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Building IP: BMY Patent Appl "INDAZOLE CARBOXAMIDES AS KINASE INHIBITORS"INDAZOLE CARBOXAMIDES AS KINASE INHIBITORSDOCUMENT IDUS 20220380355 A1 DATE PUBLISHED2022-12-01 INVENTOR INFORMATION NAMECITYSTATEZIP CODECOUNTRYChen; Jie Cambridge MA N/A US Dzierba; Carolyn Diane Medford MA N/A US Goo; Junqing Princeton NJ N/A US Hart; Amy C. Littleton CO N/A US Pitts; William J. Newtown PA N/A US Sit; Sing-Yuen Meriden CT N/A US APPLICANT INFORMATION NAME BRISTOL-MYERS SQUIBB COMPANY CITY Princeton STATE NJ ZIP CODE N/A COUNTRY US AUTHORITY N/A TYPE assignee APPLICATION NO17/762771 DATE FILED2020-10-02 DOMESTIC PRIORITY (CONTINUITY DATA)us-provisional-application US 62909920 20191003 AbstractCompounds having formula (I), and enantiomers, and diastereomers, stereoisomers, pharmaceutically-acceptable salts thereof, are useful as kinase modulators, including RIPK1 modulation. All the variables are as defined herein. ##STR00001## Background/SummaryCROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application Ser. No. 62/909,920 filed Oct. 3, 2019, which is incorporated herein in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to novel compounds that inhibit receptor interacting protein kinases and methods of making and using the same. Specifically, the present invention relates to indazolecarboxamides as receptor interacting protein kinase 1 (RIPK1) inhibitors. BACKGROUND OF THE INVENTION [0003] Apoptosis and necrosis represent two different mechanisms of cell death. Apoptosis is a highly regulated process involving the caspase family of cysteine proteases, and characterized by cellular shrinkage, chromatin condensation, and DNA degradation. In contrast, necrosis is associated with cellular and organelle swelling and plasma membrane rupture with ensuing release of intracellular contents and secondary inflammation (Kroemer et al., (2009) Cell Death Differ 16:3-11). Necrosis has been considered a passive, unregulated form of cell death; however, recent evidence indicates that some necrosis can be induced by regulated signal transduction pathways such as those mediated by receptor interacting protein kinases (RIPKs) especially in conditions where caspases are inhibited or cannot be activated efficiently (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 family of death domain receptors (DRs) is known to mediate apoptosis in most cell types through the activation of the extrinsic caspase pathway. In addition, in certain cells deficient for caspase-8 or treated with pan-caspase inhibitor Z-VAD, stimulation of death domain receptors (DR) causes a receptor interacting protein kinase 1 (RIPK1) dependent programmed necrotic 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 is termed “programmed necrosis” or “necroptosis” (Degterev et al., (2005) Nat Chem Biol 1:112-119). [0004] Necroptosis can be triggered by a number of mechanisms including of TNF receptor activation, Toll-like receptor engagement, genotoxic stress and viral infection. Downstream of the various stimuli, the signaling pathway that results in necroptosis is dependent on RIPK1 and RIPK3 kinase activity. (He et al., (2009) Cell 137:1100-1111; Cho et. al., (2009) Cell 137:1112-1123; Zhang et al., (2009) Science 325:332-336). [0005] Dysregulation of the necroptosis signaling pathway has been linked to inflammatory diseases such as macrophage necrosis in atheroscelerosis development, virus-induced inflammation, systemic inflammatory response syndrome and ethanol-induced liver injury, neurodegeneration such as detachment of the retina, ischemia, amyotrophic lateral sclerosis (ALS), and Gaucher's 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., (2016) Science 353, 603-608; Vitner et al., (2014) Nature Med. 20, 204-208). [0006] A potent, selective, small molecule inhibitor of RIPK1 activity would block RIPK1-dependent pro-inflammatory signaling and thereby provide a therapeutic benefit in inflammatory diseases characterized by increased and/or dysregulated RIPK1 kinase activity. SUMMARY OF THE INVENTION [0007] The present invention provides novel indazolecarboxamides including stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts, or solvates thereof, which are 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 pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts, or solvates thereof. [0010] The compounds of the invention may be used in the treatment and/or prophylaxis of conditions associated with aberrant RIPK1 activity. [0011] The compounds of the present invention may be used in therapy. [0012] The compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of a condition associated with aberrant RIPK1 activity. [0013] In another aspect, the present invention is directed to a method of treating diseases mediated at least partially by RIPK1 including inflammatory diseases, ischemia, neurodegeneration, and Gaucher's disease, which method comprises administering to a patient in need of such treatment a compound of the present invention as described above. [0014] The compounds of the 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 agent(s). [0015] These and other features of the invention will be set forth in expanded form as the disclosure continues. |
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