Novel compounds

Abstract

The present invention is directed to novel retinoid-related orphan receptor gamma (RORγ) modulators, processes for their preparation, pharmaceutical compositions containing these modulators, and their use in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORγ.

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is CH 3  or halo; 
         R 2 , R 3  and R 4  are H; 
         R 5  is CH 3  or halo; 
         R 6  is selected from the group consisting of C 3-5  alkyl and —CH 2 —C 3-4  cycloalkyl; 
         R 7  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         R 8  is selected from the group consisting of C 1-3  alkyl, C 1-3  alkoxy, CH 2 CN, CH 2 OH, OH, CN and halo; 
         R 9  is the group —(CHR 10 ) s —(X) t —(CHR 10 ) u —R 11 ; 
         each R 10  is independently selected from the group consisting of H, OH or CH 2 OH; 
         R 11  is —C(O)OH, or a 5 or 6-membered heteroaryl group wherein the 5- or -6 membered heteroaryl group is optionally substituted with one or two substituents selected from halo, NH 2  or CH 3  and the 6 membered heteroayl group contains two, three or four nitrogen atoms as member atoms of the ring; 
         X is CH 2 , NH, O; 
         r is 0, 1 or 2; 
         s is 0, 1 or 2; 
         t is 0 or 1; 
         u is 0, 1 or 2; 
         with the proviso that no more than two R 10  groups represent OH or CH 2 OH. 
       
     
     
         2 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  and R 5  are CH 3 . 
     
     
         3 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  is isobutyl. 
     
     
         4 . The compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 6  is isobutyl. 
     
     
         5 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7  is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein r is 1 and R 8  is CH 2 OH. 
     
     
         7 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  and R5 are CH 3 , R 6  is isobutyl, r is 1 and R 8  is CH 2 OH. 
     
     
         8 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein s is 0. 
     
     
         9 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein t is 1 and X is O. 
     
     
         10 . The compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, wherein each R 10  is H. 
     
     
         16 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  and R 5  are CH 3 , R 6  is isobutyl, r is 1, R 8  is CH 2 OH, wherein t is 1, and X is O. 
     
     
         17 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11  is 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
 4-((1H-imidazol-2-yl)methoxy)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide;   4-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide;   N-(2,4-dimethylphenyl)-N-isobutyl-4-((pyrimidin-4-yloxy)methyl)benzenesulfonamide;   N-(2,4-dimethylphenyl)-N-isobutyl-4-((4-methyl-1H-imidazol-5-yl)methoxy)benzenesulfonamide;   N-(2,4-dimethylphenyl)-N-isobutyl-4-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)benzenesulfonamide;   N-(2,4-dimethylphenyl)-N-isobutyl-4-((1-methyl-1H-imidazol-2-yl)methoxy)benzenesulfonamide;   4-((1H-imidazol-4-yl)methoxy)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide;   N-(2,4-dimethylphenyl)-N-isobutyl-3-((pyrimidin-4-ylmethoxy)methyl)benzenesulfonamide;   N-(2,4-dimethylphenyl)-N-isobutyl-4-(pyrimidin-4-ylmethoxy)benzenesulfonamide;   N-(2,4-dimethylphenyl)-N-isobutyl-4-((1-methyl-1H-imidazol-5-yl)methoxy)benzenesulfonamide;   N-(2,4-dimethylphenyl)-N-isobutyl-4-((1-methyl-1H-1,2,4-triazol-5-yl)methoxy)benzenesulfonamide;   [(4-{[(2,4-dimethylphenyl)(2-methylpropyl)amino]sulfonyl}-2,3-dimethylphenyl)oxy]acetic acid;   3-[(4-{[(4-butyl-2-methylphenyl)(2-methylpropyl)amino]sulfonyl}-2-methylphenyl)oxy]propanoic acid;   4-(4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)butanoic acid;   (R)-3-((4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)-2-methylphenyl)amino)-4-hydroxybutanoic acid;   (S)-2-((4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)amino)-3-hydroxypropanoic acid;   (S)-3-((4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)amino)-4-hydroxybutanoic acid;   N-(2,4-dimethylphenyl)-N-isobutyl-4-(2H-tetrazol-5-yl)benzenesulfonamide;   (R)-3-((4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)amino)-4-hydroxybutanoic acid;   3-(4-(N-isobutyl-N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)phenyl)propanoic acid;   3-(4-(N-isobutyl-N-(2-methyl-5-(trifluoromethyl)phenyl)sulfamoyl)phenyl)-2,2-dimethylpropanoic acid;   5-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)-2-methoxybenzoic acid;   2-((4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)amino)-3-hydroxypropanoic acid;   2-bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)benzoic acid;   2-(4-(N-(4-butyl-2-methylphenyl)-N-isobutylsulfamoyl)-2-methylphenoxy)acetic acid;   4-((2-(dideuterioamino)pyridin-4-yl)methoxy)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide;   N-(2,4-dimethylphenyl)-4-(1-hydroxy-3-(2H-tetrazol-5-yl)propyl)-N-isobutylbenzenesulfonamide;   N-(2,4-dimethylphenyl)-4-(1-hydroxy-2-(2H-tetrazol-5-yl)ethyl)-N-isobutylbenzenesulfonamide;   N-(2,4-dimethylphenyl)-4-(2-hydroxy-1-(2H-tetrazol-5-yl)propan-2-yl)-N-isobutylbenzenesulfonamide;   2-(4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)acetic acid;   4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoic acid;   4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoic acid; and   3-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoic acid.   
     
     
         19 . A pharmaceutical composition comprising a) a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients. 
     
     
         20 . A pharmaceutical composition comprising a) a compound according to  claim 18 , or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable excipients. 
     
     
         21 . A method of treatment of an inflammatory, metabolic or autoimmune disease mediated by RORγ comprising administering a safe and therapeutically effective amount of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of treatment according to  claim 21 , wherein the disease is asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic diseases, such as allergic rhinitis and atopic dermatitis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid arthritis, juvenile Rheumatoid arthritis, Osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Hashimoto's disease, pancreatisis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), Sjorgen's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, Myastehnia Gravis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease or scleritis. 
     
     
         23 . The method of treatment according to  claim 21 , wherein the disease is selected from the group consisting of multiple sclerosis, ankylosing spondylitis, and psoriasis. 
     
     
         24 . The method of treatment according to  claim 21 , wherein the disease is psoriasis.