Pyridylpyridone compounds

Abstract

The invention provides novel pyridylpyridone 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 disease, autoimmune diseases, neurodegenerative disorders, cardiovascular disorders and viral infections;wherein R1, R2, R3 and X are as defined in the specification.

1 - 44 . (canceled) 
     
     
         45 . A process for preparing a compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is C═O or a bond; 
 R 1  is selected from the group consisting of H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cyclohaloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 6 cycloalkoxymethyl, N—C 1 -C 3 alkylamino, N,N-diC 1 -C 3 alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl, provided that when R 1  is C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, N—C 1 -C 3 alkylamino N,N-diC 1 -C 3 alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 1-azetidinyl, then X is C═O; 
 R 2  is selected from the group consisting of hydrogen, C 1 -C 3 haloalkyl and C 1 -C 3 alkyl; 
 R 3  is selected from the group consisting of A, phenyl and monocyclic heteroaryl, said phenyl and said heteroaryl being optionally substituted with one or more of R 4 , R 5 , R 6  and R 7 ; 
 R 4 , R 5 , R 6  and R 7  are independently selected from halo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 3 haloalkoxy, N,N-diC 1 -C 3 alkylamino, N—C 1 -C 3 alkylamino, 1-azetidinyl, C 1 -C 6 haloalkyl, amino, NHSO 2 R 8 , SO 2 R 9  and hydroxy; 
 R 8  is C 1 -C 3 haloalkyl or C 1 -C 3 alkyl; 
 R 9  is selected from the group consisting of R 10 , 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 10  and/or one or more halo; 
 R 10  is selected from the group consisting of phenyl, monocyclic heteroaryl, C 3 -C 6 cycloalkyl, heterocyclyl, each optionally substituted with one or more R 11 ; 
 R 11  is selected from the group consisting of halo, C 1 -C 3 alkoxyC 1 -C 3 alkyl, amino, N—C 1 -C 3 alkylamino, N,N-diC 1 -C 3 alkylamino, C 1 -C 3 haloalkoxy, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 3 haloalkyl and C 1 -C 3 alkyl; 
 A represents 
 
       
         
           
           
               
               
           
         
         R 12  is selected from the group consisting of hydrogen, halo, COR 13 , C 1 -C 6 alkyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 3 cyanoalkyl, C 1 -C 3 haloalkyl; 
         R 13  is selected from the group consisting of C 1 -C 3 alkoxy, N—C 1 -C 3 alkylamino, N,N-diC 1 -C 3 alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl; 
         Y represents CH 2 , S, SO, SO 2 , NR 14 , NCOR 9 , NCOOR 15 , NSO 2 R 9 , NCOCH 2 R 9 , O, or a bond; 
         R 14  is selected from the group consisting of H, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl; and 
         R 15  is selected from the group consisting of R 10 , C 1 -C 6 alkyl 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 10  and/or one or more halo; 
         or a pharmaceutically acceptable salt thereof; 
       
       the process comprising:
 (i) providing a compound represented by Formula (III): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 3 , and X are defined as above for the compound of formula (I); and 
 R X  is selected from the group consisting of F, OCH 3 , OC(CH 3 ) 3 , and OSiR′R″R′″; and 
 R′, R″, and R′″ are each independently aryl or alkyl; and 
 (ii) converting the compound represented by Formula (II) into the compound represented by Formula (I). 
 
     
     
         46 . The process of  claim 45 , wherein R 2  is hydrogen or C 1 -C 3 alkyl;
 or a pharmaceutically acceptable salt thereof.   
     
     
         47 . The process of  claim 45 , wherein R 1  is selected from the group consisting of H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, N,N-diC 1 -C 3 alkylamino, 1-pyrrolidinyl and C 3 -C 6 cycloalkyl;
 or a pharmaceutically acceptable salt thereof.   
     
     
         48 . The process of  claim 45 , wherein R 1  is selected from the group consisting of H, methyl, methoxy, methoxymethyl, N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl. 
     
     
         49 . The process of  claim 45 , wherein R 1  is selected from the group consisting of H, methyl, methoxymethyl, N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl. 
     
     
         50 . The process of  claim 45 , wherein R 3  is selected from the group consisting of A, phenyl and monocyclic heteroaryl selected from pyridyl, thienyl, furyl, pyrimidinyl and pyrazolyl, wherein said phenyl and said heteroaryl are optionally substituted with R 4  and/or R 5 . 
     
     
         51 . The process of  claim 45 , wherein R 4 , R 5 , R 6  and R 7  are independently selected from fluoro, chloro, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 fluoroalkyl and SO 2 R 9 . 
     
     
         52 . The process of  claim 45 , wherein R 12  is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 haloalkyl and C 3 -C 6 cycloalkyl. 
     
     
         53 . The process of  claim 45 , wherein R 9  is selected from the group consisting of R 10 , 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 10 . 
     
     
         54 . The process of  claim 45 , wherein R 10  is selected from the group consisting of phenyl, pyridyl, imidazolyl, isoxazolyl, oxazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, each optionally substituted with one or more methyl and/or fluoro. 
     
     
         55 . The process of  claim 45 , wherein R 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         56 . The process of  claim 45 , wherein R 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein Y is selected from the group consisting of CH 2 , O and a bond; 
         R 4  is selected from the group consisting of CF 3 , chloro, cyclopropyl and methyl; 
         R 5  is fluoro; and 
         R 12  is selected from the group consisting of hydrogen, cyclopropyl, methyl, 1-methoxy-1-methyl-ethyl and CF 3 . 
       
     
     
         57 . The process of  claim 45 , wherein
 R 1  is selected from the group consisting of H, methyl, methoxy, methoxymethyl, N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl;   R 2  is hydrogen; and   R 3  is selected from the group consisting of   
       
         
           
           
               
               
           
         
       
     
     
         58 . The process of  claim 45 , wherein
 R 1  is selected from the group consisting of H, methyl, methoxy, methoxymethyl, N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl;   R 2  is hydrogen; and   R 3  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
     
     
         59 . The process of  claim 45 , wherein the compound is selected from the group consisting of:
 N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide;   4-(2-Amino-4-pyridyl)-6-(3-pyridyl)-1H-pyridin-2-one;   4-(2-Amino-4-pyridyl)-6-(2-chlorophenyl)-1H-pyridin-2-one;   N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-2-methoxy-acetamide;   N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide;   N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]cyclopropanecarboxamide;   N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]acetamide;   methyl N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate;   methyl N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate;   methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate;   methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate;   N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide;   N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide;   N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide;   N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide;   methyl N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]carbamate;   methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate;   N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide;   N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide;   N-[4-[2-(2-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide;   N-[4-[2-oxo-6-[4-(trifluoromethyl)-3-thienyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide;   1,1-Dimethyl-3-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]urea;   N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]pyrrolidine-1-carboxamide;   N-[4-[2-[2-(1-methoxy-1-methyl-ethyl)pyrrolidin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide;   and pharmaceutically acceptable salts thereof.   
     
     
         60 . The process of  claim 45 , wherein:
 (a) when R x  is F, converting the compound of Formula (II) comprises carrying out acidic hydrolysis of the compound of Formula (II);   (b) when R x  is OCH 3 , converting the compound of Formula (II) comprises reacting the compound of Formula (II) with trimethylsilyl iodide in a suitable solvent, reacting the compound of Formula (II) with HBr in a suitable solvent, reacting the compound of Formula (II) with BBr 3  in a suitable solvent;   (c) when R x  is OC(CH 3 ) 3 , converting the compound of Formula (II) comprises reacting the compound of Formula (II) with trifluoroacetic acid in a suitable solvent; and   (d) when R x  is OSiR′R″R′″, converting the compound of Formula (II) comprises reacting the compound of Formula (II) with HCl in a suitable solvent or by reacting the compound of Formula (II) with tetrabutyl ammonium fluoride in tetrahydrofuran.   
     
     
         61 . The process of  claim 45 , wherein wherein each of R′, R″, and R′″ is independently selected from the group consisting of phenyl, methyl, and tert-butyl.