Indazole carboxamides as kinase inhibitors

Abstract

Formula (I): Compounds having the formula (I) of formula (I) 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 to U.S. Provisional Application No. 62 / 909,920, filed October 3, 2019, which is incorporated 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 is associated with 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 activity of RIPK1. 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 the abnormal activity of RIPK1.

[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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] In one embodiment, the present invention relates to a compound of formula (I) [ka] [In the formula, Ring B is a 5-membered heterocycle containing 1 to 2 heteroatoms selected from N, S, and O, and 0 to 2 C 1-3 substituted with an alkyl group; R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is a deuterated alkyl; R 2 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkyl-C 6-10 Aryl, C 0-6 Alkyl-C 3-6 Cycloalkyl, or C 0-6 alkyl-(3-6 membered heterocycle containing 1-4 heteroatoms selected from N, S, and O), where any aryl, cycloalkyl, or heterocycle group is selected from 0-3 R 2a and any alkyl group is substituted with 0 to 1 OH; R 2a is halogen, CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, 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 3-6Cycloalkyl-C 1-6 Alkoxy-, C 3-6 Cycloalkyl-C 1-3 Deuterated alkoxy-, 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, Phenyl-C 1-3 Alkoxy-, C 6-10 Aryl-O-, Phenyl-C 1-4 Alkyl-SO2-, C 1-4 Alkyl-SO2-, C 3-6 Cycloalkyl-SO2-, NR 3 R 3 CO-, NR 3 R 3 -(CH2) n -, R 4 -C(O)-, R 4 -OC(O)-, R 4 -C(O)O-, R 3 -NH-C(O)O-, R 5 -OC(O)NH-, R 3 -NH-C(O)NR 3 -, R 5 -SO2-, R 4 -SO2NH-, R 4 -NHSO2-, heterocycle, where each heterocycle is a 4-6 membered ring having 1-2 heteroatoms independently selected from N and O, and where each alkyl, cycloalkyl, aryl, phenyl, or heterocycle is selected from 0-2 R 2b Replaced with; R 2b each independently, if present, is OH, C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, Hydroxy C 1-3 Alkoxy, halogen, C=O, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; R 3are, if present, each independently H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 is alkyl-phenyl; R 4 are, if present, each 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 5 are each independently C, if present 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 alkyl-phenyl; and n is 0, 1 or 2. or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0015] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein Ring B is thiophenyl, thiazolyl, imidazolyl, or pyrazolyl, and any ring contains 0-2 C 1-3 It is substituted with alkyl.

[0016] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-4 Alkyl-phenyl, C 0-4 Alkyl-C 3-6 Cycloalkyl, or C 0-4alkyl-(5-6 membered heterocycle), where the heterocycle is selected from pyridinyl or pyrrolyl, where any phenyl, cycloalkyl, or heterocycle group is selected from 0-3 R 2a and any alkyl is substituted with 0 to 1 OH.

[0017] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2a is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl-C 1-3 It is an alkoxy.

[0018] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2 is 0 to 3 R 2a C replaced with 1-4 It is alkyl-phenyl.

[0019] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2 is C 1-4 Alkyl-phenyl, or C 1-4 alkyl-(5-6 membered heterocycle), the heterocycle being selected from pyridinyl or pyrrolyl, and any phenyl or heterocycle group being selected from 0-3 R 2a and any alkyl is substituted with 0 to 1 OH.

[0020] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2 is 0 to 3 R 2a C replaced with1-4 It is an alkyl-phenyl, wherein the alkyl is substituted with 0-1 OH.

[0021] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2a is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 1-6 It is haloalkoxy.

[0022] Another embodiment provides a compound of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein Ring B is [ka] and any ring has 0 to 2 C 1-2 It may be substituted with an alkyl group.

[0023] Another embodiment provides a compound of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein Ring B is [ka] It is.

[0024] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2 is -(CH2)-phenyl, where phenyl is 0 to 3 R 2a is replaced by.

[0025] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2is -(CH2)-phenyl, where phenyl is 0 to 3 R 2a is replaced by.

[0026] Another embodiment provides a compound of formula (I), or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R 2 is -(CH2)-phenyl, -(CH2)-(CH2)-CH(CH3)-phenyl, -(CH2)-(CH2)-CH(OH)-phenyl, or -CH(CH3)-(CH2)-(CH2)-phenyl, where phenyl is selected from 0 to 2 R 2a is replaced by.

[0027] Another embodiment provides a compound of formula (I) or a stereoisomer, tautomer, isotope, salt, pharma- ceutically acceptable salt, solvate, or prodrug thereof, selected from the examples.

[0028] 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 the modulation of receptor interacting protein kinases, such as RIPK1.

[0029] 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).

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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 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 hematologic malignancies, and idiopathic hematologic malignancies. Selected from 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, and asthma, nonalcoholic steatohepatitis (NASH), or ischemia-reperfusion.

[0034] 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.

[0035] 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).

[0036] 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).

[0037] 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).

[0038] 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).

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] Any variable part (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 3When 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] "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.

[0054] "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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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).

[0059] 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 capable of withstanding 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-halogen, S(O)2H, or S(O)H groups.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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).

[0064] 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.

[0065] 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).

[0066] 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.

[0067] 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.

[0068] Examples of tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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 is to show

[0073] Throughout the specification, groups and substituents thereof can be selected by one 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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 risk / benefit ratio.

[0078] As used herein, "pharmaceutical acceptable salt" refers to the derivative of the disclosed compound, which is modified by making its acid or base salt from the parent compound. Examples of pharmaceutical 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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, osteoarthritis, osteoporosis, and multiple myeloma-related bone disease; proliferative disorders such as acute myeloid leukemia, chronic myeloid leukemia; solid tumors, intraocular angiogenesis, and breast cancer. The present invention is useful for treating RIPK1-related diseases, such as angiogenic disorders, such as neovascular tumors, infantile hemangiomas, infectious diseases, such as sepsis, septic shock, and bacterial dysentery, 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.

[0089] 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, and pulmonary tuberculosis. ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, myodegeneration, 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 pulmonary tuberculosis, 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] Therefore, the present invention further includes compositions comprising one or more compounds of formula (I) and a pharma- ceutically acceptable carrier.

[0097] "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 include 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 pharmacopoeia 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.

[0098] The compound of formula (I) may be administered by any means appropriate for the condition to be treated, which may vary depending on the need for site-specific treatment or the amount of drug to be delivered. Although other forms of delivery are contemplated, topical administration is generally preferred for skin-related diseases, and systemic therapy is preferred for cancer or precancerous conditions. For example, the compound may be delivered orally, such as in the form of a liquid preparation such as a tablet, capsule, granule, powder, or syrup; topically, such as in the form of a solution, suspension, gel, or ointment; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion 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 pharma- ceutically acceptable solvent or diluent may be administered. The compound may be administered in a form suitable for immediate 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.

[0099] Examples of compositions for topical administration include topical carriers such as PLASTIBASE® (mineral oil gelled with polyethylene).

[0100] 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, flow agents, flavors, colorants, and stabilizers may also be added for ease of manufacture and use.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] MLKL phosphorylation high content assay HT29-L23 human colon adenoma cells were cultured in RPMI 1640 medium containing 10% heat-inactivated FBS, 1% penicillin-streptomycin and 10 mM HEPES. Cells were seeded at 2,000 cells / well 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 min at 37°C (5% CO2 / 95% O2). Necroptosis was induced using a mixture of human TNFα (35 ng / mL) (Peprotech #300-01A), SMAC mimetic (US 2015 / 0322111 A1) (700 nM) and Z-VAD (140 nM) (BD pharmingen #51-6936). After 6 h of incubation at 37 °C (5% CO2 / 95% O2), cells were fixed with 4% formaldehyde (ACROS 11969-0010) for 15 min at room temperature and then permeabilized with 0.2% Triton-X-100 in phosphate-buffered saline (PBS) for 10 min. Phosphorylation of MLKL was detected by overnight incubation at 4°C with anti-MLKL (phospho-S358) antibody (Abcam #ab187091) (1:1000 dilution in blocking buffer [PBS supplemented with 0.1% BSA]). After three washes in PBS, anti-rabbit-goat Alexa-488 (1:1000 dilution) (Life Technologies, A11008) and Hoechst 33342 (Life Technologies, H3570) (1:2000 dilution) in blocking buffer were added for 1 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.These images were analyzed using Compartmental Analysis Bioapplication software (Cellomics). The amount of phosphorylation of MLKL was quantified as MEAN_CircRingAvgIntenRatio. The maximum inhibitory response was defined by the activity induced by Nec1s (CAS#: 852391-15-2, 6.25 μM). The IC50 value was defined as the concentration of compound that produced 50% of the maximum inhibition. The data was fitted using a four-parameter logistic equation to calculate IC50 and Ymax values.

[0106] 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.

[0107] 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. 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 cells20 (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. For large-scale protein production, 2x10 in ESF921 insect medium (Expression System) 6 Sf9 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 carried out 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 (2000 rpm) for 20 min at 4°C using a SORVALL® RC12BP centrifuge. Cell pellets were stored at -70°C prior to protein purification.

[0108] 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 5mL 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 μLtra-15, Millipore, Billerica, MA), and loaded onto a HiLoad 26 / 600 Superdex 200 column (GE Healthcare) equilibrated with 25 mM Tris 7.5, 150 mM NaCl, 2 mM TCEP, 5% glycerol. RIPK1 protein eluted from the SEC column as a dimer. 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. Using these assays, the IC 50 Values ​​were determined, see Table A. [Table 1]

[0109] 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.

[0110] 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 2]

[0111] The compounds of the present invention can 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 illustrative and are not intended to limit the possible techniques that one skilled in the art can 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 can be performed in different orders to obtain the desired compound.

[0112] Examples of compounds of the invention that are synthesized by the methods described in the general schemes are provided in the Intermediates and Examples sections below. The example compounds are generally synthesized as racemic mixtures. Synthesis of homochiral examples can be carried out by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by resolution of racemic products by chiral phase preparative HPLC. Alternatively, example compounds can be synthesized by methods known to yield enantiomerically enriched compounds. These include, but are not limited to, 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.

[0113] Scheme 1 illustrates a method for the synthesis of compound exemplified by E. Suzuki coupling reaction of A and B (Miyaura, N. and Suzuki, A. Chemical Reviews, 95:2457-2483, 1995) gives compound C. If B is an ester rather than a carboxylic acid, a hydrolysis step can be performed after the Suzuki reaction. Suitable bases include lithium hydroxide monohydrate, sodium hydroxide or other bases known to those skilled in the art. Compound exemplified by E can be formed by amide coupling with D using HATU as shown in the scheme or another amide coupling agent. Anhydrides or carboxylic acid chlorides can be used for this transformation. [ka]

[0114] Scheme 2 illustrates the synthesis of compounds exemplified by K. A was converted to the corresponding borate ester or boronic acid by in situ Suzuki reaction, followed by coupling with G to give H. Additionally, the borate converted from A may be isolated and used for the transformation. If G is an ester rather than a carboxylic acid, a hydrolysis step may be performed after the Suzuki reaction. Suitable bases include lithium hydroxide monohydrate, sodium hydroxide, or other bases known to those skilled in the art. Compounds exemplified by K may be formed by amide coupling using HATU as shown in the scheme, or using another amide coupling agent. Anhydrides or carboxylic acid chlorides may be used for this transformation. [ka]

[0115] 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 any gradient of hexane 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 with a gradient of solvent A (95% water, 5% acetonitrile, 0.1% TFA) and solvent B (5% water, 95% acetonitrile, 0.1% TFA, UV 220 nm), or with a gradient of solvent A (98% water, 2% acetonitrile, 0.05% TFA) and solvent B (98% acetonitrile, 2% water, 0.05% TFA, UV 254 nm), or with a gradient of solvent A (95% water, 5% acetonitrile with 10 mM ammonium acetate) and solvent B (95% acetonitrile, 5% water with 10 mM ammonium acetate).

[0116] In most of the examples, two analytical LCMS injections (Methods A and B, or Methods C and D) were performed to determine the final purity. Method A: Column: Waters XBridge C18, 2.1mmx50mm, particle size: 1.7μm; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0%B to 100%B over 3 min, then 100%B for 0.75 min; Flow rate: 1mL / min; Detection: MS and UV (220nm). Method B: Column: Waters XBridge C18, 2.1mmx50mm, particle size: 1.7μm; Mobile phase A: 5:95 acetonitrile:water (10mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (10mM ammonium acetate); Temperature: 50°C; Gradient: 0%B to 100%B over 3 min, then 100%B for 0.75 min; Flow rate: 1mL / min; Detection: MS and UV (220nm). Method C: Column: Waters Acquity UPLC BEH C18, 2.1x50mm, particle size: 1.7μm; Mobile phase A: 5:95 acetonitrile:water (10mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (10mM ammonium acetate); Temperature: 50°C; Gradient: 0-100% B over 3 min, followed by 100% B for 0.75 min; Flow rate: 1.11mL / min; Detection: UV (220nm) Method D: Column: Waters Acquity UPLC BEH C18, 2.1x50mm, particle size: 1.7μm; Mobile phase A: 5:95 acetonitrile:0.1% TFA in water; Mobile phase B: 95:5 acetonitrile:0.1% TFA in water; Temperature: 50°C; Gradient: 0-100% B over 3 min, followed by 100% B for 0.75 min; Flow rate: 1.11mL / min; Detection: UV (220nm)

[0117] Unless otherwise noted, NMR spectra were measured after water suppression. If the water suppression treatment affects the identification of the compound by NMR, this will be noted.

[0118] Example 1: 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)thiophen-3-yl)-N-methyl-1H-indazole-3-carboxamide [ka]

[0119] 1A: 6-bromo-1H-indazole-3-carboxylic acid A solution of methyl 6-bromo-1H-indazole-3-carboxylate (5 g, 19.60 mmol) and NaOH (1N, 49.0 mL, 49.0 mmol) in MeOH (70 mL) was heated at 80 °C for 2 h. The reaction mixture was concentrated to give the crude product, which was dissolved in water (100 mL). The resulting aqueous solution was acidified at 0 °C with HCl solution (1N) until pH 4-5. The solid was collected by vacuum filtration as 6-bromo-1H-indazole-3-carboxylic acid (4.6 g, 19.1 mmol, 97% yield). MS ESI m / z 241.1 (M+H); 1 H NMR(400MHz, CD3OD) δ 8.08 (dd, J=8.7, 0.6Hz, 1H), 7.87-7.77 (m, 1H), 7.41 (dd, J=8.7, 1.6Hz, 1H)

[0120] 1B: 6-bromo-N-methyl-1H-indazole-3-carboxamide To a solution of 6-bromo-1H-indazole-3-carboxylic acid (1.7 g, 7.05 mmol), methanamine, HCl (0.595 g, 8.82 mmol) and DIPEA (3.08 mL, 17.63 mmol) in DMF (25 mL) was added BOP (3.90 g, 8.82 mmol) and stirred at 23° C. for 16 h. The reaction mixture was concentrated and water (100 mL) was added to the crude material and the mixture was sonicated for 10 min. The resulting solid was collected by vacuum filtration as 6-bromo-N-methyl-1H-indazole-3-carboxamide (1.95 g, 7.55 mmol, quantitative yield). MS ESI m / z 254.0 (M+H)

[0121] 1C: 4-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiophene-2-carboxylic acid A solution of tert-butyl 6-bromo-3-(methylcarbamoyl)-1H-indazole-1-carboxylate (100 mg, 0.282 mmol), 4-boronthiophene-2-carboxylic acid (73 mg, 0.394 mmol), sodium carbonate (90 mg, 0.847 mmol) and Pd(Ph3P)4 (33 mg, 0.028 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was degassed and heated at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with EtOAc (2 mL). H2O (2 mL) was added and the pH was adjusted to ∼4 by adding AcOH. The mixture was triturated and the solvent was decanted. The resulting solid was dried under vacuum to give the crude product (76 mg, 89% yield), which was used as is without further purification. MS ESI m / z 301.8 (M+H)

[0122] 1: 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)thiophen-3-yl)-N-methyl-1H-indazole-3-carboxamide To a solution of 4-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiophene-2-carboxylic acid (20 mg, 0.066 mmol), (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine (16.7 mg, 0.080 mmol) and HATU (37.9 mg, 0.100 mmol) in DMF (1 mL) was added DIPEA (0.058 mL, 0.332 mmol). The resulting solution was stirred at room temperature overnight. The crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 19x200mm, particle size: 5μm; mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); gradient: 38-78% B over 19min followed by 100% B over 4min; flow rate: 20mL / min). Fractions containing the desired product were combined and dried on a centrifugal evaporator to give 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)thiophen-3-yl)-N-methyl-1H-indazole-3-carboxamide (21.7mg, 0.044mmol, 66% yield). MS ESI m / z 493.0(M+H); 1 H NMR (500MHz, DMSO-d6) δ 9.07 (t, J=5.5Hz, 1H), 8.34 (d, J=1.5Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 8.18 (d, J=1.5Hz, 2H), 7.83 (s, 1H), 7.60 (dd, J=8.4, 1.5Hz, 1H), 7.41 (br d, J=4.8Hz, 1H), 7.38-7.32 (m, 2H), 4.56 (d, J=5.5Hz, 2H), 2.86 (d, J=4.8Hz, 3H)

[0123] Table 1: The compounds in Table 1 were prepared in the same manner as in Example 1. Unless otherwise specified in the text, compounds without a description of stereochemistry are racemic or diastereomeric. [ka] [Table 3]

[0124] Example 6: 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)thiophen-2-yl)-N-methyl-1H-indazole-3-carboxamide [ka] The title compound 6 was prepared following a similar method as described in Example 1 in 3% overall yield. MS ESI m / z 493.0 (M+H); 1 H NMR (500MHz, DMSO-d6) δ 9.04 (t, J=5.7Hz, 1H), 8.22 (d, J=8.4Hz, 2H), 7.85 (s, 1H), 7.84 (d, J=3.7Hz, 1H), 7.64 (d, J=4.0Hz, 1H), 7.60 (dd, J=8.4, 1.5Hz, 1H), 7.38 (br d, J=5.1Hz, 1H), 7.37-7.33 (m, 2H), 4.54 (d, J=5.5Hz, 2H), 2.85 (d, J=4.8Hz, 3H)

[0125] Table 2: The compounds in Table 2 were prepared in the same manner as in Example 6. Unless otherwise specified in the text, those without a description of stereochemistry are racemates or diastereomers. [ka] [Table 4]

[0126] Example 10: 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)-4-methylthiophen-2-yl)-N-methyl-1H-indazole-3-carboxamide [ka] The title compound 10 was prepared in 10% overall yield following a similar method as described in Example 1. MS ESI m / z 507.1 (M+H); 1 H NMR (500MHz, DMSO-d6) δ 8.53 (br t, J=6.1Hz, 1H), 8.21 (br d, J=8.4Hz, 2H), 7.81 (s, 1H), 7.55 (dd, J=8.4, 1.1Hz, 1H), 7.48 (s, 1H), 7.38 - 7.31 (m, 3H), 4.51 (d, J=5.9Hz, 2H), 2.85 (d, J=4.8Hz, 3H), 2.47 (s, 3H)

[0127] Table 3: The compounds in Table 3 were prepared in the same manner as in Example 10. Unless otherwise specified in the text, those without a description of stereochemistry are racemic or diastereomeric. [ka] [Table 5]

[0128] Example 14: N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide [ka]

[0129] 14A: N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-carboxamide A solution of 6-bromo-N-methyl-1H-indazole-3-carboxamide (1.0 g, 3.94 mmol), bis(pinacolato)diboron (1.2 g, 4.7 mmol), potassium acetate (1.16 g, 11.8 mmol) and PdCl2(dppf)-CHCl2 adduct (0.1 g, 0.12 mmol) in 1,4-dioxane (40 mL) was degassed and stirred at 100 °C overnight. The resulting solid was filtered through Celite and the filtrate was concentrated. The residue was diluted with EtOAc (100 mL), washed with brine (2x50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude product was triturated with CHCl2 (10 mL) and the solid was collected by filtration and dried in vacuo to give the desired product (680 mg, 2.26 mmol, 57% yield). The mother liquor was purified by column chromatography (silica gel column, elution solvent: hexane / EtOAc (100 / 0 to 50 / 50)) to further give the desired product (148 mg, 0.49 mmol, 12% yield). MS ESI m / z 300.3 (M−H); 1 H NMR (400MHz, chloroform-d) δ 8.42 (dd, J=8.2, 0.9Hz, 1H), 8.00 (s, 1H), 7.72 (dd, J=8.3, 0.8Hz, 1H), 3.07 (d, J=5.0Hz, 3H), 1.39 (s, 12H)

[0130] 14B: 4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxylate ethyl A mixture of N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-carboxamide (500 mg, 1.66 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (415 mg, 1.66 mmol), Na2CO3 (618 mg, 4.98 mmol) and Pd(Ph3P)4 (192 mg, 0.166 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was degassed and stirred at 100° C. for 4 h. The solid was filtered through Celite, the Celite was rinsed with EtOAc (2×5 mL) and the filtrate was concentrated. The resulting residue was washed with HO (2x5 mL) followed by EtOAc (2x5 mL) and dried in vacuo to give crude ethyl 4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxylate (390 mg, 1.13 mmol, 68% yield), which was used directly without further purification. MS ESI m / z 345.1 (M+H).

[0131] 14C: 4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxylic acid To a solution of crude ethyl 4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxylate (390 mg, 1.13 mmol) in 1,4-dioxane (5 mL) and MeOH (2.5 mL) was added NaOH (1N, 2.5 mL, 2.50 mmol) and the reaction mixture was stirred at 95 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was triturated with EtOAc (5x2 mL). H2O (2 mL) was added and the pH was adjusted to ∼4 by adding AcOH. The precipitate was collected by filtration, washed with EtOAc (2 mL) followed by H2O (2x2 mL) and dried in vacuo to give crude 4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxylic acid, which was used as is without further purification. MS ESI m / z 317.0(M+H)

[0132] 14D: N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide To a solution of 4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxylic acid (20 mg, 0.063 mmol), (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine (14.6 mg, 0.070 mmol) and HATU (36.1 mg, 0.095 mmol) in DMF (1.5 mL) was added DIPEA (0.055 mL, 0.316 mmol) and the mixture was stirred at room temperature overnight. The crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 19x200mm, particle size: 5μm; mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); gradient: 27-67% B over 20min, followed by 100% B for 6min; flow rate: 20mL / min). Fractions containing the desired product were combined and dried on a centrifugal evaporator to give N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide (5.2mg, 0.010mol, 15% yield). MS ESI m / z 508.0 (M+H); 1 H NMR (500MHz, DMSO-d6) δ 8.79 (br t, J=5.7Hz, 1H), 8.28 (d, J=8.4Hz, 1H), 8.25 (br q, J=5.0Hz, 1H), 8.15 (s, 1H), 7.80 (dd, J=8.4, 1.5Hz, 1H), 7.41-7.32 (m, 3H), 4.53 (d, J=5.5Hz, 2H), 2.85 (d, J=4.8Hz, 2H), 2.65 (s, 3H)

[0133] Table 4: The compounds in Table 4 were prepared in the same manner as in Example 14. Unless otherwise specified in the text, those without a description of stereochemistry are racemic or diastereomeric. [ka] [Table 6]

[0134] Example 20: N-(2-fluoro-5-(trifluoromethoxy)benzyl)-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-4-carboxamide [ka] The title compound 20 was prepared following a similar method as described in Example 14 in 8% overall yield. MS ESI m / z 493.0 (M+H); 1 H NMR (500MHz, DMSO-d6) δ 9.09 (br t, J=6.2Hz, 1H), 8.35 (s, 1H), 8.28 (d, J=8.4Hz, 1H), 8.24 (s, 1H), 8.22 (br d, J=5.9Hz, 1H), 7.92 (dd, J=8.4, 1.5Hz, 1H), 7.43-7.30 (m, 3H), 4.60 (d, J=5.9Hz, 2H), 2.86 (d, J=4.8Hz, 3H)

[0135] Table 5: The compounds in Table 5 were prepared in a similar manner to Example 20. Unless otherwise specified in the text, compounds without a description of stereochemistry are racemic or diastereomeric. [ka] [Table 7]

[0136] Example 24: 2-(3-(methylcarbamoyl)-1H-indazol-6-yl)-N-(3-phenylbutyl)thiazole-5-carboxamide [ka] The title compound 24 was prepared following a similar method as described in Example 14 in 22% overall yield. MS ESI m / z 434.1 (M+H); 1 H NMR (500MHz, DMSO-d6) δ 8.37 (br t, J=5.7Hz, 1H), 8.28 (d, J=8.8Hz, 1H), 8.26-8.20 (m, 3H), 7.92 (d, J=8.4Hz, 1H), 7.33-7.23 (m, 4H), 7.17 (t, J=7.0Hz, 1H), 3.34-3.26 (m, 2H), 2.85 (d, J=4.8Hz, 3H), 2.83-2.77 (m, 1H), 1.88 (quin, J=7.2Hz, 2H), 1.25 (d, J=7.0Hz, 3H)

[0137] Table 6: The compounds in Table 6 were prepared in a manner similar to Example 24. [ka] [Table 8]

[0138] Example 26: 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)-1,4-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide [ka] The title compound 26 was prepared following a similar method as described in Example 14 in 24% overall yield. MS ESI m / z 505.2 (M+H); 1H NMR (500MHz, DMSO-d6) δ 8.51 (t, J=5.7Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 8.23 ​​(q, J=4.8Hz, 1H), 7.82 (s, 1H), 7.52 (dd, J=8.4, 1.1Hz, 1H), 7.41 (br d, J=4.8Hz, 1H), 7.38-7.31 (m, 2H), 4.55 (d, J=5.9Hz, 2H), 3.75 (s, 3H), 2.85 (d, J=4.8Hz, 3H), 2.35 (s, 3H)

[0139] Table 7: The compounds in Table 7 were prepared in a similar manner to Example 26. Unless otherwise specified in the text, those without a description of stereochemistry are racemic or diastereomeric. [ka] [Table 9]

[0140] Example 31: 6-(4-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)-1,5-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide [ka] The title compound 31 was prepared following a similar method as described in Example 14 in 42% overall yield. MS ESI m / z 505.1 (M+H); 1 H NMR (500MHz, DMSO-d6) δ 8.44 (br t, J=6.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 8.23 ​​(q, J=4.4Hz, 1H), 7.84 (s, 1H), 7.54 (dd, J=8.4, 1.1Hz, 1H), 7.35-7.25 (m, 3H), 4.50 (d, J=5.9Hz, 2H), 3.64 (s, 3H), 2.86 (d, J=4.8Hz, 3H), 2.57 (s, 3H)

[0141] Table 8: The compounds in Table 8 were prepared in the same manner as in Example 31. Unless otherwise specified in the text, those without a description of stereochemistry are racemic or diastereomeric. [ka] [Table 10]

[0142] Example 36: N-methyl-6-(1-methyl-5-((4-phenylbutan-2-yl)carbamoyl)-1H-pyrazol-3-yl)-1H-indazole-3-carboxamide [ka]

[0143] 36A: 2-Methyl-5-oxo-2,5-dihydro-1H-pyrazole-3-carboxylate methyl To a solution of dimethyl acetylenedicarboxylate (0.446 mL, 3.52 mmol) in acetic acid (5 mL) was added methylhydrazine (0.170 mL, 3.17 mmol) at 23° C. The reaction mixture was heated at 120° C. for 20 min and concentrated to give the crude product, which was triturated with MeOH (5 mL) and the solid was collected as methyl 2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-3-carboxylate (244 mg, 1.556 mmol, 44% yield). MS ESI m / z 157.1 (M+H).

[0144] 36B: 1-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylate methyl To a solution of methyl 2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-3-carboxylate (244 mg, 1.56 mmol) in CHCl (4 mL) was added EtN (0.436 mL, 3.13 mmol) dropwise at -5°C, followed by TfO (0.528 mL, 3.13 mmol), and the mixture was warmed to 23°C and stirred for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with CHCl (15 mLx3). The combined organic layers were washed with brine and dried over NaSO. Filtration and concentration gave the crude product. This was purified on a silica gel column (eluent: hexane / EtOAc (3 / 1)) to give methyl 1-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylate as a clear oil (410 mg, 1.42 mmol, 91% yield). MS ESI m / z 289.0 (M+H); 1 H NMR(400MHz, CD3OD) δ 6.80 (s, 1H), 4.15 (s, 3H), 3.93 (s, 3H)

[0145] 36C: (5-(methoxycarbonyl)-1-methyl-1H-pyrazol-3-yl)boronic acid A solution of methyl 1-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylate (325 mg, 1.13 mmol), bis(pinacolato)diboron (315 mg, 1.240 mmol), potassium acetate (332 mg, 3.38 mmol) and PdCl2(dppf)-CH2Cl2 adduct (55.3 mg, 0.068 mmol) in 1,4-dioxane (7 mL) was degassed and heated at 100 °C for 2 h. The reaction mixture was concentrated to give the crude product, to which water (5 mL) was added. The mixture was acidified to pH ~5 with HCl solution (1N) and the aqueous solution was saturated with NaCl and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product. This was purified on a C18 reversed-phase column using an ISCO system (Combiflash RF200, column: 130 g C18 RediSep, solvent A: 0.1% TFA aqueous solution / MeOH (90 / 10), solvent B: 0.1% TFA aqueous solution / MeOH (10 / 90), flow rate: 75 mL / min, initial %B: 0%, final %B: 50%, wavelength 1: 218, wavelength 2: 254) to give (5-(methoxycarbonyl)-1-methyl-1H-pyrazol-3-yl)boronic acid (213.5 mg, 1.161 mmol, quantitative yield). MS ESI m / z 185.1 (M+H); 1 H NMR(400MHz, CD3OD) δ 7.17 (s, 1H), 4.20 (s, 3H), 3.90 (s, 3H)

[0146] 36D: 1-methyl-3-(3-(methylcarbamoyl)-1H-indazol-6-yl)-1H-pyrazole-5-carboxylic acid A solution of 6-bromo-N-methyl-1H-indazole-3-carboxamide (240 mg, 0.945 mmol), (5-(methoxycarbonyl)-1-methyl-1H-pyrazol-3-yl)boronic acid (174 mg, 0.945 mmol), PdCl2(dppf)-CHCl2 adduct (46.3 mg, 0.057 mmol) and tripotassium phosphate (2 M, 1.417 mL, 2.83 mmol) in DMF (5 mL) was degassed and heated at 100 °C for 2 h. The reaction mixture was concentrated, water (30 mL) was added and the mixture was acidified to pH ~4 with concentrated HCl. The solid was recovered as 1-methyl-3-(3-(methylcarbamoyl)-1H-indazol-6-yl)-1H-pyrazole-5-carboxylic acid (292 mg, 0.878 mmol, 93% yield). MS ESI m / z 300.1(M+H)

[0147] Example 36: Using a method essentially similar to that described in 1, N-methyl-6-(1-methyl-5-((4-phenylbutan-2-yl)carbamoyl)-1H-pyrazol-3-yl)-1H-indazole-3-carboxamide (racemic, 1.2 mg, 2.79 μmol, 8% yield) was obtained. MS ESI m / z 431.1 (M+H); 1 H NMR (500MHz, DMSO-d6) δ 8.45 (br d, J=8.3Hz, 1H), 8.39 (br d, J=4.6Hz, 1H), 8.19 (d, J=8.5Hz, 1H), 7.96 (s, 1H), 7.70 (d, J=8.5Hz, 1H), 7.35 (s, 1H), 7.29-7.25 (m, 3H), 7.23-7.20 (m, 3H), 7.19-7.14 (m, 1H), 4.10 (s, 3H), 3.98 (dt, J=13.7, 6.9Hz, 1H), 2.83 (d, J=4.6Hz, 3H), 2.65-2.59 (m, 2H), 1.90-1.81 (m, 1H), 1.80-1.74 (m, 1H)

[0148] Table 9: The compounds in Table 9 were prepared in a similar manner to Example 36. Unless otherwise specified in the text, those without a description of stereochemistry are racemic or diastereomeric. [ka] [Table 11]

Claims

1. Formula (I) [Case 1] [In the formula, Ring B is a 5-membered heterocycle containing 1-2 heteroatoms selected from N, S, and O, and is substituted with 0-2 C1-3 alkyl groups; R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is a deuterated alkyl; R 2 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 0-6 Alkyl-C 6-10 Aryl, C 0-6 Alkyl-C 3-6 Cycloalkyl, or C 0-6 alkyl-(3-6 membered heterocycle containing 1-4 heteroatoms selected from N, S, and O), where any aryl, cycloalkyl, or heterocycle group is selected from 0-3 R 2a where any alkyl group is substituted with 0-1 OH; R 2a is halogen, CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, 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 3-6 Cycloalkyl-C 1-3 Deuterated alkoxy-, 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, Phenyl-C 1-3 Alkoxy-, C 6-10 Aryl-O-, Phenyl-C 1-4 Alkyl-SO 2 -, C 1-4 Alkyl-SO 2 -, C 3-6 Cycloalkyl-SO 2 -, NR 3 R 3 CO-, NR 3 R 3 -(CH 2 ) n -, R 4 -C(O)-, R 4 -OC(O)-, R 4 -C(O)O-, R 3 -NH-C(O)O-, R 5 -OC(O)NH-, R 3 -NH-C(O)NR 3 -, R 5 -SO 2 -, R 4 -SO 2 NH-, R 4 -NHSO 2 -, heterocycle, where each heterocycle is a 4-6 membered ring having 1-2 heteroatoms independently selected from N and O, and where each alkyl, cycloalkyl, aryl, phenyl, or heterocycle is selected from 0-2 R 2b Replaced with; R 2b each independently, if present, is OH, C 1-3 Alkyl, C 1-3 Alkoxy, Hydroxy C 1-3 Alkyl, Hydroxy C 1-3 Alkoxy, halogen, C=O, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; R 3 are, if present, each independently H, C 1-6 Alkyl, C 0-3 Alkyl-C 3-6Cycloalkyl, C 0-3 is alkyl-phenyl; R 4 are, if present, each 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 5 are each independently C, if present 1-6 Alkyl, C 0-3 Alkyl-C 3-6 Cycloalkyl, C 0-3 alkyl-phenyl; and n is 0, 1 or 2. or a salt thereof.

2. wherein ring B is thiophenyl, thiazolyl, imidazolyl, or pyrazolyl, and any ring contains 0 to 2 C 1-3 2. The compound of claim 1, or a salt thereof, which is alkyl substituted.

3. In the formula, R 2 But, C 1-6 Alkyl, C 1-6 Haloalkyl, C0-4 alkyl-phenyl, C0-4 alkyl-C 3-6 cycloalkyl, or C0-4 alkyl-(5-6 membered heterocycle), where the heterocycle is selected from pyridinyl or pyrrolyl, where any phenyl, cycloalkyl, or heterocycle group is selected from 0-3 R 2a and any alkyl is substituted with 0 to 1 OH, or a salt thereof.

4. In the formula, R 2a But halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl-C 1-3The compound according to any one of claims 1 to 3, or a salt thereof, which is alkoxy.

5. In the formula, R 2 But 0 to 3 R 2a C replaced with 1-4 5. The compound according to claim 1, which is alkyl-phenyl, or a salt thereof.

6. In the formula, R 2a But halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 1-6 The compound according to any one of claims 1 to 5, which is haloalkoxy, or a salt thereof.

7. Ring B is [Case 2] and any ring has 0 to 2 C 1-2 The compound according to any one of claims 1 to 6, or a salt thereof, which may be substituted with an alkyl group.

8. Ring B is [C3] The compound according to any one of claims 1 to 6, or a salt thereof.

9. The compound is 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)thiophen-3-yl)-N-methyl-1H-indazole-3-carboxamide; N-methyl-6-(5-((3-phenylbutyl)carbamoyl)thiophen-3-yl)-1H-indazole-3-carboxamide; (R)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)thiophen-3-yl)-N-methyl-1H-indazole-3-carboxamide; (S)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)thiophen-3-yl)-N-methyl-1H-indazole-3-carboxamide; (R)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)thiophen-3-yl)-N-isopropyl-1H-indazole-3-carboxamide; 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)thiophen-2-yl)-N-methyl-1H-indazole-3-carboxamide; N-methyl-6-(5-((3-phenylbutyl)carbamoyl)thiophen-2-yl)-1H-indazole-3-carboxamide; (S)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)thiophen-2-yl)-N-methyl-1H-indazole-3-carboxamide; (S)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)thiophen-2-yl)-N-isopropyl-1H-indazole-3-carboxamide; 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)-4-methylthiophen-2-yl)-N-methyl-1H-indazole-3-carboxamide; N-methyl-6-(4-methyl-5-((3-phenylbutyl)carbamoyl)thiophen-2-yl)-1H-indazole-3-carboxamide; (R)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-4-methylthiophen-2-yl)-N-methyl-1H-indazole-3-carboxamide; (S)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-4-methylthiophen-2-yl)-N-methyl-1H-indazole-3-carboxamide; N-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide; 4-Methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)-N-(3-phenylbutyl)thiazole-5-carboxamide; (R)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide; (S)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide; N-(2-fluoro-5-(trifluoromethyl)benzyl)-4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide; N-(1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl)-4-methyl-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide; N-(2-fluoro-5-(trifluoromethoxy)benzyl)-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-4-carboxamide; 2-(3-(methylcarbamoyl)-1H-indazol-6-yl)-N-(3-phenylbutyl)thiazole-4-carboxamide; (R)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-4-carboxamide; (S)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-4-carboxamide; 2-(3-(methylcarbamoyl)-1H-indazol-6-yl)-N-(3-phenylbutyl)thiazole-5-carboxamide; (R)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-(3-(methylcarbamoyl)-1H-indazol-6-yl)thiazole-5-carboxamide; 6-(5-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)-1,4-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(1,4-dimethyl-5-((3-phenylbutyl)carbamoyl)-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; (R)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-1,4-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; (S)-6-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-1,4-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)-1,4-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(4-((2-fluoro-5-(trifluoromethoxy)benzyl)carbamoyl)-1,5-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(1,5-dimethyl-4-((3-phenylbutyl)carbamoyl)-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; (R)-6-(4-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-1,5-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; (S)-6-(4-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-1,5-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)-1,5-dimethyl-1H-imidazol-2-yl)-N-methyl-1H-indazole-3-carboxamide; N-methyl-6-(1-methyl-5-((4-phenylbutan-2-yl)carbamoyl)-1H-pyrazol-3-yl)-1H-indazole-3-carboxamide; 6-(5-{[3-(4-fluorophenyl)-3-hydroxypropyl]carbamoyl}-1-methyl-1H-pyrazol-3-yl)-N-methyl-1H-indazole-3-carboxamide; 6-(5-{[3-(3,4-difluorophenyl)-3-hydroxypropyl]carbamoyl}-1-methyl-1H-pyrazol-3-yl)-N-methyl-1H-indazole-3-carboxamide; N-methyl-6-{1-methyl-5-[(3-phenylbutyl)carbamoyl]-1H-pyrazol-3-yl}-1H-indazole-3-carboxamide; and 6-(5-{[3-(4-chlorophenyl)-3-hydroxypropyl]carbamoyl}-1-methyl-1H-pyrazol-3-yl)-N-methyl-1H-indazole-3-carboxamide, 2. The compound of claim 1, selected from the group consisting of:

10. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

11. A pharmaceutical composition for inhibiting RIPK1 activity, comprising one or more compounds according to any one of claims 1 to 9 or salts thereof.

12. 12. The pharmaceutical composition according to claim 11 for treating a disease, 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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