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Building IP: BMY Patent Application re "CARBAZOLE DERIVATIVES"
CARBAZOLE DERIVATIVES Disclosed are compounds of Formula (I): ##STR00001## or a salt thereof, wherein Q, R.sub.1a, R.sub.1b, R.sub.2a, R.sub.2b, R.sub.3, R.sub.4, R.sub.5a, R.sub.5b, R.sub.6a, R.sub.6c, R.sub.7a, R.sub.7b, R.sub.7c, and R.sub.7d 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.
1-11. (canceled) 12. A compound of Formula (I) ##STR00390## or a salt thereof, wherein: the two dotted lines represent either two single or two double bonds; and R.sub.1b and R.sub.2b are present only if said two dotted lines are two single bonds; Q is: ##STR00391## R.sub.1a is H, --CN, --CF.sub.3, --CH.sub.3, --CR.sub.8aR.sub.8bOH, --CR.sub.8aR.sub.8bCR.sub.8aR.sub.8bOH, --CH(OH)CH.sub.2OH, --NHR.sub.9, --C(O)NR.sub.10aR.sub.10b, --C(O)(morpholinyl), --C(O)(piperazinyl), or --C(O)(methyl piperazinyl); R.sub.1b, when present, is H or --CH.sub.3, provided that if R.sub.1a is H then R.sub.1b is also H; R.sub.2a is H, F, or Cl, provided that if R.sub.1a is other than H then R.sub.2a is H; R.sub.2b, when present, is the same as R.sub.2a; R.sub.3 is H, F, or Cl; R.sub.7b is --C(O)CH.dbd.CH.sub.2; R.sub.7c is --C(O)CH.dbd.CH.sub.2 or --C(O)C.ident.CR.sub.12; R.sub.8a is H or --CH.sub.3; R.sub.8b is H or --CH.sub.3; R.sub.9 is C.sub.1-4 alkyl; R.sub.10a and R.sub.10b are independently H or --CH.sub.3; and R.sub.12 is H, C.sub.1-4 alkyl, or cyclopropyl. 13. The compound according to claim 12 or a salt thereof, wherein: R.sub.1a is H, --CF.sub.3, --CH.sub.3, --CR.sub.8aR.sub.8bOH, --CR.sub.8aR.sub.8bCR.sub.8aR.sub.8bOH, --NHR.sub.9, --C(O)NR.sub.10aR.sub.10b, --C(O)(piperazinyl), or --C(O)(methyl piperazinyl); R.sub.1b is H; R.sub.2a is H or F, provided that if R.sub.1a is other than H then R.sub.2a is H; R.sub.2b, when present, is the same as R.sub.2a; R.sub.3 is F or Cl; R.sub.7b is --C(O)CH.dbd.CH.sub.2; R.sub.7c is --C(O)CH.dbd.CH.sub.2 or --C(O)C.ident.CR.sub.12; R.sub.8a is H or --CH.sub.3; R.sub.8b is H or --CH.sub.3; R.sub.10a and R.sub.10b are independently H or --CH.sub.3; and R.sub.12 is H, C.sub.1-4 alkyl, or cyclopropyl. 14. The compound according to claim 12 or a salt thereof, wherein R.sub.3 is F. 15. The compound according to claim 12 or a salt thereof, having the structure of Formula (Ia): ##STR00392## 16. The compound according to claim 12 or a salt thereof, having the structure of Formula (Ib): ##STR00393## 17. The compound according to claim 12 or a salt thereof, wherein Q is: ##STR00394## 18. The compound according to claim 12 or a salt thereof, wherein said compound is: ##STR00395## 19. The compound according to claim 12 or a salt thereof, wherein said compound is: ##STR00396## 20. The compound according to claim 16 or a salt thereof, wherein Q is: ##STR00397## 21. The compound according to claim 12 or a salt thereof, wherein said compound is: ##STR00398## 22. The compound according to claim 12 or a salt thereof, wherein Q is: ##STR00399## 23. The compound according to claim 12 or a salt thereof, wherein said compound is: ##STR00400## 24. The compound according to claim 12 or a salt thereof, wherein said compound is: ##STR00401## 25. The compound according to claim 12 or a salt thereof, wherein Q is: ##STR00402## 26. The compound according to claim 12 or a salt thereof, wherein said compound is: ##STR00403## 27. The compound according to claim 12 or a salt thereof, wherein said compound is (S)-5-(3-acrylamidopiperidin-1-yl)-3,3,6-trifluoro-2,3,4,9-tetrahydro-1H-- carbazole-8-carboxamide (66); (S)-5-(3-(but-2-ynamido) piperidin-1-yl)-3,3,6-trifluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxa- mide (73); (S)-3-fluoro-4-(3-(N-methylbut-2-ynamido)piperidin-1-yl)-9H-car- bazole-1-carboxamide (74); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-3-fluoro-9H-carbazole-1-carboxami- de (75); (S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-3-fluoro-9H-c- arbazole-1-carboxamide (76); 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-fluoro-9H-carbazole-1-car- boxamide (96); (RS)-4-(1-acryloylpiperidin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (97); 4-(1-acryloylpiperidin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide, single enantiomers (98 and 99); 3-fluoro-4-((2-vinylpyridin-4-yl)methyl)-9H-carbazole-1-carboxamide (100); 4-(1-acryloylpyrrolidin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (112); 4-(1-acryloylpyrrolidin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (113 and 114); cis-4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluoro-9- H-carbazole-1-carboxamide (115); cis-4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluoro-9- H-carbazole-1-carboxamide (116 and 117); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-3-fluoro-9H-carbazole-1-carboxami- de (118); cis-4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluo- ro-9H-carbazole-1-carboxamide (119); cis-4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluoro-9H-car- bazole-1-carboxamide (120 and 121); cis-4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-fluoro-9H-carb- azole-1-carboxamide (123); cis-4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-fluoro-9H-carb- azole-1-carboxamide (124 and 125); 4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-chloro-9H-ca- rbazole-1-carboxamide (126); 4-((4aS,7aS)-1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-ch- loro-9H-carbazole-1-carboxamide and 4-((4aR,7aR)-1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-ch- loro-9H-carbazole-1-carboxamide (127 and 128); 5-((S)-3-(but-2-ynamido) piperidin-1-yl)-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-c- arbazole-8-carboxamide (130, 131, and 132); 4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-3-fluoro-9H-carbazole-1-carboxa- mide (134); 5-(1-acryloylpyrrolidin-3-yl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-- carboxamide (135); (R)-4-(3-(but-2-ynamido)piperidin-1-yl)-3-fluoro-9H-carbazole-1-carboxami- de (136); 4-(1-(but-2-ynoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-fluo- ro-9H-carbazole-1-carboxamide (137); 4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3-yl)-3-fluoro-9H-carbazole-1-car- boxamide (138); 4-(7-(but-2-ynoyl)-2,7-diazaspiro[4.4] nonan-2-yl)-3-fluoro-9H-carbazole-1-carboxamide (139); 4-(7-acryloyl-2,7-diazaspiro [4.4]nonan-2-yl)-3-fluoro-9H-carbazole-1-carboxamide (140); 4-(1-acryloyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-3-fluoro-9H-carbazo- le-1-carboxamide (141); 4-(1-(but-2-ynoyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-3-fluoro-9H-ca- rbazole-1-carboxamide (142); 4-(6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-3-fluoro-9H-carbazole-1- -carboxamide (143); 4-(6-(but-2-ynoyl)-3,6-diazabicyclo[3.2.0] heptan-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (144); 4-(7-acryloyloctahydro-2,7-naphthyridin-2(1H)-yl)-3-fluoro-9H-carbazole-1- -carboxamide (145); 4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b] pyridin-6-yl)-3-chloro-9H-carbazole-1-carboxamide (146); 4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-fluoro-7-(trifluoromethyl- )-9H-carbazole-1-carboxamide (160); 4-(1-acryloylpiperidin-3-yl)-3-fluoro-7-(trifluoromethyl)-9H-carbazole-1-- carboxamide (161 and 162); (S)-4-(3-acrylamidopiperidin-1-yl)-3-fluoro-7-(trifluoromethyl)-9H-carbaz- ole-1-carboxamide (163); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-3-fluoro-7-(trifluoromethyl)-9H-c- arbazole-1-carboxamide (164); (R)-4-(3-(but-2-ynamido)piperidin-1-yl)-3-fluoro-7-(trifluoromethyl)-9H-c- arbazole-1-carboxamide (165); (S)-4-(3-(3-cyclopropylpropiolamido)piperidin-1-yl)-3-fluoro-7-(trifluoro- methyl)-9H-carbazole-1-carboxamide (166); (S)-4-(3-cyanamidopiperidin-1-yl)-3-fluoro-7-(trifluoromethyl)-9H-carbazo- le-1-carboxamide (167); 4-(1-acryloyl-1-azaspiro[4.4]nonan-7-yl)-3-fluoro-7-(trifluoromethyl)-9H-- carbazole-1-carboxamide (171); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-3-fluoro-7-(4-methylpiperazine-1-- carbonyl)-9H-carbazole-1-carboxamide (172); (S)-4-(3-(but-2-ynamido)piperidin-1-yl)-3-fluoro-N7,N7-dimethyl-9H-carbaz- ole-1,7-dicarboxamide (173); 4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-chloro-3-fluoro-9- H-carbazole-1-carboxamide (182); 4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-chloro-3-flu- oro-9H-carbazole-1-carboxamide (183); 5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-fluoro-2-(2-hydroxypropan- -2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (184); 4-(7-(but-2-ynoyl)octahydro-2,7-naphthyridin-2(1H)-yl)-3-fluoro-9H-carbaz- ole-1-carboxamide (190); 4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-9H-carbazole-1-car- boxamide (191); 4-(1-(but-2-ynoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-9H-carbazole-- 1-carboxamide (192); or 4-((1S,4S)-2-acryloyl-2-azabicyclo[2.2.1]heptan-5-yl)-3-fluoro-9H-carbazo- le-1-carboxamide (194). 28. A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier. 29. A pharmaceutical composition comprising a compound according to claim 18 and a pharmaceutically acceptable carrier. 30. A pharmaceutical composition comprising a compound according to claim 19 and a pharmaceutically acceptable carrier. 31. A pharmaceutical composition comprising a compound according to claim 21 and a pharmaceutically acceptable carrier. 32. A pharmaceutical composition comprising a compound according to claim 23 and a pharmaceutically acceptable carrier. 33. A pharmaceutical composition comprising a compound according to claim 24 and a pharmaceutically acceptable carrier. 34. A pharmaceutical composition comprising a compound according to claim 26 and a pharmaceutically acceptable carrier. 35. 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 12, wherein said disease is systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, or Sjogren's syndrome. CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation application of U.S. application Ser. No. 16/289,878, filed Apr. 10, 2019, which is a continuation application of U.S. application Ser. No. 15/521,194, filed Apr. 21, 2017, which is a national phase application under 35 U.S.C. .sctn. 371 of International Patent Application No. PCT/US2015/057077, filed Oct. 23, 2015, which claims priority to U.S. Application Ser. No. 62/068,234, filed Oct. 24, 2014, which are expressly incorporated fully herein by reference. DESCRIPTION [0002] The present invention generally relates to tricyclic 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 tricyclic 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 RITUXAN.RTM., 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] A compound that inhibits an enzyme by reacting with the enzyme to form a covalent bond can offer advantages over a compound that does not form such a covalent bond. (See, for example, Liu, Q. et al., Chem. Biol., 20:146 (2013); Barf, T. et al., J. Med. Chem., 55:6243 (2012); Kalgutkar, A. et al., Expert Opin. Drug Discov., 7:561 (2012); and Garuti, L. et al., Curr. Med. Chem., 18:2981 (2011); and references cited therein). A compound that does not form a covalent bond can dissociate from the enzyme, releasing the enzyme from the inhibition resulting from its binding. Such reversible inhibition may require a relatively high and continuous concentration of the inhibitory compound to drive the binding equilibrium toward sufficient enzyme occupancy by the inhibitor to achieve useful enzyme inhibition. A higher concentration of the compound could require administration of a higher dose of the compound to a mammal in need of such inhibition, and at a higher concentration the inhibitor could have undesired effects due to inhibition of other, non-targeted enzymes. Such off-target inhibition could include toxicity. Additionally, more frequent dosing may be required since the inhibitory compound, after dissociation from the target enzyme, can be removed from the body by metabolism and/or elimination, lowering the concentration available to achieve inhibition of the target enzyme. [0011] In contrast, an inhibitor that forms a covalent bond with its target enzyme irreversibly inhibits the enzyme. The irreversible inhibition would result from either slow or negligible dissociation of the inhibitor, since such dissociation would require breaking a covalent bond. If the affinity of such a covalent inhibitor for its target enzyme is sufficiently great relative to affinities for other, off-target enzymes, a significantly lower concentration of the inhibitor can result in useful inhibition relative to a concentration required for reversible inhibition. The lower concentration could reduce the likelihood of undesired off-target inhibition and potential toxicity. Also, since the covalent inhibitor can bind essentially irreversibly to the target enzyme, the free (non-bound) concentration of the inhibitor can become extremely low as non-bound inhibitor is removed from the body by metabolism and/or elimination, even while useful enzyme inhibition is maintained. This can reduce the likelihood of undesired effects. Additionally, since the enzyme can be irreversibly inhibited, less frequent dosing may be required to achieve useful inhibition. [0012] Certain reactive functional groups can be attached to a compound with good affinity for the target enzyme, which will allow formation of a covalent bond with a functional group in the target enzyme. For example, an electrophilic group such as a vinylic or acetylenic group attached to an electron-withdrawing group such as a ketone, amide, sulfone, sulfonamide, or an electron-withdrawing heterocyclic ring such as a pyridyl ring can react with a nucleophilic group present in the target enzyme, such as the thiol or thiolate group of a cysteine residue, to form a covalent bond. Such a reaction can be essentially irreversible under normal physiological conditions. In order for such a reaction to be achieved, the inhibitor compound must bind to the target enzyme and present the attached electrophilic group in a correct spatial orientation to allow favorable interaction with the attacking nucleophile. If the orientation is not correct, the covalent bond may not easily form, and the desired irreversible inhibition may not be achieved. In this case, the compound would behave like a reversible inhibitor and the benefits of irreversible inhibition may not be realized. Also, if the orientation of the electrophile on the bound inhibitor is not suitable for reaction with the nucleophilic group of the target enzyme, the inhibitor will be capable of dissociation from the target enzyme, resulting in a higher concentration of the inhibitor and a greater likelihood that the reactive electrophilic group can react with other, non-target nucleophiles and cause undesired effects such as toxicity. [0013] 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. [0014] 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. [0015] There still remains a need for compounds useful as Btk inhibitors. Further, there still remains a need for compounds useful as Btk inhibitors that can be administered at lower doses or are effective at lower concentrations. Additionally, there still remains a need for compounds that have a combination of improved potency as Btk inhibitors and improved potency in the Ramos FLIPR assay. [0016] 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 their drugability. SUMMARY OF THE INVENTION [0017] The present invention provides tricyclic compounds, including prodrugs thereof, which are useful as inhibitors of Btk, and are useful for the treatment of proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases. [0018] The present invention also provides pharmaceutical compositions comprising at least one compound of Formula (IIa) and a pharmaceutically acceptable carrier. [0019] The present invention also provides a method of inhibiting Btk activity comprising administering to a mammal in need thereof at least one compound of Formula (IIa). [0020] 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 compound of Formula (IIa). [0021] 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 compound of Formula (IIa). [0022] 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 compound of Formula (IIa). [0023] The present invention also provides processes and intermediates for making the compounds of Formula (I). [0024] The present invention also provides a compound of Formula (IIa) for use in therapy. [0025] The present invention also provides the use of the compounds of Formula (IIa) 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. [0026] The present invention also provides the use of the compounds of Formula (IIa) for the manufacture of a medicament for treatment of cancer. [0027] The compounds of Formula (IIa) and compositions comprising the compounds of Formula (IIa) 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. [0028] These and other features of the invention will be set forth in expanded form as the disclosure continues. |
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