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Building IP: BMY Patent Application re "INDOLE CARBOXAMIDE COMPOUNDS"
INDOLE CARBOXAMIDE COMPOUNDS Disclosed are compounds of Formula (I): ##STR00001## or a salt thereof, wherein: X is CR.sub.4 or N; R.sub.1, R.sub.2, R.sub.3, R.sub.4, and A are defined herein. Also disclosed are methods of using such compounds as inhibitors of Bruton's tyrosine kinase (Btk), and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
1-17. (canceled) 18. A compound of Formula (I): ##STR00515## wherein: X is CR.sub.4; A is ##STR00516## Q.sub.2 is --CN, --C(O)(C.sub.1-4 alkyl substituted with zero or 1 R.sub.11), --C(O)(C.sub.3-6 cycloalkyl substituted with zero or 1 R.sub.11), --C(O)(C.sub.5-6 cycloalkenyl), --C(O)CR.sub.10.dbd.CR.sub.10R.sub.10, --C(O)C(R.sub.10).dbd.CHCH.sub.2N(CH.sub.3).sub.2, --C(O)C.ident.CR.sub.7, --C(O)C.ident.C(C.sub.1-3 hydroxyalkyl), --C(O)C.ident.C(phenyl), --C(O)C.ident.CSi(CH.sub.3).sub.3, or --S(O).sub.2CH.dbd.CHR.sub.10; R.sub.1 is H, --CH.sub.3, --CF.sub.3, or phenyl substituted with zero or 1 R.sub.12; R.sub.2 is H, --CH.sub.3, cyclopropyl, or phenyl substituted with zero or 1 R.sub.12, provided that zero or one of R.sub.1 and R.sub.2 is phenyl substituted with zero or 1 R.sub.12; R.sub.3 is F, Cl, or I; R.sub.4 is H, F, --OH, or --OCH.sub.3; each R.sub.7 is H, C.sub.1-4 alkyl, or cyclopropyl; R.sub.10, at each occurrence, is independently H or --CH.sub.3; R.sub.11 is F, Cl, --CN, --CF.sub.3, or C.sub.1-3 alkoxy; and R.sub.12 is F, Cl, --CN, --CF.sub.3, or C.sub.1-3 alkoxy. 19. The compound according to claim 18 wherein: R.sub.1 is H or --CH.sub.3; R.sub.2 is H or --CH.sub.3; R.sub.3 is F or Cl; and R.sub.4 is H or F. 20. The compound according to claim 19 wherein R.sub.3 is F. 21. The compound according to claim 19 wherein: A is ##STR00517## 22. The compound according to claim 19 wherein: A is ##STR00518## 23. The compound according to claim 19 wherein: A is ##STR00519## 24. The compound according to claim 19 wherein: R.sub.1 is --CH.sub.3; R.sub.2 is --CH.sub.3; R.sub.3 is H or F; R.sub.4 is H; and each R.sub.7 is H or --CH.sub.3. 25. The compound according to claim 18 wherein: Q.sub.2 is --CN, --C(O)CH.dbd.CH.sub.2, --C(O)CH.dbd.CHCH.sub.2N(CH.sub.3).sub.2, --C(O)C.ident.CH, --C(O)C.ident.C(CH.sub.3), or --S(O).sub.2CH.dbd.CH.sub.2. 26. The compound according to claim 18 having the structure: ##STR00520## 27. The compound according to claim 18 having the structure: ##STR00521## 28. The compound according to claim 18 having the structure: ##STR00522## 29. The compound according to claim 18 wherein said compound is: 4-((1-acryloylpiperidin-4-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (79); 4-((1-acryloylpyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carbo- xamide (86); (R)-4-((1-acryloylpyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxa- mide (87); (S)-4-((1-acryloylpyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-- 1H-indole-7-carboxamide (88); 4-((1-acryloylpiperidin-3-yl)amino)-2,3-dimethyl-1H-indole-7-carboxamide (91); 4-((1-acryloylpiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole- -7-carboxamide (92); (S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-2,3-dimethyl-1H-indole-7- -carboxamide (94); (S)-4-((1-acryloylpyrrolidin-3-yl)(methyl)amino)-5-fluoro-2,3-dimethyl-1H- -indole-7-carboxamide (96); (RS)-2,3-dimethyl-4-((1-propioloylpyrrolidin-3-yl)amino)-1H-indole-7-carb- oxamide (103); 2,3-dimethyl-4-((1-propioloylpiperidin-3-yl)amino)-1H-indole-7-carboxamid- e (106); 4-((1-(but-2-ynoyl)piperidin-4-yl)amino)-2,3-dim ethyl-1H-indole-7-carboxamide (107); 2,3-dimethyl-4-((1-propioloylpiperidin-4-yl)amino)-1H-indole-7-carboxamid- e (114); 4-((1-(but-2-ynoyl)pyrrolidin-3-yl)amino)-2,3-dimethyl-1H-indole-- 7-carboxamide (121); 4-((1-(but-2-ynoyl)piperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-- 7-carboxamide (122); (S,E)-4-((1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)amino)-2,3-dime- thyl-1H-indole-7-carboxamide (124); 2,3-dimethyl-4-((1-(vinylsulfonyl)pyrrolidin-3-yl)amino)-1H-indole-7-carb oxamide (144); (S)-4-((1-cyanopyrrolidin-3-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-c- arboxamide (147); or 4-((1-cyanopiperidin-4-yl)amino)-5-fluoro-2,3-dimethyl-1H-indole-7-carbox- amide (151). 30. A pharmaceutical composition comprising a compound according to claim 18 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier. 31. A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound according to claim 18 or a pharmaceutically-acceptable salt thereof, wherein said disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjogren's syndrome. CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This continuation application claims the priority benefit of U.S. patent application Ser. No. 14/921,347 filed Oct. 23, 2015, which claims the benefit of U.S. Application Ser. No. 62/068,225, filed Oct. 24, 2014, which is incorporated herein it its entirety. DESCRIPTION [0002] The present invention generally relates to indole carboxamide compounds useful as kinase inhibitors, including the modulation of Bruton's tyrosine kinase (Btk) and other Tec family kinases such as Itk. Provided herein are indole carboxamide compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to kinase modulation and methods of inhibiting the activity of kinases, including Btk and other Tec family kinases such as Itk, in a mammal. [0003] Protein kinases, the largest family of human enzymes, encompass well over 500 proteins. Btk is a member of the Tec family of tyrosine kinases, and is a regulator of early B-cell development, as well as mature B-cell activation, signaling, and survival. [0004] B-cell signaling through the B-cell receptor (BCR) leads to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell. The magnitude and duration of BCR signals must be precisely regulated. Aberrant BCR-mediated signaling can cause disregulated B-cell activation and/or the formation of pathogenic auto-antibodies leading to multiple autoimmune and/or inflammatory diseases. Mutation of Btk in humans results in X-linked agammaglobulinaemia (XLA). This disease is associated with the impaired maturation of B-cells, diminished immunoglobulin production, compromised T-cell-independent immune responses and marked attenuation of the sustained calcium signal upon BCR stimulation. [0005] Evidence for the role of Btk in allergic disorders and/or autoimmune disease and/or inflammatory disease has been established in Btk-deficient mouse models. For example, in standard murine preclinical models of systemic lupus erythematosus (SLE), Btk deficiency has been shown to result in a marked amelioration of disease progression. Moreover, Btk deficient mice are also resistant to developing collagen-induced arthritis and are less susceptible to Staphylococcus-induced arthritis. [0006] A large body of evidence supports the role of B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics such as rituximab, developed to deplete B-cells, represent an important approach to the treatment of a number of autoimmune and/or inflammatory diseases. Because of Btk's role in B-cell activation, inhibitors of Btk can be useful as inhibitors of B-cell mediated pathogenic activity (such as autoantibody production). [0007] Btk is also expressed in mast cells and monocytes and has been shown to be important for the function of these cells. For example, Btk deficiency in mice is associated with impaired IgE-mediated mast cell activation (marked diminution of TNF-alpha and other inflammatory cytokine release), and Btk deficiency in humans is associated with greatly reduced TNF-alpha production by activated monocytes. [0008] Thus, inhibition of Btk activity can be useful for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases including, but not limited to: SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin diseases, Evans syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathies (e.g., Guillain-Barre syndrome), pemphigus vulgaris, and asthma. [0009] In addition, Btk has been reported to play a role in controlling B-cell survival in certain B-cell cancers. For example, Btk has been shown to be important for the survival of BCR-Abl-positive B-cell acute lymphoblastic leukemia cells. Thus inhibition of Btk activity can be useful for the treatment of B-cell lymphoma and leukemia. [0010] In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of protein kinases, it is immediately apparent that new compounds capable of modulating protein kinases such as Btk and methods of using these compounds should provide substantial therapeutic benefits to a wide variety of patients. [0011] U.S. Pat. Nos. 8,084,620 and 8,685,969 disclose tricyclic carboxamide compounds useful as kinase inhibitors, including the modulation of Btk and other Tec family kinases. [0012] There still remains a need for compounds useful as Btk inhibitors. Applicants have found potent compounds that have activity as Btk inhibitors. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to this utility. SUMMARY OF THE INVENTION [0013] The present invention provides indole carboxamide compounds, including salts, solvates, and prodrugs thereof, that are useful as inhibitors of Btk and are useful for the treatment of proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases. [0014] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof. [0015] The present invention also provides a method of inhibiting Btk activity comprising administering to a mammal in need thereof at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof. [0016] The present invention also provides a method for treating allergic disorders and/or autoimmune and/or inflammatory diseases, comprising administering to a mammal in need thereof at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof. [0017] The present invention also provides a method for treating proliferative diseases, such as cancer, comprising administering to a mammal in need thereof at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof. [0018] The present invention also provides a method of treating a disease or disorder associated with Btk activity, the method comprising administering to a mammal in need thereof, at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof. [0019] The present invention also provides processes and intermediates for making the compounds of Formula (I) including salts, solvates, and prodrugs thereof. [0020] The present invention also provides at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof, for use in therapy. [0021] The present invention also provides the use of at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof, for the manufacture of a medicament for the treatment or prophylaxis of Btk related conditions, such as proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases. [0022] The present invention also provides the use of at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof, for the manufacture of a medicament for treatment of cancer. [0023] The compounds of Formula (I) and compositions comprising the compounds of Formula (I) may be used in treating, preventing, or curing various Btk related conditions. Pharmaceutical compositions comprising these compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases. [0024] These and other features of the invention will be set forth in expanded form as the disclosure continues. |
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