Substituted tricyclic acid derivatives as s1p1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders

Abstract

The present invention relates to certain substituted tricyclic acid derivatives of Formula (I) 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-associated disorders, for example, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, acne, myocardial ischemia-reperfusion injury, hypertensive nephropathy, glomerulosclerosis, gastritis, polymyositis, thyroiditis, vitiligo, hepatitis, biliary cirrhosis, microbial infections and associated diseases, viral infections and associated diseases, diseases and disorders mediated by lymphocytes, auto immune diseases, inflammatory diseases, and cancer.

1 . A compound selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 m is 1 or 2; 
 n is 1 or 2; 
 Y is N or CR 1 ; 
 Z is N or CR 4 ; 
 W is N or CR 5 ; 
 R a  is H or C 1 -C 6  alkyl; 
 R 1 , R 2 , R 3 , 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 C 3 -C 7  cycloalkyl group; and 
 R 5  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  alkylsulfonyl, cyano, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkyl, halogen, heteroaryl, and heterocyclyl. 
 
       
     
     
         2 - 22 . (canceled) 
     
     
         23 . The compound according to  claim 1 , selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 m is 1 or 2; 
 n is 1 or 2; 
 Y is N or CR 1 ; 
 Z is N or CR 4 ; 
 W is N or CR 5 ; 
 R 1  is H; 
 R 2  is selected from the group consisting of cyano, C 1 -C 6  haloalkoxy, and C 1 -C 6  haloalkyl; 
 R 3  is selected from the group consisting of H, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, and C 3 -C 7  cycloalkyl; 
 R 4  is H or cyano; and 
 R 5  is selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, and halogen. 
 
       
     
     
         24 . The compound according to  claim 1 , selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 m is 1 or 2; 
 n is 1 or 2; 
 Y is N or CR 1 ; 
 Z is N or CR 4 ; 
 W is N or CR 5 ; 
 R 1  is H; 
 R 2  is selected from the group consisting of cyano, trifluoromethoxy, and trifluoromethyl; 
 R 3  is selected from the group consisting of H, cyclohexyl, cyclopentyl, isobutyl, and isopropoxy; 
 R 4  is H or cyano; and 
 R 5  is selected from the group consisting of H, bromo, chloro, cyclobutyl, cyclopropyl, fluoro, iodo, and methyl. 
 
       
     
     
         25 . The compound according to  claim 1 , selected from compounds of Formula (Ij) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 m is 1 or 2; 
 R 1  is H or C 1 -C 6  haloalkyl; 
 
         R 2  is selected from the group consisting of H, C 1 -C 6  alkoxy, cyano, C 1 -C 6  haloalkoxy, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkyl, and halogen; 
         R 3  is selected from the group consisting of H, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, C 1 -C 6  alkylsulfonyl, carboxamide, cyano, C 3 -C 7  cycloalkoxy, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkoxy, and halogen, wherein said C 1 -C 6  alkyl and C 1 -C 6  alkoxy are each optionally substituted with one C 3 -C 7  cycloalkyl group; 
         R 4  is selected from the group consisting of H, cyano, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy; and 
         R 5  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  alkylsulfonyl, C 3 -C 7  cycloalkyl, halogen, and heteroaryl. 
       
     
     
         26 . The compound according to  claim 1 , selected from compounds of Formula (Ij) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 m is 1 or 2; 
 R 1  is H or trifluoromethyl; 
 R 2  is selected from the group consisting of H, chloro, cyano, ethoxy, trifluoromethoxy, and trifluoromethyl; 
 R 3  is selected from the group consisting of H, chloro, carboxamide, cyano, cyclohexyl, cyclohexylmethyl, cyclopentyloxy, cyclopentyl, cyclopropylmethoxy, 1,3-difluoropropan-2-yloxy, ethoxy, fluoromethoxy, isobutyl, isopropoxy, methoxy, and methylsulfonyl; 
 R 4  is selected from the group consisting of H, cyano, trifluoromethoxy, and trifluoromethyl; and 
 R 5  is selected from the group consisting of H, bromo, chloro, cyclobutyl, cyclopropyl, ethyl, fluoro, iodo, methyl, methylsulfonyl, and pyridin-2-yl. 
 
       
     
     
         27 . The compound according to  claim 1 , selected from compounds of Formula (Im) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 2  is selected from the group consisting of cyano, C 1 -C 6  haloalkoxy, and C 1 -C 6  haloalkyl; 
 R 3  is selected from the group consisting of H, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, and C 3 -C 7  cycloalkyl; and 
 R 5  is selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, and halogen. 
 
       
     
     
         28 . The compound according to  claim 1 , selected from compounds of Formula (Im) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 2  is selected from the group consisting of cyano, trifluoromethoxy, and trifluoromethyl; 
 R 3  is selected from the group consisting of H, cyclohexyl, cyclopentyl, isobutyl, and isopropoxy; and 
 R 5  is selected from the group consisting of H, bromo, chloro, cyclobutyl, cyclopropyl, fluoro, iodo, and methyl. 
 
       
     
     
         29 . The compound according to  claim 1 , selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-chloro-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-bromo-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-chloro-7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-cyclobutyl-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid; and   2-(6-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetic acid.   
     
     
         30 . The compound according to  claim 1 , selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-carbamoyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-(cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-(methylsulfonyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(2,4-bis(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-(1H-pyrazol-1-yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-(cyclopentyloxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-chloro-7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-chloro-7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-chloro-7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-methoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-cyano-4-cyclopentylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3,4-diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-chloro-7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(9-chloro-7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;   2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid;   2-(2-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid;   2-(2-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid;   2-(2-(3,4-diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid;   2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid; and   2-(2-(3-cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid.   
     
     
         31 . The compound according to  claim 1 , wherein the stereochemistry for the C(1) ring carbon of said compound is R. 
     
     
         32 . The compound according to  claim 1 , wherein the stereochemistry for the C(1) ring carbon of said compound is S. 
     
     
         33 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         34 . A method for treating an S1P1 receptor-associated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         35 . A method for treating an S1P1 receptor-associated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 , wherein said disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, hypertensive nephropathy, glomerulosclerosis, myocardial ischemia-reperfusion injury, and acne. 
     
     
         36 . A method for treating a disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 , wherein said disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, and acne. 
     
     
         37 . A method for treating a disease or disorder mediated by lymphocytes in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         38 . A method for treating an autoimmune disease or disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         39 . A method for treating an inflammatory disease or disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         40 . A method for treating a microbial or viral infection or disease in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         41 - 55 . (canceled) 
     
     
         56 . A process for preparing a composition comprising admixing a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         57 . A method of inducing lymphopenia in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         58 . A method for treating an S1P1 receptor-associated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound of  claim 1 , wherein said disorder is selected from the group consisting of diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders, cancer, conditions that have an underlying defect in vascular integrity, conditions that are associated with angiogenesis, acute or chronic rejection of cells, tissue or solid organ grafts, arthritis, psoriatic arthritis, rheumatoid arthritis, diabetes, type I diabetes, demyelinating disease, multiple sclerosis, ischemia-reperfusion injury, renal ischemia-reperfusion injury, cardiac ischemia-reperfusion injury, inflammatory skin disease, psoriasis, atopic dermatitis, acne, hyperproliferative skin disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, asthma, uveitis, myocarditis, allergy, atherosclerosis, brain inflammation, Alzheimer's disease, brain inflammatory reaction following traumatic brain injury, central nervous system disease, spinal cord injury, cerebral infarction, pathologic angiogenesis, diabetic retinopathy, atherosclerosis, chronic pulmonary disease, acute lung injury, acute respiratory disease syndrome, and sepsis.