Potent and selective inhibitors of hepatitis c virus

A compound of Formula (II)

• each R1 and R1′ are independently present or absent if present are independently selected from hydroxy, hydroxyalkyl, alkoxy(C1-6), alkoxyalkyl(C2-8), alkoxycarbonyl, alkyl(C1-8), arylalkoxycarbonyl, lower alkenyl (C2-6), lower alkynyl (C2-6), carboxy, halogen (F, Cl, Br, I), CF3, haloalkyl, N3, CN, N(R′)2, SR′, OCOR′, N(COR′)R′, N(COR′)COR′, SCOR′, S(O)2NR′2, S(O)2R′;
• each R′ is independently H, a lower alkyl (C1-6), lower haloalkyl (C1-6), lower alkoxy (C1-6), lower alkenyl (C2-6), lower alkynyl (C2-6), lower cycloalkyl (C3-6), aryl, heteroaryl, alkylaryl, arylalkyl, or if two R′ reside on the same nitrogen atom they can come together to form an alkyl ring (C3-6) containing none or one heteroatom independently selected from N, O, and S;
• wherein the R′ groups can be substituted with one or more substituents as defined above, for example, hydroxyalkyl, aminoalkyl, and alkoxyalkyl;
• u and v are independently 0, 1, 2, 3, or 4;
• A is selected from phenyl and six-membered heteroaromatic rings containing one, two, or three nitrogen atoms;
• B is selected from phenyl and a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a six-membered ring or a six-membered bridged or spiro-fused ring containing none, one, or two heteroatoms independently selected from N, O, and S, a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, a five-membered ring containing none, one, or two heteroatoms independently selected from N, O, and S;
• a four-membered ring containing none, one, or two heteroatoms independently selected from N, O, and S;
• alkylheteroaryl, or alkylaryl;
• L is selected from O, S, S(O), S(O)2, C═NCN, or selected from phenyl and a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a six-membered ring or a six-membered bridged ring containing none, one, or two heteroatoms independently selected from N, O, and S, a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, a five-membered ring containing none, one, or two heteroatoms independently selected from N, O, and S;
• C and D are independently a five-membered heteroaromatic ring containing one, two or three heteroatoms selected from nitrogen, sulfur, and oxygen;
• When R2 and R2′ are attached to a carbon they are independently selected from hydrogen, halogen (F, Cl, Br, I), CF3, hydroxy, N(R′)S(O)2R′, S(O)2R′, S(O)2N(R′)2, alkoxy (C1-6), cyano, alkynyl (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, heterocyclylalkyl, hydroxyalkyl;
• When R2 and R2′ are attached to a nitrogen they are independently selected from hydrogen, alkoxy (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, carbonylalkyl, carbonyl aryl, alkyl, heterocyclylalkyl, hydroxyalkyl (C2-6), S(O)2R′;
• R3 and R3′ are independently selected from
• each m is independently 0, 1, or 2;
• each o is independently 1, 2, or 3;
• each s is independently 0, 1, 2, or 3;
• each X is independently selected from O, S, S(O), SO2, CH2, CHR5, and C(R5)2;
• provided that when m is 0, X is selected from CH2, CHR5, and C(R5)2;
• each R5 is independently selected from CF3, N3, and haloalkyl, and C(R5)2 can also be C(O),
• each R6 is independently selected from —C(O)—, —C(S)— and —C(NRz)—;
• R7 is selected from hydrogen and alkyl;
• R8 and R9 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and hydroxyalkyl;
• or,
• R8 and R9, together with the carbon atom to which they are attached, form a five- or six-membered saturated ring optionally containing one or two heteroatoms selected from NRZ, O, and S;
• wherein IV is selected from hydrogen and alkyl;
• each R10 and R11 are independently selected from H, alkylcarboxy amino, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylamino, alkylguanasyl, alkylaryl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, cycloakylamino, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, alkylheterocyclyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, and hydroxyalkyl, wherein the groups can be substituted with one or more substituents as defined above, for example, hydroxyaryl, aminoalkyl, and alkoxyalkyl;
• each R12 and R16 are independently selected from hydrogen, R13—C(O)—, R13—C(S)—, and R′;
• each R′ is as defined above;
• and
• each R13 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, and —N(R′)2, wherein each R′ is as defined above;
• and pharmaceutically acceptable salts and prodrugs thereof,
• wherein the compounds can be in the form of the R- or S-configuration, or a mixture thereof, including a racemic or diastereomeric mixture thereof.

A compound of Formula (III)

• each R1 and R1′ is present or absent if present is independently selected from hydroxy, hydroxyalkyl, alkoxy(C1-6), alkoxyalkyl(C2-8), alkoxycarbonyl, alkyl(C1-8), arylalkoxycarbonyl, lower alkenyl (C2-6), lower alkynyl (C2-6), carboxy, halogen (F, Cl, Br, I), CF3, haloalkyl, N3, CN, N(R′)2, SR′, OCOR′, N(COR′)R′, N(COR′)COR′, SCOR′, S(O)2NR′2, S(O)2R′, wherein each R′ is independently H, a lower alkyl (C1-C6), lower haloalkyl (C1-C6), lower alkoxy (C1-6), lower alkenyl (C2-6), lower alkynyl (C2-6), lower cycloalkyl (C3-6), aryl, heteroaryl, alkylaryl, arylalkyl, or if two R′ reside on the same nitrogen atom they can come together to form an alkyl ring (C3-6) containing none or one heteroatom independently selected from N, O, and S;
• wherein the R′ groups can be substituted with one or more substituents as defined above, for example, hydroxyalkyl, aminoalkyl, and alkoxyalkyl;
• u and v are independently 0, 1, 2, 3, or 4;
• A is selected from phenyl and six-membered heteroaromatic rings containing one, two, or three nitrogen atoms;
• B is selected from phenyl and a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a six-membered ring or a six-membered bridged or spiro-fused ring containing none, one, or two heteroatoms independently selected from N, O, and S, a five-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, a five-membered ring containing none, one, or two heteroatoms independently selected from N, O, and S;
• a four-membered ring containing none, one, or two heteroatoms independently selected from N, O, and S;
• alkylheteroaryl, or alkylaryl;
• R3 is selected from
• each m is independently 0, 1, or 2;
• each o is independently 1, 2, or 3;
• each s is independently 0, 1, 2, or 3;
• each X is independently selected from O, S, S(O), SO2, CH2, CHR5, and C(R5)2;
• provided that when m is 0, X is selected from CH2, CHR5, and C(R5)2;
• each R5 is independently selected from CF3, N3, and haloalkyl, and C(R5)2 can also be C(O),
• each R6 is independently selected from —C(O)—, —C(S)— and —C(NRz)—;
• R7 is selected from hydrogen and alkyl;
• R8 and R9 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and hydroxyalkyl;
• or,
• R8 and R9, together with the carbon atom to which they are attached, form a five- or six-membered saturated ring optionally containing one or two heteroatoms selected from NRZ, O, and S;
• wherein IV is selected from hydrogen and alkyl;
• each R10 and R11 are independently selected from H, alkylcarboxy amino, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylamino, alkylguanasyl, alkylaryl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, cycloakylamino, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, alkylheterocyclyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, and hydroxyalkyl, wherein the groups can be substituted with one or more substituents as defined above, for example, hydroxyaryl, aminoalkyl, and alkoxyalkyl;
• each R12 and R16 are independently selected from hydrogen, R13—C(O)—, R13—C(S)—, and R′;
• Each R′ is as defined above;
• each R13 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, and —N(R′)2, wherein each R′ is as defined above;
• R14 and R14′ are independently selected from halogen (F, Cl, Br, I), CF3, hydroxy, alkoxy (C1-6), cyano, alkynyl (C2-6), alkoxyalkyl (C3-6), alkoxycarbonylalkyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, heterocyclylalkyl, hydroxyalkyl;
• and
• R15 and R15 are independently selected from hydrogen, alkoxy (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, carbonylalkyl, carbonyl aryl, alkyl, heterocyclylalkyl, hydroxyalkyl (C2-6), and pharmaceutically acceptable salts and prodrugs thereof,
• wherein the compounds can be in the form of the R- or S-configuration, or a mixture thereof, including a racemic or diastereomeric mixture thereof.

A compound having the formula:

• wherein:
• R3 is
• each m is independently 0, 1, or 2;
• n is 0, 1, 2, or 3,
• each s is independently 0, 1, 2, or 3;
• each X is independently selected from O, S, S(O), SO2, CH2, CHR5, and C(R5)2;
• provided that when m is 0, X is selected from CH2, CHR5, and C(R5)2;
• each R5 is independently selected from 5-membered heteroaryl, halo substituted 5-membered heteroaryl, thioalkyl, thioaryl, SCH3, SCF3, sulfoxide alkyl, sulfoxide aryl, S(O)CH3, S(O)CF3, sulfone alkyl, sulfone aryl, S(O)2CH3, S(O)2CF3, haloalkyl, CF3, N3, and CN, with the proviso that —C(R5)2 can be —C(O),
• each R′ is a defined above;
• with the proviso that C(R5)2 cannot be C(alkoxy)2, C(OH)2, C(alkoxy)(OH), or C(halo)(OH), and with the further proviso that C(R5)2 can also be C(═O),
• each R6 is independently selected from —C(O)—, —C(S)— and —C(NRz)—;
• each R10 and R11 are independently selected from H, alkylcarboxy amino, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylamino, alkylguanasyl, alkylaryl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, cycloakylamino, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, alkylheterocyclyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, and hydroxyalkyl, wherein the groups can be substituted with one or more substituents as defined above, for example, hydroxyaryl, aminoalkyl, and alkoxyalkyl;
• each R12 and R16 are independently selected from hydrogen, R13—C(O)—, R13—C(S)—, and R′;
• Each R′ is as defined above;
• each R13 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, and —N(R′)2, wherein each R′ is as defined above;
• R14 and R14′ are independently selected from halogen (F, Cl, Br, I), CF3, hydroxy, alkoxy (C1-6), aryl, 5-membered heteroaryl, lower alkyl (C1-6) or halo substituted aryl, aryl or halo substituted 5-membered heteroaryl, cyano, alkynyl (C2-6), alkoxyalkyl (C3-6), alkoxycarbonylalkyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, heterocyclylalkyl, hydroxyalkyl;
• and
• R15 and R15′ are independently selected from hydrogen, alkoxy (C2-6), alkoxyalkyl (C3-6), alkoxycarbonyl, carbonylalkyl, carbonyl aryl, alkyl, heterocyclylalkyl, hydroxyalkyl (C2-6), and pharmaceutically acceptable salts and prodrugs thereof,
• Z is C1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR′R″, —CF3, —CN, —NO2, —C2R′, —SR′, —N3, —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)O R″, —SO2R′, —SO2NR′R″, and —NR′SO2R″, where R′ and R″ are individually hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and
• j is an integer of from 0 to 3,
• wherein the compounds can be in the form of the R- or S-configuration, or a mixture thereof, including a racemic or diastereomeric mixture thereof.