Morpholinylpyridone compounds

Abstract

The invention provides novel morpholinylpyridone compounds of formula (I), pharmaceutical compositions containing such compounds, and methods for using such compounds in treatment of diseases including cancer, type II diabetes, inflammatory diseases, autoimmune diseases, neurodegenerative disorders, cardiovascular disorders and viral infections; wherein R 1 , R 2 and A are as defined in the specification.

1 - 44 . (canceled) 
     
     
         45 . A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound represented by formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 R 1  is C 1 -C 3 alkyl or cyclopropyl; 
 R 2  is selected from hydrogen, C 1 -C 3 haloalkyl and C 1 -C 3 alkyl; 
 A is 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 3  is selected from R 6 , C 1 -C 6 alkyl, amino, N—C 1 -C 3 alkylamino, N,N-diC 1 -C 3 alkylamino and C 1 -C 3 alkoxyC 1 -C 3 alkyl, said C 1 -C 6 alkyl and said C 1 -C 3 alkoxyC 1 -C 3 alkyl being optionally substituted with one R 6  and/or one or more halo; 
 R 4  is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl and phenyl, said phenyl being optionally and independently substituted with one or more of fluoro, chloro, methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl, and cyclopropyl; 
 R 5  is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 3 -C 6 cycloalkyl; 
 R 6  is selected from phenyl, monocyclic heteroaryl, C 3 -C 6 cycloalkyl, and heterocyclyl, each optionally substituted with one or more R 7 ; and 
 R 7  is selected from halogen, amino, N—C 1 -C 3 alkylamino, N,N-diC 1 -C 3 alkylamino, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 6 cycloalkyl, C 1 -C 3 haloalkyl and C 1 -C 3 alkyl. 
 
     
     
         46 . The method of  claim 45 , wherein the cancer is selected from the group consisting of breast cancer, such as triple negative breast cancer, bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, renal cancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanoma, and lung cancer. 
     
     
         47 . The method of  claim 45 , further comprising administering to the patient radiation therapy. 
     
     
         48 . The method of  claim 45 , wherein R 2  is selected from hydrogen and C 1 -C 3 alkyl, or a pharmaceutically acceptable salt thereof. 
     
     
         49 . The method of  claim 45 , wherein R 7  is selected from fluoro, cyclopropyl and methyl, or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The method of  claim 45 , wherein
 R 4  is selected from methyl, trifluoromethyl, cyclopropyl and phenyl, said phenyl being optionally meta-substituted with one of fluoro, chloro, methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl and cyclopropyl; and   R 5  is selected from chloro, cyclopropyl, methyl and trifluoromethyl, or a pharmaceutically acceptable salt thereof.   
     
     
         51 . The method of  claim 45 , wherein
 R 4  is selected from methyl, trifluoromethyl and cyclopropyl; and   R 5  is selected from chloro, cyclopropyl, methyl and trifluoromethyl, or a pharmaceutically acceptable salt thereof.   
     
     
         52 . The method of  claim 45 , wherein R 3  is selected from R 6 , C 1 -C 3 alkyl, N,N-diC 1 -C 3 alkylamino and methoxyC 1 -C 3 alkyl, said C 1 -C 3 alkyl being optionally substituted with one R 6 , or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The method of  claim 45 , wherein R 6  is selected from phenyl, pyridyl, morpholinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl and tetrahydrofuryl, each optionally substituted with one or more R 7 , or a pharmaceutically acceptable salt thereof. 
     
     
         54 . The method of  claim 45 , wherein R 6  is selected from phenyl, pyridyl, morpholinyl, imidazolyl, pyrazolyl, cyclopropyl, pyrrolidinyl, piperidinyl, and tetrahydrofuryl, each optionally substituted with one or more R 7 , or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The method of  claim 45 , wherein R 6  is selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method of  claim 45 , wherein R 3  is selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         57 . The method of  claim 45 , wherein
 R 1  is methyl or cyclopropyl;   R 2  is hydrogen;   A is   
       
         
           
           
               
               
           
         
       
       and R 3  is selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The method of  claim 45 , wherein
 R 1  is methyl;   R 2  is hydrogen;   R 4  and R 5  are CF 3 ;   A is   
       
         
           
           
               
               
           
         
       
       and R 3  is selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         59 . The method of  claim 45 , wherein
 R 1  is methyl;   R 2  is hydrogen;   R 4  is CF 3 ;   A is   
       
         
           
           
               
               
           
         
       
       and R 3  is selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         60 . The method of  claim 45 , wherein
 R 1  is methyl or cyclopropyl;   R 2  is hydrogen;   R 4  and R 5  are CF 3 ;   A is   
       
         
           
           
               
               
           
         
       
       and R 3  is selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         61 . The method of  claim 45 , wherein the compound is selected from the group consisting of:
 4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;   6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;   6-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;   4-(3-methylmorpholin-4-yl)-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;   4-(3-methylmorpholin-4-yl)-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;   N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide;   6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;   6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;   4-(3-methylmorpholin-4-yl)-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;   6-[4-Cyclopropylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;   4-(3-methylmorpholin-4-yl)-6-[4-(1-piperidylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;   4-(3-methylmorpholin-4-yl)-6-[4-morpholinosulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;   6-[4-(1,2-Dimethylimidazol-4-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;   6-[4-(1-methylcyclopropyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;   4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; and   N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)benzenesulfonamide,   or a pharmaceutically acceptable salt thereof.