Inhibitors of serine proteases, particularly hcv ns3-ns4a protease

Abstract

The present invention relates to compounds of formula I: or a pharmaceutically acceptable salts thereof that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are useful as antiviral agents. The invention further relates to pharmaceutically acceptable compositions comprising said compounds either for ex vivo use or for administration to a patient suffering from HCV infection and to processes for preparing the compounds. The invention also relates to methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a compound of this invention.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 9  and R 9′  are independently:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-hetero aryl-(C1-C12)-aliphatic-;
 wherein up to three aliphatic carbon atoms in each of R 9  and R 9′  may be replaced by O, N, NH, S, SO, or SO 2 ; 
 wherein each of R 9  and R 9′  is independently and optionally substituted with up to 3 substituents independently selected from J; 
 J is halogen, —OR′, —NO 2 , —CN, —CF 3 , —OCF 3 , —R′, oxo, thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′) 2 , —SR′, —SOR′, —SO 2 R′, —SO 2 N(R′) 2 , —SO 3 R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′) 2 , —C(O)CH 2 C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′, —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —C(S)N(R′) 2 , —(CH 2 ) 0-2 NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′) 2 , —N(R′)SO 2 R′, —N(R′)SO 2 N(R′) 2 , —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′) 2 , —N(R′)C(S)N(R′) 2 , —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′) 2 , —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′) 2 , —P(O)(R′) 2 , —P(O)(OR′) 2 , or —P(O)(H)(OR′); wherein;
 R′ is independently selected from: 
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; 
 wherein up to 5 atoms in R′ are optionally and independently substituted with J; 
 wherein two R′ groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; 
 
 
 
         R 10 , R 10′ , R 11 , and R 11′  are each independently:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
 wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; 
 wherein up to 3 aliphatic carbon atoms in each of R 10 , R 10′ , R 11 , and R 11′  may be replaced by a heteroatom selected from O, NH, S, SO, or SO 2  in a chemically stable arrangement; 
 wherein each of R 10 , R 10′ , R 11 , and R 11′  is independently and optionally substituted with up to 3 substituents independently selected from J; or 
 
 
         R 10  is —OR′ and R 10′  is H; or 
         R 10  and R 10′  are both —OR′ or —SR; or 
         R 10  and R 10′  are both fluorine; or 
         R 10  and R 10′  are taken together with the carbon atom to which they are bound to form a 5- to 7-membered saturated or partially unsaturated ring;
 wherein the R 10  and R 10′  atoms bound to the carbon atom are independently C(H), N, NH, O, S, SO, or SO 2 ; 
 wherein said ring may contain up to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 ; 
 wherein any atom is optionally singly or multiply substituted with up to 2 substituents selected independently from J; and 
 wherein said ring is optionally fused to a second ring selected from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a (C3-C10)heterocyclyl, wherein said second ring has up to 3 substituents selected independently from J; or 
 
         R 9  and R 10  are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO 2 ; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or 
         R 10  and R 11  are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO 2 ; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or 
         R 9  and R 11  are taken together with the ring atoms to which they are bound to form a bridged bicyclic saturated or partially unsaturated carbocyclic or heterocyclic ring system containing up to 10 atoms; wherein said ring system is optionally substituted with up to 3 substituents selected independently from J; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, or SO 2 ; 
         R 1  and R 3  are independently:
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
 wherein up to 3 aliphatic carbon atoms in each of R 1  and R 3  may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2  in a chemically stable arrangement; 
 wherein each of R 1  and R 3  is independently and optionally substituted with up to 3 substituents independently selected from J; 
 
 
         R 2 , R 4 , and R 7  are each independently:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or 
 (C6-C10)-aryl-(C1-C12)-aliphatic-;
 wherein up to two aliphatic carbon atoms in each of R 2 , R 4 , and R 7  may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO 2  in a chemically stable arrangement; 
 wherein each of R 2 , R 4 , and R 7  is optionally substituted with up to 3 substituents independently selected from J; 
 
 
         R 5  and R 5′  are independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R 5  is optionally substituted with sulfhydryl or hydroxy; or 
         R 5  is Ph or —CH 2 Ph and R 5′  is H, wherein said Ph or —CH 2 Ph group is optionally substituted with up to 3 substituents independently selected from J; or 
         R 5  and R 5′  together with the atom to which they are bound optionally form a 3- to 6-membered saturated or partially unsaturated ring having up to 2 heteroatoms selected from N, NH, O, SO, and SO 2 ; wherein said ring is optionally substituted with up to 2 substituents selected independently from J; 
         W is: 
       
       
         
           
           
               
               
           
         
         
           wherein each R 6  is independently:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-cycloalkyl- or cycloalkenyl-, 
 [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-, 
 wherein R 6  is optionally substituted with up to 3 J substituents; or 
 
           two R 6  groups, together with the nitrogen atom to which they are bound, optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; 
           wherein each R 8  is independently —OR; or the R 8  groups together with the boron atom, optionally form a (C3-C10)-membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NR′, O, SO, and SO 2 ; 
         
         X is —C(O)—, —S(O)—, or —S(O) 2 —, 
         V is —C(O)—, —S(O)—, —S(O) 2 —, or —N(R 13 )—;
 wherein R 13  is:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
 wherein up to two aliphatic carbon atoms in R 13  may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO 2  in a chemically stable arrangement; 
 wherein R 13  is independently and optionally substituted with up to 3 substituents independently selected from J; 
 
 
 
         R 12  and R 12′  are independently:
 hydrogen; 
 (C1-C12)-aliphatic-; 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-cycloalkyl or -cycloalkenyl-,
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, 
 
         (C5-C10)-heteroaryl-, or 
         (C5-C10)-hetero aryl-(C1-C12)-aliphatic-;
 wherein up to 3 aliphatic carbon atoms in each of R 12  or R 12′  may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2  in a chemically stable arrangement; 
 wherein each of R 12  or R 12′  is optionally substituted with up to 3 substituents independently selected from J; or 
 
         R 12  and R 12′  together with the nitrogen atom to which they are bound, form a (C3-C10)-heterocyclic ring;
 wherein said (C3-C10)-heterocyclic ring is optionally substituted with up to 3 substituents independently selected from J. 
 
       
     
     
         2 . A compound of formula I-1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         z is 0 or 1; 
         R 9  and R 9′  are independently:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-hetero aryl-, or 
 (C5-C10)-hetero aryl-(C1-C12)-aliphatic-;
 wherein up to three aliphatic carbon atoms in each of R 9  and R 9′  may be replaced by O, N, NH, S, SO, or SO 2 ; 
 wherein each of R 9  and R 9′  is independently and optionally substituted with up to 3 substituents independently selected from J; 
 J is halogen, —OR′, —NO 2 , —CN, —CF 3 , —OCF 3 , —R′, oxo, thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′) 2 , —SR′, —SOR′, —SO 2 R′, —SO 2 N(R′) 2 , —SO 3 R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′) 2 , —C(O)CH 2 C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′, —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —C(S)N(R′) 2 , —(CH 2 ) 0-2 NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′) 2 , —N(R′)SO 2 R′, —N(R′)SO 2 N(R′) 2 , —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′) 2 , —N(R′)C(S)N(R′) 2 , —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′) 2 , —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′) 2 , —P(O)(R′) 2 , —P(O)(OR′) 2 , or —P(O)(H)(OR′); wherein;
 R′ is independently selected from: 
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-; 
 wherein up to 5 atoms in R′ are optionally and independently substituted with J; 
 wherein two R′ groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; 
 
 
 
         R 10 , R 10′ , R 11 , and R 11′  are each independently:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
 wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; 
 wherein up to 3 aliphatic carbon atoms in each of R 10 , R 10′ , R 11 , and R 11′  may be replaced by a heteroatom selected from O, NH, S, SO, or SO 2  in a chemically stable arrangement; 
 wherein each of R 10 , R 10′ , R 11 , and R 11′  is independently and optionally substituted with up to 3 substituents independently selected from J; or 
 
 
         R 10  is —OR′ and R 10′  is H; or 
         R 10  and R 10′  are both —OR′ or —SR; or 
         R 10  and R 10′  are both fluorine; or 
         R 10  and R 10′  are taken together with the carbon atom to which they are bound to form a 5- to 7-membered saturated or partially unsaturated ring;
 wherein the R 10  and R 10′  atoms bound to the carbon atom are independently C(H), N, NH, O, S, SO, or SO 2 ; 
 wherein said ring may contain up to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 ; 
 wherein any atom is optionally singly or multiply substituted with up to 2 substituents selected independently from J; and 
 wherein said ring is optionally fused to a second ring selected from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a (C3-C10)heterocyclyl, wherein said second ring has up to 3 substituents selected independently from J; or 
 
         R 9  and R 10  are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO 2 ; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or 
         R 10  and R 11  are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO 2 ; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or 
         R 9  and R 11  are taken together with the ring atoms to which they are bound to form a bridged bicyclic saturated or partially unsaturated carbocyclic or heterocyclic ring system containing up to 10 atoms; wherein said ring system is optionally substituted with up to 3 substituents selected independently from J; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, or SO 2 ; 
         R 1  (if present) and R 3  are independently:
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
 wherein up to 3 aliphatic carbon atoms in each of R 1  (if present) and R 3  may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2  in a chemically stable arrangement; 
 wherein each of R 1  (if present) and R 3  is independently and optionally substituted with up to 3 substituents independently selected from J; 
 
 
         R 2 , R 4 , and R 7  (if present) are each independently:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or 
 (C6-C10)-aryl-(C1-C12)-aliphatic-;
 wherein up to two aliphatic carbon atoms in each of R 2 , R 4 , and R 7  (if present) may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO 2  in a chemically stable arrangement; 
 wherein each of R 2 , R 4 , and R 7  (if present) is optionally substituted with up to 3 substituents independently selected from J; 
 
 
         R 5  and R 5′  are independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R 5  is optionally substituted with sulfhydryl or hydroxy; or R 5  is Ph or —CH 2 Ph and R 5′  is H, wherein said Ph or —CH 2 Ph group is optionally substituted with up to 3 substituents independently selected from J; or 
         R 5  and R 5′  together with the atom to which they are bound optionally form a 3- to 6-membered saturated or partially unsaturated ring having up to 2 heteroatoms selected from N, NH, O, SO, and SO 2 ; wherein said ring is optionally substituted with up to 2 substituents selected independently from J; 
         W is: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           Y is —CO 2 H, a derivative of —CO 2 H, or a bioisostere of —CO 2 H; 
           each R 6  is independently:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-cycloalkyl- or cycloalkenyl-, 
 [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-, 
 wherein R 6  is optionally substituted with up to 3 J substituents; or 
 
           two R 6  groups, together with the nitrogen atom to which they are bound, optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; 
           wherein each R 8  is independently —OR; or the R 8  groups together with the boron atom, optionally form a (C3-C10)-membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NR′, O, SO, and SO 2 ; 
         
         X is —C(O)—, —S(O)—, or —S(O) 2 —, 
         V is —C(O)—, —S(O)—, —S(O) 2 —, or —N(R 13 )—;
 wherein R 13  is:
 hydrogen-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
 wherein up to two aliphatic carbon atoms in R 13  may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO 2  in a chemically stable arrangement; 
 wherein R 13  is independently and optionally substituted with up to 3 substituents independently selected from J; 
 
 
 
         R 12  and R 12′  are independently:
 hydrogen; 
 (C1-C12)-aliphatic-; 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-cycloalkyl or -cycloalkenyl-,
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-hetero aryl-(C1-C12)-aliphatic-; 
 wherein up to 3 aliphatic carbon atoms in each of R 12  or R 12′  may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2  in a chemically stable arrangement;
 wherein each of R 12  or R 12′  is optionally substituted with up to 3 substituents independently selected from J; or 
 
 
         R 12  and R 12′  together with the nitrogen atom to which they are bound, form a (C3-C10)-heterocyclic ring;
 wherein said (C3-C10)-heterocyclic ring is optionally substituted with up to 3 substituents independently selected from J; and 
 
         R 14  and R 15  are independently:
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C5-C10)-hetero aryl-(C1-C12)aliphatic-, 
 wherein up to 3 aliphatic carbon atoms in R 14  and R 15  may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2  in a chemically stable arrangement; 
 wherein each of R 14  and R 15  is independently and optionally substituted at each substitutable position with up to 3 substituents independently selected from J. 
 
       
     
     
         3 . The compound according to  claim 2 , wherein the 
       
         
           
           
               
               
           
         
       
       radical is: 
       
         
           
           
               
               
           
         
         wherein:
 R 12 , R 12′ , and R 13  are as defined in  claim 1  or  claim 2 . 
 
       
     
     
         4 .- 9 . (canceled) 
     
     
         10 . The compound according to  claim 2 , wherein the 
       
         
           
           
               
               
           
         
       
       radical is: 
       
         
           
           
               
               
           
         
         wherein:
 n is 0, 1, or 2; 
 Z and Z′ are independently C(H), N, NH, O, or S; 
 R 9 , R 9′ , R 11 , and R 11′  are as defined in  claim 1 ; and 
 
         the spirocyclic ring containing Z and Z′ is optionally substituted with up to 3 J substituents, wherein J is as defined in  claim 1 . 
       
     
     
         11 .- 12 . (canceled) 
     
     
         13 . The compound according to  claim 2 , wherein the 
       
         
           
           
               
               
           
         
       
       radical is: 
       
         
           
           
               
               
           
         
         wherein:
 R′ is: 
 (C6-C10)-aryl-, 
 (C6-C10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C3-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, or 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
 wherein up to 5 atoms in R′ are optionally and independently substituted with J; and 
 
 R 9 , R 9′ , R 10′ , R 11 , and R 11′  are as defined in  claim 1 . 
 
       
     
     
         14 .- 17 . (canceled) 
     
     
         18 . The compound according to  claim 2 , wherein in the 
       
         
           
           
               
               
           
         
       
       radical;
 R 9 , R 10 , R 10′ , R 11 , and R 11′  are as defined in  claim 1 ; and 
 R 9′  is: 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 (C6-C10)-aryl-, 
 (C3-C10)-heterocyclyl-, or 
 (C5-C10)-heteroaryl-; 
 wherein up to three aliphatic carbon atoms in R 9′  may be replaced by O, N, NH, S, SO, or SO 2 ; and 
 wherein R 9′  is independently and optionally substituted with up to 3 substituents independently selected from J. 
 
     
     
         19 .- 23 . (canceled) 
     
     
         24 . The compound according to  claim 2 , wherein the 
       
         
           
           
               
               
           
         
       
       radical is: 
       
         
           
           
               
               
           
         
         wherein;
 ring A is a 5- to 6-membered aromatic or a 3- to 6-membered non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, SO, or SO 2 ; 
 wherein said ring A is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; 
 wherein any ring has up to 3 substituents selected independently from J; and 
 R 9 , R 9′ , R 10′ , and R 11′  are as defined in  claim 1 . 
 
       
     
     
         25 .- 27 . (canceled) 
     
     
         28 . The compound according to  claim 2 , wherein the 
       
         
           
           
               
               
           
         
       
       radical is: 
       
         
           
           
               
               
           
         
         wherein: 
         ring B forms a 3- to a 20-membered carbocyclic or heterocyclic ring system; 
         wherein each ring B is either aromatic or nonaromatic; 
         wherein each heteroatom in the heterocyclic ring system is N, NH, O, SO, or SO 2 ; 
         wherein ring B is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; 
         wherein each ring has up to 3 substituents selected independently from J; and 
         R 9′  and R 11′  are as defined in  claim 1 . 
       
     
     
         29 . (canceled) 
     
     
         30 . The compound according to  claim 2 , wherein
 W is:   
       
         
           
           
               
               
           
         
         wherein in the W, the NR 6 R 6  is selected from —NH—(C1-C6 aliphatic), —NH—(C3-C6 cycloalkyl), —NH—CH(CH 3 )-aryl, or —NH—CH(CH 3 )-heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with up to 3 halogens. 
       
     
     
         31 .- 34 . (canceled) 
     
     
         35 . The compound according to  claim 2 , wherein R 5′  is hydrogen and R 5  is: 
       
         
           
           
               
               
           
         
       
     
     
         36 . (canceled) 
     
     
         37 . The compound according to  claim 2 , wherein R 2 , R 4 , R 7 , and R 12′ , if present, are each independently H, methyl, ethyl, or propyl. 
     
     
         38 . (canceled) 
     
     
         39 . The compound according to  claim 2 , wherein R 3  is: 
       
         
           
           
               
               
           
         
       
     
     
         40 .- 43 . (canceled) 
     
     
         44 . The compound according to claim  43 , wherein R 1 , if present, is cyclohexyl. 
     
     
         45 . The compound according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         46 . A pharmaceutical composition comprising a compound according to  claim 2 , or a pharmaceutically acceptable salt thereof in an amount effective to inhibit a serine protease; and a acceptable carrier, adjuvant or vehicle. 
     
     
         47 . The composition according to  claim 46 , wherein said composition is formulated for administration to a patient. 
     
     
         48 .- 50 . (canceled) 
     
     
         51 . A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a compound according to  claim 2 . 
     
     
         52 . The method according to  claim 51 , wherein said protease is an HCV NS3 protease. 
     
     
         53 . A method of treating an HCV infection in a patient comprising the step of administering to said patient a composition according to  claim 47 . 
     
     
         54 .- 55 . (canceled) 
     
     
         56 . A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a composition according to  claim 46 . 
     
     
         57 .- 58 . (canceled) 
     
     
         59 . A process for preparing a compound of formula I-1 as defined in  claim 2 , comprising the step of: reacting a compound of formula VII in the presence of a compound of formula VIII to provide a compound of formula IX: 
       
         
           
           
               
               
           
         
         wherein: 
         R 17  is an amine protecting group, a P3-residue of an HCV protease inhibitor described herein, or a P4-P3-residue of an HCV protease inhibitor as described herein, and wherein the P3 and the P4-P3 residues are optionally substituted with an amino-terminal capping group; R 17  is a carboxy protecting group or a P1 residue of an HCV protease inhibitor described herein, wherein the P1 residue is optionally substituted with a carboxy terminal protecting group or with W; R′ is as defined in  claim 1 ; and X is an appropriate leaving group.