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 compound of Formula (XXVI): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen or lower alkyl; 
         R 2  is optionally substituted phenyl; 
         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; 
         X is lower alkylene; 
         n is 1, 2 or 3; 
         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; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         58 . The compound according to  claim 57 , or pharmaceutically acceptable salt thereof, wherein 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. 
     
     
         59 . The compound according to  claim 58 , or a pharmaceutically acceptable salt thereof, wherein n is 1. 
     
     
         60 . The compound according to  claim 58 , or a pharmaceutically acceptable salt thereof, wherein n is 2. 
     
     
         61 . The compound according to  claim 58 , or a pharmaceutically acceptable salt thereof, wherein n is 3. 
     
     
         62 . The compound according to  claim 57 , or a pharmaceutically acceptable salt thereof, wherein
 a combination of (R 15  and R 6 ), (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.   
     
     
         63 . The compound according to  claim 62 , or a pharmaceutically acceptable salt thereof, wherein n is 1. 
     
     
         64 . The compound according to  claim 62 , or a pharmaceutically acceptable salt thereof, wherein n is 2. 
     
     
         65 . The compound according to  claim 62 , or a pharmaceutically acceptable salt thereof, wherein n is 3. 
     
     
         66 . A pharmaceutical composition comprising the compound according to  claim 57 , or a pharmaceutically acceptable salt thereof. 
     
     
         67 . The pharmaceutical composition according to  claim 66 , wherein said composition comprises at least one additional therapeutic agent selected from reverse transcriptase inhibitors and protease inhibitors. 
     
     
         68 . A process for the preparation of the compound according to  claim 57 , or a pharmaceutically acceptable salt thereof, comprising the step of deprotecting a compound of formula (XXV): 
       
         
           
           
               
               
           
         
         Wherein P 1  is a hydroxyl protecting group, to form the compound of Formula (XXVI) according to claim  1 , or a pharmaceutically acceptable salt thereof. 
       
     
     
         69 . A process for the preparation of the compound according to  claim 57 , 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):