CA2560897A1 - Macrocyclic compounds as inhibitors of viral replication - Google Patents

Macrocyclic compounds as inhibitors of viral replication Download PDF

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Publication number
CA2560897A1
CA2560897A1 CA002560897A CA2560897A CA2560897A1 CA 2560897 A1 CA2560897 A1 CA 2560897A1 CA 002560897 A CA002560897 A CA 002560897A CA 2560897 A CA2560897 A CA 2560897A CA 2560897 A1 CA2560897 A1 CA 2560897A1
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alkyl
optionally substituted
hydroxy
alkoxy
cycloalkyl
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CA002560897A
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French (fr)
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CA2560897C (en
Inventor
Lawrence M. Blatt
Steven M. Wenglowsky
Steven W. Andrews
Kevin R. Condroski
Yutong Jiang
April L. Kennedy
George A. Doherty
John A. Josey
Peter J. Stengel
Benjamin T. Woodard
Machender R. Madduru
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Intermune Inc
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Intermune, Inc.
Lawrence M. Blatt
Steven M. Wenglowsky
Steven W. Andrews
Kevin R. Condroski
Yutong Jiang
April L. Kennedy
George A. Doherty
John A. Josey
Peter J. Stengel
Benjamin T. Woodard
Machender R. Madduru
Array Biopharma Inc.
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Publication of CA2560897A1 publication Critical patent/CA2560897A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The embodiments provide macrocylic compounds, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

Claims (212)

1. A compound having the Formula I:
wherein:
Q is a core ring selected from:
wherein the core ring can be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy, substituted C1-6 alkoxy, C6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, or Q is R1-R2, wherein R1 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; and R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloallcyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro;
R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or (CO)CHR21NH(CO)R22;
R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6 or to aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4 position of the tetrapyranyl ring;
Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl, or R9 is C6 or 10 ary which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, alkoxy optionally substituted with up to 5 fluoro; or R9 is a C1-6 alkyl optionally substituted with up to 5 fluoro groups, NR6R7, NR1aR1b, or (CO)OH, or R9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C1-6 alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
wherein R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl, or R1a and R1b are each independently H and C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro, or R1a and R1b are each independently H, heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or NR1aR1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl, or NR1aR1b is a heteroaryl selected from the group consisting of wherein R1c is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R1d)2, NH(CO)R1d, or NH(CO)NHR1d, wherein each R1d is independently H, C1-6 alkyl, or C3-6 cycloalkyl, or R1c is NH(CO)OR1e, wherein R1e is C1-6 alkyl or C3-6 cycloalkyl;
p=0 or 1;

V is selected from O, S, or NH;
when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W
is selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;
the dashed lines represent an optional double bond;
R21 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and R22 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl;
with the proviso that the compound of Formula I does not include a compound having the Formula II, III, or IV:
wherein:
(aa) R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro, C6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7, NHC(S)NR6R7, C(O)NR6R7, NR6R7, C(O)R8, C(O)OR8, NHC(O)R8, NHC(O)OR8, SO m R8, NHS(O)2R8, CH n NR6R7, OCH n NR6R7, or OCH n R9 where R9 is imidazolyl or pyrazolyl; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the definition of R1 and R2 are optionally substituted by up to two halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, pyridal, phenoxy and thiophenoxy in the definition of R1 and R2 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
(bb) m = 0, 1, or 2;
(cc) R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro;
(dd) R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or (CO)CHR21NH(CO)R22;
(ee) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, alkoxy optionally substituted with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(ff) R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6 or to aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4 position of the tetrapyranyl ring;
(gg) Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl, or R9 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, alkoxy optionally substituted with up to 5 fluoro; or R9 is a C1-6 alkyl optionally substituted with up to 5 fluoro groups, NR6R7, or (CO)OH, or R9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C1-6 alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
(hh) R10 and R11 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the definition of R10 and R11 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R10 and R11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R10 and R11 are combined as O;
(ii) p= 0 or 1;

(jj) R12 and R13 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R12 and R13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R12 and R13 are each independently C1-6 alkyl optionally substituted with (CH2)n OR8;
(kk) R20 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro;
(ll) n =1-4;
(mm) V is selected from O, S, or NH;
(nn) when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;

(oo) the dashed line represents an optional double bond;
(pp) R21 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and (qq) R22 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
2. The compound of Claim 1, wherein the core ring is
3. The compound of Claim 1, wherein the coca ring is
4. The compound of Claim 1, wherein the core ring is
5. The compound of Claim 1 of the formula Ia:
6. The compound of Claim 1 of the formula Ib
7. The compound of Claim 1 of the formula Ic:
8. The compound of Claim 1 of the formula Id:
9. The compound of Claim 1 of the formula Ie:
10. The compound of Claim 1 of the formula If:
11. The compound of Claim 1 of the formula Ig:

12. The compound of Claim 1 of the formula Ih:
13. The compound of Claim 1 of the formula Ii:
14. The compound of Claim 1 of the formula Ij:

15. The compound of Claim 1 of the formula Iz:
16. The compound of Claim 1, wherein Y is sulfonimide of the formula C(O)NHS(O)2R9, where R9 is selected from the group consisting of C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, and NR1a R1b, wherein R1a and are each independently H, C1-6 alkyl, or C3-7 cycloalkyl.
17. The compound of Claim 2, wherein Y is sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is selected from the group consisting alkyl, of C1-6alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, NR1a R1b, wherein R1a and R1b are each independently H, C1-6 alkyl, or C3-7 cycloalkyl.
18. The compound of Claim 3, wherein Y is sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is selected from the group consisting of C1-6 alkyl, C3-7alkyl, cycloalkyl, C4-10 alkylcycloalkyl, NR1a R1b, wherein R1a and R1b are each independently H, C1-6 alkyl, or C3-7 cycloalkyl.
19. The compound of Claim 4, wherein Y is sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is selected from the group consisting of C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, and NR1a R1b, wherein R1a and R1b are each independently H, C1-6 alkyl, or C3-7 cycloalkyl.
20. The compound of Claim 1, wherein the C13-C14 double bond is cis.
21. The compound of Claim 1, wherein the C13-C14 double bond is trans.
22. A pharmaceutical composition comprising:
a) the compound of Claim 1; and b) a pharmaceutically acceptable carrier.
23. The pharmaceutical composition of Claim 22 in a formulation free of any alcohol and airy poly-ol.
24. The pharmaceutical composition of Claim 23, wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).
25. The pharmaceutical composition of Claim 22 in an aqueous formulation free of any excipient that reduces polarity in the aqueous formulation.
26. The pharmaceutical composition of Claim 22 in a tablet formulation.
27. The pharmaceutical composition of Claim 22 in a caplet formulation.
28. The pharmaceutical composition of Claim 22 in a capsule formulation.
29. A method of treating a hepatitis C virus infection in an individual, the method comprising administering to the individual an effective amount of the compound of Claim 1.
30. The method of Claim 29, wherein a sustained viral response is achieved.
31. The method of Claim 29, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
32. The method of Claim 31, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
33. The method of Claim 29, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
34. The method of Claim 29, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
35. The method of Claim 34, wherein the thymosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
36. The method of Claim 29, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
37. The method of Claim 36, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
38. The method of Claim 29, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
39. The method of Claim 38, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
40. The method of Claim 38, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
41. The method of Claim 38, wherein the IFN-a is INFERGEN consensus IFN-a.
42. The method of Claim 29, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
43. A method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of the compound of Claim 1.
44. The method of Claim 43, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
45. The method of Claim 44, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
46. The method of Claim 43, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
47. The method of Claim 43, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
48. The method of Claim 47, wherein the thymosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
49. The method of Claim 43, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
50. The method of Claim 49, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
51. The method of Claim 43, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
52. The method of Claim 51, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
53. The method of Claim 51, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
54. The method of Claim 51, wherein the IFN-a is INFERGEN consensus IFN-a.
55. The method of Claim 43, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
56. A method of increasing liver function in an individual having a hepatitis C
virus infection, the method comprising administering to the individual an effective amount of the compound of Claim 1.
57. The method of Claim 56, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
58. The method of Claim 57, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
59. The method of Claim 56, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
60. The method of Claim 56, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
61. The method of Claim 60, wherein the thymosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
62. The method of Claim 56, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
63. The method of Claim 62, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
64. The method of Claim 56, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
65. The method of Claim 64, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
66. The method of Claim 64, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
67. The method of Claim 64, wherein the IFN-a is INFERGEN consensus IFN-a.
68. The method of Claim 56, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
69. A compound having the Formula XI:
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H and C6 or to aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-to alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
or R1a and R1b are each independently H or heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
or NR1aR1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or NR1aR1b is a heteroaryl selected from the group consisting of:

wherein R1c is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R1d)2, NH(CO)R1d, or NH(CO)NHR1d, wherein each R1d is independently H, C1-6 alkyl, or C3-6 cycloalkyl;
or R1c is NH(CO)OR1e wherein R1e is C1-6 alkyl, or C3-6 cycloalkyl;
(b) W is O or NH;
(c) V is selected from O, S, or NH;
(d) when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;
(e) Q is a bicyclic secondary amine with the structure of:
wherein R21 and R22 are each independently H, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro, C6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7, NHC(S)NR6R7, C(O)NR6R7, NR6R7, C(O)R8, C(O)OR8, NHC(O)R8, NHC(O)OR8, SO m R8 (m = 0, 1 or 2), or NHS(O)2R8; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the definition of R21 and R22 are optionally substituted by up to two halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, pyridal, phenoxy and thiophenoxy in the definition of R21 and R22 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;

wherein R10 and R11 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, (CH2)n NR6R7, or (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C1-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or to aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro; or R10 and R11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R10 and R11 are combined as O;
wherein p = 0 or 1;
wherein R12 and R13 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or to aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-1- alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R12 and R13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
wherein R20 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, (CH2)n NR6R7, or (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, or C4-to alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
wherein n = 0-4;
wherein R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
or R2 is R2aR2b when W = NH and V = O, wherein R2a is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR2cR2d, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R2b is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR2cR2d, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
said R2c and R2d are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro; or R2c and R2d are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
(g) R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, or S(O)2R8;
(h) R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; and (i) the dashed line represents an optional double bond.
70. The compound of Claim 69 having the Formula XII:

wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from the group consisting of:
wherein R1c is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R1d)2, NH(CO)R1d, or NH(CO)NHR1d, wherein each R1d is independently H, C1-6 alkyl, or C3-6 cycloalkyl;
or NR1aR1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;
(b) R21 and R22 are each independently H, halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl;

(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-tetrahydofuryl;
(f) R10 and R11 are each independently H, halo, C1-3 alkyl, or R10 and R11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
(g) R12 and R13 are each independently H, halo, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 halo atoms; and (h) the dashed line represents an optional double bond.
71. The compound of Claim 69 having the Formula XIII:
wherein:
(a) R1a and R1b are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from the group consisting of:
wherein R1c is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R1d)2, NH(CO)R1d, or NH(CO)NHR1d, wherein each R1d is independently H, C1-6 alkyl, or C3-6 cycloalkyl;
or NR1aR1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;
(b) R21 and R22 are each independently H, halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-6 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl;
(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-tetrahydrofuryl; and (f) the dashed line represents an optional double bond.
72. The compound of Claim 69 having the Formula XIV:
wherein:
(a) R1a and R1v are each independently H, C1-6 alkyl, C3-7 cycloalkyl, or C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;
or R1a and R1b are each independently H or heteroaryl selected from a group consisting of:

wherein R1c is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R 1d)2, NH(CO)R1d, or NH(CO)NHR1d, wherein each R1d is independently H, C1-6 alkyl, or C3-6 cycloalkyl;
or NR1aR1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;
(b) Q is C6 or C10 aryl optionally substituted with up to three NR20R2d, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro;
said R2c and R2d are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or R2c and R2d are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
or R2a is an unsaturated five- or six-membered heteroaryl, or such defined heteroaryl fused to another cycle be it heterocycle or any other cycle;
(c) R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;
(d) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl;
(e) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-tetrahydrofuryl; and (f) the dashed line represents an optional double bond.
73. The compound of Claim 69 having the Formula XV:

wherein:
(a) R1 and R2 are each independently H, halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy;
(b) R5 is H, C(O)OR8 or C(O)NHR8;
(c) R8 is C1-6 alkyl, C5-6 cycloalkyl, or 3-tetrahydrofuryl;
(d) R9 is C1-3 alkyl, C3-5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy;
(e) R10 and R11 are each independently H, C1-3 alkyl, or C4-5 cycloalkyl;
(f) W is selected from O or NH; and (g) the dashed line represents an optional double bond.
74. The compound of Claim 69 having the Formula XVI;

wherein:
(a) R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy;
(b) R5 is H, C(O)OR8 or C(O)NHR8;
(c) R8 is C1-6 alkyl or C5-6 cycloalkyl;
(d) R9 is C1-3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1-3 alkyl, C1-3 alkoxy;
(e) R10 and R11 are each independently H, C1-3 alkyl, or R10 and R11 are taken together with the carbon to which they are attached to form cyclopropyl or cyclobutyl; and (f) the dashed line represents an optional double bond.
75. The compound of Claim 69 having the Formula XVII:

wherein:
(a) R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy;
(b) R5 is H, C(O)OR8 or C(O)NHR8;
(c) R8 is C1-6 alkyl or C5-6 cycloalkyl;
(d) R9 is C1-3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy; and (e) the dashed line represents an optional double bond.
76. A pharmaceutical composition comprising:
a) the compound of Claim 69; and b) a pharmaceutically acceptable carrier.
77. The pharmaceutical composition of Claim 76 in a formulation free of any alcohol and any poly-ol.
78. The pharmaceutical composition of Claim 77, wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol)(PEG).
79. The pharmaceutical composition of Claim 76 in an aqueous formulation free of any excipient that reduces polarity in the aqueous formulation.
80. The pharmaceutical composition of Claim 76 in a tablet formulation.
81. The pharmaceutical composition of Claim 76 in a caplet formulation.
82. The pharmaceutical composition of Claim 76 in a capsule formulation.
83. A method of treating a hepatitis C virus infection in an individual, the method comprising administering to the individual an effective amount of the compound of Claim 69.
84. The method of Claim 83, wherein a sustained viral response is achieved.
85. The method of Claim 83, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
86. The method of Claim 85, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
87. The method of Claim 83, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
88. The method of Claim 83, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
89. The method of Claim 88, wherein the thymosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
90. The method of Claim 83, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
91. The method of Claim 90, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
92. The method of Claim 83, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
93. The method of Claim 92, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
94. The method of Claim 92, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
95. The method of Claim 92, wherein the IFN-a is INFERGEN consensus IFN-a.
96. The method of Claim 83, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
97. A method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of the compound of Claim 69.
98. The method of Claim 97, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
99. The method of Claim 98, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
100. The method of Claim 97, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
101. The method of Claim 97, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
102. The method of Claim 101, wherein the thymosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
103. The method of Claim 97, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
104. The method of Claim 103, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
105. The method of Claim 97, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
106. The method of Claim 105, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
107. The method of Claim 105, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
108. The method of Claim 105, wherein the IFN-a is INFERGEN consensus IFN-a.
109. The method of Claim 97, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
110. A method of increasing liver function in an individual having a hepatitis C
virus infection, the method comprising administering to the individual an effective amount of the compound of Claim 69.
111. The method of Claim 110, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
112. The method of Claim 111, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
113. The method of Claim 110, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
114. The method of Claim 110, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
115. The method of Claim 114, wherein the thymosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
116. The method of Claim 110, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
117. The method of Claim 116, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
118. The method of Claim 110, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
119. The method of Claim 118, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
120. The method of Claim 118, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
121. The method of Claim 118, wherein the IFN-a is INFERGEN consensus IFN-a.
122. The method of Claim 110, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
123. A compound having the Formula XVIII:

wherein (a) R1 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR5R6, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
(b) R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR5R6, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
(c) R3 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;

(d) R4 is C1-6 alkyl, C(O)NR5R6, C(S)NR5R6, C(O)R7, C(O)OR7, or S(O)2R7;
(e) R5 and R6 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, alkoxy optionally substituted with up to 5 fluoro; or R5 and R6 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) R7 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R7 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
(g) R8 is C1-3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy; and (h) the dashed line represents an optional double bond;
or a pharmaceutically acceptable salt thereof.
124. The compound of Claim 123, wherein R1 is phenyl, benzothiazole, benzothiophene, benzofuran, or benzimidazole, each optionally substituted with up to 1-2 NR5R6, halo, cyano, vitro, hydroxy, alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R2 is H, phenyl, pyridine, pyrimidine, thiazole, oxazole, isoxazole, or pyrazole, each optionally substituted with up to 1-2 NR5R6, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro;
R3 is H;
R4 is C1-6 alkyl, C(O)NR5R6, C(S)NR5R6, C(O)R7, C(O)OR7, or S(O)2R7;

R5 and R6 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to two halo, cyano, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R5 and R6 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R7 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R7 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R8 is C1-3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy; and the dashed line represents an optional double bond.
125. The compound of Claim 123, wherein R1 is phenyl, benzothiazole, or benzothiophene each optionally substituted with up to 1-2 halo, hydroxy, C1-2 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R2 is H or phenyl optionally substituted with up to 1-2 halo, hydroxy, C1-3 alkyl, alkyl, or C1-3 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R3 is H;
R4 is C1-6 alkyl, C(O)NR5R6, C(O)R7, or C(O)OR7;
R5 is H and R6 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to two halo, cyano, hydroxy, alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro;
R7 is C1-6 alkyl or C3-7 cycloalkyl, which are all optionally substituted from one to three times with halo or phenyl; or R7 is C6 or 10 aryl which is optionally substituted by up to one halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R8 is C1-3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1-3 alkyl, or C1-3 alkoxy; and the dashed line represents an optional double bond.
126. A pharmaceutical composition comprising:
a) the compound of Claim 123; and b) a pharmaceutically acceptable carrier.
127. The pharmaceutical composition of Claim 126 in a formulation free of any alcohol and any poly-ol.
128. The pharmaceutical composition of Claim 127, wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).
129. The pharmaceutical composition of Claim 126 in an aqueous formulation free of any excipient that reduces polarity in the aqueous formulation.
130. The pharmaceutical composition of Claim 126 in a tablet formulation.
131. The pharmaceutical composition of Claim 126 in a caplet formulation.
132. The pharmaceutical composition of Claim 126 in a capsule formulation.
133. A method of treating a hepatitis C virus infection in an individual, the method comprising administering to the individual an effective amount of the compound of Claim 123.
134. The method of Claim 133, wherein a sustained viral response is achieved.
135. The method of Claim 133, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
136. The method of Claim 135, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
137. The method of Claim 133, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
138. The method of Claim 133, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
139. The method of Claim 138, wherein the thyrnosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
140. The method of Claim 133, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
141. The method of Claim 140, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
142. The method of Claim 133, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
143. The method of Claim 142, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
144. The method of Claim 142, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
145. The method of Claim 142, wherein the IFN-a is INFERGEN consensus IFN-a.
146. The method of Claim 133, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
147. A method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of the compound of Claim 123.
148. The method of Claim 147, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
149. The method of Claim 148, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
150. The method of Claim 147, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
151. The method of Claim 147, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
152. The method of Claim 151, wherein the thymosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
153. The method of Claim 147, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
154. The method of Claim 153, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
155. The method of Claim 147, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
156. The method of Claim 155, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
157. The method of Claim 155, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
158. The method of Claim 155, wherein the IFN-a is INFERGEN consensus IFN-a.
159. The method of Claim 147, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
160. A method of increasing liver function in an individual having a hepatitis C
virus infection, the method comprising administering to the individual an effective amount of the compound of Claim 123.
161. The method of Claim 160, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
162. The method of Claim 161, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
163. The method of Claim 160, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
164. The method of Claim 160, wherein the method further comprises administering to the individual an effective amount of thymosin-a.
165. The method of Claim 164, wherein the thyrnosin-a is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
166. The method of Claim 160, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-?).
167. The method of Claim 166, wherein the IFN-? is administered subcutaneously in an amount of from about 10 µg to about 300 µg.
168. The method of Claim 160, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a).
169. The method of Claim 168, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of every 8 days to every 14 days.
170. The method of Claim 169, wherein the IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a administered at a dosing interval of once every 7 days.
171. The method of Claim 169, wherein the IFN-a is INFERGEN consensus IFN-a.
172. The method of Claim 160, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, 2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.
173. A compound of the formula:
wherein:
(a) Z is a group configured to hydrogen bond to an NS3 protease His57 imidazole moiety and to hydrogen bond to a NS3 protease Gly137 nitrogen atom;
(b) P1' is a group configured to form a non-polar interaction with at least one NS3 protease S1' pocket moiety selected from the group consisting of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42, and Phe43;
(c) L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
(d) P2 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; P2 being positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81;
(e) the dashed line represents an optional double bond;
(f) R5 is selected from the group consisting of H, C(O)NR6R7 and C(O)OR8;
(g) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and (h) R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6 or to aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4 position of the tetrapyranyl ring;
with the proviso that the compound does not include a compound having the Formula II, III, or IV:
wherein:
(aa) R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro, C6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O)2NR6R7, NHC(O)NR6R7, NHC(S)NR6R7, C(O)NR6R7, NR6R7, C(O)R8, C(O)OR8, NHC(O)R8, NHC(O)OR8, SO m R8, NHS(O)2R8, CH n NR6R7, OCH n NR6R7, or OCH n R9 where R9 is imidazolyl or pyrazolyl; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the definition of R1 and R2 are optionally substituted by up to two halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, pyridal, phenoxy and thiophenoxy in the definition of R1 and R2 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
(bb) m = 0, 1, or 2;
(cc) R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro;
(dd) R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or (CO)CHR21NH(CO)R22;
(ee) R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, alkoxy optionally substituted with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(ff) R8 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4 position of the tetrapyranyl ring;
(gg) Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl, or R9 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, alkoxy optionally substituted with up to 5 fluoro; or R9 is a C1-6 alkyl optionally substituted with up to 5 fluoro groups, NR6R7, or (CO)OH, or R9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C1-6 alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
(hh) R10 and R11 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the definition of R10 and R11 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R10 and R11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R10 and R11 are combined as O;
(ii) p= 0 or 1;
(jj) R12 and R13 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, (CH2)11NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R12 and R13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R12 and R13 are each independently C1-6 alkyl optionally substituted with (CH2)n OR8;
(kk) R20 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or (CH2)n NR6R7, (CH2)n C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or to aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro;

(11)n = 1-4;
(mm) V is selected from O, S, or NH;
(nn) when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;
(oo) the dashed line represents an optional double bond;
(pp) R21 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, vitro, hydroxy, C1-6 alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or 10 to aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and (qq) R22 is C1-6 alkyl, C3-8 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
174. The compound of Claim 173 in which L consists of from 2 to 5 atoms.
175. The compound of Claim 173 in which L comprises a -W-C(=V)- group, where V and W are each individually selected from O, S or NH.
176. The compound of Claim 173 in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.
177. The compound of Claim 173 in which P2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Va178, Asp79, Gln80 and Asp81.
178. The compound of Claim 173, wherein the C13-C14 double bond is cis.
179. The compound of Claim 173, wherein the C13-C14 double bond is traps.
180. The compound of Claim 173, in which P2 is
181. The compound of Claim 173 of the formula
182. The compound of Claim 181 in which L consists of from 2 to 5 atoms.
183. The compound of Claim 181 in which L comprises a -W-C(=V)- group, where V and W are each individually selected from O, S, or NH.
184. The compound of Claim 181 in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.
185. The compound of Claim 181 in which P2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81.
186. The compound of Claim 181, wherein the C13-C14 double bond is cis.
187. The compound of Claim 181, wherein the C13-C14 double bond is trans.
188. The compound of Claim 173 of the formula
189. The compound of Claim 188 in which L consists of from 2 to 5 atoms.
190. The compound of Claim 188 in which L comprises a -W-C(=V)- group, where V and W are each individually selected from O, S, or NH.
191. The compound of Claim 188 in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.
192. The compound of Claim 188 in which P2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81.
193. The compound of Claim 188, wherein the C13-C14 double bond is cis.
194. The compound of Claim 188, wherein the C13-C14 double bond is trans.
195. A compound having the formula:

wherein:

Q is a core ring selected from:

wherein the core ring can be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy, substituted C1-6 alkoxy, C6 or to aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, or Q is R1-R2, wherein R1 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; and R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro;

R5 is C1-6 alkyl; C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or (CO)CHR21NH(CO)R22;
R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4 position of the tetrapyranyl ring;
Y is COOR9, wherein R9 is C1-6 alkyl;
p= 0 or 1;
V is selected from O, S, or NH;
when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W
is selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-alkylcycloalkyl or C1-6 alkyl optionally substituted with up to 5 fluoro;
the dashed line represents an optional double bond;
R21 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and R27 is C1-6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.

196. The compound of Claim 195 of the formula
197. A compound having the formula:

wherein:
R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro;
R5 is C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or (CO)CHR21NH(CO)R22;
R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6 or to aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-io alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4 position of the tetrapyranyl ring;
Y is a sulfonamide of the formula -C(O)NHS(O)2R9, where R9 is C1-3 alkyl, C3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C1-3 alkyl, C3-7 cycloalkyl, or C1-3 alkoxy, or Y is a carboxylic acid p= 0 or 1;
V is selected from OH, SH, or NH2;
the dashed line represents an optional double bond;
R21 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or or R21 is pyridal, pyramidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy,or thiophenoxy; and R22 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.

198. The compound of Claim 197 of the formula
199. The compound of Claim 198 wherein Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-3 alkyl, C3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C1-3 alkyl, C3-7 cycloalkyl, or C1-3 alkoxy, and wherein V is selected from OH and NH2.
200. A compound having the formula:

wherein:
Q is a core ring selected from:

wherein the core ring can be unsubstituted or substituted H, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, substituted C1-6 alkyl, C1-6 alkoxy, substituted C1-6 alkoxy, C6 or 10 aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, or Q is R1-R2, wherein R1 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; and R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro;
R4 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, Cl-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro;
R5 is C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, S(O)2R8, or (CO)CHR21NH(CO)R22;
R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or alkoxy optionally substituted with up to 5 fluoro; or R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R8 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C1-6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring linked through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring linked through the C4 position of the tetrapyranyl ring;
Y is COOR9, wherein R9 is C1-6 alkyl; or Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is C1-3 alkyl, C3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C1-3 alkyl, cycloalkyl, or C1-3 alkoxy, or Y is a carboxylic acid p= 0 or 1;
V and W are each individually selected from O, S, or NH;
the dashed line represents an optional double bond;
R21 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; or or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy,or thiophenoxy; and R22 is C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
201. The compound of claim 174 in which L is selected from the group consisting of -OCH2- and -NHCH2-.
202. The compound of claim 174 in which L is selected from the group consisting of -CH=CH- and -C.ident.C-.
203. The compound of claim 174 in which L is selected from the group consisting of -SCH2-, -SO2-, and -CH2SO-.
204. The compound of claim 174 in which L is selected from the group consisting of -WC(=V)-NH- and -WC(=V)-O-, where V and W are each individually selected from O, S
or NH.
205. The compound of claim 182 in which L is selected from the group consisting of -OCH2- and NHCH2-.
206. The compound of claim 182 in which L is selected from the group consisting of -CH=CH- and -C.ident.C-.
207. The compound of claim 182 in which L is selected from the group consisting of -SCH2-, -SO2-, and -CH2SO-.
208. The compound of claim 182 in which L is selected from the group consisting of -WC(=V)-NH- and -WC(=V)-O-, where V and W are each individually selected from O, S
or NH.
209. The compound of claim 189 in which L is selected from the group consisting of -OCH2- and -NHCH2-.
210. The compound of claim 189 in which L is selected from the group consisting of -CH=CH- and -C.ident.C-.
211. The compound of claim 189 in which L is selected from the group consisting of -SCH2-, -SO2-, and -CH2SO-.
212. The compound of claim 189 in which L is selected from the group consisting of -WC(=V)-NH- and -WC(=V)-O-, where V and W are each individually selected from O, S
or NH.
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