Novel peptides as ns3-serine protease inhibitors of hepatitis c virus

Abstract

The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

1 . A compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound, or of said prodrug, said compound having the general structure shown in Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y maybe optionally substituted with X 11  or X 12 ; 
 X 11  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X 11  may be additionally optionally substituted with X 12 ; 
 X 12  is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moieties independently selected from X 12 ; 
 R 1  is COR 5  or B (OR) 2 , wherein R 5  is H, OH, OR 8 , NR 9 R 10 , CF 3 , C 2 F 5 , C 3 F 7 , CF 2 R 6 , R 6 , or COR 7  wherein R 7  is H, OH, OR 8 , CHR 9 R 10 , or NR 9 R 10 , wherein R 6 , R 8 , R 9  and R 10  are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R 1′ )] p COOR 11 , [CH(R 1′ )] p CONR 12 R 13 , [CH(R 1′ )] p SO 2 R 11 , [CH(R 1′ )] p COR 11 , [CH(R 1′ )] p CH(OH)R 11 , CH(R 1′ )CONHCH(R 2′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )R′, CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ ) COOR 11  and CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ )CONR 12 R 13 , wherein R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 11 , R 12 , R 13 , and R′ are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; 
 Z is selected from O, N, CH or CR; 
 W maybe present or absent, and if W is present, W is selected from C═O, C═S, C(═N—CN), or SO 2 ; 
 Q maybe present or absent, and when Q is present, Q is CH, N, P, (CH 2 ) p , (CHR) p , (CRR′) p , O, NR, S, or SO 2 ; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L; 
 A is O, CH 2 , (CHR) p , (CHR—CHR′) p , (CRR′) p , NR, S, SO 2  or a bond; 
 E is CH, N, CR, or a double bond towards A, L or G; 
 G may be present or absent, and when G is present, G is (CH 2 ) p , (CHR) p , or (CRR′) p ; and when G is absent, J is present and E is directly connected to the carbon atom in Formula I as G is linked to; 
 J maybe present or absent, and when J is present, J is (CH 2 ) p , (CHR) p , or (CRR′) p , SO 2 , NH, NR or O; and when J is absent, G is present and E is directly linked to N shown in Formula I as linked to J; 
 L may be present or absent, and when L is present, L is CH, CR, O, S or NR; and when L is absent, then M may be present or absent; and if M is present with L being absent, then M is directly and independently linked to E, and J is directly and independently linked to E; 
 M may be present or absent, and when M is present, M is O, NR, S, SO 2 , (CH 2 ) p , (CHR) p , (CHR—CHR′) p , or (CRR′) p ; 
 p is a number from 0 to 6; and 
 R, R′, R 2 , R 3  and R 4  are independently selected from the group consisting of H; C 1 -C 10  alkyl; C 2 -C 10  alkenyl; C 3 -C 8  cycloalkyl; C 3 -C 8  heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; 
 
       wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate; 
       further wherein said unit N—C-G-E-L-J-N represents a five-membered or six-membered cyclic ring structure with the proviso that when said unit N—C-G-E-L-J-N represents a five-membered cyclic ring structure, or when the bicyclic ring structure in Formula I comprising N, C, G, E, L, J, N, A, Q, and M represents a five-membered cyclic ring structure, then said five-membered cyclic ring structure lacks a carbonyl group as part of the cyclic ring. 
     
     
         2 - 49 . (canceled) 
     
     
         50 . A compound having the structure shown in Formula I, or an enantiomer, a stereoisomer, a rotamer, a tautomer, or a racemate of said compound, or a pharmaceutically acceptable salt of said compound, said stereoisomer, said rotamer, said tautomer, or said racemate: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is selected from the group consisting of the following moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y may be optionally substituted with X 11  or X 12 ; 
 X 11  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl, with the proviso that X 11  may be additionally optionally substituted with X 12 ; 
 X 12  is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alkoxy may be additionally optionally substituted with moieties independently selected from those recited hereinabove in X 12 ; 
 R 1  is COR 5 , wherein R 5  is COOR 8 , CONR 9 R 10 , CF 3 , C 2 F 5 , C 3 F 7 , CF 2 R 6 , or R 6 , wherein R 6 , R 8 , R 9  and R 10  are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R 1′ )] p COOR 11 , [CH(R 1′ )] p CONR 12 R 13 , [CH(R 1′ )] p SO 2 R 11 , [CH(R 1′ )] p COR 11 , [CH(R 1′ )] p CH(OH)R 11 , CH(R 1′ )CONHCH(R 2′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )R′, CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ )COOR 11  and CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ )CONR 12 R 13 , wherein R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 11 , R 12 , and R 13  are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; 
 Z is selected from O, N, CH or CR; 
 W may be present or absent, and if W is present, W is selected from C═O, C═S, C(═N—CN), or SO 2 ; 
 Q may be present or absent, and when Q is present, Q is CH, N, P, (CH 2 ) p , (CHR) p , (CRR′) p , O, NR, S, or SO 2 ; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L; 
 A is O, CH 2 , (CHR) p , (CHR—CHR′) p , (CRR′) p , NR, S, or SO 2 ; 
 E is CH, N, CR, or a double bond towards A; or a double bond towards L, provided that R is H and L is NR; 
 G is absent, and E is directly connected to the carbon atom in Formula I as G is linked to; 
 J is present, J is (CH 2 ) p , (CHR) p , or (CRR′) p , SO 2 , NH, NR or O; 
 L is present, L is CH, CR, O, S or NR; 
 M may be present or absent, and when M is present, M is O, NR, S, SO 2 , (CH 2 ) p , (CHR) p , (CHR—CHR′) p , or (CRR′) p ; 
 p is a number from 0 to 6; and 
 R, R′, R 2 , R 3  and R 4  are independently selected from the group consisting of H; C 1 -C 10  alkyl; C 2 -C 10  alkenyl; C 3 -C 8  cycloalkyl; C 3 -C 8  heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; 
 
       wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino other than for R 2 , amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate; 
       provided that the bicyclic ring structure in Formula I comprising N, C, E, L, J, N, A, Q, and M is a bicyclic ring structure. 
     
     
         51 . The compound of  claim 50 , wherein R 1  is COR 5 , and R 5  is COOR 8  or CONR 9 R 10 . 
     
     
         52 . The compound of  claim 51 , wherein R 1  is COCONR 9 R 10 , and R 9  is H, R 10  is H, R 14 , [CH(R 1′ )] p COOR 11 , [CH(R 1′ )] p CONR 12 R 13 , [CH(R 1′ )] p SO 2 R 11 , [CH(R 1′ )] p COR 11 , CH(R 1′ )CONHCH(R 2′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONR 12 R 13 , or CH(R 1′ )CONHCH(R 2′ )(R′), wherein R 14  is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaralkyl. 
     
     
         53 . The compound of  claim 52 , wherein R 10  is H, R 14 , CH(R 1′ )COOR 11 , CH(R 1′ )CH(R 1′ )COOR 11 , CH(R 1′ )CONR 12 R 13 , CH(R 1′ )CH(R 1′ )CONR 12 R 13 , CH(R 1′ )CH(R 1′ )SO 2 R 11 , CH(R 1′ )CH(R 1′ )COR 11 , CH(R 1′ )CONHCH(R 2′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONR 12 R 13 , or CH(R 1′ )CONHCH(R 2′ )(R′), wherein R 1′  is H or alkyl, and R 2′  is phenyl, substituted phenyl, hetero atom-substituted phenyl, thiophenyl, cycloalkyl, piperidyl or pyridyl. 
     
     
         54 . The compound of  claim 53 , wherein R 1′  is H. 
     
     
         55 . The compound of  claim 54 , wherein R 11  is H, methyl, ethyl, allyl, tert-butyl, benzyl, α-methylbenzyl, α,α-dimethylbenzyl, 1-methylcyclopropyl or 1-methylcyclopentyl;
 R′ is hydroxymethyl or CH 2 CONR 12 R 13 ; 
 R 2′  is independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           wherein: 
         
         U 1  and U 2  may be same or different and are selected from H, F, CH 2 COOH, CH 2 COOMe, CH 2 CONH 2 , CH 2 CONHMe, CH 2 CONMe 2 , azido, amino, hydroxyl, substituted amino, substituted hydroxyl; 
         U 3  and U 4  may be same or different and are selected from O and S; 
         U 5  is selected from the moieties consisting of alkyl sulfonyl, aryl sulfonyl, heteroalkyl sulfonyl, heteroaryl sulfonyl, alkyl carbonyl, aryl carbonyl, heteroalkyl carbonyl, heteroaryl carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl or a combination thereof; 
         and NR 12 R 13  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein U 6  is H, OH, or CH 2 OH, and 
         R 14  is selected from the group consisting of: H, Me, Et, n-propyl, methoxy, cyclopropyl, n-butyl, 1-but-3-ynyl, benzyl, α-methylbenzyl, phenethyl, allyl, 1-but-3-enyl, OMe, cyclopropylmethyl. 
       
     
     
         56 . The compound of  claim 51 , wherein R 2  is selected from the group consisting of the following moieties: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         57 . The compound of  claim 56 , wherein R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 31 =OH or O-alkyl; 
         Y 19  is selected from the following moieties: 
       
       
         
           
           
               
               
           
         
         and Y 20  is selected from the following moieties: 
       
       
         
           
           
               
               
           
         
       
     
     
         58 . The compound of  claim 57 , wherein R 3  is selected from the group consisting of the following moieties: 
       
         
           
           
               
               
           
         
       
     
     
         59 . The compound of  claim 58 , wherein Z is N and R 4  is H. 
     
     
         60 . The compound of  claim 59 , wherein W is C═O. 
     
     
         61 . The compound of  claim 60 , wherein Y is selected from the following moieties: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein: 
         Y 11  is selected from H, COOH, COOEt, OMe, Ph, OPh, NHMe, NHAc, NHPh, CH(Me) 2 , 1-triazolyl, 1-imidazolyl, and NHCH 2 COOH; 
         Y 12  is selected from H, COOH, COOMe, OMe, F, Cl, or Br;
 Y 13  is selected from the following moieties: 
 
       
       
         
           
           
               
               
           
         
         Y 14  is selected from MeSO 2 , Ac, Boc, iBoc, Cbz, or Alloc; 
         Y 15  and Y 16  are independently selected from alkyl, aryl, heteroalkyl, and heteroaryl; 
         Y 17  is CF 3 , NO 2 , CONH 2 , OH, COOCH 3 , OCH 3 , OC 6 H 5 , C 6 H 5 , COC 6 H 5 , NH 2 , or COOH; and 
         Y 18  is COOCH 3 , NO 2 , N(CH 3 ) 2 , F, OCH 3 , CH 2 COOH, COOH, SO 2 NH 2 , or NHCOCH 3 . 
       
     
     
         62 . The compound of  claim 61 , wherein Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         63 . The compound of  claim 62 , wherein Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         64 . The compound of  claim 63 , wherein G and M are absent. 
     
     
         65 . The compound of  claim 63 , wherein: 
       
         
           
           
               
               
           
         
       
       wherein G is absent and J is selected from the group consisting of (CH 2 ) p , (CHR) p , (CHR—CHR′) p , and (CRR′) p ; A and M are independently selected from the group consisting of O, S, SO 2 , NR, (CH 2 ) p , (CHR) p , (CHR—CHR′) p , and (CRR′) p ; and Q is CH 2 , CHR, CRR′, NH, NR, O, S, SO 2 , NR, (CH 2 ) p , (CHR) p , and (CRR′) p . 
     
     
         66 . The compound of  claim 65 , wherein structure c is selected from the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         67 . The compound of  claim 63 , wherein: 
       
         
           
           
               
               
           
         
         is selected from the following structures: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         68 . The compound of  claim 67 , wherein: 
       
         
           
           
               
               
           
         
         is selected from the following structures: 
       
       
         
           
           
               
               
           
         
       
     
     
         69 . A pharmaceutical composition comprising: (A) as an active ingredient a compound of  claim 50 ; and (B) a pharmaceutically acceptable carrier or excipient. 
     
     
         70 . The pharmaceutical composition of  claim 69  which comprises a pharmaceutically acceptable carrier. 
     
     
         71 . The pharmaceutical composition of  claim 70 , additionally containing an antiviral agent. 
     
     
         72 . The pharmaceutical composition of  claim 71 , further containing an interferon. 
     
     
         73 . The pharmaceutical composition of  claim 72 , wherein said antiviral agent is ribavirin and said interferon is α-interferon or pegylated interferon. 
     
     
         74 . A method of treating hepatitis C virus (HCV), said method comprising administering to a patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of a compound of  claim 50 . 
     
     
         75 . The method of  claim 74 , wherein said administration is oral or subcutaneous. 
     
     
         76 . A method of preparing a pharmaceutical composition for treating hepatitis C virus (HCV), said method comprising bringing into intimate contact a compound of  claim 50  and a pharmaceutically acceptable carrier. 
     
     
         77 . A compound, or an enantiomer, a stereoisomer, a rotamer, a tautomer, or a racemate of said compound, or a pharmaceutically acceptable salt of said compound, said stereoisomer, said rotamer, said tautomer, or said racemate, said compound having the structure shown in Formula II: 
       
         
           
           
               
               
           
         
       
       wherein Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 1  is COR 5  and R 5  is COOR 8 , CONR 9 R 10 , CF 3 , C 2 F 5 , C 3 F 7 , CF 2 R 6 , or R 6 , wherein R 6 , R 8 , R 9  and R 10  are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, [CH(R 1′ )] p COOR 11 , [CH(R 1′ )] p CONR 12 R 13 , [CH(R 1′ )] p SO 2 R 11 , [CH(R 1′ )] p COR 11 , [CH(R 1′ )] p CH(OH)R 11 , CH(R 1′ )CONHCH(R 2′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )R′, CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )COOR 11 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONR 12 R 13 , CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ )COOR 11  and CH(R 1′ )CONHCH(R 2′ )CONHCH(R 3′ )CONHCH(R 4′ )CONHCH(R 5′ )CONR 12 R 13 , wherein R 1′ , R 2′ , R 3′ , R 4′ , R 5′ , R 11 , R 12 , and R 13  are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; 
         Z is N and R 4  is H; 
         W is C═O; 
         Q may be present or absent, and when Q is present, Q is CH, N, P, (CH 2 ) p , (CHR) p , (CRR′) p , O, NR, S, or SO 2 , and if Q is absent, M is directly linked to A; 
         A is O, CH 2 , (CHR) p , (CHR—CHR′) p , (CRR′) p , NR, S, or SO 2 ; 
         M may be present or absent, and when M is present, M is O, NR, S, SO 2 , (CH 2 ) p , (CHR) p (CHR—CHR′) p , or (CRR′) p ; 
         p is a number from 0 to 6; and 
         R, and R′ are independently selected from the group consisting of H; C 1 -C 10  alkyl; C 2 -C 10  alkenyl; C 3 -C 8  cycloalkyl; C 3 -C 8  heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen;
 (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl; 
 
       
       wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally and chemically-suitably substituted, with said term “substituted” referring to optional and chemically-suitable substitution with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino other than for R 2 , amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate; 
       further wherein R 2  is selected from the group consisting of the following moieties: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and 
       R 3  is selected from the group consisting of the following moieties: 
       
         
           
           
               
               
           
         
       
       wherein R 31 =OH or O-alkyl; and 
       provided that the bicyclic ring structure in Formula II comprising N, C, CRR′, C, CRR′, A, Q, and M is a bicyclic ring structure. 
     
     
         78 . The compound of  claim 77 , wherein the portion of Formula II between and including C═O is selected from the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         79 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         80 . The compound of  claim 79 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         81 . The compound of  claim 79 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         82 . The compound of  claim 79 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         83 . A compound having the structure: 
       
         
           
           
               
               
           
         
         or an enantiomer, a stereoisomer, a rotamer, a tautomer, or a racemate of said compound, or a pharmaceutically acceptable salt of said compound, said stereoisomer, said rotamer, said tautomer, or said racemate. 
       
     
     
         84 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of  claims 66 - 70  and a pharmaceutically acceptable carrier. 
     
     
         85 . A method of treating a human infected with HCV comprising the step of administering to said patient a therapeutically effective of the compound of any one of  claims 79 - 83 .