Claims for Patent: 9,126,932

Summary for Patent: 9,126,932

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):	Jones Robert M., Buzard Daniel J., Han Sangdon, Kim Sun Hee, Lehmann Juerg, Ullman Brett, Moody Jeanne V., Zhu Xiuwen, Stim Scott
Assignee:	Arena Pharmaceuticals, Inc.
Application Number:	US14048768
Patent Claims:	2. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is multiple sclerosis.3. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is psoriasis.4. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is rheumatoid arthritis.5. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is Crohn's disease.6. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is psoriatic arthritis.7. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is systemic lupus erythematosus.8. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is ulcerative colitis.9. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is inflammatory bowel disease.10. The method according to claim 1 , wherein said disorder associated with the S1P1 receptor is biliary cirrhosis.11. The method according to claim 1 , wherein the compound is selected from the following compounds and pharmaceutically acceptable salts claim 1 , solvates and hydrates thereof:2-(7-(4-cyclohexyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic 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-(trifluoromethyl)benzyloxy)-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; and2-(7-(4-cyclopropyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.12. The method according to claim 1 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 1 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.13. The method according to claim 1 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 1 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.14. The method according to claim 1 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 1 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.15. The method according to claim 1 , wherein the compound is 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.16. The method according to claim 1 , wherein the compound is 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.17. The method according to claim 2 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 2 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.18. The method according to claim 2 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 2 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.19. The method according to claim 2 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 2 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.20. The method according to claim 2 , wherein the compound is 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.21. The method according to claim 2 , wherein the compound is 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.22. The method according to claim 10 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 10 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.23. The method according to claim 10 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 10 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.24. The method according to claim 10 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 10 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.25. The method according to claim 10 , wherein the compound is 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.26. The method according to claim 10 , wherein the compound is 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.27. The method according to claim 3 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 3 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.28. The method according to claim 3 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 3 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.29. The method according to claim 3 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 3 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.30. The method according to claim 3 , wherein the compound is 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.31. The method according to claim 3 , wherein the compound is 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.32. The method according to claim 4 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 4 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.33. The method according to claim 4 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 4 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.34. The method according to claim 4 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 4 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.35. The method according to claim 4 , wherein the compound is 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.36. The method according to claim 4 , wherein the compound is 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.37. The method according to claim 5 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 5 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.38. The method according to claim 5 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 5 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.39. The method according to claim 5 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 5 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.40. The method according to claim 5 , wherein the compound is 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.41. The method according to claim 5 , wherein the compound is 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.42. The method according to claim 6 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 6 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.43. The method according to claim 6 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 6 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.44. The method according to claim 6 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 6 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.45. The method according to claim 6 , wherein the compound is 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.46. The method according to claim 6 , wherein the compound is 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.47. The method according to claim 7 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 7 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.48. The method according to claim 7 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 7 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.49. The method according to claim 7 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 7 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.50. The method according to claim 7 , wherein the compound is 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.51. The method according to claim 7 , wherein the compound is 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.52. The method according to claim 8 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 8 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.53. The method according to claim 8 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 8 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.54. The method according to claim 8 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 8 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.55. The method according to claim 8 , wherein the compound is 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.56. The method according to claim 8 , wherein the compound is 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.57. The method according to claim 9 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 9 , solvates and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.58. The method according to claim 9 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 9 , solvates and hydrates thereof:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.59. The method according to claim 9 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts claim 9 , solvates and hydrates thereof:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.60. The method according to claim 9 , wherein the compound is 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.61. The method according to claim 9 , wherein the compound is 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.