Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity

Abstract

A compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and a pharmaceutical composition, particularly an anti-HIV agent, of the formula: wherein R 1 , R 2 , R 3 , R 4 , B 1 and B 2 are defined in the specification.

1 . (canceled) 
     
     
         2 . A compound of the formula: 
       
         
           
           
               
               
           
         
         (wherein, 
         G ring is optionally substituted heterocycle 
         R 1  is hydrogen or lower alkyl;
 X is a single bond, a heteroatom group selected from the group consisting of O, S, SO, SO 2  and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; 
 R 2  is optionally substituted aryl; 
 R 3  is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino, 
 R 14  is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from the group consisting of O, S, SO, SO 2 , NR 5  (R 5  is independently selected from the same substitution group as R 4 ), —N═ and ═N—), hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl), 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 - 10 . (canceled) 
     
     
         11 . A compound of the formula: 
       
         
           
           
               
               
           
         
         (wherein, 
         R 1  is hydrogen or lower alkyl;
 X is a single bond, a heteroatom group selected from the group consisting of O, S, SO, SO 2  and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; 
 R 2  is optionally substituted aryl; 
 R 3  is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino, 
 C ring is optionally substituted heterocycle or optionally substituted carbocycle; 
 B 1  and B 2  are independently C, CR 23  or N; 
 R 23  is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl), 
 the broken line represents the presence or absence of a bond; 
 R 4  is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from the group consisting of CO, O, S, SO, SO 2 , NR a  (R a  is hydrogen or lower alkyl), —N═ and ═N—)); 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . A compound of the formula: 
       
         
           
           
               
               
           
         
         (wherein, 
         R 1  is hydrogen or lower alkyl;
 X is a single bond, a heteroatom group selected from the group consisting of O, S, SO, SO 2  and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; 
 R 2  is optionally substituted aryl; 
 R 3  is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino, 
 H ring is optionally substituted heterocycle; 
 R 24  is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted aryl carbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, substituted thiourea or substituted sulfonyl), 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 - 18 . (canceled)