Claims for Patent: 10,695,323

Summary for Patent: 10,695,323

Title:	Compounds useful as kinase inhibitors
Abstract:	This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton's tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton's tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.
Inventor(s):	Nicolas Guisot
Assignee:	Loxo Oncology Inc
Application Number:	US16/063,542
Patent Claims:	1. A compound according to formula (I) or a pharmaceutically acceptable salt thereof, wherein A represents a ring selected from unsubstituted or substituted: phenyl, pyridine, pyridazine, pyrimidine, or pyrazine, wherein when substituted, A is substituted with from 1 to 4 R7; R1 represents a group selected from: C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, C2-8 alkyl ether, —C(O)RA, C3-10 carbocyclic group, 3 to 10 membered heterocyclic group, C1-8 alkyl substituted with C3-10 carbocyclic group, or C1-8 alkyl substituted with 3 to 10 membered heterocyclic group, wherein each of the aforementioned groups are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of: halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C2-4 alkyl ether, —ORA, —NRARB, —CN, ═O, —OC(O)RA, —C(O)RA, —C(O)ORA, —NRAC(O)RB, —C(O)NRARB, —NRAS(O)2RB, —S(O)2NRARB, benzoyl, a 5 or 6 membered heterocycloaryl, a 3 to 6 membered heterocycloalkyl ring, C1-4 alkyl substituted with —ORA, and C1-4 alkoxy substituted with —ORA, or a single atom of R1 is substituted twice so as to form a 3 to 6 membered heterocycloalkyl or cycloalkyl ring; R2 represents a group selected from: —OH, halo, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 3 to 10 membered heterocyclic group, alkyl substituted with —ORC, C1-8 alkyl substituted with C3-10 carbocyclic group, alkyl substituted with 3 to 10 membered heterocyclic group, or —NRGRD; R3 represents —C(O)NRERF, C1-6 alkyl substituted with —ORG, or C1-6 haloalkyl; R4a and R4b are independently at each occurrence selected from the group consisting of: H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, and C1-6 alkyl substituted with —ORH; R5 is H or C1-4 alkyl; R6 is a group selected from a substituted or unsubstituted: phenyl or a 5 or 6 membered heteroaryl ring, wherein, when substituted, R6 contains from 1 to 5 substituents independently selected at each occurrence from the group consisting of: halo, —OR′, —CN, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkyl substituted with —OR′; R7 is selected from the group consisting of: H, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 alkyl substituted with —ORH; m is 1 or 2; RA and RB are, at each occurrence, independently selected from the group consisting of: H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, phenyl, benzyl, and C1-4 alkyl substituted with —ORH; RC, R1, RE and RF are, at each occurrence, independently selected from the group consisting of: H, C1-4 alkyl, C1-4 haloalkyl, unsubstituted C3-10 carbocyclic group, C1-4 alkyl substituted with unsubstituted C3-10 carbocyclic group, C1-4 alkyl substituted with C3-10 carbocyclic group substituted with 1 or 2 RH or —ORH, and 3 to 10 membered heterocyclic group; RG, RI, and RJ are independently at each occurrence selected from the group consisting of: H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 alkyl substituted with —ORH; and RH is selected from H or C1-4 alkyl. 2. The compound of claim 1, wherein A is selected from the group consisting of: unsubstituted phenyl, unsubstituted pyridine, phenyl substituted by from 1 to 4 R7, and pyridine substituted by from 1 to 4 R7. 3. The compound of claim 1, wherein A is selected from the group consisting of: 4. The compound of claim 1, wherein R6 is a group selected from a substituted: phenyl or 6 membered heteroaryl ring, optionally wherein R6 is substituted with 1 or 2 groups independently selected from: methyl, fluoro, or methoxy. 5. The compound of claim 1, wherein R6 is 2-methoxyphen-1-yl or 5-fluoro-2-methoxyphen-1-yl. 6. The compound of claim 1, wherein R5 is H. 7. The compound of claim 1, wherein R4a and R4b are independently selected at each occurrence from the group consisting of: H, methyl, ethyl, cyclopropyl, and —CH2OH. 8. The compound of claim 7, wherein R4a and R4b are H. 9. The compound of claim 1, wherein m is 1. 10. The compound of claim 1, wherein m is 1, R4a and R4b are H, R5 is H, R6 is methoxyphenyl or methoxyfluorophenyl, and A is unsubstituted phenyl or phenyl substituted by one or two R7, wherein when A is substituted R7 is selected from: fluoro, methyl, methoxy, or —CH2OH. 11. The compound of claim 1, wherein R2 represents a group selected from: halo, C1-8 alkyl, C1-8 haloalkyl, or —NRCRD, wherein RC and RD are, at each occurrence, independently selected from the group consisting of: H and C1-4 alkyl. 12. The compound of claim 1, wherein R3 represents —C(O)NH2, —C(O)NHMe, —CH2OH, CH(OH)CH3, —CF3, or —CHF2. 13. The compound of claim 1, wherein the compound is a compound according to formulae (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf): or a pharmaceutically acceptable salt thereof, wherein RC and RD are, at each occurrence, independently selected from the group consisting of: H, C1-4 alkyl, C1-4 haloalkyl, unsubstituted C3-10 carbocyclic group, and 3 to 10 membered heterocyclic group; and RE and RF are, at each occurrence, independently selected from the group consisting of: H, C1-4 alkyl, C1-4 haloalkyl, unsubstituted C3-10 carbocyclic group and, 3 to 10 membered heterocyclic group. 14. The compound of claim 13, wherein RC, RD, RE and RF are H. 15. The compound of claim 1, wherein R1 represents a group selected from: C1-6 alkyl, C1-6 haloalkyl, C2-6 alkyl ether, —C(O)RA, C3-10 cycloalkyl, C6-10 aryl, 3 to 10 membered heterocycloalkyl, 3 to 10 membered heteroaryl, C1-6 alkyl substituted with C3-10 cycloalkyl, C1-6 alkyl substituted with C6-10 aryl, C1-6 alkyl substituted with 3 to 10 membered heterocycloalkyl, or C1-6 alkyl substituted with 3 to 10 membered heteroaryl, wherein each of the aforementioned groups are unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of: halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C2-4 alkyl ether, —ORA, —CN, ═O, —C(O)ORA, —C(O)NRARB, 5 or 6 membered heteroaryl, a 3 to 6 membered heterocycloalkyl ring, C1-4 alkyl substituted with —ORA, and C1-4 alkoxy substituted with —ORA, or a single atom of R1 is substituted twice so as to form a 3 to 6 membered heterocycloalkyl or cycloalkyl ring. 16. The compound of claim 1, wherein RA is selected from: H, C1-4 alkyl, C1-4 haloalkyl, benzyl, or C1-4 alkyl substituted with —ORH. 17. The compound of claim 1, wherein R1 is selected from substituted or unsubstituted: methyl, ethyl, iso-propyl, tert-hexyl, tert-butyl, trifluoroethyl, propyl ether, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, C1-8 alkyl substituted with oxetane, C1-8 alkyl substituted with morpholine, C1-8 alkyl substituted with tetrazole, C1-8 alkyl substituted with piperidine, or C1-8 alkyl substituted with cyclohexyl, wherein R1 is substituted with 1 to 5 substituents selected from the group consisting of: —OH, ═O, —OMe, —CN, methyl, CF3, Cl, F, —OBn, and —CO2Et. 18. The compound of claim 1, wherein the compound is a compound of formula (X): or a pharmaceutically acceptable salt thereof, wherein R1A is selected from C1-2 alkyl or C1-2 haloalkyl and R1B is selected from unsubstituted C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyl substituted with OH, C1-4 alkyl substituted with OMe, 5 or 6 membered heteroaryl, 3 to 6 membered heterocycloalkyl ring, phenyl, or C3-10 carbocyclic group; provided that when R1A is C1-2 alkyl then R1B is not unsubstituted C1-4 alkyl. 19. The compound of claim 18, wherein R1A is selected from methyl, difluoromethyl or trifluoromethyl, and R1B is selected from methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluorethyl, —CH2OH, —CH2CH2OH, —CH2OMe, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; provided that when R1A is not methyl then R1B is not methyl, ethyl, or propyl. 20. The compound of claim 19, wherein R1A is trifluoromethyl. 21. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of claim 1, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients. 23. The pharmaceutical composition of claim 22, wherein the composition is a combination product and comprises an additional pharmaceutically active agent. 24. A method of treatment of a condition which is modulated by BTK, wherein the method comprises administering a therapeutic amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 25. The method of claim 24 wherein the condition modulated by BTK is selected from the group consisting of: lymphoma, leukemia, autoimmune diseases, an inflammatory disorder, a heteroimmune condition, and fibrosis. 26. A method of treating a condition selected from the group consisting of: lymphoma, leukemia, an autoimmune disease, an inflammatory disorder, a heteroimmune condition, and fibrosis, wherein the method comprises administering a therapeutic amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 27. The method of claim 26, wherein the condition is selected from the group consisting of: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjögren's syndrome, and a disorder associated with renal transplant. 28. A method of treatment of a condition selected from the group consisting of: lymphoma, leukemia, an autoimmune disease, an inflammatory disorder, a heteroimmune condition, and fibrosis comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, simultaneously, sequentially or separately with an additional anti-tumour agent to a patient in need thereof. 29. A method of claim 28, wherein the condition is selected from the group consisting of: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjögren's syndrome, and a disorder associated with renal transplant. 30. A method of treating a condition selected from the group consisting of: lymphoma, leukemia, an autoimmune disease, an inflammatory disorder, a heteroimmune condition, and fibrosis, wherein the method comprises administering a therapeutic amount of a compound of a formula below: or a mixture thereof, or a pharmaceutically acceptable salt of the compounds thereof, to a patient in need thereof. 31. The method of claim 30 wherein the compound is: or a pharmaceutically acceptable salt thereof. 32. the method of claim 31 wherein the compound is: 33. The method of claim 31 wherein the condition is selected from the group consisting of: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjögren's syndrome, and a disorder associated with renal transplant. 34. The method of claim 32 wherein the condition is selected from the group consisting of: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, Sjögren's syndrome, and a disorder associated with renal transplant. 35. The method of claim 34 wherein the condition is selected from the group consisting of: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma, and mantle cell lymphoma.