Hydroxypyrimidinone derivatives having inhibitory activity against HIV integrase

Abstract

Compounds of Formula (1), pharmaceuticals containing the same, especially anti-HIV agents having anti viral activity, especially inhibitory activity against HIV integrase, wherein X represents either one of the following groups: (wherein, C ring is nitrogen-containing aromatic heterocyclic ring in which at least one atom in atoms neighboring the atom bound to the pyrimidine ring is unsubstituted nitrogen atom; R 10 is hydrogen or lower alkyl; D ring is aryl or heteroaryl) Z 1 and Z 3 each is independently a single bond, O, S, S(═O) or SO 2 ; Z 2 is a single bond, lower alkylene or lower alkenylene; Ar is optionally substituted aryl or optionally substituted heteroaryl; R 1 is lower alkyl, substituted lower alkyl or the like; R 2 is a hydrogen atom or optionally substituted lower alkyl; or R 1 and R 2 may form, together with an adjacent atom, an optionally substituted heterocyclic ring, a pharmaceutically acceptable salt or a solvate thereof.

1 - 22 . (canceled) 
   
   
       23 . A compound of the formula: 
     
       
         
         
             
             
         
       
       wherein C ring is nitrogen-containing aromatic heterocyclic ring in which at least one of atoms neighboring the atom bound to the pyrimidine ring is unsubstituted nitrogen atom; 
       Z 1  and Z 3  each is a single bond; 
       Z 2  is lower alkylene; 
       Ar is aryl optionally substituted with halogen; and 
       R 1  and R 2  form, together with an adjacent atom, an optionally substituted heterocyclic ring, or a pharmaceutically acceptable salt thereof, 
       wherein “optionally substituted” means substituted by hydroxy, carboxy, halogen, halo alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, alkylamino, acylamino, aralkylamino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureide, amidino, guanidine, phthalimide, oxo, and heterocyclic ring. 
     
   
   
       24 . The compound according to  claim 23 , wherein Ar is phenyl optionally substituted with halogen, or a pharmaceutically acceptable salt thereof. 
   
   
       25 . The compound according to  claim 24 , wherein —Z 1 —Z 2 —Z 3 —Ar is 4-fluorobenzyl, or a pharmaceutically acceptable salt thereof. 
   
   
       26 . The compound according to  claim 23 , wherein C ring is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       27 . The compound according to  claim 26 , wherein C ring is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       28 . A compound of the formula: 
     
       
         
         
             
             
         
       
       wherein, C ring is nitrogen-containing aromatic heterocyclic ring in which at least one of atoms neighboring the atom bound to the pyrimidine ring is unsubstituted nitrogen atom; 
       Z 1  and Z 3  each is independently a single bond, O, S, S(═O) or SO 2 ; 
       Z 2  is a single bond, lower alkylene or lower alkenylene; 
       Ar is optionally substituted aryl or optionally substituted heteroaryl; 
       R 11 , R 12 , R 14 , R 15 , R 16 , and R 17  each is independently hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted hydroxy, optionally substituted thiol, optionally substituted sulfonyl, optionally substituted aminosulfonyl, or optionally substituted carbamoyl, or 
       R 11  and R 12 , R 14  and R 15 , and R 16  and R 17  may together form “═O”; 
       R 13  is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted carbamoyl, optionally substituted arylcarbonyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heteroarylcarbonyl; 
       m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; provided that 1≦m+n≦3, 
       or a pharmaceutically acceptable salt thereof 
     
   
   
       29 . A compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       Z 1  and Z 3  each is a single bond; 
       Z 2  is lower alkylene; 
       Ar is aryl optionally substituted with halogen; 
       R 10  is hydrogen or lower alkyl; 
       R 11 , R 12 , R 14 , R 15 , R 16  and R 17  may together form “═O”; 
       and R 17  each is independently hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted hydroxy, optionally substituted thiol, optionally substituted sulfonyl or optionally substituted carbamoyl, or 
       R 11  and R 12 , R 14  and R 15 , and R 16  and R 17  may together form “═O”; 
       R 13  is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted carbamoyl, optionally substituted arylcarbonyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heteroarylcarbonyl; 
       m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; provided that 1≦m+n≦3, 
       or a pharmaceutically acceptable salt thereof, 
       wherein “optionally substituted” means substituted by hydroxy, carboxy, halogen, halo alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, alkylamino, acylamino, aralkylamino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureide, amidino, guanidine, phthalimide, oxo, and heterocyclic ring, 
       wherein “optionally substituted amino” and “optionally substituted carbamoyl” mean substituted by alkyl, benzyl, carbamoylalkyl, mono or di alkylcarbamoyl alkyl, hydroxyalkyl, heterocycle alkyl, alkoxycarbonyl alkyl, mono or di alkylamino alkyl, alkoxyalkyl, acyl, arylcarbonyl, aralkyl, hydroxy, alkyl sulfonyl, arylsulfonyl optionally substituted with alkyl or halogen, cycloalkyl, aryl optionally substituted with alkyl, alkylamino sulfonyl, alkylaminocarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, sulfamoyl, alkyl carbonylamino, heterocycle and amino. 
     
   
   
       30 . The compound according to  claim 28 , wherein Z 1  is a single bond or O; Z 2  is a single bond or lower alkylene; Z 3  is a single bond; and Ar is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. 
   
   
       31 . The compound according to  claim 28 , wherein m is 1, and n is 0 or 1, or a pharmaceutically acceptable salt thereof. 
   
   
       32 . The compound according to  claim 28 , wherein R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       33 . The compound according to  claim 28 , wherein m is 1, n is 0 or 1; R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       34 . A compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       D ring is aryl or heteroaryl, wherein “heteroaryl” means a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group, said monocyclic aromatic heterocyclic group means a group, which is derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 of oxygen atom, sulfur atom, and/or nitrogen atom and which may have a bonding position at any substitutable position, said condensed aromatic heterocyclic group means a group, wherein a 5- to 8-membered aromatic ring which may contain 1 to 4 of oxygen atom, sulfur atom, and/or nitrogen atom is condensed with 1 to 4 of 5- to 8-membered aromatic carbon cycle or the other 5- to 8-membered aromatic heterocyclic ring and which may have a bonding position at the any substitutable position; 
       Z 1  and Z 3  each is a single bond; 
       Z 2  is lower alkylene; 
       Ar is aryl optionally substituted with halogen; 
       R 1  is lower alkyl, substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted 5- or 6-membered nitrogen containing heterocyclic group, or optionally substituted 5- or 6-membered nitrogen containing heterocyclic lower alkyl; and 
       R 2  is a hydrogen atom or optionally substituted lower alkyl, 
       or a pharmaceutically acceptable salt thereof, 
       wherein “optionally substituted” means substituted by hydroxy, carboxy, halogen, halo alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, alkylamino, acylamino, aralkylamino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureide, amidino, guanidine, phthalimide, oxo, and heterocyclic ring. 
     
   
   
       35 . The compound according to  claim 28 , wherein Ar is phenyl optionally substituted with halogen, or a pharmaceutically acceptable salt thereof. 
   
   
       36 . The compound according to  claim 28 , wherein —Z 1 —Z 2 —Z 3 —Ar is 4-fluorobenzyl, or a pharmaceutically acceptable salt thereof. 
   
   
       37 . The compound according to  claim 29 , wherein Ar is phenyl optionally substituted with halogen, or a pharmaceutically acceptable salt thereof. 
   
   
       38 . The compound according to  claim 29 , wherein —Z 1 —Z 2 —Z 3 —Ar is 4-fluorobenzyl, or a pharmaceutically acceptable salt thereof. 
   
   
       39 . The compound according to  claim 34 , wherein Ar is phenyl optionally substituted with halogen, or a pharmaceutically acceptable salt thereof. 
   
   
       40 . The compound according to  claim 34 , wherein —Z 1 —Z 2 —Z 3 —Ar is 4-fluorobenzyl, or a pharmaceutically acceptable salt thereof. 
   
   
       41 . The compound according to  claim 23 , wherein Z 1  is a single bond or 0; Z 2  is a single bond or lower alkylene; Z 3  is a single bond; and Ar is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. 
   
   
       42 . The compound according to  claim 23 , wherein m is 1, and n is 0 or 1, or a pharmaceutically acceptable salt thereof. 
   
   
       43 . The compound according to  claim 23 , wherein R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       44 . The compound according to  claim 23 , wherein m is 1, n is 0 or 1; R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       45 . The compound according to  claim 29 , wherein Z 1  is a single bond or 0; Z 2  is a single bond or lower alkylene; Z 3  is a single bond; and Ar is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. 
   
   
       46 . The compound according to  claim 29 , wherein m is 1, and n is 0 or 1, or a pharmaceutically acceptable salt thereof. 
   
   
       47 . The compound according to  claim 29 , wherein R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”;  and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       48 . The compound according to  claim 29 , wherein m is 1, n is 0 or 1; R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       49 . The compound according to  claim 34 , wherein Z 1  is a single bond or 0; Z 2  is a single bond or lower alkylene; Z 3  is a single bond; and Ar is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. 
   
   
       50 . The compound according to  claim 34 , wherein m is 1, and n is 0 or 1, or a pharmaceutically acceptable salt thereof. 
   
   
       51 . The compound according to  claim 34 , wherein R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof 
   
   
       52 . The compound according to  claim 34 , wherein m is 1, n is 0 or 1; R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       53 . A compound of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       D ring is aryl or heteroaryl, wherein “heteroaryl” means a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group, said monocyclic aromatic heterocyclic group means a group, which is derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 of oxygen atom, sulfur atom, and/or nitrogen atom and which may have a bonding position at any substitutable position, said condensed aromatic heterocyclic group means a group, wherein a 5- to 8-membered aromatic ring which may contain 1 to 4 of oxygen atom, sulfur atom, and/or nitrogen atom is condensed with 1 to 4 of 5- to 8-membered aromatic carbon cycle or the other 5- to 8-membered aromatic heterocyclic ring and which may have a bonding position at the any substitutable position; 
       Z 1  and Z 3  each is a single bond; 
       Z 2  is lower alkylene; 
       Ar is aryl optionally substituted with halogen; 
       R 11 , R 12 , R 14 , R 15 , R 16 , and R 17  each is independently hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted hydroxy, optionally substituted thiol, optionally substituted sulfonyl or optionally substituted carbamoyl, or 
       R 11  and R 12 , R 14  and R 15 , and R 16  and R 17  may together form “═O”; 
       R 13  is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted lower alkylsulfonyl, optionally substituted carbamoyl, optionally substituted arylcarbonyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or optionally substituted heteroarylcarbonyl; 
       m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; provided that 1≦m+n≦3, 
       or a pharmaceutically acceptable salt thereof, 
       wherein “optionally substituted” means substituted by hydroxy, carboxy, halogen, halo alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, alkylamino, acylamino, aralkylamino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, alkylcarbamoyl, sulfamoyl, acyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureide, amidino, guanidine, phthalimide, oxo, and heterocyclic ring, 
       wherein “optionally substituted amino” and “optionally substituted carbamoyl” mean substituted by alkyl, benzyl, carbamoylalkyl, mono or di alkylcarbamoyl alkyl, hydroxyalkyl, heterocycle alkyl, alkoxycarbonyl alkyl, mono or di alkylamino alkyl, alkoxyalkyl, acyl, arylcarbonyl, aralkyl, hydroxy, alkyl sulfonyl, arylsulfonyl optionally substituted with alkyl or halogen, cycloalkyl, aryl optionally substituted with alkyl, alkylamino sulfonyl, alkylaminocarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, sulfamoyl, alkyl carbonylamino, heterocycle and amino. 
     
   
   
       54 . The compound according to  claim 53 , wherein Ar is phenyl optionally substituted with halogen, or a pharmaceutically acceptable salt thereof. 
   
   
       55 . The compound according to  claim 54 , wherein —Z 1 —Z 2 —Z 3 —Ar is 4-fluorobenzyl, or a pharmaceutically acceptable salt thereof. 
   
   
       56 . The compound according to  claim 53 , wherein Z 1  is a single bond or O; Z 2  is a single bond or lower alkylene; Z 3  is a single bond; and Ar is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. 
   
   
       57 . The compound according to  claim 53 , wherein m is 1, and n is 0 or 1, or a pharmaceutically acceptable salt thereof 
   
   
       58 . The compound according to  claim 53 , wherein R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof 
   
   
       59 . The compound according to  claim 53 , wherein m is 1, n is 0 or 1; R 11  and R 12  each is independently hydrogen or lower alkyl; R 14  and R 15  both are hydrogens, or together form “═O”; and R 16  and R 17  each is independently hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       60 . The compound according to  claim 34 , wherein D ring is furan, or a pharmaceutically acceptable salt thereof. 
   
   
       61 . The compound according to  claim 53 , wherein D ring is furan, or a pharmaceutically acceptable salt thereof. 
   
   
       62 . A pharmaceutical composition comprising a compound according to  claim 23 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
   
   
       63 . A pharmaceutical composition comprising a compound according to  claim 28 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
   
   
       64 . A pharmaceutical composition comprising a compound according to  claim 29 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
   
   
       65 . A pharmaceutical composition comprising a compound according to  claim 34 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
   
   
       66 . A pharmaceutical composition comprising a compound according to  claim 53 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.