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 alkenylrene in which the hetero atom group may intervene; R 2 is optionally substituted aryl; R a is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R 4 and Z 2 part taken together forms a ring, to forma polycyclic compound, including e.g., a tricyclic or tetracyclic compound.

1 . A compound of Formula (I-1), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein,
 A ring is 
 
       
         
           
           
               
               
           
         
       
       ;
 R 41  and R X  are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, lower alkyl substituted with optionally substituted phosphoric acid residue, hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyl; 
 a broken line represents the absence of a bond; 
 R 1  is hydrogen or lower alkyl; 
 X is a single bond, a heteroatom group selected from O, S, SO, SO 2  and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; 
 R 2  is optionally substituted aryl; 
 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 heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino; 
 Z is NR 26 , wherein R 26  is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue; 
 R 21 , R 23 , R 24  and R 25  are each hydrogen, an optionally substituted lower alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and 
 R 20  and R 22  taken together with the neighboring atom form an optionally substituted 6-membered carbocycle; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen. 
     
     
         3 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein X is lower alkylene; and R 2  is a substituted phenyl substituted with one, two or three halogens. 
     
     
         4 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 3  is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino. 
     
     
         5 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 3  is hydrogen. 
     
     
         6 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen or lower alkyl; X is lower alkylene; R 2  is a substituted phenyl substituted with one, two or three halogens; and R 3  is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino. 
     
     
         7 - 12  (canceled) 
     
     
         13 . A compound according to  claim 1 , or pharmaceutically acceptable salt, or solvate thereof, wherein R X  and R 14  are independently hydrogen or an optionally substituted lower alkyl. 
     
     
         14 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R X  and R 14  are hydrogens. 
     
     
         15 - 33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 
     
     
         35 - 56 . (canceled) 
     
     
         57 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 21 , R 23 , R 24  and R 25  are hydrogen or C1-8 alkyl, or C6-C14 aryl. 
     
     
         58 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 21 , R 23 , R 24  and R 25  are each hydrogen. 
     
     
         59 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 26  is hydrogen, C3-6 cycloalkyl, heterocycle or C1-8 alkyl optionally substituted with hydroxy, C3-6 cycloalkyl, alkoxy, heterocycle, heteroaryl, C6-14 aryl or an amino, wherein said amino can be optionally substituted with C(O)C1-8 alkyl or C1-8 alkyl. 
     
     
         60 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein R 26  is hydrogen, C3-6 cycloalkyl, C1-8 alkyl or C1-8 alkyl substituted with hydroxy, alkoxy, heterocycle, heteroaryl, or an amino, wherein said amino is substituted with C(O)C1-8 alkyl. 
     
     
         61 . A compound according to  claim 3 , or pharmaceutically acceptable salt thereof, wherein the halogens are fluoros. 
     
     
         62 . A compound according to  claim 6 , or pharmaceutically acceptable salt thereof, wherein the halogens are fluoros. 
     
     
         63 . A compound according to  claim 1 , or pharmaceutically acceptable salt thereof, wherein the compound is:
 (4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;   (4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-methyl-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;   (4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(methyloxy)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;   (4aS,6aS,14aS)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;   (4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-hydroxyethyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;   (4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide; or   (4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-di-oxo-6-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide,   or a or pharmaceutically acceptable salt thereof.