2,3-dihydroisoindole-1-carboxamides useful as ror-gamma modulators

Abstract

The present specification provides a compound of formula (I):or a pharmaceutically acceptable salt thereof; a process for preparing such a compound; and to the use of such a compound in the treatment of an RORγ and/or RORγt mediated disease state.

1 - 15 . (canceled) 
     
     
         16 . A method of treating a disease state in a human suffering from said disease state, which comprises administering to the human in need of such treatment a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, (CO)R 4  or (CO)NH—C 1-6  alkyl; 
         R 2  is C 1-6  alkyl or CH 2 -cyclopropyl; 
         R 3  is C 1-6  alkyl, C 1-6  alkoxy, CN, heterocycloalkyl, heteroaryl, NR 5 R 6 , CH 2 (CO)—O—C 1-6  alkyl, CH 2 (CO)NR 7 R 8 , wherein said C 1-6  alkyl is further optionally substituted with one substituent selected from OH, halo, CN, heteroaryl, or NH(CO)Me, and wherein each heteroaryl is further optionally substituted with one methyl group; 
         R 4  is:
 H; 
 C 1-6  alkyl optionally substituted with one substituent selected from OH, C 1-6  alkoxy, COOH or NH 2 ; 
 C 3-7  cycloalkyl optionally substituted with C 1-6  alkoxy; or 
 C 1-6  alkoxy; 
 
         R 5  is H or C 1-6  alkyl; 
         R 6  is C 1-6  alkyl or heterocycloalkyl, wherein said C 1-6  alkyl is further optionally substituted with one substituent selected from OH, C 1-6  alkoxy, C 3-7  cycloalkyl (itself optionally substituted by C 1-6  alkoxy) or SO 2 Me; 
         R 7  is H or C 1-6  alkyl; 
         R 8  is C 3-7  cycloalkyl or C 1-6  alkyl wherein said C 1-6  alkyl is further optionally substituted with halo; or 
         R 7  and R 8  together with the nitrogen atom to which they are both attached form a heterocycloalkyl (itself optionally substituted with one or two substituents selected from C 1-6  alkyl or halo); 
         or a pharmaceutically acceptable salt thereof, 
         wherein the disease state is selected from ulcerative colitis, Crohn's disease, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, graft versus host disease, systemic lupus erythematosus and lupus nephritis. 
       
     
     
         17 . The method of treating according to  claim 16 , wherein
 R 1  is (CO)R 4  or (CO)NH—C 1-6  alkyl;   R 2  is C 1-6  alkyl or CH 2 -cyclopropyl;   R 3  is C 1-6  alkoxy, CN or heterocycloalkyl; and   R 4  is:
 C 1-6  alkyl optionally substituted with OH; or 
 C 1-6  alkoxy. 
   
     
     
         18 . The method of treating according to  claim 16 , wherein R 1  is (CO)R 4 . 
     
     
         19 . The method of treating according to  claim 16 , wherein R 4  is unsubstituted C 1-6  alkyl. 
     
     
         20 . The method of treating according to  claim 16 , wherein R 2  is unsubstituted C 1-6  alkyl. 
     
     
         21 . The method of treating according to  claim 16 , wherein R 3  is CN. 
     
     
         22 . The method of treating according to  claim 16 , wherein the compound is selected from:
 N-[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(2-cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   N-[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-2-[(1-methoxycyclopropyl)carbonyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   N 1 -[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-N 2 -methyl-5-(methylsulfonyl)-1,3-dihydro-2H-isoindole-1,2-dicarboxamide;   N-[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-2-(hydroxyacetyl)-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   N-[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-2-formyl-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   Methyl 1-{[4-(2-cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]carbamoyl}-5-(methylsulfonyl)-1,3-dihydro-2H-isoindole-2-carboxylate;   N-[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-2-(methoxyacetyl)-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   4-[1-{[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]carbamoyl}-5-(methylsulfonyl)-1,3-dihydro-2H-isoindol-2-yl]-4-oxobutanoic acid;   N-[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-2-glycyl-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-(3-Aminopropanoyl)-N-[4-[1-cyano-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl]-5-methylsulfonyl-isoindoline-1-carboxamide;   N-[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-5-[(cyclopropylmethyl)sulfonyl]-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(2-cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-5-[(cyclopropylmethyl)sulfonyl]-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(2-cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-5-(ethylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(pyrrolidin-1-yl)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(propylamino)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-(4-{1,1,1,3,3,3-hexafluoro-2-[(2-methoxyethyl)amino]propan-2-yl}phenyl)-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-{[(1-methoxycyclopropyl)methyl]amino}propan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(oxetan-3-ylamino)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(tetrahydro-2H-pyran-4-ylamino)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-(4-{1,1,1,3,3,3-hexafluoro-2-[(2-hydroxyethyl)amino]propan-2-yl}phenyl)-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-{[3-(methylsulfonyl)propyl]amino}propan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(morpholin-4-yl)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(methylamino)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[2-(dimethylamino)-1,1,1,3,3,3-hexafluoropropan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-{[2-(methylsulfonyl)ethyl]amino}propan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-{[2-(propan-2-yloxy)ethyl]amino}propan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-methoxypropan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(1H-1,2,3-triazol-1-yl)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(2-methyl-2H-tetrazol-5-yl)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   Methyl 4,4,4-trifluoro-3-[4-[(5-methylsulfonylisoindoline-1-carbonyl)amino]phenyl]-3-(trifluoromethyl)butanoate;   Methyl 3-[4-({[2-acetyl-5-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-yl]carbonyl}amino)phenyl]-4,4,4-trifluoro-3-(trifluoromethyl)butanoate;   2-Acetyl-5-(methylsulfonyl)-N-{4-[1,1,1-trifluoro-4-hydroxy-2-(trifluoromethyl)butan-2-yl]phenyl}-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-(4-{1,1,1,3,3,3-hexafluoro-2-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]propan-2-yl}phenyl)-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-5-(methylsulfonyl)-N-{4-[1,1,1,4-tetrafluoro-2-(trifluoromethyl)butan-2-yl]phenyl}-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[2-(cyanomethyl)-1,1,1,3,3,3-hexafluoropropan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   Ethyl 3-[4-({[2-acetyl-5-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-yl]carbonyl}amino)phenyl]-4,4,4-trifluoro-3-(trifluoromethyl)butanoate;   2-Acetyl-N-{4-[4-(cyclopropylamino)-1,1,1-trifluoro-4-oxo-2-(trifluoromethyl)butan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-5-(methylsulfonyl)-N-{4-[1,1,1-trifluoro-4-(3-fluoro-3-methylazetidin-1-yl)-4-oxo-2-(trifluoromethyl)butan-2-yl]phenyl}-2,3-dihydro-1H-isoindole-1-carboxamide;   Propan-2-yl 3-[4-({[2-acetyl-5-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-yl]carbonyl}amino)phenyl]-4,4,4-trifluoro-3-(trifluoromethyl)butanoate;   2-Acetyl-5-(methylsulfonyl)-N-(4-{1,1,1-trifluoro-4-[(2-fluoroethyl)amino]-4-oxo-2-(trifluoromethyl)butan-2-yl}phenyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[4-(dimethylamino)-1,1,1-trifluoro-4-oxo-2-(trifluoromethyl)butan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[4-(tert-butylamino)-1,1,1-trifluoro-4-oxo-2-(trifluoromethyl)butan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   tert-Butyl 3-[4-({[2-acetyl-5-(methylsulfonyl)-2,3-dihydro-1H-isoindol-1-yl]carbonyl}amino)phenyl]-4,4,4-trifluoro-3-(trifluoromethyl)butanoate; and   2-Acetyl-N-{4-[4-(acetylamino)-1,1,1-trifluoro-2-(trifluoromethyl)butan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide
 or a pharmaceutically acceptable salt thereof. 
   
     
     
         23 . The method of treating according to  claim 16 , wherein the compound is selected from:
 2-Acetyl-N-[4-(2-cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   N 1 -[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-N 2 -methyl-5-(methylsulfonyl)-1,3-dihydro-2H-isoindole-1,2-dicarboxamide;   N-[4-(2-Cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-2-(hydroxyacetyl)-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   Methyl 1-{[4-(2-cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]carbamoyl}-5-(methylsulfonyl)-1,3-dihydro-2H-isoindole-2-carboxylate;   2-Acetyl-N-[4-(2-cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-5-[(cyclopropylmethyl)sulfonyl]-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-[4-(2-cyano-1,1,1,3,3,3-hexafluoropropan-2-yl)phenyl]-5-(ethylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;   2-Acetyl-N-{4-[1,1,1,3,3,3-hexafluoro-2-(pyrrolidin-1-yl)propan-2-yl]phenyl}-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide; and   2-Acetyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-methoxypropan-2-yl)phenyl]-5-(methylsulfonyl)-2,3-dihydro-1H-isoindole-1-carboxamide;
 or a pharmaceutically acceptable salt thereof. 
   
     
     
         24 . The method of treating according to  claim 16 , wherein the disease state is ulcerative colitis. 
     
     
         25 . The method of treating according to  claim 16 , wherein the disease state is Crohn's disease. 
     
     
         26 . The method of treating according to  claim 16 , wherein the disease state is multiple sclerosis. 
     
     
         27 . The method of treating according to  claim 16 , wherein the disease state is inflammatory bowel disease. 
     
     
         28 . The method of treating according to  claim 16 , wherein the disease state is rheumatoid arthritis. 
     
     
         29 . The method of treating according to  claim 16 , wherein the disease state is graft versus host disease. 
     
     
         30 . The method of treating according to  claim 16 , wherein the disease state is systemic lupus erythematosus. 
     
     
         31 . The method of treating according to  claim 16 , wherein the disease state is lupus nephritis.