SUBSTITUTED CYCLOPENTA[4,5]OXAZOLO[3,2-a]PYRIDO[1,2-d]PYRAZINES AS HIV INTEGRASE INHIBITORS

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 compound of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         the stereochemistry of an asymmetric carbon represented by * shows R- or S-configuration, or a mixture thereof; 
         R 14  and R X  are independently hydrogen or lower alkyl which is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxy, carboxy, halogen, halo lower alkyl, halo lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, lower alkoxy, lower alkenyloxy, lower alkoxycarbonyl, nitro, nitroso, amino, alkylamino, acylamino, aralkylamino, aryl, aralkyl, cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, carbamoyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxal, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, azido, ureido, guanidino, phthalimide, oxo, phosphoric acid, lower alkyl which is substituted with phosphoric acid and may be intervened with a heteroatom, aryl substituted with phosphoric acid, aralkyl substituted with phosphoric acid, and hydroxy lower alkyl; 
         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 heterocyclyl, optionally substituted heterocyclyloxy or optionally substituted amino, wherein the optional substituents are 1 to 4 substituents selected from the group consisting of hydroxy, carboxy, halogen, halo lower alkyl, halo lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, lower alkoxy, lower alkenyloxy, lower alkoxycarbonyl, nitro, nitroso, amino, alkylamino, acylamino, aralkylamino, aryl, aralkyl, cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, carbamoyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxal, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, azido, ureido, guanidino, phthalimide, oxo, phosphoric acid, lower alkyl which is substituted with phosphoric acid and may be intervened with a heteroatom, aryl substituted with phosphoric acid, aralkyl substituted with phosphoric acid, and hydroxy lower alkyl; 
         R 1  is hydrogen or lower alkyl; 
         R is halogen; 
         m is 0, 1, 2 or 3; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         58 . The compound according to  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R X  and R 14  are independently hydrogen. 
     
     
         59 . The compound according to  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 3  is hydrogen. 
     
     
         60 . The compound according to  claim 57 , or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2. 
     
     
         61 . The compound according to  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R X  is hydrogen; R 14  is hydrogen; and R 3  is hydrogen. 
     
     
         62 . A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, according to  claim 57 , and a pharmaceutically acceptable carrier or diluent.