Heterocyclic compounds having inhibitory activity against HIV integrase

Abstract

A heterocyclic compound of the formula (I): wherein B 1 is —C(R 2 )═ or —N═; R 1 ′ is H, etc.; one of R 1 and R 2 is -Z 1 -Z 2 -Z 3 -R 5 wherein Z 1 and Z 3 are independently single bond, optionally substituted alkylene, etc.; Z 2 is single bond, optionally substituted alkylene, etc.; R 1 is optionally substituted aryl, optionally substituted heteroaryl, etc., and the other of R 1 and R 2 is H; -A 1 - is —C(—Y)═C(—R A )—C(—R 3 )═C(—R 4 )—, etc. wherein Y is OH, etc.; R A is —COR 7 wherein R 7 is OH, etc.; one of R 3 and R 4 is carboxy, etc., and the other of R 1 and R 2 is H, etc, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a solvate thereof, having an antiviral activity, more particularly, an inhibitory activity against HIV integrase, and a pharmaceutical composition containing the same, especially an anti-HIV drug.

1 - 41 . (canceled)  
     
     
         42 . A compound represented by the general formula (IV-2):  
       
         
           
           
               
               
           
         
       
       , a pharmaceutically acceptable salt or a solvate thereof;  
       wherein,  
       one of R 1  and R 2  is a group of the formula: -Z 1 -Z 2 -Z 3 -R 5  wherein 
 Z 1  and Z 3  each are independently a single bond, optionally substituted alkylene or optionally substituted alkenylene;  
 Z 2  is a single bond, optionally substituted alkylene, optionally substituted alkenylene, —CH(OH)—, —S—, —SO—, —SO 2 —, —SO 2 N(R 6 )—, —N(R 6 )SO 2 —, —O—, —N(R 6 )—, —N(R 6 )CO—, —CON(R 6 )—, —C(═O)—O—, —O—C(═O)— or —CO—;  
 R 6  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted heteroaryl; and  
 R 5  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle, and  
 the other of R 1  and R 2  is hydrogen or a substituent selected from Substituent Group A;  
 X is oxygen or sulfur;  
 Y is —OH, —SH or —NH 2 ;  
 R A  is —C(=Z)R 7  wherein Z is oxygen or sulfur; and R 7  is a substituent selected from Substituent Group A, 
 —NHOH,  
 —N═NR 10  wherein R 10  is hydrogen, alkyl, acyl, aralkyl, aryl or heteroaryl,  
 —NHSO 2 R 12  wherein R 12  is alkyl, aryl, aralkyl, hydroxy or amino,  
 —PO(OH) 2 ,  
 —PO(OH)(R 13 ) wherein R 13  is alkyl, aryl or aralkyl, or  
 a group of the formula:  
                     
 
 wherein Ring C is a nitrogen-containing heteroaromatic ring group optionally substituted by one to four of substituents selected from a group consisting of Substituent Group A and a substituent represented by the formula: -Z 1 -Z 2 -Z 3 -R 5  wherein Z 1 , Z 2 , Z 3  and R 5  are as defined above;  
 R 3  and R 4  each is independently a substituent selected from Substituent Group A or hydrogen;  
 Substituent Group A is a group consisting of halogen, optionally substituted alkoxycarbonyl, carboxy, optionally substituted alkyl, optionally substituted alkoxy, alkoxyalkyl, nitro, hydroxy, hydroxyalkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkylsulfonyl, alkyloxysulfonyl, optionally substituted amino, optionally substituted aminosulfonyl, alkylthio, alkylthioalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, cycloalkyl, cycloalkenyl, oxo, thioxo, alkylenedioxy, alkylene, alkenylene, nitroso, azido, amidino, guanidine, cyano, isocyano, mercapto, optionally substituted carbamoyl, optionally substituted carbamoylalkyl, optionally substituted sulfamoyl, sulfoamino, sulfo, formyl, alkylcarbonyl, alkylcarbonyloxy, hydrazino, morpholino, phosphono, phosphinico, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycleoxy, optionally substituted arylthio, optionally substituted heteroarylthio, optionally substituted aralkyloxy, optionally substituted heteroaralkyloxy, optionally substituted aralkylthio, optionally substituted heteroaralkylthio, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted aralkylsulfonyl, optionally substituted heteroaralkylsulfonyl, optionally substituted alkylcarbonyl alkyl, optionally substituted arylcarbonyl alkyl, alkylsulfonyloxy, sulfamoyloxy and optionally substituted arylcarbonyl.  
 
     
     
         43 . A compound of  claim 42 , a pharmaceutically acceptable salt or a solvate thereof; 
 wherein,    R 1  is a group of the formula: -Z 1 -Z 2 -Z 3 -R 5  wherein 
 Z 1  and Z 3  each are independently a single bond, optionally substituted alkylene or optionally substituted alkenylene;  
 Z 2  is a single bond, optionally substituted alkylene, optionally substituted alkenylene, —CH(OH)—, —S—, —SO—, —SO 2 —, —SO 2 N(R 6 )—, —N(R 6 )SO 2 —, —O—, —N(R 6 )—, —N(R 6 )CO—, —CON(R 6 )—, —C(═O)—O—, —O—C(═O)— or —CO—;  
 R 6  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted heteroaryl; and  
 R 5  is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle, and  
   R 2  is hydrogen;    X is oxygen;    Y is —OH;    R A  is —C(=Z)R 7  wherein Z is oxygen; R 7  is optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted amino,    R 4  is hydrogen or lower alkyl.    
     
     
         44 . A compound of  claim 42 , a pharmaceutically acceptable salt or a solvate thereof; 
 wherein,    R 1  is a group of the formula: -Z 1 -Z 2 -Z 3 -R 5  wherein    Z 1  and Z 3  each is a single bond;    Z 2  is alkylene;    R 5  is optionally substituted aryl;    R 2  is hydrogen;    X is oxygen;    Y is —OH;    R A  is —C(=Z)R 7  wherein Z is oxygen; R 7  is optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted amino,    R 4  is hydrogen or lower alkyl.    
     
     
         45 . A compound of  claim 42 , a pharmaceutically acceptable salt or a solvate thereof; 
 wherein,    R 1  is a group of the formula: -Z-Z 2 -Z 3 -R 5  wherein    Z 1  and Z 3  each is a single bond;    Z 2  is alkylene;    R 5  is aryl optionally substituted with halogen;    R 2  is hydrogen;    X is oxygen;    Y is —OH;    R A  is —C(=Z)R 7  wherein Z is oxygen; R 7  is optionally substituted amino,    R 4  is hydrogen or lower alkyl.