branched configuration, with one or more carbon-carbon double bonds, which may occur at any stable point along the chain. For example, "C 2-6 "Alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[0081] "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains in either a straight or branched configuration, with one or more carbon-carbon triple bonds, which may occur at any stable point along the chain. For example, "C 2-6 "Alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0082] When a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group is referred to, these groups are substituted with from 1 to 3 substituents as defined above for substituted alkyl groups.

[0083] The term "alkoxy" refers to an oxygen atom substituted with an alkyl or substituted alkyl as defined herein. For example, the term "alkoxy" includes -OC, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. 1-6 "Lower alkoxy" refers to an alkoxy group having 1 to 4 carbon atoms.

[0084] It should be understood that selections for all groups, eg, alkoxy, thioalkyl, and aminoalkyl, will be made by one skilled in the art to yield stable compounds.

[0085] As used herein, the term "substituted" means that any one or more hydrogens on the specified atom or group are replaced with a selection from the indicated group, provided that the normal valence of the specified atom is not exceeded. When the substituent is oxo or keto (i.e., =0), two hydrogens on the atom are replaced. Keto substituents do not occur on aromatic groups. Unless otherwise noted, substituents are named on the core structure. For example, when (cycloalkyl)alkyl is listed as a possible substituent, it is understood that the point of attachment of this substituent to the core structure is in the alkyl moiety. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0086] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is intended to mean a compound that is sufficiently robust to survive isolation of the reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent. The presently enumerated compounds preferably do not contain N-halogen, S(O)H, or S(O)H groups.

[0087] The term "carbocyclyl" or "carbocycle" refers to a saturated, unsaturated, or partially unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, more commonly 5 or 6 ring atoms. Bicyclic carbocycles have, for example, 7 to 12 ring atoms arranged as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As noted above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl." A bridged ring occurs when one or more carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. Note that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents listed for the ring may also be present on the bridge.

[0088] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl groups, each of which may be substituted. A preferred aryl group is optionally substituted phenyl.

[0089] The term "cycloalkyl" refers to cyclized alkyl groups, such as mono-, bi-, or polycyclic systems. 3-7 Cycloalkyl is intended to include C, C, C, C, and C cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like, which may be optionally substituted at any available atom of the ring.

[0090] The terms "heterocycloalkyl," "heterocyclo," "heterocycle," "heterocyclic," or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted, aromatic or non-aromatic 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, in which at least one of the rings contains at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably contains 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a heteroatom-containing group can contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further, the ring contains at least one carbon atom. The nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen atom can be optionally quaternized. The fused rings completing the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. The heterocyclo group can be attached at any available nitrogen or carbon atom. The term "heterocycle" includes "heteroaryl" groups. Where valency allows, if said further ring is cycloalkyl or heterocyclo, it may optionally be further substituted with =O (oxo).

[0091] Examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, etc. Examples of bicyclic heterocyclo groups include quinuclidinyl.

[0092] The term "heteroaryl" refers to substituted and unsubstituted, aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups containing at least one heteroatom (O, S, or N) in at least one of the rings. The heteroatom-containing rings preferably contain 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of a heteroatom-containing heteroaryl group can contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom. The fused rings completing bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. A bicyclic or tricyclic heteroaryl group must contain at least one fully aromatic ring, but the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If said further ring is cycloalkyl or heterocyclo, it may optionally be further substituted with =O (oxo), as valences allow.

[0093] Examples of monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

[0094] Examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0095] Examples of tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0096] Unless otherwise stated, when referring to a particular named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl), or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl), the reference is intended to include rings having 0 to 3, preferably 0 to 2, substituents, as appropriate.

[0097] The term "halo" or "halogen" refers to chloro, bromo, fluoro, and iodo. The term "haloalkyl" refers to a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono-, bi-, and trifluoromethyl. The term "haloalkyl" refers to a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono-, bi-, and trifluoromethyl.

[0098] The term "haloalkoxy" refers to an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF.

[0099] The term "deuterated alkyl" refers to a substituted alkyl having one or more deuterium atoms. For example, the term "deuterated alkyl" includes mono-, bi-, and tri-deuterated methyl.

[0100] The term "heteroatom" is intended to include oxygen, sulfur, and nitrogen.

[0101] When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

[0102] The notation "CO" as used herein refers to the group: [ka] It will be understood by those skilled in the art that the intended meaning is

[0103] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds, and compounds useful as pharmaceutically acceptable compounds and / or intermediate compounds useful in the preparation of pharmaceutically acceptable compounds.

[0104] The compounds of formula (I) may exist in a free form (non-ionized) or may form salts that are within the scope of the present invention. Unless otherwise specified, reference to a compound of the present invention is understood to include reference to the free form and salts. The term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, for example, when a compound of formula (I) contains both a basic group, such as an amine or a pyridine or imidazole ring, and an acidic group, such as a carboxylic acid, the term "salt" can include zwitterions (internal salts). Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts are useful, for example, in isolation or purification steps that may be used during synthesis, and are therefore considered within the scope of the present invention. Salts of compounds of formula (I) can be produced, for example, by reacting a compound of formula (I) with an equivalent or similar amount of acid or base in a solvent such as one in which the salt precipitates, or in an aqueous solvent, followed by lyophilization.

[0105] Examples of acid addition salts include acetate (such as those formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide), iodide, ... Examples of suitable salts include hydrochloride, 2-hydroxyethanesulfonate, lactate, maleate (formed with maleic acid), methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as formed with sulfuric acid), sulfonate (such as those described herein), tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, and the like.

[0106] Examples of base salts include alkali metal salts such as ammonium salts, sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromide), and others. In certain embodiments, salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0107] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk / benefit ratio.

[0108] As used herein, " pharmaceutically acceptable salts " refers to derivatives of the compounds of the present disclosure, which are modified by preparing acid or base salts of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound, which are formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0109] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic groups by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, the disclosure of which is incorporated herein by reference.

[0110] All stereoisomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers include compounds that are optical isomers due to the presence of one or more chiral atoms, as well as compounds that are optical isomers due to restricted rotation about one or more bonds (atropisomers). The definition of compounds described in this invention encompasses all possible stereoisomers and mixtures thereof. It particularly includes racemates and isolated optical isomers with the specified activity. Racemates can be resolved by physical methods, such as fractional crystallization, separation, or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by conventional methods, such as salt formation with an optically active acid followed by crystallization.

[0111] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include atoms with the same atomic number but different mass numbers. As a general example, but without limitation, isotopes of hydrogen include deuterium and tritium. By way of example, alkyl substituents are intended to include alkyl groups having either hydrogen, deuterium, and / or a combination thereof. Isotopes of carbon include: 13 C and 14 Radiolabeled compounds of the invention can generally be synthesized by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, using an appropriate radiolabeled reagent in place of the otherwise unlabeled reagent.

[0112] Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" refers to a compound that, upon administration to a subject, is chemically converted by metabolic or chemical processes to yield the compound of formula (I), and / or its salts and / or solvates. Any compound that is converted in vivo to yield a biologically active agent (i.e., a compound of formula (I)) is a prodrug within the scope and spirit of the present invention. For example, a compound containing a carboxy group can be hydrolyzed in the body to form a physiologically hydrolyzable ester that acts as a prodrug by yielding the compound of formula (I) itself. In many cases, such prodrugs are preferably administered orally, since hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester is active in itself or when hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of the compound of formula (I) include C 1-6 Alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C 1-6 Alkanoyloxy-C 1-6 Alkyl, such as acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C 1-6 Alkoxycarbonyloxy-C 1-6 Included are alkyl, such as methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl, and other known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin art. Such esters can be prepared by conventional techniques known in the art.

[0113] Various forms of prodrugs are well known in the art. For example, such prodrug derivatives exist in the following: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology,Vol. 112, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991); and c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, pp. 1-38 (1992) each of which is incorporated herein by reference.

[0114] The compounds of formula (I) and their salts may exist in tautomeric forms, in which hydrogen atoms are transferred to other parts of the molecule, resulting in rearrangement of the chemical bonds between the atoms of the molecule. It should be understood that all tautomeric forms, insofar as they exist, are included in the present invention.

[0115] The compounds of the present invention may contain one or more asymmetric centers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms of the compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms. The compounds can be isolated in optically active or racemic forms. Methods for preparing optically active forms, such as by resolution of racemates or by synthesis from optically active starting materials, are well known in the art. Unless the specific stereochemistry or isomeric form is specified, all chiral (enantiomers and diastereomers) and racemic forms of a structure, as well as all geometric isomeric forms, are intended. All geometric isomers, tautomers, atropisomers, hydrates, solvates, polymorphs, and isotopically labeled forms of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention. Methods of solvation are generally known in the art.

[0116] In some examples of the present invention, the absolute stereochemistry of the enantiomers and / or diastereomers has not been specifically identified. However, racemic mixtures and all enantiomers and diastereomers are included in the present invention. Although the absolute stereochemistry of a particular enantiomer and / or diastereomer has not been specifically determined or depicted, one skilled in the art can readily identify and depict the structure of each stereoisomer or diastereomer. For example, Examples 202, 203, 204, and 205 have the structural formula: [ka] It is shown as follows. Even if each structure of the examples is not specifically shown, the four diastereomers that can be identified by a person skilled in the art are: [ka] is.

[0117] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture, nor upon formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0118] usefulness The compounds of the present invention modulate kinase activity, such as modulating RIPK1. Thus, the compounds of formula (I) have utility in modulating kinase activity, and in particular in treating conditions associated with selective inhibition of RIPK1 activity. In another embodiment, the compounds of formula (I) have excellent selectivity for RIPK1 activity, preferably at least 10-fold or 20-fold to 1000-fold or greater selectivity over other kinases.

[0119] As used herein, the term "treating" or "treatment" includes the treatment of a disease state in a mammal, particularly a human, and includes (a) preventing or delaying the onset of the disease state in a mammal, particularly where the mammal is susceptible to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease state, i.e., halting its progression; and / or (c) completely or partially alleviating the symptoms or disease state and / or achieving relief, amelioration, relief, or cure of the disease or disorder and / or its symptoms.

[0120] In view of their activity as inhibitors of RIPK1, the compounds of formula (I) are useful in treating inflammatory diseases such as Crohn's disease and ulcerative colitis, inflammatory bowel disease, asthma, graft-versus-host disease, and chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, and psoriasis; destructive bone diseases such as bone resorption disorders, osteoarthritis, osteoporosis, and multiple myeloma-related bone disease; proliferative disorders such as acute myeloid leukemia and chronic myeloid leukemia; solid tumors, intraocular neovascularization, and infantile hemangioma. and RIPK1-related diseases such as angiogenesis disorders, such as angiogenesis disorders in the liver; infectious diseases such as sepsis, septic shock, and Shigellosis; neurodegenerative diseases caused by tumors and viral diseases such as Alzheimer's disease, Parkinson's disease, ALS, cerebral ischemia, or stress disorders, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS; fibrosis such as non-alcoholic steatohepatitis (NASH); and cardiac diseases such as ischemia-reperfusion.

[0121] In particular, specific conditions or diseases that may be treated by the compounds of the present invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, ALS, multiple sclerosis, and inflammatory bowel disease. , ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella-related arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by severe neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other joint diseases, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption disorders, allograft rejection, sensitization Fever and myalgia due to infection, cachexia secondary to infection, meloid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and shigellosis; neurodegenerative diseases resulting from Alzheimer's disease, Parkinson's disease, cerebral ischemia, or stress disorders; angiogenic disorders such as solid tumors, intraocular neovascularization, and infantile hemangioma; acute liver disease viral diseases such as inflammatory infections (hepatitis A, B, and C), HIV infection and CMV retinitis, AIDS, ARC or malignant tumors, and herpes; stroke, myocardial ischemia, ischemia in ischemic heart attack, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase 2, and pemphigus vulgaris. In another embodiment, the disease is inflammatory bowel disease, Crohn's disease and ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris, and nonalcoholic steatohepatitis (NASH), and ischemia-reperfusion.In a further aspect is a method of treatment wherein the disease is selected from multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.

[0122] Alternatively, the present invention is preferably a method for treating diseases selected from ischemia-reperfusion injury such as cerebral ischemia-reperfusion injury caused by stroke and cardiac ischemia-reperfusion injury caused by myocardial infarction.

[0123] When the terms "RIPK1-associated condition" or "RIPK1-associated disease or disorder" are used herein, each is intended to include all diseases identified above, as well as any other condition affected by RIPK1 kinase activity, as specifically recited.

[0124] Accordingly, the present invention provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I), or a salt thereof. A "therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective, when administered alone or in combination, to inhibit RIPK1.

[0125] Methods for treating RIPK1 kinase-associated diseases are characterized by administering compounds of formula (I) alone or in combination with each other and / or other suitable therapeutic agents useful in treating such conditions. As such, "therapeutically effective amount" is also intended to include the amount of the claimed combination of compounds effective to inhibit RIPK1 and / or treat RIPK1-associated diseases.

[0126] Examples of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear transport inhibitors such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib, and rofecoxib; steroids such as prednisone or dexamethasone; vedolizumab and uvexamin; These include anti-inflammatory antibodies such as sutekinumab, anti-inflammatory kinase inhibitors such as TYK2 inhibitors, antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, prograf); cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors, rapamycin (sirolimus or rapamune), or their derivatives, and agonists of FGF21.

[0127] When used in combination with the compounds of the present invention, the other therapeutic agents may be used in amounts, for example, as set forth in the Physicians' Desk Reference (PDR) or as determined by one skilled in the art. In the methods of the present invention, such other therapeutic agents may be administered before, simultaneously with, or after the administration of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating RIPK1 kinase-related diseases, such as diseases mediated by IL-1, IL-6, IL-8, IFNγ, and TNF-α, as described above.

[0128] The compositions of the present invention may contain other therapeutic agents, as described above, and may be formulated according to techniques such as those well known in the art of pharmaceutical formulation, for example, by using conventional solid or liquid solvents or diluents, as well as pharmaceutical additives (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, etc.) appropriate for the desired administration form.

[0129] Therefore, the present invention further includes compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.

[0130] A "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering physiologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to many factors well within the purview of those skilled in the art. These include, but are not limited to, the type and nature of the active agent being formulated, the recipient to whom the composition containing the agent will be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous solvents, as well as a variety of solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent; such additional components are included in the formulation for various reasons well known to those skilled in the art, such as stabilizing the active agent, binding agents, etc. Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection can be found in a variety of readily available sources, such as Remington's Pharmaceutical Sciences, 17th ed., 1985, which is incorporated herein by reference in its entirety.

[0131] The compound of formula (I) may be administered by any means appropriate for the condition to be treated, which may vary depending on the need for site-specific treatment or the amount of drug to be delivered. Although other forms of delivery are contemplated, topical administration is generally preferred for skin-related diseases, and systemic therapy is preferred for cancer or precancerous conditions. For example, the compound may be delivered orally, such as in the form of a liquid preparation such as a tablet, capsule, granule, powder, or syrup; topically, such as in the form of a solution, suspension, gel, or ointment; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion technique (e.g., a sterile injectable aqueous or non-aqueous solution or suspension); nasally, such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally, such as in the form of a suppository; or liposomally. A unit dosage form containing a non-toxic pharmaceutically acceptable solvent or diluent may be administered. The compound may be administered in a form suitable for immediate release or sustained release. Immediate release or sustained release may be achieved by appropriate pharmaceutical compositions or, particularly in the case of sustained release, by devices such as subcutaneous implants or osmotic pumps.

[0132] Examples of compositions for topical administration include topical carriers such as PLASTIBASE® (mineral oil gelled with polyethylene).

[0133] Examples of compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose to provide bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents, such as those known in the art; and immediate-release formulations, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose, and / or other excipients, binders, fillers, disintegrants, diluents, and lubricants, such as those known in the art. The compounds of the present invention may also be orally delivered by sublingual and / or buccal administration, for example, by moistened, compressed, or freeze-dried tablets. Examples of compositions include fast-dissolving diluents, such as mannitol, lactose, sucrose, and / or cyclodextrins. Such formulations may also include high molecular weight excipients such as cellulose (AVICEL®) or polyethylene glycol (PEG); excipients to aid mucoadhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), and / or maleic anhydride copolymers (e.g., GANTREZ®); and agents to control release, such as polyacrylic copolymers (e.g., CARBOPOL 934®). Lubricants, flow agents, flavoring agents, coloring agents, and stabilizers may also be added for ease of manufacture and use.

[0134] Examples of compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers, and / or other solubilizing or dispersing agents such as those known in the art, which enhance absorption and / or bioavailability.

[0135] Examples of compositions for parenteral administration include injectable solutions or suspensions which may contain a suitable non-toxic, parenterally acceptable diluent or solvent, such as mannitol, 1,3-butanediol, water, Ringer's solution, saline, or other suitable dispersing or wetting agents and suspending agents, such as synthetic mono- or diglycerides, and fatty acids, such as oleic acid.

[0136] Examples of compositions for rectal administration include suppositories, which may contain suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters or polyethylene glycols that are solid at ordinary temperatures but liquefy and / or melt in the rectal cavity to release the drug.

[0137] Therapeutically effective amounts of the compounds of the present invention can be determined by those skilled in the art. Exemplary dosages for mammals include approximately 0.05-1000 mg / kg body weight, 1-1000 mg / kg body weight, 1-50 mg / kg body weight, 5-250 mg / kg body weight, or 250-1000 mg / kg body weight of active compound per day, which may be administered as a single dose or in individual divided doses, such as 1-4 times per day. It is understood that for any particular subject, the specific dosage and frequency of administration may vary and will depend on a variety of factors, including the activity, metabolic stability, and length of action of the particular compound used; the subject's species, age, weight, health, sex, and diet; administration form and time; excretion rate; drug combination; and the severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammals such as humans, and domestic animals such as dogs, cats, and horses. Therefore, when the term "patient" is used herein, this term is intended to include all subjects, most preferably mammals, affected by modulation of RIPK1 enzyme levels.

[0138] Necroptosis is a regulated cell death pathway induced by both inflammatory factors (TNF-alpha) and virus-activated TLR agonists. Necroptosis occurs after RIPK1 is activated, phosphorylated, and forms a complex with RIPK3 (also known as the necrosome). The downstream target of the RIPK3 kinase, the mixed lineage kinase domain-like (MLKL) protein, is recruited to RIPK3, promoting phosphorylation of MLKL at Thr357 and Ser358. Phosphorylated MLKL (pMLKL) promotes MLKL oligomerization, insertion into the plasma membrane, and subsequent pore formation, which triggers membrane disruption (Moriwaki, K., and FK Chan. 2013. RIP3: a molecular switch for necrosis and inflammation. Genes Dev. 27: 1640-1649). Therefore, understanding the efficacy of RIPK1 compounds based on their direct binding to RIPK1 as well as their necroptotic activity (pMLKL) function is important for assessing RIPK1 inhibitory activity and efficacy.

[0139] MLKL phosphorylation high content assay HT29-L23 human colon adenoma cells were cultured in RPMI 1640 medium containing 10% heat-inactivated FBS, 1% penicillin-streptomycin, and 10 mM HEPES. Cells were seeded at 2,000 cells / well into 384-well tissue culture-treated microplates (Greiner # 781090-3B) and incubated at 37°C (5% CO2 / 95% O2) for 2 days. On the day of the assay, cells were treated with test compounds at final concentrations of 6.25 to 0.106 μM for 30 minutes at 37°C (5% CO2 / 95% O2). Necroptosis was induced using a mixture of human TNFα (35 ng / mL) (Peprotech #300-01A), SMAC mimetic (US 2015 / 0322111 A1) (700 nM), and Z-VAD (140 nM) (BD Pharmingen #51-6936). After 6 h of incubation at 37 °C (5% CO2 / 95% O2), cells were fixed with 4% formaldehyde (ACROS 11969-0010) for 15 min at room temperature and then permeabilized with 0.2% Triton X-100 in phosphate-buffered saline (PBS) for 10 min. Phosphorylation of MLKL was detected by overnight incubation at 4°C with anti-MLKL (phospho S358) antibody (Abcam #ab187091) (1:1000 dilution in blocking buffer [PBS supplemented with 0.1% BSA]). After three washes in PBS, anti-rabbit / goat Alexa-488 (1:1000 dilution) (Life Technologies, A11008) and Hoechst 33342 (Life Technologies, H3570) (1:2000 dilution) in blocking buffer were added for 1 hour at room temperature. After three additional wash cycles with PBS, the microplate was sealed, and cell images were acquired using a Cellomics ArrayScanVTI high-content imager equipped with an X1 camera. Fluorescence images were acquired using a 10x objective and 386-23 BGRFRN_BGRFRN and 485-20 BGRFRN_BGRFRN filter sets for nuclei and MLKL phosphorylation, respectively.These images were analyzed using Compartmental Analysis Bioapplication software (Cellomics). The amount of MLKL phosphorylation was quantified as MEAN_CircRingAvgIntenRatio. The maximum inhibitory response was defined by the activity induced by Nec1s (CAS#: 852391-15-2, 6.25 μM). The IC50 value was defined as the concentration of compound that produced 50% of the maximum inhibition. The data were fitted using a four-parameter logistic equation to calculate IC50 and Ymax values.

[0140] RIPK1 HTRF binding assay A solution containing 0.2 nM anti-GST-Tb (Cisbio, 61GSTTLB), 90.6 nM probe, and 1 nM His-GST-TVMV-hRIPK1(1-324) in FRET buffer (20 mM HEPES, 10 mM MgCl2, 0.015% Brij-35, 4 mM DTT, 0.05 mg / mL BSA) was prepared. Using a Formulatrix Tempest, 2 mL of the detection antibody / enzyme / probe solution was dispensed into wells of a 1536 plate (Black Low Binding Polystyrene 1536 Plate (Corning, 3724)) containing 10 nL of the compound of interest at the appropriate concentration in DMSO. The plate was incubated at room temperature for 1 hour. FRET was measured using an EnVision plate reader (excitation: 340 nM, emission: 520 nM / 495 nM). The total signal (0% inhibition) was calculated from wells containing 10 nL DMSO only. The blank signal (100% inhibition) was calculated from wells containing 10 nL of 15 nM staurosporine and the internal control.

[0141] Cloning and baculovirus expression of RIPK1 constructs The coding region of human RIPK1(1-324), flanked by an NdeI site at the 5' end and a stop codon TGA and an XhoI site at the 3' end, was codon optimized. The gene was synthesized by GenScript USA Inc. (Piscataway, NJ) and subcloned into the pFastBac1 vector (Invitrogen, Carlsbad, CA) modified with an N-terminal His-GST-TVMV tag to generate His-GST-TVMV-hRIPK1(1-324)-pFB. The fidelity of the synthetic fragment was confirmed by sequencing. Baculovirus was generated for the constructs using the Bac-to-Bac baculovirus expression system (Invitrogen) according to the manufacturer's protocol. Briefly, recombinant bacmids were isolated from transformed DH10Bac E. coli competent cells (Invitrogen) and used to transfect Spodoptera frugiperda (Sf9) insect cells (Invitrogen). Seventy-two hours after transfection, baculovirus was harvested and used to infect fresh Sf9 cells at a 1 / 1000 (v / v) ratio for 66 hours to prepare viral stocks. For large-scale protein production, 2x10 in ESF921 insect medium (Expression System) 6 Sf9 cells (Expression Systems, Davis, CA) grown at 100 cells / ml were infected with the virus stock at a 1 / 100 (v / v) ratio for 66 hours. Production was performed using a WAVE-Bioreactor System 20 / 50 (GE Healthcare Bioscience) at either a 10 L scale in 22 L cell bags (GE Healthcare Bioscience, Pittsburgh, PA) or a 20 L scale in 50 L cell bags. Infected cells were harvested by centrifugation (2000 rpm) for 20 minutes at 4°C using a SORVALL® RC12BP centrifuge. Cell pellets were stored at -70°C prior to protein purification.

[0142] Purification of His-GST-TVMV-hRIPK1(1-324) The RIPK1-containing cell paste was resuspended in 50 mM Tris (pH 7.5), 150 mM NaCl, 10 mM imidazole, 5% glycerol, 5 mM MgSO4, 1 mM TCEP, 25 U / mL benzonase, and Complete protease inhibitor tablets (1 / 50 ml, Roche Diagnostics, Indianapolis, IN). Cells were solubilized by nitrogen cavitation using a 525 PSI non-agitated pressure vessel (Parr Instrument Company, Moline, IL). The suspension was clarified by centrifugation at 136,000 x g for 40 minutes at 4°C. The lysate was decanted from the pellet and passed through a 5 mL NiNTA Superflow cartridge (Qiagen, Valencia, CA) using an AKTA Pure (GE Healthcare). The column was eluted with a 10-CV linear gradient in 50 mM Tris (7.5), 150 mM NaCl, 500 mM imidazole, 5% glycerol, and 1 mM TCEP. Peak fractions were pooled and loaded directly onto a 5 ml GSTrap 4B column (GE Healthcare). The column was washed with 50 mM Tris (7.0), 150 mM NaCl, 5% glycerol, and 1 mM DTT and eluted with a 10-CV linear gradient in 50 mM Tris (8.0), 150 mM NaCl, 20 mM reduced glutathione, 5% glycerol, and 1 mM DTT. Fractions identified by SDS-PAGE containing RIPK1 were pooled and concentrated using a 30 kDa MWCO spin concentrator (Amicon μLtra-15, Millipore, Billerica, MA) and loaded onto a HiLoad 26 / 600 Superdex 200 column (GE Healthcare) equilibrated with 25 mM Tris (7.5), 150 mM NaCl, 2 mM TCEP, and 5% glycerol. RIPK1 protein eluted from the SEC column as a dimer. The yield was ~8 mg / L with a purity of >95% as determined by Coomassie-stained SDS-PAGE gel analysis. LCMS analysis of the protein showed that it was missing the N-terminal methionine, had one phosphorylation site, and was partially acetylated. The protein was aliquoted and stored at -80°C.

[0143] PI3Kδ HTRF binding assay A solution containing 0.2 nM anti-GST-Tb (Cisbio, 61GSTTLB), 40 nM probe, and 1 nM GST-tagged PIK3Cδ conjugated with PIK3R1 (Invitrogen #PV5273) was prepared in FRET buffer (20 mM HEPES, 10 mM MgCl2, 0.015% Brij-35, 4 mM DTT, 0.05 mg / mL BSA). Using a Formulatrix Tempest, 2 mL of the detection antibody / enzyme / probe solution was dispensed into a 1536-well plate (Black Low Binding Polystyrene 1536 Plate (Corning, 3724)) containing 10 nL of the appropriate target compound in DMSO. The plate was incubated at room temperature for 1 hour. FRET was measured using an EnVision plate reader (excitation: 340 nm, emission: 520 nm / 495 nm). The total signal (0% inhibition) was calculated from wells containing 10 nL of DMSO only. The blank signal (100% inhibition) was calculated from wells containing 10 nL of 15 nM staurosporine and the internal control. Compounds with low or no activity against PI3K are preferred, and preferably compounds have PIK3 activity of 1 μM or greater.

[0144] Using these assays, the IC of the following compounds was determined: 50 Values ​​were determined, see Table A. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

[0145] (Manufacturing method) [Table 9] Compounds of formula (I), and intermediates used in the preparation of compounds of formula (I), can be synthesized using the methods shown in the following examples and related methods. The methods and conditions used in these examples, and the actual compounds synthesized in these examples, are not intended to be limiting, but rather to demonstrate how compounds of formula (I) can be synthesized. The starting materials and reagents used in these examples, if not synthesized by the methods described herein, are generally commercially available, or are reported in the chemical literature, or can be synthesized using methods described in the chemical literature.

[0146] Abbreviations used herein are defined as follows: "1x" means one time, "2x" means two times, "3x" means three times, "°C" means degrees Celsius, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means normal, "M" means molar, "mmol" means millimole, "min" means minute, "h" means hour, "rt" means room temperature, "overnight" means overnight, "RT" means room temperature, "overnight" means overnight, "atm" means atmosphere, "psi" means pounds per square inch, "conc." means concentrated, "sat" or "saturated" means saturated, "CV" means column volume, "MW" means molecular weight, "mp" means melting point, "ee" means enantiomeric excess, "MS" or "Mass "Spec" is mass spectrometry, "m / z" is mass per unit charge, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high-resolution mass spectrometry, "APCI" is atmospheric pressure chemical ionization, "LCMS" or "LC / MS" is liquid chromatography mass spectrometry, "HPLC" is high-performance liquid chromatography, "RP HPLC" is reversed-phase HPLC, "prep" is preparative, "SFC" is supercritical fluid chromatography, "TLC" or "tlc" is thin-layer chromatography, "Rf" is retention factor, "UV" is ultraviolet, "NMR" is nuclear magnetic resonance spectroscopy, "nOe" is nuclear Overhauser effect spectroscopy, 1 "H" is proton, "δ" is delta, "s" is singlet, "d" is doublet, "t" is triplet, "q" is quartet, "m" is multiplet, "br" is broad, "MHz" is megahertz, and "α", "β", "R", "S", "E", and "Z" are stereo designations known to those skilled in the art. [Table 10] [Table 11] The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry (Maffrand, JP et al., Heterocycles, 16(1):35-7 (1981)). General synthetic schemes for synthesizing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that one skilled in the art can use to synthesize the compounds disclosed herein. The number of R groups in the schemes is for illustrative purposes and is not intended to limit the scope of the claims. Different methods for synthesizing the compounds of the present invention will be apparent to those skilled in the art. Furthermore, various steps in the synthesis may be performed in different orders to obtain the desired compound.

[0147] Examples of compounds of the invention synthesized by methods described in the general schemes are provided in the Intermediates and Examples sections below. The example compounds are generally synthesized as racemic mixtures. Synthesis of homochiral examples can be carried out by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by resolution of racemic products by chiral phase preparative HPLC. Alternatively, example compounds can be synthesized by methods known to yield enantiomerically enriched compounds. These methods include, but are not limited to, incorporating a chiral auxiliary functional group into a racemic intermediate that controls the diastereoselectivity of the transformation, and providing the enantiomerically enriched product upon cleavage of the chiral auxiliary.

[0148] The following schemes are provided to illustrate the preparation of compounds of the present invention. The R groups in the schemes may not necessarily correspond to any R groups in the specification and are not intended to limit embodiments of the present invention.

[0149] Scheme 1 depicts a method for synthesizing compounds of the formula 4. Starting material 1 can be functionalized via Suzuki coupling (Miyaura, N. and Suzuki, A. Chemical Reviews, 95:2457-2483, 1995) to give compounds of the class 2. Ester hydrolysis of 2 gives a carboxylic acid or carboxylate salt, which can be functionalized via amidation (Tetrahedron, 61:10827-10852, 2005) to give compounds such as 4. Intermediates of the present invention used to prepare compounds similar to 4 can be appropriately functionalized via Suzuki reaction or simple reactions known to those skilled in the art. [ka]

[0150] Scheme 2 depicts an alternative route to intermediates such as 2. In this method, a halobenzene such as 5 can be boronated in situ. A second coupling occurs upon addition of 1 and aqueous base. Importantly, this route to 2 can also be reversed. Specifically, 1 can be boronated in situ and then coupled with halide 5 to provide intermediate 2. [ka]

[0151] Scheme 3 details an alternative method for preparing compounds such as 4. Carboxylic acid 6 can be amidated under a variety of conditions known to those skilled in the art to provide intermediates such as 7. Intermediates such as 7 can be boronated in situ and subsequently coupled with 1 to provide compounds similar to 4. Alternatively, compound 1 can be boronated in situ and subsequently coupled with 7 to provide compounds such as 4. [ka]

[0152] Scheme 4 details yet another method for preparing compounds similar to 4. Boronic esters such as 8 are hydrolyzed to their corresponding acids. The carboxylic acid is amidated under a variety of conditions known to those skilled in the art to give compounds such as 10. Suzuki coupling with 1 gives compounds similar to 4. [ka]

[0153] Scheme 5 depicts an alternative approach to compounds such as 3. In this method, functionalization of the N-Boc-protected starting material 11 is carried out via a Suzuki coupling reaction to give compounds such as 12 directly or a mixture of species such as 12 and 13. Intermediates such as 12 and 13, either separately or as a mixture, are converted to 3 by ester hydrolysis followed by treatment with TFA. Alternatively, intermediates such as 12 and 13 can be first treated with TFA followed by ester hydrolysis to give compounds such as 3. [ka]

[0154] Scheme 6 depicts an alternative route to intermediates such as 12 and 13. In this method, an iodobenzene or bromobenzene such as 5 is borated in situ. A second coupling occurs upon the addition of 11 and aqueous base. Importantly, this approach to access 12 alone or a mixture of 12 and 13 can also be reversed. Specifically, 11 is borated in situ and then coupled with halide 5 to provide intermediates 12 and 13. [ka]

[0155] Scheme 7 details an alternative method for preparing compounds of formula 4. An intermediate such as 7 can be boronated in situ and subsequently coupled with 11 to give a mixture of species such as 14 and 15. Alternatively, 11 can be boronated in situ and subsequently coupled with 7 to give materials such as 14 and 15. Intermediates such as 14 and 15 can be treated with TFA to give compounds analogous to 4. [ka]

[0156] Scheme 8 details yet another method for preparing compounds of formula 4. Compounds such as 11 are boronated in situ, followed by Suzuki coupling with carboxylic acid halide 6 to give 16 or a mixture of compounds of the species 16 and 17. Amides such as 16 and 17 are treated with TFA, either separately or as a mixture, to give compounds analogous to 4. [ka]

[0157] Scheme 9 shows an alternative synthesis of compounds 3. Compounds of type 1 are converted in situ to their respective boronic esters, followed by Suzuki coupling with carboxylic acid halides 6 to give intermediates such as 3. [ka]

[0158] Scheme 10 depicts an alternative method for obtaining compounds such as 4. In this example, compounds such as 11 are boronated via Suzuki coupling to give compounds such as 18. An acid such as 6 is coupled with an amine using a standard coupling agent (e.g., BOP or HATU) to give an amide such as 19. Intermediates such as 18 and 19 are coupled via Suzuki coupling to give compounds such as 16. Treatment with acid (e.g., TFA or HCl) gives compounds such as 4. [ka]

[0159] Purification of intermediates and final products was carried out by either normal-phase or reverse-phase chromatography, using pre-packed silica cartridges eluted with any gradient of hexane and ethyl acetate, or dichloromethane and methanol, unless otherwise noted. Reverse-phase preparative HPLC or LCMS was typically performed using a C18 column eluted with a gradient of solvent A (90% water, 10% methanol, 0.1% TFA) and solvent B (10% water, 90% methanol, 0.1% TFA, UV 220 nm), or with a gradient of solvent A (95% water, 5% acetonitrile, 0.1% TFA) and solvent B (5% water, 95% acetonitrile, 0.1% TFA, UV 220 nm), or with a gradient of solvent A (98% water, 2% acetonitrile, 0.05% TFA) and solvent B (98% acetonitrile, 2% water, 0.05% TFA, UV 254 nm), or with a gradient of solvent A (95% water, 5% acetonitrile with 10 mM ammonium acetate) and solvent B (95% acetonitrile, 5% water with 10 mM ammonium acetate).

[0160] In most of the examples, two analytical LCMS injections were performed to determine the final purity. Method A: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: 5:95 acetonitrile:water (10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (10 mM ammonium acetate); Temperature: 50 °C; Gradient: 0–100% B over 3 min, followed by 100% B for 0.75 min; Flow rate: 1.11 mL / min; Detection: UV (220 nm) Method B: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: 5:95 acetonitrile:0.1% TFA in water; Mobile phase B: 95:5 acetonitrile:0.1% TFA in water; Temperature: 50 °C; Gradient: 0–100% B over 3 min, followed by 100% B for 0.75 min; Flow rate: 1.11 mL / min; Detection: UV (220 nm)

[0161] In some of the examples, analytical HPLC injections were performed to determine final purity. Method A: Column: Sunfire C18, 3.0 x 150 mm, particle size: 3.5 μM; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); Gradient: 0–100% B over 10 min; Flow rate: 1 mL / min; Detection: UV (220 nm and 254 nm). Method B: Column: XBridge Phenyl, 3.0 x 150 mm, particle size: 3.5 μM; Mobile Phase A: 5:95 acetonitrile:water (containing 0.1% TFA); Mobile Phase B: 95:5 acetonitrile:water (containing 0.1% TFA); Gradient: 0–100% B over 10 min; Flow Rate: 1 mL / min; Detection: UV (220 and 254 nm) Method C: Column: XBridge C18, 3.0 x 150 mm, particle size: 3.5 μM; Mobile Phase A: 5:95 methanol:water (containing 10 mM ammonium bicarbonate); Mobile Phase B: 95:5 methanol:water (containing 10 mM ammonium bicarbonate); Gradient: 0–100% B over 15 min; Flow Rate: 1 mL / min; Detection: UV (220 nm and 254 nm). Method D: Column: XBridge Phenyl, 3.0 x 150 mm, particle size: 3.5 μM; Mobile Phase A: 5:95 methanol:water (containing 10 mM ammonium bicarbonate); Mobile Phase B: 95:5 methanol:water (containing 10 mM ammonium bicarbonate); Gradient: 0–100% B over 15 min; Flow Rate: 1 mL / min; Detection: UV (220 nm and 254 nm).

[0162] Mass spectrum measurements were carried out mainly under the following conditions. LCMS(ESI)m / z: [M+H] + BEH C18, 2.11 x 50 mm, 1.7 μm; Mobile phase A: 2:98 water:acetonitrile (containing 0.1% TFA); Mobile phase B: 98:2 acetonitrile:water (containing 0.1% TFA); Gradient: 0–100% B over 2 min; Flow rate: 0.8 mL / min; Detection: UV (220 nm)

[0163] Proton NMR was measured after water suppression unless otherwise specified.

[0164] Example 1: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide [ka] 1A: methyl 5-(2-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoate A 100 mL round-bottom flask was charged with a stir bar, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (66.0 mg, 0.102 mmol), N,N-bis-Boc-2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (1.41 g, 3.40 mmol), and methyl 4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.00 g, 3.40 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of 1,4-dioxane (17 mL) and aqueous potassium phosphate trihydrate (2 M, 5.10 mL, 10.2 mmol). The mixture was degassed by bubbling N for 5 minutes and then stirred at 80 °C for 16 hours. The resulting crude mixture was purified by flash column chromatography (silica, elution gradient: EtOAc / Hex 0% → 25% → 50%) to give methyl 5-(2-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoate (0.810 g, 2.02 mmol, 60% yield) as the major product and methyl 5-(2-(di-(tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoate (0.520 g, 1.04 mmol, 31% yield) as a minor product. 5-(2-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoate: 1 H NMR(500MHz, CDCl3) δ 8.63-8.55(m,1H), 8.15(d,J=8.1Hz,1H), 7.83(br s, 1H), 7.76(s,1H), 7.20-7.14(m,1H), 7.11(d,J=11.4Hz,1H), 3.92(s,3H), 2.67(s,3H), 1.56(d,J=0.8Hz,9H) MS ESI m / z 501.1(M+H) +

[0165] 1B: 5-(2-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid A round-bottom flask (100 mL) was charged with a stir bar and methyl 5-(2-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoate (1.06 g, 2.64 mmol), followed by THF (11 mL), MeOH (2.2 mL), and aqueous sodium hydroxide (1 M, 7.92 mL, 7.92 mmol). The mixture was stirred at room temperature for 3 h and diluted with EtOAc (100 mL) and 1 N hydrochloric acid (100 mL). The mixture was shaken and the layers separated. The organic layer was washed with brine (100 mL), dried over anhydrous MgSO4, and filtered through Celite. The resulting crude 5-(2-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid (1.00 g, 2.59 mmol) was used directly in the next step without further purification. MS ESI m / z 387.0(M+H) +

[0166] 1C: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid A 250 mL round-bottom flask was charged with a stir bar and 5-(2-((tert-butoxycarbonyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid (1.00 g, 2.59 mmol), followed by DCM (6.47 mL) and TFA (6.47 mL). The mixture was stirred at room temperature for 3 days, and the resulting reaction mixture was concentrated under reduced pressure to give 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid·TFA (850 mg, 2.12 mmol, 82% yield), which was used directly in the next step without further purification. MS ESI m / z 287.3(M+H) +

[0167] 1: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide To an 8 mL reaction vial was added a stir bar, BOP (24.9 mg, 0.0560 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol·HCl (12.5 mg, 0.0560 mmol), and 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid·TFA (15 mg, 0.037 mmol). The vial was evacuated and backfilled with nitrogen, followed by the addition of DMF (375 μL) and DIPEA (65 μL, 0.375 mmol). The resulting mixture was stirred at room temperature for 16 hours, and the crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 16% B at 0 min, followed by 16–56% B in 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide (7.3 mg, 0.016 mmol, 43% yield). 1H NMR (500MHz, DMSO-d6) δ 8.59(br d,J=6.8Hz,1H), 8.37(br t,J=5.3Hz,1H), 7.59-7.50(m,2H), 7.37(s,4H), 7.26(br d,J=11.9Hz,1H), 7.09(br d,J=7.0Hz,1H), 6.05(br s, 2H), 5.53-5.42(m,1H), 4.70-4.60(m,1H), 3.30(q,J=6.7Hz,1H), 2.39(s,3H), 1.89-1.80(m,2H) MS ESI m / z 453.9(M+H) +

[0168] Example 2: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide [ka] 2A: 3-oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile Under a nitrogen atmosphere, NaH (0.384 g, 9.60 mmol) was carefully added to a solution of methyl 4-(trifluoromethyl)benzoate (1.00 g, 4.80 mmol) in dry toluene (4.8 mL). Anhydrous acetonitrile (1.25 mL, 24.0 mmol) was added dropwise, and the mixture was heated at 80 °C overnight under a nitrogen atmosphere. The resulting slurry was diluted with hexane, and the solid was isolated by filtration and rinsed with hexane. The resulting powdered solid was then dissolved in water (50 mL), and 1 N hydrochloric acid (approximately 20 mL) was added with stirring until a precipitate formed. The addition of 1 N HCl was stopped when the pH reached 0-1. The resulting precipitate was isolated by filtration, air-dried, and then dried under high vacuum to give 3-oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile (0.892 g, 4.18 mmol, 62% purity as determined by NMR, 54% yield), which was used directly in the next step without further purification. 1H NMR(500MHz, CDCl3) δ 8.05(d,J=8.1Hz,2H), 7.81(d,J=8.1Hz,2H), 4.11(s,2H)

[0169] 2B: 3-amino-1-(4-(trifluoromethyl)phenyl)propan-1-ol A 20 mL vial was charged with a stir bar and 3-oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile (0.300 g, 1.41 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of THF (7 mL). The resulting mixture was cooled to 0°C, and dimethylsulfide borane complex (1.4 mL, 5 M THF solution, 7.04 mmol) was slowly added. The mixture was then heated to reflux for 16 hours. The resulting crude material was purified by reverse-phase HPLC (Solvent A: 10% acetonitrile, 90% HO, 0.1% TFA; Solvent B: 90% acetonitrile, 10% HO, 0.1% TFA; Column: Waters Atlantis 30x100mm S5; Gradient: 10-70% B) to give 3-amino-1-(4-(trifluoromethyl)phenyl)propan-1-ol (0.150 g, 0.684 mmol, 49% yield). 1 H NMR (500MHz, DMSO-d6) δ 7.73(br d,J=7.8Hz,2H), 7.57(br d,J=7.9Hz,2H), 4.81(dd,J=3.8, 2.9Hz,1H), 2.88(br d,J=4.4Hz,2H), 2.02-1.70(m,2H) MS ESI m / z 220.05(M+H) +

[0170] 2: The title compound was prepared in a similar manner to Example 1, using 3-amino-1-(4-(trifluoromethyl)phenyl)propan-1-ol instead of (S)-3-amino-1-(4-chlorophenyl)propan-1-ol·HCl as described in the last step to give racemic 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide (11.5 mg, 0.0240 mmol, 32% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.58(d,J=7.0Hz,1H), 8.41(br t,J=5.5Hz,1H), 7.67(d,J=8.0Hz,2H), 7.61-7.50(m,4H), 7.25(d,J=12.0Hz,1H), 7.11(br d,J=7.0Hz,1H), 4.74(dd,J=7.7, 4.9Hz,1H), 3.37-3.27(m,2H), 2.38(s,3H), 1.87(dt,J=14.6, 7.5Hz,2H) MS ESI m / z 488.0(M+H) +

[0171] Example 3: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide (Enantiomer 1) [ka] Racemic 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide was separated into its two individual stereoisomers using SFC chiral chromatography (conditions: column: Chiral OD 30x250 mm; 5μ; mobile phase: 65% CO2 / 35% IPA (containing 0.1% DEA); flow rate: 100 mL / min; detection wavelength: 220 nm; injection conditions: 1.5 mL (9.8 mg dissolved in 3 mL MeOH)). The fractions containing the first eluting peak were concentrated to give 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide (enantiomer 1, 2.9 mg, 0.0060 mmol, 8% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.63(d,J=6.7Hz,1H), 8.40(br t,J=5.3Hz,1H), 7.70(br d,J=7.9Hz,2H), 7.63-7.57(m,4H), 7.29(br d,J=11.9Hz,1H), 7.12(br d,J=7.0Hz,1H), 4.80-4.75(m,1H), 2.42(s,3H), 1.95-1.83(m,2H) MS ESI m / z 488.3(M+H) +

[0172] Example 4: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide (Enantiomer 2) [ka] The title compound: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide (enantiomer 2, 2.7 mg, 0.0060 mmol, 8% yield) was obtained as the second eluting isomer from the chiral SFC purification described in Example 3. 1 H NMR (500MHz, DMSO-d6) δ 8.64(d,J=7.0Hz,1H), 8.40(br t,J=5.5Hz,1H), 7.71(br d,J=8.2Hz,2H), 7.63-7.57(m,4H), 7.29(br d,J=11.9Hz,1H), 7.12(br d,J=7.0Hz,1H), 4.80-4.75(m,1H), 2.42(s,3H), 1.96-1.82(m,2H) MS ESI m / z 488.3(M+H) +

[0173] Table 1: The compounds in Table 1 were prepared in a manner similar to Examples 2, 3 and 4. [ka] [Table 12]

[0174] Example 11: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide [ka] 11A: ethyl 3-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate and ethyl 3-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate A 100 mL round-bottom flask was charged with a stir bar, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.125 g, 0.192 mmol), ethyl 3-bromo-2-fluoro-6-methylbenzoate (1.00 g, 3.83 mmol), and N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (2.12 g, 4.60 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of 1,4-dioxane (19.2 mL) and 2 M aqueous potassium phosphate (5.8 mL, 11.5 mmol). The mixture was stirred at 80 °C for 3 h. The resulting crude mixture was purified by flash column chromatography (silica, elution gradient: EtOAc / Hex 0% to 50%) to give ethyl 3-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (1.75 g, 3.40 mmol, 89% yield) and ethyl 3-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (0.136 g, 0.328 mmol, 9% yield). Ethyl 3-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate: 1 H NMR(500MHz, CDCl3) δ 8.56(d,J=7.3Hz,1H), 7.83(d,J=0.9Hz,1H), 7.45(t,J=7.9Hz,1H), 7.28-7.23(m,1H), 7.16(d,J=7.9Hz,1H), 4.45(q,J=7.3Hz,2H), 2.46(s,3H), 1.48(s,18H), 1.41(t,J=7.3Hz,3H) Ethyl 3-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate: 1H NMR(500MHz, CDCl3) δ 8.56(d,J=7.2Hz,1H), 7.98(s,1H), 7.71(s,1H), 7.44(t,J=7.9Hz,1H), 7.14(dd,J=7.6, 2.3Hz,2H), 4.45(q,J=7.1Hz,2H), 2.45(s,3H), 1.56(s,9H), 1.41(t,J=7.2Hz,3H) MS ESI m / z 415.2(M+H) +

[0175] 11B: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate ethyl A 100 mL round-bottom flask was charged with a stir bar and ethyl 3-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (1.75 g, 3.40 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of DCM (8.5 mL) and TFA (8.5 mL) and stirring at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the resulting crude product was used directly in the next step without further purification. MS ESI m / z 315.1(M+H) +

[0176] 11C: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoic acid A 100 mL round-bottom flask was charged with a stir bar, ethyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (1.07 g, 3.23 mmol), and lithium hydroxide monohydrate (0.679 g, 16.2 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of THF (35 mL) and HO (5.8 mL). The mixture was stirred at 60 °C for 3 days. The mixture was concentrated under reduced pressure, and the resulting crude product was diluted with 1 N hydrochloric acid (100 mL), washed with diethyl ether (50 mL), and the aqueous layer was concentrated under reduced pressure to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoic acid·HCl (2.00 g, 3.10 mmol, 96% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.76(d,J=7.0Hz,1H), 7.70-7.62(m,2H), 7.28(d,J=8.0Hz,2H), 2.39(s,3H) MS ESI m / z 286.8(M+H) +

[0177] 11: To an 8 mL vial was added a stir bar, 4,4,4-trifluoro-3-phenylbutan-1-amine (81.0 mg, 0.397 mmol), and 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoic acid·HCl (171 mg, 0.265 mmol). The vial was evacuated and backfilled with nitrogen, followed by the addition of BOP (141 mg, 0.318 mmol), N,N-diisopropylethylamine (0.230 mL, 1.33 mmol), and DMF (2.7 mL). The mixture was stirred at room temperature for 16 hours, and the crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 24% B at 0 min, followed by 24–64% B over 23 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS signal. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give racemic 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide (122 mg, 0.259 mmol, 98% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.72(t,J=5.3Hz,1H), 8.61(d,J=6.7Hz,1H), 7.59(t,J=8.1Hz,1H), 7.49(s,1H), 7.47-7.38(m,5H), 7.23(d,J=8.2Hz,1H), 7.05(br d,J=7.0Hz,1H), 3.72 (td,J=10.1, 3.2Hz,1H), 3.28-3.14(m,1H), 3.13-3.03(m,1H), 2.30(s,3H), 2.27-2.09(m,2H) MS ESI m / z 472.3(M+H) +

[0178] Example 12: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide (Enantiomer 1) [ka] Racemic 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide was separated into its two stereoisomers using SFC chiral chromatography (conditions: column: Chiral OJ 30x250mm; 5μ; mobile phase: 85% CO2 / 15% IPA (containing 0.1% DEA); flow rate: 100mL / min; detection wavelength: 220nm). The fractions containing the first eluting peak were concentrated to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide (enantiomer 1, 39.7 mg, 0.0840 mmol, 32% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.73(t,J=5.5Hz,1H), 8.61(d,J=7.0Hz,1H), 7.59(t,J=8.1Hz,2H), 7.49(s,1H), 7.47-7.38(m,5H), 7.23(d,J=8.2Hz,1H), 7.05(br d,J=7.0Hz,1H), 3.78-3.67(m,1H), 3.24-3.15(m,1H), 3.12-3.03(m,1H), 2.30(s,3H), 2.27-2.09(m,2H) MS ESI m / z 472.1(M+H) +

[0179] Example 13: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide (Enantiomer 2) [ka] The title compound: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide (enantiomer 2, 39.9 mg, 0.085 mmol, 32% yield) was obtained as the second eluting isomer from the chiral SFC purification described in Example 12. 1 H NMR (500MHz, DMSO-d6) δ 8.73(t,J=5.5Hz,1H), 8.61(d,J=7.0Hz,1H), 7.59(t,J=8.1Hz,2H), 7.49(s,1H), 7.47-7.38(m,5H), 7.23(d,J=8.2Hz,1H), 7.05(br d,J=7.0Hz,1H), 3.78-3.67(m,1H), 3.24-3.15(m,1H), 3.12-3.03(m,1H), 2.30(s,3H), 2.27-2.09(m,2H) MS ESI m / z 472.1(M+H) +

[0180] Example 14: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl-1,1,3-d3)-2-fluoro-6-methylbenzamide [ka]

[0181] 14A: 3-amino-1-(4-chlorophenyl)propan-1,3,3-d3-1-ol A 50 mL round-bottom flask was charged with a stir bar and 3-(4-chlorophenyl)-3-oxopropanenitrile (0.500 g, 2.78 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of THF (9.3 mL). The mixture was cooled to 0 °C, and lithium aluminum deuteride (98% deuteration, 0.351 g, 8.35 mmol) in THF (4.6 mL) was slowly added. The mixture was stirred at room temperature for 3 h and then quenched with 1 N aqueous NaOH. The product was extracted with diethyl ether, washed with brine, dried over anhydrous MgSO4, filtered through Celite, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. MS ESI m / z 189.2(M+H) +

[0182] 14: The title compound was prepared in a similar manner to Example 11, substituting 3-amino-1-(4-chlorophenyl)propan-1,3,3-d3-1-ol for 4,4,4-trifluoro-3-phenylbutan-1-amine in the last step to give racemic 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl-1,1,3-d3)-2-fluoro-6-methylbenzamide (46.1 mg, 0.101 mmol, 38% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.63-8.58(m,2H), 7.58(t,J=8.1Hz,1H), 7.49(s,1H), 7.43-7.35(m,4H), 7.22(d,J=7.9Hz,1H), 7.04(br d,J=6.7Hz,1H), 2.32(s,3H), 1.80(s,2H) MS ESI m / z 457.0(M+H) +

[0183] Example 15: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-methylbutyl)-2-fluoro-6-methylbenzamide [ka]

[0184] 15A: 3-(4-chlorophenyl)-3-methylbutanoic acid A stir bar and methyl 4-(4-chlorophenyl)-4-methylpentanoate (0.290 g, 1.21 mmol) were added to an 8 mL reaction vial. The vial was evacuated and backfilled with nitrogen. Lithium hydroxide monohydrate (0.152 g, 3.61 mmol), THF (4.5 mL), and HO (1.5 mL) were then added and stirred at room temperature for 16 h. The resulting crude mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL) and 1 N hydrochloric acid (50 mL). The aqueous layer was washed with EtOAc (50 mL x 2), and the combined organic extracts were washed with brine, dried over anhydrous MgSO, and filtered. The mixture was concentrated under reduced pressure and used directly in the next step (estimated yield 100%). MS ESI m / z 224.95(MH) -

[0185] 15B: A 20 mL reaction vial was charged with a stir bar and 4-(4-chlorophenyl)-4-methylpentanoic acid (272 mg, 1.20 mmol). The vial was evacuated and backfilled with nitrogen, followed by the addition of toluene (4 mL), triethylamine (669 μL, 4.80 mmol), and diphenylphosphoryl azide (516 μL, 2.40 mmol) at 0° C. This mixture was stirred at room temperature for 16 hours and then diluted with EtOAc (30 mL). The organic layer was washed with 1N hydrochloric acid and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resulting crude product was dissolved in tert-butanol (574 μL, 60.0 mmol), followed by the addition of tin(II) chloride (11.4 mg, 0.0600 mmol), and stirred at 80° C. for 2 days. This mixture was concentrated under reduced pressure and redissolved in a mixture of TFA (3 mL) and DCM (6 mL). This mixture was stirred at room temperature for 16 hours, and the resulting product was purified by reverse-phase preparative HPLC (solvent A: 10% acetonitrile, 90% HO, 0.1% TFA; solvent B: 90% acetonitrile, 10% HO, 0.1% TFA; column: Waters Atlantis OBD 30x100mm S5; gradient: 10-70% B) to give 3-(4-chlorophenyl)-3-methylbutan-1-amine·TFA (69.0 mg, 0.221 mmol, 18.5% yield). MS ESI m / z 197.85(M+H) +

[0186] 15: The title compound was prepared in a similar manner to Example 11, substituting 3-(4-chlorophenyl)-3-methylbutan-1-amine·TFA for 4,4,4-trifluoro-3-phenylbutan-1-amine in the last step to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-methylbutyl)-2-fluoro-6-methylbenzamide (8.1 mg, 0.0174 mmol, 39% yield). 1H NMR (500MHz, DMSO-d6) δ 8.60(d,J=7.0Hz,1H), 8.50(t,J=5.5Hz,1H), 7.56(t,J=8.1Hz,1H), 7.48-7.34(m,5H), 7.19(d,J=8.1Hz,1H), 7.01(br d,J=7.0Hz,1H), 6.08(s,2H), 2.99(dt,J=11.0, 5.5Hz,2H), 2.26(s,3H), 1.88-1.81(m,2H), 1.31(s,6H) MS ESI m / z 466.0(M+H) +

[0187] Example 16: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(2-(1-(4-fluorophenyl)cyclopropyl)ethyl)-6-methylbenzamide [ka]

[0188] 16A: 2-(1-(4-fluorophenyl)cyclopropyl)ethan-1-amine A 20 mL vial was charged with a stir bar and 2-(1-(4-fluorophenyl)cyclopropyl)acetonitrile (0.250 g, 1.43 mmol), and the flask was evacuated and filled with nitrogen. Then, THF (7.1 mL) was added. The flask was cooled to 0°C, and dimethylsulfide borane complex (0.86 mL, 5 M THF solution, 4.28 mmol) was slowly added. The mixture was heated to reflux for 16 h, and the resulting crude material was purified by reverse-phase preparative HPLC (Solvent A: 10% acetonitrile, 90% HO, 0.1% TFA; Solvent B: 90% acetonitrile, 10% HO, 0.1% TFA; Column: Waters Atlantis OBD 30x100mm S5; Gradient: 10-100% B) to give 2-(1-(4-fluorophenyl)cyclopropyl)ethan-1-amine·TFA (135 mg, 0.460 mmol, 32.3% yield). 1H NMR (500MHz, DMSO-d6) δ 7.41-7.26(m,2H), 7.14(br t,J=8.4Hz,2H), 2.76-2.61(m,2H), 1.90-1.70(m,2H), 0.92-0.64(m,4H) MS ESI m / z 180.1(M+H) +

[0189] 16: The title compound was prepared in a similar manner to Example 11, substituting 2-(1-(4-fluorophenyl)cyclopropyl)ethan-1-amine·TFA for 4,4,4-trifluoro-3-phenylbutan-1-amine in the last step to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(2-(1-(4-fluorophenyl)cyclopropyl)ethyl)-6-methylbenzamide (22.3 mg, 0.0498 mmol, 64% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.61(d,J=6.6Hz,1H), 8.55(t,J=5.5Hz,1H), 7.57(t,J=8.1Hz,1H), 7.47(s,1H), 7.42-7.35(m,2H), 7.20(d,J=8.1Hz,1H), 7.13(t,J=8.8Hz,2H), 7.02(br d,J=7.0Hz,1H), 3.21-3.14(m,2H), 2.28(s,3H), 1.82-1.73(m,2H), 0.77(br d,J=12.1Hz,4H) MS ESI m / z 448.0(M+H) +

[0190] Example 17: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxybutyl)-2-fluoro-6-methylbenzamide [ka] 17A: 3-(4-chlorophenyl)-3-hydroxybutanenitrile A 100 mL round-bottom flask was equipped with a stir bar and vacuum-dried twice, followed by the addition of 32.3 mL of THF. The flask was cooled to -20 °C and n-BuLi solution (7.8 mL, 2.5 M, 19.4 mmol) was added. A solution of 1.0 mL of acetonitrile (19.4 mmol) in 8.1 mL of THF was added dropwise over 10 min. The resulting mixture was stirred at -20 °C for 1 h, and 2.52 mL of 19.4 mmol of 1-(4-chlorophenyl)ethan-1-one (19.4 mmol) in 8.1 mL of THF was added dropwise over 10 min. The mixture was stirred at -20 °C for an additional 15 min and then warmed to room temperature over 15 min. The reaction was quenched with saturated aqueous NH4Cl; TLC indicated that the majority of the starting material remained unreacted. The reaction mixture was diluted with EtOAc (200 mL), washed with HO (200 mL) and brine (200 mL), dried over anhydrous MgSO, and filtered through Celite. The crude mixture was concentrated under reduced pressure and purified by flash column chromatography (eluting with 40 g silica eluting with 0% EtOAc / hexanes, gradient: 0% to 40%, 40%) to give 3-(4-chlorophenyl)-3-hydroxybutanenitrile (492 mg, 2.51 mmol, 13.0% yield). 1 H NMR(500MHz, CDCl3) δ7.45-7.40(m,2H), 7.37-7.32(m,2H), 2.85-2.74(m,2H), 1.74(s,3H)

[0191] 17B: 4-amino-2-(4-chlorophenyl)butan-2-ol·TFA A 100 mL round-bottom flask was charged with a stir bar and 3-(4-chlorophenyl)-3-hydroxybutanenitrile (0.492 g, 2.51 mmol), evacuated, and backfilled with nitrogen. Then, THF (12.6 mL) was added. The mixture was cooled to 0°C, and dimethylsulfide borane complex (1.5 mL, 5 M THF solution, 7.54 mmol) was slowly added. The mixture was then heated to reflux for 16 hours. The resulting crude material was purified by reverse-phase preparative HPLC (Solvent A: 10% acetonitrile, 90% HO, 0.1% TFA; Solvent B: 90% acetonitrile, 10% HO, 0.1% TFA; Column: Waters Atlantis OBD 30x100mm S5; Gradient: 10–60% B) to give 4-amino-2-(4-chlorophenyl)butan-2-ol·TFA (0.251 g, 0.800 mmol, 32% yield). This mixture was used directly in the next step without further purification. MS ESI m / z 199.8(M+H) +

[0192] 17: The title compound was prepared in a similar manner to Example 11, substituting 4-amino-2-(4-chlorophenyl)butan-2-ol·TFA for 4,4,4-trifluoro-3-phenylbutan-1-amine in the last step to give racemic 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxybutyl)-2-fluoro-6-methylbenzamide (0.9 mg, 0.0019 mmol, 7% yield). 1H NMR (500MHz, DMSO-d6) δ 8.60(d,J=6.6Hz,1H), 8.45(br t,J=5.3Hz,1H), 7.56(br t,J=7.9Hz,1H), 7.51-7.44(m,2H), 7.38(d,J=8.1Hz,2H), 7.19(d,J=8.1Hz,1H), 7.01(br d,J=7.0Hz,1H), 6.09(s,2H), 5.23(s,1H), 3.40-3.25(m,1H), 2.95(td,J=11.6, 5.9Hz,1H), 2.27(s,3H), 2.01-1.88(m,2H), 1.46(s,3H) MS ESI m / z 468.3(M+H) +

[0193] Example 18: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-2-fluoro-6-methylbenzamide [ka] 18A: 2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutanoic acid ethyl ester A mixture of iron (168 mg, 3.00 mmol), 1-(4-fluorophenyl)ethan-1-one (138 mg, 1.00 mmol), ethyl 2-bromo-2,2-difluoroacetate (609 mg, 3.00 mmol), and iodine (50.8 mg, 0.200 mmol) in THF (2 mL) was purged with nitrogen and stirred at 70° C. for 20 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL), and the mixture was extracted with EtOAc (3×20 mL), washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel cartridge, elution solvent: 0-60% EtOAc / Hex), and the fractions containing the desired product were collected and concentrated under reduced pressure to give ethyl 2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutanoate (166 mg, 0.633 mmol, 63% yield) as an oil. 1 H NMR(500MHz, CDCl3) δ 7.51(dd,J=8.5,5.5Hz,2H), 7.06(t,J=8.7Hz,2H), 4.19(q,J=7.2Hz,2H), 1.74(t,J=1.5Hz,3H), 1.17(t,J=7.2Hz,3H)

[0194] 18B: 2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutanamide To a solution of ethyl 2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutanoate (166 mg, 0.633 mmol) in MeOH (3 mL) was added ammonia (7N in MeOH, 0.36 mL, 2.53 mmol) at 0° C. The mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure to give crude 2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutanamide, which was used directly in the next step without further purification. MS ESI m / z 231.85(MH) -

[0195] 18C: 4-amino-3,3-difluoro-2-(4-fluorophenyl)butan-2-ol·HCl salt To a solution of 2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutanamide (148 mg, 0.635 mmol) in THF (3 mL) was added methylsulfide borane complex (2 M in THF, 1.6 mL, 3.17 mmol). The mixture was stirred at 70 °C for 24 h and quenched by the dropwise addition of methanol (1 mL). The mixture was stirred at room temperature for 30 min, concentrated under reduced pressure, and the crude product was then treated with 1 N hydrochloric acid (2 mL) at 65 °C for 1 h and then concentrated under reduced pressure. The residue was triturated with EtO, and the solvent was decanted. The residue was dried under vacuum to give crude 4-amino-3,3-difluoro-2-(4-fluorophenyl)butan-2-ol HCl salt (104 mg, 0.407 mmol, 64% yield) as a solid. 1H NMR (500MHz, DMSO-d6) δ 7.57(br dd,J=8.5, 5.6Hz,2H), 7.26-7.18(m,2H), 3.08-2.93(m,1H), 1.63(s,3H) MS ESI m / z 220.0(M+H) +

[0196] 18: The title compound was prepared in a similar manner to Example 11, substituting 4-amino-3,3-difluoro-2-(4-fluorophenyl)butan-2-ol·HCl for 4,4,4-trifluoro-3-phenylbutan-1-amine in the last step to give racemic 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-2-fluoro-6-methylbenzamide (21.0 mg, 0.043 mmol, 58% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.80(br t,J=6.3Hz,1H), 8.64(d,J=7.0Hz,1H), 7.62-7.55(m,3H), 7.51(s,1H), 7.24-7.16(m,3H), 7.09(br d,J=7.3Hz,1H), 4.03-3.86(m,2H), 2.27(s,3H), 1.63(s,3H) MS ESI m / z 488.2(M+H) +

[0197] Example 19: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-[4-(4-chlorophenyl)-4-hydroxybutan-2-yl]-2-fluoro-6-methylbenzamide (racemic 1) [ka]

[0198] 19A: 4-(4-chlorophenyl)-4-hydroxybutan-2-one (Reference: Euro. J. Med. Chem. 2009, 44, 1278-1287) To a solution of 4-chlorobenzaldehyde (1.13 g, 8.00 mmol) in acetone (200 mL) was added D-proline (0.184 g, 1.60 mmol), and the mixture was stirred at room temperature for 18 h. DMSO (10 mL) and water (2 mL) were added and stirred for an additional 24 h. The volatiles were removed under reduced pressure, and the resulting residue was partitioned between EtOAc and water, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient: 100% Hex to 50% EtOAc / Hex) to afford 4-(4-chlorophenyl)-4-hydroxybutan-2-one (1.18 g, 5.92 mmol, 74% yield) as a colorless oil. According to the literature, the desired product with the S-configuration at the OH position was obtained in ~76% ee. 1 H NMR(499MHz, CDCl3) δ 7.37-7.29(m,4H), 5.15(dd,J=8.5, 3.8Hz,1H), 3.39(s,1H), 2.95-2.75(m,2H), 2.22(s,3H)

[0199] 19B: 3-amino-1-(4-chlorophenyl)butan-1-ol To a solution of 4-(4-chlorophenyl)-4-hydroxybutan-2-one (596 mg, 3.00 mmol) in MeOH (10 mL) was added ammonium acetate (1.85 g, 24.0 mmol) and sodium cyanoborohydride (377 mg, 6.00 mmol) and stirred at room temperature for 18 h. LCMS showed two distinct peaks with m / z values ​​consistent with the desired product. The volatiles were removed in vacuo, and the resulting residue was partitioned between EtOAc and water, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give crude 3-amino-1-(4-chlorophenyl)butan-1-ol (0.60 g, 3.0 mmol, 100% crude yield) as a brown oil, which was used directly in the next step. MS ESI m / z 200.1(M+H) +

[0200] 19: A mixture of lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (29.2 mg, 0.100 mmol), BOP (66.3 mg, 0.150 mmol), 3-amino-1-(4-chlorophenyl)butan-1-ol (24.0 mg, 0.120 mmol), and Hunig's base (0.070 mL, 0.40 mmol) in DMF (0.5 mL) was stirred at room temperature for 5 hours. LCMS showed two distinct peaks with m / z values ​​consistent with the expected product. The mixture was diluted with MeOH, filtered, and the resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 19% B at 0 min, followed by 19–59% B over 25 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS signal. Fractions containing the first eluting peak, whose m / z value matched that of the desired product in LCMS, were combined and dried on a centrifugal evaporator, and the racemic mixture 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-[4-(4-chlorophenyl)-4-hydroxybutan-2-yl]-2-fluoro-6-methylbenzamide (racemic 1, 11.3 mg, 24.0 μmol, 24% yield) was obtained as the first eluting mixture by preparative HPLC separation. The relative and absolute stereochemistry have not been determined. 1H NMR (500MHz, DMSO-d6) δ 8.62(d,J=7.0Hz,1H), 8.56(d,J=8.4Hz,1H), 7.58(t,J=8.0Hz,1H), 7.50(s,1H), 7.39(s,4H), 7.23(d,J=8.1Hz,1H), 7.05(d,J=6.9Hz,1H), 6.07(s,2H), 5.37(d,J=4.6Hz,1H), 4.63(q,J=6.6Hz,1H), 4.04-3.89(m,1H), 2.33(s,3H), 1.93(dt,J=14.5, 7.4Hz,1H), 1.63(dt,J=13.5, 6.6Hz,1H), 1.16(d,J=6.6Hz,3H); 19 F NMR (471MHz, DMSO-d6) δ -121.94 MS ESI m / z 468.2(M+H) +

[0201] Example 20: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-[4-(4-chlorophenyl)-4-hydroxybutan-2-yl]-2-fluoro-6-methylbenzamide (racemic 2) [ka] Preparative HPLC purification as described in Example 19 afforded the title compound: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-[4-(4-chlorophenyl)-4-hydroxybutan-2-yl]-2-fluoro-6-methylbenzamide (racemic 2, 3.5 mg, 6.8 μmol, 7% yield) as the second eluting peak with an m / z value consistent with that of the desired product by LCMS. 1H NMR (500MHz, DMSO-d6) δ 8.61(d,J=7.0Hz,1H), 8.56(d,J=8.0Hz,1H), 7.59(t,J=8.1Hz,1H), 7.53-7.47(m,1H), 7.43-7.31(m,4H), 7.25(d,J=7.9Hz,1H), 7.06(d,J=7.1Hz,1H), 6.07(s,2H), 5.41(d,J=4.6Hz,1H), 4.70-4.61(m,1H), 4.24(s,1H), 2.36(s,3H), 1.80-1.60(m,2H), 1.19(d,J=6.6Hz,3H); 19 F NMR (471MHz, DMSO-d6) δ -122.00 MS ESI m / z 468.2(M+H) +

[0202] Example 21: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 1) [ka]

[0203] 21A: 4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-one (References: Sinha, SC; Duttan, S.; Sun, J. Tetrahedron Lett. 2000, 41, 8243-8246) In an oven-dried round-bottom flask (500 mL), dibutylboron triflate solution (1 M in CHCl, 20.0 mL, 20.0 mmol) and Hunig's base (4.2 mL, 24.0 mmol) in CHCl (100 mL) were combined at 0 °C to give a colorless solution. 1-Fluoropropan-2-one (1.52 g, 20.0 mmol) was added dropwise, resulting in a slight pink color change. After stirring at 0 °C for 1 h, 4-chlorobenzaldehyde (1.41 g, 10.0 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with EtO and slowly quenched with water and excess HO (4 mL each). The layers were separated, and the organic layer was concentrated to a residue. The crude residue was purified by silica gel flash column chromatography (gradient: 100% Hex to 80% EtOAc / Hex), and the product fractions were combined and concentrated to give 4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-one (720 mg, 3.32 mmol, 33% yield) as a colorless oil. 1 H NMR (499MHz, CDCl3) δ 7.40-7.32(m,4H), 5.24(dt,J=9.3, 2.9Hz,1H), 4.90(d,J=2.4Hz,1H), 4.82-4.80(m,1H), 3.00-2.91(m,2H); 19 F NMR (470 MHz, chloroform-d) δ -227.74

[0204] 21B: 3-amino-1-(4-chlorophenyl)-4-fluorobutan-1-ol To a solution of 4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-one (720 mg, 3.32 mmol) in MeOH (10 mL) was added ammonium acetate (1.54 g, 19.9 mmol) and sodium cyanoborohydride (313 mg, 4.99 mmol), and the resulting mixture was stirred at room temperature for 72 h. LCMS showed two distinct peaks with m / z values ​​consistent with the desired product. The volatiles were removed in vacuo, and the resulting residue was partitioned between EtOAc and water, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product: 3-amino-1-(4-chlorophenyl)-4-fluorobutan-1-ol (0.800 g, 3.32 mmol, 100% crude yield) as a light brown oil, which was used directly in the next step. MS ESI m / z 218.1(M+H) +

[0205] 21C: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide A mixture of lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (292 mg, 1.00 mmol), BOP (663 mg, 1.50 mmol), 3-amino-1-(4-chlorophenyl)-4-fluorobutan-1-ol (435 mg, 2.00 mmol), and Hunig's base (0.70 mL, 4.00 mmol) in 4 mL of DMF was stirred at room temperature for 18 hours. LCMS showed two distinct peaks with m / z values ​​consistent with the desired product. The mixture was diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography (120 g silica, gradient: 100% DCM to 10% MeOH / DCM) to give a mixture of two enantiomers of 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide. The less polar elution was the minor isolate 21C-1 (132 mg, 0.272 mmol, 27% yield), which was isolated as a brown oily semisolid. The more polar elution was the major isolate 21C-2 (164 mg, 0.338 mmol, 34% yield), which was isolated as an off-white solid. Both isolates were enantiomeric mixtures and were subjected to further chiral separation. 21C-1: MS ESI m / z 486.3(M+H) + 21C-2: MS ESI m / z 486.3(M+H) +

[0206] 21: Chiral separation of isolate 21C-2 (164 mg, 0.338 mmol) was performed (conditions: preparative SFC pre-separation analysis conditions: instrument: Shimadzu Nexera UC SFC; column: Chiral IC, 4.6 x 150 mm, 5 μ; mobile phase: 60% CO2 / 40% MeOH (containing 0.1% DEA); flow rate: 2 mL / min; detection wavelength: 220 nm; preparative SFC conditions: instrument: Waters 100 Prep SFC; column: Chiral IC, 21 x 250 mm; 5 μ; mobile phase: 60% CO2 / 40% MeOH (containing 0.1% DEA); flow rate: 60 mL / min; detection wavelength: 220 nm; injection conditions: 900 μL (164.2 mg dissolved in MeOH (3 mL))). Fractions containing the first-eluting isomer were combined and dried to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(-4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 1, 21.7 mg, 0.043 mmol, >95% ee, 13% yield). The relative and absolute stereochemistry have not been determined. 1 H NMR (500MHz, DMSO-d6) δ 8.83(d,J=8.2Hz,1H), 8.62(d,J=7.0Hz,1H), 7.61(t,J=8.1Hz,1H), 7.51(s,1H), 7.40(q,J=8.5Hz,4H), 7.24(d,J=7.9Hz,1H), 7.07(d,J=6.9Hz,1H), 6.08(s,2H), 5.52(d,J=4.4Hz,1H), 4.69(q,J=6.5Hz,1H), 4.52(dd,J=9.8, 4.8Hz,1H), 4.49-4.34(m,1H), 4.09(d,J=21.3Hz,1H), 2.34(s,3H), 2.00-1.88(m,1H), 1.84(dt,J=13.5, 6.5Hz,1H); 19 F NMR (471 MHz, DMSO-d6) δ -121.63 (other F disappeared) MS ESI m / z 486.3(M+H) +

[0207] Example 22: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 2) [ka] Chiral SFC purification as described in Example 21 afforded the title compound: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 2, 29.6 mg, 0.060 mmol, >95% ee, 18% yield) as the second eluting isomer. 1 H NMR (500MHz, DMSO-d6) δ 8.82(d,J=8.2Hz,1H), 8.63(d,J=7.0Hz,1H), 7.61(t,J=8.1Hz,1H), 7.51(s,1H), 7.40(q,J=8.4Hz,4H), 7.24(d,J=8.0Hz,1H), 7.06(d,J=7.0Hz,1H), 6.08(s,2H), 5.50(d,J=4.5Hz,1H), 4.69(q,J=6.4Hz,1H), 4.57-4.48(m,1H), 4.49-4.38(m,1H), 4.17-4.02(m,1H), 2.34(s,3H), 2.00-1.89(m,1H), 1.84(dt,J=13.7, 6.6Hz,1H); 19 F NMR (471MHz, DMSO-d6) δ -121.60 MS ESI m / z 486.3(M+H) +

[0208] Example 23: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 3) [ka] Chiral separation of isolate 21C-1 (132 mg, 0.272 mmol) was performed (conditions: preparative SFC pre-separation analysis conditions: instrument: Shimadzu Nexera UC SFC; column: Chiral IC, 4.6 x 150 mm, 5 μ; mobile phase: 65% CO2 / 35% MeOH (containing 0.1% DEA); flow rate: 2 mL / min; detection wavelength: 220 nm; preparative SFC conditions: instrument: Waters 100 Prep SFC; column: Chiral IC, 21 x 250 mm; 5 μ; mobile phase: 65% CO2 / 35% MeOH (containing 0.1% DEA); flow rate: 60 mL / min; detection wavelength: 220 nm; injection conditions: 600 μL (130.2 mg dissolved in MeOH (3 mL))). Fractions containing the first-eluting isomer were combined and dried to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 3, 10.1 mg, 0.020 mmol, >95% ee, 8% yield). Relative and absolute stereochemistry not determined. 1 H NMR (500MHz, DMSO-d6) δ 8.78(d,J=7.4Hz,1H), 8.62(d,J=7.0Hz,1H), 7.61(t,J=8.0Hz,1H), 7.51(s,1H), 7.45-7.33(m,4H), 7.26(d,J=8.0Hz,1H), 7.07(d,J=7.0Hz,1H), 6.07(s,2H), 4.70(s,1H), 4.62-4.32(m,3H), 2.37(s,3H), 1.92(s,1H), 1.76(d,J=8.6Hz,2H); 19 F NMR (471MHz, DMSO-d6) δ -121.69 MS ESI m / z 486.3(M+H) +

[0209] Example 24: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 4) [ka] Chiral SFC purification as described in Example 23 afforded the title compound: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 4 (9.7 mg, 0.020 mmol, >95% ee, 8% yield) as the second eluting isomer. 1 H NMR (500MHz, DMSO-d6) δ 8.78(d,J=7.4Hz,1H), 8.62(d,J=7.1Hz,1H), 7.61(t,J=8.0Hz,1H), 7.51(s,1H), 7.44-7.34(m,4H), 7.26(d,J=8.0Hz,1H), 7.07(d,J=6.9Hz,1H), 6.07(s,2H), 4.70(s,1H), 4.61-4.35(m,3H), 2.37(s,3H), 1.91(s,1H), 1.76(d,J=8.4Hz,2H); 19 F NMR (471MHz, DMSO-d6) δ -121.69 MS ESI m / z 486.3(M+H) +

[0210] Example 25: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide (diastereomer 1) [ka]

[0211] 25A: 1-Fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-one (References: Sinha, SC; Duttan, S.; Sun, J. Tetrahedron Lett. 2000, 41, 8243-8246) In an oven-dried round-bottom flask (500 mL), dibutylboron triflate solution (1 M in CHCl, 20.0 mL, 20.0 mmol) and Hunig's base (4.18 mL, 23.94 mmol) in CHCl (100 mL) were combined to give a colorless solution at 0 °C. 1-Fluoropropan-2-one (1.52 g, 20.0 mmol) was added dropwise, resulting in a slight pink color change. After stirring at 0 °C for 1 h, 4-fluorobenzaldehyde (1.40 mL, 13.3 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with EtO and slowly quenched with water and HO (4 mL each). The layers were separated, and the organic layer was concentrated to a residue. The crude residue was purified by silica gel flash column chromatography (gradient: 100% Hex to 80% EtOAc / Hex). The product fractions were combined and concentrated to give 1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-one (730 mg, 3.65 mmol, 27% yield) as a colorless oil. 1 H NMR(499MHz, CDCl3) δ 7.43-7.30(m,2H), 7.12-6.98(m,2H), 5.21(dd,J=9.3, 3.2Hz,1H), 4.95-4.72(m,2H), 3.00 (ddd,J=17.4, 9.3, 2.4Hz,1H), 2.86 (ddd,J=17.4, 3.3, 2.6Hz,1H)

[0212] 25B: 3-amino-1-(4-fluorophenyl)-4-fluorobutan-1-ol To a solution of 1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-one (730 mg, 3.65 mmol) in MeOH (10 mL) was added ammonium acetate (1.69 g, 21.9 mmol) and sodium cyanoborohydride (344 mg, 5.47 mmol) and stirred at room temperature for 72 h. LCMS showed two distinct peaks with m / z values ​​consistent with the desired product. The volatiles were removed in vacuo, and the resulting residue was partitioned between EtOAc and water, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as a brown oil. The resulting residue was purified by silica gel flash column chromatography (gradient: 100% DCM to 10% MeOH / DCM) to afford a less polar by-product and a more polar (silica TLC Rf: ∼0.2, elution: 10% MeOH / DCM) desired product: 3-amino-1-(4-fluorophenyl)-4-fluorobutan-1-ol (220 mg, 1.10 mmol, 30% yield) as a light brown oil. 1 H NMR(499MHz, CD3OD) δ 7.52-7.38(m,2H), 7.09(td,J=8.8, 6.6Hz,2H), 4.98(dd,J=10.0, 3.6Hz,1H), 4.81-4.51(m,2H), 3.95-3.55(m,1H), 2.10-1.86(m,2H); 19 F NMR (470 MHz, methanol-d4) δ -116.77, -230.27, -231.70; 1 1 H NMR indicated an approximate 3:1 diastereomeric ratio.

[0213] 25C: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide A mixture of lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (120 mg, 0.409 mmol), BOP (271 mg, 0.614 mmol), 3-amino-4-fluoro-1-(4-fluorophenyl)butan-1-ol (82.3 mg, 0.409 mmol), and Hunig's base (0.214 mL, 1.23 mmol) in DMF (1 mL) was stirred at room temperature for 16 h. LCMS showed two distinct peaks with m / z values ​​matching the desired product in an approximately 3:1 ratio. The mixture was diluted with water and EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc. Silica TLC showed two closely spaced but distinct spots (elution: 10% MeOH / DCM). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (24 g silica, gradient: 100% DCM to 8% MeOH / DCM) to afford a mixture of two enantiomers of 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide. The first eluting, less polar minor isolate 25C-01 (21.7 mg, 0.046 mmol, 11% yield) was obtained as an off-white powder. The second eluting, more polar major isolate 25C-02 (66.2 mg, 0.141 mmol, 35% yield) was also obtained as an off-white powder. Both isolates were enantiomeric mixtures and were subjected to further chiral separation. 25C-01: MS ESI m / z 470.3(M+H) + 25C-02: MS ESI m / z 470.4(M+H) +

[0214] 25: Chiral separation of isolate 25C-02 (66.2 mg, 0.141 mmol) was performed (conditions: preparative SFC pre-separation analysis conditions: instrument: Shimadzu Nexera UC SFC; column: Chiral IC, 4.6 x 150 mm, 5 μ; mobile phase: 60% CO2 / 40% MeOH (containing 0.1% DEA); flow rate: 2 mL / min; detection wavelength: 220 nm; preparative SFC conditions: instrument: Waters 100 Prep SFC; column: Chiral IC, 21 x 250 mm; 5 μ; mobile phase: 60% CO2 / 40% MeOH (containing 0.1% DEA); flow rate: 60 mL / min; detection wavelength: 220 nm; injection conditions: 1800 μL (66.2 mg dissolved in MeOH (3 mL))). Fractions containing the first-eluting isomer were combined and dried to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-fluorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 1, 17.9 mg, 0.037 mmol, >95% ee, 26% yield). The relative and absolute stereochemistry have not been determined. 1 H NMR (500MHz, DMSO-d6) δ 8.82(d,J=8.2Hz,1H), 8.63(d,J=7.0Hz,1H), 7.61(t,J=8.0Hz,1H), 7.51(s,1H), 7.45-7.36(m,2H), 7.25(d,J=8.0Hz,1H), 7.18(dd,J=10.0, 7.8Hz,2H), 7.07(dt,J=6.8, 1.7Hz,1H), 6.08(s,2H), 5.45(d,J=4.5Hz,1H), 4.70(q,J=6.5Hz,1H), 4.58-4.47(m,1H), 4.43 (qd,J=9.3, 4.9Hz,1H), 4.10(d,J=21.3Hz,1H), 2.35(s,3H), 1.94(dt,J=14.8, 7.6Hz,1H), 1.84(dt,J=13.4, 6.5Hz,1H); 19 F NMR (471MHz, DMSO-d6) δ -73.42, -115.94, -121.61 MS ESI m / z 470.4(M+H) +

[0215] Example 26: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide (diastereomer 2) [ka] Chiral SFC purification as described in Example 25 afforded the title compound: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide (diastereomer 2, 17.6 mg, 0.037 mmol, 26% yield) as the second eluting isomer. 1 H NMR (500MHz, DMSO-d6) δ 8.84(d,J=8.3Hz,1H), 8.60(d,J=7.1Hz,1H), 7.59(t,J=8.1Hz,1H), 7.50(s,1H), 7.39(dd,J=8.5, 5.6Hz,2H), 7.24(d,J=8.1Hz,1H), 7.17(t,J=8.8Hz,2H), 7.07(d,J=7.0Hz,1H), 6.06(s,2H), 5.52(s,1H), 4.68(t,J=7.1Hz,1H), 4.51 (qd,J=9.4, 4.7Hz,1H), 4.46-4.36(m,1H), 4.08(d,J=21.9Hz,1H), 2.33(s,3H), 1.93(dt,J=14.8, 7.5Hz,1H), 1.83(dt,J=13.4, 6.6Hz,1H); 19 F NMR (471MHz, DMSO-d6) δ -73.42, -115.94, -121.61 MS ESI m / z 470.4(M+H) +

[0216] Example 27: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide (diastereomer 3) [ka] Chiral separation of isolate 25C-01 (21.7 mg, 0.046 mmol) was performed (conditions: preparative SFC pre-separation analysis conditions: instrument: Shimadzu Nexera UC SFC; column: Chiral IC, 4.6 x 150 mm, 5 μ; mobile phase: 65% CO2 / 35% MeOH (containing 0.1% DEA); flow rate: 2 mL / min; detection wavelength: 220 nm; preparative SFC conditions: instrument: Waters 100 Prep SFC; column: Chiral IC, 21 x 250 mm; 5 μ; mobile phase: 65% CO2 / 35% MeOH (containing 0.1% DEA); flow rate: 60 mL / min; detection wavelength: 220 nm; injection conditions: 720 μL (21.6 mg dissolved in MeOH (3 mL))). Fractions containing the first-eluting isomer were combined and dried to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-fluorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide (diastereomer 3, 2.8 mg, 5.96 μmol, >95% ee, 13% yield). Relative and absolute stereochemistry not determined. 1H NMR (500MHz, DMSO-d6) δ 8.79(d,J=7.6Hz,1H), 8.60(d,J=7.0Hz,1H), 7.59(t,J=8.0Hz,1H), 7.50(s,1H), 7.37(dd,J=8.6, 5.6Hz,2H), 7.26(d,J=8.0Hz,1H), 7.14(t,J=8.8Hz,2H), 7.08(d,J=7.0Hz,1H), 6.05(s,2H), 5.54(d,J=4.7Hz,1H), 4.69(d,J=6.6Hz,1H), 4.62-4.33(m,3H), 2.36(s,3H), 1.76(t,J=6.7Hz,2H); 19 F NMR(471MHz, DMSO-d6) δ -73.60, -116.23, -121.81 MS ESI m / z 470.4(M+H) +

[0217] Example 28: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide (diastereomer 4) [ka] Chiral SFC purification as described in Example 27 afforded the title compound: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide (diastereomer 4, 3.1 mg, 6.6 μmol, 13% yield) as the second eluting isomer. 1H NMR (500MHz, DMSO-d6) δ 8.80(d,J=7.7Hz,1H), 8.59(d,J=6.9Hz,1H), 7.59(t,J=8.0Hz,1H), 7.50(s,1H), 7.39-7.34(m,2H), 7.25(d,J=7.9Hz,1H), 7.14(t,J=8.9Hz,2H), 7.11-7.05(m,1H), 6.04(s,2H), 4.75-4.66(m,1H), 4.61-4.33(m,3H), 2.35(s,3H), 1.76(t,J=6.6Hz,2H); 19 F NMR(471MHz, DMSO-d6) δ -73.62, -116.20, -121.84 MS ESI m / z 470.4(M+H) +

[0218] Example 29: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide [ka] 29A: 3-amino-1-(4-chlorophenyl)-2,2-difluoropropan-1-ol (Reference: Org. Lett. 2010, 12, 4648-4651) To a solution of 3-(4-chlorophenyl)-3-oxopropanenitrile (1.08 g, 6.00 mmol) in THF (20 mL), NaH (317 mg, 13.19 mmol) was slowly added and stirred for 2 h. Selectfluor (4.67 g, 13.2 mmol) was added and stirred at room temperature for 20 h. LAH (1 M in THF, 18.0 mL, 18.0 mmol) was slowly added and stirred under a nitrogen atmosphere for 20 h. Saturated aqueous NaSO was added, and the reaction was quenched by the careful dropwise addition of water. The resulting suspension was diluted with EtOAc, stirred, filtered, and the filtrate was washed with a mixture of EtOAc and MeOH. The combined organic solution was concentrated to a brown foam (2.55 g, 5.74 mmol, 96% yield, ~50% purity). This material was used directly in the next step. MS ESI m / z 222.2(M+H) +

[0219] 29: A mixture of lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (29.2 mg, 0.100 mmol), BOP (66.3 mg, 0.150 mmol), 3-amino-1-(4-chlorophenyl)-2,2-difluoropropan-1-ol (33.2 mg, 0.150 mmol) and Hunig's base (0.07 mL, 0.400 mmol) in DMF (0.5 mL) was stirred at room temperature for 3 hours. The mixture was diluted with MeOH, filtered, and the resulting crude filtrate was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 18% B for 0 min, followed by 18–58% B over 20 min, then 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected based on MS signal. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (10.9 mg, 0.021 mmol, 21% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.95(t,J=6.0Hz,1H), 8.62(d,J=7.0Hz,1H), 7.60(t,J=8.1Hz,1H), 7.52-7.43(m,5H), 7.23(d,J=7.9Hz,1H), 7.05(d,J=6.9Hz,1H), 4.95(d,J=16.2Hz,1H), 3.98-3.80(m,2H), 2.56(s,3H); 19 F NMR (471MHz, DMSO-d6) δ -110.63(d,J=245.0 Hz), -116.66(d,J=245.1 Hz), -121.34 MS ESI m / z 490.3(M+H) +

[0220] Example 30: (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (Enantiomer 1) [ka]

[0221] 30A: 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol To a solution of 3-(4-fluorophenyl)-3-oxopropanenitrile (1.34 g, 8.21 mmol) in THF (25 mL), NaH (0.434 g, 18.1 mmol) was slowly added and stirred at room temperature for 1.5 h. Selectfluor (6.40 g, 18.1 mmol) was added and stirred at room temperature for 20 h. LAH (1.0 M, THF, 24.6 mL, 24.6 mmol) was slowly added and stirred under a nitrogen atmosphere for 20 h. Saturated aqueous NaSO was added, and the reaction was quenched by the careful dropwise addition of water. The resulting suspension was diluted with EtOAc, stirred, filtered, and the filtrate was washed with a mixture of EtOAc and MeOH. The combined organic solution was concentrated to give 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol as a colorless oil (1.47 g, 7.14 mmol, 87%). This material was used directly in the next step. MS ESI m / z 206.1(M+H) +

[0222] 30: A mixture of 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoic acid (63.0 mg, 0.22 mmol), BOP (146 mg, 0.330 mmol), 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol (90.0 mg, 0.440 mmol) and Hunig's base (0.15 mL, 0.880 mmol) in DMF (1 mL) was stirred at room temperature for 3 hours. The mixture was diluted with MeOH, filtered, and purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 12% B at 0 min, followed by 12–52% B over 25 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. Fractions containing the desired product were combined and dried using a centrifugal evaporator. The isolate was then subjected to chiral SFC separation (conditions: Preparative SFC pre-separation analysis conditions: Instrument: Shimadzu Nexera UC SFC; Column: Chiral IC, 4.6x150mm, 5μ; Mobile phase: 75% CO2 / 25% MeOH (containing 0.1% DEA); Flow rate: 2mL / min; Detection wavelength: 220nm; Preparative SFC conditions: Instrument: Waters 100 Prep SFC; Column: Chiral IC, 30x250mm; 5μ; Mobile phase: 75% CO2 / 25% MeOH (containing 0.1% DEA); Flow rate: 60mL / min; Detection wavelength: 220nm; Injection conditions: 2500μL (22.5mg dissolved in MeOH / MeCN (6mL))). Fractions containing the first-eluting isomer were combined and dried to give (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (Enantiomer 1, 8.6 mg, 0.018 mmol, >95% ee, 8% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.58 (d, J = 7.0 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.48 (d, J = 8.0 Hz, 3H), 7.22 (q, J = 9.4, 6.8 Hz, 3H), 7.07 (d, J = 7.1 Hz, 1H), 6.54 (d, J = 5.5 Hz, 1H), 6.04 (s, 1H), 4.91 (d, J = 15.5 Hz, 1H), 2.30 (s, 3H) (CH2 and NH2 signals disappeared due to water suppression and were partially suppressed); 19 F NMR (471MHz, DMSO-d6) δ -110.75(d,J=245.4 Hz), -114.23, -116.83(d,J=244.4 Hz), -121.57 MS ESI m / z 474.4(M+H) +

[0223] Example 31: (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (Enantiomer 2) [ka] Chiral SFC purification as described in Example 30 afforded the title compound: (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (enantiomer 2, 8.5 mg, 0.018 mmol, 8% yield) as the second eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (t, J = 6.3 Hz, 1H), 8.60 (d, J = 7.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 3H), 7.23 (dt, J = 12.1, 5.6 Hz, 3H), 7.08 (d, J = 7.0 Hz, 1H), 6.54 (d, J = 5.3 Hz, 1H), 6.06 (s, 2H), 4.93 (dd, J = 16.1, 6.6 Hz, 1H), 2.31 (s, 3H) (CH2 signal disappeared due to solvent suppression); 19 F NMR (471MHz, DMSO-d6) δ -110.75(d,J=245.4 Hz), -114.23, -116.83(d,J=244.4Hz), -121.57 MS ESI m / z 474.4(M+H) +

[0224] Table 2: The compounds in Table 2 were prepared in a similar manner to Examples 11, 12 and 13. [ka] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17]

[0225] Example 63: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(3-fluorophenyl)-3-hydroxypropyl)-6-methylbenzamide (Enantiomer 1) [ka]

[0226] 63A: 3-(3-fluorophenyl)-3-oxopropanenitrile To a solution of methyl 3-fluorobenzoate (1.00 g, 6.50 mmol) in dry toluene (6 mL) was carefully added sodium hydride (60%, dispersion in mineral oil, 0.520 g, 13.0 mmol) under a nitrogen atmosphere at room temperature. The mixture was then heated to 80 °C and treated with the dropwise addition of anhydrous acetonitrile (1.6 mL, 30.9 mmol). After heating overnight, the mixture was cooled to room temperature and diluted with hexane. The solid was isolated by filtration and rinsed with fresh hexane. The solid was dissolved in water (30 mL), and 1 N hydrochloric acid was slowly added to the solution with stirring until a precipitate formed and the pH reached 4–5. The precipitate was isolated by filtration and air-dried. The filtrate was then placed under high vacuum for several hours to give 3-(3-fluorophenyl)-3-oxopropanenitrile (776 mg, 4.76 mmol, 73% yield) as a pale off-white solid. 1 H NMR(500MHz, CDCl3) δ 7.73(d,J=7.6Hz,1H), 7.66(dt,J=9.0, 2.1Hz,1H), 7.55(td,J=8.0, 5.4Hz,1H), 7.40(t,J=8.2Hz,1H), 4.09(s,2H)(no water suppression)

[0227] 63B: 3-amino-1-(3-fluorophenyl)propan-1-ol·TFA salt Under a nitrogen blanket, a solution of 3-(3-fluorophenyl)-3-oxopropanenitrile (300 mg, 1.839 mmol) in anhydrous THF (9.19 mL) was carefully treated with dimethylsulfide borane complex (5 M, diethyl ether, 1.8 mL, 9.19 mmol) and heated at 70 °C for 16 h. Methanol (5 mL) was added dropwise to the mixture, and the solution was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, and the resulting crude mixture was dissolved in MeOH and purified by reverse-phase preparative HPLC (Waters Sunfire C18, 50 x 250 mm, 10 μL, Solvent A = 90% HO, 10% acetonitrile, 0.1% TFA; Solvent B = 90% acetonitrile, 10% HO, 0.1% TFA; 100 mL / min, gradient: 0–100% B over 15 min, followed by 100% B over 4 min). The fractions containing the desired product were combined and concentrated under reduced pressure, and the resulting residue was then placed under high vacuum overnight to afford 3-amino-1-(3-fluorophenyl)propan-1-ol TFA salt (224 mg, 1.32 mmol, 43% yield) as a clear, colorless oil. MS ESI m / z 169.9(M+H) +

[0228] 63: To a solution of 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoic acid·HCl (25 mg, 0.077 mmol) and 3-amino-1-(3-fluorophenyl)propan-1-ol·TFA salt (28.5 mg, 0.101 mmol) in DMF (1 mL) was added BOP (44.5 mg, 0.101 mmol) followed by DIPEA (0.068 mL, 0.387 mmol). The mixture was stirred at room temperature for 2 hours, then filtered and purified by preparative LCMS (conditions: column: XBridge C18, 19x200mm, particle size: 5µm; mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); gradient: 13% B for 0 minutes, followed by 13-53% B over 25 minutes, then 100% B for 4 minutes; flow rate: 20mL / min; column temperature: 25°C). The fractions containing the racemic product were combined and dried to a residue using a centrifugal evaporator. The resulting residue was further purified by SFC chiral chromatography (conditions: column: Chiral OD 30x250 mm, particle size: 5 μm; mobile phase: 65% CO2 / 35% IPA (containing 0.1% DEA); flow rate: 100 mL / min; injection conditions: 1 mL (residue dissolved in MeOH (3 mL)) to separate the enantiomers. The preparative SFC purification gave 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(3-fluorophenyl)-3-hydroxypropyl)-6-methylbenzamide (enantiomer 1, 5.3 mg, 0.0121 mmol, 14.9% yield) as the first-eluting isomer. 1H NMR (500 MHz, DMSO-d₆) δ 8.67-8.58 (m, 2H), 7.61 (br t, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.45-7.32 (m, 1H), 7.27-7.16 (m, 3H), 7.14-6.99 (m, 2H), 6.09 (s, 2H), 5.46 (d, J = 4.7 Hz, 1H), 4.75-4.65 (m, 1H), 2.34 (s, 3H), 1.86 (q, J = 6.7 Hz, 2H) (unsuppressed water); two protons obscured by water peaks. MS ESI m / z 438.3(M+H) +

[0229] Example 64: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(3-fluorophenyl)-3-hydroxypropyl)-6-methylbenzamide (Enantiomer 2) [ka] Chiral SFC purification as described in Example 63 afforded the title compound: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(3-fluorophenyl)-3-hydroxypropyl)-6-methylbenzamide (enantiomer 2, 5.4 mg, 0.0123 mmol, 15.9% yield) as the second eluting isomer. 1 H NMR (500MHz, DMSO-d6) δ 8.61(br d,J=6.9Hz,2H), 7.59(t,J=8.1Hz,1H), 7.50(s,1H), 7.43-7.34(m,1H), 7.27-7.14(m,3H), 7.10-7.01(m,2H), 6.07(s,2H), 5.47(d,J=4.4Hz,1H), 4.74-4.65(m,1H), 2.33(s,3H), 1.85(q,J=6.5Hz,2H) MS ESI m / z 438.3(M+H) +

[0230] Table 3: The compounds in Table 3 were prepared in a similar manner to Examples 63 and 64. Various alkyl benzoates were used in place of methyl 3-fluorobenzoate in the first step. [ka] [Table 18] [Table 19] [Table 20]

[0231] Table 4: The compounds in Table 4 were prepared in a similar manner to Examples 11, 12 and 13, except that ethyl 3-bromo-2-fluoro-6-methylbenzoate in the first step was replaced with ethyl 3-bromo-6-chloro-2-fluorobenzoate. [ka] [Table 21] [Table 22] [Table 23]

[0232] Example 90: (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)benzamide [ka]

[0233] 90A: N,N-bis-Boc-2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine To a suspension of 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (8.00 g, 37.6 mmol) in DCM (80 mL) and MeCN (80 mL), (Boc)2O (21.8 mL, 94.0 mmol) and DMAP (1.84 g, 15.0 mmol) were added and stirred at room temperature for 1.5 h. The mixture was concentrated to one-third volume under reduced pressure and diluted with HO (50 mL). Further removal of the organic solvent under reduced pressure gave a suspension of solid in water. The solid was collected by filtration, washed with water (3 x 25 mL), and dried under vacuum to give N,N-bis-Boc-2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (15.5 g, 37.5 mmol, 100% yield) as a solid. 1 H NMR(400MHz, CDCl3) δ 8.41(d,J=7.3Hz,1H), 7.91(d,J=2.0Hz,1H), 7.17(dd,J=7.3, 2.0Hz,1H), 1.48(s,18H) MS m / z 412.9(M+H) +

[0234] 90B: methyl 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate and methyl 5-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate A mixture of N,N-bis-Boc-2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (500 mg, 1.21 mmol), (4-chloro-3-(methoxycarbonyl)phenyl)boronic acid (259 mg, 1.21 mmol), PdCl(dtbpf) (39.4 mg, 0.060 mmol), and KPO (2 M aqueous solution, 1.82 mL, 3.63 mmol) in 1,4-dioxane (6 mL) was purged with N and then stirred at 100 °C for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel cartridge, elution solvent: 0–50%, followed by 50% EtOAc / Hex). Fractions containing the two desired products were collected and concentrated under reduced pressure to give methyl 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate (262 mg, 0.521 mmol, 43% yield) and methyl 5-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate (173 mg, 0.429 mmol, 36% yield). Methyl 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate: 1 H NMR(500MHz, CDCl3) δ 8.61(d,J=7.2Hz,1H), 8.14(d,J=2.3Hz,1H), 7.89-7.86(m,1H), 7.72(dd,J=8.3, 2.4Hz,1H), 7.62(d,J=8.3Hz,1H), 7.29(dd,J=7.2, 1.9Hz,1H), 4.00(s,3H), 1.49(s,18H) MS ESI m / z 503.3(M+H) + Methyl 5-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate: 1H NMR(500MHz, CDCl3) δ 8.61(d,J=7.0Hz,1H), 8.13(d,J=2.4Hz,1H), 7.75(d,J=1.2Hz,1H), 7.70(dd,J=8.3, 2.4Hz,1H), 7.61(d,J=8.3Hz,1H), 7.18(dd,J=7.1, 2.0Hz,1H), 3.99(s,3H), 1.57(s,9H) MS ESI m / z 403.2(M+H) +

[0235] 90C: Methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate·TFA To a mixture of methyl 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate (262 mg, 0.521 mmol) and methyl 5-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate (173 mg, 0.429 mmol) in DCM (3 mL) was added TFA (1.20 mL, 15.6 mmol), and the solution was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to give crude methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate TFA salt as a solid, which was used directly in the next step without further purification. MS ESI m / z 303.1(M+H) +

[0236] 90D: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate lithium To a solution of crude methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate·TFA (288 mg, 0.951 mmol) in THF (4 mL) and MeOH (2 mL) was added a solution of LiOH·HO (140 mg, 3.33 mmol) in HO (2 mL), and the slurry was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and dried in vacuo to give crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoate as a solid, which was used directly in the next step without further purification. MS ESI m / z 289.1(M+H) +

[0237] 90: A suspension of crude 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chlorobenzoic acid lithium salt (20 mg, 0.068 mmol), (R)-3-amino-1-(4-chlorophenyl)propan-1-ol hydrochloride (15 mg, 0.068 mmol), BOP (36 mg, 0.081 mmol), and DIPEA (0.060 mL, 0.34 mmol) in DMF (1 mL) was stirred at room temperature overnight, and the crude material was purified by preparative LCMS (conditions: Column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile:water (with 0.05% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.05% trifluoroacetic acid); The column was purified using a gradient of 14% B for 0 min, followed by 14–54% B over 20 min, followed by 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25°C. Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried in a centrifugal evaporator to give (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)benzamide (24.5 mg, 0.053 mmol, 79% yield). 1H NMR (500MHz, DMSO-d6) δ 8.61(d,J=7.0Hz,1H), 8.53(t,J=5.3Hz,1H), 7.87(dd,J=8.4, 2.4Hz,1H), 7.82(d,J=2.3Hz,1H), 7.72(d,J=1.0Hz,1H), 7.60(d,J=8.4Hz,1H), 7.39(s,4H), 7.25(dd,J=6.9, 1.8Hz,1H), 4.68(br t,J=6.2Hz,1H), 1.84(q,J=7.3Hz,2H) MS ESI m / z 455.9(M+H) +

[0238] Table 5: The compounds in Table 5 were prepared in a manner similar to Example 90. [ka] [Table 24]

[0239] Example 94: (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3-fluoro-2-methylbenzamide [ka]

[0240] 94A: N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine A mixture of N,N-bis-Boc-2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (10.0 g, 24.2 mmol), bis(pinacolato)diboron (7.37 g, 29.0 mmol), potassium acetate (7.12 g, 72.6 mmol), and PdCl(dppf) CHCl adduct (0.988 g, 1.21 mmol) in 1,4-dioxane (100 mL) was purged with N, stirred at 100 °C for 1 h, and then concentrated under reduced pressure. The resulting residue was diluted with EtOAc (400 mL) and filtered. The filtrate was washed with HO (100 mL), followed by brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was triturated with ether / Hex (10 mL / 90 mL). The resulting solid was collected by filtration, rinsed with hexanes (2 x 10 mL), and dried under vacuum to give N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (10.93 g, 23.7 mmol, 98% yield) as a solid. 1 H NMR(500MHz, CDCl3) δ 8.51(dd,J=6.8, 1.0Hz,1H), 8.16(s,1H), 7.37(dd,J=6.8, 1.1Hz,1H), 1.45(s,18H), 1.38(s,12H) MS ESI m / z 379.4(M+H) + (as boronic acid)

[0241] 94B: methyl 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate and methyl 5-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate A mixture of N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (279 mg, 0.607 mmol), methyl 5-bromo-3-fluoro-2-methylbenzoate (150 mg, 0.61 mmol), PdCl(dtbpf) (19.8 mg, 0.030 mmol), and KPO (2 M aqueous solution, 0.91 mL, 1.82 mmol) in 1,4-dioxane (3 mL) was purged with N and stirred for 30 min at 100° C. The reaction mixture was diluted with EtOAc (20 mL), filtered, and the filtrate was washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel cartridge, elution solvent: 0-50%, followed by 50% EtOAc / Hex). Fractions containing the desired product were collected and concentrated under reduced pressure to give methyl 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate (183 mg, 0.366 mmol, 60.2% yield) and methyl 5-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate (73.0 mg, 0.182 mmol, 30% yield). Methyl 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate: 1 H NMR(500MHz, CDCl3) δ 8.60(dd,J=7.2, 0.7Hz,1H), 8.01(s,1H), 7.88(d,J=1.0Hz,1H), 7.50(dd,J=10.1, 1.6Hz,1H), 7.29(dd,J=7.2, 1.9Hz,1H), 3.97(s,3H), 2.57(d,J=1.9Hz,3H), 1.49(s,18H) MS ESI m / z 501.4(M+H) + Methyl 5-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate:1 H NMR(500MHz, CDCl3) δ 8.62(d,J=7.2Hz,1H), 8.52(s,1H), 8.00(s,1H), 7.77(d,J=1.0Hz,1H), 7.48(dd,J=10.1, 1.7Hz,1H), 7.19(dd,J=7.1, 1.8Hz,1H), 3.96(s,3H), 2.57(d,J=1.9Hz,3H), 1.57(s,9H) MS ESI m / z 401.3(M+H) +

[0242] 94C: Methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate·TFA To a mixture of methyl 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate (183 mg, 0.366 mmol) and methyl 5-(N-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate (73.0 mg, 0.182 mmol) in DCM (2 mL) was added TFA (0.85 mL, 11.0 mmol), and the solution was stirred at room temperature for 2.5 h. The mixture was concentrated under reduced pressure to give crude methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate·TFA as a solid, which was used directly in the next step without further purification. MS ESI m / z 301.2(M+H) +

[0243] 94D: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoic acid lithium salt To a solution of crude methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate·TFA (165 mg, 0.549 mmol) in THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH·HO (81 mg, 1.92 mmol) in HO (1.5 mL), and the resulting slurry was stirred at 50 °C for 1 h. The mixture was concentrated under reduced pressure and dried in vacuo to give crude 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoic acid·lithium salt as a solid, which was used directly in the next step without further purification. MS ESI m / z 287.1(M+H) +

[0244] 94: A suspension of crude 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoic acid lithium salt (20 mg, 0.068 mmol), (R)-3-amino-1-(4-chlorophenyl)propan-1-ol hydrochloride (15.2 mg, 0.068 mmol), BOP (36 mg, 0.082 mmol), and DIPEA (0.060 mL, 0.341 mmol) in DMF (1 mL) was stirred at room temperature for 1 hour. This crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 16% B at 0 min, followed by 16–56% B in 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected based on MS signal. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3-fluoro-2-methylbenzamide (10.2 mg, 0.022 mmol, 33% yield). 1H NMR (500MHz, DMSO-d6) δ 8.59(d,J=7.0Hz,1H), 8.46(br t,J=5.2Hz,1H), 7.76-7.71(m,2H), 7.57(s,1H), 7.38(s,4H), 7.30-7.23(m,1H), 6.05(s,2H), 4.70-4.63(m,1H), 2.27(s,3H), 1.85(q,J=6.8Hz,2H) MS ESI m / z 454.0(M+H) +

[0245] Table 6: The compounds in Table 6 were prepared in a manner similar to Example 94. [ka] [Table 25]

[0246] Example 97: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide (Enantiomer 1) [ka]

[0247] 97A: 4-Fluoro-5-iodo-2-methylbenzoic acid To a mixture of 4-fluoro-2-methylbenzoic acid (5.00 g, 32.4 mmol) in AcOH (40 mL), I2 (9.06 g, 35.7 mmol), sodium periodate (3.47 g, 16.2 mmol), and sulfuric acid (0.259 mL, 4.87 mmol) were added and stirred at 110–120 °C for 6 h. Further I2 (4.00 g, 15.8 mmol) was added and stirred at 120 °C for 4 h. LCMS indicated that the addition of I2 did not accelerate the reaction. The mixture was poured into ice-cold water with stirring, and aqueous Na2S2O3 was added until the color became pale yellow. The resulting solid was isolated by filtration and then dissolved in EtOAc. The organic layer was washed with aqueous Na2S2O3, followed by water, and then concentrated under reduced pressure. The resulting residue was recrystallized from IPA / water (approximately 10:1) with cooling. The solid was isolated by filtration to give a solid (2.2 g), which, as determined by LCMS, contained a significant amount of unreacted starting material: 4-fluoro-2-methylbenzoic acid. The solid was removed, and the recrystallization mother liquor was concentrated under reduced pressure to give impure 4-fluoro-5-iodo-2-methylbenzoic acid (3.50 g, 12.5 mmol, 39% yield, ∼50% purity). The crude material was used directly in the next step without further purification or characterization.

[0248] 97B: 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid A mixture of N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.543 mmol), 4-fluoro-5-iodo-2-methylbenzoic acid (319 mg, 1.14 mmol, approximately 50% pure), PdCl(dtbpf) (17.7 mg, 0.0270 mmol), and aqueous KPO (2 M, 1.09 mL, 2.17 mmol) in 1,4-dioxane (2 mL) was degassed by bubbling nitrogen into a sealed pressure-resistant vial. The mixture was stirred at 80 °C for 1 h and then cooled to room temperature. LCMS of this mixture showed the desired bis-Boc product (M+H=486.2), but also the mono-Boc product (M+H=387.2) as the major product. The reaction mixture was diluted with EtOAc and water, and the off-white precipitate was isolated by filtration and rinsed with water and EtOAc. LCMS of the isolated gray solid showed an m / z consistent with the mono-Boc product (98.5 mg, 0.255 mmol, 47% yield). This was removed as isolate 1, and the organic filtrate was concentrated under reduced pressure to isolate 2. LCMS of isolate 2 showed an m / z consistent with the desired product: 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid (97 mg, 0.20 mmol, 37% yield), slightly contaminated with the above mono-Boc product. Isolate 2 was used directly in the next step. MS ESI m / z 387.2, 486.2 (M+H) +

[0249] 97C: 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide A mixture of 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-methylbenzoic acid (0.097 g, 0.20 mmol), BOP (0.133 g, 0.300 mmol), 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol (0.082 g, 0.40 mmol) and Hunig's base (0.140 mL, 0.800 mmol) in DMF (1 mL) was stirred at room temperature for 24 hours, diluted with EtOAc and water, vortexed and the layers separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed twice with water, then with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide (135 mg, 0.20 mmol, 100% crude yield) as a brown oil, which was used directly in the next reaction without further purification. MS ESI m / z 674.5(M+H) +

[0250] 97: To a solution of 5-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide (135 mg, 0.200 mmol) in CHCl (1 mL) was added TFA (0.60 mL, 7.8 mmol) and stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure, and the resulting residue was dissolved in MeOH and purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 12% B at 0 min, followed by 12–52% B over 25 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried in a centrifugal evaporator, and the isolated racemate was further subjected to SFC chiral separation (conditions: Preparative SFC pre-separation analysis conditions: Instrument: Shimadzu Nexera UC SFC; Column: Chiral IC, 4.6x150mm, 5μ; Mobile phase: 60% CO2 / 40% MeOH (containing 0.1% DEA); Flow rate: 2mL / min; Detection wavelength: 220nm; Preparative SFC conditions: Instrument: Waters 100 Prep SFC; Column: Chiral IC, 21x250mm, 5μ; Mobile phase: 60% CO2 / 40% MeOH (containing 0.1% DEA); Flow rate: 60mL / min; Detection wavelength: 220nm; Injection conditions: 1500μL (10.6mg dissolved in MeOH (3mL))). Fractions containing the first-eluting isomer were combined and dried to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (Enantiomer 1, 2.2 mg, 4.43 μmol, >95% ee, 2% yield). Absolute stereochemistry not determined. 1H NMR (500MHz, DMSO-d6) δ 8.72(t,J=6.1Hz,1H), 8.64(d,J=7.0Hz,1H), 7.66-7.57(m,2H), 7.52(dd,J=8.3, 5.5Hz,2H), 7.31(d,J=12.0Hz,1H), 7.22(t,J=8.7Hz,2H), 7.11(d,J=7.1Hz,1H), 6.44(d,J=5.3Hz,1H), 6.09(s,2H), 5.04-4.88(m,1H), 3.98-3.75(m,2H), 2.42(s,3H); 19 F NMR (471MHz, DMSO-d6) δ -110.25(d,J=245.5Hz), -114.46, -115.49~-116.84(m) MS ESI m / z 474.4(M+H) +

[0251] Example 98: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide (Enantiomer 2) [ka] Chiral SFC purification as described in Example 97 afforded the title compound: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide (enantiomer 2, 3.4 mg, 7.0 μmol, 4% yield) as the second eluting isomer. 1H NMR (500MHz, DMSO-d6) δ 8.71(t,J=5.7Hz,1H), 8.63(d,J=7.0Hz,1H), 7.65-7.57(m,2H), 7.56-7.48(m,2H), 7.31(d,J=11.8Hz,1H), 7.22(t,J=8.7Hz,2H), 7.11(d,J=6.9Hz,1H), 6.45(d,J=5.2Hz,1H), 6.08(s,2H), 4.95(d,J=14.9Hz,1H), 3.97-3.75(m,2H), 2.41(s,3H); 19 F NMR (471MHz, DMSO-d6) δ -110.25(d,J=245.5Hz), -114.46, -115.49~-116.84(m) MS ESI m / z 474.4(M+H) +

[0252] Example 99: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide [ka]

[0253] 99A: 5-Bromo-3,4-difluoro-2-methylbenzoic acid 3,4-Difluoro-2-methylbenzoic acid (1.72 g, 9.99 mmol) was dissolved in concentrated sulfuric acid (7.0 mL, 131 mmol) and cooled in an ice-water bath. 1,3-Dibromo-5,5-dimethylhydantoin (1.43 g, 5.00 mmol) was slowly added and stirred at 0-10 °C for 30 minutes, resulting in the formation of a large amount of precipitate. Ice was added to the mixture, and the off-white solid was isolated by filtration, rinsed with water, and then air-dried overnight to give crude 5-bromo-3,4-difluoro-2-methylbenzoic acid (3.0 g, 11.9 mmol, 120% yield). This material was used directly in the next step. MS ESI m / z 251.1(M+H) +

[0254] 99B: 5-bromo-3,4-difluoro-2-methylbenzoic acid methyl ester To a solution of crude 5-bromo-3,4-difluoro-2-methylbenzoic acid (3.0 g, 11.9 mmol) in DMF (15 mL) was added potassium carbonate (2.76 g, 20.0 mmol), followed by iodomethane (1.6 mL, 25.0 mmol) and stirred at room temperature for 2 h. EtOAc (50 mL) was added, and the mixture was washed with water and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (40 g silica, gradient: 100% hexane to 5% EtOAc / Hex). Fractions containing pure product were combined and concentrated to give methyl 5-bromo-3,4-difluoro-2-methylbenzoate (560 mg, 2.11 mmol, 18% yield). 1 H NMR (499 MHz, chloroform-d) δ 8.06-7.85 (m, 1H), 3.93 (s, 3H), 2.53 (d, J = 2.9 Hz, 3H)

[0255] 99C: 3,4-difluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester To a mixture of methyl 5-bromo-3,4-difluoro-2-methylbenzoate (0.530 g, 2.00 mmol) in dioxane (10 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.609 g, 2.40 mmol), PdCl(dppf) CHCl adduct (0.114 g, 0.140 mmol), and potassium acetate (0.491 g, 5.00 mmol) were added. The mixture was sparged with N and then stirred at 115 °C for 4 h. To the crude reaction mixture containing methyl 3,4-difluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (624 mg, 2.00 mmol), 1,4-dioxane (11 mL), 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (426 mg, 2.00 mmol), PdCl(dppf) CHCl adduct (65.3 mg, 0.080 mmol), and aqueous KPO (2 M, 2.50 mL, 5.00 mmol) were added. The mixture was sparged with N gas for 5 min and then stirred at 115 °C for 5 h. This was diluted with EtOAc and water, and the precipitated solid was isolated by filtration and washed with water and EtOAc to give crude methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoate (390 mg) as isolate 1. This was removed, the filtrate layer separated, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (gradient: 100% DCM to 10% MeOH / DCM) to further give methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoate (110 mg) as a dark solid, isolate 2. Isolates 1 and 2 were combined to give the desired methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoate (500 mg total, 1.57 mmol, 79% yield). MS ESI m / z 319.1(M+H) +

[0256] 99D: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoic acid To a mixture of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoate (500 mg, 1.57 mmol) in THF (4 mL) was added aqueous LiOH (2 M, 3.20 mL, 6.40 mmol) and MeOH (4 mL) and stirred at room temperature for 18 hours. The reaction mixture was filtered, and the filtered solid was rinsed with water and EtOAc to give a dark solid (143 mg) as isolate 1. This was removed, and the filtrate was neutralized with HCl (1N, 4 mL) to form a precipitate. The resulting gray solid was isolated by filtration and rinsed with water and EtOAc to give isolate 2 (267 mg). The filtrate layers were separated, and the organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give isolate 3 (36 mg) as a tan solid. Isolates 1, 2, and 3 were combined to give crude 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoic acid (446 mg, 1.46 mmol, 93% yield), which was used directly in the next step. MS ESI m / z 304.9(M+H) +

[0257] 99: A mixture of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoic acid (30 mg, 0.099 mmol), BOP (65.4 mg, 0.148 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol hydrochloride (26.3 mg, 0.118 mmol) and Hunig's base (0.086 mL, 0.49 mmol) in DMF (0.5 mL) was stirred at room temperature overnight. The mixture was diluted with MeOH, and the resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 17% B at 0 min, followed by 17–57% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (8.7 mg, 0.018 mmol, 19% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.65(d,J=7.0Hz,1H), 8.47(t,J=5.5Hz,1H), 7.62(s,1H), 7.42(d,J=6.8Hz,1H), 7.38(s,4H), 7.13(d,J=7.0Hz,1H), 6.11(s,2H), 5.43(d,J=4.6Hz,1H), 4.66(q,J=6.0Hz,1H), 3.43-3.26(m,2H), 2.35(d,J=2.3Hz,3H), 1.86(q,J=7.0Hz,2H); 19 F NMR (471MHz, DMSO-d6) δ -140.05, -141.17 MS ESI m / z 472.4(M+H) +

[0258] Example 100: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide (racemic 1) [ka] A mixture of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoic acid (30.4 mg, 0.100 mmol), BOP (66.3 mg, 0.150 mmol), 3-amino-1-(4-chlorophenyl)butan-1-ol (19B, 23.9 mg, 0.120 mmol), and Hunig's base (0.070 mL, 0.40 mmol) in DMF (0.5 mL) was stirred at room temperature for 5 h, diluted with MeOH, filtered, and the resulting crude product was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); The column was purified using a gradient of 17% B at 0 min, followed by 17–55% B over 28 min, followed by 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected based on MS signal. Fractions containing the first eluting peak, whose m / z value matched that of the desired product in LCMS, were combined and dried in a centrifugal evaporator to give 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide (racemic 1, 5.4 mg, 10.9 μmol, 11% yield). The absolute stereochemistry has not been determined. 1H NMR (500MHz, DMSO-d6) δ 8.66(d,J=6.9Hz,1H), 8.34(d,J=8.3Hz,1H), 7.63(s,1H), 7.38(d,J=1.6Hz,5H), 7.13(d,J=7.0Hz,1H), 6.12(s,2H), 5.37(d,J=4.5Hz,1H), 4.64(q,J=5.9Hz,1H), 4.02(dt,J=16.2, 8.0Hz,1H), 2.36(d,J=2.2Hz,3H), 1.96 (dq, J=15.5, 7.8Hz,1H), 1.68(dt,J=13.0, 6.4Hz,1H), 1.18(d,J=6.6Hz,3H); 19 F NMR (471MHz, DMSO-d6) δ -140.19(d,J=21.8Hz), -141.36(d,J=21.8Hz) MS ESI m / z 486.2(M+H) +

[0259] Example 101: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide (racemic mixture 2) [ka] Preparative HPLC purification as described in Example 100 afforded the title compound: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide (racemic 2, 3.9 mg, 7.6 μmol, 8% yield) as the second eluting peak with an m / z value consistent with the desired product by LCMS. 1H NMR (500MHz, DMSO-d6) δ 8.67(d,J=6.9Hz,1H), 8.36(d,J=8.0Hz,1H), 7.63(s,1H), 7.37(d,J=1.5Hz,4H), 7.13(d,J=7.0Hz,1H), 6.12(s,2H), 4.70-4.61(m,1H), 4.23-4.07(m,1H), 2.37(d,J=2.3Hz,3H), 1.86-1.78(m,1H), 1.76-1.68(m,1H), 1.20(d,J=6.6Hz,3H); 19 F NMR (471MHz, DMSO-d6) δ -140.09(d,J=21.0Hz), -141.35(d,J=21.1Hz) MS ESI m / z 486.2(M+H) +

[0260] Example 102: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide (racemic 1) [ka] A mixture of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoic acid (30.4 mg, 0.100 mmol), BOP (66.3 mg, 0.150 mmol), 3-amino-1-(4-chlorophenyl)-4-fluorobutan-1-ol (21B, 43.5 mg, 0.200 mmol), and Hunig's base (0.070 mL, 0.400 mmol) in DMF (0.5 mL) was stirred at room temperature for 4 h, diluted with MeOH, filtered, and the resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 Purification was performed using acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: 12% B at 0 min, followed by 12–52% B over 23 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected based on MS signal. Fractions containing the first eluting peak, whose m / z value matched that of the desired product in LCMS, were combined and dried in a centrifugal evaporator to give 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide (racemic 1, 1.1 mg, 2.2 μmol, 2% yield). Absolute stereochemistry has not been determined. 1 H NMR (500MHz, DMSO-d6) δ 8.67(d,J=7.0Hz,1H), 8.57(d,J=8.4Hz,1H), 7.64(s,1H), 7.41-7.31(m,5H), 7.13(d,J=7.0Hz,1H), 6.12(s,2H), 4.72(t,J=6.7Hz,1H), 4.48(dd,J=47.4, 4.9Hz,2H), 4.19(d,J=13.8Hz,1H), 2.36(d,J=2.2Hz,3H), 1.98(dt,J=14.7, 7.5Hz,1H), 1.89(dt,J=13.5, 6.0Hz,1H); 19F NMR(471MHz, DMSO-d6) δ -73.45, -140.02, -140.92 MS ESI m / z 504.3(M+H) +

[0261] Example 103: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide (racemic mixture 2) [ka] Preparative HPLC purification as described in Example 102 afforded the title compound: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide (racemic 2, 1.4 mg, 2.73 μmol, 3% yield) as the second eluting peak with an m / z value consistent with that of the desired product by LCMS. 1 H NMR (500MHz, DMSO-d6) δ 8.67(d,J=6.9Hz,1H), 8.57(d,J=8.4Hz,1H), 7.64(s,1H), 7.38(d,J=2.3Hz,4H), 7.33(d,J=6.8Hz,1H), 7.13(d,J=7.0Hz,1H), 6.12(s,2H), 4.72(dt,J=8.1, 4.6Hz,1H), 4.53(d,J=4.9Hz,1H), 4.43(d,J=4.8Hz,1H), 4.28-4.11(m,1H), 2.36(d,J=2.2Hz,3H), 1.97(q,J=7.2Hz,1H), 1.94-1.85(m,1H); 19 F NMR(471MHz, DMSO-d6) δ -73.44, -140.07, -140.99 MS ESI m / z 504.3(M+H) +

[0262] Example 104: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (Enantiomer 1) [ka] A mixture of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoic acid (45.6 mg, 0.150 mmol), BOP (100 mg, 0.225 mmol), 3-amino-1-(4-chlorophenyl)-2,2-difluoropropan-1-ol (29A, 49.9 mg, 0.225 mmol), and Hunig's base (0.105 mL, 0.600 mmol) in DMF (0.8 mL) was stirred at room temperature for 18 h, diluted with MeOH, filtered, and the resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: Purification was performed using a 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: 19% B at 0 min, followed by 19–59% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C. Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried in a centrifugal evaporator, and the resulting racemate was then subjected to chiral SFC separation (conditions: preparative SFC pre-separation analysis conditions: instrument: Shimadzu Nexera UC SFC; column: Chiral IC, 4.6x150mm, 5μ; mobile phase: 55% CO2 / 45% MeOH (containing 0.1% DEA); flow rate: 2mL / min; detection wavelength: 220nm; preparative SFC conditions: instrument: Waters 100 Prep SFC; column: Chiral IC, 21x250mm; 5μ; mobile phase: 55% CO2 / 45% MeOH (containing 0.1% DEA); flow rate: 60mL / min; detection wavelength: 220nm; injection conditions: 1500μL (7.4mg dissolved in MeOH (3mL))). Fractions containing the first-eluting isomer were combined and dried to give 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (Enantiomer 1, 1.4 mg, 2.8 μmol, >95% ee, 2% yield).The absolute stereochemistry has not been determined. 1 H NMR (500MHz, DMSO-d6) δ 8.80(t,J=6.3Hz,1H), 8.67(d,J=6.9Hz,1H), 7.64(s,1H), 7.55-7.43(m,4H), 7.13(d,J=7.0Hz,1H), 6.48(d,J=5.3Hz,1H), 6.12(s,2H), 5.02-4.91(m,1H), 3.91-3.79(m,2H), 2.35(s,3H); 19 F NMR (471MHz, DMSO-d6) δ -109.98(d,J=246.9Hz), -115.93(d,J=246.2Hz), -139.87(d,J=22.3Hz), -140.66(d,J=20.8Hz) MS ESI m / z 508.2(M+H) +

[0263] Example 105: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (Enantiomer 2) [ka] Chiral SFC purification as described in Example 104 gave the title compound: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (enantiomer 2, 1.7 mg, 3.1 μmol, 2% yield) as the second eluting isomer. 1H NMR (500MHz, DMSO-d6) δ 8.81(t,J=6.0Hz,1H), 8.66(d,J=7.1Hz,1H), 7.63(s,1H), 7.50(d,J=8.4Hz,2H), 7.46(d,J=8.1Hz,2H), 7.13(d,J=7.0Hz,1H), 6.51(d,J=5.5Hz,1H), 6.12(s,1H), 5.03-4.92(m,1H), 3.86(td,J=16.3, 13.5, 8.9Hz,2H), 2.35(d,J=2.2Hz,3H); 19 F NMR (471MHz, DMSO-d6) δ -109.98(d,J=246.9Hz), -115.93(d,J=246.2Hz), -139.87(d,J=22.3Hz), -140.66(d,J=20.8Hz) MS ESI m / z 508.2(M+H) +

[0264] Example 106: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (Enantiomer 1) [ka] A mixture of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,4-difluoro-2-methylbenzoic acid (45.6 mg, 0.150 mmol), BOP (100 mg, 0.225 mmol), 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol (30A, 61.6 mg, 0.300 mmol), and Hunig's base (0.105 mL, 0.600 mmol) in DMF (0.8 mL) was stirred at room temperature for 18 h, diluted with MeOH, filtered, and the resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: Purification was performed using a 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: 15% B at 0 min, followed by 15–55% B over 25 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C. Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried in a centrifugal evaporator, and the resulting racemate was then subjected to SFC chiral separation (conditions: preparative SFC pre-separation analysis conditions: instrument: Shimadzu Nexera UC SFC; column: Chiral IC, 4.6x150mm, 5μ; mobile phase: 55% CO2 / 45% MeOH (containing 0.1% DEA); flow rate: 2mL / min; detection wavelength: 220nm; preparative SFC conditions: instrument: Waters 100 Prep SFC; column: Chiral IC, 21x250mm; 5μ; mobile phase: 55% CO2 / 45% MeOH (containing 0.1% DEA); flow rate: 60mL / min; detection wavelength: 220nm; injection conditions: 3000μL (39.2mg dissolved in MeOH / MeCN (6mL))).Fractions containing the first-eluting isomer were combined and dried to give 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (Enantiomer 1, 10 mg, 0.020 mmol, >95% ee, 13% yield). Absolute stereochemistry not determined. 1 H NMR (500MHz, DMSO-d6) δ 8.81(t,J=6.3Hz,1H), 8.65(d,J=7.0Hz,1H), 7.63(s,1H), 7.51(dd,J=8.6, 5.6Hz,2H), 7.45(d,J=6.7Hz,1H), 7.21(t,J=8.7Hz,2H), 7.13(d,J=7.0Hz,1H), 6.46(d,J=5.3Hz,1H), 6.11(s,2H), 5.01-4.89(m,1H), 3.92-3.79(m,2H), 2.34(d,J=2.4Hz,3H); 19 F NMR (471MHz, DMSO-d6) δ 110.21(d,J=245.7Hz), -114.42, -116.11(d,J=245.6Hz), -139.86(d,J=21.3Hz), -140.68(d,J=21.1Hz) MS ESI m / z 492.2(M+H) +

[0265] Example 107: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (Enantiomer 2) [ka] Chiral SFC purification as described in Example 106 gave the title compound: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide (enantiomer 2, 12 mg, 0.024 mmol, 16% yield) as the second eluting isomer. 1 H NMR (500MHz, DMSO-d6) δ 8.81(t,J=6.2Hz,1H), 8.66(d,J=6.9Hz,1H), 7.63(s,1H), 7.51(dd,J=8.5, 5.6Hz,2H), 7.45(d,J=6.7Hz,1H), 7.21(t,J=8.7Hz,2H), 7.13(d,J=7.0Hz,1H), 6.45(d,J=5.2Hz,1H), 6.11(s,2H), 4.99-4.90(m,1H), 3.91-3.79(m,2H), 2.34(d,J=2.1Hz,3H); 19 F NMR (471MHz, DMSO-d6) δ -110.21(d,J=245.7Hz), -114.42, -116.11(d,J=245.6Hz), -139.86(d,J=21.3Hz), -140.68(d,J=21.1Hz) MS ESI m / z 492.2(M+H) +

[0266] Example 108: (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (Enantiomer 1) [ka] A mixture of 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluorobenzoic acid (67.5 mg, 0.220 mmol), BOP (146 mg, 0.330 mmol), 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol (30A, 90 mg, 0.44 mmol), and Hunig's base (0.154 mL, 0.880 mmol) in DMF (1 mL) was stirred at room temperature for 24 hours, and the resulting crude material was purified by preparative LCMS (conditions: Column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); Gradient: The column was purified using a flow rate of 20 mL / min (elution with 12% B for 0 min, followed by 12–52% B over 25 min, followed by 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. Fractions containing the desired product were combined and dried in a centrifugal evaporator to give racemic 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide. This racemate was then subjected to SFC chiral separation (conditions: Preparative SFC pre-separation analysis conditions: Instrument: Shimadzu Nexera UC SFC; Column: Chiral IC, 4.6x150mm, 5μ; Mobile phase: 75%CO2 / 25%MeOH (containing 0.1%DEA); Flow rate: 2mL / min; Detection wavelength: 220nm; Preparative SFC conditions: Instrument: Waters 100 Prep SFC; Column: Chiral IC, 30x250mm; 5μ; Mobile phase: 75%CO2 / 25%MeOH (containing 0.1%DEA); Flow rate: 60mL / min; Detection wavelength: 220nm; Injection conditions: 3000μL (21.2mg dissolved in MeOH / MeCN (6mL))).Fractions containing the first eluting isomer were combined and dried to give (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (8.3 mg, 0.016 mmol, >95% ee, 7% yield). 1 H NMR (500MHz, DMSO-d6) δ 9.16(t,J=6.4Hz,1H), 8.65(d,J=7.0Hz,1H), 7.76(t,J=8.3Hz,1H), 7.57-7.44(m,4H), 7.24(t,J=8.6Hz,2H), 7.06(d,J=7.1Hz,1H), 6.12(s,2H), 5.02-4.86(m,1H), 3.98-3.77(m,2H); 19 F NMR (471MHz, DMSO-d6) δ -110.76(d,J=245.4Hz), -114.36, -116.81(d,J=245.0Hz), -117.27 MS ESI m / z 494.3(M+H) +

[0267] Example 109: (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (enantiomer 2) [ka] Chiral SFC purification as described in Example 108 afforded the title compound: (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (enantiomer 2, 7.7 mg, 0.015 mmol, 7% yield) as the second eluting isomer. 1H NMR (500MHz, DMSO-d6) δ 9.15(t,J=6.2Hz,1H), 8.64(d,J=6.9Hz,1H), 7.75(t,J=8.4Hz,1H), 7.57-7.44(m,4H), 7.23(t,J=8.7Hz,2H), 7.06(d,J=7.0Hz,1H), 6.45(d,J=5.4Hz,1H), 6.12(s,2H), 4.95(d,J=16.0Hz,1H), 4.01-3.76(m,2H); 19 F NMR (471MHz, DMSO-d6) δ -110.76(d,J=245.4Hz), -114.36, -116.81(d,J=245.0Hz), -117.27 MS ESI m / z 494.3(M+H) +

[0268] Example 110: 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-6-chloro-N-[3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl]-2-fluorobenzamide [ka] 110A: Ethyl 3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropanoate In a sealed glass pressure vessel (40 mL), 3,4-dichlorobenzaldehyde (1.00 g, 5.71 mmol), THF (15 mL), and zinc (0.478 g, 7.31 mmol) were added and heated at 85 °C for 30 min, followed by the addition of ethyl bromodifluoroacetate (1.28 mL, 9.75 mmol) in portions over 10 min. The mixture was heated at 85 °C overnight, cooled to room temperature, and filtered through Celite. The filtrate was acidified by the dropwise addition of 1N hydrochloric acid with stirring. The acidified filtrate was diluted with EtOAc (30 mL), and the organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to an orange oil. The resulting residue was subjected to flash column chromatography (24 g silica column, elution gradient: 0–40% EtOAc / Hex). The pure fractions were concentrated to give ethyl 3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropanoate (1.30 g, 4.40 mmol, 76% yield) as an off-white solid. 1 H NMR(400MHz, CDCl3) δ 7.59(d,J=1.8Hz,1H), 7.50(d,J=8.2Hz,1H), 7.31(d,J=8.1Hz,1H), 5.21-5.14(m,1H), 4.45-4.32(m,2H), 2.80(d,J=5.1Hz,1H), 1.43-1.21(m,3H)

[0269] 110B: tert-butyl (3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl)carbamate To a solution of ethyl 3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropanoate (1.20 g, 4.01 mmol) in MeOH (6 mL), ammonia (7 M, MeOH solution, 6.0 mL, 42 mmol) was added and stirred at room temperature for 20 hours. The solvent was concentrated to give crude 3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropanamide. A round-bottom flask (50 mL) was charged with 3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropanamide (600 mg, 2.22 mmol) and THF (6 mL). Dimethylsulfide borane complex (2.0 M, THF solution, 4.4 mL, 8.89 mmol) was added portionwise over 5 minutes at room temperature and stirred at 60 °C for 2 hours. The mixture was then cooled to room temperature, and methanol (5 mL) was added slowly, dropwise, to quench the reaction. The mixture was stirred for 30 minutes, and the solvent was removed under reduced pressure to give a clear, thick, colorless oil. The oily residue was dissolved in 1 M hydrochloric acid (10 mL) and heated at 60 °C for 1 hour. The suspension mixture became clear by the end of heating. The mixture was concentrated under reduced pressure to give crude 3-amino-1-(3,4-dichlorophenyl)-2,2-difluoropropan-1-ol as a white solid. The resulting crude 3-amino-1-(3,4-dichlorophenyl)-2,2-difluoropropan-1-ol was then mixed with THF (10 mL) and triethylamine (0.97 mL, 6.7 mmol), and di-tert-butyl dicarbonate (0.61 mL, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give a thick oil. The resulting residue was subjected to flash column chromatography (24 g silica gel column, elution solvent gradient: 0–20% EtOAc / Hex). Pure fractions were concentrated to give tert-butyl (3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl)carbamate (600 mg, 1.68 mmol, 76% yield) as a white solid.

[0270] 110: tert-Butyl (3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl)carbamate (34.8 mg, 0.098 mmol) was dissolved in DCM (1 mL) and TFA (0.2 mL) and stirred at room temperature for 2 hours. The solvent was concentrated to give crude 3-amino-1-(3,4-dichlorophenyl)-2,2-difluoropropan-1-ol TFA salt. The resulting residue was mixed with 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluorobenzoic acid (30 mg, 0.098 mmol), DIPEA (0.068 mL, 0.39 mmol), and DMF (1 mL). BOP (47.6 mg, 0.108 mmol) was added and the mixture was stirred at room temperature for 1 hour. The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 27% B at 0 min, followed by 27–67% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected based on MS signal. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give racemic 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-6-chloro-N-[3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl]-2-fluorobenzamide (44.7 mg, 0.0820 mmol, 84% yield). 1H NMR (500MHz, DMSO-d6) δ 9.16(br t,J=6.1Hz,1H), 8.65(d,J=7.0Hz,1H), 7.76(t,J=8.4Hz,1H), 7.68(s,1H), 7.69(d,J=6.7Hz,1H), 7.57-7.49(m,2H), 7.45(br d,J=7.9Hz,1H), 7.05(br d,J=7.0Hz,1H), 6.64(d,J=5.5Hz,1H), 6.12(s,2H), 5.07-4.88(m,1H), 4.00-3.80(m,2H) MS ESI m / z 544.2(M+H) +

[0271] Table 7: The compounds in Table 7 were prepared in a similar manner to Example 110. Where stereochemistry is not defined, the compounds were isolated as racemates or diastereomeric mixtures unless otherwise noted. [ka] [Table 26] [Table 27]

[0272] Example 119: 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl]-6-ethyl-2-fluorobenzamide [ka]

[0273] 119A: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate methyl ester Methyl 3-bromo-6-ethyl-2-fluorobenzoate (0.800 g, 3.06 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.01 g, 3.98 mmol), PdCl(dppf) CHCl adduct (0.125 g, 0.153 mmol), 1,4-dioxane (15.3 mL), and potassium acetate (0.601 g, 6.13 mmol) were added to a 40 mL vial containing a stir bar. The vial was evacuated and backfilled with nitrogen three times, then fitted with a condenser and heated at 110 °C under nitrogen for 4 h. To this mixture was added 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.653 g, 3.06 mmol) and 2.0 M aqueous potassium phosphate trihydrate (2.0 mL, 6.13 mmol). The vial was evacuated and backfilled with nitrogen three times and heated at 90 °C for 1 h. The mixture was cooled to room temperature and adsorbed onto silica gel. The crude material was purified by flash column silica chromatography (40 g silica, elution gradient: 50–100% EtOAc / hexanes) on a dusted column. The product fractions were combined and concentrated to give a solid, which was triturated with EtOAc (15 mL) and isolated by filtration to give methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate (0.600 g, 1.91 mmol, 62% yield). 1 H NMR (499MHz, DMSO-d6) δ 8.61(d,J=6.9Hz,1H), 7.73(t,J=8.1Hz,1H), 7.52(s,1H), 7.33(d,J=8.1Hz,1H), 7.04(dt,J=7.0, 1.7Hz,1H), 6.08(s,2H), 3.92(s,3H), 2.68(q,J=7.6Hz,2H), 1.19(t,J=7.5Hz,3H) MS ESI m / z 315.1(M+H) +

[0274] 119B: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoic acid lithium salt To an 8 mL vial was added a stir bar, methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate (0.200 g, 0.636 mmol), THF (2 mL), MeOH (2 mL), and aqueous NaOH (1 M, 0.127 mL, 1.27 mmol), and the resulting mixture was stirred at 60° C. for 16 h. The solvent was removed under reduced pressure to give a solid residue (estimated yield 100%) that was used directly in the next step. MS ESI m / z 301.3(M+H) +

[0275] 119: The title compound was prepared in a manner similar to the final step of the preparation of Example 110, except that tert-butyl (3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl)carbamate was replaced with tert-butyl (2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl)carbamate, and 3-(2-amino-[ Lithium 1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate was used to give the desired product 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide (10.7 mg, 0.022 mmol, 33% yield). 1H NMR (499MHz, DMSO-d6) δ 8.99(br t,J=6.0Hz,1H), 8.61(d,J=7.1Hz,1H), 8.57(s,1H), 7.81(td,J=8.8, 2.6Hz,1H), 7.68(t,J=6.9Hz,1H), 7.63(t,J=7.8Hz,1H), 7.50(s,1H), 7.27(d,J=7.9Hz,1H), 7.06(br d,J=7.0Hz,1H), 6.61(d,J=5.8Hz,1H), 6.07(s,1H), 5.07-4.91(m,1H), 4.06-3.86(m,2H), 3.46(br s, 1H), 2.64(q,J=7.2Hz,2H), 1.19(t,J=7.6Hz,3H) MS ESI m / z 489.1(M+H) +

[0276] Example 120: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide [ka] A mixture of 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (30 mg, 0.061 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine [S-Phos] (6.23 mg, 0.0150 mmol), palladium acetate (2.73 mg, 0.0120 mmol), and 6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione (22.2 mg, 0.121 mmol) in 1,4-dioxane (1 mL) was purged with nitrogen for 1 minute. 2M aqueous potassium phosphate tribasic (0.17 mL, 0.334 mmol) was added and heated at 115°C for 1.5 h. The mixture was filtered through Celite, washed with EtOAc (2x), the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in MeOH (3 mL). 10% Pd / C (25 mg, wet) was added, and the mixture was evacuated and backfilled with H2 via a balloon and stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product. This material was dissolved in DMF (2 mL) and purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 18% B at 0 min, followed by 18–58% B over 21 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. Fractions containing the desired product were combined and dried using a centrifugal evaporator.This material was further separated into its enantiomers using SFC chiral chromatography (Conditions: Instrument: Waters 100 Prep SFC; Column: Chiral OJ, 30x250 mm; 5μ; Mobile Phase: 80% CO2 / 20% MeOH (containing 0.1% DEA); Flow Rate: 100 mL / min; Detection Wavelength: 220 nm; Injection Conditions: 1000 μL (11.3 mg dissolved in 3 mL MeOH)). The first eluting peak was collected as the desired homochiral product: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide (2.80 mg, 5.74 μmol, 9% yield, >95% chiral purity). Absolute stereochemistry not determined. 1 H NMR (500MHz, DMSO-d6) δ 8.98(br t,J=6.3Hz,1H), 8.62(d,J=7.0Hz,1H), 7.64(t,J=8.1Hz,1H), 7.55-7.44(m,3H), 7.31-7.18(m,3H), 7.05(br d,J=6.7Hz,1H), 6.07(s,2H), 4.94(br d,J=15.0Hz,1H), 4.00-3.80(m,2H), 2.64(q,J=7.4Hz,2H), 2.58-2.54(m,1H), 1.19(t,J=7.5Hz,3H) MS ESI m / z 488.1(M+H) +

[0277] Table 8: The compounds in Table 8 were prepared in a manner similar to Example 120. Where stereochemistry is not defined, the compounds were isolated as racemates or diastereomeric mixtures unless otherwise noted. [ka] [Table 28]

[0278] Example 124: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide (Enantiomer 1) [ka] 124A: 3-bromo-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide To a mixture of 3-bromo-2-fluoro-6-methoxybenzoic acid (20 mg, 0.080 mmol), 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol (16.5 mg, 0.0800 mmol), and BOP (39.1 mg, 0.0880 mmol) in DMF (5 mL) was added Hunig's base (0.0280 mL, 0.161 mmol) and stirred at room temperature for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO (2 × 20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification. MS ESI m / z 436.1(M+H) +

[0279] 124: A mixture of 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (25.0 mg, 0.117 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (35.8 mg, 0.141 mmol), potassium acetate (34.6 mg, 0.352 mmol), and PdCl(dppf) CHCl adduct (4.79 mg, 5.87 μmol) in 1,4-dioxane (2 mL) was purged with N and stirred at 110 °C for 3 h. To this mixture were added 3-bromo-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide (46.1 mg, 0.106 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (3.82 mg, 5.87 μmol), and 2.0 M aqueous potassium phosphate tribasic (0.18 mL, 0.352 mmol) and stirred at 110 °C for 1.5 h. EtOAc (10 mL) and EtO (10 mL) were added, and the organic layer was washed with 1 N NaOH (2 × 10 mL). The combined aqueous layers were acidified with concentrated HCl to pH = 4-5, resulting in a precipitate. The solid was isolated by filtration, washed with water, and dried to give the crude product. This was dissolved in DMF and purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: 8% B for 0 min, 8–48% B over 20 min, then 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected based on MS signal.Fractions containing the desired product were combined and dried in a centrifugal evaporator, and the resulting material was further purified by SCP using SFC chiral chromatography (Waters 100 Prep SFC, column: Chiral OJ, 30x250mm; 5μ, mobile phase: 80% CO2 / 20% MeOH (containing 0.1% DEA), flow rate: 100mL / min, detection wavelength: 220nm, injection conditions: 1000μL (39.9mg dissolved in 30mL MeOH / ACN)). The first eluting peak was collected as the desired homochiral product: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide (Enantiomer 1, 7.4 mg, 0.015 mmol, 13% yield, chiral purity >95%). Absolute stereochemistry has not been determined. 1 H NMR (500MHz, DMSO-d6) δ 8.91-8.75(m,1H), 8.58(d,J=7.0Hz,1H), 7.72-7.63(m,1H), 7.56-7.37(m,3H), 7.26-7.16(m,2H), 7.10-6.95(m,2H), 6.04(s,2H), 5.05-4.77(m,1H), 4.04-3.50(m,5H) MS ESI m / z 488.1(M+H) +

[0280] Example 125: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide (Enantiomer 2) [ka] Chiral SFC purification as described in Example 124 afforded the title compound: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide (enantiomer 2, 5.9 mg, 0.012 mmol, 10% yield) as the second eluting isomer. Absolute stereochemistry not assigned. 1H NMR (500MHz, DMSO-d6) δ 8.94-8.79(m,1H), 8.66-8.44(m,1H), 7.69 (quin, J=8.7Hz,1H), 7.52-7.38(m,3H), 7.29-7.16(m,2H), 7.12-6.97(m,2H), 6.14-5.94(m,2H), 4.92(br dd,J=16.7, 6.8Hz,1H), 3.97-3.63(m,5H) MS ESI m / z 490.2(M+H) +

[0281] Example 126: 3-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide [ka] 126A: 3-bromo-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide To a mixture of 3-bromo-6-chloro-2-fluorobenzoic acid (150 mg, 0.592 mmol), 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol (121 mg, 0.592 mmol), and BOP (288 mg, 0.651 mmol) in DMF (5 mL) was added Hunig's base (0.207 mL, 1.18 mmol) and stirred at room temperature for 1 hour. The mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO (2 x 20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (12 g silica, gradient: 0 to 10% EtOAc / Hex, gradient time = 12 min, flow rate: 25 mL / min) to give 3-bromo-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (240 mg, 0.545 mmol, 92% yield). 1 H NMR (499MHz, CDCl3) δ7.62(dd,J=8.7, 7.3Hz,1H), 7.53-7.45(m,2H), 7.20(dd,J=8.6, 1.4Hz,1H), 7.15-7.08(m,2H), 6.36-6.26(m,1H), 5.04-4.92(m,1H), 4.55-4.39(m,1H), 4.02(br dd,J=15.1, 10.4Hz,1H), 3.67-3.54(m,1H) MS ESI m / z 442.2(M+H) +

[0282] 126B: 3-(2-amino-3-fluoropyridin-4-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide A mixture of 3-bromo-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (88 mg, 0.20 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (60.9 mg, 0.240 mmol), potassium acetate (58.9 mg, 0.600 mmol), and PdCl(dppf) CHCl adduct (16.3 mg, 0.0200 mmol) in 1,4-dioxane (2 mL) was purged with N and stirred at 110 °C for 3 h. To this mixture were added 3-fluoro-4-iodopyridin-2-amine (57.1 mg, 0.240 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (13.0 mg, 0.0200 mmol), and 2 M aqueous potassium phosphate triphosphatase (300 μL, 0.600 mmol). This was degassed by bubbling N for 2 minutes and then stirred at 110° C. for 1.5 hours. The reaction mixture was partitioned between EtOAc (20 mL) and HO (10 mL), and the organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (12 g silica gel, gradient: EtOAc / Hex=0 to 100%) to give 3-(2-amino-3-fluoropyridin-4-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (78.0 mg, 0.165 mmol, 83% yield). 1 H NMR (500MHz, DMSO-d6) δ 9.18(br t,J=6.0Hz,1H), 7.87(d,J=5.5Hz,1H), 7.64-7.42(m,4H), 7.28-7.19(m,2H), 7.17-7.00(m,1H), 6.65(t,J=4.9Hz,1H), 4.93(br dd,J=16.2, 6.7Hz,1H), 3.97-3.76(m,2H) MS ESI m / z 472.3(M+H) +

[0283] 126C: 3-(2-amino-3-fluoropyridin-4-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide A mixture of 3-(2-amino-3-fluoropyridin-4-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide (74.0 mg, 0.157 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine [S-Phos] (12.9 mg, 0.0310 mmol), palladium acetate (3.52 mg, 0.0160 mmol), and 6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione (57.4 mg, 0.314 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen for 1 minute, and 2 M aqueous potassium phosphate (0.43 mL, 0.863 mmol) was added and heated at 115 °C for 1.5 hours. The mixture was cooled to room temperature and filtered through Celite, which was washed with EtOAc (20 mL). The filtrate and washings were concentrated under reduced pressure, and the resulting residue was dissolved in MeOH (3 mL). 10% Pd / C (wet, 25 mg) was added, and the mixture was evacuated and charged with H2 from a balloon and stirred at room temperature overnight. The mixture was filtered and concentrated to give crude 3-(2-amino-3-fluoropyridin-4-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide (68.0 mg, 0.146 mmol, 93% yield), which was used in the next step without further purification. 1 H NMR (500MHz, DMSO-d6) δ 8.97(t,J=6.2Hz,1H), 7.81(d,J=5.1Hz,1H), 7.53-7.33(m,3H), 7.31-7.18(m,3H), 6.54(t,J=4.8Hz,1H), 6.41(br d,J=5.5Hz,1H), 6.30(s,2H), 4.97-4.84(m,1H), 3.95-3.76(m,2H), 2.63(q,J=7.6Hz,2H), 1.18(t,J=7.5Hz,3H) MS ESI m / z 466.5(M+H) +

[0284] 126: To a reaction vial (8 mL) was added a stir bar and 3-(2-amino-3-fluoropyridin-4-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide (40 mg, 0.086 mmol), the vessel was evacuated and backfilled with nitrogen, and then 1,4-dioxane (1 mL), DCM (1 mL), and ethyl isothiocyanatoformate (0.015 mL, 0.129 mmol) were added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours, then at 45° C. for 2 hours, concentrated under reduced pressure, and the desired intermediate (MS ESI m / z 597.5 (M+H)) was obtained. + The residue containing the thiourea intermediate was purified by flash column chromatography (4 g silica, gradient: MeOH / DCM = 0-6%, gradient time = 10 min, flow rate: 15 mL / min). The purified thiourea intermediate (51.3 mg, 0.0860 mmol) was obtained in a vial (8 mL) and mixed with hydroxylamine hydrochloride (29.9 mg, 0.430 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of ethanol (1 mL) and Hunig's base (0.0450 mL, 0.258 mmol). The mixture was stirred at room temperature for 15 min and then at 80 °C overnight. The solid was collected by filtration and washed with water. The resulting material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: 8% B at 0 min, followed by 8–48% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS signal. The fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired racemic product (30 mg, 0.059 mmol, 69% yield). 1H NMR (500MHz, DMSO-d6) δ 9.47-9.13(m,1H), 8.94-8.48(m,1H), 7.92-7.12(m,6H), 6.83-6.30(m,2H), 5.38-4.90(m,1H), 4.39-3.86(m,1H), 3.67-3.20(m,2H), 3.01-2.75(m,3H), 1.68-1.07(m,3H) MS ESI m / z 506.4(M+H) +

[0285] Example 127: 3-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide [ka] Example 127 was prepared in a similar manner to Example 124, except that 3-bromo-2-fluoro-6-methoxybenzoic acid was replaced with 5-bromo-2,4-dichlorobenzoic acid in the first step, and the desired racemate was not purified by chiral SFC in the last step, yielding racemic 3-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide (5.6 mg, 0.011 mmol, 24% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.90(br t,J=6.0Hz,1H), 8.64(d,J=7.0Hz,1H), 7.88(s,1H), 7.56-7.42(m,4H), 7.21(t,J=7.3Hz,2H), 6.97(dd,J=6.9, 1.7Hz,1H), 6.11(s,2H), 5.00-4.89(m,1H), 3.91(s,1H), 3.88-3.67(m,2H) MS ESI m / z 510.1(M+H) +

[0286] Example 128: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomer mixture 1) [ka] 128A: Ethyl 3-(4-chlorophenyl)-2-fluoro-3-hydroxypropanoate To a suspension of zinc (5.58 g, 85.0 mmol) in THF (85 mL), a solution of ethyl 2-bromo-2-fluoroacetate (6.0 mL, 51.2 mmol) and 4-chlorobenzaldehyde (6.00 g, 42.7 mmol) in THF (15 mL) was added dropwise over 15 min via a dropping funnel, and the mixture was heated to reflux for 30 min. After filtration, 1N hydrochloric acid and ether were added, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (elution solvent: 0-15% ethyl acetate / hexane) to give ethyl 3-(4-chlorophenyl)-2-fluoro-3-hydroxypropanoate (6.50 g, 26.4 mmol, 62% yield). 1 H NMR(500MHz, CDCl3) δ 7.40-7.25(m,4H), 5.20-5.08(m,1H), 5.08-4.94(m,1H), 4.31-4.20(m,2H), 2.19(s,1H), 1.25(dt,J=11.8, 7.2Hz,3H)

[0287] 128B: 3-(4-chlorophenyl)-2-fluoro-3-hydroxypropanamide To a solution of ethyl 3-(4-chlorophenyl)-2-fluoro-3-hydroxypropanoate (1.37 g, 5.55 mmol) in MeOH (13.9 mL) was added 7 M ammonia in methanol (4.0 mL, 27.8 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hours. The solvent was removed to give 3-(4-chlorophenyl)-2-fluoro-3-hydroxypropanamide (1.21 g, 5.56 mmol, 100% yield) as a white solid, which was used directly in the next step. MS ESI / APCI m / z 216.1 [MH] -

[0288] 128C: 3-amino-1-(4-chlorophenyl)-2-fluoropropan-1-ol To a solution of 3-(4-chlorophenyl)-2-fluoro-3-hydroxypropanamide (158 mg, 0.726 mmol) in THF (1.45 mL) was added borane-dimethyl sulfide complex (2 M, THF solution, 1.09 mL, 2.178 mmol) at room temperature and heated to reflux for 2 hours. Methanol was added, and the reaction mixture was stirred at room temperature for 20 minutes. The resulting residue was azeotroped with methanol (5x) to remove boronic acid and afforded 3-amino-1-(4-chlorophenyl)-2-fluoropropan-1-ol (149 mg, 0.732 mmol, 101% yield) as a colorless oil, which was used directly in the next step. MS ESI / APCI m / z 203.8 [M+H] +

[0289] 128D-1: 3-bromo-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomer mixture 1) A mixture of 3-bromo-6-chloro-2-fluorobenzoic acid (20 mg, 0.079 mmol), 3-amino-1-(4-chlorophenyl)-2-fluoropropan-1-ol (17.7 mg, 0.0870 mmol), BOP (41.9 mg, 0.0950 mmol), and diisopropylethylamine (21 μL, 0.118 mmol) in DCM (158 μL) was stirred at room temperature for 3 h. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative TLC (silica gel, thickness: 0.50 mm, elution: 30% ethyl acetate / hexane) to give a mixture of two enantiomers. 3-Bromo-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 1, 11 mg, 0.025 mmol, 32% yield) was isolated as the less polar, faster eluting material by preparative silica TLC. 1 H NMR(500MHz, CDCl3) δ 7.59(t,J=7.7Hz,1H), 7.43-7.34(m,4H), 7.19(d,J=8.4Hz,1H), 6.38(br s, 1H), 4.84(t,J=7.3Hz,1H), 4.69-4.53(m,1H), 4.30-4.15(m,1H), 3.95(br s, 1H), 3.70(dddd,J=17.7, 14.9, 5.6, 3.2Hz,1H) MS ESI / APCI m / z 437.8 [M+H] +

[0290] 128D-2: 3-bromo-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomer mixture 2) In the preparative TLC separation described for Intermediate 128D-1, 3-bromo-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 2, 11 mg, 0.025 mmol, 32% yield) was isolated as the more polar, slower-eluting material on preparative silica TLC. 1H NMR(500MHz、CDCl3) δ 7.54(dd,J=8.6, 7.3Hz,1H), 7.42-7.31(m,4H), 7.13(dd,J=8.6, 1.4Hz,1H), 6.28(br s, 1H), 4.88(dd,J=18.1, 5.0Hz,1H), 4.81(dt,J=7.0, 4.7Hz,1H), 3.96-3.50(m,2H) MS ESI / APCI m / z 437.8 [M+H] +

[0291] 128: In a 1-dram vial containing a stir bar, 3-bromo-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 1, 23 mg, 0.052 mmol), N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (28.9 mg, 0.063 mmol), potassium phosphate tripotassium (79.0 μL, 0.157 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (2.0 mg, 2.5 μmol) in 1,4-dioxane (250 μL) were combined to give a brown suspension. The mixture was degassed by evacuating and filling with nitrogen three times. The vial was sealed and heated at 60°C for 2 hours. Hydrogen chloride (4 M in 1,4-dioxane, 196 µL, 0.79 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under a gentle stream of nitrogen, dissolved in DMF, and filtered through a PTFE frit (0.45 µm). The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); gradient: 10% B at 0 min, followed by 10–50% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried using a centrifugal evaporator to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 1)·2TFA (3.5 mg, 0.0049 mmol, 8% yield). 1H NMR (500MHz, DMSO-d6) δ 9.01(s,1H), 8.61(br d,J=6.7Hz,1H), 7.71(br t,J=8.1Hz,1H), 7.54-7.45(m,2H), 7.43(s,3H), 7.25(s,1H), 7.15(s,1H), 7.05(br s, 2H), 4.79(br s, 1H), 4.72-4.55(m,1H) MS ESI / APCI m / z 491.9 [M+H] +

[0292] Example 129: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomer mixture 2) [ka] In a 1-dram vial containing a stir bar, 3-bromo-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 2, 22 mg, 0.050 mmol), N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (27.7 mg, 0.060 mmol), potassium phosphate tripotassium (75.0 μL, 0.150 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (2.0 mg, 2.5 μmol) in 1,4-dioxane (250 μL) were added to give a brown suspension. The mixture was degassed by evacuating and filling with nitrogen three times, and the vial was sealed. The mixture was heated at 60°C for 2 hours, and hydrogen chloride (4 M in 1,4-dioxane, 188 µL, 0.75 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated under a gentle stream of nitrogen, dissolved in DMF, and filtered through a PTFE frit (0.45 µm). The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); gradient: 9% B at 0 min, followed by 9–49% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried using a centrifugal evaporator to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 2)·2TFA (6.8 mg, 0.0094 mmol, 19% yield). 1H NMR (500MHz, DMSO-d6) δ 9.03(br t,J=5.3Hz,1H), 8.61(d,J=7.0Hz,1H), 7.71(t,J=8.4Hz,1H), 7.52-7.47(m,2H), 7.42(s,4H), 7.04(br d,J=6.9Hz,1H), 6.06(s,2H), 4.86-4.76(m,1H), 4.75-4.57(m,1H), 3.61(br s, 2H) MS ESI / APCI m / z 491.9 [M+H] +

[0293] Example 130: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-fluorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomer mixture 1) [ka] 130A: A mixture of ethyl 2-chloro-2-fluoroacetate (5.1 mL, 44.3 mmol), 4-fluorobenzaldehyde (4.3 mL, 40.3 mmol), and zinc (3.69 g, 56.4 mmol) in DMF (101 mL) was heated in an oil bath at 80 °C for 12 h. The reaction mixture was filtered through Celite, 1N HCl was added, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The resulting residue was purified by silica gel flash column chromatography (elution gradient: 0-15% ethyl acetate / hexane) to give ethyl 2-fluoro-3-(4-fluorophenyl)-3-hydroxypropanoate (2.00 g, 8.69 mmol, 22% yield). 1 H NMR(500MHz, CDCl3) δ 7.42-7.34(m,2H), 7.11-7.03(m,2H), 5.18-5.08(m,1H), 5.08-4.92(m,1H), 4.30-4.16(m,2H), 2.87-2.65(m,1H), 1.61-1.57(m,1H), 1.29-1.19(m,3H)

[0294] 130B: 2-fluoro-3-(4-fluorophenyl)-3-hydroxypropanamide To a solution of ethyl 2-fluoro-3-(4-fluorophenyl)-3-hydroxypropanoate (850 mg, 3.69 mmol) in methanol (9.2 mL) was added ammonia (7 M in methanol, 2.6 mL, 18.5 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure to give 2-fluoro-3-(4-fluorophenyl)-3-hydroxypropanamide (750 mg, 3.73 mmol, 101% yield) as a white solid. A 1:1 mixture of two diastereomers was obtained, which was used directly in the next step. MS ESI / APCI m / z 200.1 [MH] -

[0295] 130C: 3-amino-1-(4-fluorophenyl)-2-fluoropropan-1-ol To a solution of 2-fluoro-3-(4-fluorophenyl)-3-hydroxypropanamide (160 mg, 0.795 mmol) in THF (1.6 mL) was added borane-dimethyl sulfide complex (2 M in THF, 1.2 mL, 2.386 mmol), and the reaction mixture was heated to reflux for 2 h. After cooling, methanol was added, and the reaction mixture was stirred at room temperature for 30 min. The methanol was removed under reduced pressure, and the resulting residue was azeotroped three times with methanol to remove boronic acid, affording 3-amino-2-fluoro-1-(4-fluorophenyl)propan-1-ol (150 mg, 0.801 mmol, 101% yield) as a colorless oil, which was used directly in the next step. MS ESI / APCI m / z 187.9 [M+H] +

[0296] 130D-1: 3-bromo-6-chloro-N-(3-(4-fluorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomer mixture 1) A solution of 3-bromo-6-chloro-2-fluorobenzoic acid (190 mg, 0.748 mmol), 3-amino-2-fluoro-1-(4-fluorophenyl)propan-1-ol (140 mg, 0.748 mmol), diisopropylethylamine (196 μL, 1.12 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (397 mg, 0.897 mmol) in dichloromethane (2.5 mL) was stirred at room temperature for 3 hours. The crude product was purified by preparative TLC (silica gel, thickness: 0.50 mm, elution: 30% ethyl acetate / hexane) to give a mixture of two enantiomers. 3-Bromo-6-chloro-2-fluoro-N-(2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide (enantiomeric mixture 1, 63.0 mg, 0.149 mmol, 20% yield) was isolated as the less polar, faster eluting material by preparative silica TLC. 1 H NMR(500MHz, CDCl3) δ 7.60(dd,J=8.6, 7.3Hz,1H), 7.44(dd,J=8.7, 5.4Hz,2H), 7.19(dd,J=8.6, 1.4Hz,1H), 7.10(t,J=8.3Hz,2H), 6.36-6.27(m,1H), 4.89-4.82(m,1H), 4.71-4.55(m,1H), 4.31-4.16(m,1H), 3.88-3.81(m,1H), 3.78-3.67(m,1H) MS ESI / APCI m / z 419.9 [MH] -

[0297] 130D-2: 3-bromo-6-chloro-N-(3-(4-fluorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomer mixture 2) In the preparative TLC separation described for Intermediate 130D-1, 3-bromo-6-chloro-N-(3-(4-fluorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 2, 67.0 mg, 0.159 mmol, 21% yield) was isolated as the more polar, slower-eluting material on preparative silica TLC. 1 H NMR(500MHz, CDCl3) δ 7.56(t,J=7.9Hz,1H), 7.43(t,J=6.7Hz,2H), 7.19-7.02(m,3H), 6.28(br s, 1H), 4.90(dd,J=17.5, 5.3Hz,1H), 4.86-4.69(m,1H), 3.94-3.49(m,2H) MS ESI / APCI m / z 419.8 [MH] -

[0298] 130: In a 1-dram vial containing a stir bar, 3-bromo-6-chloro-N-(3-(4-fluorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 1, 23 mg, 0.054 mmol), N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (30.1 mg, 0.065 mmol), 2 M aqueous potassium phosphate tribasic (82.1 μL, 0.163 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (2.2 mg, 2.7 μmol) in 1,4-dioxane (270 μL) were combined to give a brown suspension. The mixture was degassed by evacuating and filling with nitrogen three times, the vial was sealed, and heated at 60° C. for 2 h. Hydrogen chloride (4 M in 1,4-dioxane, 204 μL, 0.82 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under a gentle stream of nitrogen, and the residue was dissolved in DMF and filtered through a PTFE frit (0.45 μm). The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 9% B at 0 min, followed by 9-49% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C), and fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried in a centrifugal evaporator to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-(2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide (enantiomeric mixture 1, 8.4 mg, 0.018 mmol, 32% yield). 1H NMR (500MHz, DMSO-d6) δ 9.05-8.99(m,1H), 8.61(br d,J=7.0Hz,1H), 7.71(br t,J=8.2Hz,1H), 7.54-7.42(m,4H), 7.18(t,J=8.3Hz,2H), 7.04(br d,J=7.0Hz,1H), 6.06(s,2H), 4.87-4.71(m,1H), 4.71-4.51(m,1H) MS ESI / APCI m / z 475.9 [M+H] +

[0299] Example 131: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomer mixture 2) [ka] In a 1-dram vial containing a stir bar, 3-bromo-6-chloro-N-(3-(4-fluorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide (enantiomeric mixture 2, 23 mg, 0.054 mmol), N,N-bis-Boc-2-amino-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (30.1 mg, 0.065 mmol), 2 M aqueous potassium phosphate tribasic solution (82.1 μL, 0.163 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (2.2 mg, 2.7 μmol) in 1,4-dioxane (270 μL) were combined to give a brown suspension. The mixture was degassed by evacuating and filling with nitrogen three times, the vial was sealed, and heated at 60°C for 2 h. Hydrogen chloride (4 M in 1,4-dioxane, 204 µL, 0.82 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under a gentle stream of nitrogen, dissolved in DMF, and filtered through a PTFE frit (0.45 µm). The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); gradient: 5% B at 0 min, followed by 5–45% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried using a centrifugal evaporator to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-(2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide (enantiomeric mixture 2)·2TFA (4.8 mg, 0.0068 mmol, 11% yield). 1H NMR (500MHz, DMSO-d6) δ 9.03(br s, 1H), 8.63(d,J=7.0Hz,1H), 7.71(t,J=8.2Hz,1H), 7.57-7.39(m,4H), 7.25(d,J=3.6Hz,1H), 7.22-7.13(m,3H), 7.12-7.00(m,2H), 4.84-4.76(m,1H), 4.74-4.57(m,1H) MS ESI / APCI m / z 475.9 [M+H] +

[0300] Example 132: (S)-3-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide [ka] 132A: (S)-3-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide A stir bar and BOP (197 mg, 0.446 mmol) were added to an 8 mL reaction vial. The flask was evacuated and backfilled with nitrogen, followed by the addition of DMF (3.43 mL), N,N-diisopropylethylamine (239 μL, 1.37 mmol), 3-bromo-2-fluoro-6-methylbenzoic acid (80.0 mg, 0.343 mmol), and (S)-3-amino-1-(4-chlorophenyl)propan-1-ol·HCl (91.0 mg, 0.412 mmol). The mixture was stirred at room temperature for 3 days, diluted with aqueous LiCl (30 mL, 10% w / w), and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with HO (50 mL x 2) and brine (50 mL), dried over anhydrous MgSO, and filtered through Celite. The crude mixture was concentrated under reduced pressure and a 12 g silica gel cartridge pre-wetted with 4% EtN / hexane (50 mL) was used. The crude material was purified by flash column chromatography (gradient: 0% to 50% EtOAc / Hex, then 50% pure silica, pre-treated silica: 12 g) to give (S)-3-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (120 mg, 0.299 mmol, 87% yield). 1 H NMR(500MHz, CDCl3) δ 7.46(dd,J=8.0, 7.3Hz,1H), 7.32(m,4H), 6.92(d,J=8.1Hz,1H), 6.32(br s, 1H), 4.84(dt,J=9.3, 3.5Hz,1H), 3.95-3.87(m,1H), 3.43 (dq, J=14.1, 5.2Hz,1H), 3.10(d,J=3.5Hz,1H), 2.37(s,3H), 2.03-1.87(m,2H) MS ESI m / z 382.00 and 384.00 (M-OH) +

[0301] 132B: 8-Fluoro-7-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-amine A 20 mL reaction vial was charged with a stir bar and 3-fluoro-4-iodopyridin-2-amine (1.00 g, 4.20 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of 1,4-dioxane (10.5 mL), DCM (10.5 mL), and ethyl isothiocyanatoformate (0.74 mL, 6.30 mmol). The mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. The crude product was purified by flash column chromatography (gradient: 0% to 100% EtOAc / Hex; 12 g silica) to afford the thiourea intermediate (1.50 g, 4.06 mmol). A 250 mL round-bottom flask was charged with a stir bar, the thiourea intermediate (1.50 g, 4.06 mmol), and hydroxyamine hydrochloride (1.41 g, 20.3 mmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of ethanol (27 mL) and DIPEA (2.1 mL, 12.2 mmol). The mixture was stirred at room temperature for 15 minutes and then at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with DMSO (10 mL), filtered, and the filtrate was purified by reverse-phase HPLC column chromatography (Solvent A: 10% acetonitrile, 90% HO, 0.1% NHOAc; Solvent B: 90% acetonitrile, 10% HO, 0.1% NHOAc; gradient: elution from 0% to 50% B, then 100% B) to give 8-fluoro-7-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.500 g, 1.80 mmol, 44% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.25(d,J=6.9Hz,1H), 7.18(dd,J=6.9, 5.5Hz,1H), 6.26(s,2H) MS ESI m / z 278.85(M+H) +

[0302] 132C: (2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid A 20 mL reaction vial was charged with a stir bar, 8-fluoro-7-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.100 g, 0.360 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (0.030 g, 0.036 mmol), bis(pinacolato)diboron (0.240 g, 0.936 mmol), and potassium acetate (0.212 g, 2.16 mmol). The vial was evacuated and backfilled with nitrogen, followed by the addition of 1,4-dioxane (3.6 mL). The mixture was stirred at 80 °C for 4 days. This mixture was diluted with 1,4-dioxane (total volume 7.2 mL) and used directly in the next step without further purification.

[0303] 132: To an 8 mL reaction vial was added a stir bar, (S)-3-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (26.4 mg, 0.0660 mmol), PdCl(dtbpf) (3.91 mg, 6.00 μmol), and (2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (1 / 6 of the crude mixture, 1.2 mL, estimated 0.060 mmol) in 1,4-dioxane, followed by potassium phosphate (150 μL, 2 M, HO, 0.300 mmol). The mixture was degassed by bubbling N for 5 minutes and then stirred at 80 °C for 3 hours. The mixture was concentrated under reduced pressure, diluted with DMSO (2 mL), and filtered. The resulting crude filtrate was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 12% B for 0 min, followed by 12–52% B over 20 min, then 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25°C), and fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-3-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (7.0 mg, 0.015 mmol, 25% yield). 1H NMR (500MHz, DMSO-d6) δ 8.63(br t,J=5.3Hz,1H), 8.53(d,J=6.9Hz,1H), 7.48(t,J=7.8Hz,1H), 7.43-7.33(m,4H), 7.25(d,J=8.0Hz,1H), 6.88(t,J=6.7Hz,1H), 6.36-6.18(m,2H), 5.39(d,J=4.5Hz,1H), 4.72-4.58(m,1H), 3.40-3.31(m,1H), 2.33(s,3H), 1.81(q,J=6.9Hz,2H) MS ESI m / z 471.93(M+H) +

[0304] Table 9: The compounds in Table 9 were prepared in a similar manner to Example 132. [ka] [Table 29]

[0305] Table 10: The compounds in Table 10 were prepared in a similar manner to Example 132. (Synthesis of Intermediate 132A) In the first step of the procedure, 3-amino-2,2-difluoro-1-(4-fluorophenyl)propan-1-ol was used instead of (S)-3-amino-1-(4-chlorophenyl)propan-1-ol·HCl. Furthermore, Examples 135 and 136 were separated from the racemate by chiral SFC chromatography (Waters 100 Prep SFC, column: Chiral OJ, 30x250 mm; 5μ, mobile phase: 80% CO2 / 20% MeOH (containing 0.1% DEA), flow rate: 100 mL / min, detection wavelength: 220 nm). Additionally, Examples 137 and 138 were separated from the racemate by chiral SFC chromatography (Waters 100 Prep SFC, column: Chiral IC, 21x250mm; 5μ, mobile phase: 65% CO2 / 35% MeOH (containing 0.1% DEA), flow rate: 60 mL / min, detection wavelength: 220 nm). [ka] [Table 30]

[0306] Example 139: 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[(3S)-3-(4-cyanophenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide [ka] A reaction vial (8 mL) was charged with a stir bar, (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (22.7 mg, 0.050 mmol), potassium hexacyanoferrate(II) trihydrate (10.6 mg, 0.0250 mmol), XPhos second-generation precatalyst (3.93 mg, 5.00 μmol), and XPhos (2.38 mg, 5.00 μmol). The flask was evacuated and backfilled with nitrogen three times, followed by the addition of degassed 1,4-dioxane (0.3 mL) and degassed aqueous potassium acetate (0.30 mL, 0.1 M, HO, 0.030 mmol). The mixture was stirred at 100 °C for 1 h, diluted with DCM (10 mL) and iPrOH (5 mL), washed with HO (10 mL) and brine (10 mL), dried over anhydrous MgSO, and filtered through Celite. The crude mixture was concentrated under reduced pressure, redissolved in DMF (2 mL), and filtered. The crude filtrate was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 6% B at 0 min, followed by 6–46% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by UV signal. Fractions containing the desired product were combined and dried in a centrifugal evaporator to give (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-cyanophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (11.8 mg, 0.0265 mmol, 51% yield). 1H NMR (600MHz, DMSO-d6) δ 8.69(br t,J=5.1Hz,1H), 8.56(d,J=7.0Hz,1H), 7.77(d,J=7.7Hz,2H), 7.58-7.49(m,3H), 7.47(s,1H), 7.21(d,J=8.1Hz,1H), 7.06(br d,J=6.6Hz,1H), 6.03(s,2H), 5.83-5.71(m,1H), 4.78-4.67(m,1H), 3.41-3.25(m,2H), 2.28(s,3H), 1.91-1.74(m,2H) MS ESI m / z 445.3(M+H) +

[0307] Table 11: The compounds in Table 11 were prepared from the corresponding aryl chlorides in a manner similar to Example 139. [ka] [Table 31]

[0308] Example 142: 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[(3S)-3-(4-ethynylphenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide [ka] To an 8 mL vial was added a stir bar, (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (22 mg, 0.048 mmol), cesium carbonate (39.5 mg, 0.121 mmol), XPhos (6.93 mg, 0.0150 mmol), and Xphos 2nd generation Pd catalyst (7.63 mg, 9.69 μmol). The flask was evacuated and backfilled with nitrogen, followed by the addition of acetonitrile (969 μL) and trimethylsilylacetylene (68.0 μL, 0.485 mmol). The mixture was stirred at room temperature for 5 min and then at 90 °C for 3 h. LCMS showed the disilylated alkyne product as the major component. The mixture was concentrated and purified by preparative TLC (elution: 5% MeOH / EtOAc). The product was not stable on silica and decomposed into two components. The resulting crude material was collected and purified by preparative LC / MS (conditions: Column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Gradient: 9% B at 0 min, followed by 9–49% B over 20 min, then 100% B at 0 min; Flow rate: 20 mL / min; Column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-ethynylphenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (0.70 mg, 0.0016 mmol, 3.3% yield). MS ESI m / z 444.0(M+H) +

[0309] Example 143: 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[3-(4-chlorophenyl)-3-oxopropyl]-2-fluoro-6-methylbenzamide [ka] A stir bar and sulfur trioxide·pyridine complex (75.0 mg, 0.474 mmol) were added to an 8 mL reaction vial. The flask was evacuated and backfilled with nitrogen, followed by the addition of DMSO (1.4 mL). This mixture was stirred at room temperature for 30 min. To another 8 mL reaction vial, a stir bar, (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (43 mg, 0.095 mmol), triethylamine (0.13 mL, 0.947 mmol), and DMSO (0.6 mL) were added, followed by the slow addition of the prepared SO3·pyridine / DMSO solution via syringe. This mixture was stirred at room temperature for 2.5 h, and the reaction was quenched by the addition of iPrOH. The reaction mixture was diluted with EtOAc (50 mL), washed with HO (50 mL) and brine (50 mL), dried over anhydrous MgSO, and filtered through Celite. The crude material was concentrated under reduced pressure and purified by preparative TLC (5% MeOH / DCM) to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-oxopropyl)-2-fluoro-6-methylbenzamide (13.7 mg, 0.0300 mmol, 32% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.67(s,1H), 8.60(d,J=7.0Hz,1H), 8.03-7.95(m,2H), 7.65-7.59(m,2H), 7.59-7.54(m,1H), 7.47(s,1H), 7.19(d,J=8.2Hz,1H), 7.01(d,J=7.0Hz,1H), 6.07(s,2H), 4.62-4.56(m,4H), 2.27(s,3H) MS ESI m / z 452.0(M+H) +

[0310] Example 144: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide [ka] 144A: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-2-methylbenzoate methyl A mixture of 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (256 mg, 1.20 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (366 mg, 1.44 mmol), PdCl(dppf) CHCl adduct (49.0 mg, 0.0600 mmol), and potassium acetate (294 mg, 3.00 mmol) in 1,4-dioxane (5 mL) was stirred at 110-115 °C for 2 hours. To this mixture was added methyl 4-chloro-5-iodo-2-methylbenzoate (298 mg, 0.960 mmol), followed by PdCl(dppf) CHCl adduct (49.0 mg, 0.0600 mmol) and 2.0 M aqueous potassium phosphate (1.50 mL, 3.00 mmol). The mixture was refluxed for 2 h, water was added, and the solid was collected to give methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-2-methylbenzoate (300 mg, 0.947 mmol, 79% yield). MS ESI m / z 317.2(M+H) +

[0311] 144B: Lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-2-methylbenzoate To a solution of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-2-methylbenzoate (300 mg, 0.947 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (50 mg, 1.2 mmol) in water (1 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure to give crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-2-methylbenzoate (242 mg, 0.947 mmol, 100% yield). This material was used directly in the next step. MS ESI m / z 303.2(M+H) +

[0312] 144: To a mixture of crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-2-methylbenzoate (30.3 mg, 0.100 mmol) in DMF (0.5 mL) was added BOP (53.1 mg, 0.120 mmol) followed by DIPEA (0.035 mL, 0.200 mmol). After stirring at room temperature for 10 minutes, (S)-3-amino-1-(4-chlorophenyl)propan-1-ol hydrochloride (26.7 mg, 0.120 mmol) was added and the mixture was stirred at room temperature overnight. DMF / MeOH was added, and the solid was filtered and discarded. The resulting crude filtrate was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 30 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: 14% B for 0 min, followed by 14-54% B over 20 min, then 100% B for 0 min; flow rate: 45 mL / min; column temperature: 25°C). Fractions were collected based on their MS signal, and the fractions containing the desired product were combined and dried in a centrifugal evaporator to give (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide (18.8 mg, 0.040 mmol, 40% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.63(d,J=7.0Hz,1H), 8.39(br t,J=5.0Hz,1H), 7.52(s,1H), 7.45(s,1H), 7.41(s,1H), 7.37(s,4H), 7.02(dd,J=6.7, 1.5Hz,1H), 4.64(br t,J=6.3Hz,1H), 3.33-3.26(m,2H), 2.39(s,3H), 1.83(q,J=6.7Hz,2H) MS ESI m / z 470.2(M+H) +

[0313] Example 145: (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-methylbenzamide [ka] 145A: 3-Bromo-6-chloro-2-methylbenzoic acid and 3-Bromo-2-chloro-6-methylbenzoic acid 2-Chloro-6-methylbenzoic acid (0.341 g, 2.0 mmol) was dissolved in concentrated sulfuric acid (2 mL), cooled in an ice / brine bath, and 1,3-dibromo-5,5-dimethylhydantoin (0.286 g, 1.00 mmol) was slowly added. After stirring at 0 °C for 30 minutes, ice was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to give a crude mixture of 3-bromo-2-chloro-6-methylbenzoic acid and 3-bromo-6-chloro-2-methylbenzoic acid. This material was used directly in the next step.

[0314] 145B: Methyl 3-bromo-2-chloro-6-methylbenzoate and Methyl 3-bromo-6-chloro-2-methylbenzoate To a solution of the resulting crude mixture of 3-bromo-6-chloro-2-methylbenzoic acid and 3-bromo-2-chloro-6-methylbenzoic acid (499 mg, 2.00 mmol) in DMF (6 mL) was added potassium carbonate (553 mg, 4.00 mmol), followed by MeI (0.38 mL, 6.00 mmol). The mixture was stirred overnight at room temperature, EtOAc (50 mL) was added, and the organic layer was washed with brine and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (24 g silica, gradient: hexane / ~10% EtOAc) to give an inseparable mixture of methyl 3-bromo-6-chloro-2-methylbenzoate (360 mg, 1.37 mmol, 68% yield) and methyl 3-bromo-2-chloro-6-methylbenzoate (90 mg, 0.342 mmol, 17% yield). 1 The ratio was 4:1 by 1 H NMR analysis. Methyl 3-bromo-6-chloro-2-methylbenzoate: 1 H NMR (499MHz, CDCl3) δ 7.54(d,J=8.6Hz,1H), 7.13(d,J=8.6Hz,1H), 3.98(s,3H), 2.38(s,3H) Methyl 3-bromo-2-chloro-6-methylbenzoate: 1 H NMR(499MHz, CDCl3) δ 7.56(d,J=8.2Hz,1H), 7.01(d,J=8.2Hz,1H), 3.98(s,3H), 2.30(s,3H) MS ESI m / z 265.1(M+H) +

[0315] 145C: Methyl 2-chloro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and Methyl 6-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate A solution of methyl 3-bromo-2-chloro-6-methylbenzoate (360 mg, 1.37 mmol) and methyl 3-bromo-6-chloro-2-methylbenzoate (90 mg, 0.342 mmol) in 1,4-dioxane (5 mL) was added with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (520 mg, 2.05 mmol), PdCl(dppf) CHCl adduct (112 mg, 0.137 mmol), and potassium acetate (402 mg, 4.10 mmol), purged with nitrogen, and then stirred at 110–115 °C for 3 h until LCMS indicated the consumption of starting material and the formation of the desired boronated product. This reaction mixture was used directly in the next step. MS ESI m / z 311.3(M+H) +

[0316] 145D: methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-6-methylbenzoate and methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-methylbenzoate To a reaction mixture of methyl 2-chloro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (424 mg, 1.366 mmol) and methyl 6-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (106 mg, 0.342 mmol), 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (364 mg, 1.71 mmol), PdCl(dppf) CHCl adduct (44.6 mg, 0.055 mmol), and aqueous KPO (2 M, 2.1 mL, 4.10 mmol) were added. After purging with nitrogen for 5 minutes, the mixture was stirred at 115 °C for 1 hour, water (50 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (24 g silica, gradient: DCM to 10% MeOH / DCM) to afford an inseparable mixture of methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-methylbenzoate (350 mg, 1.11 mmol, 81% yield) and methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-6-methylbenzoate (80 mg, 0.253 mmol, 18% yield). MS ESI m / z 317.2(M+H) +

[0317] 145E: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-6-methylbenzoate lithium and 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-methylbenzoate lithium To a mixture of methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-methylbenzoate (350 mg, 1.11 mmol) and methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-6-methylbenzoate (88 mg, 0.276 mmol) in THF (4 mL) was added a solution of LiOH (66.2 mg, 2.76 mmol) in water (1 mL). The reaction was stirred overnight at room temperature, then at 60 °C for 3 days and then at 85 °C for 1 day. The reaction mixture was concentrated to dryness under reduced pressure to give a crude mixture of the two lithium carboxylates. The crude residue was used directly in the next step. MS ESI m / z 303.2(M+H) +

[0318] 145: To a mixture of lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-methylbenzoate (30.3 mg, 0.1 mmol) and lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-6-methylbenzoate (7.57 mg, 0.025 mmol) in DMF (1 mL) was added BOP (88 mg, 0.200 mmol) followed by DIPEA (0.070 mL, 0.400 mmol). After stirring at room temperature for 10 minutes, (S)-3-amino-1-(4-chlorophenyl)propan-1-ol hydrochloride (44.4 mg, 0.200 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was dissolved in DMF and filtered. The filtrate containing the crude product was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 18% B at 0 min, followed by 18–48% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. Fractions containing the desired product were combined and dried on a centrifugal evaporator, and this material was further purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: 10% B at 0 min, followed by 10–50% B over 25 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS signal. The fractions containing the desired product were combined and dried in a centrifugal evaporator to give the desired (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-methylbenzamide (2.3 mg, 4.9 μmol, 5% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.64(d,J=6.7Hz,1H), 8.59(t,J=5.5Hz,1H), 7.44-7.34(m,7H), 6.94(dd,J=6.9, 1.7Hz,1H), 4.68(t,J=6.4Hz,1H), 3.36-3.26(m,1H), 3.39-3.25(m,2H), 2.31(s,3H), 1.83(q,J=6.6Hz,2H) MS ESI m / z 470.0(M+H) +

[0319] Example 146: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2,4-dimethylbenzamide [ka] 146A: (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid In a medium-sized sealable pressure-resistant glass vessel, a mixture of 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (250 mg, 1.17 mmol), bis(pinacolato)diboron (447 mg, 1.76 mmol), and potassium acetate (346 mg, 3.52 mmol) in 1,4-dioxane (5 mL) was added with PdCl(dppf) CHCl adduct (48 mg, 0.059 mmol) and heated at 100 °C for 45 min. The resulting crude mixture was used directly in the next step without further purification (estimated yield 100%). MS ESI m / z 178.9(M+H) +

[0320] 146B: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,4-dimethylbenzoate methyl To the crude mixture described in 146A in a medium-sized sealable pressure-resistant glass vessel, methyl 5-iodo-2,4-dimethylbenzoate (250 mg, 0.862 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (28 mg, 0.043 mmol) were added. The mixture was degassed, treated with aqueous KPO (2 M, 1.3 mL, 2.59 mmol), and the vessel was sealed and heated to 100 °C for 15 min. The crude reaction mixture was concentrated onto Celite and purified by silica gel flash column chromatography (elution: ethyl acetate / hexanes) to give methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,4-dimethylbenzoate (222 mg, 0.712 mmol, 95% yield). MS ESI m / z 297.1(M+H) +

[0321] 146C: Lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,4-dimethylbenzoate To a solution of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,4-dimethylbenzoate (222 mg, 0.749 mmol) in THF (8 mL) and a few drops of methanol was added a solution of lithium hydroxide monohydrate (39.3 mg, 0.936 mmol) in water (1.5 mL), stirred at 55 °C for 18 hours, and the solvent was removed under reduced pressure to give crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,4-dimethylbenzoate (217 mg, 0.692 mmol, 92% yield), which was used directly in the next step without further purification.

[0322] 146: To a mixture of crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,4-dimethylbenzoate (13 mg, 0.046 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol (7.8 mg, 0.042 mmol) and N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) in DMF (1.0 mL) was added BOP (31 mg, 0.069 mmol) and the reaction was stirred at 44 °C for 72 h. The mixture was diluted with methanol (2 mL), filtered, and purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 17% B at 0 min, followed by 17–57% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2,4-dimethylbenzamide (11.1 mg, 0.0250 mmol, 54% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.57(d,J=6.8Hz,1H), 8.26(t,J=5.3Hz,1H), 7.37(s,4H), 7.32(s,1H), 7.22(d,J=19.6Hz,2H), 6.89(dd,J=6.9, 1.8Hz,1H), 6.03(s,2H), 5.41(d,J=4.5Hz,1H), 4.71-4.57(m,1H), 3.53-3.45(m,1H), 3.35-3.23(m,1H), 2.36(s,3H), 2.29(s,3H), 1.88-1.77(m,2H) MS ESI m / z 450.28(M+H) +

[0323] Example 147: (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide [ka] 147A: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methoxybenzoic acid A mixture of (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (180 mg, 1.01 mmol) and 3-bromo-2-fluoro-6-methoxybenzoic acid (233 mg, 0.936 mmol) in 1,4-dioxane (10 mL) was treated with 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (31 mg, 0.047 mmol) in a medium-sized sealable pressure-resistant glass vessel. The mixture was degassed and treated with aqueous KPO (2 M, 1.40 mL, 2.81 mmol), and the vessel was then sealed and heated at 100 °C for 18 h. Additional 3-bromo-2-fluoro-6-methoxybenzoic acid (250 mg, 1.00 mmol), aqueous KPO (2 M, 2.0 mL, 4.0 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (50 mg, 0.080 mmol) were added and heated at 100 °C for 3 h. The mixture was diluted with aqueous phosphate buffer (2 mL), extracted with ethyl acetate, and the aqueous layer was acidified with 6 N HCl to precipitate a solid. The resulting solid was collected by filtration to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methoxybenzoic acid (202 mg, 0.601 mmol, 64% yield). MS ESI m / z 302.99(M+H) +

[0324] 147: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methoxybenzoic acid (22 mg, 0.073 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol (7.8 mg, 0.042 mmol) and N,N-diisopropylethylamine (0.064 mL, 0.36 mmol) in DMF (1.0 mL) was added to a mixture of BOP (48.3 mg, 0.109 mmol) and stirred at 44° C. for 18 hours. The reaction was diluted with methanol (2 mL), filtered, and purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 11% B at 0 min, followed by 11–51% B over 24 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS signal. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide (14.9 mg, 0.032 mmol, 43% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.57(d,J=7.1Hz,1H), 8.53(t,J=5.9Hz,1H), 7.66(br t,J=9.0Hz,1H), 7.44(s,1H), 7.42-7.34(m,4H), 7.09-7.00(m,2H), 6.05(s,2H), 4.66(br d,J=4.8Hz,1H), 3.85(s,3H), 3.61-3.54(m,1H), 3.33-3.16(m,2H), 1.79(q,J=6.7Hz,2H) MS ESI m / z 469.98(M+H) +

[0325] Example 148: (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide [ka] The title compound was prepared in a similar manner to 147, using (R)-3-amino-1-(4-chlorophenyl)propan-1-ol instead of (S)-3-amino-1-(4-chlorophenyl)propan-1-ol in the final step to give (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide (15.1 mg, 0.031 mmol, 43% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.60-8.52(m,2H), 7.65(t,J=9.0Hz,1H), 7.44(s,1H), 7.42-7.33(m,4H), 7.09-7.01(m,2H), 6.04(s,2H), 4.66(br d,J=3.3Hz,1H), 3.98(br s, 1H), 3.84(s,3H), 3.38-3.21(m,2H), 1.86-1.74(m,2H) MS ESI m / z 469.98(M+H) +

[0326] Example 149: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide [ka] 149A: 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester To a mixture of methyl 5-bromo-2-methylbenzoate (2.00 g, 8.73 mmol) in 1,4-dioxane (30 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.66 g, 10.5 mmol), PdCl(dppf) CHCl adduct (0.356 g, 0.437 mmol), and potassium acetate (2.57 g, 26.2 mmol) were added, sparged with nitrogen gas for several minutes, and then stirred at 110 °C for 1 h. This mixture (estimated yield: 100%) was used directly in the next step. MS ESI m / z 277.1(M+H) +

[0327] 149B: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate methyl To the crude mixture containing methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.41 g, 8.69 mmol), 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.85 g, 8.69 mmol), PdCl(dppf) CHCl adduct (0.284 g, 0.348 mmol), and aqueous KPO (2 M, 10.9 mL, 21.8 mmol) were added. The reaction was degassed and heated to 110 °C for 1 h. The mixture was diluted with water (50 mL), and the aqueous layer was extracted with ethyl acetate (2 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The desired product was crystallized from a mixed solvent of hexane and ethyl acetate to give methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate (2.30 g, 8.15 mmol, 94% yield). MS ESI m / z 283.1(M+H) +

[0328] 149C: Lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate To a solution of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate (261 mg, 0.925 mmol) in THF (5 mL) and a few drops of methanol was added a solution of lithium hydroxide monohydrate (48.5 mg, 1.16 mmol) in water (1.5 mL) and stirred at 60 °C for 3 hours. The solvent was removed under reduced pressure to give crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate (245 mg), which was used directly in the next step. MS ESI m / z 269.11(M+H) +

[0329] 149: To a mixture of lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate (20 mg, 0.075 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol, HCl (21 mg, 0.093 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) in DMF (1 mL) was added BOP (49.5 mg, 0.112 mmol) and stirred at 44° C. for 18 hours. The mixture was diluted with methanol (2 mL), filtered, and purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 15% B at 0 min, followed by 15–55% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide (9.8 mg, 0.022 mmol, 30% yield). 1H NMR (500MHz, DMSO-d6) δ 8.59(d,J=7.0Hz,1H), 8.39(t,J=5.4Hz,1H), 7.76(dd,J=7.9, 1.9Hz,1H), 7.70(d,J=9.5Hz,2H), 7.42-7.36(m,5H), 7.24(dd,J=7.0, 1.8Hz,1H), 6.04(s,2H), 5.43(d,J=4.5Hz,1H), 4.71-4.65(m,1H), 3.46-3.29(m,1H), 2.39(s,3H), 1.86(q,J=6.8Hz,2H) MS ESI m / z 436.08(M+H) +

[0330] Example 150: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-ethylbenzamide [ka] 150A: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethylbenzoate methyl A mixture of (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid (142 mg, 0.800 mmol) and methyl 5-bromo-2-ethylbenzoate (180 mg, 0.740 mmol) in 1,4-dioxane (5 mL) was added to a medium-sized sealable pressure-resistant glass vessel, and the mixture was treated with aqueous KPO (2 M, 1.1 mL, 2.2 mmol) and heated at 100 °C for 30 min. The resulting crude mixture was adsorbed onto Celite and purified on a silica gel flash column chromatography (eluent: methanol / dichloromethane) to give methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethylbenzoate (205 mg, 0.692 mmol, 93% yield). MS ESI m / z 297.0(M+H) +

[0331] 150B: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethylbenzoate lithium To a solution of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethylbenzoate (205 mg, 0.692 mmol) in THF (5 mL) and a few drops of methanol was added a solution of lithium hydroxide monohydrate (36.3 mg, 0.865 mmol) in water (1 mL) and stirred at 60° C. for 18 hours. The solvent was removed under reduced pressure to give crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethylbenzoate (189 mg), which was used directly in the next step. MS ESI m / z 283.09(M+H) +

[0332] 150: To a mixture of crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethylbenzoate (17 mg, 0.060 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol (7.8 mg, 0.042 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.30 mmol) in DMF (1.0 mL) was added BOP (40 mg, 0.090 mmol) and stirred at 44° C. for 3 days. The mixture was diluted with methanol (2 mL), filtered, and the crude filtrate was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 16% B at 0 min, followed by 16–56% B in 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-ethylbenzamide (12.7 mg, 0.028 mmol, 46% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.59(d,J=7.0Hz,1H), 8.40(t,J=5.3Hz,1H), 7.79(dd,J=8.1, 2.0Hz,1H), 7.68(s,1H), 7.68(d,J=4.1Hz,1H), 7.42-7.38(m,5H), 7.24(dd,J=7.0, 1.8Hz,1H), 6.03(s,2H), 5.41(d,J=4.6Hz,1H), 4.76-4.59(m,1H), 2.77(q,J=7.3Hz,2H), 1.86(q,J=7.2Hz,2H), 1.18(t,J=7.5Hz,3H) MS ESI m / z 450.09(M+H) +

[0333] Example 151: (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide [ka] 151A: 3-bromo-2-fluoro-6-methylbenzoic acid methyl ester To a solution of 3-bromo-2-fluoro-6-methylbenzoic acid (307 mg, 1.32 mmol) in DMF (6 mL) was added potassium carbonate (455 mg, 3.29 mmol) and stirred at room temperature for 10 minutes. Iodomethane (0.12 mL, 1.98 mmol) was added, and the mixture was stirred overnight. The resulting mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The EtOAc layer was washed with 10% aqueous LiCl (2x), followed by brine (1x), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3-bromo-2-fluoro-6-methylbenzoate (277 mg, 1.11 mmol, 84% yield) as a yellow oil, which solidified upon standing under high vacuum.

[0334] 151B: N,N-bis-Boc-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid A mixture of bis-Boc-7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 1.210 mmol), bis(pinacolato)diboron (384 mg, 1.51 mmol), potassium acetate (356 mg, 3.63 mmol), and PdCl(dppf) CHCl adduct (49 mg, 0.060 mmol) in 1,4-dioxane (6 mL) was heated at 100 °C for 45 min, and the resulting crude reaction mixture (estimated yield 100%) was used directly in the next step. MS ESI m / z 379.2(M+H) +

[0335] 151C: 3-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate methyl To the crude reaction mixture described in 151B containing N,N-bis-Boc-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid, methyl 3-bromo-2-fluoro-6-methylbenzoate (275 mg, 1.11 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (36 mg, 0.056 mmol) were added and degassed by bubbling nitrogen through for 5 min. Aqueous KPO (2 M, 1.7 mL, 3.34 mmol) was added quickly, and the mixture was heated with stirring at 100 °C for 15 min. The resulting crude reaction mixture was concentrated onto Celite and purified by flash silica column chromatography (elution gradient: 0–100% EtOAc / Hex) to afford methyl 3-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (475 mg, 0.949 mmol, 85% yield) as a beige crystalline solid. MS ESI m / z 501.3(M+H) +

[0336] 151D: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate methyl A solution of methyl 3-(N,N-bis-Boc-2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (475 mg, 0.949 mmol) in 5 mL of TFA was stirred at room temperature overnight. The reaction mixture was concentrated to give methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (285 mg, 0.902 mmol, 95% yield) as a tan solid. MS ESI m / z 301.1(M+H) +

[0337] 151E: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate lithium To a solution of methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (175 mg, 0.583 mmol) in THF (8 mL) and a few drops of methanol, a solution of lithium hydroxide monohydrate (30.6 mg, 0.728 mmol) in water (1.5 mL) was added. This was stirred overnight at 60 ° C. and then concentrated to give crude lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (163 mg, 0.512 mmol, 88% yield) as a solid. This was used directly in the next step. MS ESI m / z 287.2(M+H) +

[0338] 151: A mixture of crude lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoate (15 mg, 0.052 mmol) and BOP (35 mg, 0.079 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol (7.8 mg, 0.042 mmol) and Hunig's base (0.046 mL, 0.26 mmol) in DMF (1.0 mL) was stirred at 42° C. for 3 hours. The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); gradient: 10% B for 0 min, then 10–50% B over 20 min, then 100% B for 4 min; flow rate: 20 mL / min; column temperature: 25°C), and fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (14.1 mg, 0.031 mmol, 59.3% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.65(br t,J=4.5Hz,1H), 8.59(br d,J=7.0Hz,1H), 7.57(br t,J=8.0Hz,1H), 7.48(s,1H), 7.42-7.33(m,4H), 7.22(d,J=8.0Hz,1H), 7.05(br d,J=7.0Hz,1H), 4.66(br t,J=6.2Hz,1H), 3.39-3.24(m,2H), 2.30(s,3H), 1.81(q,J=7.0Hz,2H) MS ESI m / z 454.0(M+H) +

[0339] Example 152: (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide [ka] 152A: 3-Bromo-2-fluoro-6-methylbenzoic acid A mixture of LDA (2.0 M in THF / heptane / ethylbenzene, 34.9 mL, 69.8 mmol) and THF (127 mL) was cooled to −78 °C, and 4-bromo-3-fluorotoluene (8.03 mL, 63.5 mmol) was added dropwise to the cooled mixture with stirring. After the addition was complete, the mixture was stirred at −78 °C for 20 min, and solid powdered charcoal (5.59 g, 127 mmol) was then added in one portion. The yellow mixture quickly turned red and then light yellow. The resulting mixture was stirred at −78 °C for 20 min, and the reaction was quenched by the addition of water and allowed to warm to room temperature. The mixture was further diluted with water and extracted with EtOAc (2x), and the basic aqueous layer was adjusted to pH 1 with the addition of 1 N hydrochloric acid. The resulting suspension was filtered and the solid was dried under vacuum to give 3-bromo-2-fluoro-6-methylbenzoic acid (3.44 g, 14.8 mmol, 23% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.72-7.61(m,1H), 7.11(d,J=8.2Hz,1H), 2.32(s,3H)

[0340] 152B: (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid A stirred mixture of potassium acetate (691 mg, 7.04 mmol), 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 2.35 mmol), PdCl(dppf) CHCl adduct (96.0 mg, 0.117 mmol), and bis(pinacolato)diboron (894 mg, 3.52 mmol) in 1,4-dioxane (10 mL) was heated at 100 °C for 1 h. This mixture (estimated yield: 100%) was used directly in the next step. MS ESI m / z 179.0(M+H) +

[0341] 152C: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoic acid To a stirred crude mixture containing (2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)boronic acid described in 152B, 3-bromo-2-fluoro-6-methylbenzoic acid (750 mg, 3.22 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (120 mg, 0.183 mmol) were added and degassed by bubbling nitrogen through for 5 minutes. Aqueous KPO (2 M, 5.22 mL, 10.4 mmol) was added quickly and heated to 100 °C for 3 hours. The mixture was cooled to room temperature, then diluted with aqueous NaOH (1 N, 50 mL) and extracted with EtOAc (1x). The aqueous layer was acidified with HCl (6 N), causing the product to precipitate out of solution. The solid was isolated by filtration and dried to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoic acid (515 mg, 1.62 mmol, 75% yield) as a tan solid. MS ESI m / z 287.1(M+H) +

[0342] 152: A mixture of 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzoic acid (20 mg, 0.070 mmol), BOP (46.3 mg, 0.105 mmol), (R)-3-amino-1-(4-chlorophenyl)propan-1-ol HCl (19.4 mg, 0.087 mmol), and Hunig's base (0.073 mL, 0.42 mmol) in DMF (1 mL) was stirred at 44 °C for 3 days. The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); mobile phase B: 95:5 Purification was performed using acetonitrile:water (containing 0.1% trifluoroacetic acid); gradient: 15% B at 0 min, followed by 15–55% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C. Fractions were collected as determined by MS and UV signals. Fractions containing the desired product were combined and dried in a centrifugal evaporator to give (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (10.6 mg, 0.023 mmol, 33% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.63(br d,J=6.7Hz,2H), 7.58(br t,J=7.9Hz,1H), 7.52(s,1H), 7.44-7.32(m,4H), 7.29-7.19(m,1H), 7.18-7.08(m,1H), 7.10-6.96(m,1H), 4.66(br t,J=6.4Hz,1H), 3.39-3.25(m,2H), 2.31(s,3H), 1.82(q,J=7.1Hz,2H) MS ESI m / z 454.3(M+H) +

[0343] Table 12: The compounds in Table 12 were prepared in a similar manner to Example 152, using 3-bromo-6-chloro-2-fluorobenzoic acid instead of 3-bromo-2-fluoro-6-methylbenzoic acid in the third step. [ka] [Table 32]

[0344] Example 155: (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide [ka] 155A: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluorobenzoate methyl A stirred mixture of potassium acetate (380 mg, 3.87 mmol), 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (275 mg, 1.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (53 mg, 0.065 mmol), and bis(pinacolato)diboron (492 mg, 1.94 mmol) in 1,4-dioxane (5 mL) was heated at 100 °C for 1 h, and methyl 3-bromo-6-chloro-2-fluorobenzoate (300 mg, 1.12 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium(II) (37 mg, 0.056 mmol) were added. Nitrogen was bubbled through the mixture for 5 minutes to degas the reaction. Aqueous tripotassium phosphate (2 M, 1.68 mL, 3.36 mmol) was quickly added and stirred at room temperature overnight. The crude reaction mixture was concentrated onto Celite and purified by flash column chromatography (24 g silica, elution gradient: 0–100% ethyl acetate / Hex, followed by 0–10% methanol / dichloromethane). Pure fractions were combined and concentrated under reduced pressure to give methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluorobenzoate (335 mg, 0.992 mmol, 88% yield) as a beige solid. MS ESI m / z 321.2(M+H) +

[0345] 155B: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-vinylbenzoate methyl ester A mixture of methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluorobenzoate (350 mg, 1.09 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (49.3 mg, 0.120 mmol), palladium(II) acetate (12.3 mg, 0.055 mmol), and 6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione (399 mg, 2.18 mmol) in 1,4-dioxane (6.5 mL) was purged with nitrogen for 1 minute, and aqueous potassium phosphate (2 M, 3.00 mL, 6.00 mmol) was added. The mixture was heated at 100°C for 1 hour. The yellow reaction mixture turned orange within 40 minutes of heating to 100 °C. The resulting crude reaction mixture was concentrated onto Celite and purified by flash column chromatography (24 g silica, elution gradient: 0–100% ethyl acetate / Hex, followed by 0–10% methanol / dichloromethane). Pure fractions were combined and concentrated in vacuo to give methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-vinylbenzoate (217 mg, 0.695 mmol, 64% yield). MS ESI m / z 313.2(M+H) +

[0346] 155C: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate methyl To a solution of methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-vinylbenzoate (217 mg, 0.695 mmol) in ethanol (6.5 mL) was added 10% palladium on carbon (73.9 mg, 0.069 mmol). The vessel was placed under vacuum for 5 minutes to degas the mixture, and then filled with hydrogen gas. The mixture was stirred under a hydrogen atmosphere overnight at room temperature, and the reaction mixture was filtered and concentrated under reduced pressure to give solid methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate (220 mg, 0.630 mmol, 91% yield). The product was used directly without further purification. MS ESI m / z 315.2(M+H) +

[0347] 155D: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate lithium To a solution of methyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate (220 mg, 0.700 mmol) in tetrahydrofuran (5 mL) and a few drops of methanol was added a solution of lithium hydroxide monohydrate (36.7 mg, 0.875 mmol) in water (1 mL), and the resulting mixture was stirred at 65° C. overnight. The mixture was concentrated to a solid to give crude lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate. This material was used directly without further purification. MS ESI m / z 301.2(M+H) +

[0348] 155: A mixture of crude lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate (15 mg, 0.050 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (33 mg, 0.075 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol (7.8 mg, 0.042 mmol) and diisopropylethylamine (0.044 mL, 0.25 mmol) in dimethylformamide (1.0 mL) was stirred at 40° C. for 3 days. The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 17% B at 0 min, then 17-57% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C), and fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide (11.8 mg, 0.025 mmol, 51% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.66(t,J=5.7Hz,1H), 8.61(d,J=7.1Hz,1H), 7.62(t,J=8.1Hz,1H), 7.49(s,1H), 7.42-7.36(m,4H), 7.26(d,J=8.0Hz,1H), 7.05(d,J=7.0Hz,1H), 6.09(s,2H), 5.44(d,J=4.5Hz,1H), 4.69-4.63(m,1H), 3.38-3.26(m,1H), 2.64(q,J=7.5Hz,2H), 1.81(q,J=7.0Hz,2H), 1.20 (t, J = 7.6 Hz, 3H); some proton signals disappeared due to water suppression. MS ESI m / z 468.1(M+H) +

[0349] Example 156: (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide [ka] A mixture of crude lithium 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-ethyl-2-fluorobenzoate (22 mg, 0.073 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (48.6 mg, 0.110 mmol), (R)-3-amino-1-(4-chlorophenyl)propan-1-ol hydrochloride (20 mg, 0.092 mmol), and diisopropylethylamine (0.077 mL, 0.440 mmol) in dimethylformamide (1.0 mL) was stirred at 44 °C for 3 days. The resulting crude material was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 15% B at 0 min, followed by 15–52% B over 25 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected based on MS signal. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide (10.6 mg, 0.023 mmol, 31% yield). 1H NMR (500MHz, DMSO-d6) δ 8.65-8.60(m,2H), 7.62(t,J=8.1Hz,1H), 7.50(s,1H), 7.42-7.36(m,4H), 7.26(d,J=7.9Hz,1H), 7.05(br d,J=7.0Hz,1H), 6.07(s,2H), 5.40(d,J=4.6Hz,1H), 4.73-4.60(m,1H), 2.65(q,J=7.3Hz,2H), 1.92-1.77(m,1H), 1.82(br d,J=6.7Hz,1H), 1.21(t,J=7.6Hz,3H) MS ESI m / z 468.3(M+H) +

[0350] Example 157: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-ethyl-4-fluorobenzamide [ka] 157A: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-4-fluorobenzoate methyl ester A stirred mixture of potassium acetate (380 mg, 3.87 mmol), 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (275 mg, 1.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (53 mg, 0.065 mmol), and bis(pinacolato)diboron (492 mg, 1.94 mmol) in 1,4-dioxane (5 mL) was heated at 100 °C for 1 h. To this reaction mixture was added methyl 5-bromo-2-chloro-4-fluorobenzoate (300 mg, 1.12 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium(II) (37 mg, 0.056 mmol). Nitrogen was bubbled through the mixture for 5 minutes to degas the reaction. Aqueous potassium phosphate trihydrate (2 M, 1.7 mL, 3.36 mmol) was quickly added, and the mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated onto Celite and purified by flash column chromatography (24 g silica, elution gradient: 0–100% ethyl acetate / Hex, followed by 0–10% methanol / dichloromethane). Pure fractions were concentrated under reduced pressure to afford methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-4-fluorobenzoate (293 mg, 0.868 mmol, 77% yield) as a beige solid. MS ESI m / z 321.2(M+H) +

[0351] 157B: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-vinylbenzoate methyl ester A mixture of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-4-fluorobenzoate (293 mg, 0.914 mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (41.3 mg, 0.100 mmol), palladium(II) acetate (10 mg, 0.046 mmol), and 6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione (334 mg, 1.83 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen for 1 min. Aqueous potassium phosphate (2 M, 2.51 mL, 5.02 mmol) was added, and the mixture was heated at 100 °C for 1 h. The yellow reaction mixture turned orange within 40 minutes of initiating heating at 100 °C. The resulting crude reaction mixture was concentrated onto Celite and purified by flash column chromatography (24 g silica, elution gradient: 0–100% ethyl acetate / Hex, followed by 0–10% methanol / dichloromethane). Pure fractions were combined and concentrated under reduced pressure to give methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-vinylbenzoate (111 mg, 0.355 mmol, 39% yield). MS ESI m / z 313.1(M+H) +

[0352] 157C: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethyl-4-fluorobenzoate methyl To a solution of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-2-vinylbenzoate (111 mg, 0.355 mmol) in ethanol (6.5 mL) was added 10% palladium on carbon (38 mg, 0.036 mmol). The mixture was degassed under vacuum for 5 minutes, then the vessel was filled with hydrogen gas and stirred under a hydrogen atmosphere at room temperature for 3 days. The reaction mixture was filtered and concentrated under reduced pressure to give a solid methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethyl-4-fluorobenzoate (79 mg, 0.25 mmol, 71% yield). The product was used directly without further purification. MS ESI m / z 315.2(M+H) +

[0353] 157D: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethyl-4-fluorobenzoate lithium To a solution of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethyl-4-fluorobenzoate (79 mg, 0.25 mmol) in tetrahydrofuran (5 mL) and a few drops of methanol, a solution of lithium hydroxide monohydrate (13.2 mg, 0.314 mmol) in water (1 mL) was added and stirred at 60 ° C. overnight. The mixture was concentrated under reduced pressure to a solid to give crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethyl-4-fluorobenzoate (75 mg, 0.25 mmol, 99% yield). The resulting material was used directly without further purification. MS ESI m / z 301.1(M+H) +

[0354] 157: A mixture of crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-ethyl-4-fluorobenzoate (13 mg, 0.043 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (29 mg, 0.065 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol (7.8 mg, 0.042 mmol) and diisopropylethylamine (0.038 mL, 0.22 mmol) in dimethylformamide (1.0 mL) was stirred at 40° C. for 3 days. The resulting crude mixture was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing ammonium acetate); gradient: 20% B at 0 min, followed by 20–60% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-ethyl-4-fluorobenzamide (8.1 mg, 0.017 mmol, 39% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.62(d,J=6.9Hz,1H), 8.41(t,J=5.4Hz,1H), 7.58(s,1H), 7.55(d,J=8.0Hz,1H), 7.38(s,4H), 7.30(d,J=12.1Hz,1H), 7.10(br d,J=7.0Hz,1H), 6.09(s,2H), 5.43(d,J=4.5Hz,1H), 4.71-4.61(m,1H), 3.36-3.25(m,1H), 2.78(q,J=7.3Hz,2H), 1.84(q,J=6.8Hz,2H), 1.18(t,J=7.5Hz,3H) MS ESI m / z 468.1(M+H)+

[0355] Example 158: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3-fluoro-2-methylbenzamide [ka] 158A: 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate methyl A stirred mixture of potassium acetate (691 mg, 7.04 mmol), 7-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 2.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (96 mg, 0.12 mmol), and bis(pinacolato)diboron (894 mg, 3.52 mmol) in 1,4-dioxane (10 mL) was heated at 100 °C for 1 h. To this reaction mixture was added methyl 5-bromo-3-fluoro-2-methylbenzoate (600 mg, 2.43 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium(II) (79 mg, 0.12 mmol). Nitrogen was bubbled through the mixture for 5 minutes to degas the reaction. Aqueous potassium phosphate trihydrate (2 M, 3.64 mL, 7.29 mmol) was quickly added and heated to 100 °C for 30 minutes. The crude reaction mixture was concentrated onto Celite and purified by flash column chromatography (40 g silica, elution gradient: 0–100% ethyl acetate / Hex, followed by 0–10% methanol / dichloromethane). Pure fractions were combined and concentrated under reduced pressure to give methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate (677 mg, 2.21 mmol, 91% yield). MS ESI m / z 301.1(M+H) +

[0356] 158B: Lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate To a solution of methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate (677 mg, 2.21 mmol) in tetrahydrofuran (10 mL) and a few drops of methanol, a solution of lithium hydroxide monohydrate (114 mg, 2.71 mmol) in water (1.5 mL) was added and stirred at 60 °C for 3 days. An additional solution of lithium hydroxide monohydrate (5 mg) in water (0.5 mL) was added and stirred at 60 °C for 6 hours. The mixture was concentrated under reduced pressure to give crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate (599 mg, 1.99 mmol, 88% yield) as a beige solid. The resulting material was used directly without further purification.

[0357] 158: A mixture of lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-2-methylbenzoate (22 mg, 0.077 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (51 mg, 0.115 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol hydrochloride (21.3 mg, 0.096 mmol), and diisopropylethylamine (0.081 mL, 0.461 mmol) in dimethylformamide (1.0 mL) was stirred at 44 °C overnight. The resulting crude mixture was purified by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 15% B for 0 min, followed by 15–55% B over 20 min, then 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3-fluoro-2-methylbenzamide (8.1 mg, 0.018 mmol, 23% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.60(d,J=7.3Hz,1H), 8.47(br t,J=5.2Hz,1H), 7.76(s,1H), 7.74(d,J=11.4Hz,1H), 7.58(s,1H), 7.40(s,4H), 7.28(dd,J=7.0, 1.8Hz,1H), 6.06(s,2H), 5.43(d,J=4.6Hz,1H), 4.76-4.65(m,1H), 3.33(br s, 1H), 2.31-2.26(m,3H), 1.92-1.83(m,2H) MS ESI m / z 454.0(M+H) + Example 159: (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide [ka] 159A: Ethyl 5-bromo-2-methylbenzoate A solution of 5-bromo-2-methylbenzoic acid (1.50 g, 6.98 mmol) in ethanol (20 mL) and sulfuric acid (0.558 mL, 10.5 mmol) was heated to reflux and stirred overnight. The ethanol was removed under reduced pressure, and the remaining mixture was neutralized by careful addition of 10% aqueous sodium bicarbonate. The resulting crude residue was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 5-bromo-2-methylbenzoate (1.45 g, 5.67 mmol, 81% yield) as an oil.

[0358] 159B: methyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate A stirred mixture of potassium acetate (346 mg, 3.52 mmol), 7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (250 mg, 1.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex·dichloromethane adduct (48 mg, 0.059 mmol), and bis(pinacolato)diboron (447 mg, 1.76 mmol) in 1,4-dioxane (5 mL) was heated at 100 °C for 45 min. To this reaction mixture was added ethyl 5-bromo-2-methylbenzoate (310 mg, 1.275 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium(II) (42 mg, 0.064 mmol). Nitrogen was bubbled through the mixture for 5 minutes to degas the reaction. Aqueous potassium phosphate trihydrate (2 M, 1.9 mL, 3.83 mmol) was quickly added and heated to 100 °C for 30 minutes. The crude reaction mixture was concentrated onto Celite and purified by flash column chromatography (24 g silica, elution gradient: 0–100% ethyl acetate / Hex, followed by 0–10% methanol / dichloromethane). Pure fractions were combined and concentrated under reduced pressure to give ethyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate (261 mg, 0.872 mmol, 68% yield) as a beige solid. MS ESI m / z 297.3(M+H) +

[0359] 159C: Lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate To a solution of ethyl 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate (261 mg, 0.872 mmol) in tetrahydrofuran (5 mL) and a few drops of methanol was added a solution of lithium hydroxide monohydrate (48.5 mg, 1.16 mmol) in water (1.5 mL) and stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate (245 mg, 0.822 mmol, 89% yield) as a light brown solid. The resulting material was used directly without further purification. MS ESI m / z 269.1(M+H) +

[0360] 159: A mixture of crude lithium 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methylbenzoate (20 mg, 0.075 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (49.5 mg, 0.112 mmol), (R)-3-amino-1-(4-chlorophenyl)propan-1-ol hydrochloride (21 mg, 0.093 mmol), and diisopropylethylamine (0.078 mL, 0.48 mmol) in dimethylformamide (1.0 mL) was stirred at 44 °C for 3 days. The resulting crude mixture was analyzed by preparative LCMS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.05% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.05% trifluoroacetic acid); gradient: 10% B at 0 min, followed by 10–50% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected as determined by MS and UV signals. Fractions containing the desired product were combined and dried in a centrifugal evaporator to give (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide (17.4 mg, 0.038 mmol, 51% yield). 1 H NMR (500MHz, DMSO-d6) δ 8.66(d,J=7.0Hz,1H), 8.39(br t,J=5.3Hz,1H), 7.78(br d,J=7.9Hz,1H), 7.75-7.68(m,2H), 7.42-7.35(m,7H), 4.68(t,J=6.6Hz,1H), 3.33(br d,J=7.0Hz,1H), 2.39(s,3H), 1.87(q,J=6.8Hz,2H) MS ESI m / z 436.1(M+H) +

[0361] Example 160: 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-fluoropropyl)-2-fluoro-6-methylbenzamide [ka] Under a nitrogen atmosphere, a mixture of (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (25 mg, 0.055 mmol) in DCM (1 mL) at 0° C. was treated with a solution of Deoxo-Fluor (0.015 mL, 0.083 mmol) in DCM (1 mL) via syringe over 30 min, stirred at 0° C. for 1 h, and then warmed to room temperature. The mixture was quenched by the addition of several drops of methanol. The resulting crude mixture was concentrated under reduced pressure and then redissolved in methanol and purified by preparative LC / MS (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 23% B at 0 min, followed by 23–63% B over 20 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions were collected as determined by MS and UV signals. The fractions containing the desired product were combined and dried on a centrifugal evaporator to give 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-fluoropropyl)-2-fluoro-6-methylbenzamide (5.2 mg, 0.011 mmol, 21% yield). 1H NMR (600MHz, DMSO-d6) δ 8.70(t,J=5.5Hz,1H), 8.56(d,J=6.6Hz,1H), 7.54(t,J=8.1Hz,1H), 7.47-7.42(m,3H), 7.41-7.36(m,2H), 7.18(d,J=8.1Hz,1H), 6.98(br d,J=7.0Hz,1H), 6.04(s,2H), 5.71-5.53(m,1H), 3.46-3.20(m,2H), 2.26(s,3H), 2.19-1.92(m,2H) MS ESI m / z 456.0(M+H) +

[0362] Example 161: 3-(3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzamido)-2,2-difluoro-1-(4-fluorophenyl)propyl phosphate (racemic) [ka] To a solution of 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide (47 mg, 0.099 mmol) and di-tert-butyl diisopropylphosphoramidite (0.066 mL, 0.208 mmol) in DMF (1 mL) was added 1H-tetrazole (14.60 mg, 0.208 mmol) at 0 °C and stirred overnight at 0 °C to RT. The reaction mixture was partitioned between EtOAc (30 mL) and water (25 mL). The organic layer was washed with 10% LiCl solution (2 × 20 mL) and brine (20 mL). After drying over anhydrous sodium sulfate, the organic layer was concentrated, and the resulting residue was chromatographed (4 g silica gel cartridge, elution gradient: 0 to 9% MeOH / CHCl). The product-containing fractions were concentrated to give a mixture of 3-(3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzamido)-2,2-difluoro-1-(4-fluorophenyl)propyl di-tert-butylphosphate and di-tert-butyl (7-(3-((3-((di-tert-butoxyphosphoryl)oxy)-2,2-difluoro-3-(4-fluorophenyl)propyl)carbamoyl)-2-fluoro-4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)phosphoramidate (55 mg) as a white solid. This mixture was dissolved in TFA (1 mL) and allowed to stand at room temperature for 1.5 hours. Volatiles were removed under reduced pressure, and the resulting residue was dissolved in DMF and purified by preparative LC / MS (conditions: column: XBridge C18, 2...

Claims

1. Formula (Ie): 【Chemical 1】 [In the formula, R ６ａ and R ６ｂ is F, R １ is CH ３ , CDs ３ , C.F. ３ or Cl, R ２ is F, R ３ is H, R ４ is H, and Y is F or Cl. or a salt thereof.

2. The compound of formula (Ie) may be a compound of formula (If): 【Chemistry 2】 or 【Chemistry 3】 2. The compound of claim 1, which is a compound of the formula:

3. The compound has the formula (If): 【Chemistry 4】 3. The compound of claim 2, which is a compound of the formula:

4. The compound has the formula (Ig): 【Chemistry 5】 3. The compound of claim 2, which is a compound of the formula:

5. The compound of formula (Ie) has the following formula: 【Chemistry 6】 2. The compound of claim 1, which is a compound of the formula:

6. The compound of formula (Ie) has the following formula: 【Chemistry 7】 2. The compound of claim 1, which is a compound of the formula:

7. The compound of formula (Ie) has the following formula: 【Chemistry 8】 2. The compound of claim 1, which is a compound of the formula:

8. The compound of formula (Ie) has the following formula: 【Chemistry 9】 2. The compound of claim 1, which is a compound of the formula:

9. The compound of formula (Ie) has the following formula: 【Chemistry 10】 2. The compound of claim 1, which is a compound of the formula:

10. The compound of formula (Ie) has the following formula: 【Chemistry 11】 2. The compound of claim 1, which is a compound of the formula:

11. The compound of formula (Ie) has the following formula: 【Chemistry 12】 2. The compound of claim 1, which is a compound of the formula:

12. The compound of formula (Ie) has the following formula: 【Chemistry 13】 2. The compound of claim 1, which is a compound of formula:

13. The compound of formula (Ie) has the following formula: 【Chemistry 14】 2. The compound of claim 1, which is a compound of formula:

14. The compound of formula (Ie) has the following formula: 【Chemistry 15】 2. The compound of claim 1, which is a compound of formula:

15. The compound of formula (Ie) has the following formula: 【Chemistry 16】 2. The compound of claim 1, which is a compound of formula:

16. The compound of formula (Ie) has the following formula: 【Chemistry 17】 2. The compound of claim 1, which is a compound of formula:

17. The compound of formula (Ie) has the following formula: 【Chemistry 18】 2. The compound of claim 1, which is a compound of formula:

18. The compound of formula (Ie) has the following formula: 【Chemistry 19】 2. The compound of claim 1, which is a compound of formula:

19. below: (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(5-chloropyridin-2-yl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-fluoro-N-(3-(4-fluorophenyl)-3-hydroxypropyl)-2-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(4,4,4-trifluoro-3-phenylbutyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl-1,1,3-d 3 )-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-methylbutyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(2-(1-(4-fluorophenyl)cyclopropyl)ethyl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxybutyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-[4-(4-chlorophenyl)-4-hydroxybutan-2-yl]-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(3,4-dichlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-cyclohexyl-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(3-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(5-chloropyridin-2-yl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(4-fluorophenyl)-3-hydroxypropyl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-cyclohexylpropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl-1,1,3-d 3 )-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(3-methyl-3-phenylbutyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxybutyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(3-fluorophenyl)-3-hydroxypropyl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chloro-2-methoxyphenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(3,4-difluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chloro-2-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(2-fluorophenyl)-3-hydroxypropyl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(3-fluoro-2-methoxyphenyl)-3-hydroxypropyl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(2,6-difluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl-1,1,3-d 3 )-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-(3-(4-fluorophenyl)-3-hydroxypropyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(5-chloropyridin-2-yl)-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-(2-(1-(4-fluorophenyl)cyclopropyl)ethyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)propyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-2-fluorobenzamide; (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)benzamide; (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)benzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-phenylbutyl)benzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-hydroxy-3-phenylbutyl)benzamide; (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3-fluoro-2-methylbenzamide; 5-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-3-fluoro-2-methyl-N-(3-phenylbutyl)benzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-fluoro-N-(3-hydroxy-3-phenylbutyl)-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-4-fluoro-2-methylbenzamide; (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(4-(4-chlorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-3,4-difluoro-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-3,4-difluoro-2-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-6-chloro-N-[3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl]-2-fluorobenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl]-2-fluoro-6-methoxybenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[3-(5,6-dichloropyridin-2-yl)-2,2-difluoro-3-hydroxypropyl]-2-fluoro-6-methoxybenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-6-chloro-N-[2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl]-2-fluorobenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl]-2-fluoro-6-methoxybenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl]-6-ethyl-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-cyclopropyl-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide; 3-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide; 3-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-fluorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide; (S)-3-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-{2-amino-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[(3S)-3-(4-cyanophenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[3-(3-cyanophenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[3-(4-cyanophenyl)-3-hydroxybutyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[(3S)-3-(4-ethynylphenyl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[3-(4-chlorophenyl)-3-oxopropyl]-2-fluoro-6-methylbenzamide; (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-methylbenzamide; (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2,4-dimethylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methoxybenzamide; (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide; (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-ethylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide; (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-ethyl-4-fluorobenzamide; (S)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-3-fluoro-2-methylbenzamide; (R)-5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-fluoropropyl)-2-fluoro-6-methylbenzamide; 3-(3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzamido)-2,2-difluoro-1-(4-fluorophenyl)propyl phosphate; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chloro-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(2-fluoro-4-(trifluoromethyl)phenyl)-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(2,3-difluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-6-chloro-N-[2,2-difluoro-3-(3-fluorophenyl)-3-hydroxypropyl]-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(3-chloro-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-hydroxy-3-(p-tolyl)propyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-hydroxy-3-(m-tolyl)propyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(2,5-difluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(5-chloro-2-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(2-fluoro-4-methylphenyl)-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-hydroxy-3-(4-methoxyphenyl)propyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-(difluoromethoxy)phenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(3,5-difluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chloro-3-fluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(3-chlorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-(difluoromethyl)-2-fluoro-N-(2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl-4,4,4-d3)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(3,4-difluorophenyl)-2,2-difluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-hydroxy-3-(4-methyl-d 3 )phenyl)propyl)-2-fluoro-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(2-fluoro-3-(4-fluorophenyl)-3-hydroxy-2-methylpropyl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(2-fluoro-3-methyl-d 3 )phenyl)-3-hydroxypropyl)-2-fluoro-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)propyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)propyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2S,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2R,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2S,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2R,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((2S,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((2R,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((2S,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((2R,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-6-(methyl-d 3 ) benzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2,4-difluorobenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2,4-difluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-fluorobenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxybutyl)-4-fluoro-2-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-hydroxy-3-(4-(trifluoromethyl)phenyl)butyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-fluorobutyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl-1,1-d 2 )-2-fluorobenzamide; 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-3-fluoro-2-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-methoxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-(methoxy-d 3 )propyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-(2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl-4,4,4-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-2-fluoro-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxybutyl-4,4,4-d 3 )-2-fluoro-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-2-(3-(4-fluorophenyl)oxetan-3-yl)ethyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-2-(3-(4-fluorophenyl)oxetan-3-yl)ethyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-cyclopentyl-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,6-difluoro-N-(2-(1-(4-fluorophenyl)cyclopropyl)ethyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl-1,1,3-d 3 )-2,6-difluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-2,2-difluoro-3-hydroxybutyl)-2-fluoro-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-hydroxy-3-(6-(trifluoromethyl)pyridin-2-yl)propyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4,4-difluorocyclohexyl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(3,3-difluorocyclobutyl)-2,2-difluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)propyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(6-chloropyridin-2-yl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-6-chloro-N-[3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl]-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl)-6-ethyl-2-fluorobenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[3-(3,4-dichlorophenyl)-2,2-difluoro-3-hydroxypropyl]-2-fluoro-6-methoxybenzamide; 3-{2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-N-[2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-hydroxypropyl]-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(5,6-dichloropyridin-2-yl)-2,2-difluoro-3-hydroxypropyl)-2-fluorobenzamide; Methyl 4-(3-(3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluorobenzamido)propyl)benzoate; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methyl-N-(2,2,4,4-tetrafluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide; N-(3-amino-2,2-difluoro-3-(4-fluorophenyl)propyl)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzamide; (S)-3-(3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-6-methylbenzamido)-2,2-difluoro-1-(4-fluorophenyl)propylcarbamate; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2,4-difluoro-6-methylbenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2,4-difluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(3-(4-fluorophenyl)-2-hydroxy-2-methyl-3-oxopropyl)-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-oxopropyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-oxopropyl)-2-fluoro-6-methylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-(2,2,3-trifluoro-3-(4-fluorophenyl)propyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-hydroxy-3-(2,4,6-trifluorophenyl)propyl)-2-fluoro-6-methylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,6-difluoro-N-(2,2,3-trifluoro-3-(4-fluorophenyl)propyl)benzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(2,2,3-trifluoro-3-(4-fluorophenyl)propyl)-6-(trifluoromethyl)benzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,6-difluoro-N-(2,2,3-trifluoro-3-(4-fluorophenyl)propyl)benzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-(2,2,3-trifluoro-3-(4-fluorophenyl)propyl)benzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(2,2,3-trifluoro-3-(4-fluorophenyl)propyl)-6-(trifluoromethyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3,3-difluoro-3-(4-fluorophenyl)-2-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-(1-fluoro-4-(4-fluorophenyl)-4-hydroxybutan-2-yl)-6-methylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-(fluoromethyl)benzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-(difluoromethyl)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2S,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2R,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2R,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2S,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((2R,3S)-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((2S,3R)-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((2S,3S)-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((2R,3R)-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-cyclopropyl-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; (R)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-cyclopropyl-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluorobenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-6-(difluoromethoxy)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((1-((4-fluorophenyl)(hydroxy)methyl)cyclopropyl)methyl)-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((1-((4-fluorophenyl)(hydroxy)methyl-d)cyclopropyl)methyl)-6-(methyl-d 3 ) benzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-(difluoromethyl)phenyl)-2,2-difluoro-3-hydroxypropyl-3-d)-2-fluorobenzamide; 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypentyl)-2-fluorobenzamide; (S)-3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(2,2-difluoro-3-(4-fluorophenyl)-3-hydroxypropyl)-2-fluoro-6-(trifluoromethyl)benzamide; and 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3-phenylbutyl)benzamide or a salt thereof.

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. 20. A pharmaceutical composition for therapeutic use comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

22. 22. The pharmaceutical composition for treating the disease of claim 21, wherein the disease is selected from inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis (RA), NASH, and heart failure.

23. 22. The pharmaceutical composition for treating the disease of claim 21, wherein the disease is selected from multiple sclerosis, amyotrophic lateral sclerosis, or Alzheimer's disease.

24. 22. The pharmaceutical composition for treating the disease of claim 21, wherein the disease is selected from inflammatory bowel disease, ulcerative colitis, and Crohn's disease.

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