Hepatitis b capsid assembly modulators

Abstract

Described herein are hepatitis B capsid assembly modulators and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of hepatitis B.

What is claimed is: 
     
         1 . A compound of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         Ring A is aryl; 
         each R 11  is independently halogen; 
         n is 2 or 3; 
         R 12  is hydrogen; 
       
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
         R 13  is hydrogen, halogen, or C 1 -C 6 alkyl; 
         R 16  is hydrogen or C 1 -C 6 alkyl; 
         R 17  is cycloalkyl optionally substituted with one, two, or three R 7 ; 
         each R 7  is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 7a ; 
         each R 7a  is independently halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , or —C(═O)NR b R c ; 
         each R a  is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; and 
         each R b  and R c  are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
 Ring A is phenyl; n is 2 or 3; and each R 11  is independently fluorine.   
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
 R 13  is halogen.   
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
 R 16  is hydrogen.   
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
 R 17  is cyclohexyl optionally substituted with one, two, or three R 7 .   
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
 each R 7  is independently C 1 -C 6 alkyl optionally substituted with one R 7a .   
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
 each R 7a  is independently —C(═O)OR b .   
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. 
     
     
         11 . A method of treating hepatitis B in a subject, comprising administering to the subject a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
     
     
         12 . A combination of:
 (i) an antiviral suitable for the treatment of chronic hepatitis B infection; and   (ii) a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
         R 12  is hydrogen or C 1 -C 6 alkyl; 
         R 13  is hydrogen or C 1 -C 6 alkyl; 
         R 14  is hydrogen or C 1 -C 6 alkyl; 
         R 15  is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 hydroxyalkyl; 
         R 16  is hydrogen or C 1 -C 6 alkyl; 
         R 17  is hydrogen, —CN, —OR 20 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C 1 -C 6 alkyl(aryl), —C 1 -C 6 alkyl(heteroaryl), —C 1 -C 6 alkyl(cycloalkyl), or —C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 7 ; 
         or R 16  and R 17  are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl or a heterocycloalkenyl; each optionally substituted with one, two, or three R 8 ; 
         each R 20  is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 7 ; 
         each R 8  is independently oxo,
 halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, 
 heteroaryl, —C 1 -C 6 alkyl(aryl), —C 1 -C 6 alkyl(heteroaryl), —C 1 -C 6 alkyl(cycloalkyl), or —C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, 
 halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; 
 
         each R 7  is independently oxo,
 halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, 
 heteroaryl, —C 1 -C 6 alkyl(aryl), —C 1 -C 6 alkyl(heteroaryl), —C 1 -C 6 alkyl(cycloalkyl), or —C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 7a ; 
 
         each R 7a  is independently oxo, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl; 
         each R a  is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one, two, or three oxo,
 halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; and 
 
         each R b  and R c  are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; 
         or R b  and R c  are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three oxo, 
         halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. 
       
     
     
         13 . The combination of  claim 12 , wherein:
 R 17  is —OR 20 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, —C 1 -C 6 alkyl(heteroaryl), or —C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one, two, or three R 7 .   
     
     
         14 . The combination of  claim 12 , wherein:
 R 17  is C 1 -C 6 alkyl or cycloalkyl; each optionally substituted with one, two, or three R 7 .   
     
     
         15 . The combination of  claim 12 , wherein:
 R 17  is C 1 -C 6 alkyl optionally substituted with one, two, or three R 7 .   
     
     
         16 . The combination of  claim 12 , wherein:
 each R 7  is independently halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, and heteroayl is independently optionally substituted with one, two, or three R 7a .   
     
     
         17 . A method of treating a hepatitis B infection in a subject; the method comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an antiviral suitable for the treatment of chronic hepatitis B infection: 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
         R 12  is hydrogen or C 1 -C 6 alkyl; 
         R 13  is hydrogen or C 1 -C 6 alkyl; 
         R 14  is hydrogen or C 1 -C 6 alkyl; 
         R 15  is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 hydroxyalkyl 
         R 16  is hydrogen or C 1 -C 6 alkyl; 
         R 17  is hydrogen, —CN, —OR 20 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C 1 -C 6 alkyl(aryl), —C 1 -C 6 alkyl(heteroaryl), —C 1 -C 6 alkyl(cycloalkyl), or —C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 7 ; 
         or R 16  and R 17  are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl or a heterocycloalkenyl; each optionally substituted with one, two, or three R 8 ; 
         each R 20  is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 7 ; 
         each R 8  is independently oxo, 
         halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl,
 heteroaryl, —C 1 -C 6 alkyl(aryl), —C 1 -C 6 alkyl(heteroaryl), —C 1 -C 6 alkyl(cycloalkyl), or —C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, 
 halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; 
 
         each R 7  is independently oxo,
 halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, 
 heteroaryl, —C 1 -C 6 alkyl(aryl), —C 1 -C 6 alkyl(heteroaryl), —C 1 -C 6 alkyl(cycloalkyl), or —C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 7a ; 
 
         each R 7a  is independently oxo, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl; 
         each R a  is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one, two, or three oxo,
 halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; and 
 
         each R b  and R c  are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three oxo, halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; 
         or R b  and R c  are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three oxo, 
         halogen, —CN, —OH, —OMe, —S(═O)Me, —S(═O) 2 Me, —NH 2 , —S(═O) 2 NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. 
       
     
     
         18 . The method of  claim 17 , wherein:
 R 17  is —OR 20 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, —C 1 -C 6 alkyl(heteroaryl), or —C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one, two, or three R 7 .   
     
     
         19 . The method of  claim 17 , wherein:
 R 17  is C 1 -C 6 alkyl or cycloalkyl; each optionally substituted with one, two, or three R 7 .   
     
     
         20 . The method of  claim 17 , wherein:
 R 17  is C 1 -C 6 alkyl optionally substituted with one, two, or three R 7 .   
     
     
         21 . The method of  claim 17 , wherein:
 each R 7  is independently halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, and heteroayl is independently optionally substituted with one, two, or three R 7a .