Hcv ns3 protease inhibitors

A compound of formula (Ia):

• R1 is:
• MM is CO or a bond;
• XX is O, NH, N(C1-C4 alkyl), a bond or CH2;
• Het1 is a heterocycle and can be substituted with up to ten groups selected independently from WW or R5;
• Rf is A3;
• each WW is independently H, halo, OR77, C1-C6 alkyl, CN, CF3, NO2, SR77, CO2R77, CON(R77)2, C(O)R77, N(R100)C(O)R77, SO2(C1-C6 alkyl), S(O)(C1-C6 alkyl), C3-C8 cycloalkyl, C3-C6 cycloalkoxy, C1-C6 haloalkyl, N(R77)2, NH(C1-C6 alkyl)O(C1-C6 alkyl), halo(C1-C6 alkoxy), NR100SO2R77, SO2N(R77)2, NHCOOR77, NHCONHR77, aryl, heteroaryl or heterocyclyl;
• wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated nonaromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen;
• and wherein 2 adjacent WW moieties are optionally taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, unsaturated non-aromatic, or aromatic cyclic ring having 0-2 heteroatoms selected from N, 0 and S;
• A3 is independently selected from PRT, H, —OH, —C(O)OH, cyano, alkyl, alkenyl, alkynyl, amino, amido, imido, imino, halogen, CF3, CH2CF3, cycloalkyl, nitro, aryl, aralkyl, alkoxy, aryloxy, heterocycle, —C(A2)3, —C(A2)2—C(O)A2, —C(O)A2, —C(O)OA2, —O(A2), —N(A2)2, —S(A2), —CH2P(Y1)(A2)(OA2), —CH2P(Y1)(A2)(N(A2)2), —CH2P(Y1)(OA2)(OA2), —OCH2P(Y1)(OA2)(0A2), —OCH2P(Y1)(A2)(OA2), —OCH2P(Y1)(A2)(N(A2)2), —C(O)OCH2P(Y1)(OA2)(OA2), —C(O)OCH2P(Y1)(A2)(OA2), —C(O)OCH2P(Y1)(A2)(N(A2)2), —CH2P(Y1)(OA2)(N(A2)2), —OCH2P(Y1)(OA2)(N(A2)2), —C(O)OCH2P(Y1)(OA2)(N(A2)2), —CH2P(Y1)(N(A2)2)(N(A2)2), —C(O)OCH2P(Y1)(N(A2)2)(N(A2)2), —OCH2P(Y1)(N(A2)2)(N(A2)2), —(CH2)m-heterocycle, —(CH2)mC(O)Oalkyl, —O—(CH2)m—O—C(O)—Oalkyl, —O—(CH2)r—O—C(O)—(CH2)m-alkyl, —(CH2)mO—C(O)—O-alkyl, —(CH2)mO—C(O)—O-cycloalkyl, —N(H)C(Me)C(O)O-alkyl, SRr, S(O)Rr, S(O)2Rr, or alkoxy arylsulfonamide, wherein each A3 may be optionally substituted with
• 1 to 4
• —R111, —P(Y1)(OA2)(OA2), —P(Y1)(OA2)(N(A2)2), —P(Y1)(A2)(OA2), —P(Y1)(A2)(N(A2)2), or P(Y1)(N(A2)2)(N(A2)2), —C(═O)N(A2)2), halogen, alkyl, alkenyl, alkynyl, aryl, carbocycle, heterocycle, aralkyl, aryl sulfonamide, aryl alkylsulfonamide, aryloxy sulfonamide, aryloxy alkylsulfonamide, aryloxy arylsulfonamide, alkyl sulfonamide, alkyloxy sulfonamide, alkyloxy alkylsulfonamide, arylthio, —(CH2)mheterocycle, —(CH2)m—C(O)O-alkyl, —O(CH2)mOC(O)Oalkyl, —O—(CH2)m—O—C(O)—(CH2)m-alkyl, —(CH2)m—O—C(O)—O-alkyl, —(CH2)m—O—C(O)-β-cycloalkyl, —N(H)C(CH3)C(O)O-alkyl, or alkoxy arylsulfonamide, optionally substituted with R111;
• A2 is independently selected from PRT, H, alkyl, alkenyl, alkynyl, amino, amino acid, alkoxy, aryloxy, cyano, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulfonamide, or arylsulfonamide, wherein each A2 is optionally substituted with A3;
• R111 is independently selected from H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, halogen, haloalkyl, alkylsulfonamido, arylsulfonamido, —C(O)NHS(O)2—, or —S(O)2—, optionally substituted with one or more A3;
• R2 is C2-C6 alkyl, C2-C6 alkenyl or C3-C6 cycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo;
• R3 is C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6)alkyl, aryl(C1-C8)alkyl, or Het, wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR10, SR10, N(R10)2, NH(C1-C6 alkyl)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6haloalkyl, halo(C1-C6 alkoxy), NO2, CN, CF3, SO2(C1-C6 alkyl), S(O)(C1-C6 alkyl), NR10SO2R6, SO2N(R6)2, NHCOOR6, NHCOR6, NHCONHR6, CO2R10, C(O)R10, and CON(R10)2;
• Het is a 5-6 membered saturated cyclic ring having 1 or 2 heteroatoms selected from N, 0 and S, wherein said ring is optionally substituted with 1 to 3 substituents selected from halo, OR10, SR10, N(R10)2, NH(C1-C6 alkyl)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo(C1-C6 alkoxy), NO2, CN, CF3, SO2(C1-C6 alkyl), S(O)(C1-C6 alkyl), NR10SO2R6, SO2N(R6)2, NHCOOR6, NHCOR6, NHCONHR6, CO2R10, C(O)R10, and CON(R10)2;
• R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl(C1-C8)alkyl, or aryl(C1-C8)alkyl;
• wherein aryl is phenyl or naphthyl and said alkyl, cycloalkyl, or aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halo, OR10, SR10, N(R10)2, NH(C1-C6 alkyl)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo(C1-C6 alkoxy), NO2, CN, CF3, SO2(C1-C6 alkyl), S(O)(C1-C6 alkyl), NR10SO2R6, SO2N(R6)2, NHCOOR6, NHCOR6, NHCONHR6, CO2R10, C(O)R10, and CON(R10)2;
• R5 is H, halo, OR10, C1-C6 alkyl, CN, CF3, SR10, SO2(C1-C6 alkyl), C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C1-C6 haloalkyl, N(R7)2, aryl, heteroaryl or heterocyclyl;
• wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen;
• and wherein said aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, OR10, SR10, N(R7)2, NH(C1-C6 alkyl)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 haloalkyl, halo(C1-C6 alkoxy), C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NO2, CN, CF3, SO2(C1-C6 alkyl), NR10SO2R6, SO2N(R6)2, S(O)(C1-C6 alkyl), NHCOOR6, NHCOR6, NHCONHR6, CO2R10, C(O)R10, and CON(R10)2;
• wherein the 2 adjacent substituents of said cycloalkyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl are optionally taken together to form a 3-6 membered cyclic ring containing 0-3 heteroatoms selected from N, 0 and S;
• R6 is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C5)alkyl, aryl, aryl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl, or heterocyclyl(C1-C8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted or heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents;
• and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen;
• each R77 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C8)alkyl, aryl, aryl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl, or heterocyclyl(C1-C6 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W′ substituents;
• and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1,2, 3 or 4 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen;
• each W′ is independently halo, OR100, C1-C6 alkyl, CN, CF3, NO2, SR100, CO2R100, CON(R100)2, C(O)R100, N(R100)C(O)R100, SO2(C1-C6 alkyl), S(O)(C1-C6 alkyl), C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C6 haloalkyl, N(R100)2, NH(C1-C6 alky1)O(C1-C6 alkyl), halo(C1-C6 alkoxy), NR100SO2R100, SO2N(R100)2, NHCOOR100, NHCONHR100, aryl, heteroaryl or heterocyclyl;
• wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1,2, 3 or 4 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen;
• and wherein 2 adjacent W′ moieties are optionally taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, unsaturated non-aromatic, or aromatic cyclic ring having 0-2 heteroatoms selected from N, 0 and S;
• each Rr is independently H, (C2-C10)alkenyl, (C2-C10) alkynyl, (C1-C10)alkanoyl, or (C1-C10)alkoxycarbonyl;
• Y is C(═O), 502, or C(═N—CN);
• Y1 is independently O, S, N(A3), N(O)(A3), N(OA3), N(O)(OA3) or N(N(A3)(A3));
• Z is C(R10)2, or N(R4):
• M is C1-C12 alkylene or C2-C12 alkenylene, wherein said alkylene or alkenylene is optionally substituted with 1 or 2 substituents selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl(C1-C8 alkyl), and aryl(C1-C8 alkyl) and further which M can be substituted by up to nine halo;
• and 2 substituents of M are optionally taken together to form a 3-6 membered cyclic ring containing 0-3 heteroatoms selected from N, 0 and S;
• and optionally one substituent of M can be taken together with a ring atom within M to form a 3-6 membered ring system containing 0-3 heteroatoms selected, from N, 0, and S where the 3-6 membered ring system is fused to the macrocyclic ring system;
• each R7 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C5)allyl, aryl, aryl(C1-C4)alkyl, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl, or heterocyclyl(C1-C8 alkyl), wherein said alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 W substituents;
• and wherein each aryl is independently phenyl or naphthyl, each heteroaryl is independently a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen, and each heterocyclyl is independently a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen;
• each W is independently halo, OR10, C1-C6 alkyl, CN, CF3, NO2, SR10, CO2R10, CON(R10)2, C(O)R10, N(R10)C(O)R10, SO2(C1-C6 alkyl), S(O)(C1-C6 alkyl), C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C1-C6 haloalkyl, N(R10)2, NH(C1-C6 alky1)O(C1-C6 alkyl), halo(C1-C6 alkoxy), NR10SO2R10, SO2N(R10), NHCOOR10, NHCONHR10, aryl, heteroaryl or heterocyclyl;
• wherein aryl is phenyl or naphthyl, heteroaryl is a 5- or 6-membered aromatic ring having 1, 2 or 3 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen, and heterocyclyl is a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, attached through a ring carbon or nitrogen;
• each R10 is independently H or C1-06 alkyl;
• each R100 is independently H or C1-C6 alkyl;
• r is 0 to 6;
• m is 0 to 6.