Hepatitis c virus ns3/4a protease inhibitors

Abstract

The invention provides novel classes of HCV therapeutics that are orally available, safe and effective HCV NS3/4A protease inhibitors and are less susceptible to drug resistance than existing therapeutics. The invention also relates to pharmaceutical composition of these compounds and methods of preparation and use thereof.

1 - 21 . (canceled) 
     
     
         22 . A compound having the structural formula (II), 
       
         
           
           
               
               
           
         
         wherein
 each of X and Y is independently selected from O, NR and CRR′, provided that at least one of X and Y is NR; 
 R 1  is selected from H, a C 1 -C 6  alkoxy, aryloxy, C 1 -C 6  alkyl, halogen, —(C═O)N—R, —N(C═O)R, —(SO 2 )NR 2  group; 
 R 2  is selected from H, halogen, a C 1 -C 6  alkyl, aryl, —CN, CF 3 , CHF 2 , CH 2 F; 
 R 3  is selected from H, a C 1 -C 6  alkyl, CH 2 F, CHF 2 ; 
 R 4  is selected from an alkyl, hetero-alkyl, aryl, hetero-aryl group, —NH—C(═O)—R; 
 R 5  is H, halogen, or an alkyl group; 
 R 6  is H, halogen, or an alkyl group; 
 R 7  is H, halogen, or an alkyl group; 
 each R 8  is independently selected from H, halogen, or an alkyl group; 
 each R 9  is independently selected from H, halogen, or an alkyl group; 
 each R 10  is independently selected from H, halogen, or an alkyl group; 
 each R 11  is independently selected from H, halogen, or an alkyl group; and 
 each R and R′ is independently a H or an alkyl group, 
 
         or a pharmaceutically acceptable form thereof. 
       
     
     
         23 . The compound of  claim 22 , having the structural formula (IIa), 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 23 , wherein each of R 5 , R 6 , R 7 , R 1 , R 9 , R 10 , R 11  is H, having the structural formula (IIb), 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 24 , wherein R 1  is at the 7-position, having the structural formula (III), 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 25 , wherein R 3  is H. 
     
     
         27 . The compound of  claim 25 , wherein R 3  is a C 1 -C 6  alkyl group. 
     
     
         28 . The compound of  claim 27 , wherein R 3  is a C 1 -C 2  alkyl group. 
     
     
         29 . The compound of  claim 25 , wherein R 1  is H. 
     
     
         30 . The compound of  claim 25 , wherein R 1  is a C 1 -C 6  alkoxy group. 
     
     
         31 . (canceled) 
     
     
         32 . The compound of  claim 25 , wherein R 2  is a C 1 -C 6  alkyl group. 
     
     
         33 . The compound of  claim 25 , wherein R 2  is a halogen. 
     
     
         34 . The compound of  claim 25 , wherein R 2  is an aryl group. 
     
     
         35 . The compound of  claim 34 , wherein R 2  is 2-thiophene. 
     
     
         36 . The compound of  claim 25 , wherein R 4  is a C 1 -C 6  alkyl group. 
     
     
         37 . (canceled) 
     
     
         38 . The compound of  claim 22 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 22 , having the structural formula of (IV): 
       
         
           
           
               
               
           
         
         wherein
 R 12  is H, halogen, or an alkyl group; 
 R 13  is H, halogen, an alkyl group, hetero-alkyl, aryl, or hetero-aryl group; and 
 each R and R′ is independently a H or an alkyl group. 
 
       
     
     
         40 - 55 . (canceled) 
     
     
         56 . The compound of  claim 39 : 
       
         
           
           
               
               
           
         
       
     
     
         57 . (canceled) 
     
     
         58 . A pharmaceutical composition comprising a compound of  claim 22  effective to treat or reduce HCV infection or a related disease or disorder, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         59 .- 66 . (canceled) 
     
     
         67 . A method for treating or reducing HCV infection, or a related disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of  claim 22 . 
     
     
         68 - 75 . (canceled) 
     
     
         76 . A method for inhibiting or inactivating HCV NS3/4A protease, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of  claim 22 . 
     
     
         77 - 81 . (canceled)