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 alkylane 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 compound of Formula (I-1-1): 
       
         
           
           
               
               
           
         
       
       wherein the stereochemistry of an asymmetric carbon represented by * is in the R-configuration or S-configuration, or is a mixture thereof;
 R X  is hydrogen; 
 R 14  is hydrogen; 
 R 3  is hydrogen; 
 R 1  is hydrogen; 
 each R is independently a halogen; 
 m is an integer of 0 to 3; 
 ring A is an unsubstituted bicyclic ring residue having a chemical formula C 6 H 9 NO; and 
 the carbon represented by * is directly bonded to an oxygen. 
 
     
     
         58 . The compound of  claim 57 , wherein ring A includes two carbon-nitrogen single bonds, two carbon-oxygen single bonds, five carbon-carbon single bonds, and nine carbon-hydrogen single bonds. 
     
     
         59 . The method according to  claim 58 , wherein one of the rings of the unsubstituted bicyclic ring of ring A is 
       
         
           
           
               
               
           
         
       
       wherein Z is oxygen. 
     
     
         60 . The compound of  claim 59 , wherein each R is fluorine. 
     
     
         61 . The compound of  claim 60 , wherein m is 2 or 3. 
     
     
         62 . The compound of  claim 61 , wherein a fluorine is at the para position and a fluorine is at the orthe position. 
     
     
         63 . The compound of  claim 62  wherein the compound has a diastereomeric purity of greater than 10:1. 
     
     
         64 . The compound of  claim 62 , wherein the asymmetric carbon represented by * is in the R-configuration. 
     
     
         65 . The compound of  claim 62 , wherein the compound has an enantiomeric excess of greater than 95%. 
     
     
         66 . A pharmaceutical composition comprising the compound of  claim 57  or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent. 
     
     
         67 . A pharmaceutical composition comprising the compound of  claim 59  or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent.