Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b

Abstract

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 (Ia) 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or tautomeric form thereof, wherein:
 B represents a monocyclic 5 to 6 membered aromatic ring, optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 5 to 6 membered aromatic ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1 -C 3 alkyl, CN, CFH 2 , CF 2 H and CF 3 ; 
 R 1  represents hydrogen or C 1 -C 3 alkyl; 
 R 2  represents C 1 -C 6 alkyl, C 1 -C 3 alkyl-R 5 , benzyl, C(═O)—R 5 , CFH 2 , CF 2 H, CF 3  or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or C 1 -C 6 alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyloxy, oxo, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 ;
 Or R 1  R 2  together with the Nitrogen to which they are attached form a 1,4-dioxa-8-azaspiro[4.5] moiety or a 5-7 membered saturated ring, optionally containing one or more additional heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyloxy, oxo C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 ; 
 
 Each R 4  is independently selected from hydrogen, halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H, CF 3  or a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N; 
 R 5  represents C 1 -C 6 alkyl, CFH 2 , CF 2 H, CF 3  or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyloxy, oxo, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 ; 
 
       or a pharmaceutically acceptable salt or a solvate thereof. 
     
     
         2 . The compound according to  claim 1 , wherein R 2  represents a 3-7 membered saturated ring, containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyloxy, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 ;
 Or R 1  R 2  together with the Nitrogen to which they are attached form a 5-7 membered saturated ring, optionally containing one or more additional heteroatoms each independently selected from the group consisting of O, S and N, such 5-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1  C 4 alkyloxy, oxo, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 . 
 
     
     
         3 . The compound according to  claim 1  or  2 , wherein R 2  represents a 4-7 membered saturated ring containing carbon and one or more oxygen atoms, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1  C 4 alkyloxy, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 . 
     
     
         4 . A compound according any one of  claims 1  to  3 , wherein B represents phenyl or thiophene, optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, CN, CFH 2 , CF 2 H and CF 3 . 
     
     
         5 . A compound of Formula (I) according to any one of the previous claims, wherein
 R 2  represents C 1 -C 3 alkyl-R 6  or a 4-7 membered saturated ring consisting of carbon atoms and one or more heteroatoms each independently selected from the group consisting of O or S, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyloxy, oxo, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 ;   Each R 4  is independently selected from hydrogen, halo, C 1 -C 4 alkyloxy, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H, CF 3  or a 3-5 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O and N; and   R 6  represents a 4-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O or S, such 4-7 membered saturated ring optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyloxy, oxo, C(═O)—C 1 -C 3 alkyl, C 1 -C 4 alkyl, OH, CN, CFH 2 , CF 2 H and CF 3 .   
     
     
         6 . A compound according to any one of the previous claims, which is of Formula (Ib) 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 4  are defined as in any one of the previous claims and R 3  is selected from the group comprising hydrogen, halo, C 1 -C 3 alkyl, CN, CFH 2 , CF 2 H, CF 3 . 
       
     
     
         7 . A compound according to any one of the previous claims, wherein at least one R 4  represents Fluor, C 1 -C 3 alkyl or cyclopropyl. 
     
     
         8 . A compound according to any one of the previous claims, wherein one R 4  on the para position represents Fluor and the other one R 4  on the meta position represents methyl and such compound is not 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to any one of the previous claims, wherein R 3  represents Fluor. 
     
     
         10 . A compound according to any one of  claims 1  to  9 , wherein B represents phenyl or thiophene, optionally being substituted with one or more substituents each independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, CN, CFH 2 , CF 2 H and CF 3 . 
     
     
         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 product containing (a) a compound of formula I as defined in any one of  claims 1  to  10 , and (b) another HBV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infections.