Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b

Abstract

Inhibitors of HBV replication of formula (I) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein X, R 1 to R 7 have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a stereoisomer or tautomeric form thereof, wherein: 
       
       
         
           
           
               
               
           
         
         represents 
       
       
         
           
           
               
               
           
         
         
           each of Ra, Rb, Rc, Rd, Re, Rf and Rg are independently selected from the group consisting of Hydrogen and methyl; 
           Rh is Hydrogen; 
           Ri is Hydrogen; 
           R 1 , R 2 and R 3  are independently selected from the group consisting of Hydrogen, Fluoro, Chloro, Bromo, —CHF 2 , —CH 2 F, —CF 3 , —CN and methyl; 
           R 6  is selected from the group consisting of C 1 -C 6 alkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of 0, S and N, such C i -C 6 alkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, C 1 -C 3 alkyl optionally substituted with one or more Fluoro, CN, OH; 
           R 7  represents hydrogen; 
         
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         2 . A compound of according to  claim 1  with Formula (II) 
       
         
           
           
               
               
           
         
         or a stereoisomer or tautomeric form thereof, wherein:
 n indicates an integer of 1 or 2; 
 R 1 , R 2 and R 3  are independently selected from the group consisting of Hydrogen, Fluoro, Chloro, Bromo, —CHF 2 , —CH 2 F, —CF 3 , —CN and methyl; 
 R 4  and R 5  are independently selected from Hydrogen or methyl; 
 R 6  is selected from the group consisting of C 1 -C 6 alkyl and a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of 0, S and N, such C i -C 6 alkyl or 3-7 membered saturated ring optionally substituted with one or more substituents selected from the group consisting of Fluoro, C 1 -C 3 alkyl optionally substituted with one or more Fluoro, —CN, OH; 
 R 7  represents hydrogen; 
 
         or a pharmaceutically acceptable salt or a solvate thereof 
       
     
     
         3 . A compound according to  claim 1  or  2 , wherein R 1  is selected from hydrogen, Fluoro, Chloro, —CHF 2 , —CN, —CF 3  or methyl. 
     
     
         4 . A compound according to anyone of  claims 1  to  3  wherein at least two of R 1 , R 2  and R 3  are Fluoro, Chloro or Bromo. 
     
     
         5 . A compound according to any one of the previous claims wherein R 4  is methyl. 
     
     
         6 . A compound according to any one of the previous claims wherein R 6  contains a 3-7 membered saturated ring optionally containing one oxygen, such 3-7 membered saturated ring optionally substituted with methyl. 
     
     
         7 . A compound according to any one of the previous claims wherein R 6  is a 4 or 5 membered saturated ring containing one oxygen, such 4 or 5 membered saturated ring optionally substituted with methyl. 
     
     
         8 . A compound according to any one of  claims 1  to  5 , wherein R 6  is a branched C 1 -C 6 alkyl optionally substituted with one or more Fluoro. 
     
     
         9 . A compound according to any one of the previous claims with Formula (III) 
       
         
           
           
               
               
           
         
         wherein R 1  is not Hydrogen. 
       
     
     
         10 . A compound according to any one of the previous claims, wherein the stereochemical configuration of atom (*) is as follows 
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound according to any one of the previous claims for use in the prevention or treatment of an HBV infection in a mammal. 
     
     
         12 . A pharmaceutical composition comprising a compound according to any of  claims 1  to  10 , and a pharmaceutically acceptable carrier. 
     
     
         13 . A compound according to any one of  claims 1  to  10 , or a pharmaceutical composition according to  claim 12  in combination with at least one other anti-HBV agent.