Hepatitis b core protein modulators

Abstract

The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.

1 .- 21 . (canceled) 
     
     
         22 . A compound represented by: 
       
         
           
           
               
               
           
         
         wherein 
         Y is SO 2 ; 
         R Y  is selected from the group consisting of H, methyl, ethyl, propyl, propenyl, butyl, phenyl and benzyl; 
         R Z  is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl; 
         R c  is selected from the group consisting of H, C 1-6 alkyl and C 2-6 alkenyl; 
         X 2  is selected from the group consisting of S(O) w  (wherein w is 0, 1, or 2), 0, —C(O)— and NR′; 
         R 58  and R 59  are each independently selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, NR′R″, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, phenyl, heteroaryl, C 3-6 cycloalkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), —S(O) w —NR′R″ (where w is 0, 1 or 2), and —NR′—S(O) w —C 1-6 alkyl (where w is 0, 1 or 2); or form a phenyl, heterocyclic or heteroaryl ring (optionally substituted by one, two, or three substituents selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR′R″) and fused to the ring to which they are attached; 
         R′ is selected, independently for each occurrence, from H, methyl, ethyl, cyclopropyl, cyclobutyl, and propyl; 
         R″ is selected, independently for each occurrence, from H, methyl, ethyl, propyl (optionally substituted by hydroxyl), butyl (optionally substituted by hydroxyl), —C(O)-methyl and —C(O)-ethyl, or R′ and R″ taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle optionally substituted by one or more substituents selected from the group consisting of halogen, NH 2 , —C(O)—O—C 1-6 alkyl, —C(O)—C 1-6 alkyl, carboxy and C 1-6 alkyl; 
         R″, for each occurrence, is selected from the group consisting of H, halogen, and C 1-6 alkyl (optionally substituted with one, two, or three halogens); 
         each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR′R″; 
         wherein for each occurrence, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, NR′R″, —NR′—S(O) w —C 1-2 alkyl (where w is 0, 1 or 2), NR′—C(O)—C 1-3 alkyl, NR′—C(O)—O—C 1-3 alkyl, —NR′—S(O) w , and S(O) w —NR′R″; C 1-6 alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 1-3 alkyl, NR′R″, —NR′—S(O) w —C 1-2 alkyl (where w is 0, 1 or 2), and S(O) w —NR′R″ (where w is 0, 1 or 2); C 1-6 alkylene may be optionally substituted by a substituent selected from the group consisting of C 3-6 cycloalkyl, hydroxyl, cyano, and halogen; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 .- 28 . (canceled) 
     
     
         29 . The compound of  claim 22 , which is compound (1553) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . A method for modifying a viral core protein comprising administering a compound of  claim 22 . 
     
     
         31 . The method of  claim 30 , further comprising affecting function upstream of viral assembly. 
     
     
         32 . The method of  claim 32 , wherein one or more of cccDNA transcription, RNA stability and protein-protein interaction is modulated in the viral assembly. 
     
     
         33 . The method of  claim 30 , further comprising administering one or more additional active compounds selected from one or more of entecavir, lamivudine, telbivudine, adefovir dipivoxil, tenofovir, prodrugs of tenofavir, clevudine, and besifovir. 
     
     
         34 . The method of  claim 33 , wherein the one or more additional active compounds is entecavir. 
     
     
         35 . A method for modifying a viral core protein comprising administering a compound of  claim 29 . 
     
     
         36 . The method of  claim 35 , further comprising affecting function upstream of viral assembly. 
     
     
         37 . The method of  claim 36 , wherein one or more of cccDNA transcription, RNA stability and protein-protein interaction is modulated in the viral assembly. 
     
     
         38 . The method of  claim 35 , further comprising administering one or more additional active compounds selected from one or more of entecavir, lamivudine, telbivudine, adefovir dipivoxil, tenofovir, prodrugs of tenofavir, clevudine, and besifovir. 
     
     
         39 . The method of  claim 38 , wherein the one or more additional active compounds is entecavir.