Antiviral compounds

Abstract

The disclosure is related to anti-viral compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

1 . A compound of formula (I):
   E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b   (I)
   
       wherein:
 W 1a  is 
 
       
         
           
           
               
               
           
         
       
       and W 1a  is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, optionally substituted aryl, optionally substituted heterocycle, and cyano;
 Y 5  is —O—CH 2 —, —CH 2 —O—, —O—C(═O)—, or —C(═O)—O—; X 5  is —CH 2 —CH 2 — or —CH═CH—; 
 E 1a  is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl); or E 1a -V 1a  taken together are R 9a ; 
 E 1b  is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl); or E 1b -V 1b  taken together are R 9b ; 
 V 1a  and V 1b  are each independently selected from: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         P 1a  is selected from: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         P 1b  is selected from: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and
 R 9a  and R 9b  are each independently selected from: 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof; 
         provided that when Y 5  is —O—CH 2 —, or —CH 2 —O—, then at least one of the following occurs: 
         (1) at least one of V 1a  and V 1b  is selected from (af), (ag), (ah), (ai), (aj), (ak), (al), (am), (an), (ao), (ap) or (aq); or 
         (2) P 1a  is selected from (be), (bf), (bg), (bh), (bi), (bj), (bk), (bl), (bm), (bn), (bo), (bq) or (br); or 
         (3) P 1b  is selected from (be), (bf), (bg), (bh), (bi), (bj), (bk), (bl), (bm), (bn), (bo), (bp), (bq) or (br). 
       
     
     
         2 . The compound of  claim 1 , wherein the compound of formula (I) is represented by formula: 
       
         
           
           
               
               
           
         
         wherein the imidazole ring shown in formula (A1), (A2), (A3) and (A4) is optionally substituted with one or more groups independently selected from halo, haloalkyl, cyano, and alkyl; 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein the compound of formula (I) is represented by formula: 
       
         
           
           
               
               
           
         
         wherein the imidazole ring shown in formula (A2) and (A4) is optionally substituted with one or more groups independently selected from halo, haloalkyl, cyano, and alkyl; 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         4 . The compound of  claim 1 , wherein at least one of E 1a  and E 1b  is —N(H)(alkoxycarbonyl). 
     
     
         5 . The compound of  claim 1 , wherein at least one of E 1a  and E 1b  is —N(H)C(═O)OMe. 
     
     
         6 . The compound of  claim 1 , wherein both of E 1a  and E 1b  are —N(H)C(═O)OMe. 
     
     
         7 . The compound of  claim 1 , wherein at least one of E 1a  and E 1b  is —N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl). 
     
     
         8 . The compound of  claim 1 , wherein at least one of E 1a  and E 1b  is cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino. 
     
     
         9 . The compound of  claim 1 , wherein E 1a  and E 1b  are each independently selected from cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopropyloxycarbonylamino and methoxycarbonylamino. 
     
     
         10 . The compound of  claim 1 , wherein at least one of V 1a  and V 1b  is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein E 1a -V 1a  taken together are R 9a  or wherein E 1b -V 1b  taken together are R 9b . 
     
     
         12 . The compound of  claim 1 , wherein at least one of P 1a  and P 1b  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , wherein P 1a  and P 1b  are each independently selected from: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein at least one of —V 1a —C(═O)—P 1a — and —P 1b —C(═O)—V 1b — is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein at least one of —V 1a —C(═O)—P 1a — and —P 1b —C(═)—V 1b — is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein —V 1a —C(═O)—P 1a — and —P 1b —C(═O)—V 1b — are each independently: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1 , wherein one of —V 1a —C(═O)—P 1a — and —P 1b —C(═O)—V 1b — is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and the other of —V 1a —C(═O)—P 1a — and —P 1b —C(═O)—V 1b — is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         19 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         20 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         21 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         22 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         23 . A compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         24 . A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt or prodrug thereof, and at least one pharmaceutically acceptable carrier. 
     
     
         25 . The pharmaceutical composition of  claim 24 , further comprising at least one additional therapeutic agent for treating HCV. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein said additional therapeutic agent is selected from ribavirin, an NS3 protease inhibitor, a nucleoside or nucleotide inhibitor of HCV NS5B polymerase, an alpha-glucosidase 1 inhibitor, a hepatoprotectant, a non-nucleoside inhibitor of HCV polymerase, or combinations thereof. 
     
     
         27 . The pharmaceutical composition according to  claim 24 , further comprising a nucleoside or nucleotide inhibitor of HCV NS5B polymerase. 
     
     
         28 . The pharmaceutical composition according to  claim 27 , wherein said nucleoside or nucleotide inhibitor of HCV NS5B polymerase is selected from ribavirin, viramidine, levovirin, a L-nucleoside, or isatoribine. 
     
     
         29 . The pharmaceutical composition according to  claim 27 , further comprising an interferon or pegylated interferon. 
     
     
         30 . The pharmaceutical composition of  claim 27 , wherein the nucleoside or nucleotide inhibitor of HCV NS5B polymerase is sofosbuvir. 
     
     
         31 . A method of treating disorders associated with hepatitis C, said method comprising administering to an individual a pharmaceutical composition which comprises a therapeutically effective amount of the compound of any  claim 1  or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         32 . The method of  claim 31 , further comprising administering to the patient an interferon or pegylated interferon. 
     
     
         33 . The method of  claim 31 , further comprising administering to the patient ribavirin.