Oxadiazepinone derivatives and methods of treating hepatitis b infections

Abstract

Provided herein are compounds 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 - 25 . (canceled) 
     
     
         26 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
       
       wherein
 R 1  is C 1 -C 6 -alkyl; 
 R 2  is, at each occurrence, independently selected from C 1 -C 6 -alkyl and C 1 -C 6 -alkyl-OR 6 , wherein alkyl is optionally substituted with 1,2, or 3 groups, each independently selected from —OH and halo; 
 or R 2  is at each occurrence, independently selected from —CH 2 OCH 2 -cyclopropyl, —CH 2 OCH 2 CH═CH 2 , —CH 2 SCH 3 , —CH 2 S(O)CH 3 , —CH 2 —S(O) 2 CH 3 , —CH 2 OC(O)OCH 3 , —CH 2 OC(O)OCH(CH 3 ) 2 , —CH 2 OC(O)OC(CH 3 ) 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)C(CH 3 ) 3 , —C(O)OH, —C(O)OCH 3 , —CH 2 OC(O)NH 2 , —CH 2 OC(O)N(CH 3 ) 2 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , and —CH 2 N(CH 3 ) 2 ; 
 R 3  is, at each occurrence, independently selected from C 1 -C 6 -alkyl; 
 R 4  is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl; 
 R 5  is H; 
 R 6  is C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl; and 
 n is 0, 1, or 2. 
 
     
     
         27 . The compound of  claim 26 , wherein R 1  is CH 3 . 
     
     
         28 . The compound of  claim 26 , wherein R 2  is, at each occurrence, independently selected from —CH 3 —CH 2 OH, —CH 2 F, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH 2 CH 2 CH 3 , —CH 2 OCH 2 CHF 2 , and —CH 2 OCH 2 CF 3 . 
     
     
         29 . The compound of  claim 26 , wherein R 2  is C 1 -C 6 -alkyl optionally substituted with 1, 2, or 3 halo groups. 
     
     
         30 . The compound of  claim 26 , wherein R 2  is (CH 2 ) 1-2 —O—C 1 -C 3 -alkyl, wherein C 1 -C 3 -alkyl is optionally substituted with 1,2, or 3 halo groups. 
     
     
         31 . The compound of  claim 26 , wherein R 3  is C 1 -C 3 -alkyl. 
     
     
         32 . The compound of  claim 26 , wherein R 3  is —CH 3 . 
     
     
         33 . The compound of  claim 26 , wherein R 4  is phenyl substituted with 1-3 groups independently selected from halo, —CN, C 1 -C 6 -alkyl, and C 1 -C 6 -haloalkyl. 
     
     
         34 . The compound of  claim 26 , wherein R 5  is H. 
     
     
         35 . The compound of  claim 26 , wherein
 R 1  is C 1 -C 6 -alkyl;   R 4  is phenyl substituted with at least one halogen; and   R 5  is H.   
     
     
         36 . The compound of  claim 26 , wherein
 R 1  is C 1 -C 6 -alkyl;   R 2  is selected from the group consisting of CH 2 OH, —CH 2 OCH 2 CHF 2  or —CH 2 OCH 2 CF 3 ;   R 4  is phenyl substituted with at least one halogen; and   R 5  is H.   
     
     
         37 . The compound of  claim 26 , wherein the compound of Formula II is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . A pharmaceutical composition comprising a compound of  claim 26 , and a pharmaceutically acceptable carrier. 
     
     
         39 . 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 26 . 
     
     
         40 . 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 26 . 
     
     
         41 . The method of  claim 40 , 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.