Methods and compositions of treating a flaviviridae family viral infection

Abstract

Briefly described, embodiments of this disclosure include compounds, pharmaceutical compositions, methods of treating a host infected with a virus from the Flaviviridae family of viruses, methods of inhibiting HCV replication in a host, methods of inhibiting the binding of NS4B polypeptide to the 3′UTR of HCV negative strand RNA in a host, methods of treating liver fibrosis in a host, and the like.

What is claimed is: 
     
         1 . A compound of Formula II-a, or a pharmaceutically acceptable salt or an isomer thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of: —H or 
       
       
         
           
           
               
               
           
         
       
       wherein V is selected from alkyl, cycloalkyl, heterocyclo, aryl or heteroaryl, and m is 0, 1 or 2;
 R 3  is —H, —OH, —O(CH 2 ) n X, or —(CH 2 ) n X, wherein n is 1, 2, 3, or 4, and X is —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —O-alkyl, —O-aryl, —SO 2 (alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), NHSO 2 (alkyl), heteroaryl, N-attached heterocyclo, or C-attached heterocyclo; 
 each of R 4 -R 7  is independently selected from the group consisting of: —H, —Br, —Cl, —F, —I, —CH 3 , —CN, —OH, —OCH 3 , —NO 2 , —NH 2 , —NHCO(alkyl), —NHCO(aryl), 
 
       
         
           
           
               
               
           
         
         or, optionally, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are joined together with a bond to form a 5, 6, or 7-membered ring; or, optionally, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are joined together to form a 1,2-(methylenedioxy)benzene ring system; provided that the compound of Formula II-a is not 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of: —H and 
       
         
           
           
               
               
           
         
       
       wherein V is selected from the group consisting of alkyl,
 cycloalkyl, heterocyclo, aryl, and heteroaryl, wherein V is optionally substituted or unsubstituted; 
 R 3  is selected from the group consisting of —H, —OH, —O(CH 2 ) n X, or —(CH 2 ) n X, wherein n is 1, 2, 3, or 4, and X is selected from the group consisting of —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —O-alkyl, —O-aryl, —SO 2 (alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), NHSO 2 (alkyl), heteroaryl, N-attached heterocyclo, and C-attached heterocyclo; 
 each of R 4 -R 7  is independently selected from the group consisting of: —H, —Br, —Cl, —F, —I, —CH 3 , —CN, —OH, —OCH 3 , —NO 2 , —NH 2 , —NHCO(alkyl), —NHCO(aryl), 
 
       
         
           
           
               
               
           
         
         or, optionally, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are joined together with a bond to form a 5, 6, or 7-membered ring; or, optionally, R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are joined together to form a 1,2-(methylenedioxy)benzene ring system. 
       
     
     
         3 . The compound of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       and V is aryl. 
     
     
         4 . The compound of  claim 1 , wherein R 3  is —H, —OH, —O(CH 2 ) n X, or —(CH 2 ) n X, wherein n is 1, 2, 3, or 4, and X is —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, or N-attached heterocyclo. 
     
     
         5 . The compound of  claim 1 , wherein X is selected from the group consisting of: —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein R 3  is selected from: —O(CH 2 ) 2 NMe 2 , —O(CH 2 ) 2 NEt 2 , —O(CH 2 ) 3 NEt 2 , 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein R 1  is —CH 2 V, wherein V is selected from cycloalkyl, heterocyclo, or heteroaryl. 
     
     
         8 . The compound of  claim 1 , wherein R 4  and R 7  are both hydrogen, and R 5  and R 6  are both a substituent other than hydrogen. 
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, an isomer, a tautomer or a prodrug thereof. 
     
     
         10 . The pharmaceutical composition of  claim 9 , further comprising one or more additional anti-HCV therapeutic agent. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the therapeutic agent is ribavirin or interferon-alpha. 
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein the 1,2-(methylenedioxy)benzene ring system formed by joining R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  results in 
       
         
           
           
               
               
           
         
       
     
     
         13 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic agent includes an HCV NS3 protease inhibitor. 
     
     
         14 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic is selected from the group consisting of: an HCV NS5B RNA-dependent RNA polymerase inhibitor and a nucleoside analog. 
     
     
         15 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic agent is selected from the group consisting of: a thiazolide and a sustained release thiazolide. 
     
     
         16 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic agent is selected from the group consisting of: an interferon-alpha and a pegylated interferon. 
     
     
         17 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic agent is selected from the group consisting of: ribavirin, levovirin, and viramidine. 
     
     
         18 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic agent is a TLR7 agonist. 
     
     
         19 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic agent is a TLR9 agonist. 
     
     
         20 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic agent is a cyclophilin inhibitor. 
     
     
         21 . The pharmaceutical compound of  claim 10 , wherein the anti-HCV therapeutic agent is an alpha-glucosidase inhibitor. 
     
     
         22 . The pharmaceutical compound of  claim 10 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt.