Macrocyclic proline derived hcv serine protease inhibitors

Abstract

The present invention discloses compounds of Formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is absent, —(C═O)—, —S(O) 2 —, —C(═N—OR 1 )— or —C(═N—CN)—; 
 
       
         
           
           
               
               
           
         
          is selected from —C 3 -C 12  cycloalkyl, substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, substituted —C 3 -C 12  cycloalkenyl; —C 3 -C 12  heterocycloalkyl, and substituted —C 3 -C 12  heterocycloalkyl; 
         or 
       
       
         
           
           
               
               
           
         
          is 
       
       
         
           
           
               
               
           
         
          wherein R 7  and R 8  are each independently C 1 -C 8  alkyl or C 2 -C 8  alkenyl and are each independently optionally substituted with one or more halo; 
         M 1  and M 2  are each independently selected from O or NR 1 ; 
         each R 1  is independently selected at each occurrence from the group consisting of: 
         (i) hydrogen; 
         (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; 
         (iii) heterocycloalkyl or substituted heterocycloalkyl; and 
         (iv) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl, or —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl, or substituted —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkyl, substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; 
         L 1  and L 2  are each independently selected from —C 1 -C 8  alkylene, —C 2 -C 8  alkenylene, or —C 2 -C 8  alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8  alkylene, substituted —C 2 -C 8  alkenylene, or substituted —C 2 -C 8  alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkylene, or substituted —C 3 -C 12  cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkenylene, and substituted —C 3 -C 12  cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; 
         W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-; 
         X and Y taken together with the carbon atoms to which they are attached to form a cyclic moiety which selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocylic, carbocyclic, and substituted carbocyclic; 
         X′ is N or —C(R 2 )—, where R 2  is selected from the group consisting of: 
         (i) hydrogen, halogen, CN, CF 3 , NO 2 , OR 3 , SR 3 , —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , NR 4 R 5 , CO 2 R 3 , COR 3 , CONR 4 R 5 , N(R 1 )COR 3 ; aryl; substituted aryl; heteroaryl; or substituted heteroaryl; 
         (ii) heterocycloalkyl or substituted heterocycloalkyl; and 
         (iii) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl, or —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8  alkyl, 
         substituted —C 2 -C 8  alkenyl, or substituted —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkyl, substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; 
         each R 3  is independently selected from C 1 -C 8  alkyl, —C 2 -C 8  alkenyl, or —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl, or substituted —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; and —C 3 -C 12  cycloalkyl, substituted —C 3 -C 12  cycloalkyl; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; or substituted heteroaryl; 
         each R 4  and R 5  are independently selected from H and R 3 , or R 4  and R 5  combined together with the N they are attached to form a heterocyclic ring; 
         R and R′ are each independently selected from the group consisting of: 
         (i) —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl, or —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl, or substituted —C 2 -C 8  alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12  cycloalkyl, r substituted —C 3 -C 12  cycloalkyl; —C 4 -C 12  alkylcycloalkyl, substituted —C 4 -C 12  alkylcycloalkyl; —C 3 -C 12  cycloalkenyl, substituted —C 3 -C 12  cycloalkenyl; —C 4 -C 12  alkylcycloalkenyl, or substituted —C 4 -C 12  alkylcycloalkenyl; 
         (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; 
         (iii) heterocycloalkyl or substituted heterocycloalkyl; and 
         (iv) hydrogen or deuterium; 
         G is selected from —OH, —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , and NR 4 R 5 ; and 
         R″ is selected from hydrogen, methyl, ethyl, and allyl. 
       
     
     
         2 - 26 . (canceled)