Inhibitors of hepatitis c virus replication

Abstract

The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5A inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5A activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.

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         11 . A compound having structural formula (I): 
       
         
           
           
               
               
           
         
         and/or a pharmaceutically acceptable salt thereof, wherein: 
       
       
         
           
           
               
               
           
         
         
           is chosen from the group consisting of 9-membered bicyclic aryl ring systems that contain from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and that are substituted on C or N atoms by u substituents R 1 ,
 each R 1  is independently chosen from the group consisting of hydrogen, halogen, —OR 3a , —CN, —(CH 2 ) 0-6 C(O)R 3 , —CO 2 R 3a , —C(O)N(R 3a ) 2 , —SR 3a , —S(O)R 3a , —S(O 2 )R 3a , 
 
         
       
       —(CH 2 ) 0-6 N(R 3a ) 2 , —N(R 3a )SO 2 R 3a , —N(R 3a )CO 2 R 3a , —N(R 3a )C(O)R 3 , —N(R 3a )COR 3a , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, C 3-8 carbocycle containing from 0 to 3 heteroatoms chosen from N, O and S, and phenyl, and the C 1-6 alkyl, C 3-8 carbocycle and phenyl are substituted by from 0 to 3 substitutents independently chosen from the group consisting of hydrogen, halogen, —OR 3a , —CN, 
       —CO 2 R 3a , —C(O)N(R 3a ) 2 , —N(R 3a ) 2 , —N(R 3a )CO 2 R 3a , —SR 3a , —S(O)R 3a , —S(O 2 )R 3a , —N(R 3a )SO 2 R 3a , 
       —N(R 3a )CO 2 R 3a , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, and C 3-8 cycloalkyl,
 u is from 0 to 4, 
 each R 3  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl, —OH, —O—C 1-6 alkyl and C 3-8 cycloalkyl, and 
 each R 3a  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; 
 
       
         
           
           
               
               
           
         
         is a group chosen from the group consisting of
 (a) —C≡C— and 
 (b) aryl ring systems B′ chosen from the group consisting of:
 (i) 5- to 7-membered monocyclic ring systems and 
 (ii) 8- to 10-membered bicyclic ring systems, 
 and the aryl ring systems B′ containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by v substituents R 2 , 
 each R 2  is independently chosen from the group consisting of hydrogen, halogen, —OR 4a , —CN, —CO 2 R 4a , —C(O)R 4a , —C(O)N(R 4a ) 2 , —N(R 4a ) 2 , —N(R 4a )COR 4 , 
 
 
       
       —N(R 4a )CO 2 R 4a , —N(R 4a )C(O)N(R 4a ), —N(R 4a )SO 2 R 4a , —SR 4a , —S(O)R 4a , —S(O 2 )R 4a , C 1-6 alkyl substituted by from 0 to 4 R 4  and C 3-8 cycloalkyl substituted by from 0 to 4 R 4 ,
 v is from 0 to 4, 
 each R 4  is independently chosen from the group consisting of hydrogen, —OH, C 1-6 alkyl and C 3-8 cycloalkyl; 
 each R 4a  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; 
 wherein said 
 
       
         
           
           
               
               
           
         
       
       and said 
       
         
           
           
               
               
           
         
       
       are taken together with one said substituent R 1  and one said substituent R 2  to form a 5- to 9-membered carbocyclic ring containing 1 or 2 heteroatoms independently chosen from the group consisting of N, O and S, represented by a group chosen from the group consisting of: 
       
         
           
           
               
               
           
         
       
       where
 W is chosen from the group consisting of —(CH 2 ) 1-3 —, —(CH 2 ) 0-2 NH(CH 2 ) 0-2 —, 
 
       —(CH 2 ) 0-2 N(C 1-6 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 0-2 O(CH 2 ) 0-2 — and —(CH 2 ) 0-2 C(O)(CH 2 ) 0-2 —, where W is substituted by from 0 to 4 R w , where each R w  is independently selected from C 1-6 alkyl and C 3-8 cycloalkyl;
 V is chosen from the group consisting of —C(O)— and —CH 2 —, and where V is 
 
       —CH 2 —, V is substituted by from 0 to 2 R v , where each R v  is independently selected from the group consisting of C 1-6 alkyl, phenyl, and C 3-8 cycloalkyl;
 each D is a group independently chosen from the group consisting of:
 (a) a single bond, 
 (b) —C(O)N(R 5 )—, 
 (c) —N(R 5 )C(O)—, and 
 (d) a 5- or 6-membered aryl ring system D′ containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by from 0 to 2 substituents R 5 ,
 each R 5  is independently chosen from the group consisting of hydrogen, halogen, —OR 6 , —CN, —CO 2 R 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )COR 6 , —SR 6 , —S(O)R 6 , 
 
 
 
       —S(O 2 )R 6 , —N(R 6 )SO 2 R 6 , —NCO 2 R 6 , —NC(O)N(R 6 ) 2 , C 1-6 alkyl substituted by from 0 to 3 R 6  and C 3-8 cycloalkyl substituted by from 0 to 3 R 6 , and
 each R 6  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; 
 each E is a group independently chosen from the group consisting of:
 (a) a single bond, 
 (b) —(C(R 7 ) 2 ) 0-2 NR 7 C(O)O 0-1 —, and 
 (c) a pyrrolidinyl derivative chosen from the group consisting of: 
 
 
       
         
           
           
               
               
           
         
         
           
             I is a bivalent group chosen from —C(O)—, —CO 2 — and —C(O)N(R 7 )—, 
             J is a fused ring system chosen from the group consisting of 3- to 7-membered carbocycles and 5- or 6-membered aryl rings containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by substituents R 9 , 
             each R 8a  is independently chosen from the group consisting of hydrogen, halogen, —OH, —OC 1-6 alkyl and C 1-6 alkyl, or two R 8a  may be taken together to form oxo, 
             each R 8b  is independently chosen from the group consisting of hydrogen, halogen, —OH, —OC 1-6 alkyl and C 1-6 alkyl, or two R 8b  may be taken together to form oxo, 
             each R 8c  is independently chosen from the group consisting of hydrogen and C 1-6 alkyl, 
             or any two groups selected from R 8a , R 8b  and R 8c  may be taken together to form a spiro-bicyclic or bridged bicyclic ring; 
             each R 9  is independently chosen from the group consisting of hydrogen, halogen, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NH—C 1-6 alkyl and —NHC(O)—C 1-6 alkyl, 
           
           each R 7  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and phenyl, and the C 1-6 alkyl and phenyl are substituted by from 0 to 3 substitutents independently chosen from the group consisting of hydrogen, halogen, C 1-6 alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl; and 
         
         each G is independently chosen from the group consisting of:
 (a) hydrogen, 
 (b) —OR 10a , 
 (c) —CN, 
 (d) —CO 2 R 10a , 
 (e) —C(O)N(R 10 ) 2 , 
 (f) —SR 10a , 
 (g) —S(O)R 10a , 
 (h) —S(O 2 )R 10a , 
 (i) —N(R 10 ) 2 , 
 (j) —N(R 10 )SO 2 R 10a , 
 (k) —NCO 2 R 10a , 
 (l) —NC(O)N(R 10 ) 2 , 
 (m) C 1-6 alkyl having 0 to 4 substituents R 11 ,
 each R 11  is independently chosen from the group consisting of:
 (i) —OH, 
 (ii) —N(R 10 ) 2 , 
 (iii) ═NR 10 , 
 (iv) —O—C 1-6 alkyl, 
 (v) —C(O)R 10 , 
 (vi) —S—C 1-6 alkyl, 
 (vii) —SO 2 —C 1-6 alkyl, 
 (viii) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 12  on N or C atoms, and each R 12  is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl having from 0 to 3 substituents chosen from R 10 , 
 
 
 
       
       —O—C 1-6 alkyl, —S—C 1-6 alkyl, —OR 10a , —CN, —C(O)R 10 , —CO 2 R 10a , —C(O)N(R 10 ) 2 , —SR 10a , —S(O)R 10a , 
       —S(O 2 )R 10a , —N(R 10 )SO 2 R 10a , —NCO 2 R 10a , —NC(O)N(R 10 ) 2 , and —N(R 10 ) 2 , or two R 12  are taken together to form oxo, and
 (ix) 5- or 6-membered aryl containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 13  on N or C atoms, and each R 13  is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, —O—C 1-6 alkyl and 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, 
 (n) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 10  on N or C atoms; and 
 (o) aryl ring systems G′ chosen from the group consisting of:
 (i) 5- to 7-membered monocyclic ring systems and 
 (ii) 8- to 10-membered bicyclic ring systems, 
 and the aryl ring systems G′ containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by 0 to 3 substitutents R 10 ; 
 
 each R 10  is independently chosen from the group consisting of
 (i) hydrogen, 
 (ii) —CN, 
 (iii) C 1-6 alkyl, 
 (iv) —O—C 0-6 alkyl, 
 (v) —S—C 0-6 alkyl, 
 (vi) C 1-6 alkyl-O—R 14 , 
 (vii) —C(O)R 14 , 
 (viii) —CO 2 R 14 , 
 (ix) —SO 2 R 14 , 
 (x) —N(R 14 ) 2 , 
 (xi) —N(R 14 )SO 2 R 14 , 
 (xii) —NCO 2 R 14 , 
 (xiii) —NC(O)N(R 14 ) 2 , and 
 (xiv) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, 
 
 or two R 10  may be taken together to form oxo; 
 each R 10a  is independently chosen from the group consisting of
 (i) hydrogen, 
 (ii) —CN, 
 (iii) C 1-6 alkyl, 
 (iv) C 1-6 alkyl-O—R 14 , 
 (v) —C(O)R 14 , 
 (vi) —CO 2 R 14 , 
 (vii) —SO 2 R 14 , 
 (x) —N(R 14 ) 2 , 
 (xi) —N(R 14 )SO 2 R 14 , 
 (xii) —NCO 2 R 14 , 
 (xiii) —NC(O)N(R 14 ) 2 , and 
 (xiv) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, 
 
 and two R 10  or R 10a  groups can be taken together with the N to which they are attached to form a ring, which may be substituted by from 0 to 3 substituents R 14 , and 
 each R 14  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, —(CH 2 ) 0-3 C 3-8 cycloalkyl and phenyl. 
 
     
     
         12 . The compound according to  claim 11 , wherein said 
       
         
           
           
               
               
           
         
       
       and said 
       
         
           
           
               
               
           
         
       
       taken together with one said substituent R 1  and one said substituent R 2 , are represented by a group chosen from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 12 , wherein W is chosen from the group consisting of —CH 2 —, —O—, —NH—, —N(C 1-6 alkyl)-, —C(O)—, —CH 2 NH—, —CH 2 N(C 1-6 alkyl)-, —CH 2 CH 2 —, —C(O)CH 2 —, —CH 2 C(O)—, —CH 2 O—, —CH 2 CH 2 CH 2 —, —C(O)CH 2 CH 2 —, —CH 2 C(O)CH 2 —, —CH 2 OCH 2 —, —CH 2 CH 2 C(O)—, —CH 2 CH 2 O—, —CH 2 CH 2 NH—, —CH 2 CH 2 N(C 1-6 alkyl)-, —CH 2 NHCH 2 —, —CH 2 N(C 1-6 alkyl)CH 2 —, —NHCH 2 CH 2 —, and —N(C 1-6 alkyl)CH 2 CH 2 —. 
     
     
         14 . The compound according to  claim 11 , wherein each D is independently chosen from the group consisting of a single bond,
 C(O)N(R 5 )—, —NR 5 C(O)—,   
       
         
           
           
               
               
           
         
       
       where
 R 5  is independently chosen from the group consisting of hydrogen, halogen, —OR 6 , —CN, —CO 2 R 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )COR 6 , —SR 6 , —S(O)R 6 , —S(O 2 )R 6 , 
 
       —N(R 6 )SO 2 R 6 , —NCO 2 R 6 , —NC(O)N(R 6 ) 2 , C 1-6 alkyl substituted by from 0 to 3 substituents R 6  and C 3-8 cycloalkyl substituted by from 0 to 3 substituents R 6 , and
 each R 6  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl. 
 
     
     
         15 . The compound according to  claim 14 , wherein each D is independently chosen from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound according to  claim 11 , wherein each E is independently chosen from the group consisting of a single bond, —CH 2 NHC(O)—, —CH 2 N(CH 3 )C(O)—, —C(CH 3 )HNHC(O)—, —C(CH 3 )HN(CH 3 )C(O)—, —C(CH 3 ) 2 NHC(O)—, —C(CH 3 ) 2 N(CH 3 )C(O)—, —CH 2 NHC(O)O—, —CH 2 N(CH 3 )C(O)O—, —C(CH 3 )HNHC(O)O—, —C(CH 3 )HN(CH 3 )C(O)O—, —C(CH 3 ) 2 NHC(O)O—, —C(CH 3 ) 2 N(CH 3 )C(O)O—, 
       
         
           
           
               
               
           
         
       
       where one of R 8a  and R 8b  is —OH or fluorine. 
     
     
         17 . The compound according to  claim 16 , wherein each E is independently chosen from the group consisting of a single bond, 
       
         
           
           
               
               
           
         
       
       where one of R 8a  and R 8b  is —OH or fluorine. 
     
     
         18 . The compound according to  claim 11 , wherein each G is independently chosen from the group consisting of:
 (a) C 1-6 alkyl having 0 to 4 substituents R 11 ,   (b) 3- to 8-membered carbocycles containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, and having from 0 to 3 substitutents R 10  on N or C atoms; and   (c) aryl ring systems G′ chosen from the group consisting of:
 (i) 5- to 7-membered monocyclic ring systems and 
 (ii) 8- to 10-membered bicyclic ring systems, 
 and the aryl ring systems G′ containing from 0 to 4 heteroatoms independently chosen from the group consisting of N, O and S, and substituted on C or N atoms by 0 to 3 substitutents R 10 . 
   
     
     
         19 . The compound according to  claim 11 , wherein each G is independently chosen from the group consisting of
 (a) hydrogen,   (b) —CN,   (c) C 1-5 alkyl having 1 to 3 substituents R 11 ,
 each R 11  is independently chosen from the group consisting of —OH, —NH 2 , —NCH 3 H, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , ═NH, ═NCH 3 , —C(O)H, —C(O)OH, —C(O)CH 3 , —C(O)OCH 3 , —NHC(O)H, —NHC(O)OH, —NHC(O)CH 3 , —NHC(O)OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl, and oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl and pyrrolyl, where 
 the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and oxacyclohexyl are substituted by from 0 to 2 substitutents R 12  on N or C atoms, and each R 12  is independently selected from the group consisting of hydrogen, halogen, carboxy, C 1-6  alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl; and 
 the phenyl, pyridinyl, pyrimidinyl and pyrrolyl are substituted by from 0 to 3 substitutents R 13  on N or C atoms, and each R 13  is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and 3- to 8-membered cycloalkyl containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, 
   (d) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and oxacyclohexyl having from 0 to 3 substitutents R 10  on N or C atoms, said R 10  independently selected from the group consisting of hydrogen, halogen, carboxy, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, phenyl and benzyl, and   (e) aryl ring systems G′ chosen from the group consisting of: phenyl, pyridinyl and 9-membered bicyclic ring systems containing from 0 to 2 heteroatoms independently chosen from the group consisting of N and O.   
     
     
         20 . The compound according to  claim 19 , wherein each G is independently chosen from the group consisting of C 1-4 alkyl having 1 to 2 substituents R 11 , wherein each R 11  is independently chosen from the group consisting of —OH, —NH 2 , —NCH 3 H, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —C(O)OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl, oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl and pyrrolyl. 
     
     
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         27 . The compound according to  claim 11 , wherein the compound having structural formula (Ia) is a compound having structural formula (Ib): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein said 
       
         
           
           
               
               
           
         
       
       is substituted by u substituents R 1 , and said 
       
         
           
           
               
               
           
         
       
       and said 
       
         
           
           
               
               
           
         
       
       taken together with one said substituent R 1  and one said substituent R 2 , are represented by a group chosen from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound according to according to  claim 27 , wherein said 
       
         
           
           
               
               
           
         
       
       and said 
       
         
           
           
               
               
           
         
       
       taken together with one said substituent R 1  and one said substituent R 2 , are represented by 
       
         
           
           
               
               
           
         
       
       wherein V is —CH 2 —, W is —(CH 2 ) 0-2 O(CH 2 ) 0-2 —, R 1  is fluorine, 
       and both instances of G are 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound according to according to  claim 11 , wherein the compound having structural formula (Ia) is a compound having structural formula (Ib): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein said 
       
         
           
           
               
               
           
         
       
       and said 
       
         
           
           
               
               
           
         
       
       taken together with one said substituent R 1  and one said substituent R 2 , are represented by 
       
         
           
           
               
               
           
         
       
       wherein V is —CH 2 —, W is —(CH 2 ) 0-2 O(CH 2 ) 0-2 —, R 1  is fluorine, and both instances of G are 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound according to  claim 11 , wherein
 said   
       
         
           
           
               
               
           
         
       
       and said 
       
         
           
           
               
               
           
         
       
       taken together with one said substituent R 1  and one said substituent R 2 , are represented by a group chosen from the group consisting of: 
       
         
           
           
               
               
           
         
       
       where
 W is chosen from the group consisting of —(CH 2 ) 1-3 —, —(CH 2 ) 0-2 NH(CH 2 ) 0-2 —, 
 
       —(CH 2 ) 0-2 N(C 1-6 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 0-2 O(CH 2 ) 0-2 — and —(CH 2 ) 0-2 C(O)(CH 2 ) 0-2 —, where W is substituted by from 0 to 4 R w , where each R w  is independently selected from C 1-6 alkyl and 
       C 3-8 cycloalkyl; and
 V is chosen from the group consisting of —C(O)— and —CH 2 —, and where V is 
 
       —CH 2 —, V is substituted by from 0 to 2 R v , where each R v  is independently selected from the group consisting of C 1-6 alkyl and C 3-8 cycloalkyl;
 each R 1  is independently chosen from the group consisting of hydrogen, halogen, —OR 3 , —CN, —C(O)R 3 , —CO 2 R 3 , —C(O)N(R 3a ) 2 , —SR 3 , —S(O)R 3 , —S(O 2 )R 3 , —N(R 3a ) 2 , 
 
       —(CH 2 ) 0-6 N(R 3a ) 2 , —N(R 3a )SO 2 R 3 , —N(R 3a )CO 2 R 3 , —N(R 3a )COR 3 , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, 
       C 3-8 carbocycle containing from 0 to 3 heteroatoms chosen from N, O and S, and phenyl, and the C 1-6 alkyl, C 3-8 carbocycle and phenyl are substituted by from 0 to 3 substitutents independently chosen from the group consisting of hydrogen, halogen, —OR 3a , —CN, —CO 2 R 3a , —C(O)N(R 3a ) 2 , 
       —N(R 3a ) 2 , —N(R 3a )CO 2 R 3a , —SR 3a , —S(O)R 3a , —S(O 2 )R 3a , —N(R 3a )SO 2 R 3a , —N(R 3a )CO 2 R 3a , —N(R 3a )C(O)N(R 3a ), C 1-6 alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl,
 each R 3  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl, —OH, —O—C 1-6 alkyl and C 3-8 cycloalkyl, and 
 each R 3a  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; 
 each R 2  is independently chosen from the group consisting of hydrogen, halogen, —OR 4a , —CN, —CO 2 R 4a , —C(O)N(R 4a ) 2 , —N(R 4a ) 2 , —N(R 4a )CO 2 R 4a , —SR 4a , —S(O)R 4a , —S(O 2 )R 4a , 
 
       —N(R 4a )SO 2 R 4a , —N(R 4a )CO 2 R 4a , —N(R 4a )C(O)N(R 4a ), C 1-6 alkyl substituted by from 0 to 4 R 4  and C 3-8 cycloalkyl substituted by from 0 to 4 R 4 ,
 each R 4  is independently chosen from the group consisting of hydrogen, 
 
       —OH, C 1-6 alkyl and C 3-8 cycloalkyl, and
 each R 4a  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; 
 wherein each D is independently chosen from the group consisting of a single bond, —C(O)N(R 5 )—, —NR 5 C(O)—, 
 
       
         
           
           
               
               
           
         
       
       where
 R 5  is independently chosen from the group consisting of hydrogen, halogen, —OR 6 , —CN, —CO 2 R 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , —N(R 6 )COR 6 , —SR 6 , —S(O)R 6 , —S(O 2 )R 6 , 
 
       —N(R 6 )SO 2 R 6 , —NCO 2 R 6 , —NC(O)N(R 6 ) 2 , C 1-6 alkyl substituted by from 0 to 3 substituents R 6  and C 3-8 cycloalkyl substituted by from 0 to 3 substituents R 6 , and
 each R 6  is independently chosen from the group consisting of hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; 
 wherein each E is independently chosen from the group consisting of a single bond, —CH 2 NHC(O)—, —CH 2 N(CH 3 )C(O)—, —C(CH 3 )HNHC(O)—, —C(CH 3 )HN(CH 3 )C(O)—, 
 
       —C(CH 3 ) 2 NHC(O)—, —C(CH 3 ) 2 N(CH 3 )C(O)—, —CH 2 NHC(O)O—, —CH 2 N(CH 3 )C(O)O—, —C(CH 3 )HNHC(O)O—, —C(CH 3 )HN(CH 3 )C(O)O—, —C(CH 3 ) 2 NHC(O)O—, —C(CH 3 ) 2 N(CH 3 )C(O)O—, 
       
         
           
           
               
               
           
         
       
       where one of R 8a  and R 8b  is —OH or fluorine;
 wherein each G is independently chosen from the group consisting of 
 (a) hydrogen, 
 (b) —CN, 
 (c) C 1-5 alkyl having 1 to 3 substituents R 11 ,
 each R 11  is independently chosen from the group consisting of —OH, —NH 2 , —NCH 3 H, —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , ═NH, ═NCH 3 , —C(O)H, —C(O)OH, —C(O)CH 3 , —C(O)OCH 3 , —NHC(O)H, —NHC(O)OH, —NHC(O)CH 3 , —NHC(O)OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl, and oxacyclohexyl, phenyl, pyridinyl, pyrimidinyl and pyrrolyl, where 
 the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and oxacyclohexyl are substituted by from 0 to 2 substitutents R 12  on N or C atoms, and each R 12  is independently selected from the group consisting of hydrogen, halogen, carboxy, C 1-6 alkyl, —O—C 1-6 alkyl and —S—C 1-6 alkyl; and 
 the phenyl, pyridinyl, pyrimidinyl and pyrrolyl are substituted by from 0 to 3 substitutents R 13  on N or C atoms, and each R 13  is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and 3- to 8-membered cycloalkyl containing from 0 to 3 heteroatoms independently chosen from the group consisting of N, O and S, 
 
 (d) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, pyrrolidinyl, piperidinyl, oxacyclopentyl and oxacyclohexyl having from 0 to 3 substitutents R 10  on N or C atoms, said R 10  independently selected from the group consisting of hydrogen, halogen, carboxy, C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, phenyl and benzyl, and 
 (e) aryl ring systems G′ chosen from the group consisting of: phenyl, pyridinyl and 9-membered bicyclic ring systems containing from 0 to 2 heteroatoms independently chosen from the group consisting of N and O. 
 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . A compound according to  claim 11 , chosen from the group consisting of:
 methyl [(2S)-1-{(2S)-2-[5-(12-fluoro-10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate;   methyl [(2S)-1-{(2S)-2-[5-(3-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-6,6-dimethylindolo[1,2-c][1,3] benzoxazin-10-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate;   methyl [(2S)-1-{(2S)-2-[5-(12-fluoro-10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-6-methylindolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate;   methyl [(2S)-1-{(2S)-2-[5-(10′-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}spiro [cyclohexane-1,6′-indolo[1,2-c][1,3]benzoxazin]-3′-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate;   methyl [(2S)-1-{(2S)-2-[5-(1,12-difluoro-10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate;   methyl [(2S)-1-{(2S)-2-[5-(12-cyano-10-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}indolo[1,2-c][1,3]benzoxazin-3-yl)-1H-imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; and   pharmaceutically acceptable salts thereof.   
     
     
         34 . A pharmaceutical composition comprising an effective amount of the compound according to  claim 11 , and a pharmaceutically acceptable carrier. 
     
     
         35 . The pharmaceutical composition according to  claim 34 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents. 
     
     
         36 . The pharmaceutical composition  claim 11 , further comprising a second therapeutic agent selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors. 
     
     
         37 . A use of the compound according to  claim 11 , in the preparation of a medicament for preventing and/or treating infection by HCV in a subject in need thereof. 
     
     
         38 . A method of treating a patient infected with HCV comprising the step of administering an amount of the compound according to  claim 11 , effective to prevent and/or treat infection by HCV in a subject in need thereof. 
     
     
         39 . A method of treating a patient infected with HCV comprising the step of administering an amount of the compound according  claim 11 , effective to inhibit HCV viral replication and/or viral production. 
     
     
         40 - 49 . (canceled) 
     
     
         50 . A compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 each occurrence of R a  is independently C 1-6  alkyl or phenyl; 
 Rb is H, halogen or —CN; 
 Rc is H or halogen; 
 each occurrence of R d  is independently selected from H and C 1-6  alkyl, or one occurrence of R d  is H and the other occurrence of R d  is phenyl, or both R d  groups and the common carbon atom to which they are attached combine to form a spirocyclic C 3-8  cycloalkyl group; and 
 p is 0, 1 or 2. 
 
       
     
     
         51 . The compound of  claim 50 , wherein each occurrence of R a  is C 1-6  alkyl; R b  and R c  are each H or F; and p is 0. 
     
     
         52 . The compound of  claim 51 , wherein each occurrence of R a  is isopropyl. 
     
     
         53 . The compound of  claim 52 , wherein one occurrence of R d  is H and the other occurrence of R d  is phenyl. 
     
     
         54 . A pharmaceutical composition comprising an effective amount of the compound of  claim 50 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         55 . The pharmaceutical composition of  claim 54 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents. 
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein the second therapeutic agent is selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors. 
     
     
         57 . A method of treating a patient infected with HCV comprising the step of administering to the patient an amount of the compound of  claim 50 , or a pharmaceutically acceptable salt thereof, effective to prevent and/or treat infection by HCV in a subject in need thereof. 
     
     
         58 . A method of treating a patient infected with HCV comprising the step of administering to the patient an amount of the compound of  claim 50 , or a pharmaceutically acceptable salt thereof, effective to inhibit HCV viral replication and/or viral production. 
     
     
         59 . The method of  claim 57 , further comprising administering to the patient a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents. 
     
     
         60 . The method of  claim 58 , wherein the second therapeutic agent is selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors. 
     
     
         61 . The method of  claim 57 , wherein the patient is a human.