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

Abstract

including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein B, R1, R2 and R4 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 (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  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 . The compound according to  claim 1 , 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 . The compound according to  claim 1 , 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 . The compound according to  claim 1 , having the structure 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 . The compound according to  claim 1 , wherein at least one R 4  represents Fluor, C 1 -C 3 alkyl or cyclopropyl. 
     
     
         8 . The compound according to  claim 1 , 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 . The compound according to  claim 1 , wherein R 3  represents Fluor. 
     
     
         10 . The compound according to  claim 1 , 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 method of preventing or treating an HBV infection in a mammal, comprising administering the compound of  claim 1 . 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 . The method of  claim 11 , further comprising an additional HBV inhibitor. 
     
     
         13 . The method of  claim 12 , wherein the additional HBV inhibitor is administered simultaneously, separately or sequentially. 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier.