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

Abstract

Inhibitors of HBV replication of Formula (I-A)including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein Ra to Rd, and R1 to R8 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-A) 
       
         
           
           
               
               
           
         
         or a stereoisomer or tautomeric form thereof, wherein 
       
       
         
           
           
               
               
           
         
          represents a monocyclic 5 membered aryl optionally containing one nitrogen or sulfur, such aryl optionally being substituted with one or more substituents each independently selected from the group consisting of C 1 -C 3 alkyl, in particular methyl, C 3 -C 4 cycloalkyl, —CN and halogen; 
       
       
         
           
           
               
               
           
         
          represents a 6 membered aryl optionally containing one nitrogen atom; 
         X represents —CR 2 R 3 —; 
         Y represents C 1 -C 7 alkanediyl or C 2 -C 7 alkenediyl, each optionally substituted with one or more substituents each independently selected from the group consisting of C 1 -C 4 alkyl, fluoro, and —OH; 
         Z represents a heteroatom or a single bond; 
         R a , R b , R c  and R d  are each independently selected from the group consisting of hydrogen, halogen, —CHF 2 , —CF 2 -methyl, —CH 2 F, —CF 3 , —OCF 3 , —CN, C 3 -C 4 cycloalkyl and —C 1 -C 4 alkyl; 
         R 1  is hydrogen or C 1 -C 10 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of —OH, fluoro, and oxo; 
         R 2  is selected from the group consisting of hydrogen; C 1 -C 10 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of —OH, fluoro, methoxy, oxo, and —C(═O)OC 1 -C 4 alkyl; C 1 -C 3 alkyl-R 7 ; C 2 -C 4 alkynyl; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; and monocyclic aryl optionally containing one or two heteroatoms; wherein the C 1 -C 3 alkyl-R 7 , 3-7 membered saturated ring or the monocyclic aryl are each optionally substituted with one or more R 8  substituents; 
         R 3  is hydrogen or C 1-6 alkyl optionally substituted with —OH; 
         or R 2  and R 3  taken together with the carbon atom to which they are attached form a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, and optionally being substituted with one or more substituents each independently selected from the group consisting of —OH, fluoro, methoxy, oxo, —C(═O)OC 1 -C 4 alkyl, benzyl, and C 1 -C 4 alkyl optionally substituted with one or more substituents each independently selected from fluoro and/or OH; 
         R 7  represents a monocyclic aryl optionally containing one or two heteroatoms, and optionally being substituted with one or two substituents each independently selected from the group consisting of halo and C 1-3 alkyl; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or —NR 9 R 10 ; 
         wherein R 9  and R 10  are each independently selected from hydrogen and C 1 -C 3 alkyl optionally substituted with one or more fluoro substituents; 
         each R 8  is independently selected from the group consisting of —OH, fluoro, methoxy, oxo, —C(═O)OC 1 -C 4 alkyl, C 1 -C 4 alkyloxyC 1 -C 4 alkyloxy, and C 1 -C 4 alkyl optionally substituted with one or more substituents each independently selected from fluoro and/or OH; 
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
          represents a monocyclic 5 membered aryl optionally containing one nitrogen or sulfur, such aryl optionally being substituted with one or more substituents each independently selected from the group consisting of C 1 -C 3 alkyl, in particular methyl, C 3 -C 4 cycloalkyl, —CN and halogen; 
       
       
         
           
           
               
               
           
         
          represents a 6 membered aryl optionally containing one nitrogen atom; 
         X represents —CR 2 R 3 —; 
         Y represents C 1 -C 7 alkanediyl or C 2 -C 7 alkenediyl each optionally being substituted with one or more substituents each independently selected from C 1 -C 4 alkyl and —OH; 
         Z represents a heteroatom, preferably oxygen, or a single bond; 
         R a , R b , R c  and R d  are each independently selected from the group consisting of Hydrogen, halogen, —CHF 2 , —CF 2 -methyl, —CF 3 , —OCF 3 , —CN, C 3 -C 4 cycloalkyl and —C 1 -C 4 alkyl; 
         R 1  is Hydrogen or C 1 -C 6 alkyl, such C 1 -C 6 alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of —OH, Fluoro, oxo, and C 1 -C 4 alkyl optionally substituted with one or more Fluoro and/or —OH; 
         R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkyl-R 7 , a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, and monocyclic aryl optionally containing one or two heteroatoms, such C 1 -C 6 alkyl, C 1 -C 3 alkyl-R 7 , 3-7 membered saturated ring or monocyclic aryl optionally being substituted with one or more R 8 ; 
         R 3  is hydrogen or C 1-6 alkyl; 
         or R 2  and R 3  taken together form together with the carbon atom to which they are attached 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 R 8 ; 
         R 7  represents a monocyclic aryl optionally containing one or two heteroatoms; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or —NR 9 R 10 ; 
         wherein R 9  and R 10  are each independently selected from Hydrogen and C 1 -C 3 alkyl; 
         each R 8  independently is selected from the group consisting of —OH, Fluoro, methoxy, oxo, —C(═O)OC 1 -C 4 alkyl and C 1 -C 4 alkyl optionally substituted with one or more substituents each independently selected from Fluoro and/or OH. 
       
     
     
         3 . The compound according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
          represents a monocyclic 5 membered aryl optionally containing one nitrogen or sulfur, such aryl optionally being substituted with one or more substituents each independently selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, —CN and halogen; 
       
       
         
           
           
               
               
           
         
          represents a 6 membered aryl; 
         X represents —CR 2 R 3 —; 
         Y represents C 1 -C 7 alkanediyl or C 2 -C 7 alkenediyl each optionally being substituted with one or more substituents each independently selected from C 1 -C 4 alkyl and —OH; 
         Z represents a heteroatom, preferably oxygen, or a single bond; 
         R a , R b , R c  and R d  are each independently selected from the group consisting of hydrogen, halogen, —CHF 2 , —CF 2 -methyl, —CH 2 F, —CF 3 , —OCF 3 , —CN, C 3 -C 4 cycloalkyl and —C 1 -C 4 alkyl; 
         R 1  is Hydrogen or C 1 -C 6 alkyl, such C 1 -C 6 alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of —OH, Fluoro, oxo, and C 1 -C 4 alkyl optionally substituted with one or more Fluoro and/or —OH; 
         R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkyl-R 7 , a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, and monocyclic aryl optionally containing one or two heteroatoms, such C 1 -C 6 alkyl, C 1 -C 3 alkyl-R 7 , 3-7 membered saturated ring or monocyclic aryl optionally being substituted with one or more R 8 ; 
         R 3  is hydrogen; 
         or R 2  and R 3  taken together form together with the carbon atom to which they are attached 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 R 8 ; 
         R 7  represents a monocyclic aryl optionally containing one or two heteroatoms; a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or —NR 9 R 10 ; 
         wherein R 9  and R 10  are each independently selected from Hydrogen and C 1 -C 3 alkyl; 
         each R 8  independently is selected from the group consisting of —OH, Fluoro, methoxy, oxo, —C(═O)OC 1 -C 4 alkyl and C 1 -C 4 alkyl optionally substituted with one or more substituents each independently selected from Fluoro and/or OH. 
       
     
     
         4 . The compound according to  claim 1 , having Formula (A) 
       
         
           
           
               
               
           
         
         or a stereoisomer or tautomeric form thereof, wherein: 
       
       
         
           
           
               
               
           
         
          represents a monocyclic 5 membered aryl optionally containing one nitrogen or sulfur, such aryl optionally substituted with one or more methyl, —CN or halogen; 
       
       
         
           
           
               
               
           
         
          represents a 6 membered aryl optionally containing one nitrogen atom; 
         X represents —CR 2 R 3 —; 
         Y represents a C 1 -C 7 alkanediyl or C 2 -C 7 alkenediyl each optionally substituted with one or more C1-C4alkyl or —OH; 
         Z represents a heteroatom, preferably oxygen, or a single bond; 
         R a , R b , R c  and R d  are independently selected from the group consisting of Hydrogen, halogen, —CHF 2 , —CF 2 -methyl, —CH 2 F, —CF 3 , —OCF 3 , —CN, C 3 -C 4 cycloalkyl and —C 1 -C 4 alkyl; 
         R 1  is hydrogen or C 1 -C 6 alkyl, such C 1 -C 6 alkyl optionally being substituted with one or more substituents each independently selected from the group consisting of —OH, Fluoro, oxo, and C 1 -C 4 alkyl optionally substituted with one or more Fluoro and/or —OH; 
         R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkyl-R 7 , a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, and monocyclic aryl optionally containing one or two heteroatoms, such C 1 -C 6 alkyl, C 1 -C 3 alkyl-R 7 , 3-7 membered saturated ring or monocyclic aryl optionally being substituted with one or more R 8 ; 
         R 3  is hydrogen; 
         or R 2  and R 3  taken together form together with the carbon atom to which they are attached 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 substituted with one or more R 8 ; 
         R 7  represents a monocyclic aryl optionally containing one or two heteroatoms; 
         each R 8  independently is selected from the group consisting of —OH, Fluoro, methoxy, oxo, —C(═O)OC 1 -C 4 alkyl and C 1 -C 4 alkyl optionally substituted with one or more Fluoro and/or OH; 
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         5 . The compound according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       represents 
       
         
           
           
               
               
           
         
       
       or, wherein R 4  is hydrogen or methyl; and R 6  is selected from hydrogen. 
     
     
         6 . The compound according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       represents 
       
         
           
           
               
               
           
         
       
       wherein R 5  is hydrogen or halogen; and R 6  is selected from hydrogen, methyl, —CN and halogen. 
     
     
         7 . The compound according to  claim 1 , wherein ring C consists of 6 to 8 atoms. 
     
     
         8 . The compound according to  claim 1 , wherein Y—Z is a C 2 alkenediyl. 
     
     
         9 . The compound according to  claim 1  wherein Z is an oxygen. 
     
     
         10 . The compound according to  claim 1 , wherein R 2  is C 1 -C 6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of OH, fluoro, and methoxy. 
     
     
         11 . The compound according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       represents phenyl, and R a  is selected from hydrogen and halogen; R b  is hydrogen or a halogen; R c  is selected from halogen, CH 3 , CHF 2 , CF 3 , and —CN; and R d  is selected from hydrogen and halogen. 
     
     
         12 . The compound according to  claim 1 , wherein R 2  is C 1 -C 4 alkyl optionally substituted with one or more Fluoro. 
     
     
         13 . The compound according to  claim 1 , wherein R 2  is C 1 -C 6 alkyl optionally substituted with one or more OH substituents. 
     
     
         14 . The compound according to  claim 1 , R 1  is hydrogen. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         18 . (canceled) 
     
     
         19 . A method of treating a human, infected by HBV, or being at risk of infection by HBV, said method comprising the administration of a therapeutically effective amount of a compound of  claim 1 . 
     
     
         20 . A process for the preparation of a compound of  claim 1 , comprising the step of
 (a) reacting a compound of Formula (V) with an amine of Formula (VI) in the presence of a base in a solvent to form a compound of Formula (Ia) and optionally subjecting the compound of Formula (Ia) to hydrogenation   
       
         
           
           
               
               
           
         
          or 
         (b) subjecting a compound of Formula (XXXIV) to Heck conditions to form a compound of Formula (Ia) and optionally subjecting the compound of Formula (Ia) to hydrogenation 
       
       
         
           
           
               
               
           
         
          or 
         (c) reacting a compound of Formula (XXXX) with an amine of Formula (VI) in the presence of a suitable base in a suitable solvent 
       
       
         
           
           
               
               
           
         
         wherein the amine of Formula (VI) is 
       
       
         
           
           
               
               
           
         
          Y* is C 2 -C 7 alkenediyl, Y** is C 1 -C 7 alkanediyl, and all other variables are as defined in any one of  claims 1  to  14 . 
       
     
     
         21 - 24 . (canceled)