Diazepinone derivatives and their use in the treatment of hepatitis b infections

Abstract

Provided herein are compounds of formula (I) and (V) useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.

1 - 32 . (canceled) 
     
     
         33 . A compound of Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein 
         R 1  is C 1 -C 6 -alkyl; 
         R 2  is, at each occurrence, independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 0 -C 6 -alkyl-OR 6 , C 0 -C 6 -alkyl-N(R 7 ) 2 , C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, C 0 -C 6 -alkyl-C 2 -C 6 -heterocycloalkyl, C 0 -C 6 -alkyl-SR 8 , C 0 -C 6 -alkyl-S(O)R 8 , C 0 -C 6 -alkyl-S(O) 2 R 8 , C 0 -C 6 -alkyl-C(O)OR 9 , and C 0 -C 6 -alkyl-C(O)N(R) 2 , wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1 or 2 groups, each independently selected from —OH and halo. 
         R 3  is, at each occurrence, independently selected from —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH; 
         R 4  is phenyl or pyridyl, wherein phenyl or pyridyl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF 5 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH; 
         R 5  is selected from H, C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH; 
         R 6  is selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkenyl, and C 0 -C 6 -alkyl-C 3 -C 6 -cycloalkyl; 
         R 7  is, at each occurrence, independently selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C(O) C 1 -C 6 -alkyl and C 1 -C 6 -alkyl-OH; 
         R 8  is selected from H and C 1 -C 6 -alkyl; 
         R 9  is selected from H and C 1 -C 6 -alkyl; 
         R a  is, at each occurrence, independently selected from H, —OH, halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, —O—C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-OH; 
         R b  is, at each occurrence, independently selected from H and C 1 -C 6 -alkyl; 
         m is 0, 1, or 2; 
         n is 0, 1, or 2; and 
         p is 0, 1, 2, 3, or 4. 
       
     
     
         34 . The compound of  claim 33 , wherein R 1  is —CH 3 . 
     
     
         35 . The compound of  claim 33 , wherein at least one R 2  is halo. 
     
     
         36 . The compound of  claim 33 , wherein at least one R 2  is C 0 -C 6 -alkyl-OR 6 . 
     
     
         37 . The compound of  claim 33 , wherein n is 0 or 1. 
     
     
         38 . The compound of  claim 33 , wherein at least one R 3  is C 1 -C 6 -alkyl. 
     
     
         39 . The compound of  claim 33 , wherein at least one R 3  is —CH 3 . 
     
     
         40 . The compound of  claim 33 , wherein R 4  is phenyl or pyridyl, wherein phenyl or pyridyl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl. 
     
     
         41 . The compound of  claim 33 , wherein R 5  is H. 
     
     
         42 . The compound of  claim 33 , wherein the compound of Formula III is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . A pharmaceutical composition comprising a compound of  claim 33 , and a pharmaceutically acceptable carrier. 
     
     
         44 . A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of  claim 33 . 
     
     
         45 . A method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual, comprising administering to the individual a therapeutically effective amount of a compound of  claim 33 . 
     
     
         46 . The method of  claim 45 , further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of an HBV polymerase inhibitor, immunomodulatory agents, interferon, viral entry inhibitor, viral maturation inhibitor, capsid assembly modulator, reverse transcriptase inhibitor, cyclophilin/TNF inhibitor, TLR-agonist, HBV vaccine, and any combination thereof.