1,3,4,8-Tetrahydro-2H-Pyrido[1,2-a]Pyrazine Derivative and Use of the Same as HIV Integrase Inhibitor

Abstract

wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

1 . A compound represented by the following formula [I]or a pharmaceutically acceptable salt thereof, or a solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is 
 (1) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from
 (i) a C 3-8  cycloalkyl group, and 
 (ii) a C 1-6  alkoxy group, 
 
 (2) a C 3-8  cycloalkyl group, or 
 (3) a saturated monocyclic heterocyclic group containing, besides carbon atom, 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, 
 R 2 , R 3 , R 4  and R 5  are the same or different and each is 
 (1) a hydrogen atom, 
 (2) a carboxyl group, 
 (3) —CO—NR a R b  wherein R a  and R b  are the same or different and each is
 (i) a hydrogen atom, 
 (ii) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, or 
 (iii) a C 3-8  cycloalkyl group, or 
 R a  and R b  optionally form, together with the nitrogen atom bonded thereto, a saturated monocyclic hetero ring optionally containing, besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and optionally substituted by the same or different 1 to 5 substituents selected from the following group B, 
 
 (4) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group A, or 
 (5) a cyano group, or 
 R 2  and R 3 , or R 4  and R 5  optionally form, together with the carbon atom bonded thereto, 
 i) C 3-8  cycloalkane, or 
 ii) a saturated monocyclic hetero ring containing, besides carbon atom, 1 to 6 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, 
 wherein R 2 , R 3 , R 4  and R 5  are not hydrogen atoms at the same time, 
 R 6  is 
 (1) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 halogen atoms, 
 (2) a C 1-6  alkoxy group, 
 (3) a halogen atom, or 
 (4) a C 3-8  cycloalkyl group, 
 Y is 
 a nitrogen atom, 
 m is an integer of 1 to 5, and when m is an integer of 2 to 5, then each R 6  may be the same or different, and 
 n is an integer of 1 to 3, 
 and wherein group A is selected from 
 (a) —CO—NR A1 R A2  
 wherein R A1  and R A2  are the same or different and each is
 (i) a hydrogen atom, 
 (ii) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, or 
 (iii) a C 3-8  cycloalkyl group, or 
 
 R A1  and R A2  optionally form, together with the nitrogen atom bonded thereto, a saturated monocyclic hetero ring optionally containing, besides carbon atom and one nitrogen atom, 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and optionally substituted by the same or different 1 to 5 substituents selected from the following group B, 
 
 (b) a hydroxyl group, 
 (c) a C 1-6  alkoxy group, 
 (d) a C 1-6  alkoxy-C 1-6  alkoxy group, 
 (e) a cyano group, 
 (f) —NR A3 R A4  
 wherein R A3  and R A4  are the same or different and each is
 (i) a hydrogen atom, 
 (ii) a C 1-6  alkyl group, 
 (iii) a C 1-6  alkyl-carbonyl group, or 
 (iv) a C 1-6  alkyl-sulfonyl group, or 
 
 R A3  and R A4  optionally form, together with the nitrogen atom bonded thereto, a hetero ring optionally containing, besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and optionally substituted by 1 or 2 oxo groups, 
 
 (g) a carboxyl group, 
 (h) a C 1-6  alkyl-sulfonyl group, and 
 (i) a C 1-6  alkyl-carbonyl group; 
 and group B is selected from 
 (a) a hydroxyl group, 
 (b) a C 1-6  alkoxy group, 
 (c) a C 1-6  alkoxy-C 1-6  alkyl group 
 (d) a C 3-8  cycloalkyl group, and 
 (e) an oxo group. 
 
     
     
         2 . The compound according to  claim 1 , wherein R 1  is a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from
 (i) a C 3-8  cycloalkyl group, and   (ii) a C 1-6  alkoxy group,   or a pharmaceutically acceptable salt thereof, or a solvate thereof.   
     
     
         3 . The compound according to  claim 2 , wherein R 1  is a C 1-6  alkyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         4 . The compound according to  claim 2 , wherein R 1  is a C 1-6  alkyl group substituted by a C 3-8  cycloalkyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         5 . The compound according to  claim 1 , wherein R 1  is a C 3-8  cycloalkyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof, 
     
     
         6 . The compound according to  claim 1 , wherein one of R 2 , R 3 , R 4  and R 5  is —CO—NR a R b  
 wherein R a  and R b  are the same or different and each is
 (i) a hydrogen atom, 
 (ii) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or 
 (iii) a C 3-8  cycloalkyl group, or 
 
 R a  and R b  optionally form, together with the nitrogen atom bonded thereto, a saturated monocyclic hetero ring optionally containing, besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and optionally substituted by the same or different 1 to 5 substituents selected from group B, 
 or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
 
     
     
         7 . The compound according to  claim 1 , wherein one of R 2 , R 3 , R 4  and R 5  is a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A,
 or a pharmaceutically acceptable salt thereof, or a solvate thereof.   
     
     
         8 . The compound according to  claim 1 , wherein R 6  is a halogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The compound according to  claim 1 , wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The compound according to  claim 1 , wherein n is 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         13 . The compound according to  claim 1 , which is represented by the following formula [I-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 11  is 
 (1) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from
 (i) a C 3-8  cycloalkyl group, and 
 (ii) a C 1-6  alkoxy group, or 
 
 (2) a C 3-8  cycloalkyl group, 
 R 21 , R 31 , R 41  and R 51  are the same or different and each is 
 (1) a hydrogen atom, 
 (2) —CO—NR a R b  wherein R a  and R b  are the same or different and each is
 (i) a hydrogen atom, 
 (ii) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or 
 (iii) a C 3-8  cycloalkyl group, or 
 R a  and R b  optionally form, together with the nitrogen atom bonded thereto, a saturated monocyclic hetero ring optionally containing, besides carbon atom and one nitrogen atom, 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and optionally substituted by the same or different 1 to 5 substituents selected from group B, or 
 
 (3) a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, 
 wherein R 21 , R 31 , R 41  and R 51  are not hydrogen atoms at the same time, 
 R 61  is a halogen atom, and 
 R 62  is a hydrogen atom or a halogen atom. 
 
     
     
         14 . The compound according to  claim 13 , wherein R 21  is a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, and
 R 31 , R 41  and R 51  are each a hydrogen atom,   or a pharmaceutically acceptable salt thereof, or a solvate thereof.   
     
     
         15 . The compound according to  claim 13 , wherein R 21  is a C 1-6  alkyl group, and
 R 31 , R 41  and R 51  are each a hydrogen atom,   or a pharmaceutically acceptable salt thereof, or a solvate thereof.   
     
     
         16 . The compound according to  claim 13 , wherein R 41  is a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, and
 R 21 , R 31  and R 51  are each a hydrogen atom,   or a pharmaceutically acceptable salt thereof, or a solvate thereof.   
     
     
         17 . The compound according to  claim 13 , wherein R 21  is a C 1-6  alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A,
 R 41  is a C 1-6  alkyl group, and   R 31  and R 51  are each a hydrogen atom,   or a pharmaceutically acceptable salt thereof, or a solvate thereof.   
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         21 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         22 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         23 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         24 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         25 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         26 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         27 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         28 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         29 . The compound according to  claim 1 , which is represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a solvate thereof. 
     
     
         30 . A pharmaceutical composition comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         31 . An anti-HIV agent comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. 
     
     
         32 . An HIV integrase inhibitor comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. 
     
     
         33 . An anti-HIV agent comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with one or more other kinds of anti-HIV active substances. 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . A method for the prophylaxis or treatment of an HIV infectious disease in a mammal, which comprises administering an effective amount of the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate thereof, to said mammal. 
     
     
         37 . The method according to  claim 36 , which further comprises administering an effective amount of one or more other kinds of anti-HIV active substances to the mammal. 
     
     
         38 . A method for inhibiting HIV integrase in a mammal, which comprises administering an effective amount of the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate thereof, to said mammal. 
     
     
         39 . An anti-HIV composition comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         40 . A pharmaceutical composition for inhibiting HIV integrase, comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         41 . A commercial package comprising the pharmaceutical composition according to  claim 30  and a written matter associated therewith, which states that the pharmaceutical composition can or should be used for treating HIV, 
     
     
         42 . A kit comprising the pharmaceutical composition according to  claim 30  and a written matter associated therewith, which states that the pharmaceutical composition can or should be used for treating HIV. 
     
     
         43 . A pharmaceutical composition according to  claim 30 , which further comprises one or more other anti-HIV active substances.