1H-Indazole carboxamides as receptor-interacting protein kinase 1 (RIPK1) inhibitors

Abstract

Formula (I): Compounds having the formula: and their enantiomers, diastereomers, stereoisomers, and pharmaceutically acceptable salts are useful as kinase modulators, such as for RIPK1 modulation. All variables are as defined herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority pursuant to 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 730,602, filed September 13, 2018, which is incorporated herein by reference in its entirety.

[0002] 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 indazole carboxamides as receptor interacting protein kinase 1 (RIPK1) inhibitors. [Background technology]

[0003] Apoptosis and necrosis represent two distinct mechanisms of cell death. Apoptosis is a highly regulated process that involves the caspase family of cysteine ​​proteases and is characterized by cell shrinkage, chromatin condensation, and DNA degradation. In contrast, necrosis is associated with cell and organelle swelling and plasma membrane rupture, with release of intracellular contents and secondary inflammation (Kroemer et al., (2009) Cell Death Differ 16:3-11). Necrosis is considered to be 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 kinase (RIPK), especially 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 activation of the extrinsic caspase pathway. Furthermore, in some caspase-8-deficient cells or in 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).

[0004] Necroptosis can be triggered by many mechanisms, including TNF receptor activation, Toll-like receptor engagement, genotoxic stress, and viral infection. Downstream of various stimuli, the signaling pathway that results in necroptosis 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).

[0005] Dysregulation of the necroptosis signaling pathway has been linked to macrophage necrosis in the development of atherosclerosis, viral-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), and Gaucher disease (Trichonas et al., (2010) Proc. Natl. Acad. Sci. 107, 21695-21700; Lin et al., (2013) Cell Rep. 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; Vandenabeele 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. al., (2016) Science 353, 603-608; Vitner et al., (2014) Nature Med. 20, 204-208).

[0006] Potent and selective small molecule inhibitors of RIPK1 activity would inhibit RIPK1-dependent proinflammatory signaling, thereby providing therapeutic benefit in inflammatory diseases characterized by elevated and / or dysregulated RIPK1 kinase activity. Summary of the Invention

[0007] The present invention provides novel indazole carboxamides, stereoisomers, tautomers, isotopes, prodrugs, pharma- ceutically acceptable salts, salts, or solvates thereof, useful as inhibitors of RIPK1.

[0008] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0009] The present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and at least one compound of the present invention, or a stereoisomer, tautomer, isotope, prodrug, pharma- ceutically acceptable salt, salt, or solvate thereof.

[0010] The compounds of the present invention may be used in the treatment and / or prevention of pathologies associated with abnormal RIPK1 activity. The compounds of the invention may be used in therapy.

[0011] 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 abnormal RIPK1 activity.

[0012] 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, comprising administering to a patient in need of such treatment a compound of the present invention as described above.

[0013] 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. These and other features of the invention will be described in expanded form as the disclosure continues.

[0014] Detailed Description of the Invention In one aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, R a H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuteroalkyl, C 1-4 Deuteroalkoxy, cyclopropyl, or N(R e )2; R b H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Deuteroalkyl, C 1-4 Deuteroalkoxy, or N(R e )2; R c , H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 deuteroalkyl, or halo; R d are independently H, halo, or C 1-3 is alkyl; R e are independently H, C 1-4 Alkyl, or C 1-4 is a deuteroalkyl; R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 Alkyl-phenyl, C 0-3Alkyl-heterocycle, where the heterocycle is a 3-6 membered ring having 1-3 heteroatoms selected from N, S, and O, where the alkyl, cycloalkyl, phenyl, or heterocycle are independently selected from =O, halo, OH, C 1-3 Alkyl, C 1-3 Deuteroalkyl, -C(O)-C 1-3 Alkyl, -SO2-C 1-3 Alkyl, -N(R 1e )2, phenyl, or phenyl-OC 1-3 substituted with 0-2 of alkyl; R 1e are independently H, C 1-4 Alkyl, or C 1-4 is a deuteroalkyl; L is -C(O)NR e - and; A is A 1 or -A 1 -L 1 - where A 1 is C substituted with 0-1 OH. 1-6 Alkyl, C substituted with 0-1 OH 1-6 Deuteroalkyl, C substituted with 0-1 OH 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Haloalkyl, C 0-3 Alkyl-C 3-10 Cycloalkyl-C 0-3 -Alkyl, C 0-3 -Alkyl-phenyl, C 0-3 -alkyl-heterocycle, where the heterocycle is a 3-6 membered ring having 1-3 heteroatoms selected from N, S, and O, where the cycloalkyl, phenyl, and heterocycle are each independently selected from 0-2 R 8 Replaced with; L 1 is -O-, -S-, -C(O)-, -C(O)NR e , -SO2NH-, -NHSO2-, -C(O)O-, -NR e -C(O)-, -NR e -C(O)O-, -NRe -C(O)NR e -, -SO2-, or -NH-R e - and; Alternatively, -LA- is [ka] and; R 2 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-3 Alkyl-C 6-10 Aryl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C having 1 to 4 heteroatoms selected from N, S, and O 0-3 alkyl-3-6 membered heterocycle, where each aryl, cycloalkyl, or heterocycle group is selected from 0-3 R 2a Replaced with; R 2a is halo, CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy-C 1-6 Alkoxy, C 1-6 Deuteroalkyl, C 1-6 Deuteroalkoxy, C 1-6 -Haloalkyl, C 1-6 Haloalkoxy, C 0-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl, C 3-6 Halocycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl-C 1-6 Alkoxy, C 6-10 Aryl, Phenyl-C 1-3 Alkoxy-, C 3-6 Cycloalkyl-C 1-3 Deuteroalkoxy-, C 3-6 Cycloalkyl-C 1-3 Haloalkoxy-, C 1-6 Alkoxy-C 1-3 Alkyl-, C 3-6 Cycloalkoxy-C 1-3Alkyl-, C 6-10 Aryl-O-, Phenyl C 1-4 Alkyl-SO2-, C 3-6 Cycloalkyl-SO2-, C 6-10 Aryl-S-, NR 6 R 6 CO-, NHR 6 -(CH2) n -, R 5 -C(O)-, R 5 -OC(O)-, R 5 -C(O)O-, R 6 -NH-C(O)O-, R 7 -OC(O)NH-, R 6 -NH-C(O)NR 6 , R 7 -SO2-, R 5 -SO2NH-, R 5 -NHSO2-, Heterocycle, Heterocycle-O-, or Heterocycle-C 0-6 alkyl-, where each heterocycle is a 4-6 membered ring having 1-2 heteroatoms independently selected from N, S, and O, and where each alkyl, cycloalkyl, phenyl, or heterocycle is independently selected from 0-3 R 2b Replaced with; R 2b are independently halo, OH, C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy-C 1-3 Alkoxy, Hydroxy-C 1-3 Alkyl, C=O, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; R 5 are independently H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 Alkyl-phenyl, or C 1-6 is haloalkyl; R 6 are independently H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6Cycloalkyl, C 0-3 is alkyl-phenyl; R 7 In each event, independently, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 is alkyl-phenyl; R 8 are independently H, halo, C=O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocycle, -(CH2) n -NR 6 R 6 CO, -(CH2) n -NR 6 R 6 CONR 6 R 6 , -(CH2) n -NR 6 , -(CH2) n -C(O)-R 5 , -(CH2) n -C(O)OR 5 , -(CH2) n -OC(O)-R 5 , -(CH2) n -OC(O)-NH-R 6 , -(CH2) n -NHC(O)-OR 7 , -(CH2) n -SO2-R 7 , -(CH2) n -SO2NH-R 5 , -(CH2) n -NHSO2-R 5 wherein each heterocycle is a 4-6 membered ring having 1-2 heteroatoms independently selected from N, S, and O; n is 0, 1, or 2.] or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0015] In another embodiment, a compound of formula (I): [ka] [In the formula, R a H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuteroalkyl, C 1-4 Deuteroalkoxy, cyclopropyl, or N(R e )2; R b H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Deuteroalkyl, C 1-4 Deuteroalkoxy, halo, or NR e 2; R c , H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 deuteroalkyl, or halo; R d are independently H, halo, or C 1-3 is alkyl; R e are independently H, C 1-4 Alkyl, or C 1-4 is a deuteroalkyl; R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 Alkyl-phenyl, C 0-3Alkyl-heterocycle, where the heterocycle is a 3-6 membered ring having 1-3 heteroatoms selected from N, S, and O, where the alkyl, cycloalkyl, phenyl, or heterocycle are independently selected from =O, halo, OH, C 1-3 Alkyl, C 1-3 Deuteroalkyl, phenyl, or phenyl-OC 1-3 substituted with 0-2 of alkyl; L is -C(O)NR e - and; A is A 1 or -A 1 -L 1 - where A 1 is C substituted with 0-1 OH. 1-6 Alkyl, C substituted with 0-1 OH 1-6 Deuteroalkyl, C substituted with 0-1 OH 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Haloalkyl, C 0-3 Alkyl-C 3-10 Cycloalkyl-C 0-3 -Alkyl, C 0-3 -Alkyl-phenyl, C 0-3 -alkyl-heterocycle, where the heterocycle is a 3-6 membered ring having 1-3 heteroatoms selected from N, S, and O, where the cycloalkyl, phenyl, and heterocycle are each independently selected from 0-2 R 8 Replaced with; L 1 is -O-, -S-, -C(O)-, -C(O)NR e , -SO2NH-, -NHSO2-, -C(O)O-, -NR e -C(O)-, -NR e -C(O)O-, -NR e -C(O)NR e -, -SO2-, or -NR e - and; Alternatively, -LA- is [ka] and; R 2 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-3 Alkyl-C 6-10 Aryl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C having 1 to 4 heteroatoms selected from N, S, and O 0-3 alkyl-3-6 membered heterocycle, where either the aryl, cycloalkyl, or heterocycle group is selected from 0-3 R 2a Replaced with; R 2a is halo, CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy-C 1-6 Alkoxy, C 1-6 Deuteroalkyl, C 1-6 Deuteroalkoxy, C 1-6 -Haloalkyl, C 1-6 Haloalkoxy, C 0-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl, C 3-6 Halocycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl-C 1-6 Alkoxy, C 6-10 Aryl, Phenyl-C 1-3 Alkoxy-, C 3-6 Cycloalkyl-C 1-3 Deuteroalkoxy-, C 3-6 Cycloalkyl-C 1-3 Haloalkoxy-, C 1-6 Alkoxy-C 1-3 Alkyl-, C 3-6 Cycloalkoxy-C 1-3 Alkyl-, C 6-10 Aryl-O-, Phenyl C 1-4 Alkyl-SO2-, C 3-6 Cycloalkyl-SO2-, C 6-10 Aryl-S-, NR 6 R 6 CO-, NR 6 -(CH2) n -, R5 -C(O)-, R 5 -OC(O)-, R 5 -C(O)O-, R 6 -NH-C(O)O-, R 7 -OC(O)NH-, R 6 -NH-C(O)NR 6 , R 7 -SO2-, R 5 -SO2NH-, R 5 -NHSO2-, Heterocycle, Heterocycle-O-, Heterocycle-C 0-6 alkyl-, where each heterocycle is a 4-6 membered ring having 1-2 heteroatoms independently selected from N, S, and O, and where each alkyl, cycloalkyl, phenyl, or heterocycle is independently selected from 0-3 R 2b Replaced with; R 2b are independently halo, OH, C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy-C 1-3 Alkoxy, Hydroxy-C 1-3 Alkyl, C=O, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; R 5 are independently H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 Alkyl-phenyl, or C 1-6 is haloalkyl; R 6 are independently H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 is alkyl-phenyl; R 7 In each event, independently, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 is alkyl-phenyl; R 8 are independently H, halo, C=O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocycle, -(CH2) n -NR 6 R 6 CO, -(CH2) n -NR 6 R 6 CONR 6 R 6 , -(CH2) n -NR 6 , -(CH2) n -C(O)-R 5 , -(CH2) n -C(O)OR 5 , -(CH2) n -OC(O)-R 5 , -(CH2) n -OC(O)-NH-R 6 , -(CH2) n -NHC(O)-OR 7 , -(CH2) n -SO2-R 7 , -(CH2) n -SO2NH-R 5 , -(CH2) n -NHSO2-R 5 wherein each heterocycle is independently a 4-6 membered ring having 1-2 heteroatoms selected from N, S, and O; n is 0, 1, or 2. or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof is provided.

[0016] Another embodiment is R a H, Cl, F, Br, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuteroalkyl, C 1-4 Deuteroalkoxy, cyclopropyl, or N(Re )2; R b H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Deuteroalkyl, C 1-4 Deuteroalkoxy, or NR e 2 and; R c But, H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 deuteroalkyl, or halo; R d is independently H or F; R e In each event, independently, H, C 1-4 Alkyl, or C 1-4 is a deuteroalkyl; R 1 But, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 Alkyl-piperidinyl, C 0-3 Alkyl-pyrrolidinyl, C 0-3 Alkyl-morpholinyl, C 0-3 alkyl-pyrrolidinyl, where alkyl, cycloalkyl, piperidinyl, pyrrolidinyl, or morpholinyl are independently selected from =O, halo, OH, C 1-3 Alkyl, C 1-3 Deuteroalkyl, phenyl, or phenyl-OC 1-3 substituted with 0-2 of alkyl; L is -C(O)NR e - and; A is A 1 or -A 1 -L 1 - where A1 is C substituted with 0-1 OH. 1-6 Alkyl, C substituted with 0-1 OH 1-6 Deuteroalkyl, C substituted with 0-1 OH 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Haloalkyl, C 0-3 Alkyl-C 3-10 Cycloalkyl-C 0-3 -Alkyl, C 0-3 -Alkyl-C 3-6 Cycloalkyl-C 0-3 -Alkyl, C 0-3 -Alkyl-imidazolyl, C 0-3 -Alkyl-pyrrolidinyl, C 0-3 -Alkyl-tetrahydropyranyl, C 0-3 -alkyl-pyridinyl, where pyrrolidinyl is selected from 0 to 2 R 8 Replaced with; L 1 -O-, -C(O)-, -C(O)NR e , -SONH-, -C(O)O-, -NR e -C(O)-, -SO2-, or -NR e - and; Or, -LA- is [ka] and; R 2 But, C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-3 Alkyl-phenyl, C 0-3 Alkyl-C 3-6 cycloalkyl or C having 1 to 4 heteroatoms selected from N, S, and O 0-3 alkyl-3-6 membered heterocycle, where either the phenyl or heterocycle group is selected from 0-3 R 2a Replaced with; R 2a But halo, CN, =O, C 1-6 Alkyl, C 1-6Alkoxy, Hydroxy-C 1-6 Alkoxy, C 1-6 Deuteroalkyl, C 1-6 Deuteroalkoxy, C 1-6 -Haloalkyl, C 1-6 Haloalkoxy, C 1-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl, C 3-6 Halocycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl-C 1-3 Alkoxy-, C 3-6 Cycloalkyl-C 1-3 Deuteroalkoxy-, C 3-6 Cycloalkyl-C 1-3 Haloalkoxy-, C 1-6 Alkoxy-C 1-3 Alkyl-, C 3-6 Cycloalkoxy-C 1-3 Alkyl-, Phenyl-O-, C 1-4 Alkyl-SO2-, C 3-6 Cycloalkyl-SO2-, C 6-10 Aryl-S-, NR 6 R 6 CO-, NR 6 -(CH2) n -, R 5 -C(O)-, R 6 -NH-C(O)O-, R 7 -OC(O)NH-, R 7 -SO2-, R 5 -SO2NH-, heterocycle-, heterocycle-O-, heterocycle-CH2-, where each heterocycle is independently a 4-6 membered ring having 1-2 heteroatoms selected from N, S, and O, and where each alkyl, cycloalkyl, phenyl, or heterocycle is independently selected from 0-3 R 2b Replaced with; R 2b In each event, independently, C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy-C 1-3 Alkoxy, halo, C=O, C 1-3 Haloalkyl, or C1-3 haloalkoxy; R 5 In each event, independently, H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 is alkyl-phenyl; R 6 In each event, independently, H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 is alkyl-phenyl; R 7 In each event, independently, H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 is alkyl-phenyl; R 8 is F, =O, or C 1-3 is alkyl; n is 0, 1, or 2; Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0017] Another embodiment is L is -C(O)NR e - and; A is A 1 or -A 1 -L 1 - where A 1 is C substituted with 0-1 OH. 1-6 Alkyl, C substituted with 0-1 OH 1-6 Deuteroalkyl, C substituted with 0-1 OH 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Haloalkyl, C 0-3 Alkyl-C 3-10 Cycloalkyl-C 0-3 -Alkyl, C 0-3 -Alkyl-C3-6 Cycloalkyl-C 0-3 -Alkyl, C 0-3 -Alkyl-imidazolyl, C 0-3 -Alkyl-pyrrolidinyl, C 0-3 -Alkyl-tetrahydropyranyl, C 0-3 -alkyl-pyridinyl, where pyrrolidinyl is selected from 0 to 2 R 8 has been replaced by Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0018] Another embodiment is R a is H, Cl, F, or C 1-4 Alkyl, C 1-4 Alkoxy, or C 1-4 is deuteroalkoxy; R b But, H, C 1-3 Alkyl, or C 1-3 is alkoxy; R c But H or C 1-4 is alkyl, Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0019] Another embodiment is A 1 C substituted with 0-1 OH 1-6 Alkyl, C substituted with 0-1 OH 1-6 Deuteroalkyl, and C 0-3 Alkyl-C 3-6 is cycloalkyl; L 1 -O-, -C(O)-, -C(O)NR e -, and -SO2NH-, Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0020] Another embodiment is R a But, H, C 1-4 Alkyl, C 1-4 Alkoxy, or C 1-4 is deuteroalkoxy; R b But H or C 1-3 is alkyl; R c But H. Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0021] Another embodiment is R 1 But, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 Alkyl-piperidinyl, C 0-3 Alkyl-pyrrolidinyl, C 0-3 Alkyl-morpholinyl, C 0-3 alkyl-pyrrolidinyl, where alkyl, cycloalkyl, piperidinyl, pyrrolidinyl, or morpholinyl are independently selected from =O, halo, OH, C 1-3 Alkyl, C 1-3 Deuteroalkyl, or NR 1e substituted with 0 to 2 of 2, Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0022] Another embodiment is R 1 But, C 1-3 Alkyl, C 1-3 Deuteroalkyl, or C 0-1 alkyl-cyclopropyl; R 2 But, C 1-6Alkyl, phenyl, (CH2) n -C 3-6 Cycloalkyl, or (CH2) n - a 3- to 6-membered heterocycle, where the heterocycle is selected from morpholinyl, tetrahydro-2H-pyranyl, or pyrrolidinyl, where either the phenyl or the heterocycle group is selected from 0-3 R 2a Replaced with; R 2a F, Cl, CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuteroalkyl, C 1-3 Deuteroalkoxy, C 1-2 Haloalkyl, C 1-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl-C 1-3 Alkoxy-, C 3-6 Cycloalkyl-C 1-3 Deuteroalkoxy-, C 3-6 Cycloalkoxy-C 1-3 Alkyl-, Phenyl C 1-4 Alkyl-SO2-, C 3-6 Cycloalkyl-SO2-, NR 6 R 6 CO-, NR 6 -(CH2) n -, R 5 -C(O)-, R 6 -OC(O)-NH-, R 7 -NHC(O)-O-, R 7 -SO2-, R 5 -SO2NH-, -(CH2) n -piperidinyl, -(CH2) n -morpholinyl, where each of alkyl, cycloalkyl, phenyl, or heterocycle is selected from 0 to 3 R 2b has been replaced by Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0023] Another embodiment is -LA-, [ka] or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0024] Another embodiment is R a is H, Cl, F, or C 1-4 Alkyl, C 1-4 Alkoxy, or C 1-4 is deuteroalkoxy; R b But, H, C 1-3 Alkyl, or C 1-3 is alkoxy; R c But H or C 1-4 is alkyl; R 1 But, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 Alkyl-piperidinyl, C 0-3 Alkyl-pyrrolidinyl, C 0-3 Alkyl-morpholinyl, C 0-3 alkyl-pyrrolidinyl, where alkyl, cycloalkyl, piperidinyl, pyrrolidinyl, or morpholinyl are independently selected from =O, halo, OH, C 1-3 Alkyl, C 1-3 Deuteroalkyl, NR 1e substituted with 0 to 2 of 2; R 2 But, C 0-3 Alkyl-phenyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, or C 0-3alkyl-3-6 membered heterocycle, where the heterocycle is selected from morpholinyl, tetrahydro-2H-pyranyl, or pyrrolidinyl, where either the phenyl or the heterocycle group is selected from 0-3 R 2a Replaced with; R 2a F, Cl, CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuteroalkyl, C 1-3 Deuteroalkoxy, C 1-2 Haloalkyl, C 1-3 Alkyl-C 3-6 Cycloalkyl-C 0-3 Alkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl-C 1-3 Alkoxy-, C 3-6 Cycloalkyl-C 1-3 Deuteroalkoxy-, C 3-6 Cycloalkoxy-C 1-3 Alkyl-, Phenyl C 1-4 Alkyl-SO2-, C 3-6 Cycloalkyl-SO2-, NR 6 R 6 CO-, NR 6 -(CH2) n -, R 5 -C(O)-, R 6 -OC(O)-NH-, R 7 -NHC(O)-O-, R 7 -SO2-, R 5 -SO2NH-, -(CH2) n -piperidinyl, -(CH2) n -morpholinyl, where each of alkyl, cycloalkyl, phenyl, or heterocycle is selected from 0 to 3 R 2b has been replaced by Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0025] Another embodiment is The compound is selected from the examples Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0026] Another embodiment is R 1 is CH2-cyclopropyl, cyclopropyl, CH3, CD3, or CD2CD3; Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0027] Another embodiment is L is -CONH-; A is C substituted with 0 to 1 OH 1-6 Alkyl, C substituted with 0-1 OH 1-6 is a deuteroalkyl; R 2 However, 0 to 3 R 2a phenyl substituted with Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0028] Another embodiment is R 2a is F, CH3, OCH3, CF3, or OCF3; Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0029] Another embodiment is L is -C(O)NH-; A is A 1 where A 1 is C substituted with 0 to 1 OH. 1-6 Alkyl, C substituted with 0-1 OH 1-6 Deuteroalkyl, C substituted with 0-1 OH 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C1-6 Haloalkyl-, C 0-3 Alkyl-C 3-10 Cycloalkyl-C 0-3 -Alkyl-, C 0-3 -Alkyl-C 3-6 Cycloalkyl-C 0-3 -Alkyl, -C 0-3 -Alkyl-imidazolyl-, -C 0-3 -Alkyl-pyrrolidinyl-, C 0-3 -Alkyl-tetrahydropyranyl-, -C 0-3 -alkyl-pyridinyl-, where pyrrolidinyl is selected from 0 to 2 R 8 has been replaced by Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0030] Another embodiment is R 2a But halo, CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkoxy, C 3-6 Cycloalkyl-C 1-3 Alkoxy-, Phenyl-O-, C 1-4 Alkyl-SO2-, C 3-6 Cycloalkyl-SO2-, -C(O)-R 5 , -NHC(O)-OR 7 , -SO2-R 7 , -SO2NH-R 5 , heterocycle-, heterocycle-O-, heterocycle-CH2-, where heterocycle is selected from tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, or piperazinyl, where alkyl, cycloalkyl, phenyl, or heterocycle each may be selected from 0 to 3 R 2b has been replaced by Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0031] Another embodiment is -LAR 2 but, [ka] and; m is 0, 1, 2, or 3; Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0032] Another embodiment is -LA-, [ka] and R 2 but, [ka] and; m is 0, 1, or 2; Provided are compounds of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof:

[0033] Another embodiment provides a compound of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is selected from the examples.

[0034] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically 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.

[0035] The present invention further relates to a method for treating diseases associated with kinase modulation, such as the modulation of receptor interacting protein kinases, such as RIPK1, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I).

[0036] The present invention also provides processes and intermediates for making the compounds of the present invention, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0037] 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 of treatment a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharma-ceutically acceptable salt, solvate, or prodrug thereof.

[0038] 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), 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.

[0039] The present invention also provides a method for treating a condition comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), wherein the disease 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 rheumatoid arthritis, and rheumatoid arthritis. The disease is selected from: chronic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), graft rejection, type I diabetes mellitus, 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, asthma, nonalcoholic steatohepatitis (NASH), or ischemia-reperfusion.

[0040] The present invention also provides a method for treating a medical condition comprising administering to a patient in need of treatment 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's disease.

[0041] The present invention also provides a method for treating a condition, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), 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).

[0042] The invention also provides a method for treating a condition, wherein the condition is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, and psoriasis, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0043] 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 of treatment a therapeutically effective amount of a compound of formula (I).

[0044] The present invention also provides a method for treating rheumatoid arthritis, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I).

[0045] 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 pharma- ceutically acceptable salt thereof, in combination with another therapeutic agent.

[0046] The present invention also provides the compounds of the present invention, or stereoisomers, tautomers, isotopes, salts, pharma- ceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.

[0047] In another embodiment, a compound of formula (I) is selected from the exemplified examples, or a combination of the exemplified examples, or other embodiments described herein.

[0048] The invention also provides the use of a compound of the invention, or a stereoisomer, tautomer, isotope, salt, pharma- ceutically 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.

[0049] 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 further embodiments. It is also understood that each individual element of an embodiment is an independent embodiment in itself. Furthermore, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe further embodiments.

[0050] The following are definitions of terms used in this specification and the appended claims. The initial 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.

[0051] Any variable (e.g., R 3 When any radical R 2 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. Thus, for example, a radical R 2 3 When indicated as being substituted with, the group may contain up to two R 3 optionally substituted with R 3 are each independently R 3 Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0052] When a substituent is shown to have a bond across 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.

[0053] 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 give 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.

[0054] According to the practice used in the art, [ka] is used in structural formulas herein to represent a bond that is the site of attachment of a group or substituent to a core or backbone structure.

[0055] A dash "-" that is not between two letters or symbols is used to indicate the point of attachment of the substituent, for example, -CONH2 is attached through a carbon atom.

[0056] The term "optionally substituted" with respect to a particular moiety of 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 of skill 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.

[0057] 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 any of the following alkyl groups: 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 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted such that one or more hydrogen atoms are 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.

[0058] When the term "alkyl" is used with other groups, such as "arylalkyl," the connection is more specifically defined by at least one substituent that 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.

[0059] "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.

[0060] "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.

[0061] When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with from 1 to 3 substituents as defined above for substituted alkyl groups.

[0062] The term "alkoxy" refers to an oxygen atom substituted by 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.

[0063] It should be understood that selections for all groups, for example alkoxy, thioalkyl, and aminoalkyl, will be made by one of ordinary skill in the art to yield stable compounds.

[0064] The term "substituted" as used herein 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. If the substituent is oxo or keto (i.e., =O), two hydrogens on the atom are replaced. Keto substituents do not occur on aromatic groups. Unless otherwise noted, the substituents are named on the core structure. For example, if (cycloalkyl)alkyl is listed as a possible substituent, it is understood that the attachment point of this substituent to the core structure is in the alkyl moiety. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0065] 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 durable to survive isolation of the reaction mixture to a useful degree of purity, and subsequent formulation into an effective therapeutic agent. The presently recited compounds preferably do not contain N-halo, S(O)2H, or S(O)H groups.

[0066] The term "carbocyclyl" or "carbocycle" refers to a saturated or 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 link 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 recited for the ring may also be present on the bridge.

[0067] The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups 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 phenyl, which may be optionally substituted.

[0068] The term "cycloalkyl" refers to cyclized alkyl groups, such as mono-, bi-, or polycyclic ring systems. 3-7 Cycloalkyl is intended to include C3, C4, C5, C6, and C7 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.

[0069] 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, 7- to 11-membered bicyclic, and 10- to 15-membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S, or N), and the ring having said heteroatom preferably has 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a group containing a heteroatom 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. If valency allows, said further ring, when cycloalkyl or heterocyclo, may be further substituted with =O (oxo).

[0070] 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., as exemplary groups listed under "heteroaryl." Examples of bicyclic heterocyclo groups include quinuclidinyl.

[0071] The term "heteroaryl" refers to substituted and unsubstituted, aromatic 5- or 6-membered monocyclic, 9- or 10-membered bicyclic, and 11- to 14-membered tricyclic groups having at least one heteroatom (O, S, or N) in at least one of the rings, the heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of a heteroatom-containing heteroaryl group may 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 has at least 1 carbon atom. The fused rings completing the 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. Heteroaryl groups that are bicyclic or tricyclic 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 valences allow, said further ring, if cycloalkyl or heterocyclo, may optionally be further substituted with =O (oxo).

[0072] 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.

[0073] 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.

[0074] Examples of tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0075] 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 0-3, preferably 0-2, substituents, as appropriate.

[0076] 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.

[0077] The term "haloalkoxy" refers to an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3. 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. The term "heteroatom" is intended to include oxygen, sulfur, and nitrogen.

[0078] 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. The designation "CO" as used herein refers to the group: [ka] It will be understood by those skilled in the art that what is intended to refer to is

[0079] Throughout the specification, groups and substituents thereof can be chosen by those skilled in the art to provide stable moieties and compounds, as well as compounds useful as pharma-ceutically acceptable compounds and / or intermediate compounds useful in the preparation of pharma-ceutically acceptable compounds.

[0080] The compounds of formula (I) may exist in free form (non-ionized) or may form salts that are within the scope of the present invention. Unless otherwise specified, reference to the compounds 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. In addition, when, for example, 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" may include zwitterions (internal salts). Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts, in which the cation does not contribute significantly 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 to be 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.

[0081] Examples of acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfate, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), iodides, and the like. These 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.

[0082] Examples of base salts include alkali metal salts, such as ammonium, 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 pharma- ceutically acceptable amines, and salts with amino acids, such as arginine, lysine, and the like. Basic nitrogen-containing groups may 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 bromides), and other agents. In certain embodiments, salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0083] The phrase "pharmacologically 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 benefit / risk ratio.

[0084] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, which is modified by making its acid or base salt from 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, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isethionic acid.

[0085] The pharma- ceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic groups by conventional chemical methods.In general, 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 in 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.

[0086] All stereoisomers of the compounds of the present invention are contemplated, either in mixtures or in pure or substantially pure form. Stereoisomers include compounds that are optical isomers by having one or more chiral atoms, as well as compounds that are optical isomers by having restricted rotation of one or more bonds (atropisomers). The definition of the compounds described in the present invention includes all possible stereoisomers and mixtures thereof. In particular, it includes racemates and isolated optical isomers with the specified activity. Racemates can be resolved by physical methods, such as, for example, fractional crystallization, separation, or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0087] 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 combinations thereof. Isotopes of carbon include: 13 C and 14 Radiolabeled compounds of the invention can generally be synthesized by conventional techniques known to those of skill in the art, or by methods analogous to those described herein, using an appropriate radiolabeled reagent in place of the non-labeled reagent that would otherwise be used.

[0088] 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 produce a compound of formula (I), and / or a salt and / or solvate thereof. Any compound that is converted in vivo to produce 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 producing 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 may be used when the ester is active in itself or when hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds 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, such as those used in the penicillin and cephalosporin arts. Such esters can be prepared by conventional techniques known in the art.

[0089] 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.

[0090] 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.

[0091] The compounds of the present invention may have 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 exist 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 may 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 racemic forms or by synthesis from optically active starting materials, are well known in the art. All chiral (enantiomers and diastereomers) and racemic forms, as well as all geometric isomeric forms of the structures, are intended, unless a specific stereochemistry or isomeric form is specified. All geometric isomers, tautomers, atropisomers, hydrates, solvates, polymorphs, and isotopically labeled forms of the compounds referred to herein, and mixtures thereof, are considered to be within the scope of the present invention. Methods of solvation are generally known in the art.

[0092] usefulness The compounds of the present invention modulate kinase activity, such as RIPK1 regulation.Therefore, the compounds of formula (I) have utility in the regulation of kinase activity, and in particular in the treatment of pathologies associated with selective inhibition of RIPK1 activity.In another embodiment, the compounds of formula (I) have favorable selectivity for RIPK1 activity, preferably at least 20-fold to 1000-fold or more selectivity over other kinases.

[0093] The term "treating" or "treatment" as used herein includes the treatment of a disease condition in a mammal, particularly a human, and includes (a) preventing or delaying the onset of the disease condition 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 condition, i.e., halting its progression; and / or (c) completely or partially alleviating the symptoms or disease condition and / or achieving relief, amelioration, relief, or cure of the disease or disorder and / or its symptoms.

[0094] In view of their activity as selective inhibitors of RIPK1, the compounds of formula (I) are useful in treating, but not limited to, 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, osteoarthropathy, osteoporosis, and multiple myeloma-related bone disease; proliferative disorders such as acute myeloid leukemia, chronic myeloid leukemia; solid tumors, intraocular neovascularization, and the like. The present invention is useful for treating RIPK1-related diseases such as angiogenic disorders, such as infantile hemangioma; infectious diseases, such as sepsis, septic shock, and shigellosis; neurodegenerative diseases caused by Alzheimer's disease, Parkinson's disease, ALS, cerebral ischemia, or stress disorders, neoplastic and viral diseases, such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS; fibrosis, such as nonalcoholic steatohepatitis (NASH); and cardiac diseases, such as ischemia-reperfusion.

[0095] 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, 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 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, infections Fever and myalgia due to osteoporosis, 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 angiogenesis, and infantile hemangioma; acute hepatitis infections (hepatitis A, B, and C), HIV infection and CMV retinitis, AIDS, ARC or malignant tumors, and viral diseases such as herpes; stroke, myocardial ischemia, ischemia in ischemic heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, pathologies associated with prostaglandin-endoperoxidase synthase 2, and pemphigus vulgaris. Preferred methods of treatment are those where the disease is selected from 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.Alternatively, the preferred method of treatment is where the disease is selected from ischemia-reperfusion injury, such as cerebral ischemia-reperfusion injury caused by stroke, and cardiac ischemia-reperfusion injury caused by myocardial infarction.

[0096] When the term "RIPK1-associated condition" or "RIPK1-associated disease or disorder" is used herein, each is intended to include all diseases identified above, as well as any other condition affected by RIPK1 kinase activity, as recited in detail.

[0097] Accordingly, the present invention provides a method for treating such conditions, comprising administering to a subject in need of treatment a therapeutically effective amount of at least one compound of formula (I), or a salt thereof. "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective to inhibit RIPK1 when administered alone or in combination.

[0098] The method for treating RIPK1 kinase-related diseases is characterized by administering a compound of formula (I) alone or in combination with each other and / or other suitable therapeutic agents useful in treating such conditions. Thus, "therapeutically effective amount" is also intended to include the amount of the combination of compounds claimed that is effective for inhibiting RIPK1 and / or treating diseases associated with RIPK1.

[0099] 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; anti-inflammatory antibodies such as sutekinumab, anti-inflammatory kinase inhibitors such as TYK2 inhibitors, antivirals such as abacavir; anti-proliferative 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 derivatives thereof, and agonists of FGF21.

[0100] Said other therapeutic agent may be used in the amount, for example, as shown in the Physicians' Desk Reference (PDR) or as determined by a person skilled in the art, when used in combination with the compound of the present invention. In the method of the present invention, such other therapeutic agent may be administered before, simultaneously, or after the administration of the compound of the present invention. The present invention also provides a pharmaceutical composition that can treat RIPK1 kinase-related diseases, such as diseases mediated by IL-1, IL-6, IL-8, IFNγ and TNF-α, as described above.

[0101] 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 mode of administration.

[0102] As such, the present invention further includes compositions comprising one or more compounds of formula (I) and a pharma- ceutically acceptable carrier.

[0103] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a physiologically active agent to an animal, particularly a mammal. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of one skilled in the art. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to 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, and such additional components are included in the formulation for a variety of reasons well known to those skilled in the art, such as, for example, stabilization of 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, for example, Remington's Pharmaceutical Sciences, 17th ed., 1985, which is incorporated herein by reference in its entirety.

[0104] 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, local 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 techniques (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 suitable pharmaceutical compositions or, particularly in the case of sustained release, by devices such as subcutaneous implants or osmotic pumps.

[0105] Examples of compositions for topical administration include topical carriers such as PLASTIBASE® (mineral oil gelled with polyethylene).

[0106] Examples of compositions for oral administration include suspensions that 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 that 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 delivered orally by sublingual and / or buccal administration, for example, by moist, 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 hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (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, glidants, flavors, colors, and stabilizers may also be added for ease of manufacture and use.

[0107] Exemplary 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.

[0108] 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, for example, mannitol, 1,3-butanediol, water, Ringer's solution, physiological saline, or other suitable dispersing or wetting agents and suspending agents, such as synthetic mono- or diglycerides, and fatty acids, such as oleic acid.

[0109] 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 which are solid at ordinary temperatures but liquefy and / or melt in the rectal cavity to release the drug.

[0110] The therapeutically effective amount of the compounds of the present invention can be determined by one skilled in the art, and exemplary dosages for mammals include about 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; 250-1000 mg / kg body weight of active compound per day, which may be administered in the form of a single dose or 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, such as the activity, metabolic stability, and length of action of the particular compound used, the species, age, weight, health, sex, and diet of the subject, the form and time of administration, excretion rate, drug combination, and the severity of the particular pathology. Preferred subjects for treatment include animals, most preferably mammalian species 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 mammalian species, that are affected by modulation of the amount of RIPK1 enzyme.

[0111] MLKL phosphorylation high content assay HT29-L23 human colon adenoma cells were maintained in RPMI 1640 medium containing 10% heat-inactivated FBS, 1% penicillin-streptomycin and 10 mM HEPES. Cells were seeded at 2,000 cells / well in 384-well tissue culture treated microplates (Greiner # 781090-3B) and incubated for 2 days at 37°C (5% CO2 / 95% O2). 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. MLKL phosphorylation 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 h at room temperature. After three further cycles of washing with PBS, the microplate was sealed and cell images were acquired on a Cellomics ArrayScan VTI high-content imager equipped with an X1 camera. Fluorescent 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.Image sets were analyzed using Compartmental Analysis Bioapplication software (Cellomics). MLKL phosphorylation was quantified as MEAN_CircRingAvgIntenRatio. Maximal inhibitory response was defined by the activity induced by Nec1s (CAS#:852391-15-2, 6.25 μM). IC50 value was defined as the concentration of compound that produced 50% of maximal inhibition. Data were fitted using a four-parameter logistic equation to calculate IC50 and Ymax values.

[0112] RIPK1 HTRF binding assay A solution was prepared by incorporating 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). Using Formulatrix Tempest, the detection antibody / enzyme / probe solution (2 mL) was dispensed into the 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 only 10 nL DMSO. The blank signal (100% inhibition) was calculated from wells containing 10 nL of 15 nM staurosporine and the internal control.

[0113] 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 the stop codon TGA and an XhoI site at the 3' end was codon optimized and the gene was synthesized by GenScript USA Inc. (Piscataway, NJ) and subcloned into 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.

[0114] 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). 72 hours after transfection, baculovirus was harvested and infected into fresh Sf9 cells at a ratio of 1 / 1000 (v / v) for 66 hours to prepare viral stocks.

[0115] For large-scale protein production, 2x10 in ESF921 insect medium (Expression System) 6Sf9 cells (Expression System, Davis, CA) grown at 1000 cells / ml were infected with virus stock at 1 / 100 (v / v) ratio for 66 hours. Production was performed using a WAVE-Bioreactor System 20 / 50 (GE Healthcare Bioscience) at either 10 L scale in 22 L cell bags (GE Healthcare Bioscience, Pittsburgh, PA) or 20 L scale in 50 L cell bags. Infected cells were harvested by centrifugation at 2000 rpm for 20 min at 4° C. in a SORVALL® RC12BP centrifuge. Cell pellets were stored at −70° C. prior to protein purification.

[0116] Purification of His-GST-TVMV-hRIPK1(1-324) 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 136,000xg for 40 min 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, 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, 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, 1 mM DTT. Fractions identified by SDS-PAGE containing RIPK1 were pooled, concentrated using a 30 kDa MWCO spin concentrator (Amicon Ultra-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, 5% glycerol. RIPK1 protein eluted from the SEC column as a dimer.

[0117] The yield was ~8mg / 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 an N-terminal methionine, had one phosphorylation site, and was partially acetylated. The protein was aliquoted and stored at -80°C.

[0118] Using these assays, the IC 50 Values ​​were determined, see Table A. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0119] Manufacturing method 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. Starting materials and reagents used in these examples, if not synthesized by the methods described herein, are generally commercially available or reported in the chemical literature or can be synthesized using methods described in the chemical literature.

[0120] Abbreviations used herein are defined as follows: "1x" is one time, "2x" is two times, "3x" is three times, "aq" or "aq." is aqueous, "°C" is temperature in degrees Celsius, "eq" is equivalent, "g" is gram, "mg" is milligram, "L" is liter, "mL" is milliliter, "μL" is microliter, "N" is normal, "M" is molar, "mmol" is millimole, "min" is minute, "h" is hour, "rt" is room temperature, "ON" is overnight, "RT" is retention time, "atm" is atmosphere, "psi" is pounds per square inch, "conc." is concentrated, "sat" or "saturated" is saturated, "CV" is column volume, "MW" is molecular weight, "mp" is melting point, "ee" is enantiomeric excess, "MS" or "Mass "Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometry, "LCMS" or "LC / MS" is liquid chromatography mass spectrometry, "HPLC" is high performance liquid chromatography, "RP HPLC" is reversed phase HPLC, "TLC" or "tlc" is thin layer chromatography, "SFC" is supercritical fluid chromatography, "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 of skill in the art. [Table 6] [Table 7] [Table 8]

[0121] The compounds of the present invention may be synthesized by many methods available to one 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 exemplary and are not intended to limit the possible techniques that one skilled in the art may use to synthesize the compounds disclosed herein. Different methods for synthesizing the compounds of the present invention will be apparent to one skilled in the art. Furthermore, various steps in the synthesis may be performed in an alternative order to obtain the desired compound.

[0122] Examples of compounds of the invention synthesized by the methods described in the general schemes are shown in the Intermediates and Examples sections below. The example compounds are generally synthesized as racemic mixtures. The 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, the example compounds can be synthesized by methods known to yield enantiomerically enriched compounds. These include, but are not limited to, the incorporation of chiral auxiliary functional groups into racemic intermediates that control the diastereoselectivity of the transformation, and cleavage of the chiral auxiliary to provide enantiomerically enriched products.

[0123] Scheme 1 illustrates an approach to the synthesis of the compound exemplified by 6. Amide formation of starting material 1 can be achieved by a BOP coupling reaction to give 2. Other coupling agents known to those skilled in the art, such as mixed anhydrides or carboxylic acid chlorides, can also be used for the transformation. Protection of 2 can be achieved using BOC2O in conjunction with a base to give 3. Suzuki coupling reaction of 3 and 7 (Miyaura, N. and Suzuki, A. Chemical Reviews, 95:2457-2483, 1995) can give compound 4. If 4 is an ester instead of a carboxylic acid, a hydrolysis step can be performed after the Suzuki reaction. Suitable bases include lithium hydroxide monohydrate, sodium hydroxide, or others known to those skilled in the art. The compound exemplified by 6 can be formed by amide coupling mediated by a BOP reagent as shown in the scheme, or other amide coupling agents. The use of anhydrides or carboxylic acid chlorides can also affect this transformation. [ka]

[0124] Scheme 2 illustrates an approach to the synthesis of compounds exemplified by 10. The Suzuki reaction can be accomplished by in situ conversion of 7 to the respective boronic ester or boronic acid, followed by coupling with 3. Additionally, separate isolation of the boronic acid derived from 7 can also be used in the transformation. If 9 is an ester instead of a carboxylic acid, the Suzuki reaction can be followed by hydrolysis. Suitable bases include lithium hydroxide monohydrate, sodium hydroxide, or others known in the art. Compounds exemplified by 10 can be generated by amide coupling mediated by BOP as shown in the scheme, or other amide coupling agents. The use of anhydrides or carboxylic acid chlorides can also be used in this transformation. [ka]

[0125] Scheme 3 highlights another route that allows the access of compounds exemplified by 18. Nicotinate derivatives such as 11 can undergo hydrolysis with lithium hydroxide monohydrate or sodium hydroxide to generate nicotinic acid derivatives. In addition to amide coupling under various conditions, 12 can also be obtained by anhydride or acid chloride coupling. Conversion of 12 to the corresponding boronic ester 13 can proceed under anhydrous Suzuki conditions. 13 can be carefully isolated or used in situ in the next Suzuki reaction with 15 to generate compound 16. As in the previous example, compound 16 can be hydrolyzed to obtain compounds such as 17. Compounds exemplified by 18 can be generated by amide coupling mediated by BOP as shown in the scheme, or by other amide coupling agents. [ka]

[0126] As shown in Scheme 3, compound 2 can be converted to 19 under Suzuki conditions with 20. Alkylation reaction with alkyl bromides under basic conditions can produce compounds exemplified by 21. [ka]

[0127] Purification of intermediates and final products was performed by either normal or reverse phase chromatography. Normal phase chromatography on an ISCO system was performed using pre-packed SiO2 cartridges eluted with gradients of either hexanes and ethyl acetate, or dichloromethane and methanol, unless otherwise noted. Reverse phase preparative HPLC or LCMS was 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 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 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 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).

[0128] For most of the examples, two analytical LCMS injections were used to determine the final purity. Method A: Column: Waters Acquity UPLC BEH C18, 2.1x50mm, 1.7μM particles; Mobile phase A: 5:95 acetonitrile:water with 10mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then hold at 100% B for 0.75 minutes; Flow rate: 1.11mL / min; Detection: UV at 220nm. Method B: Column: Waters Acquity UPLC BEH C18, 2.1x50mm, 1.7μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature: 50°C; Gradient: 0-100% B over 3 min, then hold at 100% B for 0.75 min; Flow rate: 1.11 mL / min; Detection: UV at 220 nm.

[0129] In a few of the examples, analytical HPLC injections were used to determine final purity. Method C: Column: Sunfire C18, 3.0x150mm, 3.5μM particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 0-100% B over 10 min; Flow rate: 1mL / min; Detection: UV at 220 and 254nm. Method D: Column: Xbridge Phenyl, 3.0x150mm, 3.5μM particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 0-100% B over 10 min; Flow rate: 1mL / min; Detection: UV at 220 and 254nm. Method E: Column: XBridge C18, 3.0x150mm, 3.5μM particles; Mobile phase A: 5:95 methanol:water with 10mM ammonium bicarbonate; Mobile phase B: 95:5 methanol:water with 10mM ammonium bicarbonate; Gradient: 0-100% B over 15 min; Flow rate: 1mL / min; Detection: UV at 220 and 254nm. Method F: Column: XBridge Phenyl, 3.0x150mm, 3.5μM particles; Mobile phase A: 5:95 methanol:water with 10mM ammonium bicarbonate; Mobile phase B: 95:5 methanol:water with 10mM ammonium bicarbonate; Gradient: 0-100% B over 15 min; Flow rate: 1mL / min; Detection: UV at 220 and 254nm.

[0130] Most of the mass spectra were performed as follows: LCMS (ESI) m / z: [M+H] + BEH C18, 2.11x50mm, 1.7μm; Mobile phase A: 2:98 water:acetonitrile with 0.1% TFA; Mobile phase B: 98:2 acetonitrile:water with 0.1% TFA; Gradient: 0-100% B over 2 min; Flow rate: 0.8mL / min; Detection: UV at 220nm.

[0131] NMR spectra were performed with water suppression unless otherwise noted. If water suppression affects the characterization of a compound by NMR, this will be noted in the text.

[0132] Example 1 N-[(1,1,2,2,2-deuteroethyl]-6-(5-{[(1S)-1-[2-fluoro-5-(trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide [ka] 1A: (S,E)-N-(2-Fluoro-5-(trifluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide: Titanium(IV) isopropoxide (5.69 mL, 19.22 mmol) was added to a solution of 2-fluoro-5-(trifluoromethoxy)benzaldehyde (2.0 g, 9.61 mmol) and (S)-(-)-2-methyl-2-propanesulfinamide (1.165 g, 9.61 mmol) in THF (20 mL) at room temperature and stirred for 72 hours. The reaction was quenched by the addition of brine (10 mL) and hexanes (10 mL) at 0° C. The mixture was filtered through a pad of Celite and the pad was rinsed with ethyl acetate (2×10 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified on a silica gel column with hexane / EtOAc (100 / 0 to 50 / 50) to give (S,E)-N-(2-fluoro-5-(trifluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2.83 g, 8.73 mmol, 91% yield). MS ESI m / z 312.0 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.83 (s, 1H), 7.90 (dd, J=4.7, 3.4 Hz, 1H), 7.64 - 7.53 (m, 1H), 7.48 - 7.35 (m, 1H), 1.30 (s, 9H).

[0133] 1B: (S)-N-((R)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfinamide (a) and (S)-N-((S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfinamide (b): To a solution of (S,E)-N-(2-fluoro-5-(trifluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2.827 g, 9.08 mmol) in THF (40 mL) was added methyl-d3-magnesium iodide (1 M in Et2O) (13.62 mL, 13.62 mmol) dropwise at -40°C, which was maintained for 6 h and then allowed to warm to 23°C over 12 h. The reaction mixture was concentrated to a volume of 10 mL and quenched with saturated NH4Cl solution (50 mL) at 0°C. The aqueous layer was extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. Filtration and concentration gave (S)-N-((RS)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfinamide (3.2 g, 9.12 mmol, 100% yield). (S)-N-((RS)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfinamide (3.2 g, 9.12 mmol) was separated by preparative SFC under the following conditions: preparative column: (R,R) Whelk-O1 (5x50 cm, 10 μm), BPR pressure: 100 bar, temperature: 49 °C, flow rate: 320 mL / min, mobile phase: CO2 / IPA:heptane [60:40 (v / v)] (85 / 15), detection wavelength: 215 nm. Fractions from peak 1 were combined to give (S)-N-((R)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfinamide (1.61 g, 4.84 mmol, 50% yield, chiral purity: 99.9%). MS ESI m / z 331.0 (M+H).

[0134] Fractions from peak 2 were combined to give (S)-N-((S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfinamide (0.97 g, 2.87 mmol, 30% yield, chiral purity: 99.9%). MS ESI m / z 331.0 (M+H).

[0135] 1C(a): (R)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethane-2,2,2-d3-1-amine, HCl: A solution of (S)-N-((R)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfinamide (1.61 g, 4.87 mmol) and HCl (4 M in dioxane) (7.30 mL, 29.2 mmol) in THF (10 mL) was stirred at 23° C. for 1 h. The reaction mixture was concentrated and triturated with ether (10 mL). The solid was recovered as (R)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethane-2,2,2-d3-1-amine, HCl (996 mg, 3.79 mmol, 78% yield). MS ESI m / z 227.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 7.57 - 7.34 (m, 3H), 4.75 (s, 1H).

[0136] (b): (S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethane-2,2,2-d3-1-amine, HCl: A solution of (S)-N-((S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfinamide (0.97 g, 2.94 mmol) and HCl (4 M in dioxane) (4.40 mL, 17.62 mmol) in THF (8 mL) was stirred at 23° C. for 1 h. The reaction mixture was concentrated and triturated with ether (10 mL). The solid was recovered as (S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethane-2,2,2-d3-1-amine, HCl (592 mg, 2.25 mmol, 77% yield). MS ESI m / z 227.1 (M+H). 1 H NMR (400 MHz, CD3OD) δ 7.50 (dd, J=5.8, 2.8 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.41 - 7.34 (m, 1H), 4.75 (s, 1H).

[0137] 1D: 2-Ethyl d5-isoindoline-1,3-dione: A solution of potassium phthalamide (1.0 g, 5.40 mmol) and iodoethane-d5 (0.446 mL, 5.40 mmol) in NMP (15 mL) was heated at 150 °C for 60 min under microwave. The reaction mixture was diluted with EtOAc (120 mL) and then washed with water (50 mL), 10% LiCl solution (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4. Filtration and concentration gave the crude product, which was purified on a silica gel column with hexane / EtOAc (100 / 0 to 50 / 50) to give 2-ethyl d5-isoindoline-1,3-dione (637.3 mg, 3.54 mmol, 66% yield). MS ESI m / z 181.1 (M+H).

[0138] 1E: Ethan-d5-1-amine, HCl: A solution of 2-ethyl d5-isoindoline-1,3-dione (637.3 mg, 3.54 mmol) in HCl (6N solution) (0.589 mL, 3.54 mmol) was heated in a microwave at 160° C. for 60 min. The reaction mixture was filtered and the aqueous layer was concentrated. The crude material was triturated in ether (20 mL). The solid was recovered as Ethan-d5-1-amine, HCl (319.3 mg, 3.69 mmol, 100% yield).

[0139] 1F: 6-Bromo-N-(ethyl-d5)-1H-indazole-3-carboxamide: To a solution of 6-bromo-1H-indazole-3-carboxylic acid (0.5 g, 2.074 mmol), ethane-d5-1-amine, HCl (0.180 g, 2.074 mmol), and DIPEA (0.906 mL, 5.19 mmol) in DMF (10 mL) was added BOP (1.147 g, 2.59 mmol). The reaction mixture was stirred at 23° C. for 16 h. The reaction mixture was concentrated and transferred to a separatory funnel with EtOAc (100 mL). The organic layer was washed with water (20 mL×2) and brine (20 mL) and dried over Na2SO4. Filtration and concentration gave the crude product, which was triturated in MeOH (3 mL). The solid was collected to give the desired product. The filtrate was concentrated and purified on a silica gel column with hexane / EtOAc (100 / 0 to 0 / 100) to give a second batch of the desired product, which was collected as 6-bromo-N-(ethyl-d5)-1H-indazole-3-carboxamide (416 mg, 1.52 mmol, 74% yield). MS ESI m / z 273.1 (M+H).

[0140] 1G: tert-Butyl 6-bromo-3-((ethyl-d5)carbamoyl)-1H-indazole-1-carboxylate: To a solution of 6-bromo-N-(ethyl-d5)-1H-indazole-3-carboxamide (416 mg, 1.523 mmol), DMAP (18.61 mg, 0.152 mmol) and TEA (0.212 mL, 1.523 mmol) in CHCl (6 mL) was added Boc anhydride (0.354 mL, 1.523 mmol) at 0 °C and the reaction mixture was allowed to warm to 23 °C and stirred for 6 h. The reaction mixture was concentrated and purified on a silica gel column with hexane / EtOAc (100 / 0 to 0 / 100) to give tert-butyl 6-bromo-3-((ethyl-d5)carbamoyl)-1H-indazole-1-carboxylate (430 mg, 1.149 mmol, 75% yield). MS ESI m / z 373.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.38 (d, J=1.1 Hz, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.60 (dd, J=8.6, 1.6 Hz, 1H), 1.76 (s, 9H).

[0141] 1H: Methyl d35-bromo-2-methoxy d3-nicotinate: Sodium (1.156 g, 50.3 mmol) was added to CD3OD (20 mL) and stirred until the reaction was complete. Methyl 5-bromo-2-chloronicotinate (4.5 g, 17.97 mmol) was added to the mixture and stirring was continued for 16 h. The reaction mixture was acidified with concentrated HCl solution until pH 7. The solution was diluted with CH2Cl2 (100 mL), washed with water (20 mL) and brine (20 mL), and dried over Na2SO4. Filtration and concentration gave methyl d35-bromo-2-methoxy d3-nicotinate (4.189 g, 15.99 mmol, 89% yield). MS ESI m / z 251.1 (M+H).

[0142] 1I: Methyl-d3 2-(methoxy-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate: A degassed solution of methyl d3 5-bromo-2-methoxy d3-nicotinate (330 mg, 1.309 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (399 mg, 1.571 mmol), potassium acetate (193 mg, 1.964 mmol), and PdCl2(dppf)-CH2Cl2 adduct (64.1 mg, 0.079 mmol) in dioxane (6 mL) was heated at 65° C. for 16 h. The reaction mixture was filtered through Celite. The solution was concentrated to give the product, which was used as is. MS ESI m / z 218.1 (M+H of boronic acid).

[0143] 1J: tert-Butyl 3-((ethyl-d5)carbamoyl)-6-(6-(methoxy-d3)-5-((methoxy-d3)carbonyl)pyridin-3-yl)-1H-indazole-1-carboxylate: A degassed solution of tert-butyl 6-bromo-3-((ethyl-d5)carbamoyl)-1H-indazole-1-carboxylate (430 mg, 1.152 mmol), (6-methoxy d3-5-(methoxy d3-carbonyl)pyridin-3-yl)boronic acid (275 mg, 1.267 mmol), PdCl2(dppf)-CHCl2 adduct (56.4 mg, 0.069 mmol) and potassium phosphate tribasic, 2 M solution (1.728 mL, 3.46 mmol) in DMF (6 mL) was stirred at 23 °C for 2 h. EtOAc (100 mL) was added to the reaction mixture. The organic layer was washed with 10% LiCl solution (20 mL×2) and brine (20 mL) and dried over Na2SO4. Filtration and concentration gave the crude product, which was purified on a silica gel column with CHCl / MeOH (100 / 0 to 90 / 10) to give tert-butyl 3-((ethyl-d5)carbamoyl)-6-(6-(methoxy-d3)-5-((methoxy-d3)carbonyl)pyridin-3-yl)-1H-indazole-1-carboxylate (536 mg, 1.152 mmol, 100% yield). MS ESI m / z 466.3 (M+H).

[0144] 1K: 5-(3-((ethyl-d5)carbamoyl)-1H-indazol-6-yl)-2-(methoxy-d3)nicotinic acid, sodium salt: A solution of tert-butyl 3-((ethyl-d5)carbamoyl)-6-(6-(methoxy-d3)-5-((methoxy-d3)carbonyl)pyridin-3-yl)-1H-indazole-1-carboxylate (536 mg, 1.151 mmol) and NaOH (1 M solution) (2.88 mL, 2.88 mmol) in MeOH (10 mL) was heated at 110° C. for 15 min under microwave. The reaction mixture was concentrated to give 5-(3-((ethyl-d5)carbamoyl)-1H-indazol-6-yl)-2-(methoxy-d3)nicotinic acid, sodium salt (651 mg, 1.76 mmol, quantitative crude yield). MS ESI m / z 349.1 (M+H).

[0145] 1: To a solution of 5-(3-((ethyl-d5)carbamoyl)-1H-indazol-6-yl)-2-(methoxy-d3)nicotinic acid, sodium salt (20 mg, 0.057 mmol), (S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethane-2,2,2-d3-1-amine, HCl (15.08 mg, 0.057 mmol), and DIPEA (0.030 mL, 0.172 mmol) in DMF (1 mL) was added BOP (30.5 mg, 0.069 mmol). The reaction mixture was stirred at 23° C. for 2 h. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 19x200mm, 5μm particles; Mobile phase A: 5:95 acetonitrile:water with 10mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Gradient: 34-74% B over 20 min, then hold at 100% B for 4 min; Flow rate: 20mL / min. Fractions containing the desired product were combined and dried by centrifugal evaporation. N-[(1,1,2,2,2-deutero)ethyl]-6-(5-{[(1S)-1-[2-fluoro-5-(trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide (7.3 mg, 13.1 μmol, 23% yield) was isolated. MS ESI m / z 557.3 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.89 (br d, J=7.6 Hz, 1H), 8.72 (d, J=2.1 Hz, 1H), 8.40 (s, 1H), 8.31 - 8.23 ​​(m, 2H), 7.85 (s, 1H), 7.62 - 7.53 (m, 2H), 7.42 - 7.29 (m, 2H), 5.37 (br d, J=7.3 Hz, 1H).

[0146] Example 2 (R)-N-(ethyl-d5)-6-(6-(methoxy-d3)-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide [ka] 2A: (R,E)-2-Methyl-N-(2-(trifluoromethoxy)benzylidene)propane-2-sulfinamide: Using a method substantially similar to that described in 1A, (R,E)-2-methyl-N-(2-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (2.61 g, 8.89 mmol, 85% yield) was obtained. MS ESI m / z 294.1 (M+H) 1 H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.12 (dd, J=7.8, 1.7 Hz, 1H), 7.64 - 7.51 (m, 1H), 7.47 - 7.33 (m, 2H), 1.30 (s, 9H).

[0147] 2B: (R)-2-Methyl-N-((S)-1-(2-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (a) and (R)-2-Methyl-N-((R)-1-(2-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (b): Using a method substantially similar to that described in 1B, (R)-2-Methyl-N-((S)-1-(2-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (a) (1.67 g, 5.40 mmol, 60% yield, chiral purity: 99.8%) was obtained. MS ESI m / z 310.1 (M+H) 1H NMR (400 MHz, CDCl3) δ 7.51 - 7.46 (m, 1H), 7.34 - 7.25 (m, 3H fused with chloroform), 4.98 (dd, J=6.7, 4.6 Hz, 1H), 1.59 - 1.55 (m, 3H), 1.21 (s, 9H).

[0148] (R)-2-Methyl-N-((R)-1-(2-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (b) (0.773 g, 2.474 mmol, 27% yield, chiral purity: 98.5%). MS ESI m / z 310.1 (M+H) 1 H NMR (400 MHz, CDCl3) δ 7.55 - 7.48 (m, 1H), 7.36 - 7.25 (m, 3H fused with chloroform), 4.92 (qd, J=6.6, 4.6 Hz, 1H), 3.55 - 3.42 (m, 1H), 1.53 (d, J=6.6 Hz, 3H), 1.25 (s, 9H).

[0149] 2C(a): (S)-1-(2-(trifluoromethoxy)phenyl)ethanamine, HCl: Using a method substantially similar to that described in 2C, (S)-1-(2-(trifluoromethoxy)phenyl)ethanamine, HCl (1.3 g, 5.38 mmol, 100% yield) was obtained. MS ESI m / z 206.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 7.66 (dd, J=7.5, 2.0 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.48 - 7.44 (m, 1H), 4.80 (q, J=6.8 Hz, 1H), 1.64 (d, J=7.0 Hz, 3H).

[0150] (b): (R)-1-(2-(trifluoromethoxy)phenyl)ethanamine, HCl: (R)-1-(2-(trifluoromethoxy)phenyl)ethanamine, HCl (548 mg, 2.27 mmol, 91% yield). MS ESI m / z 206.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 7.66 (dd, J=7.5, 2.0 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.48 - 7.44 (m, 1H), 4.81 (q, J=6.8 Hz, 1H), 1.64 (d, J=6.8 Hz, 3H)

[0151] 2: To a solution of 5-(3-((ethyl-d5)carbamoyl)-1H-indazol-6-yl)-2-(methoxy-d3)nicotinic acid (1H) (20 mg, 0.057 mmol), (R)-1-(2-(trifluoromethoxy)phenyl)ethan-1-amine, HCl (2C-b) (13.87 mg, 0.057 mmol), and DIPEA (0.030 mL, 0.172 mmol) in DMF (1 mL) was added BOP (30.5 mg, 0.069 mmol). The reaction mixture was stirred at 23 °C for 2 h. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 19x200mm, 5μm particles; Mobile phase A: 5:95 acetonitrile:water with 10mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Gradient: 34-74% B over 20 min, then hold at 100% B for 4 min; Flow rate: 20mL / min. Fractions containing the desired product were combined and dried by centrifugal evaporation. (R)-N-(ethyl-d5)-6-(6-(methoxy-d3)-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide (9.2mg, 17.2μmol, 30% yield) was isolated. MS ESI m / z 536.2 (M+H) 1H NMR (500 MHz, DMSO-d6) δ 8.80 (br d, J=7.6 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.40 (s, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.85 (s, 1H), 7.71 - 7.66 (m, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.38 (br s, 1H), 5.44 (br t, J=7.2 Hz, 1H), 1.48 (d, J=7.0 Hz, 3H)

[0152] Example 3 (R)-6-(6-(methoxy-d3)-5-((1-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide [ka] 3A: (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine, HCl: Using a procedure similar to that of 1C(a), (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine, HCl (201 mg, 0.836 mmol, 80% yield) was obtained. MS ESI m / z 190.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.79 - 7.74 (m, 2H), 7.73 - 7.66 (m, 1H), 4.59 (q, J=6.8 Hz, 1H), 1.67 (d, J=6.8 Hz, 3H).

[0153] 3B: 2-(Methoxy-d3)-5-(3-((methyl-d3)carbamoyl)-1H-indazol-6-yl)nicotinic acid: Using a procedure similar to that for 1H, 2-(methoxy-d3)-5-(3-((methyl-d3)carbamoyl)-1H-indazol-6-yl)nicotinic acid (283 mg, 0.852 mmol) was obtained.

[0154] Using a method substantially similar to that described in 3:1, (R)-6-(6-(methoxy-d3)-5-((1-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide (10.9 mg, 21.6 μmol, 48% yield) was obtained. MS ESI m / z 504.3 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.85 (br d, J=7.9 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.35 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.76 (br d, J=6.7 Hz, 1H), 7.66 - 7.56 (m, 3H), 5.26 (quin, J=7.2 Hz, 1H), 1.52 (d, J=7.0 Hz, 3H).

[0155] Example 4 (R)-6-(5-((1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, TFA [ka] 4A: (R)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethane-2,2,2-d3-1-amine, HCl: Using a procedure similar to that of 1C(a), (R)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethane-2,2,2-d3-1-amine, HCl (624 mg, 2.472 mmol, 98% yield). MS ESI m / z 211.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 7.91 (br d, J=6.6 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.48 (t, J=9.4 Hz, 1H), 4.82 (s, 1H).

[0156] 4B: 2-(Methoxy-d3)-5-(3-(methylcarbamoyl)-1H-indazol-6-yl)nicotinic acid: Using a procedure similar to that for 1H, 2-(methoxy-d3)-5-(3-(methylcarbamoyl)-1H-indazol-6-yl)nicotinic acid (266 mg, 0.808 mmol) was obtained. MS ESI m / z 330.1 (M+H).

[0157] Using a method substantially similar to that described in 4:1, (R)-6-(5-((1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, TFA (7.2 mg, 11.3 μmol, 25% yield) was obtained. MS ESI m / z 522.2 (M+H) 1H NMR (500 MHz, DMSO-d6) δ 8.92 (d, J=7.6 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.34 (br d, J=4.9 Hz, 1H), 8.25 - 8.18 (m, 2H), 7.90 (br d, J=5.2 Hz, 1H), 7.81 (s, 1H), 7.74 - 7.66 (m, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.43 (t, J=9.3 Hz, 1H), 5.37 (d, J=7.6 Hz, 1H), 2.80 (d, J=4.6 Hz, 3H).

[0158] Example 5 (S)-6-(5-((1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide [ka] 5A: (S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethan-1-amine, HCl: Using the same method as in 1C(b), (S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethan-1-amine, HCl was obtained.

[0159] Using a method substantially similar to that described in 5:1, (S)-6-(5-((1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide (10.4 mg, 19.3 μmol, 43% yield) was obtained. MS ESI m / z 538.2 (M+H) 1H NMR (500 MHz, DMSO-d6) δ 8.90 (br d, J=7.6 Hz, 1H), 8.72 (d, J=2.1 Hz, 1H), 8.35 (s, 1H), 8.30 - 8.24 (m, 2H), 7.86 (s, 1H), 7.61 - 7.51 (m, 2H), 7.44 - 7.30 (m, 2H), 5.39 (br t, J=7.2 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H).

[0160] Example 6 (R)-6-(5-((1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide [ka]

[0161] 6A: (R)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethan-1-amine, HCl: Using the same method as in 1C(a), (R)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethan-1-amine, HCl was obtained.

[0162] Using a method substantially similar to that described in 6:1, (R)-6-(5-((1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide (9.2 mg, 17.6 μmol, 39% yield) was obtained. MS ESI m / z 522.3 (M+H) 1H NMR (500 MHz, DMSO-d6) δ 8.96 (br d, J=7.6 Hz, 1H), 8.72 (d, J=2.1 Hz, 1H), 8.35 (s, 1H), 8.30 - 8.19 (m, 2H), 7.96 (br d, J=5.2 Hz, 1H), 7.86 (s, 1H), 7.75 (br d, J=3.1 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.48 (br t, J=9.3 Hz, 1H), 5.44 (br t, J=7.3 Hz, 1H), 1.51 (d, J=7.0Hz, 3H).

[0163] Example 7 (R)-6-(6-(methoxy-d3)-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide [ka] Using a method substantially similar to that described in 1, (R)-6-(6-(methoxy-d3)-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide (21.1 mg, 40.6 μmol, 90% yield) was obtained. MS ESI m / z 520.4 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.80 (br d, J=7.6 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.37 - 8.30 (m, 2H), 8.26 (d, J=8.5 Hz, 1H), 7.85 (s, 1H), 7.71 - 7.65 (m, 1H), 7.58 (br d, J=8.5 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.38 (br s, 1H), 5.49 - 5.38 (m, 1H), 1.48 (d, J=7.0 Hz, 3H).

[0164] Example 8 (R)-6-(6-(methoxy-d3)-5-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide, TFA [ka]

[0165] 8A: (R)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine, HCl: Using a procedure similar to that of 1C(a), (R)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine, HCl (R)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine, HCl (542 mg, 2.158 mmol, 90% yield). MS ESI m / z 206.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 7.65 - 7.56 (m, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.44 (s, 1H), 7.38 (br d, J=8.2 Hz, 1H), 4.56 (q, J=6.8 Hz, 1H), 1.66 (d, J=6.8 Hz, 3H).

[0166] Using a method substantially similar to that described in 8:1, (R)-6-(6-(methoxy-d3)-5-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide, TFA (11 mg, 17.4 μmol, 39% yield) was obtained. MS ESI m / z 520.2 (M+H) 1H NMR (500 MHz, DMSO-d6) δ 8.72 - 8.64 (m, 2H), 8.31 (d, J=2.4 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.19 (s, 1H), 7.83 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.44 (s, 1H), 7.24 (br d, J=7.5 Hz, 1H), 5.29 - 5.17 (m, 1H), 1.52 (d, J=7.1 Hz, 3H).

[0167] Example 9 (R)-6-(5-((1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, TFA [ka] Using a method substantially similar to that described in 1, (R)-6-(5-((1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, TFA (3.1 mg, 4.8 μmol, 10% yield) was obtained. MS ESI m / z 537.9 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=7.6 Hz, 1H), 8.71 (d, J=2.1 Hz, 1H), 8.38 (br d, J=4.9 Hz, 1H), 8.30 - 8.23 ​​(m, 2H), 7.85 (s, 1H), 7.63 - 7.51 (m, 2H), 7.43 - 7.33 (m, 2H), 5.37 (d, J=7.6 Hz, 1H), 2.84 (d, J=4.6 Hz, 3H).

[0168] Example 10 (S)-6-(5-((1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide [ka] Using a method substantially similar to that described in 1, (S)-6-(5-((1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (5 mg, 9.3 μmol, 20% yield) was obtained. MS ESI m / z 538 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.89 (br d, J=7.6 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.38 (br d, J=4.9 Hz, 1H), 8.30 - 8.20 (m, 2H), 7.85 (s, 1H), 7.62 - 7.54 (m, 2H), 7.44 - 7.32 (m, 2H), 5.37 (br d, J=7.6 Hz, 1H), 2.85 (d, J=4.6 Hz, 3H).

[0169] Example 11 (R)-6-(6-(methoxy-d3)-5-((1-(3-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, TFA [ka]

[0170] 11A: (R)-1-(3-(trifluoromethoxy)phenyl)ethane-2,2,2-d3-1-amine: Using the same method as 1C(a), (R)-1-(3-(trifluoromethoxy)phenyl)ethane-2,2,2-d3-1-amine (345.2 mg, 1.636 mmol, 90% yield) was obtained. MS ESI m / z 209.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 7.64 - 7.57 (m, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.44 (s, 1H), 7.37 (dt, J=8.2, 1.1 Hz, 1H), 4.53 (s, 1H).

[0171] Using a method essentially similar to that described in 11:1, (R)-6-(6-(methoxy-d3)-5-((1-(3-(trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, TFA (7.6 mg, 12 μmol, 25% yield) was obtained. MS ESI m / z 520.2 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.78 (br d, J=7.9 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.37 (br d, J=4.6 Hz, 1H), 8.31 - 8.22 (m, 2H), 7.85 (s, 1H), 7.58 (br d, J=8.5 Hz, 1H), 7.54 - 7.40 (m, 3H), 7.26 (br d, J=7.3 Hz, 1H), 5.20 (br d, J=7.6 Hz, 1H), 2.84 (d, J=4.9 Hz, 3H).

[0172] Example 12 6-(5-(((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-methoxy d3-pyridin-3-yl)-N-methyl d3-1H-indazole-3-carboxamide [ka] 12A: 1-tert-butyl 3-methyl 6-bromo-1H-indazole-1,3-dicarboxylate: To a solution of methyl 6-bromo-1H-indazole-3-carboxylate (0.5 g, 1.960 mmol), DMAP (0.024 g, 0.196 mmol), and TEA (0.478 mL, 3.43 mmol) in CHCl (14 mL) was added Boc anhydride (0.683 mL, 2.94 mmol) at 0° C. The reaction mixture was warmed to 23° C. and stirred for 24 h. The reaction mixture was concentrated and triturated with MeOH (5 mL). The solid was recovered as 1-tert-butyl 3-methyl 6-bromo-1H-indazole-1,3-dicarboxylate (520 mg, 1.45 mmol, 74% yield). MS ESI m / z 355.1 (M+H)

[0173] 12B: Methyl d3 5-bromo-2-methoxy d3-nicotinate: Sodium (0.51 g, 22.36 mmol) was added to CD3OD (10 mL) and stirred until the reaction was complete. Methyl 5-bromo-2-chloronicotinate (2.0 g, 7.98 mmol) was added to the reaction mixture and stirring was continued for 16 h. The reaction mixture was acidified with concentrated HCl solution and diluted with dichloromethane (100 mL). The organic layer was washed with water (20 mL), brine (20 mL) and dried over Na2SO4. Filtration and concentration gave methyl d3 5-bromo-2-methoxy d3-nicotinate (1.67 g, 6.62 mmol, 83% yield). MS ESI m / z 251.1 (M+H) 1H NMR (400 MHz, CD3OD) δ 8.40 (d, J=2.6 Hz, 1H), 8.28 (d, J=2.6 Hz, 1H).

[0174] 12C: 5-Bromo-2-methoxy d3-nicotinic acid, sodium salt: A solution of methyl d3 5-bromo-2-methoxy d3-nicotinate (800 mg, 3.17 mmol) and NaOH (4.76 mL, 4.76 mmol) in MeOH (15 mL) was heated in a microwave at 100° C. for 30 minutes. The reaction mixture was concentrated to give 5-bromo-2-methoxy d3-nicotinic acid, sodium salt. The material was used directly in the next reaction. MS ESI m / z 236.9 (M+H).

[0175] 12D: (3R,4S)-tert-Butyl 3-(5-bromo-2-methoxy d3-nicotinamide)-4-fluoropyrrolidine-1-carboxylate: To a solution of 5-bromo-2-methoxy d3-nicotinic acid, sodium salt (750 mg, 3.19 mmol), cis-1-boc-3-amino-4-fluoropyrrolidine (652 mg, 3.19 mmol), and DIPEA (0.669 mL, 3.83 mmol) in DMF (15 mL) was added BOP (1693 mg, 3.83 mmol). The reaction mixture was stirred at 23° C. for 1 h. The reaction mixture was concentrated. EtOAc (150 mL) was added to the crude material. The organic layer was washed with water (50 mL), brine (50 mL), and dried over Na2SO4. Filtration and concentration gave the crude product, which was triturated in water (50 mL). The solid was recovered as a mixture of cis isomers of (3R,4S)-tert-butyl 3-(5-bromo-2-methoxy d3-nicotinamide)-4-fluoropyrrolidine-1-carboxylate (1.23 g, 2.92 mmol, 92% yield). MS ESI m / z 421.1 (M+H) 1H NMR (400 MHz, CD3OD) δ 8.43 - 8.31 (m, 2H), 5.34 - 5.07 (m, 1H), 4.80 - 4.64 (m, 1H), 3.99 - 3.85 (m, 1H), 3.78 - 3.54 (m, 2H), 3.22 (td, J=10.3, 4.8 Hz, 1H), 1.49 (s, 9H).

[0176] The racemic mixture was separated using chiral SFC conditions to give two peaks, 12D-1 (414.6 mg, 0.984 mmol) and 12D-2 (426.0 mg, 1.011 mmol), which was used in the next chemistry. 12D-1: MS ESI m / z 421.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.41 - 8.39 (m, 1H), 8.38 (d, J=2.6 Hz, 1H), 5.33 - 5.11 (m, 1H), 4.81 - 4.65 (m, 1H), 3.98 - 3.87 (m, 1H), 3.77 - 3.55 (m, 2H), 3.22 (td, J=10.3, 5.0 Hz, 1H), 1.49 (s, 9H). 12D-2: MS ESI m / z 421.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.41 - 8.39 (m, 1H), 8.38 (d, J=2.6 Hz, 1H), 5.33 - 5.08 (m, 1H), 4.80 - 4.64 (m, 1H), 3.97 - 3.88 (m, 1H), 3.77 - 3.55 (m, 2H), 3.22 (td, J=10.4, 5.0 Hz, 1H), 1.49 (s, 9H).

[0177] 12E: 5-Bromo-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxy d3-nicotinamide, TFA: To a solution of (3R,4S)-tert-butyl 3-(5-bromo-2-methoxy d3-nicotinamide)-4-fluoropyrrolidine-1-carboxylate (200 mg, 0.475 mmol) in CHCl (2 mL) was added TFA (0.914 mL, 11.87 mmol). After stirring at 23° C. for 1 h, the reaction mixture was concentrated and triturated in diethyl ether (5 mL). The solid was recovered as 5-Bromo-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxy d3-nicotinamide, TFA. MS ESI m / z 320.9 (M+H).

[0178] 12F: 5-Bromo-N-((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxy d3-nicotinamide: 5-Bromo-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxy d3-nicotinamide, TFA (207 mg, 0.476 mmol), 3,3-difluorocyclobutanecarboxylic acid (64.7 mg, 0.476 mmol), and DIPEA (0.291 mL, 1.665 mmol) in DMF (3 mL) was added BOP (252 mg, 0.571 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and transferred to a separatory funnel with EtOAc (80 mL). The organic layer was washed with water (20 mLx3), brine (20 mL) and dried over Na2SO4. Filtration and concentration gave the crude product, which was purified on a silica gel column with hexane / EtOAc (100 / 0 to 0 / 100) to give 5-bromo-N-((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxy d3-nicotinamide (183 mg, 0.417 mmol, 88% yield). MS ESI m / z 439.1 (M+H) 1H NMR (400 MHz, CD3OD) δ 8.43 - 8.35 (m, 2H), 5.40 - 5.14 (m, 1H), 4.82 - 4.68 (m, 1H), 4.14 - 4.02 (m, 1H), 3.95 - 3.63 (m, 2H), 3.44 (t, J=10.2 Hz, 1H), 3.24 - 3.10 (m, 1H), 2.92 - 2.76 (m, 4H).

[0179] 12G: N-((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxy d3-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide: 5-bromo-N-((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxy A degassed solution of d3-nicotinamide (183 mg, 0.417 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (138 mg, 0.542 mmol), potassium acetate (65.4 mg, 0.667 mmol), and PdCl2(dppf)-CH2Cl2 adduct (27.2 mg, 0.033 mmol) in dioxane (3 mL) was heated at 65 °C for 8 h. The reaction mixture was filtered through Celite. The solution was concentrated to give the product, which was used as is. MS ESI m / z 405.1 (M+H of boronic acid).

[0180] 12H: 1-tert-butyl 3-methyl 6-(5-(((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-methoxy d3-pyridin-3-yl)-1H-indazole-1,3-dicarboxylate: N-((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxy d3-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (205 mg, 0.421 mmol), 1-tert-butyl 3-methyl 6-bromo-1H-indazole-1,3-dicarboxylate (136 mg, 0.383 mmol), potassium phosphate tribasic A degassed solution of 2M solution (0.57 mL, 1.149 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (18.76 mg, 0.023 mmol) in DMF (3 mL) was stirred at 23°C for 2 h. The reaction mixture was concentrated. EtOAc (80 mL) was added to the residue, which was washed with water (20 mL), brine (20 mL) and dried over Na2SO4. Filtration and concentration gave the crude product, which was triturated with MeOH (2 mL). The solid was recovered as 1-tert-butyl 3-methyl 6-(5-(((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-methoxy d3-pyridin-3-yl)-1H-indazole-1,3-dicarboxylate (167.6 mg, 0.264 mmol, 69% yield). MS ESI m / z 635.1 (M+H) 1H NMR (400 MHz, DMSO-d6) δ 8.78 (dd, J=5.1, 2.6 Hz, 1H), 8.57 (dd, J=10.0, 7.9 Hz, 1H), 8.45 (dd, J=7.0, 2.6 Hz, 1H), 8.41 (s, 1H), 8.27 (dd, J=8.4, 2.0 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 5.46 - 5.18 (m, 1H), 4.92 - 4.61 (m, 1H), 4.09 - 3.58 (m, 6H), 3.42 - 3.26 (m, 1H fused with water), 3.24 - 3.11 (m, 1H), 2.92 - 2.70 (m, 4H), 1.71 (s, 9H).

[0181] 12I: 6-(5-(((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-methoxy d3-pyridin-3-yl)-1H-indazole-3-carboxylic acid: Using a method substantially similar to that described in 1H, 6-(5-(((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-methoxy d3-pyridin-3-yl)-1H-indazole-3-carboxylic acid (130 mg, 0.245 mmol, 93% yield) was obtained. MS ESI m / z 521.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.71 (t, J=3.0 Hz, 1H), 8.68 - 8.63 (m, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 5.45 - 5.23 (m, 1H), 4.94 - 4.81 (m, 1H fused with MeOH), 4.21 - 3.68 (m, 4H), 3.28 - 3.18 (m, 1H), 2.91 - 2.78 (m, 4H).

[0182] Using a method essentially similar to that described in J. Med. Sci. 12:1, 6-(5-(((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-methoxy d3-pyridin-3-yl)-N-methyl d3-1H-indazole-3-carboxamide (3.9 mg, 7.3 μmol, 38% yield) was obtained. MS ESI m / z 537.3 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.72 (dd, J=5.5, 2.4 Hz, 1H), 8.49 (br dd, J=11.9, 7.7 Hz, 1H), 8.44 (dd, J=8.6, 2.5 Hz, 1H), 8.27 (dd, J=8.4, 2.4 Hz, 1H), 8.20 (s, 1H), 7.85 (s, 1H), 7.57 (br d, J=8.4 Hz, 1H), 5.42 - 5.22 (m, 1H), 4.87 - 4.62 (m, 1H), 4.12 - 3.29 (m, 4H) below the water peak), 3.24 - 3.11 (m, 1H), 2.87 - 2.71 (m, 4H).

[0183] Example 13 (R)-N-cyclopropyl-6-(6-methoxy d3-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide [ka] Using a protocol similar to that used to obtain 1, (R)-N-cyclopropyl-6-(6-methoxy d3-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide (6.5 mg, 12 μmol, 29% yield) was obtained. MS ESI m / z 543.3 (M+H) 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J=7.7 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.45 (d, J=4.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 7.84 (s, 1H), 7.69 - 7.65 (m, 1H), 7.58 (dd, J=8.5, 1.0 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.36 (dd, J=3.8, 1.7 Hz, 1H), 5.43 (t, J=7.2 Hz, 1H), 2.95 - 2.85 (m, 1H), 1.47 (d, J=7.0 Hz, 3H), 0.74 - 0.62 (m, 4H).

[0184] Example 14 (R)-6-(6-Methoxy d3-5-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide [ka] Using a procedure similar to that used to obtain 8, (R)-6-(6-methoxy d3-5-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (25.8 mg, 50 μmol, 26% yield) was obtained. MS ESI m / z 517.1 (M+H) 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J=2.6 Hz, 1H), 8.49 (d, J=2.6 Hz, 1H), 8.33 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.56 (dd, J=8.5, 1.4 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.39 (s, 1H), 7.24 - 7.17 (m, 1H), 5.31 (q, J=7.1 Hz, 1H), 3.00 (s, 3H), 1.62 (d, J=7.1 Hz, 3H).

[0185] Example 15 6-(6-Methoxy d3-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, homochiral, unknown enantiomer [ka]

[0186] 15A: (+ / -)-1-(2-(trifluoromethoxy)phenyl)ethanamine, HCl: A solution of 1-(2-(trifluoromethoxy)phenyl)ethanone (3.82 g, 18.71 mmol), ammonium acetate (8.65 g, 112 mmol) and sodium cyanoborohydride (2.94 g, 46.8 mmol) in ethanol (37 mL) was heated at 80° C. for 16 h. The reaction mixture was filtered to remove solids and the filtrate was concentrated. Saturated brine solution (80 mL) was added. The aqueous layer was extracted with ether (50 mL×3). The organic layers were combined and dried over Na2SO4. Filtration and concentration gave the crude product. The crude product was dissolved in ether (100 mL). 4.0 M HCl in 1,4-dioxane (7.02 mL, 28.1 mmol) was added to the reaction mixture and stirred for 30 min. The white solid was recovered as (+ / -)-1-(2-(trifluoromethoxy)phenyl)ethanamine, HCl (1.36 g, 5.63 mmol, 30% yield). MS ESI m / z 206.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 7.66 (dd, J=7.6, 2.0 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.48 - 7.44 (m, 1H), 4.84 - 4.78 (m, 1H), 1.64 (d, J=6.8 Hz, 3H).

[0187] Using a similar procedure up to 15:1, (+ / -)-6-(6-methoxy d3-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (123 mg, 0.237 mmol, 65% yield) was obtained. MS ESI m / z 517.4 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (br d, J=7.6 Hz, 1H), 8.67 (s, 1H), 8.38 (br d, J=4.6 Hz, 1H), 8.30 (s, 1H), 8.23 ​​(br d, J=8.5 Hz, 1H), 7.84 (s, 1H), 7.64 (br d, J=4.6 Hz, 1H), 7.56 (br d, J=8.2 Hz, 1H), 7.45 - 7.30 (m, 3H), 5.41 (br t, J=7.2 Hz, 1H), 2.83 (br d, J=4.3 Hz, 3H), 1.46 (br d, J=7.0 Hz, 3H).

[0188] 6-(6-Methoxy d3-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (123 mg, 0.237 mmol) was separated by preparative SFC using the following conditions: Cellulose-4 (3x25 cm, 5 μm, #637399), BPR pressure: 100 bar, temperature: 35 °C, flow rate: 200 mL / min, mobile phase: CO2 / MeOH (65 / 35), detection wavelength: 220 nm. Fractions from peak 1 were combined to give 6-(6-methoxy d3-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (26.9 mg, 52.1 μmol, 22.1%. Chiral purity: 99.5%). MS ESI m / z 517.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.67 (d, J=2.6 Hz, 1H), 8.54 (d, J=2.6 Hz, 1H), 8.33 (d, J=8.6 Hz, 1H), 7.80 (s, 1H), 7.65 - 7.60 (m, 1H), 7.56 (dd, J=8.6, 1.4 Hz, 1H), 7.43 - 7.31 (m, 3H), 5.57 (q, J=7.0 Hz, 1H), 3.00 (s, 3H), 1.61 (d, J=7.0 Hz, 3H).

[0189] Example 16 6-(6-Methoxy D3-5-((2-(trifluoromethoxy)benzyl D2)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide [ka] Using a method substantially similar to that described in 1, 6-(6-methoxy D3-5-((2-(trifluoromethoxy)benzyl D2)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (7.8 mg, 12.6 μmol, 27% yield) was obtained. MS ESI m / z 505 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.73 (d, J=2.1 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.38 (br d, J=4.6 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 7.85 (s, 1H), 7.58 (br d, J=8.5 Hz, 1H), 7.53 (dd, J=7.0, 1.8 Hz, 1H), 7.45 - 7.36 (m, 3H), 2.84 (d, J=4.6 Hz, 3H).

[0190] Example 17 6-(6-Methoxy-5-((3-pivalamidocyclohexyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, chiral, unknown isomer [ka] 17A: tert-Butyl (3-(2-methoxy-5-(3-(methylcarbamoyl)-1H-indazol-6-yl)nicotinamido)cyclohexyl)carbamate (diastereomeric mixture): To a solution of 2-methoxy-5-(3-(methylcarbamoyl)-1H-indazol-6-yl)nicotinic acid (300 mg, 0.919 mmol), 1-N-Boc-1,3-cyclohexyldiamine (236 mg, 1.10 mmol), and DIPEA (0.482 mL, 2.76 mmol) in DMF (4 mL) was added BOP (488 mg, 1.103 mmol). The reaction mixture was stirred at 23° C. for 1 h. The reaction mixture was concentrated to give the crude product, which was triturated with water (30 mL). The solid was recovered as tert-butyl (3-(2-methoxy-5-(3-(methylcarbamoyl)-1H-indazol-6-yl)nicotinamido)cyclohexyl)carbamate (mixture of diastereomers). MS ESI m / z 523.1 (M+H)

[0191] 17B: 6-(5-((3-aminocyclohexyl)carbamoyl)-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, 2TFA (mixture of diastereomers): To a solution of tert-butyl (3-(2-methoxy-5-(3-(methylcarbamoyl)-1H-indazol-6-yl)nicotinamide)cyclohexyl)carbamate (480 mg, 0.918 mmol) in CHCl (5 mL) was added TFA (1.769 mL, 22.96 mmol). The reaction mixture was stirred at 23° C. for 2 h. The reaction mixture was concentrated to give 6-(5-((3-aminocyclohexyl)carbamoyl)-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, 2TFA (diastereomeric mixture, 517 mg, 0.793 mmol, 86% yield). MS ESI m / z 423.3 (M+H).

[0192] Using a method essentially similar to that described in 17:1, 6-(6-methoxy-5-((3-pivalamidocyclohexyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (mixture of diastereomers, 331 mg, 0.653 mmol) was obtained.

[0193] The crude mixture was separated by preparative SFC using the following conditions: Chiral IC (3x25cm, 5um), BPR pressure: 100 bar, temperature: 35°C, flow rate: 250mL / min, mobile phase: CO2 / MeOH (65 / 35), detection wavelength: 220nm. Fractions from peak 3 were combined to give 6-(6-methoxy-5-((3-pivalamidocyclohexyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (32.7mg, 65μmol, 9.88%, chiral purity: 92%). MS ESI m / z 507.4 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=2.4 Hz, 1H), 8.40 (br d, J=2.3 Hz, 2H), 8.34 (br d, J=7.2 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.17 (br d, J=4.8 Hz, 1H), 4.25 (br s, 1H), 4.08 (s, 3H), 3.99 - 3.90 (m, 1H), 2.83 (d, J=4.6 Hz, 3H), 1.77 (br d, J=13.0 Hz, 1H), 1.70 - 1.52 (m, 6H), 1.35 (br d, J=9.5 Hz, 1H), 1.11 - 1.07 (m, 9H).

[0194] Example 18 6-(6-Methoxy-5-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide, homochiral, unknown enantiomer [ka] 18A: (rac)-(1-Bromopropyl)benzene: A solution of 1-phenylpropan-1-ol (0.5 g, 3.67 mmol) and phosphorus tribromide (0.693 mL, 7.34 mmol) in CHCl3 (10 mL) was heated at 70 °C for 16 h. The reaction mixture was quenched with ice (20 mL) and diluted with ethyl acetate (100 mL). The organic layer was separated and washed with water (20 mL) followed by brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified using silica gel chromatography with hexane / CHCl2 (4 / 1) to give (rac)-(1-Bromopropyl)benzene (540 mg, 2.71 mmol, 74% yield). 1 H NMR (400 MHz, CDCl3) δ 7.45 - 7.29 (m, 5H), 4.91 (dd, J=7.9, 7.0 Hz, 1H), 2.41 - 2.12 (m, 2H), 1.03 (t, J=7.2 Hz, 3H).

[0195] 18B: 5-Bromo-2-methoxy-3-(1H-tetrazol-5-yl)pyridine: A solution of 5-bromo-2-methoxynicotinonitrile (1.09 g, 5.12 mmol) and azidotributyltin (1.402 mL, 5.12 mmol) in DMF (15 mL) was heated at 150° C. for 2.5 h under microwave. The reaction mixture was concentrated and diluted with a mixture of MeOH (19 mL) / water (13.5 mL) / HOAc (5.5 mL). A white solid precipitated. The mixture was stirred at room temperature for 1 h. The solid was collected and triturated in toluene (10 mL). The white solid was recovered as 5-bromo-2-methoxy-3-(1H-tetrazol-5-yl)pyridine (1.172 g, 4.45 mmol, 87% yield). MS ESI m / z 256.0 (M+H) 1H NMR (400 MHz, DMSO-d6) δ 8.57 - 8.53 (m, 2H), 4.04 (s, 3H).

[0196] 18C: (rac)-(5-Bromo-2-methoxy-3-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridine: A solution of 5-bromo-2-methoxy-3-(1H-tetrazol-5-yl)pyridine (300 mg, 1.172 mmol), (+ / -)-(1-bromopropyl)benzene (292 mg, 1.465 mmol), and KCO (243 mg, 1.757 mmol) in DMF (8 mL) was stirred at 23 °C for 24 h. The reaction mixture was concentrated. The organic layer was washed with 10% LiCl solution (30 mL), brine (30 mL) and dried over Na2SO4. Filtration and concentration gave the crude product which was purified using silica gel chromatography with hexane / EtOAc (2 / 1) to give (rac)-(5-bromo-2-methoxy-3-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridine (286.7 mg, 0.738 mmol, 63% yield). MS ESI m / z 374.0 (M+H) 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.6 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.43 - 7.31 (m, 3H), 5.87 (dd, J=8.9, 6.8 Hz, 1H), 4.08 (s, 3H), 2.76 - 2.57 (m, 1H), 2.50 - 2.30 (m, 1H), 0.98 (t, J=7.3 Hz, 3H).

[0197] 18D: (rac)-2-Methoxy-3-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine: A degassed solution of (rac)-5-bromo-2-methoxy-3-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridine (276 mg, 0.738 mmol), bis(pinacolato)diboron (225 mg, 0.885 mmol), potassium acetate (109 mg, 1.106 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (60.2 mg, 0.074 mmol) in dioxane (5 mL) was heated at 80° C. for 16 h. The reaction mixture was concentrated and purified on a silica gel column with hexane / EtOAc (100 / 0 to 60 / 40) to give (rac)-2-methoxy-3-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (312 mg, 0.741 mmol, 100% yield). MS ESI m / z 422.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.60 (d, J=1.8 Hz, 1H), 8.54 (d, J=1.8 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.45 - 7.28 (m, 3H), 6.01 (dd, J=8.9, 6.6 Hz, 1H), 4.08 (s, 3H), 2.76 - 2.26 (m, 2H), 1.39 (s, 12H), 0.97 (t, J=7.3 Hz, 3H).

[0198] 18E: tert-butyl 6-bromo-3-(methylcarbamoyl)-1H-indazole-1-carboxylate: Using a similar procedure to 1G, tert-butyl 6-bromo-3-(methylcarbamoyl)-1H-indazole-1-carboxylate (346 mg, 0.978 mmol, 34% yield) was obtained. MS ESI m / z 354.1 (M+H)

[0199] 18: (rac)-6-(6-methoxy-5-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide: tert-butyl 6-bromo-3-(methylcarbamoyl)-1H-indazole-1-carboxylate (130 mg, 0.367 mmol), 2-methoxy-3-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (155 mg, 0.367 mmol), PdCl2(dppf)-CH2Cl2 adduct (17.98 mg, 0.022 mmol), and potassium phosphate tribasic. A degassed solution of the 2M solution (0.551 mL, 1.101 mmol) in DMF (2 mL) was heated at 100° C. for 2 h. The reaction mixture was concentrated and purified on a Combiflash RF200 with: Column: 100g C18 RediSep Rf High performance Gold, Solvent A: Water / MeOH (90 / 10) with 0.1% TFA, Solvent B: Water / MeOH (10 / 90) with 0.1% TFA, Flow rate: 60mL / min, Starting %B: 10%, Final %B: 100%, Wavelength 1:254, Wavelength 1:220 to give (rac)-6-(6-Methoxy-5-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (92.7mg, 0.198mmol, 54% yield). MS ESI m / z 469.0 (M+H) 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=2.6 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.53 (dd, J=8.5, 0.7 Hz, 1H), 7.03 (s, 1H), 6.78 (dd, J=8.4, 1.5 Hz, 1H), 6.76 - 6.72 (m, 2H), 6.65 - 6.53 (m, 3H), 5.23 (dd, J=8.9, 6.7 Hz, 1H), 3.32 (s, 3H), 2.20 (s, 3H), 1.95 - 1.81 (m, 1H), 1.65 (dt, J=14.2, 6.9 Hz, 1H), 0.18 (t, J=7.3 Hz, 3H).

[0200] The materials were separated by preparative SFC using the following conditions: Chiralcel OJ-H (3x25cm, 5μm), BPR pressure: 100 bar, temperature: 40°C, flow rate: 160mL / min, mobile phase: CO2 / MeOH w 0.1% NH4OH (78 / 22), detection wavelength: 250nm.

[0201] 18-1: Fractions from peak 1 were combined to give 6-(6-methoxy-5-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (a) (32 mg, 0.068 mmol, 35%, chiral purity: 99.5%). MS ESI m / z 469.1 (M+H) 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J=2.4 Hz, 1H), 8.61 (d, J=2.6 Hz, 1H), 8.35 (d, J=8.7 Hz, 1H), 7.84 (s, 1H), 7.62 - 7.53 (m, 3H), 7.45 - 7.35 (m, 3H), 6.04 (dd, J=9.0, 6.7 Hz, 1H), 4.13 (s, 3H), 3.01 (s, 3H), 2.74 - 2.64 (m, 1H), 2.52 - 2.40 (m, 1H), 0.99 (t, J=7.3 Hz, 3H).

[0202] 18-2: Fractions from peak 2 were combined to give 6-(6-methoxy-5-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide (b) (32 mg, 0.068 mmol, 35%, chiral purity: 99.4%). MS ESI m / z 469.1 (M+H) 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J=2.6 Hz, 1H), 8.57 (d, J=2.6 Hz, 1H), 8.37 (q, J=4.4 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.61 (dd, J=8.6, 1.5 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.46 - 7.34 (m, 3H), 6.17 (dd, J=8.8, 6.6 Hz, 1H), 4.03 (s, 3H), 2.84 (d, J=4.8 Hz, 3H), 2.62 - 2.50 (m, 1H) (fused with DMSO), 2.41 - 2.29 (m, 1H), 0.90 (t, J=7.2 Hz, 3H).

[0203] Example 19 6-(5-(2-(1-(4-fluorophenyl)ethyl)-2H-tetrazol-5-yl)-6-methoxypyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide, homochiral, unknown enantiomer [ka] 19A: 6-Bromo-N-(methyl-d3)-1H-indazole-3-carboxamide: Using a procedure similar to that of 1F, 6-bromo-N-(methyl-d3)-1H-indazole-3-carboxamide (231 mg, 0.895 mmol) was obtained. MS ESI m / z 257.1 (M+H)

[0204] 19B: tert-Butyl 6-bromo-3-((methyl-d3)carbamoyl)-1H-indazole-1-carboxylate: Using a method similar to that for 1G, tert-butyl 6-bromo-3-((methyl-d3)carbamoyl)-1H-indazole-1-carboxylate (149 mg, 0.414 mmol, 79% yield) was obtained. MS ESI m / z 357.0 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.43 - 8.37 (m, 1H), 8.26 - 8.19 (m, 1H), 7.61 (dd, J=8.6, 1.6 Hz, 1H), 1.76 (s, 9H).

[0205] 19C: 6-(5-cyano-6-methoxypyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide: Using a method essentially similar to that described for 1L, 6-(5-cyano-6-methoxypyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide (97 mg, 0.305 mmol, 73% yield) was obtained. MS ESI m / z 311.1 (M+H)

[0206] 19D: 6-(6-Methoxy-5-(1H-tetrazol-5-yl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide: Using a method substantially similar to that described in 18B, 6-(6-methoxy-5-(1H-tetrazol-5-yl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide (32 mg, 0.091 mmol, 29% yield) was obtained. MS ESI m / z 354.1 (M+H)

[0207] 19E: (+ / -)-6-(5-(2-(1-(4-fluorophenyl)ethyl)-2H-tetrazol-5-yl)-6-methoxypyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide: Using a method substantially similar to that described in 18C, (+ / -)-6-(5-(2-(1-(4-fluorophenyl)ethyl)-2H-tetrazol-5-yl)-6-methoxypyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide (16 mg, 0.033 mmol, 37% yield) was obtained. MS ESI m / z 476.1 (M+H).

[0208] Using a method substantially similar to that described in 19-1:180, 6-(5-(2-(1-(4-fluorophenyl)ethyl)-2H-tetrazol-5-yl)-6-methoxypyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide PK1(a) (2.1 mg, 0.0042 mmol, 13% yield) was obtained. MS ESI m / z 476.1 (M+H) 1H NMR (400 MHz, CDCl3) δ 10.41 (br s, 1H), 8.57 (q, J=2.5 Hz, 2H), 8.51 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.56 (dd, J=8.5, 1.3 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.14 - 7.00 (m, 3H), 6.18 (q, J=7.2 Hz, 1H), 4.15 (s, 3H), 2.15 (d, J=7.1 Hz, 3H).

[0209] 19-2: PK2(b): 6-(5-(2-(1-(4-fluorophenyl)ethyl)-2H-tetrazol-5-yl)-6-methoxypyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide PK2(b) (4.6 mg, 0.0097 mmol, 29% yield). MS ESI m / z 476.1 (M+H) 1 H NMR (400 MHz, CD3OD) δ 8.65 (d, J=2.6 Hz, 1H), 8.59 (d, J=2.6 Hz, 1H), 8.33 (dd, J=8.4, 0.6 Hz, 1H), 7.82 (s, 1H), 7.61 - 7.51 (m, 3H), 7.19 - 7.12 (m, 2H), 6.32 (q, J=7.1 Hz, 1H), 4.11 (s, 3H), 2.12 (d, J=7.1 Hz, 3H).

[0210] Example 20 6-[5-(2-benzyl-2H-1,2,3,4-tetrazol-5-yl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide [ka] Using a similar method to 19, 6-[5-(2-benzyl-2H-1,2,3,4-tetrazol-5-yl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide (6.0 mg, 0.013 mmol, 19 c% yield) was obtained. MS ESI m / z 441.2 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 13.69 (s, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.41 (br d, J=4.5 Hz, 1H), 8.26 (br d, J=8.3 Hz, 1H), 7.89 (s, 1H), 7.61 (br d, J=8.4 Hz, 1H), 7.47 - 7.33 (m, 5H), 6.04 (s, 2H), 4.01 (s, 3H), 2.83 (br d, J=4.4 Hz, 3H).

[0211] Example 21 6-{6-methoxy-5-[(3-phenylcyclohexyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide, homochiral, unknown isomer [ka]

[0212] 21A: 2-Methoxy-5-(3-(methylcarbamoyl)-1H-indazol-6-yl)nicotinic acid: Using a similar procedure as for 1H, 2-methoxy-5-(3-(methylcarbamoyl)-1H-indazol-6-yl)nicotinic acid (735 mg, 2.072 mmol, 96% yield) was obtained. MS ESI m / z 327.1 (M+H)

[0213] Using a method substantially similar to that described in 21:1, 6-{6-methoxy-5-[(3-phenylcyclohexyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide (diastereomeric mixture, 251 mg, 0.510 mmol, 83% yield) was obtained. The crude mixture was separated by preparative SFC using the following conditions: Chiralpak OD (3x25 cm, 5 μm), BPR pressure: 100 bar, temperature: 40° C., flow rate: 170 mL / min, mobile phase: CO2 / MeOH (68 / 32), detection wavelength: 220 nm.

[0214] 21-1: Fractions from peak 1 were combined to give 6-{6-methoxy-5-[(3-phenylcyclohexyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide (78 mg, 158 μmol, 30%, chiral purity: 98.7%). MS ESI m / z 484.1 (M+H) 1 H NMR (400 MHz, DMSO-d6) δ 13.65 (br s, 1H), 8.72 (d, J=2.6 Hz, 1H), 8.44 - 8.34 (m, 3H), 8.26 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.59 (dd, J=8.5, 1.4 Hz, 1H), 7.35 - 7.25 (m, 4H), 7.23 - 7.15 (m, 1H), 4.37 - 4.26 (m, 1H), 4.10 (s, 3H), 2.96 - 2.80 (m, 4H), 2.02 - 1.47 (m, 8H).

[0215] 21-2: Fractions from peak 3 were combined to give 6-{6-methoxy-5-[(3-phenylcyclohexyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide (11.4 mg, 24 μmol, 4.5%, chiral purity: 99.5%). MS ESI m / z 484.1 (M+H) 1H NMR (400 MHz, DMSO-d6) δ 13.64 (br s, 1H), 8.68 (d, J=2.6 Hz, 1H), 8.40 - 8.32 (m, 2H), 8.27 - 8.22 (m, 1H), 8.19 (d, J=7.8 Hz, 1H), 7.83 (s, 1H), 7.57 (dd, J=8.5, 1.4 Hz, 1H), 7.36 - 7.24 (m, 4H), 7.23 - 7.16 (m, 1H), 4.02 (s, 3H), 3.97 (dq, J=11.7, 3.9 Hz, 1H), 2.83 (d, J=4.8 Hz, 3H), 2.75 - 2.65 (m, 1H), 2.09 - 1.95 (m, 2H), 1.93 - 1.85 (m, 1H), 1.83 - 1.76 (m, 1H), 1.58 - 1.32 (m, 4H).

[0216] 21-3: Fractions from peak 2 were combined to give 6-{6-methoxy-5-[(3-phenylcyclohexyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide (63 mg, 130 μmol, 25%, chiral purity: 98.7%). MS ESI m / z 484.1 (M+H) 1 H NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 8.72 (d, J=2.6 Hz, 1H), 8.44 - 8.34 (m, 3H), 8.26 (d, J=8.6 Hz, 1H), 7.86 (s, 1H), 7.59 (dd, J=8.5, 1.4 Hz, 1H), 7.35 - 7.25 (m, 4H), 7.22 - 7.15 (m, 1H), 4.36 - 4.28 (m, 1H), 4.11 (s, 3H), 2.84 (d, J=4.8 Hz, 4H), 2.01 - 1.47 (m, 8H).

[0217] 21-4: Fractions from peak 4 were combined to give 6-{6-methoxy-5-[(3-phenylcyclohexyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide (8.4 mg, 17 μmol, 3.4%, chiral purity: 92.6%). MS ESI m / z 484.1 (M+H) 1 H NMR (400 MHz, DMSO-d6) δ 13.64 (br s, 1H), 8.68 (d, J=2.6 Hz, 1H), 8.43 - 8.31 (m, 2H), 8.27 - 8.22 (m, 1H), 8.19 (d, J=7.7 Hz, 1H), 7.83 (s, 1H), 7.57 (dd, J=8.6, 1.5 Hz, 1H), 7.35 - 7.24 (m, 4H), 7.23 - 7.16 (m, 1H), 4.02 (s, 3H), 4.00 - 3.91 (m, 1H), 2.83 (d, J=4.8Hz, 3H), 2.76 - 2.65 (m, 1H), 2.10 - 1.94 (m, 2H), 1.93 - 1.85 (m, 1H), 1.83 - 1.76 (m, 1H), 1.59 - 1.10 (m, 4H).

[0218] Example 22 (rac)-N-isopropyl-6-(6-methoxy d3-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide [ka]

[0219] 22A: 5-(3-(isopropylcarbamoyl)-1H-indazol-6-yl)-2-methoxy d3-nicotinic acid: Using a procedure similar to that of 1H, 5-(3-(isopropylcarbamoyl)-1H-indazol-6-yl)-2-methoxy d3-nicotinic acid (273 mg) was obtained. MS ESI m / z 358.2 (M+H)

[0220] Using a method substantially similar to that described in 22:1, (rac)-N-isopropyl-6-(6-methoxy d3-5-((1-(2-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide (5.1 mg, 8.99 μmol, 21% yield) was obtained. MS ESI m / z 545.1 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (br d, J=7.3 Hz, 1H), 8.69 (d, J=2.1 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.24 (br d, J=8.2 Hz, 1H), 8.10 (br d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.70 - 7.62 (m, 1H), 7.56 (br d, J=8.5 Hz, 1H), 7.45 - 7.28 (m, 4H), 5.48 - 5.36 (m, 1H), 4.18 (dq, J=13.7, 6.5 Hz, 1H), 1.47 (br d, J=7.0 Hz, 3H), 1.21 (br d, J=6.7 Hz, 6H).

[0221] Example 23 N-(4-(dimethyl d6-amino)cyclohexyl)-6-(6-methoxy d3-5-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide (diastereomeric mixture) [ka] 23A: tert-Butyl (4-(bis(methyl-d3)amino)cyclohexyl)carbamate (mixture of diastereomers): To a solution of N-4-Boc-aminocyclohexanone (100 mg, 0.469 mmol), dimethyl d6-amine (103 mg, 1.172 mmol), and triethylamine (0.163 mL, 1.172 mmol) in MeOH (2 mL) and THF (2 mL) at 23 °C was added sodium cyanoborohydride (73.7 mg, 1.172 mmol). The reaction mixture was stirred for 16 h and concentrated. The residue was partitioned between EtOAc (30 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The dried solution was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (4-(bis(methyl-d3)amino)cyclohexyl)carbamate (diastereomeric mixture, 93 mg, 372 μmol, 79% yield). MS ESI m / z 249.4 (M+H)

[0222] 23B: N1,N1-bis(methyl-d3)cyclohexane-1,4-diamine (diastereomeric mixture): A solution of tert-butyl (4-(dimethyl d6-amino)cyclohexyl)carbamate (92.5 mg, 0.372 mmol) and TFA (0.717 mL, 9.31 mmol) in CHCl (2 mL) was stirred for 1 h at 23° C. The reaction mixture was concentrated to give N1,N1-bis(methyl-d3)cyclohexane-1,4-diamine (diastereomeric mixture, 148 mg, 393 μmol, 100% yield).

[0223] 23C: 5-(3-((4-(bis(methyl-d3)amino)cyclohexyl)carbamoyl)-1H-indazol-6-yl)-2-(methoxy-d3)nicotinic acid (diastereomeric mixture): Using a procedure similar to that for 1H, 5-(3-((4-(bis(methyl-d3)amino)cyclohexyl)carbamoyl)-1H-indazol-6-yl)-2-(methoxy-d3)nicotinic acid (diastereomeric mixture, 93 mg) was obtained. MS ESI m / z 447.1 (M+H)

[0224] Using a method substantially similar to that described in 23:1, N-(4-(bis(methyl-d3)amino)cyclohexyl)-6-(6-(methoxy-d3)-5-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide (diastereomeric mixture, 4.4 mg, 6.80 μmol, 17% yield) was obtained. MS ESI m / z 634.3 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (br d, J=7.6 Hz, 1H), 8.70 (s, 1H), 8.36 - 8.04 (m, 3H), 7.87 (br d, J=7.0 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.53 - 7.42 (m, 3H), 7.25 (br d, J=7.3 Hz, 1H), 5.21 (br t, J=7.2 Hz, 1H), 4.27 - 3.82 (m, 1H), 2.10 - 1.93 (m, 3H), 1.90 - 1.76 (m, 2H), 1.76 - 1.44 (m, 7H).

[0225] Example 24 4-Fluoro-6-[6-methoxy-5-({1-[2-(trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide [ka] Using a method substantially similar to that described in 1, 4-fluoro-6-[6-methoxy-5-({1-[2-(trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide (racemic, 6.3 mg, 11 μmol, 34% yield) was obtained. MS ESI m / z 532.3 (M+H) 1 H NMR (500 MHz, DMSO-d6) δ 8.80 (br d, J=7.6 Hz, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.38 (br d, J=4.6 Hz, 1H), 8.32 (d, J=1.8 Hz, 1H), 7.70 (s, 1H), 7.67 - 7.63 (m, 1H), 7.46 - 7.33 (m, 4H), 5.47 - 5.36 (m, 1H), 4.04 (s, 3H), 2.82 (d, J=4.6 Hz, 3H), 1.47 (d, J=7.0 Hz, 3H).

[0226] Table 1. The compounds in Table 1 were synthesized in a manner similar to that of Example 1. Unless otherwise noted in the text, stereochemistry not depicted is racemic. [Table 9] [Table 10]

[0227] Table 2. The compounds in Table 2 were synthesized in a similar manner to Example 1. Unless otherwise noted in the text, stereochemistry not depicted is racemic or diastereomeric. All amines are indicated in the R group column when R1 is not hydrogen. [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21]

[0228] Table 3. The compounds in Table 3 were synthesized similarly to Example 26. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 22]

[0229] Table 4. The compounds in Table 4 were synthesized in a similar manner to Examples 1 and 12. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 23]

[0230] Table 5. The compounds shown in Table 5 were synthesized in a manner similar to that of Example 1. Unless otherwise indicated in the text, any stereochemistry not depicted is in racemic or diastereomeric form. [Table 24]

[0231] Table 6. The compounds in Table 6 were synthesized in a manner similar to that of Example 1. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 25]

[0232] Table 7. The compounds in Table 7 were synthesized in a manner similar to that of Example 1. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 26]

[0233] Table 8. The compounds in Table 8 were synthesized in a manner similar to that of Example 1. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 27]

[0234] Table 9. The compounds in Table 9 were synthesized in a similar manner to Examples 24 and 25. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 28] [Table 29] [Table 30]

[0235] Table 10. The compounds in Table 10 were synthesized in a manner similar to Examples 12, 24, and 25. All compounds are homochiral. [Table 31]

[0236] Table 11. The compounds in Table 11 were synthesized in a similar manner to Examples 1 and 12. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 32] [Table 33]

[0237] Table 12. The compounds in Table 12 were synthesized in a similar manner to Examples 1 and 12. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 34] [Table 35]

[0238] Table 13. The compounds in Table 13 were synthesized in a similar manner to Examples 1 and 12. Unless otherwise indicated in the text, any stereochemistry not depicted is racemic or diastereomeric. [Table 36] [Table 37]

Claims

1. Formula (I): [Formula 1] [In the formula, R ａ H, halo, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Deuteroalkyl, C １－４ deuteroalkoxy, cyclopropyl, or N(R ｅ ) ２ and R ｂ H, halo, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Deuteroalkyl, C １－４ deuteroalkoxy, halo, or N(R ｅ ) ２ and R ｃ is H, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ deuteroalkyl, or halo; R ｄ are independently H, halo, or C １－３ is alkyl; R ｅ are independently H, C １－４ Alkyl, or C １－４ is deuteroalkyl; R １ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuteroalkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ Alkyl-phenyl, C ０－３ Alkyl-heterocycle, where the heterocycle is a 3-6 membered ring having 1-3 heteroatoms selected from N, S, and O, where the alkyl, cycloalkyl, phenyl, or heterocycle are independently selected from =O, halo, OH, C １－３ Alkyl, C １－３ Deuteroalkyl, —C(O)—C １－３ Alkyl, -SO ２ -C １－３ Alkyl, -N(R １ｅ ) ２ , phenyl, or phenyl-O—C １－３ substituted with 0 to 2 alkyl; R １ｅ are independently H, C １－４ Alkyl, or C １－４ is deuteroalkyl; L is -C(O)NR ｅ -, where N is attached to A; A is A １ Or -A １ -L １ -, where A １ is bonded to L and is C substituted with 0 to 1 OH １－６ Alkyl, C substituted with 0-1 OH １－６ Deuteroalkyl, C substituted with 0-1 OH １－６ Haloalkyl, C １－６ Deuteroalkyl, C １－６ Haloalkyl, C ０－３ Alkyl-C ３－１０ Cycloalkyl-C ０－３ -Alkyl, C ０－３ -alkyl-phenyl, C ０－３ -alkyl-heterocycle, where the heterocycle is a 3-6 membered ring having 1-3 heteroatoms selected from N, S, and O, where the cycloalkyl, phenyl, and heterocycle are each independently selected from 0-2 R ８ is replaced by; L １ is -O-, -S-, -C(O)-, -C(O)NR ｅ , -SO ２ NH-, -NHSO ２ -, -C(O)O-, -NR ｅ -C(O)-, -NR ｅ -C(O)O-, -NR ｅ -C(O)NR ｅ -, -SO ２-, or -NH-R ｅ - and Alternatively, -L-A- is [chemical 2] and R ２ is C １－６ Alkyl, C １－６ Haloalkyl, C ０－３ Alkyl-C ６－１０ Aryl, C ０－３ Alkyl-C ３－６ cycloalkyl or C having 1 to 4 heteroatoms selected from N, S, and O ０－３ alkyl-3 to 6 membered heterocycle, where any of the aryl, cycloalkyl, or heterocycle groups is selected from 0 to 3 R ２ａ is replaced by; R ２ａ is halo, CN, =O, C １－６ Alkyl, C １－６ Alkoxy, Hydroxy-C １－６ Alkoxy, C １－６ Deuteroalkyl, C １－６ Deuteroalkoxy, C １－６ -Haloalkyl, C １－６ Haloalkoxy, C ０－３ Alkyl-C ３－６ Cycloalkyl-C ０－３ Alkyl, C ３－６ Halocycloalkyl, C ３－６ Cycloalkoxy, C ３－６ Cycloalkyl-C １－６ Alkoxy, C ６－１０ Aryl, Phenyl-C １－３ Alkoxy-, C ３－６ Cycloalkyl-C １－３ Deuteroalkoxy-, C ３－６ Cycloalkyl-C １－３ Haloalkoxy-, C １－６ Alkoxy-C １－３ Alkyl-, C ３－６ Cycloalkoxy-C １－３ Alkyl-, C ６－１０ Aryl-O-, Phenyl C １－４ Alkyl-SO ２-, C ３－６ Cycloalkyl-SO ２ -, C ６－１０ Aryl-S-, NR ６ R ６ CO-, NHR ６ - (CH ２ ) ｎ -, R ５ -C(O)-, R ５ -OC(O)-, R ５ -C(O)O-, R ６ -NH-C(O)O-,R ７ -OC(O)NH-,R ６ -NH-C(O)NR ６ , R ７ -SO ２ -, R ５ -SO ２ N-H, R ５ -NHSO ２ -, heterocycle, heterocycle-O-, or heterocycle-C ０－６ alkyl-, where each heterocycle is a 4-6 membered ring having 1-2 heteroatoms independently selected from N, S, and O, and where each alkyl, cycloalkyl, phenyl, or heterocycle is independently selected from 0-3 R ２ｂ is replaced by; R ２ｂ are independently halo, OH, C １－３ Alkyl, C １－３ Alkoxy, Hydroxy-C １－３ Alkoxy, Hydroxy-C １－３ Alkyl, C=O, C １－３ Haloalkyl, or C １－３ haloalkoxy; R ５ are independently H, C １－６ Alkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ Alkyl-phenyl, or C １－６ haloalkyl; R ６ are independently H, C １－６ Alkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ alkyl-phenyl; R ７ In each event, independently, C １－６ Alkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ alkyl-phenyl; R ８ is independently, at each occurrence, H, halo, C=O, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ３－６ Cycloalkyl, phenyl, 3- to 6-membered heterocycle, -(CH ２ ) ｎ -NR ６ R ６ CO, -(CH ２ ) ｎ -NR ６ R ６ C.O.N.R. ６ R ６ , -(CH ２ ) ｎ -N.H.R. ６ , -(CH ２ ) ｎ -C(O)-R ５ , -(CH ２ ) ｎ -C(O)O-R ５ , -(CH ２ ) ｎ -OC(O)-R ５ , -(CH ２ ) ｎ -OC(O)-NH-R ６ , -(CH ２ ) ｎ -NHC(O)-OR ７ , -(CH ２ ) ｎ -SO ２ -R ７ , -(CH ２ ) ｎ -SO ２ N.H.R. ５ , -(CH ２ ) ｎ -NHSO ２ -R ５wherein each heterocycle is independently a 4-6 membered ring having 1-2 heteroatoms selected from N, S, and O; n is 0, 1, or 2. or a salt thereof.

2. R ａ H, Cl, F, Br, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Deuteroalkyl, C １－４ deuteroalkoxy, cyclopropyl, or N(R ｅ ) ２ and R ｂ H, F, Cl, Br, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Deuteroalkyl, C １－４ Deuteroalkoxy, or NR ｅ ２ and R ｃ But, H, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ deuteroalkyl, or halo; R ｄ is independently H or F; R ｅ In each event, independently, H, C １－４ Alkyl, or C １－４ is deuteroalkyl; R １ But, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuteroalkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ Alkyl-piperidinyl, C ０－３ Alkyl-pyrrolidinyl, C ０－３ Alkyl-morpholinyl, C ０－３ alkyl-pyrrolidinyl, where alkyl, cycloalkyl, piperidinyl, pyrrolidinyl, or morpholinyl are independently selected from =O, halo, OH, C １－３ Alkyl, C １－３ Deuteroalkyl, phenyl, or phenyl-O—C １－３ substituted with 0-2 of alkyl; L is -C(O)NR ｅ - and A is A １ Or -A １ -L １ -, where A １ is C substituted with 0 to 1 OH １－６ Alkyl, C substituted with 0-1 OH １－６ Deuteroalkyl, C substituted with 0-1 OH １－６ Haloalkyl, C １－６ Deuteroalkyl, C １－６ Haloalkyl, C ０－３ Alkyl-C ３－１０ Cycloalkyl-C ０－３ -Alkyl, C ０－３ -Alkyl-C ３－６ Cycloalkyl-C ０－３ -Alkyl, C ０－３ -Alkyl-imidazolyl, C ０－３ -alkyl-pyrrolidinyl, C ０－３ -alkyl-tetrahydropyranyl, C ０－３ -alkyl-pyridinyl, where pyrrolidinyl is selected from 0 to 2 R ８ is replaced by; L １ is -O-, -C(O)-, -C(O)NR ｅ , -SO ２ NH-, -C(O)O-, -NR ｅ -C(O)-, -SO ２ -, or -N-R ｅ - and Alternatively, -L-A- is [C3] and R ２ But, C １－６ Alkyl, C １－６ Haloalkyl, C ０－３ Alkyl-phenyl, C ０－３ Alkyl-C ３－６ cycloalkyl or C having 1 to 4 heteroatoms selected from N, S, and O ０－３ alkyl-3-6 membered heterocycle, where either the phenyl or heterocycle group is selected from 0-3 R ２ａ is replaced by; R ２ａ But halo, CN, =O, C １－６ Alkyl, C １－６ Alkoxy, Hydroxy-C １－６ Alkoxy, C １－６ Deuteroalkyl, C １－６ Deuteroalkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C １－３ Alkyl-C ３－６ Cycloalkyl-C ０－３ Alkyl, C ３－６ Halocycloalkyl, C ３－６ Cycloalkoxy, C ３－６ Cycloalkyl-C １－３ Alkoxy-, C ３－６ Cycloalkyl-C １－３ Deuteroalkoxy-, C ３－６ Cycloalkyl-C １－３ Haloalkoxy-, C １－６ Alkoxy-C １－３ Alkyl-, C ３－６ Cycloalkoxy-C １－３ Alkyl-, phenyl-O-, C １－４ Alkyl-SO ２ -, C ３－６ Cycloalkyl-SO ２ -, C ６－１０ Aryl-S-, NR ６ R ６ CO-, NHR ６ - (CH ２ ) ｎ -, R ５ -C(O)-, R ６ -NH-C(O)O-,R ７-OC(O)NH-,R ７ -SO ２ -, R ５ -SO ２ NH-, heterocycle-, heterocycle-O-, heterocycle-CH ２ -, where each heterocycle is independently a 4-6 membered ring having 1-2 heteroatoms selected from N, S, and O, and where each alkyl, cycloalkyl, phenyl, or heterocycle is independently selected from 0-3 R ２ｂ is replaced by; R ２ｂ In each event, independently, C １－３ Alkyl, C １－３ Alkoxy, Hydroxy-C １－３ Alkoxy, halo, C=O, C １－３ Haloalkyl, or C １－３ haloalkoxy; R ５ In each event, independently, H, C １－６ Alkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ alkyl-phenyl; R ６ In each event, independently, H, C １－６ Alkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ alkyl-phenyl; R ７ In each event, independently, H, C １－６ Alkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ alkyl-phenyl; R ８ is F, ═O, or C １－３ is alkyl; n is 0, 1, or 2; 2. The compound according to claim 1, or a salt thereof.

3. L is -C(O)NR ｅ - and A is A １ Or -A １ -L １ -, where A １ is C substituted with 0 to 1 OH １－６ Alkyl, C substituted with 0-1 OH １－６ Deuteroalkyl, C substituted with 0-1 OH １－６ Haloalkyl, C １－６ Deuteroalkyl, C １－６ Haloalkyl, C ０－３ Alkyl-C ３－１０ Cycloalkyl-C ０－３ -Alkyl, C ０－３ -Alkyl-C ３－６ Cycloalkyl-C ０－３ -Alkyl, C ０－３ -Alkyl-imidazolyl, C ０－３ -alkyl-pyrrolidinyl, C ０－３ -alkyl-tetrahydropyranyl, C ０－３ -alkyl-pyridinyl, where pyrrolidinyl is selected from 0 to 2 R ８ has been replaced by 2. The compound according to claim 1, or a salt thereof.

4. R ａ is H, Cl, F, or C １－４ Alkyl, C １－４ Alkoxy, or C １－４ is deuteroalkoxy; R ｂ But, H, C １－３ Alkyl, or C １－３ is alkoxy; R ｃ is H or C １－４ is alkyl, The compound according to claim 3, or a salt thereof.

5. A １ is C substituted with 0 to 1 OH １－６ Alkyl, C substituted with 0-1 OH １－６ Deuteroalkyl, or C ０－３ Alkyl-C ３－６ is cycloalkyl; L １ is -O-, -C(O)-, -C(O)NR ｅ - or -SO ２ NH-, 5. A compound according to claim 3 or 4, or a salt thereof.

6. R ａ But, H, C １－４ Alkyl, C １－４ Alkoxy, or C １－４ is deuteroalkoxy; R ｂ is H or C １－３ is alkyl; R ｃ is H, The compound according to any one of claims 3 to 5, or a salt thereof.

7. R １ But, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuteroalkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ Alkyl-piperidinyl, C ０－３ Alkyl-pyrrolidinyl, C ０－３ Alkyl-morpholinyl, C ０－３ alkyl-pyrrolidinyl, where alkyl, cycloalkyl, piperidinyl, pyrrolidinyl, or morpholinyl are independently selected from =O, halo, OH, C １－３ Alkyl, C １－３ Deuteroalkyl, or N(R １ｅ ) ２ is substituted with 0 to 2 of The compound according to any one of claims 3 to 6, or a salt thereof.

8. R １ But, C １－３ Alkyl, C １－３ Deuteroalkyl, or C ０－１ alkyl-cyclopropyl; R ２ But, C １－６Alkyl, phenyl, (CH ２ ) ｎ -C ３－６ Cycloalkyl, or (CH ２ ) ｎ - a 3- to 6-membered heterocycle, where the heterocycle is selected from morpholinyl, tetrahydro-2H-pyranyl, or pyrrolidinyl, where either the phenyl or the heterocycle group is selected from 0-3 R ２ａ is replaced by; R ２ａ is F, Cl, CN, =O, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Deuteroalkyl, C １－３ Deuteroalkoxy, C １－２ Haloalkyl, C １－３ Alkyl-C ３－６ Cycloalkyl-C ０－３ Alkyl, C ３－６ Cycloalkoxy, C ３－６ Cycloalkyl-C １－３ Alkoxy-, C ３－６ Cycloalkyl-C １－３ Deuteroalkoxy-, C ３－６ Cycloalkoxy-C １－３ Alkyl-, phenyl, C １－４ Alkyl-SO ２ -, C ３－６ Cycloalkyl-SO ２ -, N.R. ６ R ６ CO-, NHR ６ - (CH ２ ) ｎ -, R ５ -C(O)-, R ６ -OC(O)-NH-, R ７ -NHC(O)-O-,R ７ -SO ２ -, R ５ -SO ２ NH-, -(CH ２ ) ｎ -piperidinyl, -(CH ２ ) ｎ -morpholinyl, where each of alkyl, cycloalkyl, phenyl, or heterocycle is selected from 0 to 3 R ２ｂ has been replaced by 7. The compound according to claim 6, or a salt thereof.

9. -L-A-, [C4] 2. The compound of claim 1, wherein:

10. R ａ is H, Cl, F, or C １－４ Alkyl, C １－４ Alkoxy, or C １－４ is deuteroalkoxy; R ｂ But, H, C １－３ Alkyl, or C １－３ is alkoxy; R ｃ is H or C １－４ is alkyl; R １ But, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuteroalkyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, C ０－３ Alkyl-piperidinyl, C ０－３ Alkyl-pyrrolidinyl, C ０－３ Alkyl-morpholinyl, C ０－３ alkyl-pyrrolidinyl, where alkyl, cycloalkyl, piperidinyl, pyrrolidinyl, or morpholinyl are independently selected from =O, halo, OH, C １－３ Alkyl, C １－３ Deuteroalkyl, or N(R １ｅ ) ２ substituted with 0 to 2 of: R ２ But, C ０－３ Alkyl-phenyl, C ０－３ Alkyl-C ３－６ Cycloalkyl, or C ０－３alkyl-3 to 6 membered heterocycle, where the heterocycle is selected from morpholinyl, tetrahydro-2H-pyranyl, or pyrrolidinyl, where either the phenyl or the heterocycle group is selected from 0 to 3 R ２ａ is replaced by; R ２ａ is F, Cl, CN, =O, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Deuteroalkyl, C １－３ Deuteroalkoxy, C １－２ Haloalkyl, C １－３ Alkyl-C ３－６ Cycloalkyl-C ０－３ Alkyl, C ３－６ Cycloalkoxy, C ３－６ Cycloalkyl-C １－３ Alkoxy-, C ３－６ Cycloalkyl-C １－３ Deuteroalkoxy-, C ３－６ Cycloalkoxy-C １－３ Alkyl-, Phenyl C １－４ Alkyl-SO ２ -, C ３－６ Cycloalkyl-SO ２ -, N.R. ６ R ６ CO-, NHR ６ - (CH ２ ) ｎ -, R ５ -C(O)-, R ６ -OC(O)-NH-, R ７ -NHC(O)-O-,R ７ -SO ２ -, R ５ -SO ２ NH-, -(CH ２ ) ｎ -piperidinyl, or -(CH ２ ) ｎ -morpholinyl, where each of alkyl, cycloalkyl, phenyl, or heterocycle is selected from 0 to 3 R ２ｂ has been replaced by 10. The compound according to claim 9, or a salt thereof.

11. The compound is: N-[(1,1,2,2,2-deuteroethyl]-6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; (R)-N-(ethyl-d5)-6-(6-(methoxy-d3)-5-((1-(2-trifluoromethoxy)phenyl)ethyl) carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide; (R)-6-(6-(methoxy-d3)-5-((1-(3-trifluoromethyl)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide; (R)-6-(5-((1-(2-fluoro-5-trifluoromethyl)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; (S)-6-(5-((1-(2-fluoro-5-trifluoromethoxy)phenyl)ethyl)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide; (R)-6-(5-((1-(2-fluoro-5-trifluoromethyl)phenyl)ethyl)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide; (R)-6-(6-(methoxy-d3)-5-((1-(2-trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide; (R)-6-(6-(methoxy-d3)-5-((1-(3-trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide; (R)-6-(5-((1-(2-fluoro-5-trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; (S)-6-(5-((1-(2-fluoro-5-trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)-6-(methoxy-d3)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; (R)-6-(6-(methoxy-d3)-5-((1-(3-trifluoromethoxy)phenyl)ethyl-2,2,2-d3)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-(((3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-methoxy-d3-pyridin-3-yl)-N-methyl-d3-1H-indazole-3-carboxamide; (R)-N-cyclopropyl-6-(6-methoxy-d3-5-((1-(2-trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide; (R)-6-(6-methoxy-d3-5-((1-(3-trifluoromethoxy)phenyl) ethyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-Methoxy-d3-5-((1-(2-trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-Methoxy-D3-5-((2-trifluoromethoxy)benzyl-D2)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-((3-pivalamidocyclohexyl)carbamoyl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-(2-(1-phenylpropyl)-2H-tetrazol-5-yl)pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-(2-(1-(4-fluorophenyl)ethyl)-2H-tetrazol-5-yl)-6-methoxypyridin-3-yl)-N-(methyl-d3)-1H-indazole-3-carboxamide; 6-[5-(2-benzyl-2H-1,2,3,4-tetrazol-5-yl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-{6-methoxy-5-[(3-phenylcyclohexyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; (rac)-N-isopropyl-6-(6-methoxy-d3-5-((1-(2-trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide; N-(4-dimethyl-d6-amino)cyclohexyl)-6-(6-methoxy-d3-5-((1-(3-trifluoromethoxy)phenyl)ethyl)carbamoyl)pyridin-3-yl)-1H-indazole-3-carboxamide; 4-Fluoro-6-[6-methoxy-5-({1-[2-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1S)-1-[3-trifluoromethoxy)phenyl]ethyl]carbamoyl}pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; tert-Butyl 3-{[2-(deutero)methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl]formamido}propanoate; 6-(5-{[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; tert-Butyl 3-{[2-(deutero)methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl]formamido}-2,2-dimethylpropanoate; tert-Butyl (3R)-3-{[2-(deutero)methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl]formamido}butanoate; 6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethoxy)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethyl)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethyl)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1R)-1-[2-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1R)-1-[3-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1S)-1-[3-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({1-[5-fluoro-2-trifluoromethyl)phenyl]ethyl}carbamoyl)-6-(deutero)methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-{6-methoxy-5-[(3-phenylbutyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-hydroxy-3-(4-methoxyphenyl)propyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(3,4-difluorophenyl)-3-hydroxypropyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(4-fluorophenyl)-3-hydroxypropyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(4-fluorophenyl)butyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-(3-fluorophenyl)cyclopropyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[(1R,2S)-2-phenylcyclopropyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[(1S,2R)-2-phenylcyclopropyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[2-(phenylsulfamoyl)ethyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-(3-fluorophenyl)cyclopropyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide, cis; 6-[5-({[2-(3-fluorophenyl)cyclopropyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide, cis; 6-[5-({[4-fluoro-2-(oxan-4-yloxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[(1S,2R)-2-phenylcyclopropyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[(1R,2S)-2-phenylcyclopropyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-(morpholin-4-yl)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-{5-[({2-[dimethylamino)methyl]phenyl}methyl)carbamoyl]-6-methoxypyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-{6-methoxy-5-[(3-phenoxypropyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-{5-[(2-hydroxy-3-phenoxypropyl)carbamoyl]-6-methoxypyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-{5-[({2-[4-(hydroxymethyl)piperidin-1-yl]phenyl}methyl)carbamoyl]-6-methoxypyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[(2-methoxyphenyl)methyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-(2-methylpropoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(tert-butoxy)propyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[3-(oxan-2-yloxy)propyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(cyclohexyloxy)propyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(4-fluorophenoxy)propyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[3-(2-methylpropoxy)propyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(5-chloropyridin-2-yl)-3-hydroxypropyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(2-methanesulfonylphenyl)methyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[(1S,3R)-3-phenylcyclopentyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[1-(phenoxymethyl)cyclopropyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-(propane-1-sulfonyl)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[(1R,2R)-2-(4-fluorophenyl)cyclopropyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide, trans; 6-[5-({[1-(4-fluorophenyl)cyclopropyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-{6-methoxy-5-[({1-[2-trifluoromethoxy)phenyl]cyclopropyl}methyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; tert-Butyl N-{2-[({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)methyl]phenyl}carbamate; tert-Butyl 3-({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)propanoate; 6-[6-methoxy-5-({[2-(2,2,2-trifluoroethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-methoxy-5-trifluoromethyl)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; tert-butyl N-[(1R,2S)-2-[({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)methyl]cyclohexyl]carbamate; 6-[5-({[2-(difluoromethoxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[(2-phenyloxan-3-yl)methyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-(propane-2-sulfonyl)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(2,2-dimethylcyclohexyl)methyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(2-ethylphenyl)methyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(2-tert-butyloxan-3-yl)methyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(2-cyanophenyl)methyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-(cyclopropylsulfamoyl)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-(cyclobutylmethoxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[3-(2,2,2-trifluoroethoxy)cyclohexyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; Ethyl 3-({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)-2,2-dimethylpropanoate; 6-(5-{[(3,5-difluoro-2-methoxyphenyl)methyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; tert-Butyl 3-({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)-2,2-dimethylpropanoate; 6-{5-[(2-{[(4-fluorophenyl)methyl]carbamoyl}-2,2-dimethylethyl)carbamoyl]-6-methoxypyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[3-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-(propan-2-yloxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[(2-methoxypyridin-3-yl)methyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-{6-methoxy-5-[(3-phenyladamantan-1-yl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-2-yl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[3-(morpholine-4-carbonyl)cyclohexyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(6-methoxy-5-{[3-(pyrrolidine-1-carbonyl)cyclohexyl]carbamoyl}pyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({1-[3-trifluoromethyl)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[3-trifluoromethyl)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[2,2-difluoro-3-(propan-2-yloxy)propyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[4-fluoro-3-trifluoromethyl)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({1-[4-fluoro-3-trifluoromethyl)phenyl]ethyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[3-(cyclopropylmethoxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[3-(cyclopentyloxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethyl)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({1-[2-trifluoromethyl)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-(cyclopentylmethoxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[3-(propan-2-yloxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-(cyclobutylmethoxy)pyridin-3-yl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-(cyclohexyloxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-fluoro-3-trifluoromethyl)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[3-(cyclobutylmethoxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(2,2-dimethylcyclopentyl)methyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[3-(cyclobutylmethoxy)pyridin-2-yl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-{6-methoxy-5-[(3-phenoxycyclohexyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-fluoro-3-trifluoromethoxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-dimethylcarbamoyl)cyclohexyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(diethylcarbamoyl)cyclohexyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[5-({3-[ethyl(methyl)carbamoyl]cyclohexyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({3-[(cyclopropylmethyl)(propyl)carbamoyl]cyclohexyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({3-[(cyclobutylmethyl)(ethyl)carbamoyl]cyclohexyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({3-[cyclopropyl(methyl)carbamoyl]cyclohexyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[3,5-difluoro-2-(propan-2-yloxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-fluoro-6-(propan-2-yloxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-(cyclopropylmethoxy)-3,5-difluorophenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({1-[2-trifluoromethyl)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[5-fluoro-2-(propan-2-yloxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-{6-methoxy-5-[({2-[(3-methylcyclopentyl)oxy]phenyl}methyl)carbamoyl]pyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl]carbamoyl}-6-methoxypyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; Cyclohexyl 1-[({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)methyl]cyclopropane-1-carboxylate; 6-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxypyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; tert-Butyl 4-({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)butanoate; tert-Butyl (3S)-3-{2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridine-3-amide}pyrrolidine-1-carboxylate; 6-[5-({[2-fluoro-5-trifluoromethoxy)phenyl]methyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-{5-[(cyclohexylmethyl)carbamoyl]-6-methoxypyridin-3-yl}-N-methyl-1H-indazole-3-carboxamide; tert-Butyl (3S)-3-({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)butanoate; Cyclopentyl 1-[({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)methyl]cyclopropane-1-carboxylate; tert-Butyl (3R)-3-({2-methoxy-5-[3-(methylcarbamoyl)-1H-indazol-6-yl]pyridin-3-yl}formamido)butanoate; 6-[5-({3-[cyclopropyl(cyclopropylmethyl)carbamoyl]propyl}carbamoyl)-6-methoxypyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[4-trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; tert-Butyl 3-({5-[4-fluoro-3-(methylcarbamoyl)-1H-indazol-6-yl]-2-methoxypyridin-3-yl}formamido)-2,2-dimethylpropanoate; 6-(5-{[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]carbamoyl}-6-methoxypyridin-3-yl)-4-fluoro-N-methyl-1H-indazole-3-carboxamide; tert-Butyl (3S)-3-({5-[4-fluoro-3-(methylcarbamoyl)-1H-indazol-6-yl]-2-methoxypyridin-3-yl}formamido)butanoate; 4-Fluoro-6-[6-methoxy-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; Oxan-4-yl 3-[(2-methoxy-5-{3-[(deutero)methylcarbamoyl]-1H-indazol-6-yl}pyridin-3-yl)formamide]-2,2-dimethylpropanoate; tert-Butyl 3-[(2-methoxy-5-{3-[(deutero)methylcarbamoyl]-1H-indazol-6-yl}pyridin-3-yl)formamido]-2,2-dimethylpropanoate; tert-Butyl 3-[(2-methoxy-5-{3-[(deutero)methylcarbamoyl]-1H-indazol-6-yl}pyridin-3-yl)formamido]propanoate; 6-[6-methoxy-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({1-[2-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; N-methyl-6-(6-methyl-5-{[(1S,3R)-3-phenylcyclopentyl]carbamoyl}pyridin-3-yl)-1H-indazole-3-carboxamide; N-methyl-6-[6-methyl-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-methyl-6-[6-methyl-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; 6-[5-({[2-(cyclopentyloxy)-5-fluorophenyl]methyl}carbamoyl)-6-methylpyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-2-methyl-5-({1-[2-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[(2,2-dimethylcyclopentyl)methyl]carbamoyl}-6-methoxy-2-methylpyridin-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-[6-methoxy-2-methyl-5-({[3-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[5-({[2-fluoro-5-trifluoromethoxy)phenyl]methyl}carbamoyl)-6-methoxy-2-methylpyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[2,6-dimethyl-5-({1-[2-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[2,6-dimethyl-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; 6-[2,6-dimethyl-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-N-methyl-1H-indazole-3-carboxamide; tert-Butyl 3-[(5-{3-[(cyclopropylmethyl)carbamoyl]-1H-indazol-6-yl}-2-(deutero)methoxypyridin-3-yl)formamido]propanoate; N-(cyclopropylmethyl)-6-[6-(deutero)methoxy-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; 6-(5-{[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(cyclopropylmethyl)-1H-indazole-3-carboxamide; N-(cyclopropylmethyl)-6-[6-(deutero)methoxy-5-({1-[2-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-(1-methanesulfonylpiperidin-4-yl)-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-ethyl-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-[(1R)-1-cyclopropylethyl]-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-(cyclopropylmethyl)-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-[3-(morpholin-4-yl)propyl]-1H-indazole-3-carboxamide; N-cyclopropyl-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-butyl-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-propyl-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-(propan-2-yl)-1H-indazole-3-carboxamide; N-(1-acetylpiperidin-4-yl)-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-[5-oxo-1-(propan-2-yl)pyrrolidin-3-yl]-1H-indazole-3-carboxamide; N-(2-hydroxyethyl)-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-[4-(diethylamino)cyclohexyl]-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; N-[4-dimethylamino)cyclohexyl]-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-[1-(2-methoxyphenyl)-5-oxopyrrolidin-3-yl]-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-(1-methyl-5-oxopyrrolidin-3-yl)-1H-indazole-3-carboxamide; N-{4-[di(deutero)methylamino]cyclohexyl}-6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; 6-[6-methoxy-5-({[2-trifluoromethoxy)phenyl]methyl}carbamoyl)pyridin-3-yl]-N-[(1r,4r)-4-hydroxycyclohexyl]-1H-indazole-3-carboxamide; N-cyclopropyl-6-(5-{[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; 6-(5-{[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(3,3-difluorocyclobutyl)-1H-indazole-3-carboxamide; 6-(5-{[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-[(1,1,2,2,2-deutero)ethyl]-1H-indazole-3-carboxamide; 6-(5-{[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(2-fluoro-2-methylpropyl)-1H-indazole-3-carboxamide; N-cyclopropyl-6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethyl)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; tert-Butyl (3S)-3-({5-[3-(cyclopropylcarbamoyl)-1H-indazol-6-yl]-2-(deutero)methoxypyridin-3-yl}formamido)butanoate; tert-butyl (3R)-3-({5-[3-(cyclopropylcarbamoyl)-1H-indazol-6-yl]-2-(deutero)methoxypyridin-3-yl}formamido)butanoate; N-cyclopropyl-6-[6-(deutero)methoxy-5-({1-[3-trifluoromethoxy)phenyl]ethyl}carbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide; 6-(5-{[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-cyclopropyl-1H-indazole-3-carboxamide; N-cyclopropyl-6-(5-{[(3R,4S)-1-(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; tert-Butyl 3-({5-[3-(cyclopropylcarbamoyl)-1H-indazol-6-yl]-2-(deutero)methoxypyridin-3-yl}formamido)-2,2-dimethylpropanoate; N-cyclopropyl-6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethoxy)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-cyclopropyl-6-[6-(deutero)methoxy-5-{[(1R)-1-[3-trifluoromethoxy)phenyl]ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-cyclopropyl-6-(5-{[3-(3,3-difluoropyrrolidine-1-carbonyl)cyclohexyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-cyclopropyl-6-[6-(deutero)methoxy-5-{[3-(pyrrolidine-1-carbonyl)cyclohexyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-cyclopropyl-6-[6-(deutero)methoxy-5-{[(1R)-1-[3-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-cyclopropyl-6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-cyclopropyl-6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-cyclopropyl-6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethyl)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-cyclopropyl-6-[6-(deutero)methoxy-5-{[(1R)-1-[2-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-cyclopropyl-6-[6-(deutero)methoxy-5-{[(1R)-1-[3-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-cyclopropyl-6-[6-(deutero)methoxy-5-{[(1S)-1-[3-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; 6-[5-({1-[5-fluoro-2-trifluoromethyl)phenyl]ethyl}carbamoyl)-6-(deutero)methoxypyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethyl)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1S)-1-[3-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethyl)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1R)-1-[3-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}pyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethoxy)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1R)-1-[2-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1S)-1-[3-trifluoromethoxy)phenyl]ethyl]carbamoyl}pyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-[6-(deutero)methoxy-5-{[(1S)-1-[3-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}pyridin-3-yl]-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(deutero)methyl-1H-indazole-3-carboxamide; 6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethyl)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-(deutero)methyl-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethoxy)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethoxy)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethyl)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethyl)phenyl]ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-[5-({1-[5-fluoro-2-trifluoromethyl)phenyl]ethyl}carbamoyl)-6-(deutero)methoxypyridin-3-yl]-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-[6-(deutero)methoxy-5-{[(1R)-1-[3-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-[6-(deutero)methoxy-5-{[(1S)-1-[3-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-[6-(deutero)methoxy-5-{[(1R)-1-[3-trifluoromethoxy)phenyl]ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-[6-(deutero)methoxy-5-{[(1R)-1-[3-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethoxy)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-(5-{[(1R)-1-[2-fluoro-5-trifluoromethyl)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-[6-(deutero)methoxy-5-{[(1R)-1-[2-trifluoromethyl)phenyl]ethyl]carbamoyl}pyridin-3-yl]-1H-indazole-3-carboxamide; N-[(1,1,2,2,2-deutero)ethyl]-6-(5-{[(1S)-1-[2-fluoro-5-trifluoromethyl)phenyl](2,2,2-deutero)ethyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-1H-indazole-3-carboxamide; 6-(5-{[(3R)-3-(4-chlorophenyl)-3-hydroxypropyl]carbamoyl}-6-(deutero)methoxypyridin-3-yl)-N-[(1,1,2,2,2-deutero)ethyl]-1H-indazole-3-carboxamide; and tert-Butyl (3S)-3-{[5-(3-{[(1,1,2,2,2-deutero)ethyl]carbamoyl}-1H-indazol-6-yl)-2-(deutero)methoxypyridin-3-yl]formamido}butanoate 2. The compound of claim 1, or a salt thereof, selected from:

12. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

13. An agent for inhibiting casein kinase RIPK1 activity in a patient comprising one or more compounds according to any one of claims 1 to 11.

14. 12. A method for treating a disease comprising administering to the patient one or more of the compounds of claim 1, wherein the disease is selected from inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis (RA), and heart failure.

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