Claims for Patent: 8,580,841

Summary for Patent: 8,580,841

Title:	Substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders
Abstract:	The present invention relates to certain substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives of Formula (Ia): and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1 receptor-associated disorders, for example, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, acne, microbial infections or diseases and viral infections or diseases.
Inventor(s):	Robert M Jones, Daniel J Buzard, Sangdon Han, Sun Hee Kim, Juerg Lehmann, Brett Ullman, Jeanne V Moody, Xiuwen Zhu, Scott Stirn
Assignee:	Arena Pharmaceuticals Inc
Application Number:	US13/055,333
Patent Claims:	1. A compound selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof: wherein: m is 1; n is 1 or 2; Y is N or CR1; Z is N or CR4; R1, R2, and R4 are each independently selected from the group consisting of H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylsulfonyl, C1-C6 alkylthio, carboxamide, cyano, C3-C7 cycloalkoxy, C3-C7 cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, halogen, heteroaryl and heterocyclyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one or two substituents selected from C3-C7 cycloalkyl and halogen; and R3 is C3-C7 cycloalkyl. 2. The compound according to claim 1, wherein n is 1. 3. The compound according to claim 1, wherein n is 2. 4. The compound according to claim 1, wherein Y is N. 5. The compound according to claim 1, wherein Y is CR1. 6. The compound according to claim 5, wherein R1 is H or C1-C6 haloalkyl. 7. The compound according to claim 5, wherein R1 is H or trifluoromethyl. 8. The compound according to claim 1, wherein R2 is selected from the group consisting of H, cyano, C1-C6 haloalkoxy and C1-C6 haloalkyl. 9. The compound according to claim 1, wherein R2 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl. 10. The compound according to claim 1, wherein R3 is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl. 11. The compound according to claim 1, wherein Z is N. 12. The compound according to claim 1, wherein Z is CR4. 13. The compound according to claim 12, wherein R4 is selected from the group consisting of H, cyano, C1-C6 haloalkoxy and C1-C6 haloalkyl. 14. The compound according to claim 12, wherein R4 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl. 15. The compound according to claim 1, wherein R1, R2, and R4 are each independently selected from the group consisting of H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkylsulfonyl, C1-C6 alkylthio, carboxamide, cyano, C3-C7 cycloalkoxy, C3-C7 cycloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, halogen, heteroaryl and heterocyclyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each optionally substituted with one C3-C7 cycloalkyl group. 16. The compound according to claim 15, wherein R3 is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl. 17. The compound according to claim 15, wherein R4 is selected from the group consisting of H, cyano and C1-C6 haloalkyl. 18. The compound according to claim 15, wherein R4 is selected from the group consisting of H, cyano and trifluoromethyl. 19. The compound according to claim 1, selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof: wherein: Y is N or CR1; Z is N or CR4; R1 is H or C1-C6 haloalkyl; R2 is selected from the group consisting of H, cyano, C1-C6 haloalkoxy and C1-C6 haloalkyl; R3 is C3-C7 cycloalkyl; and R4 is selected from the group consisting of H, cyano, C1-C6 haloalkoxy and C1-C6 haloalkyl. 20. The compound according to claim 1, selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof: wherein: Y is N or CR1; Z is N or CR4; R1 is H or C1-C6 haloalkyl; R2 is selected from the group consisting of H, cyano, C1-C6 haloalkoxy and C1-C6 haloalkyl; R3 is C3-C7 cycloalkyl; and R4 is selected from the group consisting of H, cyano and C1-C6 haloalkyl. 21. The compound according to claim 1, selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof: wherein: Y is N or CR1; Z is N or CR4; R1 is H or trifluoromethyl; R2 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl; R3 is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl; and R4 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl. 22. The compound according to claim 1, selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof: wherein: Y is N or CR1; Z is N or CR4; R1 is H or trifluoromethyl; R2 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl; R3 is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl; and R4 is selected from the group consisting of H, cyano and trifluoromethyl. 23. The compound according to claim 1, selected from compounds of Formula (Im) and pharmaceutically acceptable salts, solvates and hydrates thereof: wherein: R2 is selected from the group consisting of H, cyano, C1-C6 haloalkoxy and C1-C6 haloalkyl; and R3 is selected from the group consisting of C3-C7 cycloalkyl. 24. The compound according to claim 1, selected from compounds of Formula (Im) and pharmaceutically acceptable salts, solvates and hydrates thereof: wherein: R2 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl; and R3 is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl. 25. The compound according to claim 1, selected from the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclohexyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)pacetic acid; (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; (S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-(7-(4-cyclopentyl-3-(trifluoromethyebenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl) acetic acid; 2-(7-(3-cyano-4-cyclohexylbenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3yl)acetic acid; 2-(7-((6-cyclopentyl-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; 2-(7-(4-cyclobutyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and 2-(7-(4-cyclopropyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 26. The compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclohexyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 27. The compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 28. The compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: (S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 29. The compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(3-cyano-4-cyclohexylbenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 30. The compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-((6-cyclopentyl-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 31. A salt according to claim 1 selected from the following salt and pharmaceutically acceptable solvates and hydrates thereof: Calcium salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 32. A salt according to claim 1 selected from the following salt and pharmaceutically acceptable solvates and hydrates thereof: L-Arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 33. A hydrate according to claim 1 selected from the following hydrate: D-Lysine salt of (S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid hydrate. 34. A solvate according to claim 1 selected from the following solvate: (R)-1-Phenethylamine salt of (S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid acetonitrile solvate. 35. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 36. The compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 37. The compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclobutyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 38. The compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclopropyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid. 39. A pharmaceutical composition comprising a compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclohexyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and a pharmaceutically acceptable carrier. 40. A pharmaceutical composition comprising a compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and a pharmaceutically acceptable carrier. 41. A pharmaceutical composition comprising a compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: (S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and a pharmaceutically acceptable carrier. 42. A pharmaceutical composition comprising a compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(3-cyano-4-cyclohexylbenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and a pharmaceutically acceptable carrier. 43. A pharmaceutical composition comprising a compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-((6-cyclopentyl-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and a pharmaceutically acceptable carrier. 44. A pharmaceutical composition comprising a salt according to claim 1, selected from the following salt and pharmaceutically acceptable solvates and hydrates thereof: Calcium salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and a pharmaceutically acceptable carrier. 45. A pharmaceutical composition comprising a salt according to claim 1, selected from the following salt and pharmaceutically acceptable solvates and hydrates thereof: L-Arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and a pharmaceutically acceptable carrier. 46. A pharmaceutical composition comprising a hydrate according to claim 1, selected from the following hydrate: D-Lysine salt of (S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid hydrate and a pharmaceutically acceptable carrier. 47. A pharmaceutical composition comprising a solvate according to claim 1 selected from the following solvate: (R)-1-Phenethylamine salt of (S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid acetonitrile solvate and a pharmaceutically acceptable carrier. 48. A pharmaceutical composition comprising a compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and a pharmaceutically acceptable carrier. 49. A pharmaceutical composition comprising a compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclobutyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and a pharmaceutically acceptable carrier. 50. A pharmaceutical composition comprising a compound according to claim 1, selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof: 2-(7-(4-cyclopropyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and a pharmaceutically acceptable carrier. 51. A pharmaceutical composition comprising a compound according to claim 1, selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof: wherein: Y is N or CR1; Z is N or CR4; R1 is H or C1-C6 haloalkyl; R2 is selected from the group consisting of H, cyano, C1-C6 haloalkoxy and C1-C6 haloalkyl; R3 is C3-C7 cycloalkyl; and R4 is selected from the group consisting of H, cyano, C1-C6 haloalkoxy and C1-C6 haloalkyl; and a pharmaceutically acceptable carrier.