Disubstituted Octahydropyrrolo[3,4-C]Pyrroles As Orexin Receptor Modulators

Abstract

Disubstituted octahydropyrrolo[3,4-c]pyrrole compounds are described, which are useful as orexin receptor modulators. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.

What is claimed is: 
     
         1 . A chemical entity that is a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is phenyl substituted or unsubstituted with one R a  and R b  in the ortho position;
 R a  is halo, C 1-4 alkyl, or C 1-4 alkoxy, 
 R b  is triazole or pyrimidine substituted or unsubstituted with halo or C 1-4 alkyl, 
 
 R 2  is a 6-membered heteroaryl ring containing two nitrogen members substituted with one or more member selected from the group consisting of halo, C 1-4 alkyl, CD 3 , D, C 1-4 alkoxy, cyclopropyl, morpholin-2-yl, CO 2 C 1-4 alkyl, CO 2 H, CH 2 OH, C(O)N(C 1-4 alkyl) 2 , CF 3 , CN, OH, NO 2 , N(C 1-4 alkyl) 2 , phenyl, furan-2-yl, thiophen-2-yl, 1H-pyrazol-4-yl, and pyrrolidin-1-yl, 
 or a pharmaceutically acceptable salt of a compound of Formula (I). 
 
     
     
         2 . The chemical entity of  claim 1 , wherein R 1  is (1-methylethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl, 2-(1H-1,2,3-triazol-1-yl)phenyl, 2-(2H-1,2,3-triazol-2-yl)phenyl, 2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl, 2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl, 3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl, 3-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl, 3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl, 3-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl, 3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl, 3-methyl-2-(1H-1,2,3-triazol-1-yl)phenyl, 4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl, 4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl, 4-methoxy-2-(1H-1,2,3-triazol-2-yl)phenyl, 4,5-dimethoxy-2-[1,2,3]triazol-1-yl-phenyl, 4,5-dimethoxy-2-[2,3]triazol-2-yl-phenyl, 5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl, 5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl, 5-iodo-2-(2H-1,2,3-triazol-2-yl)phenyl, 5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl, 5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl, 2-(1H-1,2,4-triazol-1-yl)phenyl, 2-(1H-1,2,4-triazol-5-yl)phenyl, 2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl, 2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl, 2-(4H-1,2,4-triazol-3-yl)phenyl, 2-(4H-1,2,4-triazol-4-yl)phenyl, or 4,5-difluoro-2-(4H-1,2,4-triazol-4-yl)phenyl). 
     
     
         3 . The chemical entity of  claim 1 , wherein R 2  is pyrimidine substituted with one or more —Cl, —F, —CH 3 , —CF 3 , —N(CH 3 ) 2 , -D, or —CD 3 . 
     
     
         4 . The chemical entity of  claim 1 , wherein R 2  is 4,6-dimethylpyrimidin-2-yl, 4,5-dimethylpyrimidin-2-yl, 4,6-dimethoxypyrimidin-2-yl, 4-phenyl-pyrimidin-2-yl, 4-furan-2-ylpyrimidin-2-yl, 4-methylpyrimidin-2-yl, 4-methoxypyrimidin-2-yl, 4-thiophen-2-ylpyrimidin-2-yl, N,N,6-trimethyl-pyrimidin-4-amine, 4-(trifluoromethyl)pyrimidin-2-yl, 4,5,6-trimethylpyrimidin-2-yl, 4-(trifluoromethyl)pyrimidine-5-carboxylate, 4-(trifluoromethyl)pyrimidine-5-carboxylic acid, 5-nitro-pyrimidin-2-yl, 6-methylpyrimidine-4-carboxylic acid, N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamide, N,N,6-trimethylpyrimidine-carboxamide, 6-methylpyrimidine-4-carbonitrile, 4,6-bis(trifluoromethyl)pyrimidin-2-yl, 6-methyl-pyrimidin-4-ol, 4-(furan-2-yl)-6-methylpyrimidin-2-yl, 5-fluoro-4-methylpyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 4-methoxy-6-methylpyrimidin-2-yl, 4-ethyl-6-methylpyrimidin-2-yl, 4-isopropyl-6-methylpyrimidin-2-yl, 4-tertbutyl-6-methylpyrimidin-2-yl, 4-cyclopropyl-6-methylpyrimidin-2-yl, 4-methyl-6-morpholin-4-ylpyrimidin-2-yl, 5-chloro-4-methylpyrimidin-2-yl, 5-chloro-4,6-dimethylpyrimidin-2-yl, 5-fluoro-4,6-dimethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 4,6-bis[( 2 H3)methyl]( 2 H)pyrimidin-2-yl, or 5-ethyl-4,6-dimethylpyrimidin-2-yl. 
     
     
         5 . The chemical entity of  claim 1 , wherein R 2  is 4,6-dimethylpyrimidin-2-yl, 4,5-dimethylpyrimidin-2-yl, 4,6-dimethoxypyrimidin-2-yl, 4-methylpyrimidin-2-yl, 4-methoxypyrimidin-2-yl, N,N,6-trimethyl-pyrimidin-4-amine, 4-(trifluoromethyl)pyrimidin-2-yl, 4,5,6-trimethylpyrimidin-2-yl, 4,6-bis(trifluoromethyl)pyrimidin-2-yl, 6-methyl-pyrimidin-4-ol, 5-fluoro-4-methylpyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 4-methoxy-6-methylpyrimidin-2-yl, 5-chloro-4-methylpyrimidin-2-yl, 5-chloro-4,6-dimethylpyrimidin-2-yl, 5-fluoro-4,6-dimethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, or 4,6-bis[( 2 H3)methyl]( 2 H)pyrimidin-2-yl. 
     
     
         6 . A pharmaceutical composition for treating a disease, disorder or medical condition mediated by orexin activity comprising:
 (a) an effective amount of at least one chemical entity of Formula (I):   
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is phenyl substituted or unsubstituted with one R a  and R b  in the ortho position;
 R a  is halo, C 1-4 alkyl, or C 1-4 alkoxy, 
 R b  is triazole or pyrimidine substituted or unsubstituted with halo or C 1-4 alkyl, 
 
 R 2  is a 6-membered heteroaryl ring containing two nitrogen members substituted with one or more member selected from the group consisting of halo, C 1-4 alkyl, CD 3 , D, C 1-4 alkoxy, cyclopropyl, morpholin-2-yl, CO 2 C 1-4 alkyl, CO 2 H, CH 2 OH, C(O)N(C 1-4 alkyl) 2 , CF 3 , CN, OH, NO 2 , N(C 1-4 alkyl) 2 , phenyl, furan-2-yl, thiophen-2-yl, 1H-pyrazol-4-yl, and pyrrolidin-1-yl, 
 or a pharmaceutically acceptable salt of a compound of Formula (I); and 
 (b) at least one pharmaceutically acceptable excipient. 
 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said chemical entity is [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrol[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]-triazol-2-yl-phenyl)methanone or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The pharmaceutical composition of  claim 6 , wherein said chemical entity is the HCl salt of [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrol[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]-triazol-2-yl-phenyl)methanone. 
     
     
         9 . The pharmaceutical composition of  claim 6 , wherein said chemical entity is [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrol[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]-triazol-2-yl-phenyl)methanone. 
     
     
         10 . The pharmaceutical composition of  claim 6 , wherein said chemical entity is 2-(4,6-dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The pharmaceutical composition of  claim 6 , wherein said chemical entity is 2-(4,6-dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole. 
     
     
         12 . A method of treating a disease, disorder or medical condition mediated by orexin activity, comprising administering to a patient in need thereof at least one chemical entity of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is phenyl substituted or unsubstituted with one R a  and R b  in the ortho position;
 R a  is halo, C 1-4 alkyl, or C 1-4 alkoxy, 
 R b  is triazole or pyrimidine substituted or unsubstituted with halo or C 1-4 alkyl, 
 
 R 2  is a 6-membered heteroaryl ring containing two nitrogen members substituted with one or more member selected from the group consisting of halo, C 1-4 alkyl, CD 3 , D, C 1-4 alkoxy, cyclopropyl, morpholin-2-yl, CO 2 C 1-4 alkyl, CO 2 H, CH 2 OH, C(O)N(C 1-4 alkyl) 2 , CF 3 , CN, OH, NO 2 , N(C 1-4 alkyl) 2 , phenyl, furan-2-yl, thiophen-2-yl, 1H-pyrazol-4-yl, and pyrrolidin-1-yl, 
 or a pharmaceutically acceptable salt of a compound of Formula (I), and at least one pharmaceutically acceptable excipient. 
 
     
     
         13 . The method of  claim 12 , wherein said disease, disorder, or medical condition is a sleep-wake transition disorder, insomnia, restless legs syndrome, jet-lag, disturbed sleep, or a sleep disorder secondary to neurological disorders. 
     
     
         14 . The method of  claim 13 , wherein said disease, disorder, or medical condition is insomnia. 
     
     
         15 . The method of  claim 13 , wherein said disease, disorder, or medical condition is a sleep disorder secondary to depression. 
     
     
         16 . The method of  claim 13 , wherein said disease, disorder, or medical condition is a sleep disorder secondary to dementia. 
     
     
         17 . The method of  claim 13 , wherein said disease, disorder, or medical condition is a sleep disorder secondary to Alzheimer's disease. 
     
     
         18 . The method of  claim 12 , wherein said chemical entity is [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrol[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]-triazol-2-yl-phenyl)methanone or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 12 , wherein said chemical entity is the HCl salt of [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrol[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]-triazol-2-yl-phenyl)methanone. 
     
     
         20 . The method of  claim 12 , wherein said chemical entity is [5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrol[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]-triazol-2-yl-phenyl)methanone. 
     
     
         21 . The method of  claim 12 , wherein said chemical entity is 2-(4,6-dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 12 , wherein said chemical entity is 2-(4,6-dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole.