Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity

Abstract

The present invention is to provide a novel compound (I) shown below, having the anti-virus activity; particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. (wherein Z 1 is NR 4 ; R 1 is hydrogen or lower alkyl; X is a single bond, a hetero atom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene in which the hetero atom group may intervene; R 2 is optionally substituted aryl; R 3 is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R 4 and Z 2 part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.

1 - 56 . (canceled) 
     
     
         57 . A process for the preparation of the compound of Formula (XXVI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, comprising the step of deprotecting a compound of formula (XXV): 
       
       
         
           
           
               
               
           
         
         wherein P 1  is a hydroxyl protecting group, 
         R 1  is hydrogen or lower alkyl; 
         R 2  is optionally substituted phenyl; 
         R 3  is hydrogen; 
         X is lower alkylene; 
         n is 1, 2 or 3; and 
         R 15  to R 18  are each independently hydrogen, C 1 -C 8 alkyl, C 6 -C 14 arylC 1 -C 8 alkyl, C 6 -C 14 aryl, or alkoxy or any combination of (R 15  and R 16 ), (R 17  and R 18 ), or (R 16  and R 18 ), taken together with the neighboring atom(s), form an optionally substituted 5- to 6-membered carbocycle or an optionally substituted 5- to 6-membered heterocycle. 
       
     
     
         58 . A process for the preparation of the compound of formula (XXV), or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of Formula (XVI): 
       
         
           
           
               
               
           
         
         wherein P 1  is a hydroxy protecting group and P 3  is a carboxy protecting group, with an amine of Formula (XXIV): 
       
       
         
           
           
               
               
           
         
         to form a compound of Formula (XXV): 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen or lower alkyl; 
 R 2  is optionally substituted phenyl; 
 R 3  is hydrogen; 
 X is lower alkylene; 
 n is 1, 2 or 3; and 
 R 15  to R 18  are each independently hydrogen, C 1 -C 8 alkyl, C 6 -C 14 arylC 1 -C 8 alkyl, C 6 -C 14 aryl, or alkoxy or any combination of (R 15  and R 16 ), (R 17  and R 18 ), or (R 16  and R 18 ), taken together with the neighboring atom(s), form an optionally substituted 5- to 6-membered carbocycle or an optionally substituted 5- to 6-membered heterocycle.