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.

1 - 58 . (canceled) 
     
     
         59 . A composition comprising a compound selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         and a pharmaceutically acceptable carrier; 
         wherein:
 m is 1 or 2; 
 n is 1 or 2; 
 Y is N or CR 1 ; 
 Z is N or CR 4 ; and 
 R 1 , R 2 , and R 4  are each independently selected from the group consisting of H, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, C 1 -C 6  alkylamino, C 1 -C 6  alkylsulfonyl, C 1 -C 6  alkylthio, carboxamide, cyano, C 3 -C 7  cycloalkoxy, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkoxy, C 1 -C 6  haloalkyl, halogen, heteroaryl and heterocyclyl, wherein said C 1 -C 6  alkyl and C 1 -C 6  alkoxy are each optionally substituted with one or two substituents selected from C 3 -C 7  cycloalkyl and halogen; and 
 R 3  is C 3 -C 7  cycloalkyl. 
 
       
     
     
         60 . The composition according to  claim 59 , wherein n is 1. 
     
     
         61 . The composition according to  claim 59 , wherein Y is CR 1 . 
     
     
         62 . The composition according to  claim 61 , wherein R 1  is H or C 1 -C 6  haloalkyl. 
     
     
         63 . The composition according to  claim 61 , wherein R 1  is H or trifluoromethyl. 
     
     
         64 . The composition according to  claim 59 , wherein R 2  is selected from the group consisting of H, cyano, C 1 -C 6  haloalkoxy and C 1 -C 6  haloalkyl. 
     
     
         65 . The composition according to  claim 59 , wherein R 2  is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl. 
     
     
         66 . The composition according to  claim 59 , wherein R 3  is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl. 
     
     
         67 . The composition according to  claim 59 , wherein Z is CR 4 . 
     
     
         68 . The composition according to  claim 67 , wherein R 4  is selected from the group consisting of H, cyano, C 1 -C 6  haloalkoxy and C 1 -C 6  haloalkyl. 
     
     
         69 . The composition according to  claim 67 , wherein R 4  is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl. 
     
     
         70 . The composition according to  claim 59 , the compound selected from compounds of Formula (Im) and pharmaceutically acceptable salts, solvates and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl; and 
         R 3  is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl. 
       
     
     
         71 . The composition according to  claim 59 , wherein the compound is 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)acetic acid (Compound 2);   (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 3);   (S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 9);   2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 12);   2-(7-(3-cyano-4-cyclohexylbenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3yl)acetic acid (Compound 17);   2-(7-((6-cyclopentyl-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 19);   2-(7-(4-cyclobutyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 21); and   2-(7-(4-cyclopropyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 22).   
     
     
         72 . The composition according to  claim 59 , wherein the compound is:
 (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.   
     
     
         73 . The composition according to  claim 59 , wherein the compound is:
 L-Arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.   
     
     
         74 . The composition according to  claim 59 , wherein the composition is suitable for oral administration. 
     
     
         75 . The composition according to  claim 59 , wherein the pharmaceutically acceptable carrier comprises a diluent. 
     
     
         76 . The composition according to  claim 59 , wherein the pharmaceutically acceptable carrier comprises a lubricant. 
     
     
         77 . A process for the preparation of a compound of the formula 
       
         
           
           
               
               
           
         
         wherein
 Y is N or CR 1 ; 
 Z is N or CR 4 ; and 
 R 1 , R 2 , and R 4  are each independently selected from the group consisting of H, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, C 1 -C 6  alkylamino, C 1 -C 6  alkylsulfonyl, C 1 -C 6  alkylthio, carboxamide, cyano, C 3 -C 7  cycloalkoxy, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkoxy, C 1 -C 6  haloalkyl, halogen, heteroaryl and heterocyclyl, wherein said C 1 -C 6  alkyl and C 1 -C 6  alkoxy are each optionally substituted with one or two substituents selected from C 3 -C 7  cycloalkyl and halogen; 
 R 3  is C 3 -C 7  cycloalkyl; and 
 R 5  is ethyl; 
 the process comprising coupling of a compound of the formula 
 
       
       
         
           
           
               
               
           
         
         
           wherein X is Br or Cl, 
           with a compound of the formula 
         
       
       
         
           
           
               
               
           
         
         
           to give a compound of the formula 
         
       
       
         
           
           
               
               
           
         
       
     
     
         78 . A compound of the formula 
       
         
           
           
               
               
           
         
         wherein 
         Y is N or CR 1 ; 
         Z is N or CR 4 ; and 
         R 1 , R 2 , and R 4  are each independently selected from the group consisting of H, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, C 1 -C 6  alkylamino, C 1 -C 6  alkylsulfonyl, C 1 -C 6  alkylthio, carboxamide, cyano, C 3 -C 7  cycloalkoxy, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkoxy, C 1 -C 6  haloalkyl, halogen, heteroaryl and heterocyclyl, wherein said C 1 -C 6  alkyl and C 1 -C 6  alkoxy are each optionally substituted with one or two substituents selected from C 3 -C 7  cycloalkyl and halogen; 
         R 3  is C 3 -C 7  cycloalkyl; and 
         R 5  is ethyl.