CA2560897C - Macrocyclic compounds as inhibitors of viral replication - Google Patents

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.

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

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MACROCYCLIC COMPOUNDS AS INHIBITORS OF VIRAL REPLICATION
Background of the Inventi on Field of the Invention [00021 The present invention relates to compounds, processes for their syntheses, pharmaceutical compositions, and methods for the treatment of flaviviral infections, such as hepatitis C virus (HCV) infection. In particular, the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of flaviviral infection.

Description of the Related Art [00031 Hepatitis C virus (HCV) infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States. Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1 % of all deaths.
Studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults.

[vuu4) Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with significant improvements seen in the efficacy of treatment.
Nevertheless, even with combination therapy using pegylated IFN-a plus ribavirin, 40% to 50%
of patients fail therapies, i.e., are nonresponders or relapsers. These patients currently have no effective therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis on liver biopsy are at significant risk of developing complications of advanced liver disease, including ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure, as well as a markedly increased risk of hepatocellular carcinoma.

[00051 The high prevalence of chronic HCV infection has important public health implications for the future burden of chronic liver disease in the United States. Data derived from the National Health and Nutrition Examination Survey (NHANES III) indicate that a large increase in the rate of new HCV infections occurred from the late 1960s to the early 1980s, particularly among persons between 20 to 40 years of age. It is estimated that the number of persons with long-standing HCV infection of 20 years or longer could more than quadruple from 1990 to 2015, from 750,000 to over 3 million. The proportional increase in persons infected for 30 or 40 years would be even greater. Since the risk of HCV-related chronic liver disease is related to the duration of infection, with the risk of cirrhosis progressively increasing for persons infected for longer than 20 years, this increase in the number of persons with long-standing HCV infection could result in a substantial increase in cirrhosis-related morbidity and mortality among patients infected between the years of 1965-1985.

[0006) HCV is an enveloped positive strand RNA virus in the Flaviviridae family. The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins of the virus.
In the case of HCV, the generation of mature nonstructural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first viral protease cleaves at the NS2-NS3 junction of the polyprotein. The second viral protease is serine protease contained within the N-terminal region of NS3 (herein referred to as "NS3 protease"). NS3 protease mediates all of the subsequent cleavage events at sites downstream relative to the position of NS3 in the polyprotein (i.e., sites located between the C-terminus of NS3 and the C-terminus of the polyprotein). NS3 protease exhibits activity both in cis, at the N93-NS4 cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is believed to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. Apparently, the formation of the complex between NS3 and NS4A is necessary for NS3-mediated processing events and enhances proteolytic efficiency at all sites recognized by NS3. The NS3 protease also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is an RNA-dependent RNA polymerase involved in the replication of HCV RNA.
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Patent Nos. 6,172,046; 6,245,740; 5,824,784; 5,372,808; 5,980,884; published international patent applications WO 96/21468; WO 96/11953; WO 00/59929; WO 00/66623;
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4:63-68; Chang et al. (1999) Nat. Biotechnol. 17:793-797; Adolf (1995) Multiple Sclerosis 1 Suppl. 1:544-S47; Chu et al., Tet. Lett. (1996), 7229-7232; Ninth Conference on Antiviral Research, Urabandai, Fukyshima, Japan (1996) (Antiviral Research, (1996), 30:
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Ingallinella et al., Biochem., 37: 8906-8914.

Summary of the Invention [0008] The embodiments provide a compound having the Formula I:
Q
v=~
W
O N
NH I

[0009] wherein:

[0010] Q is a core ring selected from:

I
( p I \ fN

/ [0011] 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, [0012] 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, ilnidazole, isoxazole, pyrazole, isothiazole, napthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR6R7, halo, cyan, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o 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 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;
[0013] R4 is H, C1_6 alkyl, C3.7 cycloalkyl, 04.10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, 04.10 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;

[0014] 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;

[0015] 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 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;
[0016] 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 flydroxy, C1_6 alkyl, C3_7 cycloalkyl, C¾-lo 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;

[0017] 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, C1_6 alkoxy optionally substituted with up to 5 fluoro; or R9 is a C1_6 alkyl optionally substituted with up to 5 fluoro groups, NR6R7, NR1aRlb, 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;
[0018] wherein Rla and Rlb 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, [0019] or Rla and Rlb 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_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1.6 alkoxy optionally substituted with up to 5 fluoro, [0020] or Rla and Rlb 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, [0021] or NRlaRlb 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, [0022] or NR1aRlb is a heteroaryl selected from the group consisting of--`N^N `-N~N
ANN
R1c ~'\R1c and Rtc [0023] wherein Rle is H, halo, C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3_6 cycloalkoxy, NO2, N(RId)2, NH(CO)RId, or NH(CO)NHRId, wherein each Rld is independently H, C1_6 alkyl, or C3_6 cycloalkyl, [0024] or Ric is NH(CO)OR", wherein Rle is C1_6 alkyl or C3_6 cycloalkyl;
[0025] p= 0 or 1;

[0026] V is selected from 0, S, or NH;

[0027] when V is 0 or S, W is selected from 0, 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;

[0028] the dashed lines represent an optional double bond;

[0029] R21 is C1_6 alkyl, C3_7 cycloalkyl, C4_i0 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 [0030] 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 having the Formula I does not include a compound having the Formula II, III, or IV as defined below.

[0031] The embodiments provide a compound having the Formula II, III, or IV:

R11 R11 R11 \1 R10 -I~ R10 R1 R10 Z-R2 1 \ \ R2 R I \" R
N R13 N \~ N 13 V=< R12 V=< Ra V=~ R12 W W W
ON NH Y O N N N 7r ~
NH Y O r NH Y
:7, 9 14 9 14 g 14 II III IV
[0032] wherein:
[0033] a) R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o 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 1o 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)ORS, NHC(O)R8, NHC(O)OR8, SO,,,R8, NHS(O)2R8, CH INR6R7, OCHõNR6R7, or OCHIR9 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;

[0034] b) m = 0, 1, or 2;
[0035] c) 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, nyaroxy-U1_6 alkyl, c;1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0036] d) 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;

[0037] e) 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, 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;

[0038] f) 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;

[0039] g) 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, C1_6 alkoxy optionally substituted with up to 5 fluoro; or R9 is a CI-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;
[0040] h) R10 and R11 are each independently H, C1.6 alkyl, C3_7 cycloalkyl, alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1.6 alkyl, C1.6 alkyl optionally substituted with up to 5 fluoro, (CH2).NR6R7, (CH2)õC(O)OR14 where R14 is H, Cl_6 alkyl, C3_7 cycloalkyl, or C4-1o 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 R'1 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 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 0;

[0041] i) p= 0 or 1;

[0042] j) Ri2 and R13 are each independently H, C1-6 alkyl, C3.7 cycloalkyl, alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1-6 alkyl optionally substituted with up to fluoro, (CH2)õNR6R7, (CH2)õC(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-i0 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, C3-7 cycloalkyl, C4-1o alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1.6 alkyl optionally substituted with up to 5 fluoro, or CI-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)õ ORB;
[0043] k) 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)õNR6R7, (CH2)õ C(O)OR14 where R14 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-lo 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, CI-6 alkyl optionally substituted with up to 5 fluoro, or CI-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-lo alkylcycloalkyl, C2_6 alkenyl, CI-6 alkoxy, hydroxy-C1_6 alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro, CI -6 alkoxy optionally substituted with up to 5 fluoro;
[0044] 1) n = 1-4;
[0045] m) V is selected from 0, S, or NH;
[0046] n) when V is 0 or S, W is selected from 0, NR15, or CR'5; when V is NH, W is selected from NO or CR15, where R15 is H, C1.6 alkyl, C3_7 cycloalkyl, C4-io alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;
[0047] o) the dashed line represents an optional double bond;
[0048] p) 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, C4-1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C,.6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and [0049] q) 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.
[0050] The embodiments provide a compound having the Formula XI:

V=<
W

1s 1 O
O N 2 NH O~ 0 13N~S\NR1aR1b XI

[0051] wherein:

[0052] a) Rh and Rib 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;
[0053] or Rla and Rib 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_6 alkyl, C1.6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro;
[0054] or Rla and RIb 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;
[0055] or NRIaRlb 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;
[0056] or NR1aR]b is a heteroaryl selected from the group consisting of:
'IN
ENV N ~N > \
LJ~R1c ~~R1c and R1c [0057] wherein Ric is H, halo, Cl-6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3-6 cycloalkoxy, NO2, N(RId)2, NH(CO)RII, or NH(CO)NHRId, wherein each Rid is independently H, Ci_6 alkyl, or C3_6 cycloalkyl;
[0058] or R1c is NH(CO)OR" wherein Rle is C1_6 alkyl, or C3.6 cycloalkyl;
[0059] b) W is 0 or NH;
[0060] c) V is selected from 0, S, or NH;
[0061] d) when V is 0 or S, W is selected from 0, NR's, or CR15; when V is NH, W is selected from NR15 or CRIS, where R15 is H, C1_6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;
[0062] e) R2 is a bicyclic secondary amine with the structure of:

R20 ~R22 P

~! R12 fõ~=õ,aaõ.t. ,,,,,n ,: ,~,r, ,,r ....i~ 2~1 22 [0063] wherein R and R are each independently H, halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o 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, SO1õ 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;

[0064] wherein R10 and R'1 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4-1o alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, (CH2)nNR6R7, or (CH2)nC(O)OR14 where R14 is H, CI-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, 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, 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 R10 and R1' are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R10 and R" are combined as 0;

[0065] wherein p = 0 or 1;

[0066] wherein 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)nNR6R7, (CH2)nC(O)OR14 where R14 is H, C1.6 alkyl, " C3"~ 'cyclo`alky~ 'or` C4-io"alky cycloalkyl, 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-CI.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, C1_6 alkyl, C3_7 cycloalkyl, C4-lo alkylcycloalkyl, C2_6 alkenyl, CI-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;

[0067] wherein R20 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_Io alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, (CH2)1NR6R7, or (CH2)I,C(O)OR14 where R14 is H, CI-6 alkyl, C3_7 cycloalkyl, or C4_1o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, CI.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, CI-6 alkoxy, hydroxy-CI.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_1o alkylcycloalkyl, C2_6 alkenyl, CI.6 alkoxy, hydroxy-CI.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0068] wherein n = 0-4;

[0069] 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-CI.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, or 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;
[0070] or R2 is R2aR2b when W = NH and V = O, wherein :,.,:.R`"is C16 `alk 1 C3_7 cYcloalkY1, C4-lo alkYlcYcloalkY1, phenyl, pyridine, pyrazine, pyrilnidine, 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;

[0072] R2b is H, phenyl, pyridine, pyrazine, pyriunidine, 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 NR2oR2d, halo, cyano, nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 alkyl, CI-6 alkyl optionally substituted with up to 5 fluoro, or C1.6 alkoxy optionally substituted with up to 5 fluoro;

[0073] said R2o and Red are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4_ to 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 C1_6 alkoxy optionally substituted with up to 5 fluoro; or R2o and Red are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

[0074] 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;

[0075] g) R5 is H, C1.6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, or S(O)2R8;
[0076] 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) Elie "dashed line represents an optional double bond.

[0078] The embodiments provide a compound having the Formula XVIII:

O=<
NH

O O O
O N I ~S
NH .~`k N~ Rs R~ :T7r N a H

XVIII
[0079] wherein [0080] a) R1 is C1.6 alkyl, C3.7 cycloalkyl, C4_1o 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_1o 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;
[0081] 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-lo 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;
[0082] 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;

. ` "Irisf 1.6' alkyl, C(O)NR5R6, C(S)NR5R6, C(O)R7, C(O)OR7 or S(O)2R7;

[0084] 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_lo 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; or R5 and R6 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

[0085] 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;

[0086] 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 [0087] h) the dashed line represents an optional double bond;
[0088] or a pharmaceutically acceptable salt thereof.

[0089] The embodiments provide a compound of the formula:

L
O N O
7 jNH Z'P1, [0090] wherein:

[0091] 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;

[0092] b) Pi' is a group configured to form a non-polar interaction with at least one NS3 protease Si' pocket moiety selected from the group consisting of Lys136, Gly137, Ser139, His57, G1y58, Gln41, Ser42, and Phe43;

~b93 c I, is anlinker group consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;

[0094] 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, Argl55, Va178, Asp79, G1n80 and Asp81;

[0095] e) the dashed line represents an optional double bond;

[0096] f) R5 is selected from the group consisting of H, C(O)NR6R7 and C(O)ORS;

[0097] g) R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4-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 [0098] h) R8 is C1_6 alkyl, C3_7 cycloalkyl, C44o 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 o,= 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o 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 as defined above.

[0099] The embodiments provide a compound having the formula:

V V
O N O N
NH Y NH Y

11 or 10 11 [0100] wherein:
[0101] R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4-1o 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 C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0102] 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;

[0103] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, 04.10 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 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;

[0104] 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;

[0105] 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, or Y is a carboxylic acid [0107] V is selected from OH, SH, or NH2;
[0108] the dashed line represents an optional double bond;
[0109] R21 is C1_6 alkyl, C3_7 cycloalkyl, C410 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-Cl-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 [0110] 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.
[0111] The embodiments provide a compound having the formula:
Q
v W
O N
N H 1 ~~Y
R4RSN`~~ O

[0112] wherein:
[0113] Q is a core ring selected from:
,Na [0114] 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- p1_6'a1kT,` Ci='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, alkoxyainino, alkyoxyheterocyclyl, alkylainino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, [0115] 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;
[0116] 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 C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0117] R5 is C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)ORB, S(O)2R8, or (CO)CHR21NH(CO)R22;
[0118] 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, 04.10 alkylcycloalkyl, C2_6 alkenyl, 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 R6 and R7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

[0119] R8 is C1_6 alkyl, C3.7 cycloalkyl, C4-lo 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, C4.1o 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;
[0120] 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 CI-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 [0122] V and W are each individually selected from 0, S, or NH;
[0123] the dashed line represents an optional double bond;
[0124] R21 is C1_6 alkyl, C3_7 cycloalkyl, C4_1o 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 o, to aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4_1o 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 [0125] R22 is C1_6 alkyl, C3_7 cycloalkyl, C4-lo 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.
[0126] The embodiments provide pharmaceutical compositions comprising preferred compounds and pharmaceutically acceptable carriers.
[0127] The embodiments provide a method of treating a hepatitis C virus infection in an individual, the method comprising administering to the individual an effective amount of the preferred compounds.

[0128] The embodiments provide a method of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of the preferred compounds.
[0129] The embodiments provide 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 preferred compounds.
[0130] The chemical formulas representing the compounds described herein also represent pharmaceutically acceptable salts, solvates, esters, and prodrug derivatives thereof.
[0130A] Various embodiments of this invention provide use of a compound or composition of this invention for curative or prophylactic treatment of a hepatitis C virus infection or for preparation of a medicament for such treatment.
[0130B] Various embodiments of this invention provide use of a compound or composition of this invention for curative or prophylactic treatment of liver fibrosis or for preparation of a medicament for such treatment.
[0130C] Various embodiments of this invention provide use of a compound or composition of this invention for curative or prophylactic treatment for increasing liver function in an individual having a hepatitis C virus infection or for preparation of a medicament for such treatment.
[0130D] Various embodiments of this invention provide a commercial package containing as an active pharmaceutical ingredient a compound or composition of this invention together with instructions for use of the compound or composition.

Detailed Description of the Preferred Embodiment Definitions [0131] As used herein, the term "hepatic fibrosis," used interchangeably herein with "liver fibrosis," refers to the growth of scar tissue in the liver that may occur in the context of a chronic hepatitis infection.
[0132] The terms "individual," "host," "subject," and "patient" are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.
[0133] As used herein, the term "liver function" refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, y-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids;
a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
[0134] As used herein, the terms "HCV NS3 protease inhibitor" and "NS3 protease inhibitor" refer to any agent that inhibits the protease activity of HCV
NS3/NS4A complex. Unless specifically stated otherwise, the term "NS3 inhibitor" is used interchangeably with the terms "HCV
NS3 protease inhibitor" and "NS3 protease inhibitor."
[0134A] Various embodiments of this invention may exclude from their scope, a compound disclosed in W02005/03 7214 having the following formula.

O N

O O P

-23a-[0135] As used herein, the term "polyol" or "poly-ol" denotes a hydrocarbon including at least two hydroxyls bonded to carbon atoms, and includes sugars (reducing and nonreducing sugars), sugar alcohols and sugar acids. Polyols may include other functional groups. Examples of polyols include sugar alcohols such as mannitol and trehalose, and polyethers. A "reducing sugar" is one which contains a hemiacetal group that can reduce metal ions or react covalently with lysine and other amino groups in proteins and a "nonreducing sugar" is one which does not have these properties of a reducing sugar.
Examples of reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose and glucose. Nonreducing sugars include sucrose, trehalose, sorbose, melezitose and raffinose. Mannitol, xylitol, erythritol, threitol, sorbitol and glycerol are examples of sugar alcohols. As to sugar acids, these include L-gluconate and metallic salts thereof.
[0136] The term "polyether" as used herein denotes a hydrocarbon containing at least three ether bonds. Polyethers may include other functional groups.
Polyethers include polyethylene glycol (PEG).
[0137] The term "sustained viral response" (SVR; also referred to as a "sustained response" or a "durable response"), as used herein, refers to the response of an individual to a treatment regimen for HCV infection, in terms of serum HCV
titer.
Generally, a "sustained viral response" refers to no detectable HCV RNA (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.
[0138] "Treatment failure patients" as used herein generally refers to HCV-infected patients who failed to respond to previous therapy for HCV (referred to as "non-responders") or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as "relapsers"). The previous therapy generally may include treatment with IFN-a monotherapy or 1FN-a combination therapy, where the combination therapy may include administration of IFN-a and an antiviral agent such as ribavirin.
[0139] As used herein, the terms "treatment," "treating," and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment," as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
[0140] The terms "individual," "host," "subject," and "patient" are used interchangeably herein, and refer to a mammal, including, but not limited to, murines, simians, humans, mammalian farm animals, mammalian sport animals, and mammalian pets.
[0141] As used herein, the term "pirfenidone" refers to 5-methyl-l-phenyl-2-(1H)-pyridone. As used herein, the term "pirfenidone analog" refers to any compound of Formula I, IIA or IIB in the section entitled "Pirfenidone and Analogs Thereof" below. A
"specific pirfenidone analog," and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table I in the section entitled "Pirfenidone and Analogs Thereof" below.
[0142] As used herein, the term "a Type I interferon receptor agonist" refers to any naturally occurring or non-naturally occurring ligand of human Type I
interferon receptor, which binds to and causes signal transduction via the receptor. Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
[0143] As used herein, the term "Type II interferon receptor agonist" refers to any naturally occurring or non-naturally occurring ligand of human Type II
interferon receptor that binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include native human interferon-y, recombinant IFN-y species, glycosylated IFN-y species, pegylated IFN-y species, modified or variant IFN-y species, IFN-y fusion proteins, antibody agonists specific for the receptor, non-peptide agonists, and the like.
[0144] As used herein, the term "a Type III interferon receptor agonist"
refers to any naturally occurring or non-naturally occurring ligand of humanlL-28 receptor c ("IL-28R"), the amino acid sequence of which is described by Sheppard, et al., infra., that binds to and causes signal transduction via the receptor.
[0145] As used herein, the term "interferon receptor agonist" refers to any Type I interferon receptor agonist, Type II interferon receptor agonist, or Type III
interferon receptor agonist.
[0146] The term "dosing event" as used herein refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device. Thus, the term "dosing event," as used herein, includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.
[0147] "Continuous delivery" as used herein (e.g., in the context of "continuous delivery of a substance to a tissue") is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.
[0148] "Controlled release" as used herein (e.g., in the context of "controlled drug release") is meant to encompass release of substance (e.g., a Type I or Type III
interferon receptor agonist, e.g., IFN-(x) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use.
"Controlled release" thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).
[0149] "Patterned" or "temporal" as used in the context of drug delivery is meant to encompass delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection). "Patterned" or "temporal" drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.
[0150] The term "controlled drug delivery device" is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially.

i1 luericec]` by `Th6 environment of use, or releasing at a rate that is reproducible within the environment of use.

[0151] By "substantially continuous" as used in, for example, the context of "substantially continuous infusion" or "substantially continuous delivery" is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero. Furthermore, "substantially continuous" drug delivery may also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.

[0152] By "substantially steady state" as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20%
below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUC8hr average). The AUC8hr average is defined as the quotient (q) of the area under the curve of the biological parameter over the entirety of the time course (AUCtotal) divided by the number of 8 hour intervals in the time course (total/3days), i.e., q = (AUCtotal)/
(total/3days). For example, in the context of a serum concentration of a drug, the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum concentration of the drug over time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below the average area under the curve of serum concentration of the drug over an 8 hour period in the time course (AUC8hr average), i.e., the AUC8hr is no more than 20% above or 20% below the AUC8hr average for the serum concentration of the drug over the time course.
[0153] As used herein, "hydrogen bond" refers to an attractive force between an electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a hydrogen atom which is linked covalently to another electronegative atom (such as oxygen, nitrogen, sulfur or halogen). See, e.g., Stryer et. al. "Biochemistry", Fith Edition 2002, Freeman & Co.

ypically, "ihe 11yc1r"ogeri." bond is between a hydrogen atom and two unshared electrons of another atom. A hydrogen bond between hydrogen and an electronegative atom not covalently bound to the hydrogen may be present when the hydrogen atom is at a distance of about 2.5 angstroms to about 3.8 angstroms from the not-covalently bound electronegative atom, and the angle formed by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom not-covalently bound electronegative atom) deviates from 180 degrees by about 45 degrees or less.
The distance between the hydrogen atom and the not-covalently bound electronegative atom may be referred to herein as the "hydrogen bond length," and the the angle fonned by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom not-covalently bound electronegative atom) may be referred to herein as the "hydrogen bond angle." In some instances, stronger hydrogen bonds are formed when the hydrogen bond length is shorter; thus, in some instances, hydrogen bond lengths may range from about 2.7 angstroms to about 3.6 angstroms, or about 2.9 angstroms to about 3.4 angstroms. In some instances, stronger hydrogen bonds are formed when the hydrogen bond angle is closer to being linear; thus, in some instances, hydrogen bond angles may deviate from 180 degrees by about 25 degrees or less, or by about 10 degrees or less.

[0154] As used herein, "non-polar interaction" refers to proximity of non-polar molecules or moieties, or proximity of molecules or moieties with low polarity, sufficient for van der Waals interaction between the moieties and/or sufficient to exclude polar solvent molecules such as water molecules. See, e.g., Stryer et. al.
"Biochemistry", Fith Edition 2002, Freeman & Co. N.Y. Typically, the distance between atoms (excluding hydrogen atoms) of non-polar interacting moieties may range from about 2.9 angstroms to about 6 angstroms. In some instances, the space separating non-polar interacting moieties is less than the space that would accommodate a water molecule. As used herein a non-polar moiety or moiety with low polarity refers to moieties with low dipolar moments (typically dipolar moments less than the dipolar moment of 0-H bonds of H2O
and N-H
bonds of NH3) and/or moieties that are not typically present in hydrogen bonding or electrostatic interactions. Exemplary moieties with low polarity are alkyl, alkenyl, and unsubstituted aryl moieties.
[0155] As used herein, an NS3 protease S1' pocket moiety refers to a moiety of the NS3 protease that interacts with the amino acid positioned one residue C-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease muienes that interact with amino acid S in the polypeptide substrate DLEVVT-STWVLV).
Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids Lys136, G1y137, Ser139, His57, G1y58, G1n41, Ser42, and Phe43, see Yao. et. al., Structure 1999, 7, 1353.
[0156) As used herein, an NS3 protease S2 pocket moiety refers to a moiety of the NS3 protease that interacts with the amino acid positioned two residues N-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease moieties that interact with amino acid V in the polypeptide substrate DLEVVT-STWVLV). Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids His57, Arg155, Va178, Asp79, G1n80 and Asp81, see Yao. et. al., Structure 1999, 7, 1353.
[0157] As used herein, a first moiety "positioned by" a second moiety refers to the spatial orientation of a first moiety as determined by the properties of a second moiety to which the first atom or moiety is covalently bound. For example, a phenyl carbon may position an oxygen atom bonded to the phenyl carbon in a spatial position such that the oxygen atom hydrogen bonds with a hydroxyl moiety in an NS3 active site.
[0158] Before the embodiments are fur her described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
[0159] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the embodiments.
The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the embodiments, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the embodiments.
[0160] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments belong. Although any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the embodiments, the preferred methods and materials are now described.

[0161] It must be noted that as used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes a plurality of such methods and reference to "a dose" includes reference to one or more doses and equivalents thereof known to those skilled in the art, and so forth.
[0162] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
[0163] The embodiments provide compounds of Formulas I-XIX, as well as pharmaceutical compositions and formulations comprising any compound of Formulas I-XIX. A subject compound is useful for treating flaviviral infection, such as HCV infection.
and other disorders, as discussed below.

Compositions [0164] Various embodiments of compositions are described below. For ease of discussion, the description of these embodiments is divided into Sections A, B, C, D and E.
Various terms that may be defined within a particular Section are understood to apply within that Section, and also to apply elsewhere herein when reference to that particular Section is made, Likewise, any references within a Section to a particular number or label should be understood in the context of the corresponding numbering or labeling scheme used within that Section, rather than in the context of a possibly similar or identical numbering or labeling scheme used in an unrelated section, unless otherwise indicated.
Section A
[0165] Section A embodiments provide compounds having the general Formula I:

Q
V
W
O N
NY

[0166] wherein:

[0167] Q is a core ring selected from:

)P P
fN / and /N

[0168] 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, [0169] 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, 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, or benzimidazole, each optionally substituted with up to f~iree""` IRst' halo; `cyano, nitro, hydroxy, G1_6 alkyl, C3_7 cycloalkyl, G¾_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;
[0170] 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 C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0171] 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;

[0172] 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 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;

[0173] 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;

[0174] 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, C1_6 alkoxy optionally substituted with up to 5 fluoro; or R9 is a C1_6 alkyl optionally substituted with up to 5 fluoro groups, NR6R7, NRlaRlb, or (CO)OH, or R9 is a heteroaromatic ring optionally substituted up to two times L.. +6ur 7F .: 'i ~i5ud= 'nnir u"ur r' rrriwx ri,õn a :r with halo,,xcyano, nitro, hydroxyl, or C1_6 alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof, [0175] wherein Rla and Rlb are each independently H, C1_6 alkyl, C3_7 cycloalkyl, or C4-1o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1_6 alkoxy, amido, or phenyl, [0176] or Rla and Rib 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_1o 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, [0177] or Rla and Rib 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, [0178] or NRiaRib 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, [0179] or NRiaRib is a heteroaryl selected from the group consisting of:
-'K--N _"~_N -N~N -'*-N
~'\Rlc R1c and C_z R1c [0180] wherein Rio is H, halo, C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3_6 cycloalkoxy, NO2, N(Rid)2, NH(CO)Rid, or NH(CO)NHRid, wherein each Rid is independently H, C1_6 alkyl, or C3_6 cycloalkyl, [0181] or Rio is NH(CO)ORie, wherein Rie is C1_6 alkyl or C3_6 cycloalkyl;
[0182] p= 0 or l;

[0183] V is selected from 0, S, or NH;

[0184] when V is 0 or S, W is selected from 0, 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;
[0185] the dashed lines represent an optional double bond;
[0186] 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 o,. 10 aryl which if if ' is optionall y subs'tituted' byup 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 [0187] R22 is C1_6 alkyl, C3_7 cycloalkyl, or C4-lo 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.

[0188] In preferred embodiments, Section A embodiments provide compounds ( p I ~

having the general Formula I, in which the core ring is [0189] In preferred embodiments, Section A embodiments provide compounds fN
I ~ having the general Formula I, in which the core ring is [0190] In preferred embodiments, Section A embodiments provide compounds ( p f N
having the general Formula I, in which the core ring is [0191] In preferred embodiments, Section A embodiments provide compounds Q
v=~
W
O N

F24R5N s O

having the general Formula Ia: la In pre erred embodiments, Section A embodiments provide compounds Q
v=~
w R4R5N (-; 9 14 r 11 Ib having the general Formula lb:

[0193] In preferred embodiments, Section A embodiments provide compounds v w O N
NHY

R4R5N $ O

Ic having the general Formula Ic:

[0194] In preferred embodiments, Section A embodiments provide compounds Q
v=<
w O N
NH Y

10 11 Id having the general Formula Id:

[0`I'0~ 'f iii preferre embodiments, Section A embodiments provide compounds v ==< Q
w O N
NY
7 r R4R5N 8 O

having the general Formula le:

[0196] In preferred embodiments, Section A embodiments provide compounds Q
v=~
w O N
f NH 1 Y

If having the general Formula If:

[0197] In preferred embodiments, Section A embodiments provide compounds v =~ Q
w O N

j 1 having the general Formula Ig:

Tnpreterred embodiments, Section A embodiments provide compounds Q
v=<
w o N

R4R5N a O

11 Ih having the general Formula Ih:

[0199] In preferred embodiments, Section A embodiments provide compounds Q
v=<
w O N

R4R5N a O

9 12 j 13 having the general Formula Ii:

[0200] In preferred embodiments, Section A embodiments provide compounds v w O N
jNY
... R4R5N 3 O

having the general Formula Ij:

iii' pre` er`r`ed embodiments, Section A embodiments provide compounds v=~
W
O N
NH \Y
R4R5N ~ , a O

having the general Formula Iz:

[0202] In preferred embodiments, Section A embodiments provide compounds having the general Formula I, in which Y is sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is selected from the group consisting of C1_6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, and NRiaRlb, wherein Rla and Rib are each independently H, C1_6 alkyl, or C3_7 cycloalkyl.

[0203] In preferred embodiments, Section A embodiments provide compounds having the general Formula I, in which the C13-C14 double bond is cis.

[0204] In preferred embodiments, Section A embodiments provide compounds having the general Formula I, in which the C13-C14 double bond is trans.

[0205] In certain embodiments, the compounds of general Formula I do not include the compounds disclosed in PCT/USO4/33970. For example, in certain embodiments, the compounds of general Formula I do not include the compounds of Formulas II, III, and IV in Section B below.

Section B

[0206] Section B embodiments provide compounds having the general Formulas II, III, and IV:

R1+r= R
R11 R11 R11 \1 R10 d= Rio R1 R10 Z-R
R20 P R2 R20 )P I i) R20 )P
N R13 N \ N-~ R13 V=< R12 V= R2 V=~ R12 W W W

O N O N O N

:7r R4R5N 8 O R4R5N ""8 O R4R5N 8 O
9 j 14 9 14 14 II III IV
[0207] wherein:

[0208] R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4.1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-Cl_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 to 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)ORS, NHC(O)R8, NHC(O)OR8, SO,,,R8, NHS(O)2R8, CHõNR6R7, OCHINR 6R7, or OCHõ 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, C4-1o 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;

[0209] m = 0, 1, or 2;

[0210] 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- 1.6 alkyl, Ci_6 alkyl` optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0211] 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;

[0212] 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, 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;

[0213] 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, Cl_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;

[0214] 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-lo 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 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;
[0215] R10 and R11 are each independently H, C1.6 alkyl, C3_7 cycloalkyl, C4.1o alkylcycloalkyl, C6 or to aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to fluoro, (CH2)õNR6R7, (CH2)õ C(O)OR14 where R14 is H, C1_6 alkyl, C3_7 cycloalkyl, or C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, 7i=== inm= ii = ' F v":tt 41 f: i dt r irt6. r f; ..-ff ' - rz cyano, intro, hydroxy, 1.6 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, C4.1o 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, 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 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 0;

[0216] p= 0 or 1;

[0217] 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 fluoro, (CH2)nNR6R7, (CH2)nC(O)OR14 where R14 is H, Cl_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 R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyan, 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, 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; or R12 and R13 are each independently CI-6 alkyl optionally substituted with (CH2)nOR8;

[0218] 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)0NR6R7, (CH2)nC(O)OR14 where R14 is H, 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 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 ail oxy optionall"y subst tuted `wit`h up to 5 fluoro; said C6 o 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, C4-1o alkylcycloalkyl, C2_6 alkenyl, C1_6 alkoxy, hydroxy-C1_6 allcyl, or C1_6 alkyl optionally substituted with up to 5 fluoro, C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0219] n = 1-4;

[0220] V is selected from 0, S, or NH;

[0221] when V is 0 or S, W is selected from 0, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C1_6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro;

[0222] the dashed line represents an optional double bond;

[0223] 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 [0224] 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.

[0225] Section B embodiments provide compounds having the general Formula II, R1o R20 ) P R2 V~ R12 W
O N

NH i R4R5N s 0 II
[0226] wherein:

[0227] R1 is 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, or C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0228] R2 is H, OCH11NR6R7, OCH11R16, halo, cyano, nitro, hydroxy, Cl_6 alkyl, C3_7 cycloalkyl, C4-1o 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 R6 and R7 in the definition of R2 being each independently H, C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl; or said R6 and R7 in the definition of R2 taken together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

[0229] n = 1-3;
[0230] R4 = H;

[0231] R5 is H, C(O)NR6R7 or C(O)OR8, said R6 and R7 in the definition of R5 being each independently H, C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl;
[0232] R8 is C1_6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl; 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;

[0233] 'Y is a sulfommide of the formula -C(O)NHS(O)2R 9 , where R9 is C1_6 alkyl, C3_7 cycloalkyl, or 04.10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, C1_6 alkoxy, or phenyl;
[0234] Rio, R11, R12 and R13 are H;
[0235] p = 0 or 1;

[0236] V = O; and [0237] W is selected from 0, NH, or CH2.

[0238] In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV, in which p may be 0. In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV, in which p maybe 1.

[0239] In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV, in which either or both of R1 and R2 are H. In some embodiments, p is 0. In other embodiments p is 1.

[0240] In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV, in which neither R1 nor R2 is H.
In some embodiments, p is 0. In other embodiments, p is 1.

[0241] In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV, in which R2 is OCHnNR6R7 or OCH0R16.

[0242] In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV in which R9 is C1_6 alkyl, C3_7 cycloalkyl, or C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C1_6 alkoxy, or phenyl.

[0243] In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV in which 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, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro.

[0244] In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV in which R9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C1_6 alkoxy.

WA' " In pre er`r`e embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV in which R9 is a C1_6 alkyl optionally substituted with up to 5 fluoro groups, NR6R7, or (CO)OH.

[0246] In preferred embodiments, Section B embodiments provide compounds having the general Formulas II, III, and IV in which the dashed line in Formula (II), (III), or (IV) represents a single bond.

[0247] Section B embodiments provide compounds having the general Formula II:

V-\ R12 O N
:7r NH i R4R5N s O

II
[0248] wherein:

[0249] R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, 04.10 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, SO11R8, NHS(O)2R8, OCHnNR6R7, or OCH1,R16 where R16 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, 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, C'1_6 akyi, 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;

[0250] in = 0, 1, or 2;
[0251] 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, CI-6 alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0252] 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;

[0253] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4.1o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-1o 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;

[0254] 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; 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;
[0255] Y is a sulfonimide of the formula -C(O)NHS(O)2R9, where R9 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 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, C1_6 alkyl optionally substituted with up to 5 fluoro, or C1_6 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 tt.., tf - thrt+ = m% 7t- ~rr, ff" :f f:. if It (C'O)OH, or is a l eteroaromatic 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;

[0256] R10 and R11 are each independently H, C1.6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, C6 or 1o aryl, hydroxy-C1.6 alkyl, C1_6 alkyl optionally substituted with up to fluoro, (CH2)11NR6R7, or (CH2)11C(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, 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, 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 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 0;

[0257] p= 0 or 1;

[0258] 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, or (CH2)11C(O)OR14 where R14 is H, 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 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, 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, or R12 and R13 are each independently C1_6 alkyl optionally substituted with (CH2),OR8;

[025'x]" ".."C1-6" alky1 , C3-7 cycloalky1, C4_10 alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, (CH2),1NR6R7, or (CH2)11C(O)OR14 where R14 is H, 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 R14 is C6 or 10 aryl which is optionally substituted by up to three halo, cyan, 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, 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;

[0260] n = 0-4;

[0261] V is selected from O. S, or NH;

[0262] when V is 0 or S, W is selected from 0, 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;

[0263] the dashed line represents an optional double bond;

[0264] R21 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, 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 R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and [0265] 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.
[0266] Section B embodiments provide compounds having the general Formula IIa:

R10 -~~

N
O=~
W
O N
NH 1 \\Y 'T7 R
5, N O

IIa [0267] wherein:

[0268] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0269] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0270] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl;

[0271] R8 is C1.6 alkyl, C3_7 cycloalkyl, C4_i0 alkylcycloalkyl, or 3-tetrahydofuryl.

[0272] 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, Ci_3 alkyl, C3.7 cycloalkyl, or C1_3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
[0273] R10 and R1' are each independently H or 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;

[0274] W is selected from 0 or NH; and [0275] the dashed line represents an optional double bond.

[0276] Section B embodiments provide compounds having the general Formula IIIa:

t R2 N
O=
W
O N
NH 1 ~~Y
:7r R

Ma [0277] wherein:

[0278] Ri and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0279] R4 is H;

[0280] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0281] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-tetrahydrofuryl.

[0282] 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, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;

[0283] W is selected from 0 or NH; and [0284] the dashed line represents an optional double bond.

[0285] Section B embodiments provide compounds having the general Formula IIb:

R10 d=~

N
O=~
W
O N J~ O /O
NH 1 N=S=R
R5, H R9 N =, a O

IIb [0286] wherein:

[0287] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0288] R5 is H, C(O)OR8 or C(O)NHR8;

[0289] R8 is C1_6 alkyl, C5_6 cycloalkyl, or 3-tetrahydrofuryl;

[0290] 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;

[0291] R10 and R11 are each independently H or 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;

[0292] W is selected from 0 or NH; and [0293] the dashed line represents an optional double bond.

[0294] Section B embodiments provide compounds having the general Formula IIIb:

&---R2 N
O=~
W
O N 1~ Qv/O
R 7 NH 1'`\N N~S'R9 H
N O d,BB
H
g 14 IIlb [0295] wherein:

[0296] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0297] R5 is H, C(O)OR8 or C(O)NHR8;

[0298] R8 is C1_6 alkyl, C5_6 cycloalkyl, or 3-tetrahydrofuryl;

[0299] 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;

[0300] R10 and R11 are each independently H, C1.3 alkyl, or C4_5 cycloalkyl;
[0301] W is selected from 0 or NH; and [0302] the dashed line represents an optional double bond.

[0303] Section B embodiments provide compounds having the general Formula Ilc:

N
O=<
O
0 N iJ 0/O
NH NR

N s He [X04] ` wherein:

[0305] R1 and R2 are each independently H, chloro, fluoro, cyan, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0306] R5 is H, C(O)OR8 or C(O)NHR8;
[0307] R8 is C1_6 alkyl or C5_6 cycloalkyl;

[0308] 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;
(e) R10 and R11 are each independently H or 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.

[0309] Section B embodiments provide compounds having the general Formula IIIc:

N
o=~
O

O N \\i/
AS...
NH ,~
R H Rs N ',8 0 H
9 ~ 14 IIIc [0310] wherein:

[0311] R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C1.3 alkyl, or C1_3 alkoxy;

[0312] R5 is H, C(O)OR8 or C(O)NHR8;
[0313] R8 is C1_6 alkyl or C5_6 cycloalkyl;

[0314] R9 is C1_3 alkyl, C34 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy; and [0315] the dashed line represents an optional double bond.

[0316] Section B embodiments provide compounds having the general Formula IIId:

N
O==< R2 W

NXY
4R5N $ O
R
9 i 14 12 i IIId [0317] wherein:

[0318] R1 and R2 are each independently H, halo, cyano, hydroxy, C1.3 alkyl, or C1_3 alkoxy;

[0319] R4 is H;

[0320] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0321] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-tetrahydrofuryl;

[0322] 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, cyan, nitro, hydroxy, C1_3 alkyl, C3_7 cycloalkyl, or C1_3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
[0323] R10 and R11 are each independently H or 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;
[0324] R20 is H, C1_6 alkyl, C3_7 cycloalkyl, C4.1o alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, (CH2)õNR6R7, or (CH2)õ C(O)OR14 where R14 is H, C1.6 alkyl, C3_7 cycloalkyl, or C4-lo 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 rr =:ror ~i 1~ 7o-isopd' =:G,r 7iori% m~~6 :=' r:rEbr %~:e: _....
and R tionally substituted by up to three halo, cyan, 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;
[0325] W is selected from 0 or NH; and [0326] the dashed line represents an optional double bond.

[0327] Section B embodiments provide compounds having the general Formula IVa:

P

O=< R12 W

O\/N

~ Cx, 9 If 14 IVa [0328] wherein:

[0329] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0330] R4 is H;

[0331] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0332] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-tetrahydrofuryl;
[0333] 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, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
[0334] R10 and Rii are each independently H or C1.3 alkyl, or R10 and Rii are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0335] R is H, C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C6 ,. 10 aryl, hydroxy-C1_6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, (CH2)õNR6R7, and (CH2)õC(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-lo 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 o, 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, C4-1o 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;

[0336] W is selected from 0 or NH;

[0337] the dashed line represents an optional double bond; and [0338] where Z is a fused or appended aryl heteroaryl ring system.
Section C

[0339] Section C embodiments provide compounds having the general Formula XI.

V==<
W

S
N NH O O
13 N' \NR1aR1b XI
[0340] wherein:
[0341] Rla and Rib are each independently H, C1_6 alkyl, C3_7 cycloalkyl, or C4-1o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1.6 alkoxy, amido, or phenyl;

104111111.:P :111W 6r -bra ahd"` R'1 b are each independently H or C6 ,. io aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-lo 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;

[0343] or Ria and Rlb 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;

[0344] or NRIaRIb 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;

[0345] or NR1aRIb is a heteroaiyl selected from the group consisting of:
-`NON -'*--N/N~ ANN
R1c V=~R1c , and Ric [0346] wherein Rl is H, halo, C1_6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(Rld)2, NH(CO)RId, or NH(CO)NHRId, wherein each RId is independently H, C1_6 alkyl, or C3-6 cycloalkyl;

[0347] or R1c is NH(CO)ORIe wherein Rle is C1.6 alkyl or C3-6 cycloalkyl;
[0348] W is 0 or NH;

[0349] V is selected from 0, S, or NH;

[0350] when V is 0 or S, W is selected from 0, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, Cl-6 alkyl, C3-7 cycloalkyl, alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;

[0351] R2 is a bicyclic secondary amine with the structure of.

[0352] 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, or C1_6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro, C6 or to aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl; p' epoxy,"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, SO11R8 (in = 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;

[0353] wherein R10 and R'1 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4-1o alkylcycloalkyl, C6 or 10 aryl, hydroxy-C1_6 alkyl, or C1_6 alkyl optionally substituted with up to 5 fluoro, (CH2)nNR6R7, or (CH2)õC(O)OR14 where R14 is H, C1.6 alkyl, C3_7 cycloalkyl, or C4-lo 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, C4-1o 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 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; or R10 and R'1 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 0;

[0354] wherein p = 0 or 1;

[0355] wherein R12 and R13 are each independently H, C1.6 alkyl, C3_7 cycloalkyl, 04.10 alkylcycloalkyl, C6 or 1o aryl, hydroxy-C1.6 alkyl, C1_6 alkyl optionally substituted with up to 5 fluoro, (CH2)0NR6R7, (CH2)nC(O)OR14 where R14 is H, 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 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 witli'up to5"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, 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 R12 and R13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0356] 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)õNR6R7, (CH2)õC(O)OR14 where R14 is H, CI-6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyan, 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, 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;

[0357] wherein n = 0-4;

[0358] 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, 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;
[0359] or R2 is R2aR2b when W = NH and V = O, wherein [0360] 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, benzimidazole, each optionally substituted with up to three NR2 R2d, halo, cyano, nitro, hydroxy, C1.6 alkyl, C3_7 cycloalkyl, " C4'lo' alky'1cycoaYy1,"''fC2-`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;

[0361] R2b 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 NR2CR2d, 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;

[0362] said R2o and Red are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4_ 1o 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 C1_6 alkoxy optionally substituted with up to 5 fluoro; or R2o and Red are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

[0363] R4 is H, C1_6 alkyl, C3_7 cycloalkyl, C4_1o alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C1_6 alkyl, C3_7 cycloalkyl, C4-1o 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;

[0364] R5 is H, C1_6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, or S(O)2R8;

[0365] 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,,r 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 [0366] the dashed line represents an optional double bond.

[0367] Section C embodiments provide compounds having the general Formula XII.

R1o O~ R12 O
18' O N 2 NH iL 'S' 4 1 a 1 b R5 14 O N' 'NR R
N '' 13 s e H

XII
[0368] wherein:

[0369] Rla and Rib are each independently H, C1_6 alkyl, C3-7 cycloalkyl, or C4_1o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1_6 alkoxy, amido, or phenyl;
[0370] or Ria and Rib are each independently H or heteroaryl selected from a group consisting of:

S'N O N HN O N O' N RN N
~1) _ N--' , `I , and N=N
R1c R1c R1c R1c R1c [0371] wherein Ric is H, halo, C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3-6 cycloalkoxy, NO2, N(Rid)2, NH(CO)R1d, or NH(CO)NHRid, wherein each Rid is independently H, C1_6 alkyl, or C3.6 cycloalkyl;

[0372] or NRlaRib 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;
[0373] R21 and R22 are each independently H, halo, cyano, hydroxy, C1_3 alkyl, or C1-3 alkoxy;

[0374] R5 is H, C(O)NR6R7, C(O)R$, or C(O)ORB;
[0375] R6 and R7 are each independently H, C1_6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl;

is O1_6 alkyl, C3_7 cycloalkyl, C4_1 alkylcycloalkyl, or 3-tetrahydrofuryl;

[0377] R10 and R11 are each independently H, halo, or C1.3 alkyl, or R10 and Rii are taken together with the carbon to which they are attached to fonn cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0378] R12 and R13 are each independently H, halo, C1.6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C6 0110 aryl, hydroxy-C1_6 alkyl, or C1_6 alkyl optionally substituted with up to 5 halo atoms; and [0379] the dashed line represents an optional double bond.

[03801 Section C embodiments provide compounds having the general Formula XIII.

~ 22 \ R
N
O~
O

ON 2 NH a,,,~ O~ O
R
~NJ=;a N'SNR1aR1b / 13 5 ~I g H
H 1 i 7 XIII
[0381] wherein:

[0382] R 1 a and Rib are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1_6 alkoxy, amido, or phenyl;

[0383] or Ria and Rlb are each independently H or heteroaryl selected from a group consisting of:

/~ ' ' N O" N O' N /~
S N O N HN \`~ RN N
N =N , and N=N
R1C R1c R1c R1c Ric [03g4]'t "" wHer`eiii k' I'S' H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(Rid)2, NH(CO)RId, or NH(CO)NHRId, wherein each RId is independently H, C1_6 alkyl, or C3-6 cycloalkyl;

[0385] or NRlaRlb 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, ainido or phenyl;

[0386] R21 and R22 are each independently H, halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0387] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0388] R6 and R7 are each independently H, C1_6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl;

[0389] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, or 3-tetrahydrofuryl; and [0390] the dashed line represents an optional double bond.

[0391] Section C embodiments provide compounds having the general Formula XIV.

R 2a O=~
NH

O N 2 NH 4 0 O~ O
, ~1 $
R 1I Ni NR1aR1b N i 13 5 8 H

XIV
[0392] wherein:

[0393] Rla and Rib are each independently H, C1-6 alkyl, C3_7 cycloalkyl, C4-alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C1-6 alkoxy, amido, or phenyl;

[039" ] or . "and' - are each independently H or heteroaryl selected from a group consisting of:

S"N O N HNC N > OWN ON RN"N
N `t N and N=N
R1c R1c R1c R1c R1c [0395] wherein R10 is H, halo, C1_6 alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3_6 cycloalkoxy, NO2, N(Rld)2, NH(CO)RId, or NH(CO)NHRId, wherein each RId is independently H, C1_6 alkyl, or C3_6 cycloalkyl;

[0396] or NR1aR11' 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;

[0397] R2' is C6 or Clo aryl optionally substituted with up to three NR2 R2d, 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;

[0398] said R2c and Red are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4_ to 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 C1_6 alkoxy optionally substituted with up to 5 fluoro; or R2 and Red are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

[0399] or Rea is an unsaturated five- or six-membered heteroaryl, or such defined heteroaryl fused to another cycle be it heterocycle or any other cycle;

[0400] R5 is H, C(O)NR6R7, C(O)R8, or C(O)OR8;

[0401] R6 and R7 are each independently H, C1_6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, or phenyl;
[0402] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-tetrahydrofuryl; and [0403] the dashed line represents an optional double bond.

[0404] Section C embodiments provide compounds having the general Formula Xv.

N
O==~
W
O N ~~ 0 O
NH N'R s R~ 7H
N '"e O
H s 14 xv [0405] wherein:
[0406] R1 and R2 are each independently H, halo, cyano, hydroxy, C1_3 alkyl, or C1.3 alkoxy;
[0407] R5 is H, C(O)OR8 or C(O)NHR8;
[0408] R8 is CI-6 alkyl, C5_6 cycloalkyl, or 3-tetrahydrofuryl;
[0409] 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;
[0411] W is selected from 0 or NH; and [0412] the dashed line represents an optional double bond.
[0413] Section C embodiments provide compounds having the general Formula XVI.

N
OQ
O

O N II \\i/
Rs, NH \ 'IS\R9 :7~N ", s O H

XVI
[0414] wherein:

[0415] R' and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0416] R5 is H, C(O)OR8 or C(O)NHR8;
[0417] R8 is C1_6 alkyl or C5_6 cycloalkyl;

[0418] 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;

[0419] R10 and R11 are each independently H or C1_3 alkyl, or R10 and R11 are taken together with the carbon to which they are attached to form cyclopropyl or cyclobutyl;
and [0420] the dashed line represents an optional double bond.

[0421] Section C embodiments provide compounds having the general Formula XVII.

N
O=~
O
O N k /
s NH 1' , NHS"R9 N O
H

XVII
[0422] wherein:

[0423] R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy;

[0424] R5 is H, C(O)OR8 or C(O)NHR8;
[0425] R8 is C1_6 alkyl or C5.6 cycloalkyl;

[0426] R9 is C1_3 alkyl, C34 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy; and [0427] the dashed line represents an optional double bond.
Section D

[0428] Section D embodiments provide compounds having the general Formula XVIII:

O=<
NH
O N O
NH N.S.RB

3 R,N ~

12 ~

XVIII

[0429] wherein:

[0430] 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;

[0431] 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-lo 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;

[0432] 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;

[0433] R4 is C1_6 alkyl, C(O)NRSR6, C(S)NR5R6, C(O)R7, C(O)OR7, or S(O)2R7;

[0434] 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, 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;

[0435] 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, liydroxy= 16 alky; C` `6`'alkyl optionally substituted with up to 5 fluoro, or C1_6 alkoxy optionally substituted with up to 5 fluoro;

[0436] R8 is C1_3 alkyl, C34 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C1_3 alkyl, or C1_3 alkoxy; and [0437] the dashed line represents an optional double bond.
Section E

[0438] Section E embodiments provide compounds having the general Formula XIX:

L

O N O
NH zP11 XIX
[0439] wherein:

[0440] 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;

[0441] P1' is a group configured to form a non-polar interaction with at least one NS3 protease Si' pocket moiety selected from the group consisting of Lys136, G1y137, Ser139, His57, G1y58, G1n41, Ser42, and Phe43;

[0442] L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;

[0443] 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, Va178, Asp79, G1n80 and Asp81;
[0444] the dashed line represents an optional double bond;

[0445] R 'is selected from the group consisting of C(O)NR6R7 and C(O)OR8;
[0446] 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_1o 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 [0447] R8 is C1_6 alkyl, C3_7 cycloalkyl, C4-1o 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_1o 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.
[0448] As used herein, "hydrogen bond" refers to an attractive force between an electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a hydrogen atom which is linked covalently to another electronegative atom (such as oxygen, nitrogen, sulfur or halogen). See, e.g., Stryer et. al. "Biochemistry", Fith Edition 2002, Freeman & Co.
N.Y. Typically, the hydrogen bond is between a hydrogen atom and two unshared electrons of another atom. A hydrogen bond between hydrogen and an electronegative atom not covalently bound to the hydrogen may be present when the hydrogen atom is at a distance of about 2.5 angstroms to about 3.8 angstroms from the not-covalently bound electronegative atom, and the angle formed by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom not-covalently bound electronegative atom) deviates from 180 degrees by about 45 degrees or less.
The distance between the hydrogen atom and the not-covalently bound electronegative atom may be referred to herein as the "hydrogen bond length," and the the angle formed by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom not-covalently bound electronegative atom) may be referred to herein as the "hydrogen bond angle." In some instances, stronger hydrogen bonds are formed when the hydrogen bond length is shorter; thus, in some instances, hydrogen bond lengths may range fr'om' about2:'7 a'igsffoms 'to' about 3.6 angstroms, or about 2.9 angstroms to about 3.4 angstroms. In some instances, stronger hydrogen bonds are formed when the hydrogenbond angle is closer to linear; thus, in some instances, hydrogen bond angles may deviate from 180 degrees by about 25 degrees or less, or by about 10 degrees or less.

[0449] As used herein, non-polar interaction refers to proximity of non-polar molecules or moieties, or proximity of molecules or moieties with low polarity, sufficient for van der Waals interaction between the moieties and/or sufficient to exclude polar solvent molecules such as water molecules. See, e.g., Stryer et. al.
"Biochemistry", Fith Edition 2002, Freeman & Co. N.Y. Typically, the distance between atoms (excluding hydrogen atoms) of non-polar interacting moieties may range from about 2.9 angstroms to about 6 angstroms. In some instances, the space separating non-polar interacting moieties is less than the space that would accommodate a water molecule. As used herein a non-polar moiety or moiety with low polarity refers to moieties with low dipolar moments (typically dipolar moments less than the dipolar moment of O-H bonds of H2O
and N-H
bonds of NH3) and/or moieties that are not typically present in hydrogen bonding or electrostatic interactions. Exemplary moieties with low polarity are alkyl, alkenyl, and unsubstituted aryl moieties.

[0450] As used herein, an NS3 protease S 1' pocket moiety refers to a moiety of the NS3 protease that interacts with the amino acid positioned one residue C-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease moieties that interact with amino acid S in the polypeptide substrate DLEVVT-STWVLV).
Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids Lys136, Gly137, Ser139, His57, Gly58, G1n41, Ser42, and Phe43, see Yao. et. al., Structure 1999, 7, 1353.

[0451] As used herein, an NS3 protease S2 pocket moiety refers to a moiety of the NS3 protease that interacts with the amino acid positioned two residues N-terminal to the cleavage site of the substrate polypeptide cleaved by NS3 protease (e.g., the NS3 protease moieties that interact with amino acid V in the polypeptide substrate DLEVVT-STWVLV). Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids His57, Arg155, Va178, Asp79, G1n80 and Asp8l, see Yao. et. al., Structure 1999, 7, 1353.
[0452] As used herein, a first moiety "positioned by" a second moiety refers to the spatial orientation of a first moiety as determined by the properties of a second moiety H P A: ~ d, ,; ndLr ri,"rfr it .n' tr o' w ich is first atom or moiety is covalently bound. For example, a phenyl carbon may position an oxygen atom bonded to the phenyl carbon in a spatial position such that the oxygen atom hydrogen bonds with a hydroxyl moiety in an NS3 active site.

[0453] Also provided herein are compounds containing moieties configured to interact with particular regions, particular amino acid residues, or particular atoms of NS3 protease. Some compounds provided herein contain one or more moieties configured to form a hydrogen bond with NS3 protease at a particular region, amino acid residue, or atom. Some compounds provided herein contain one or more moieties configured to form a non-polar interaction with NS3 protease at a particular region, amino acid residue, or atom. For example, the compound having the general Formula XIX may contain one or more moieties that form a hydrogen bond with a peptide backbone atom or side chain moiety located in the substrate binding pocket of NS3 protease. In another example, the compound having the general Formula XIX may contain one or more moieties that form non-polar interactions with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease. In the compound of formula XIX, the dashed line between carbons 13 and 14 may be a single bond or a double bond.

[0454] As provided in the compound having the general formula XIX, Z may be configured to form a hydrogen bond with a peptide backbone atom or side chain moiety located in the substrate binding pocket of NS3 protease, including, but not limited to, NS3 protease His57 imidazole moiety and NS3 protease G1y137 nitrogen atom. In some instances, Z may be configured to form a hydrogen bond with both the NS3 protease His57 imidazole moiety and the NS3 protease Glyl37 nitrogen atom.

[0455] The P 1' group of the compound having the general formula XIX may be configured to form a non-polar interaction with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease Si' pocket. For example the P1' group may form a non-polar interaction with at least one amino acid selected from Lys136, Gly137, Ser139, His57, G1y58, G1n41, Ser42, and Phe43.

[0456] The P2 group of the compound having the general formula XIX may be configured to form a non-polar interaction with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket. For example the P2 group may form a non-polar interaction with at least one amino acid selected from His57, Arg155, V a1'/ 8, Asp 7p, Ciln6U and Asp81-: The P2 group also maybe configured to form a hydrogen bond with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket. For example the P2 group may form a hydrogen bond with at least one amino acid selected from His57, Arg155, Va178, Asp79, G1n80 and Asp8l. In some instances, P2 may form both a non-polar interaction and a hydrogen bond with peptide backbone or side chain moieties or atoms located in the substrate binding pocket of NS3 protease, such amino acids selected from His57, Argl55, Va178, Asp79, G1n80 and Asp8 1.
Such hydrogen bond and non-polar interactions may occur with the same amino acid residue or with different amino acid residues in the NS3 protease S2 pocket.
In some embodiments, P2 may be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic.

[0457] In some embodiments, the position of the P2 group is determined by the linker L. For example, P2 may be positioned by linker L to form a non-polar interaction with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket. For example the P2 group may be positioned by L to form a non-polar interaction with at least one amino acid selected from His57, Arg155, Va178, Asp79, Gln80 and Asp8 1. In another example, P2 may be positioned by linker L to form a hydrogen bond with peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, including, but not limited to amino acid residues that form the NS3 protease S2 pocket. For example the P2 group may be positioned by L to form a hydrogen bond with at least one amino acid selected from His57, Argl55, Va178, Asp79, G1n80 and Asp8 1. In some instances, P2 may be positioned to form both a non-polar interaction and a hydrogen bond peptide backbone or side chain atom or atoms located in the substrate binding pocket of NS3 protease, such as an amino acid selected from His57, Arg155, Va178, Asp79, G1n80 and Asp81. Such hydrogen bond and non-polar interactions may occur with the same amino acid residue or with different amino acid residues in the NS3 protease S2 pocket.
[0458] As provided in the compound having the general formula XIX, L may be a linker group that links P2 to the heterocyclic backbone of the compound of formula XIX.
Linker L may contain any of a variety of atoms and moieties suitable for positioning P2 in the NS3 proteasesubstrate binding pocket. In one embodiment, L may contain 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. In another embodiment, L may contain 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. For example, L may contain a group having the formula -W-C(=V)-, where V and W are each individually selected from 0, S or NH. Specific exemplary groups for L include, but are not limited to, ester, amide, carbamate, thioester, and thioamide.

[0459] The compound of formula XIX also may contain an R5 group, where the R5 group may contain a carboxyl moiety. Exemplary carboxyl moieties of R5 include C(O)NR6R7 and C(O)OR8 where 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, C4-1o 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, pyrTolidinyl, piperidinyl, piperazinyl, or morpholinyl; and where 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 1o 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 [0460] In some embodiments, several bonds of the compound of formula XIX
may have a particular chirality.

[0461] Section E embodiments provide compounds wherein the C13-C14 double bond is cis. Section E embodiments provide compounds wherein the C13-double bond is trans.

[0462] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIX, in which L consists of from 2 to 5 atoms.

.. 0463 In ' "referfed embodiments Section E embodiments provide compounds having the general Formula XIX, in which L comprises a -W-C(=V)- group, where V and W are each individually selected from 0, S or NH.

,[0464] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIX, in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.

[0465] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIX, 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, G1n80 and Asp81.

[0466] In preferred embodiments, Section E embodiments provide compounds having the the formula XIXa:

L

O N O
7 NH 1 J z'P1, XIXa.
[0467] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXa, in which L consists of from 2 to 5 atoms.

[0468] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXa, in which L comprises a -W-C(=V)- group, where V and W are each individually selected from 0, S, or NH.

[0469] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXa, in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.

[0470] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXa, 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, G1n80 and Asp81.

[04711 In preferred embodiments, Section E embodiments provide compounds H
N
c N~
having the general Fonnula XIX, in which P2 is [0472] In preferred embodiments, Section E embodiments provide compounds having the the formula XIXb:

L

o N o NH 1 . J~Z.P1 H g }14 XIXb [0473] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXb, in which L consists of from 2 to 5 atoms.

[0474] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXb, in which L comprises a -W-C(=V)- group, where V and W are each individually selected from 0, S, or NH.

[0475] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXb, in which L is selected from the group consisting of ester, amide, carbainate, thioester, and thioamide.

[0476] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXb, 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, G1n80 and Asp8l.

[0477] In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXb, wherein the C13-C14 double bond is cis.

[04781 In preferred embodiments, Section E embodiments provide compounds having the general Formula XIXb, wherein the C13-C14 double bond is trans.

[0479] Compounds of the Formula XIX may be prepared in the same general manner as the compounds of the Formulas I - XVII.

[0480] In certain embodiments, the compounds of general Formula XIX do not include the compounds disclosed in PCT/USO4/33970. For example, in certain embodiments, the compounds of general Formula I do not include the compounds of Formulas II, III, and IV in Section B above.

Pharmaceutical Compositions [0481] The embodiments further provide compositions, including pharmaceutical compositions, comprising compounds of the general formulas I-XIX, and salts, esters, or other derivatives thereof. A subject pharmaceutical composition comprises a subject compound; and a pharmaceutically acceptable excipient. A wide variety of pharmaceutically acceptable excipients is known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington:
The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, &
Wilkins;
Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 31d ed. Amer. Pharmaceutical Assoc.

[0482] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
Examples of suitable pharmaceutical composition embodiments and methods for making them are described in greater detail below.

Inhibiting Enzymatic Activity of a Flavivirus [0483] In many embodiments, a subject compound inhibits the enzymatic activity of a flavirus. Whether a subject compound inhibits flavivirus may be readily determined using any known method. Flaviviral infections include those caused by flaviviruses including, but not limited to, hepatitis virus C, West Nile Virus, GB virus, Japanese Encephalitis, Dengue virus and Yellow Fever virus. In many embodiments, a subject compound inhibits the enzymatic activity of a hepatitis virus C (HCV) protease NS3. Whether a subject compound inhibits HCV NS3 may be readily determined using any known method. Typical methods involve a determination of whether an HCV
polyprotein or other polypeptide comprising an NS3 recognition site is cleaved by NS3 in the presence of the agent. In many embodiments, a subject compound inhibits enzymatic activity by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the enzymatic activity of NS3 in the absence of the compound.
[0484] In many embodiments, a subject compound inhibits enzymatic activity of an HCV NS3 protease with an IC50 of less than about 50 M, e.g., a subject compound inhibits an HCV NS3 protease with an ICSO of less than about 40 M, less than about 25 M, less than about 10 M, less than about 1 M, less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, or less.
[0485] In many embodiments, a subject compound inhibits HCV viral replication. For example, a subject compound inhibits HCV viral replication by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to HCV viral replication in the absence of the compound. Whether a subject compound inhibits HCV viral replication may be determined using methods known in the art, including an in vitro viral replication assay.
Treatine a Flaviviral Infection [0486] The methods and compositions described herein are generally useful in treatment of a flaviviral infection.
[0487] Whether a subject method is effective in treating a flaviviral infection may be determined by a reduction in viral load, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, or other indicator of disease response.

[64,99f,'"" " to general, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral load or achieve a sustained viral response to therapy.

[0489] Whether a subject method is effective in treating a flaviviral infection may be determined by measuring viral load, or by measuring a parameter associated with a flaviviral infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.

[0490] The method involves administering an effective amount of a compound of formulas I-XIX, optionally in combination with an effective amount of one or more additional antiviral agents. In some embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral titers to undetectable levels, e.g., to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum.
In some embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral load to lower than 100 genome copies/mL serum.

[0491] In some embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum of the individual.

[0492] In many embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to achieve a sustained viral response, e.g., no detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
[0493] As noted above, whether a subject method is effective in treating a flaviviral infection may be determined by measuring a parameter associated with a flaviviral infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.

[0494] As one non-limiting example, levels of serum alanine aminotransferase (ALT) are measured, using standard assays. In general, an ALT level of less than about 45 international units is considered normal. In some embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount effective to reduce ALT levels to less than about 45 IU/ml serum.

[0495] A therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual. Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[0496] In many embodiments, an effective amount of a compound of formulas I-XIX and an additional antiviral agent is synergistic amount. As used herein, a "synergistic combination" or a "synergistic amount" of a compound of formulas I-XIX and an additional antiviral agent is a combined dosage that is more effective in the therapeutic or prophylactic treatment of an HCV infection than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the compound of formulas I-XIX when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy.
[0497] In some embodiments, a selected amount of a compound of formulas I-XIX and a selected amount of an additional antiviral agent are effective when used in combination therapy for a disease, but the selected amount of the compound of formulas I-XIX and/or the selected amount of the additional antiviral agent is ineffective when used in monotherapy for the disease. Thus, the embodiments encompass (1) regimens in which a selected amount of the additional antiviral agent enhances the therapeutic benefit of a selected amount of the compound of formulas I-XIX when used in combination therapy for a disease, where the selected amount of the additional antiviral agent provides no WO 2005/095403 PCT/US2005/010494 .41 ff-i lierie t' when" Used in monotherapy for the disease (2) regimens in which a selected amount of the compound of formulas I-XIX enhances the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, where the selected amount of the compound of formulas I-XIX provides no therapeutic benefit when used in monotherapy for the disease and (3) regimens in which a selected amount of the compound of formula I and a selected amount of the additional antiviral agent provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the compound of formulas I-XIX
and the additional antiviral agent, respectively, provides no therapeutic benefit when used in monotherapy for the disease. As used herein, a "synergistically effective amount" of a compound of formulas I-XIX and an additional antiviral agent, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (1)-(3) above.

Treating a Hepatitis Virus Infection [0498] The methods and compositions described herein are generally useful in treatment of an HCV infection.

[0499] Whether a subject method is effective in treating an HCV infection may be determined by a reduction in viral load, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, or other indicator of disease response.

[0500] In general, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral load or achieve a sustained viral response to therapy.

[0501] Whether a subject method is effective in treating an HCV infection may be determined by measuring viral load, or by measuring a parameter associated with HCV
infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.

[0502] The method involves administering an effective amount of a compound of formulas I-XIX, optionally in combination with an effective amount of one or more additional antiviral agents. In some embodiments, an effective amount of a compound of formulas'"t-XlX, aridopti'onally one or more additional antiviral agents, is an amount that is effective to reduce viral titers to undetectable levels, e.g., to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum.
In some embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to reduce viral load to lower than 100 genome copies/mL serum.

[0503] In some embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum of the individual.

[0504] In many embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to achieve a sustained viral response, e.g., no detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.

[0505] As noted above, whether a subject method is effective in treating an HCV infection may be determined by measuring a parameter associated with HCV
infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.

[0506] As one non-limiting example, levels of serum alanine aminotransferase (ALT) are measured, using standard assays. In general, an ALT level of less than about 45 international units is considered normal. In some embodiments, an effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount effective to reduce ALT levels to less than about 45 IU/ml serum.
[0507] A therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the If }:: fr F! 'i I :~
: r r:( :i i::i:if =: it mark er in ari untreated individual, or to a placebo-treated individual.
Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioiminunoassays, and the like, using antibody specific for a given serum marker.

[0508] In many embodiments, an effective amount of a compound of formulas I-XIX and an additional antiviral agent is synergistic amount. As used herein, a "synergistic combination" or a "synergistic amount" of a compound of formulas I-XIX and an additional antiviral agent is a combined dosage that is more effective in the therapeutic or prophylactic treatment of an HCV infection than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the compound of formulas I-XIX when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy.

[0509] In some embodiments, a selected amount of a compound of formulas I-XIX and a selected amount of an additional antiviral agent are effective when used in combination therapy for a disease, but the selected amount of the compound of formulas I-XIX and/or the selected amount of the additional antiviral agent is ineffective when used in monotherapy for the disease. Thus, the embodiments encompass (1) regimens in which a selected amount of the additional antiviral agent enhances the therapeutic benefit of a selected amount of the compound of formulas I-XIX when used in combination therapy for a disease, where the selected amount of the additional antiviral agent provides no therapeutic benefit when used in monotherapy for the disease (2) regimens in which a selected amount of the compound of formulas I-XIX enhances the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, where the selected amount of the compound of formulas I-XIX provides no therapeutic benefit when used in monotherapy for the disease and (3) regimens in which a selected amount of the compound of formula I and a selected amount of the additional antiviral agent provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the compound of formulas I-XIX
and the additional antiviral agent, respectively, provides no therapeutic benefit when used in monotherapy for the disease. As used herein, a "synergistically effective amount" of a compound of formulas I-XIX and an additional antiviral agent, and its grammatical t W" 6:,m -If 4F F' ..... N Wit I "Ho I'd IF
equivalentss "al'l` be stn erstdo to include any regimen encompassed by any of (1)-(3) above.

Treating Fibrosis [0510] The embodiments provide methods for treating liver fibrosis (including forms of liver fibrosis resulting from, or associated with, HCV infection), generally involving administering a therapeutic amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents. Effective amounts of compounds of formulas I-XIX, with and without one or more additional antiviral agents, as well as dosing regimens, are as discussed below.

[0511] Whether treatment with a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is effective in reducing liver fibrosis is determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Liver fibrosis reduction is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components:
necroinflammation assessed by "grade" as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage" as being reflective of long-term disease progression. See, e.g., Brunt (2000) Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis.
These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[0512] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows:
score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score:
2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[01 1 .. ...... Knode1l's` scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis;
III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score:
0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis;
score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage. Knodell (1981) Hepatol. 1:431.

[0514] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis;
score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score:
4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13:372.

[0515] The Ishak scoring system is described in Ishak (1995) J. Hepatol.
22:696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.

[0516] The benefit of anti-fibrotic therapy may also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy.
Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease:
A, B, or C.

[0517] In some embodiments, a therapeutically effective amount of a compound of formula I, and, optionally one or more additional antiviral agents, is an amount that effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies. In particular embodiments, a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, reduces liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.
[0518] Secondary, or indirect, indices of liver function may also be used to evaluate the efficacy of treatment with a compound of formulas I-XIX.
Morphometric computerized semi automated"'as'sessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis may also be measured as an indication of the efficacy of a subject treatment method.
Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothromnbin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[0519] An effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or to a placebo-treated individual. Those skilled in the art may readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[0520] Serum markers of liver fibrosis may also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV
collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include a-2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[0521] A therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual. Those skilled in the art may readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.
Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[0522] Quantitative tests of functional liver reserve may also be used to assess the efficacy of treatment with an interferon receptor agonist and pirfenidone (or a pirfenidone analog). These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.
[0523] As used herein, a "complication associated with cirrhosis of the liver"
refers to a disorder that is a sequellae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but it not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.
[0524] A therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount that is effective in reducing the incidence (e.g., the likelihood that an individual will develop) of a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or to a placebo-treated individual.
[0525] Whether treatment with a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is effective in reducing the incidence of a disorder associated with cirrhosis of the liver may readily be determined by those skilled in the art.
[0526] Reduction in liver fibrosis increases liver function. Thus, the embodiments provide methods for increasing liver function, generally involving administering a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, yglutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[027] Whe't'her a fiver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, may be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays.
Splanchnic circulation and portal hemodynamics may be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions may be measured by measuring the level of ammonia in the serum.

[0528] Whether serum proteins normally secreted by the liver are in the normal range may be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples. The normal level of alanine transaminase is about 45 IU per milliliter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL.
Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[0529] A therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is one that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, a therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is an amount effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. A therapeutically effective amount of a compound of formulas I-XIX, and optionally one or more additional antiviral agents, is also an amount effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.

Type I interferon receptor monists [0530] In any of the above-described methods, in some embodiments a Type I
interferon receptor agonist is administered. Type I interferon receptor agonists include an IFN-a; an IFN-(3; an IFN-tau; an IFN-w; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists.
Interferon-Alpha [0531] Any known IFN-a may be used in the embodiments. The term "interferon-alpha" as used herein refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response. The term "IFN-a"
includes naturally occurring IFN-a; synthetic IFN-a; derivatized IFN-a (e.g., PEGylated IFN-a, glycosylated IFN-(x, and the like); and analogs of naturally occurring or synthetic IFN-a; essentially any IFN-a that has antiviral properties, as described for naturally occurring IFN-a.
[0532] Suitable alpha interferons include, but are not limited to, naturally-occurring IFN-a (including, but not limited to, naturally occurring IFN-a2a, IFN-(x2b);
recombinant interferon alpha-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, N.J.; recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N. J.; recombinant interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.; interferon alpha-n1, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-n1 (INS) available from the Glaxo-Wellcome Ltd., London, Great Britain; and interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.
[0533] The term "IFN-a" also encompasses consensus IFN-a. Consensus IFN-a (also referred to as "CIFN" and "IFN-con" and "consensus interferon") encompasses but is not limited to the amino acid sequences designated IFN-con 1, IFN-con2 and IFN-con3 which are disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471; and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (e.g., Infergen , InterMune, Inc., Brisbane, Calif.). IFN-conl is the consensus interferon agent in the Infergen alfacon-1 product. The Infergen consensus interferon product is referred to herein by its brand name (Infergen ) or by its generic name (interferon alfacon-1). DNA sequences encoding IFN-con may be synthesized as described in the aforementioned patents or other standard methods. Use of CIFN is of particular interest.
[0534] Also suitable for use in the embodiments are fusion polypeptides comprising an IFN-a and a heterologous polypeptide. Suitable IFN-a fusion polypeptides include, but are not limited to, Albuferon-alphaTM (a fusion product of human albumin and IFN-(x; Human Genome Sciences; see, e.g., Osborn et al. (2002) J. Pharmacol.
Exp.
Therap. 303:540-548). Also suitable for use in the present embodiments are gene-shuffled forms of IFN-a. See., e.g., Masci et al. (2003) Curr. Oncol. Rep. 5:108-113.
PEGylated Interferon-Alpha [0535] The term "IFN-a" also encompasses derivatives of IFN-a that are derivatized (e.g., are chemically modified) to alter certain properties such as serum half-life.
As such, the term "IFN-a" includes glycosylated IFN-a; IFN-a derivatized with polyethylene glycol ("PEGylated 1FN-(x"); and the like. PEGylated IFN-a, and methods for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709;
and 5,951,974. PEGylated IFN-a encompasses conjugates of PEG and any of the above-described IFN-a molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, N.J.), interferon alpha 2b (Intron, Schering-Plough, Madison, N.J.), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen , InterMune, Inc., Brisbane, Calif.).
[0536] Any of the above-mentioned IFN-a polypeptides may be modified with one or more polyethylene glycol moieties, i.e., PEGylated. The PEG
molecule of a PEGylated IFN-a polypeptide is conjugated to one or more amino acid side chains of the IFN-a polypeptide. In some embodiments, the PEGylated IFN-a contains a PEG
moiety on only one amino acid. In other embodiments, the PEGylated IFN-a contains a PEG
moiety on two or more amino acids, e.g., the IFN-a contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.
[0537] IFN-a may be coupled directly to PEG (i.e., without a linking group) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.

[0538] In some embodiments, the PEGylated IFN-a is PEGylated at or near the amino terminus (N-terminus) of the IFN-a polypeptide, e.g., the PEG moiety is conjugated to the IFN-a polypeptide at one or more amino acid residues from amino acid 1 through amino acid 4, or from amino acid 5 through about 10.
[0539] In other embodiments, the PEGylated IFN-a is PEGylated at one or more amino acid residues from about 10 to about 28.
[0540] In other embodiments, the PEGylated IFN-a is PEGylated at or near the carboxyl terminus (C-terminus) of the IFN-a polypeptide, e.g., at one or more residues from amino acids 156-166, or from amino acids 150 to 155.
[0541] In other embodiments, the PEGylated IFN-a is PEGylated at one or more amino acid residues at one or more residues from amino acids 100-114.
[0542] The polyethylene glycol derivatization of amino acid residues at or near the receptor-binding and/or active site domains of the IFN-a protein may disrupt the functioning of these domains. In certain embodiments , amino acids at which PEGylation is to be avoided include amino acid residues from amino acid 30 to amino acid 40; and amino acid residues from amino acid 113 to amino acid 149.
[0543] In some embodiments, PEG is attached to IFN-a via a linking group.
The linking group is any biocompatible linking group, where "biocompatible"
indicates that the compound or group is non-toxic and may be utilized in vitro or in vivo without causing injury, sickness, disease, or death. PEG may be bonded to the linking group, for example, via an ether bond, an ester bond, a thiol bond or an amide bond. Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)), a nitro phenyl group (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteine group, a histidine group or a primary amine.

[0544] Methods for making succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) ester-activated PEGs are described in U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.
[0545] Methods for attaching a PEG to an IFN-a polypeptide are known in the art, and any known method may be used. See, for example, by Park et al, Antimaycer Res., 1:373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry:
Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenum Press, NY, Chapter 21 (1992); U.S.
Patent No. 5,985,265; U.S. Pat. No. 5,672,662 (Harris, et al.) and WO
97/03106.
[0546] Pegylated IFN-a, and methods for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709; 5,985,265; and 5,951,974. Pegylated IFN-a encompasses conjugates of PEG and any of the above-described IFN-a molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, N.J.), where PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, N.J.), where PEGylated Intron is known as PEG-Intron (Schering-Plough); interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen , InterMune, Inc., Brisbane, Calif.), where PEGylated Infergen is referred to as PEG-Infergen.
[0547] In many embodiments, the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-a polypeptide. Methods of modifying polypeptides with monomethoxy PEG via reductive alkylation are known in the art. See, e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.
[0548] In one non-limiting example, PEG is linked to IFN-a via an SPA
linking group. SPA esters of PEG, and methods for making same, are described in U.S.
Patent No. 5,672,662. SPA linkages provide for linkage to free amine groups on the IFN-a polypeptide.
[0549] For example, a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN-a polypeptide. Such a bond may be formed, e.g., by condensation of an a-methoxy, omega propanoic acid activated ester of PEG (mPEGspa).

[0550] As one non-limiting example, one monopegylated CIFN conjugate preferred for use herein has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from 1ys31, 1ys50, 1ys71, 1ys84, lys121 lys'22, lys134 lyS135 and lys165, and the amide bond is formed by condensation of an a-methoxy, omega propanoic acid activated ester of PEG.
Polyethylene glycol [0551] Polyethylene glycol suitable for conjugation to an IFN-a polypeptide is soluble in water at room temperature, and has the general formula R(O-CH2-CH2)õ O-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons.
[0552] In many embodiments, PEG has at least one hydroxyl group, e.g., a terminal hydroxyl group, which hydroxyl group is modified to generate a functional group that is reactive with an amino group, e.g., an epsilon amino group of a lysine residue, a free amino group at the N-terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.
[0553] In other embodiments, PEG is derivatized so that it is reactive with free carboxyl groups in the IFN-a polypeptide, e.g., the free carboxyl group at the carboxyl terminus of the IFN-a polypeptide. Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN-a include, but are not limited to PEG-amine, and hydrazine derivatives of PEG (e.g., PEG-NH-NH2).
[0554] In other embodiments, PEG is derivatized such that it comprises a terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives. Because of the reactive nature of the thio acid, selectivity of certain amino groups over others is achieved. For example, -SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH
conditions such that the s-amino groups in lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions under suitable pH conditions may make some of the accessible lysine residues to react with selectivity.
[0555] In other embodiments, the PEG comprises a reactive ester such as an N-hydroxy succinimidate at the end of the PEG chain. Such an N-hydroxysuccinimidate-containing PEG molecule reacts with select amino groups at particular pH
conditions such as neutral 6.5-7.5. For example, the N-terminal amino groups may be selectively modified under neutral pH conditions. However, if the reactivity of the reagent were extreme, accessible-NH2 groups of lysine may also react.
[0556] The PEG may be conjugated directly to the IFN-a polypeptide, or through a linker. In some embodiments, a linker is added to the IFN-a polypeptide, forming a linker-modified IFN-a polypeptide. Such linkers provide various functionalities, e.g., reactive groups such sulfhydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN-a polypeptide.
[0557] In some embodiments, the PEG conjugated to the IFN-a polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-a polypeptide is branched.
Branched PEG derivatives such as those described in U.S. Pat. No. 5,643,575, "star-PEG's"
and multi-armed PEG's such as those described in Shearwater Polymers, Inc.
catalog "Polyethylene Glycol Derivatives 1997-1998." Star PEGs are described in the art including, e.g., in U.S. Patent No. 6,046,305.
[0558] PEG having a molecular weight in a range of from about 2 kDa to about 100 kDa, is generally used, where the term "about," in the context of PEG, indicates that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight. For example, PEG suitable for conjugation to IFN-a has a molecular weight of from about 2 kDa to about 5 kDa, from about 5 kDa to about 10 kDa, from about 10 kDa to about 15 kDa, from about 15 kDa to about 20 kDa, from about 20 kDa to about 25 kDa, from about 25 kDa to about 30 kDa, from about 30 kDa to about 40 kDa, from about 40 kDa to about 50 kDa, from about 50 kDa to about 60 kDa, from about 60 kDa to about 70 kDa, from about 70 kDa to about 80 kDa, from about 80 kDa to about 90 kDa, or from about 90 kDa to about 100 kDa.
Preparing PEG-IFN-a conjugates [0559] As discussed above, the PEG moiety may be attached, directly or via a linker, to an amino acid residue at or near the N-terminus, internally, or at or near the C-terminus of the IFN-a polypeptide. Conjugation may be carried out in solution or in the solid phase.
N-terminal linkage [0560] Methods for attaching a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-a polypeptide are known in the art. See, e.g., U.S. Patent No. 5,985,265.
[0561] In some embodiments, known methods for selectively obtaining an N-terminally chemically modified IFN-a are used. For example, a method of protein modification by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available for derivatization in a particular protein may be used. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved. The reaction is performed at pH which allows one to take advantage of the pKa differences between the c-amino groups of the lysine residues and that of the a-amino group of the N-terminal residue of the protein. By such selective derivatization attachment of a PEG moiety to the IFN-a is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of the IFN-a and no significant modification of other reactive groups, such as the lysine side chain amino groups, occurs.
C-terminal linkage [0562] N-terminal-specific coupling procedures such as described in U.S.
Patent No. 5,985,265 provide predominantly monoPEGylated products. However, the purification procedures aimed at removing the excess reagents and minor multiply PEGylated products remove the N-terminal blocked polypeptides. In terms of therapy, such processes lead to significant increases in manufacturing costs. For example, examination of the structure of the well-characterized Infergen Alfacon-1 CIFN polypeptide amino acid sequence reveals that the clipping is approximate 5% at the carboxyl terminus and thus there is only one major C-terminal sequence. Thus, in some embodiments, N-terminally PEGylated IFN-a is not used; instead, the IFN-a polypeptide is C-terminally PEGylated.
[0563] An effective synthetic as well as therapeutic approach to obtain mono PEGylated Infergen product is therefore envisioned as follows:
[0564] A PEG reagent that is selective for the C-terminal may be prepared with or without spacers. For example, polyethylene glycol modified as methyl ether at one end and having an amino function at the other end may be used as the starting material.
[0565] Preparing or obtaining a water-soluble carbodiimide as the condensing agent may be carried out. Coupling IFN-a (e.g., Infergen Alfacon-1 CIFN or consensus interferon) with a water-soluble carbodiimide as the condensing reagent is generally carried out in aqueous medium with a suitable buffer system at an optimal pH to effect the amide linkage. A high molecular weight PEG may be added to the protein covalently to increase the molecular weight.
[0566] The reagents selected will depend on process optimization studies. A
non-limiting example of a suitable reagent is EDAC or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. The water solubility of EDAC allows for direct addition to a reaction without the need for prior organic solvent dissolution. Excess reagent and the isourea formed as the by-product of the cross-linking reaction are both water-soluble and may easily be removed by dialysis or gel filtration. A concentrated solution of EDAC in water is prepared to facilitate the addition of a small molar amount to the reaction. The stock solution is prepared and used immediately in view of the water labile nature of the reagent. Most of the synthetic protocols in literature suggest the optimal reaction medium to be in pH range between 4.7 and 6Ø However the condensation reactions do proceed without significant losses in yields up to pH 7.5. Water may be used as solvent. In view of the contemplated use of Infergen, preferably the medium will be 2-(N-morpholino)ethane sulfonic acid buffer pre-titrated to pH between 4.7 and 6Ø However, 0.1M phosphate in the pH 7-7.5 may also be used in view of the fact that the product is in the same buffer. The ratios of PEG amine to the IFN-a molecule is optimized such that the C-terminal carboxyl residue(s) are selectively PEGylated to yield monoPEGylated derivative(s).
[0567] Even though the use of PEG amine has been mentioned above by name or structure, such derivatives are meant to be exemplary only, and other groups such as hydrazine derivatives as in PEG-NH-NH2 which will also condense with the carboxyl group of the IFN-a protein, may also be used. In addition to aqueous phase, the reactions may also be conducted on solid phase. Polyethylene glycol may be selected from list of compounds of molecular weight ranging from 300-40000. The choice of the various polyethylene glycols will also be dictated by the coupling efficiency and the biological performance of the purified derivative in vitro and in vivo i.e., circulation times, anti viral activities etc.
[0568] Additionally, suitable spacers may be added to the C-terminal of the protein. The spacers may have reactive groups such as SH, NH2 or COOH to couple with appropriate PEG reagent to provide the high molecular weight IFN-a derivatives. A
combined solid/solution phase methodology may be devised for the preparation of C-terminal pegylated interferons. For example, the C-terminus of FN-(x is extended on a solid phase using a Gly-Gly-Cys-NH2 spacer and then monopegylated in solution using activated dithiopyridyl-PEG reagent of appropriate molecular weights. Since the coupling at the C-terminus is independent of the blocking at the N-terminus, the envisioned processes and products will be beneficial with respect to cost (a third of the protein is not wasted as in N-terminal PEGylation methods) and contribute to the economy of the therapy to treat virus infection.
[0569] There may be a more reactive carboxyl group of amino acid residues elsewhere in the molecule to react with the PEG reagent and lead to monoPEGylation at that site or lead to multiple PEGylations in addition to the -COOH group at the C-terminus of the IFN-a. It is envisioned that these reactions will be minimal at best owing to the steric freedom at the C-terminal end of the molecule and the steric hindrance imposed by the carbodiimides and the PEG reagents such as in branched chain molecules. It is therefore the preferred mode of PEG modification for Infergen and similar such proteins, native or expressed in a host system, which may have blocked N-termini to varying degrees to improve efficiencies and maintain higher in vivo biological activity.
[0570] Another method of achieving C-terminal PEGylation is as follows.
Selectivity of C-terminal PEGylation is achieved with a sterically hindered reagent which excludes reactions at carboxyl residues either buried in the helices or internally in IFN-a.
For example, one such reagent could be a branched chain PEG -40kd in molecular weight and this agent could be synthesized as follows:
[0571] OH3C-(CH2CH2O)n-CH2CH2NH2 + Glutamic Acid i.e., HOCO-CH2CH2CH(NH2)-COOH is condensed with a suitable agent e.g., dicyclohexyl carbodiimide or water-soluble EDC to provide the branched chain PEG agent OH3C-(CH2CH2O)õCH2CH2NH000H(NH2)CH2OCH3-(CH2CH2O).-CH2CH2NHC0CH2.

Ii3C-O-(Clf'CH20)n-CI12Ci12NI12 110 C-CIi2C1i2Ci1-COO11 I
C11NH, EUAC

I1.3C-O-(CI{1_CI120)õ-CI12C112N H-Co I
(CI12)2 I
H3C-O-(CH>CH20)11-C H wCH2N H-C) [0572] This reagent may be used in excess to couple the amino group with the free and flexible carboxyl group of IFN-a to form the peptide bond.
[0573] If desired, PEGylated IFN-a is separated from unPEGylated IFN-a using any known method, including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. For example, where the PEG-IFN-a conjugate is a monoPEGylated IFN-a, the products are first separated by ion exchange chromatography to obtain material having a charge characteristic of monoPEGylated material (other multi-PEGylated material having the same apparent charge may be present), and then the monoPEGylated materials are separated using size exclusion chromatography.
MonoPEG (30 kD, linear)-ylated IFN-a [0574] PEGylated IFN-a that is suitable for use in the embodiments includes a monopegylated consensus interferon (CIFN) molecule comprised of a single CIFN
polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG
moiety is linear and about 30 kD in molecular weight and is directly or indirectly linked through a stable covalent linkage to either the N-terminal residue in the CIFN polypeptide or a lysine residue in the CIFN polypeptide. In some embodiments, the monoPEG (30 kD, linear)-ylated IFN-a is monoPEG (30 kD, linear)-ylated consensus IFN-a.
[0575] In some embodiments, the PEG moiety is linked to either the alpha-amino group of the N-terminal residue in the CIFN polypeptide or the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN
polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG noiety`and ei iffier the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN
polypeptide, thereby forming a hydrolytically stable linkage between the PEG moiety and the CIFN
polypeptide.

[0576] In some embodiments, the PEG moiety is linked to the N-terminal residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG
moiety and the alpha-amino group of the N-terminal residue in the CIFN
polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N-terminal residue of the CIFN polypeptide.

[0577] In some embodiments, the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the lysine residue in the CIFN polypeptide.

[0578] In some embodiments, the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a surface-exposed lysine residue in the CIFN
polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG
moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN
polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the C1FN
polypeptide.
[0579] In some embodiments, the PEG moiety is linked to a lysine chosen from 1ys31, 1ys50, 1ys71, lys84, 1ys121, 1ys122, lys134, lys'35, and lys'65 of the CIFN polypeptide.
In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from 1ys31, lys50, 1ys71, 1ys84, lys121, lys'22, 1ys134lys'35, and lys165 of the CIFN
polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN
polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG
moiety and the epsilon-amino group of the chosen lysine residue in the CIFN
polypeptide.
[0580] me embodiments, the PEG moiety is linked to a lysine chosen from 1ys1 , lys , lys , and lys'65 of the CIFN polypeptide. In other embodiments, the PEG
21'34'35 moiety is linked to the epsilon-amino group of a lysine chosen from 1ys121, 1ys134, lys135, and 1ys165 of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN
polypeptide.
[0581] In connection with the above-described monopegylated CIFN
molecules, the invention contemplates embodiments of each such molecule where the CIFN
polypeptide is chosen from interferon alpha-cons, interferon alpha-cone, and interferon alpha-con3, the amino acid sequences of which CIFN polypeptides are disclosed in U.S.
Pat. No. 4,695,623.
Populations of IFN-a [0582] In addition, any of the methods of the embodiments may employ a PEGylated IFN-a composition that comprises a population of monopegylated IFN-a molecules, where the population consists of one or more species of monopegylated IFN-a molecules as described above. The subject composition comprises a population of modified IFN-a polypeptides, each with a single PEG molecule linked to a single amino acid residue of the polypeptide.
[0583] In some of these embodiments, the population comprises a mixture of a first IFN-a polypeptide linked to a PEG molecule at a first amino acid residue; and at least a second IFN-a polypeptide linked to a PEG molecule at a second amino acid residue, wherein the first and second IFN-a polypeptides are the same or different, and wherein the location of the first amino acid residue in the amino acid sequence of the first IFN-a polypeptide is not the same as the location of the second amino acid residue in the second IFN-a polypeptide. As one non-limiting example, a subject composition comprises a population of PEG-modified IFN-a polypeptides, the population comprising an IFN-a polypeptide linked at its amino terminus to a linear PEG molecule; and an IFN-a polypeptide linked to a linear PEG molecule at a lysine residue.
[0584] Generally, a given modified IFN-a species represents from about 0.5% to about 99.5% of the total population of monopegylated IFN-a polypeptide molecules in a population, e.g, a given modified IFN-a species represents about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5% of the total population of monopegylated IFN-a polypeptide molecules in a population. In some embodiments, a subject composition comprises a population of monopegylated IFN-a polypeptides, which population comprises at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, IFN-a polypeptides linked to PEG at the same site, e.g., at the N-terminal amino acid.
[0585] In particular embodiments of interest, a subject composition comprises a population of monopegylated CIFN molecules, the population consisting of one or more species of molecules, where each species of molecules is characterized by a single CIFN polypeptide linked, directly or indirectly in a covalent linkage, to a single linear PEG moiety of about 30 kD in molecular weight, and where the linkage is to either a lysine residue in the CIFN polypeptide, or the N-terminal amino acid residue of the CIFN
polypeptide.

The" ammo acid residue to which the PEG is attached is in many embodiments the N-terminal amino acid residue. In other embodiments, the PEG
moiety is attached (directly or via a linker) to a surface-exposed lysine residue. In additional embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from 1ys31, 1ys50, 1ys71, lys84, lys121, 1ys122, lys134, 1ys135, and 1ys165 of the CIFN
polypeptide. In further embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from 1Ys121, 1Y5134' lYs13s' and 1Ys165 of the CIFN
polypeptide.

[0587] As an example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different.
A subject composition may further comprise at least one additional monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[0588] In connection with each of the above-described populations of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG
moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
[0589] As another example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species ofinolecules `characteized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of 1Ys31, 1Ys50' 1Y571' 1Ys84, 1Y6121' 1Y6122' 1Y6134' 1Y ~ 5135 and lY5165 in a second CIFN
polypeptide, where the first and second CIFN polypeptides are the same or different. A
subject composition may further comprise a third monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of 1Ys31, lYs50, 1Y571, 1Ys84, 1Y5121, 1Y5122, 1Y6134, 1Y5135, and 1Y6165 in a third CIFN
polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN
polypeptide. A subject composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG
moiety linked to one of 1ys31, 1ys50, 1ys71, lys84, 1ys121, 1ys122, 1ys134, 1ys135, and 1ys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[0590] As another example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys 121, 1Y5134, 1Ys135 , and 1Ys165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A subject composition may further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys121,1y5134, 1y5135, and 1ys165 in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN
polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A subject composition may further comprise at least one " ad'di Tonal' moiopegyl'ate ,CIPN"'polypeptide species of molecules characterized by a PEG
moiety linked to one of 1ys121,1yS134, lys135, and 1ys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[0591] As another non-limiting example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. A subject composition may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[0592] As another non-limiting example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys 31, 1Ys50, 1YS71, 1YS84, 1Ys121, 1Y5122, 1Ys134, lYS135, and 1Y5165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from 1ys31, lys50, 1ys71, 1ys84, 1ys121, 1ys122, lys134, 1yS135, and 1ys165 in a second CIFN
polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN
polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide.
The composition may further comprise at least one additional monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to one of 1ys31, 1Ys50,1Y571, 1YS84, 1Y5121, 1Y5122, 1Y5134, 1Ys13s, and 1Ys16s' where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the"linkagesite in any of er secies. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[0593] As another non-limiting example, a subject composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from 1Ys121, 1Ys134, 1Ys13s, and lys 165 in a first CIFN
polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG
moiety linked at a second lysine residue chosen from lys121, 1ys134, lys135, and lysl65 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of 1 sl2t 1 s134 1 s13s and 1 s16s y y y y y ,where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG
moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[0594] As another non-limiting example, a subject composition comprises a monopegylated population of CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a second surface-exposed lysine residue in a second CIFN polypeptide, where the first and second CIFN
polypeptides are the same or different, and where the first surface-exposed lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second surface-exposed lysine residue in the amino acid sequence of the second CIFN polypeptide. A subject composition may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG
moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG
moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

in "coi nectori with each of the above-described populations of monopegylated CIFN roolecules, the invention contemplates embodiments where the molecules in each such population comprise a CIFN polypeptide chosen from interferon alpha-cons, interferon alpha-cone, and interferon alpha-con3.

[0596] Certain embodiments further feature a product that is produced by the process of reacting CIFN polypeptide with a succinimidyl ester of alpha-methoxy, omega-propionylpoly(ethylene glycol) (mPEGspa) that is linear and about 30 kD in molecular weight, where the reactants are initially present at a molar ratio of about 1:1 to about 1:5 CIFN:mPEGspa, and where the reaction is conducted at a pH of about 7 to about 9, followed by recovery of the monopegylated CIFN product of the reaction. In one embodiment, the reactants are initially present at a molar ratio of about 1:3 CIFN:mPEGspa and the reaction is conducted at a pH of about 8. In another embodiment where the product is generated by a scaled-up procedure needed for toxicological and clinical investigations, the reactants are initially present in a molar ratio of 1:2 CIFN:mPEGspa and the reaction is conducted at a pH of about 8Ø

[0597] In connection with the above-described product-by-process, the invention contemplates embodiments where the CIFN reactant is chosen from interferon alpha-cons, interferon alpha-cone, and interferon alpha-con3.
IFN-B

[0598] The term interferon-beta ("IFN-13") includes IFN-B polypeptides that are naturally occurring; non-naturally-occurring IFN-B polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-B that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-B.

[0599] Any of a variety of beta interferons may be delivered by the continuous delivery method of the present embodiments. Suitable beta interferons include, but are not limited to, naturally-occurring IFN-B; IFN-B 1 a, e.g., Avonex (Biogen, Inc.), and Rebif (Serono, SA); IFN-B1b (Betaseron ; Berlex); and the like.

[0600] The IFN-B formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-B.

[0601] IFN-B polypeptides may be produced by any known method. DNA
sequences encoding IFN-B may be synthesized using standard methods. In many embodiments, IFN-B polypeptides are the products of expression of manufactured DNA

sequences ' transformed or trarisf6cted into bacterial hosts, e.g., E. cols, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-13 is "recombinant IFN-B." Where the host cell is a bacterial host cell, the IFN-B is modified to comprise an N-terminal inethionine.

[0602] It is to be understood that IFN-B as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.

IFN-tau [0603] The term interferon-tau includes IFN-tau polypeptides that are naturally occurring; non-naturally-occurring IFN-tau polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-tau that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-tau.

[0604] Suitable tau interferons include, but are not limited to, naturally-occurring IFN-tau; Tauferon (Pepgen Corp.); and the like.

[0605] IFN-tau may comprise an amino acid sequence as set forth in any one of GenBank Accession Nos. P15696; P56828; P56832; P56829; P56831; Q29429; Q28595;
Q28594; S08072; Q08071; Q08070; Q08053; P56830; P28169; P28172; and P28171.
The sequence of any known IFN-tau polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups:
(glycine, alanine);
(valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
[0606] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
[0607] The IFN-tau formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-tau.
[0608] IFN-tau polypeptides may be produced by any known method. DNA
sequences encoding IFN-tau may be synthesized using standard methods. In many embodiments, IFN-tau polypeptides are the products of expression of manufactured DNA
sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-tau is "recombinant IFN-tau." Where the host cell is a bacterial host cell, the IFN-tau is modified to comprise an N-terminal methionine.
[0609] It is to be understood that IFN-tau as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
IFN-co [0610] The term interferon-omega ("IFN-o)") includes IFN-w polypeptides that are naturally occurring; non-naturally-occurring IFN-w polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-w that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-co.
[0611] Any known omega interferon may be delivered by the continuous delivery method of the present embodiments. Suitable IFN-w include, but are not limited to, naturally-occurring IFN-co; recombinant IFN-co, e.g., Biomed 510 (BioMedicines); and the like.
[0612] IFN-w may comprise an amino acid sequence as set forth in GenBank Accession No. NP_002168; or AAA70091. The sequence of any known IFN-w polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine);

(aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine);
(lysine, arginine); or (phenylalanine, tyrosine).
[0613] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
[0614] The IFN-co formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-w.
[0615] IFN-co polypeptides may be produced by any known method. DNA
sequences encoding IFN-co may be synthesized using standard methods. In many embodiments, IFN-co polypeptides are the products of expression of manufactured DNA
sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-co is "recombinant IFN-co." Where the'host cell is a bacterial host cell, the IFN-co is modified to comprise an N-terminal methionine.
[0616] It is to be understood that IFN-co as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.

Type III interferon receptor agonists [0617] In any of the above-described methods, the interferon receptor agonist is in some embodiments an agonist of a Type III interferon receptor (e.g., "a Type III
interferon agonist"). Type III interferon agonists include an IL-28b polypeptide; and IL-28a polypeptide; and IL-29 polypeptide; antibody specific for a Type III
interferon receptor; and any other agonist of Type III interferon receptor, including non-polypeptide agonists.

IU- '8A, L-"29B, and IL-29 (referred to herein collectively as "Type III
interferons" or "Type III IFNs") are described in Sheppard et al. (2003) Nature 4:63-68.
Each polypeptide binds a heterodiineric receptor consisting of IL- 10 receptor 13 chain and an IL-28 receptor a. Sheppard et al. (2003), supra. The amino acid sequences of IL-28A, IL-28B, and IL-29 are found under GenBank Accession Nos. NP_742150, NP_742151, and NP742152, respectively.

[0619] The amino acid sequence of a Type III IFN polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A
variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine);
(aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine);
(lysine, arginine); or (phenylalanine, tyrosine).

[0620] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.

[0621] Included in the embodiments are polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone of the peptide may be cyclized to enhance stability (see Friedler et al. (2000) J. Biol. Chem. 275:23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e.g. D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability. The polypeptides may be fused to albumin.
[0622] The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines may be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.

Type II Interferon receptor agonists [0623] Type II interferon receptor agonists include any naturally-occurring or non-naturally-occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
[0624] A specific example of a Type II interferon receptor agonist is IFN-y and variants thereof. While the present embodiments exemplify use of an IFN-y polypeptide, it will be readily apparent that any Type II interferon receptor agonist may be used in a subject method.
Interferon-Gamma [0625] The nucleic acid sequences encoding IFN-y polypeptides may be accessed from public databases, e.g., Genbank, journal publications, etc.
While various mammalian IFN-y polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN-y coding sequence may be found in Genbank, accession numbers X13274; V00543; and NM_000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265;
and V00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274);
and Rinderknecht et al. (1984) J.B. C. 259:6790.
[0626] IFN-yl b (Actimmune ; human interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinantly in Ecoli and is unglycosylated.
Rinderknecht et at. (1984) J. Biol. Chem. 259:6790-6797. Recombinant IFN-y as discussed in U.S. Patent No. 6,497,871 is also suitable for use herein.
[0627] The IFN-y to be used in the methods of the present embodiments may be any of natural IFN-ys, recombinant IFN-ys and the derivatives thereof so far as they have an IFN-y activity, particularly human IFN-y activity. Human IFN-y exhibits the antiviral and anti-proliferative properties characteristic of the interferons, as well as a number of other immunomodulatory activities, as is known in the art. Although IFN-y is based on the sequences as provided above, the production of the protein and proteolytic processing may result in processing variants thereof. The unprocessed sequence provided by Gray et al., supra, consists of 166 amino acids (aa). Although the recombinant IFN-y produced in E.
coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN-y is cleaved after residue 23, to produce a 143 as protein, or 144 as if the terminal methionine is present, as required for expression in bacteria. During purification, the mature protein may additionally be cleaved at the C
terminus after reside 162 (referring to the Gray et al. sequence), resulting in a protein of 139 amino acids, or 140 amino acids if the initial methionine is present, e.g.
if required for bacterial expression. The N-terminal methionine is an artifact encoded by the mRNA
translational "start" signal AUG that, in the particular case of E. coli expression is not processed away. In other microbial systems or eukaryotic expression systems, methionine may be removed.
[0628] For use in the subject methods, any of the native IFN-y peptides, modifications and variants thereof, or a combination of one or more peptides may be used.
IFN-y peptides of interest include fragments, and may be variously truncated at the carboxyl terminus relative to the full sequence. Such fragments continue to exhibit the characteristic properties of human gamma interferon, so long as amino acids 24 to about 149 (numbering from the residues of the unprocessed polypeptide) are present. Extraneous sequences may be substituted for the amino acid sequence following amino acid 155 without loss of activity. See, for example, U.S. Patent No. 5,690,925. Native IFN-y moieties include molecules variously extending from amino acid residues 24-150; 24-151, 24-152;
24- 153, 24-155; and 24-157. Any of these variants, and other variants known in the art and having IFN-y activity, may be used in the present methods.
[0629] The sequence of the IFN-y polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e., will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
[0630] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. One embodiment contemplates the use of IFN-y variants with one or more non-naturally occurring glycosylation and/or pegylation sites that are engineered to provide glycosyl- and/or PEG-derivatized polypeptides with reduced serum clearance, such as the IFN-y polypeptide variants described in International Patent Publication No.
WO 01/36001.
Also included are modifications of glycosylation, e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g., by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g., phosphotyrosine, phosphoserine, or phosphothreonine.
[0631] Included in the embodiments are polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone of the peptide may be cyclized to enhance stability (see Friedler et at. (2000) J. Biol. Chem. 275:23783-23789). Analogs may be used that `include"'residues other `than `naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability.

[0632] The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines may be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.

[0633] The polypeptides may also be isolated and purified in accordance with conventional methods of recombinant synthesis. A lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. For the most part, the compositions which are used will comprise at least 20% by weight of the desired product, more usually at least about 75% by weight, preferably at least about 95% by weight, and for therapeutic purposes, usually at least about 99.5% by weight, in relation to contaminants related to the method of preparation of the product and its purification.
Usually, the percentages will be based upon total protein.

Pirfenidone and Analogs Thereof [0634] Pirfenidone (5-methyl- 1 -phenyl-2-(l H)-pyridone) and specific pirfenidone analogs are disclosed for the treatment of fibrotic conditions. A
"fibrotic condition" is one that is amenable to treatment by administration of a compound having anti-fibrotic activity.

Pirfenidone Me / N,Ph Pirfenidone analogs I
R2rN.RI
O
X

IIA JIB

RI X,' O RI X, LO

Descriptions for Substituents R1, R2, X

[0635] R1: carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alkyls (saturated and unsaturated). Examples include phenyl, benzyl, pyrrmidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.

[0636] Rl may further include substitutions on the carbocyclic or heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2, 5-dichlorocyclohexyl, guanidinyl-cyclohexenyl and the like.

[0637] R2: alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.

[0638] X: may be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring. The substituents may be the same or different.
Substituents may include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like.
[0639] The substituents may be optionally further substituted with 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halo groups. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.
[0640] Specific Examples include the compounds listed in Table 1:

Table 1 IIA IIB
5-Methyl-l-(2'-pyridyl)-2-(1H) pyridine, 6-Methyl-I-phenyl-3-(1H) pyridone, 6-Methyl-l-phenyl-2-(IH) pyridone, 5-Methyl-l-p-tolyl-3-(1H) pyridone, 5-Methyl-3-phenyl-l-(2'-thienyl)-2-(1H) 5-Methyl-l-(2'-naphthyl)-3-(iH) pyridone, pyridone, 5-Methyl-l-(2'-naphthyl)-2-(1H) pyridone, 5-Methyl-l-phenyl-3-(lH) pyridone, 5-Methyl-l-p-tolyl-2-(iH) pyridone, 5-Methyl-l-(5'-quinolyl)-3-(1H) pyridone, 5-Methyl-l-(1'naphthyl)-2-(II) pyridone, 5-Ethyl-I-phenyl-3-(iH) pyridone, 5-Ethyl-l-phenyl-2-(iH) pyridone, 5-Methyl-l-(4'-methoxyphenyl)-3-(iH) pyridone, 5-Methyl-l-(5'-quinolyl)-2-(iH) pyridone, 4-Methyl-I-phenyl-3-(1H) pyridone, 5-Methyl-l-(4'-quinolyl)-2-(1H) pyridone, 5-Methyl-l-(3'-pyridyl)-3-(iH) pyridone, 5-Methyl-l-(4'-pyridyl)-2-(iH) pyridone, 5-Methyl-l-(2'-Thienyl)-3-(iH) pyridone, 3-Methyl-1 -phenyl-2-(1 H) pyridone, 5 -Methyl- I -(2'-pyridyl)-3 -(I H) pyridone, 5-Methyl-l-(4'-methoxyphenyl)-2-(1H) pyridone, 5-Methyl-l-(2'-quinolyl)-3-(lH) pyridone, I -Phenyl-2-(l H) pyridone, I-Phenyl-3-(1H) pyridine, 1,3-Diphenyl-2-(lH) pyridone, 1-(2'-Furyl)-5-methyl-3-(iH) pyridone, 1,3 -Diphenyl-5 -methyl-2-(l H) pyridone, 1-(4'-Chlorophenyl)-5-inethyl-3-(1H) pyridine.
5-Methyl-I -(3'-trifluoroinethylphenyl)-2-(1H)-pyridone, 3 -Ethyl- l -phenyl-2-(1 H) pyridone, 5-Methyl-l-(3'-pyridyl)-2-(1H) pyridone, 5-Methyl-l-(3-nitrophenyl)-2-(lH) pyridone, 3-(4'-Chlorophenyl)-5-Methyl-l -phenyl-2-(l H) pyridone, 5-Methyl-l-(2'-Thienyl)-2-(1H) pyridone, 5-Methyl-l-(2'-thiazolyl)-2-(lH) pyridone, 3,6-Dimethyl-l-phenyl-2-(lH) pyridone, 1-(4'Chlorophenyl)-5-Methyl-2-(1H) pyridone, 1-(2'-Imidazolyl)-5-Methyl-2-(1H) pyridone, 1-(4' Nirrophenyl)-2-(1H) pyridone, 1-(2'-Furyl)-5-Methyl-2-(1 H) pyridone, 1-Phenyl-3-(4'-chlorophenyl)-2-(1 H) pyridine.

[0641] U.S. Pat. Nos. 3,974,281; 3,839,346; 4,042,699; 4,052,509; 5,310,562;
5,518,729; 5,716,632; and 6,090,822 describe methods for the synthesis and formulation of pirfenidone and specific pirfenidone analogs in pharmaceutical compositions suitable for use in the methods of the present embodiments.

Thymosin-a [0642] Thymosin-a (ZadaxinTM; available from SciClone Pharmaceuticals, Inc., San Mateo, CA) is a synthetic form of thymosin alpha 1, a hormone found naturally in the circulation and produced by the thymus gland. Thymosin-a increases activity of T cells and NK cells. ZadaxinTM formulated for subcutaneous injection is a purified sterile lyophilized preparation of chemically synthesized thymosin alpha 1 identical to human thymosin alpha 1. Thymosin alpha 1 is an acetylated polypeptide with the following sequence: Ac - Ser - Asp - Ala - Ala - Val - Asp - Thr - Ser - Ser - Glu - Ile - Thr - Thr - Lys - Asp - Leu - Lys - Glu - Lys - Lys - Glu - Val - Val - Glu - Glu - Ala - Glu -Asn - OH,and having a molecular weight of 3,108 daltons. The lyophilized preparation contains 1.6 mg synthetic thymosin-a, 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8.
Ribavirin [0643] Ribavirin, 1-(3-D-ribofuranosyl-LH-1,2,4-triazole-3-carboxamide, is a nucleoside analog available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., and is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. The embodiments also contemplate use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830). The ribavirin may be administered orally in capsule or tablet form. Of course, other types of administration of ribavirin, as they become available are contemplated, such as by nasal spray, transdermally, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.
[0644] Ribavirin is generally administered in an amount ranging from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day. In some embodiments, ribavirin is administered throughout the entire course of NS3 inhibitor therapy.

Levovirin [0645] Levovirin is the L-enantiomer of ribavirin, and exhibits the property of enhancing a Thl immune response over a Th2 immune response. Levovirin is manufactured by ICN Pharmaceuticals.
[0646] Levovirin has the following structure:

II N \~

OH
HO OH

Viramidine [06471 Viramidine is a 3-carboxamidine derivative of ribavirin, and acts as a prodrug of ribavirin. It is efficiently converted to ribavirin by adenosine deaminases.
[0648] Viramidine has the following structure:

NH
N
H2N ) N--N
HO

HO OH
Nucleoside Analogs [0649] Nucleoside analogs that are suitable for use in a subject combination therapy include, but are not limited to, ribavirin, levovirin, viramidine, isatoribine, an L-ribofuranosyl nucleoside as disclosed in U.S. Patent No. 5,559,101 and encompassed by Formula I of U.S. Patent No. 5,559,101 (e.g., 1-0-L-ribofuranosyluracil, 1-0-L-ribofuranosyl-5-fluorouracil, 1-P-L-ribofuranosylcytosine, 9-5-L-ribofuranosyladenine, 9-(3-L-ribofuranosylhypoxanthine, 9-0-L-ribofuranosylguanine, 9-0-L-ribofuranosyl-6-thioguanine, 2-amino-a-L-ribofuranl[1',2':4,5]oxazoline, 02,02-anhydro-l-a-L-ribofuranosyluracil, 1-a-L-ribofuranosyluracil, 1-(2,3,5-tri-O-benzoyl-a-ribofuranosyl)-4-thiouracil, I-a-L-ribofuranosylcytosine, 1-a-L-ribofuranosyl-4-thiouracil, 1-a-L-ribofuranosyl-5-fluorouracil, 2-amino-(3-L-arabinofurano[ 1',2' :4,5]oxazoline, 02,02-anhydro-(3-L-arabinofuranosyluracil, 2'-deoxy-(3-L-uridine, 3'5'-Di-O-benzoyl-2'deoxy-4-thio (3-L-uridine, 2'-deoxy-(3-L-cytidine, 2'-deoxy-(3-L-4-thiouridine, 2'-deoxy-(3-L-thymidine, 2'-deoxy-p-L-5-fluorouridine, 2',3'-dideoxy-f -L-uridine, 2'-deoxy-(3-L-5-fluorouridine, and 2'-deoxy-(3-L-inosine); a compound as disclosed in U.S.
Patent No.
6,423,695 and encompassed by Formula I of U.S. Patent No. 6,423,695; a compound as disclosed in U.S. Patent Publication No. 2002/0058635, and encompassed by Formula I of U.S. Patent Publication No. 2002/0058635; a nucleoside analog as disclosed in WO
01/90121 A2 (Idenix); a nucleoside analog as disclosed in WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.); a nucleoside analog as disclosed in WO 02/057287 A2 or WO
02/057425 A2 (both Merck/Isis); and the like.

TNF Antagonists [0650] In some embodiments, a subject method comprises administering an effective amount of a NS3 inhibitor and an effective amount of a tumor necrosis factor-a (TNF-(x) antagonist. Suitable TNF-a antagonists for use herein include agents that decrease the level of TNF-a synthesis, agents that block or inhibit the binding of TNF-a to a TNF-a receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction. Unless otherwise expressly stated, every reference to a "TNF-a antagonist"
or "TNF antagonist" herein will be understood to mean a TNF-a antagonist other than pirfenidone or a pirfenidone analog.
[0651] As used herein, the terms "TNF receptor polypeptide" and "TNFR
polypeptide" refer to polypeptides derived from TNFR (from any species) which are capable of binding TNF. Two distinct cell-surface TNFRs have described: Type II TNFR
(or p75 TNFR or TNFRII) and Type I TNFR (or p55 TNFR or TNFRI). The mature full-length human p75 TNFR is a glycoprotein having a molecular weight of about 75-kilodaltons (kD). The mature full-length human p55 TNFR is a glycoprotein having a molecular weight of about 55-60 kD. Exemplary TNFR polypeptides are derived from TNFR Type I and/or TNFR type II. Soluble TNFR includes p75 TNFR polypeptide;
fusions of p75 TNFR with heterologous fusion partners, e.g., the Fc portion of an immunoglobulin.

[0652] TNFR polypeptide may be an intact TNFR or a suitable fragment of TNFR. U.S. Pat. No. 5,605,690 provides examples of TNFR polypeptides, including soluble TNFR polypeptides, appropriate for use in the present embodiments. In many embodiments, the TNFR polypeptide comprises an extracellular domain of TNFR.
In some embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR linked to a constant domain of an immunoglobulin molecule. In other embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 TNFR linked to a constant domain of an IgGI molecule. In some embodiments, when administration to humans is contemplated, an Ig used for fusion proteins is human, e.g., human IgGi.
[0653] Monovalent and multivalent forms of TNFR polypeptides may be used in the present embodiments. Multivalent forms of TNFR polypeptides possess more than one TNF binding site. In some embodiments, the TNFR is a bivalent, or dimeric, form of TNFR. For example, as described in U.S. Pat. No. 5,605,690 and in Mohler et al., 1993, J. Immunol., 151:1548-1561, a chimeric antibody polypeptide with TNFR
extracellular domains substituted for the variable domains of either or both of the immunoglobulin heavy or light chains would provide a TNFR polypeptide for the present embodiments.
Generally, when such a chimeric TNFR:antibody polypeptide is produced by cells, it forms a bivalent molecule through disulfide linkages between the immunoglobulin domains. Such a chimeric TNFR:antibody polypeptide is referred to as TNFR:Fc.
[0654] In one embodiment, a subject method involves administration of an effective amount of the soluble TNFR ENBREL . ENBREL is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNFR linked to the Fc portion of human IgG1. The Fc component of ENBREL
contains the CH2 domain, the CH3 domain and hinge region, but not the CH 1 domain of IgG 1.
ENBREL is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al. (1990) Science 248:1019-1023;
Mohler et al.
(1993) J. Immunol. 151:1548-1561; U.S. Pat. No. 5,395,760; and U.S. Pat. No.
5,605,690.
[0655] Also suitable for use are monoclonal antibodies that bind TNF-a.
Monoclonal antibodies include "humanized" mouse monoclonal antibodies;
chimeric antibodies; monoclonal antibodies that are at least about 80%, at least about 90%, at least about 95%, or 100% human in amino acid sequence; and the like. See, e.g., WO
90/10077;

WO 90/04036; and WO 92/02190. Suitable monoclonal antibodies include antibody fragments, such as Fv, F(ab')2 and Fab; synthetic antibodies; artificial antibodies; phage display antibodies; and the like.
[0656] Examples of suitable monoclonal antibodies include Infliximab (REMICADE , Centocor); and Adalimumab (HUMIRATM, Abbott). REMICADE is a chimeric monoclonal anti-TNF-cs antibody that includes about 25% mouse amino acid sequence and about 75% human amino acid sequence. REMICADE comprises a variable region of a mouse monoclonal anti-TNF-a antibody fused to the constant region of a human IgG 1. Elliott et al. (1993) Arthritis Rheum. 36:1681-1690; Elliott et at. (1994) Lancet 344:1105-1110; Baert et al. (1999) Gastroenterology 116:22-28. HUMIRATM
is a human, full-length IgGI monoclonal antibody that was identified using phage display technology. Piascik (2003) J. Am. Pharm. Assoc. 43:327-328.
[0657] Also included in the term "TNF antagonist," and therefore suitable for use in a subject method, are stress-activated protein kinase (SAPK) inhibitors. SAPK
inhibitors are known in the art, and include, but are not limited to 2-alkyl imidazoles disclosed in U.S. Patent No. 6,548,520; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,489,325; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,569,871; heteroaryl aminophenyl ketone compounds disclosed in Published U.S.
Patent Application No. 2003/0073832; pyridyl imidazole compounds disclosed in U.S.
Patent No. 6,288,089; and heteroaryl aminobenzophenones disclosed in U.S.
Patent No.
6,432,962. Also of interest are compounds disclosed in U.S. Patent Application Publication No. 2003/0149041; and U.S. Patent No. 6,214,854. A stress-activated protein kinase is a member of a family of mitogen-activated protein kinases which are activated in response to stress stimuli. SAPK include, but are not limited to, p38 (Lee et al. (1994) Nature 372:739) and c-jun N-terminal kinase (JNK).
[0658] Methods to assess TNF antagonist activity are known in the art and exemplified herein. For example, TNF antagonist activity may be assessed with a cell-based competitive binding assay. In such an assay, radiolabeled TNF is mixed with serially diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions of the suspension are centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions determined. TNF antagonist activity is assessed by inhibition of TNF binding to the cells in the presence of the TNF antagonist.

[
s"`another"examp le TNF antagonists may be analyzed for the ability to neutralize TNF activity in vitro in a bioassay using cells susceptible to the cytotoxic activity of TNF as target cells. In such an assay, target cells, cultured with TNF, are treated with varying amounts of TNF antagonist and subsequently are examined for cytolysis.
TNF
antagonist activity is assessed by a decrease in TNF-induced target cell cytolysis in the presence of the TNF antagonist.

NS5B Inhibitors [0660] Some embodiments provides a method comprising administering an effective amount of a subject NS3 inhibitor and an effective amount of an HCV
non-structural protein-5 (NS5; RNA-dependent RNA polymerase) inhibitor to an HCV
patient in need thereof. Suitable NS5B inhibitors include, but are not limited to, a compound as disclosed in U.S. Patent No. 6,479,508 (Boehringer-Ingelheim); a compound as disclosed in any of International Patent Application Nos. PCT/CA02/01127, PCT/CA02/01128, and PCT/CA02/01129, all filed on July 18, 2002 by Boehringer Ingelheim; a compound as disclosed in U.S. Patent No. 6,440,985 (ViroPharma); a compound as disclosed in WO
01/47883, e.g., JTK-003 (Japan Tobacco); a dinucleotide analog as disclosed in Zhong et al. (2003) Anthnicrob. Agents Chernother. 47:2674-2681; a benzothiadiazine compound as disclosed in Dhanak et al. (2002) J. Biol Chein. 277(41):38322-7; an NS5B
inhibitor as disclosed in WO 02/100846 Al or WO 02/100851 A2 (both Shire); an NS5B
inhibitor as disclosed in WO 01/85172 Al or WO 02/098424 Al (both Glaxo SmithKline); an inhibitor as disclosed in WO 00/06529 or WO 02/06246 Al (both Merck); an NS5B
inhibitor as disclosed in WO 03/000254 (Japan Tobacco); an NS5B inhibitor as disclosed in EP 1 256,628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan Tobacco); and the like.
[0661] Of particular interest in many embodiments are NS5 inhibitors that are specific NS5 inhibitors, e.g., NS5 inhibitors that inhibit NS5 RNA-dependent RNA
polymerase and that lack significant inhibitory effects toward other RNA
dependent RNA
polymerases and toward DNA dependent RNA polymerases.

Additional antiviral agents [0662] Additional antiviral therapeutic agents that may be administered in combination with a subject NS3 inhibitor compound include, but are not limited to, iiTibitorg" of iriosirie" 'inohdphosphate dehydrogenase (IMPDH); ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors; and the like.
IMPDH Inhibitors [0663] IMPDH inhibitors that are suitable for use in a subject combination therapy include, but are not limited to, VX-497 ((S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl-carbainic acid tetrahydrofuran-3-yl-ester); Vertex Pharmaceuticals;
see, e.g., Markland et al. (2000) Antimicrob. Agents Chemother. 44:859-866);
ribavirin;
levovirin (Ribapharm; see, e.g., Watson (2002) Curr Opin Investig Drugs 3(5):680-3);
viramidine (Ribapharm); and the like.

Ribozyme and Antisense [0664] Ribozyme and antisense antiviral agents that are suitable for use in a subject combination therapy include, but are not limited to, ISIS 14803 (ISIS
Pharmaceuticals/Elan Corporation; see, e.g., Witherell (2001) Curr Opin Investig Drugs.
2(11):1523-9); HeptazymeTM; and the like.

[0665] In some embodiments, an additional antiviral agent is administered during the entire course of NS3 inhibitor compound treatment. In other embodiments, an additional antiviral agent is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent treatment may begin before the NS3 inhibitor compound treatment begins and end before the inhibitor compound treatment ends; the additional antiviral agent treatment may begin after the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment may begin after the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; or the additional antiviral agent treatment may begin before the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends.

Dosages, Formulations, and Routes of Administration [0666] In the subject methods, the active agent(s) (e.g., compound of formula I, and optionally one or more additional antiviral agents) may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agent may be incorporated into a variety of formulations for therapeutic administration.

More parricular`fy'; tle`" `agerifs "of the present embodiments may be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and maybe formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

Formulations [0667] The above-discussed active agent(s) may be formulated using well-known reagents and methods. Compositions are provided in formulation with a pharmaceutically acceptable excipient(s). A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein.
Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins;
Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H.
Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.

[0668] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

[0669] In some embodiments, an agent is formulated in an aqueous buffer.
Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers varying in strengths from 5mM to 100mM. In some embodiments, the aqueous buffer includes reagents that provide for an isotonic solution. Such reagents include, but are not limited to, sodium chloride; and sugars e.g., mannitol, dextrose, sucrose, and the like. In some embodiments, the aqueous buffer further includes a non-ionic surfactant such as polysorbate 20 or 80. Optionally the formulations may further include a preservative. Suitable preservatives include, but are not limited to, a benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the formulation is stored at about 4 C. Formulations may also be lyophilized, in which case they generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, `f"mannito;an``"ll~e`lllk' ' Iftyopl it zed formulations may be stored over extended periods of time, even at ambient temperatures.

[0670] As such, administration of the agents may be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdennal, intratracheal,etc., administration. In many embodiments, administration is by bolus injection, e.g., subcutaneous bolus injection, intramuscular bolus injection, and the like.

[0671] The pharmaceutical compositions of the present embodiments may be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection are preferred.

[0672] Subcutaneous administration of a pharmaceutical composition of the present embodiments is accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328. A combination of a subcutaneous injection port and a device for administration of a pharmaceutical composition of the embodiments to a patient through the port is referred to herein as "a subcutaneous injection port delivery system." In many embodiments, subcutaneous administration is achieved by bolus delivery by needle and syringe.

[0673] In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.

[0674] For oral preparations, the agents may be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[0675] The agents may be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic .` acids or propylene"glycol'; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0676] Furthermore, the agents may be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The compounds of the present embodiments may be administered rectally via a suppository. The suppository may include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

[0677] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.

[0678] The term "unit dosage form," as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds of the embodiments calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the novel unit dosage forms of the present embodiments depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0679] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
Other antiviral agents [0680] As discussed above, a subject method will in some embodiments be carried out by administering an NS3 inhibitor that is a compound of formulas I-XIX, and optionally one or more additional antiviral agent(s).
[0681] In some embodiments, the method further includes administration of one or more interferon receptor agonist(s). Interferon receptor agonists are described above.

[x`6$2] 1 'Bt ter embodiments, the method further includes administration of pirfenidone or a pirfenidone analog. Pirfenidone and pirfenidone analogs are described above.

[0683] Additional antiviral agents that are suitable for use in combination therapy include, but are not limited to, nucleotide and nucleoside analogs.
Non-limiting examples include azidothyinidine (AZT) (zidovudine), and analogs and derivatives thereof, 2',3'-dideoxyinosine (DDI) (didanosine), and analogs and derivatives thereof;
2',3'-dideoxycytidine (DDC) (dideoxycytidine), and analogs and derivatives thereof;
2'3,'-didehydro-2',3'-dideoxythymidine (D4T) (stavudine), and analogs and derivatives thereof;
combivir; abacavir; adefovir dipoxil; cidofovir; ribavirin; ribavirin analogs;
and the like.

[0684] In some embodiments, the method further includes administration of ribavirin. Ribavirin, 1-13-D-ribofiuanosyl-1H-1,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No.
4,211,771. The embodiments also contemplate use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830). The ribavirin may be administered orally in capsule or tablet form, or in the same or different administration form and in the same or different route as the interferon receptor agonist. Of course, other types of administration of both medicaments, as they become available are contemplated, such as by nasal spray, transdermally, intravenously, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.

[0685] In some embodiments, an additional antiviral agent is administered during the entire course of NS3 inhibitor compound treatment. In other embodiments, an additional antiviral agent is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent treatment may begin before the NS3 inhibitor compound treatment begins and end before the inhibitor compound treatment ends; the additional antiviral agent treatment may begin after the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment may begin after the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; or the additional antiviral agent treatment may begin before the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends.

[0686] The NS3 inhibitor compounds of the embodiments are suitable for use in formulations that require good solubility in water. For example, the compounds of the embodiments may be used in formulations that are free of sugar alcohols and polyols, such as trihydric or higher sugar alcohols, e.g., glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol, and free of other alcohols, such as propylene glycol and poly (ethylene glycol) (PEG), or other agent used to compensate for inadequate solubility in water. In one aspect, the embodiments provide the subject NS3 inhibitor compound in a capsule, tablet or caplet formulation, where the capsule, tablet or caplet formulation provides an adequate bioavailability because of the superior water solubility of the compound. In some embodiments, the solubility of the subject compound permits the administration of dosages equal to or greater than I mg of drug compound/kg of patient body weight.

Methods of Treatment [0686a] The compounds described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity may be used for the treatment of an individual in need thereof as described herein.
Monotheranies [0687] The NS3 inhibitor compound of the embodiments may be used in acute or chronic therapy for HCV disease. In many embodiments, the NS3 inhibitor compound is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about I month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
The NS3 inhibitor compound may be administered 5 times per day, 4 times per day, tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly. In other embodiments, the NS3 inhibitor compound is administered as a continuous infusion.
[0688] In many embodiments, an NS3 inhibitor compound of the embodiments is administered orally.
[0689] In connection with the above-described methods for the treatment of HCV
disease in a patient, an NS3 inhibitor compound of the embodiments may be administered to the patient at a dosage from about 0.01 mg to about 100 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day. In some embodiments, the NS3 inhibitor compound is administered at a dosage of about 0.5 mg to about 75 mg/kg patient bodyweight per day, in I to 5 divided doses per day.

The amount of active ingredient that may be combined with carrier materials to produce a dosage form may vary depending on the host to be treated and the particular mode of administration. A typical pharmaceutical preparation may contain from about 5% to about 95% active ingredient (w/w). In other embodiments, the phanmaceutical preparation may contain from about 20% to about 80% active ingredient.

[0691] Those of skill will readily appreciate that dose levels may vary as a function of the specific NS3 inhibitor compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given NS3 inhibitor compound are readily determinable by those of skill in the art by a variety of means. A
preferred means is to measure the physiological potency of a given interferon receptor agonist.

[0692] In many embodiments, multiple doses of NS3 inhibitor compound are administered. For example, an NS3 inhibitor compound is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

Combination therapies with ribavirin [0693] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ribavirin. Ribavirin may be administered in dosages of about 400 mg, about 800 mg, about 1000 mg, or about 1200 mg per day.
[0694] One embodiment provides any of the above-described methods modified to include co-administering to the patient a therapeutically effective amount of ribavirin for the duration of the desired course of NS3 inhibitor compound treatment.
[0695] Another embodiment provides any of the above-described methods modified to include co-administering to the patient about 800 mg to about 1200 mg ribavirin orally per day for the duration of the desired course of NS3 inhibitor compound treatment.
[0696] Another embodiment provides any of the above-described methods modified to include co-administering to the patient (a) 1000 mg ribavirin orally per day if the patient has a body weight less than 75 kg or (b) 1200 mg ribavirin orally per day if the patient has a body weight greater than or equal to 75 kg, where the daily dosage of ribavirin is optionally divided into to 2 doses for the duration of the desired course of NS3 inhibitor compound treatment.

Combination therapies with levovirin [0697] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of levovirin. Levovirin is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, levovirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day for the desired course of NS3 inhibitor compound treatment.

Combination therapies with viramidine [0698] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of viramidine. Viramidine is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, viramidine is administered orally in dosages of about 800, or about 1600 mg per day for the desired course of NS3 inhibitor compound treatment.

Combination therapies with thymosin-a [0699] In some embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of thymosin-a. Thymosin-a (ZadaxinTM) is generally administered by subcutaneous injection. Thymosin-a may be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously for the desired course of NS3 inhibitor compound treatment. In many embodiments, thymosin-a is administered twice per week for the desired course of NS3 inhibitor compound treatment.
[0700] Effective dosages of thymosin-a range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In particular embodiments, thymosin-a is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
[0701] Thymosin-a may be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In one emobidment, thymosin-a is administered for the desired course of NS3 inhibitor compound treatment.

Combination therapies with interferon(s) [0702] In many embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of an interferon receptor agonist. In some embodiments, a compound of formula I
and a Type I or III interferon receptor agonist are co-administered in the treatment methods of the embodiments. Type I interferon receptor agonists suitable for use herein include any interferon-(x (IFN-a). In certain embodiments, the interferon-a is a PEGylated interferon-a.
In certain other embodiments, the interferon-a is a consensus interferon, such as INFERGEN interferon alfacon-1. In still other embodiments, the interferon-a is a monoPEG (30 kD, linear)-ylated consensus interferon.
[0703] Effective dosages of an IFN-a range from about 3 g to about 27 g, from about 3 MU to about 10 MU, from about 90 gg to about 180 g, or from about 18 g to about 90 g. Effective dosages of Infergen consensus IFN-a include about 3 g, about 6 jig, about 9 g, about 12 g, about 15 jig, about 18 g, about 21 g, about 24 g, about 27 g, or about 30 g, of drug per dose. Effective dosages of IFN-a2a and IFN-a2b range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGASYS PEGylated IFN-a2a contain an amount of about 90 g to 270 g, or about g, of drug per dose. Effective dosages of PEG-INTRON PEGylated IFN-a2b contain an amount of about 0.5 g to 3.0 g of drug per kg of body weight per dose.
Effective dosages of PEGylated consensus interferon (PEG-CIFN) contain an amount of about 18 g to about 90 g, or from about 27 g to about 60 g, or about 45 g, of CIFN
amino acid weight per dose of PEG-CIFN. Effective dosages of monoPEG (30 kD, linear)-ylated CIFN contain an amount of about 45 gg to about 270 g, or about 60 gg to about 180 g, or about 90 g to about 120 g, of drug per dose. IFN-a may be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
[0704] In many embodiments, the Type I or Type III interferon receptor agonist and/or the Type II interferon receptor agonist is administered for a period of about 1 day to about 7 days, or about I week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. Dosage regimens may include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or monthly administrations. Some embodiments provide any of the above-described methods in which the desired dosage of IFN-a is administered subcutaneously to the patient by bolus delivery qd, qod, tiw, biw, qw, qow, three times per month, or monthly, or is administered subcutaneously to the patient per day by substantially continuous or continuous delivery, for the desired treatment duration.
Other embodiments provide any of the above-described methods in which the desired dosage of PEGylated IFN-a (PEG-IFN-a) is administered subcutaneously to the patient by bolus delivery qw, qow, three times per month, or monthly for the desired treatment duration.
[0705] In other embodiments, an NS3 inhibitor compound and a Type II
interferon receptor agonist are co-administered in the treatment methods of the embodiments. Type II interferon receptor agonists suitable for use herein include any interferon-y (IFN-y).
[0706] Effective dosages of IFN-y may range from about 0.5 g/m2 to about 500 g/m2, usually from about 1.5 gg/m2 to 200 g/m2, depending on the size of the patient.
This activity is based on 106 international units (U) per 50 gg of protein.
IFN-y may be administered daily, every other day, three times a week, or substantially continuously or continuously.
[0707] In specific embodiments of interest, IFN-y is administered to an individual in a unit dosage form of from about 25 gg to about 500 g, from about 50 gg to about 400 g, or from about 100 jig to about 300 g. In particular embodiments of interest, the dose is about 200 g IFN-y. In many embodiments of interest, IFN-yl b is administered.
[0708] Where the dosage is 200 g IFN-y per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 jig IFN-y per kg body weight to about 1.48 g IFN-y per kg body weight.
[0709] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 g/m2 to about 20 gg/m2. For example, an IFN-y dosage ranges from about 20 g/m2 to about 30 g/m2, from about 30 g/m2 to about 40 g/m2, from about 40 g/m2 to about 50 gg/m2, from about 50 g/m2 to about 60 gg/m2, from about 60 g/m2 to about 70 g/m2, from about 70 g/m2 to about 80 g/m2, from about 80 gg/m2 to about 90 g/m2, from about 90 g/m2 to about 100 g/m2, from about 100 g/m2 to about 110 gg/m2, from about 110 gg/m2 to about 120 g/m2, from about 120 gg/m2 to about 130 g/m2, from about 130 g/m2 to about 140 g/m2, or from about 140 g/m2 to about 150 gg/m2. In some embodiments, the dosage groups range from about 25 g/m2 to about 100 g/m2.
In other embodiments, the dosage groups range from about 25 g/m2 to about 50 g/m2.
[0710] In some embodiments, a Type I or a Type III interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen. The first dosing regimen of Type I or a Type III interferon receptor agonist (also referred to as "the induction regimen") generally involves administration of a higher dosage of the Type I or Type III interferon receptor agonist. For example, in the case of Infergen consensus IFN-ct (CIFN), the first dosing regimen comprises administering CIFN at about 9 g, about 15 g, about 18 g, or about 27 g. The first dosing regimen may encompass a single dosing event, or at least two or more dosing events. The first dosing regimen of the Type I or Type III interferon receptor agonist may be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
[0711] The first dosing regimen of the Type I or Type III interferon receptor agonist is administered for a first period of time, which time period may be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.
[0712] The second dosing regimen of the Type I or Type III interferon receptor agonist (also referred to as "the maintenance dose") generally involves administration of a lower amount of the Type I or Type III interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CIFN at a dose of at least about 3 g, at least about 9 g, at least about 15 g, or at least about 18 g. The second dosing regimen may encompass a single dosing event, or at least two or more dosing events.
[0713] The second dosing regimen of the Type I or Type III interferon receptor agonist may be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
[0714] In some embodiments, where an "induction"P'maintenance" dosing regimen of a Type I or a Type III interferon receptor agonist is administered, a "priming"
dose of a Type II interferon receptor agonist (e.g., IFN-y) is included. In these embodiments, IFN-y is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type III interferon receptor agonist. This period of time is referred to as the "priming" phase.
[0715] In some of these embodiments, the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type III
interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist. In these embodiments, the total time of treatment with Type II interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days. In still other embodiments, the Type II interferon receptor agonist treatment is discontinued once Type I or a Type III
interferon receptor agonist treatment begins.
[0716] In other embodiments, the Type I or Type III interferon receptor agonist is administered in single dosing regimen. For example, in the case of CIFN, the dose of CIFN is generally in a range of from about 3 g to about 15 g, or from about 9 g to about 15 g. The dose of Type I or a Type III interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times per month, once monthly, or substantially continuously. The dose of the Type I or Type III
interferon receptor agonist is administered for a period of time, which period may be, for example, from at least about 24 weeks to at least about 48 weeks, or longer.
[0717] In some embodiments, where a single dosing regimen of a Type I or a Type III interferon receptor agonist is administered, a "priming" dose of a Type II
interferon receptor agonist (e.g., IFN-y) is included. In these embodiments, IFN-y is administered for a period of time from about I day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type III interferon receptor agonist. This period of time is referred to as the "priming" phase. In some of these embodiments, the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type III
interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist. In these embodiments, the total time of treatment with the Type II
interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about days to about 18 days, or from about 12 days to about 16 days. In still other embodiments, Type II interferon receptor agonist treatment is discontinued once Type I or a Type III interferon receptor agonist treatment begins.
[0718] In additional embodiments, an NS3 inhibitor compound, a Type I or III interferon receptor agonist, and a Type II interferon receptor agonist are co-administered for the desired duration of treatment in the methods of the embodiments. In some embodiments, an NS3 inhibitor compound, an interferon-a, and an interferon-y are co-administered for the desired duration of treatment in the methods of the embodiments.
[0719] Some embodiments provide methods using an amount of a Type I or Type III interferon receptor agonist, a Type II interferon receptor agonist, and an NS3 inhibitor compound, effective for the treatment of HCV infection in a patient.
In some embodiments, the embodiments provide methods using an effective amount of an IFN-a, IFN-y, and an NS3 inhibitor compound in the treatment of HCV infection in a patient. One embodiment provides a method using an effective amount of a consensus IFN-a, IFN-y and an NS3 inhibitor compound in the treatment of HCV infection in a patient.
[0720] In general, an effective amount of a consensus interferon (CIFN) and IFN-y suitable for use in the methods of the embodiments is provided by a dosage ratio of 1 tg CIFN: 10 g IFN-y, where both CIFN and IFN-y are unPEGylated and unglycosylated species.
[0721] One embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN containing an amount of about I g to about 30 g, of drug per dose of INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 10 jig to about 300 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0722] Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN containing an amount of about 1 gg to about 9 g, of drug per dose of INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 10 gg to about 100 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0723] Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN containing an amount of about 1 gg of drug per dose of INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 10 .tg to about 50 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0724] Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN containing an amount of about 9 g of drug per dose of INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 90 g to about 100 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0725] Another embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN containing an amount of about 30 gg of drug per dose of INFERGEN
, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 200 g to about 300 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0726] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-a and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 4 g to about 60 gg of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 30 g to about 1,000 gg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0727] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-a and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 18 g to about 24 g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 100 tg to about 300 tg of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0728] In general, an effective amount of IFN-a 2a or 2b or 2c and IFN-y suitable for use in the methods of the embodiments is provided by a dosage ratio of 1 million Units (MU) IFN-a 2a or 2b or 2c : 30 g ITN-y, where both IFN-a 2a or 2b or 2c and IFN-y are unPEGylated and unglycosylated species.
[0729] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 30 g to about 600 gg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0730] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of FN-(x 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 100 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.

[0731] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 300 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0732] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYS PEGylated IFN-a2a and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS containing an amount of about 90 g to about 360 g, of drug per dose of PEGASYS , subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 30 gg to about 1,000 g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0733] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYS PEGylated IFN-a2a and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS containing an amount of about 180 g of drug per dose of PEGASYS , subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 100 g to about 300 g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0734] Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON containing an amount of about 0.75 gg to about 3.0 g of drug per kilogram of body weight per dose of PEG-INTRON , subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 30 g to about 1,000 gg of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0735] Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and IFN-y in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON containing an amount of about 1.5 g of drug per kilogram of body weight per dose of PEG-INTRON , subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 100 tg to about 300 gg of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0736] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 g INFERGEN consensus IFN-a administered subcutaneously qd or tiw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0737] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 g INFERGEN consensus IFN-a administered subcutaneously qd or tiw; 50 gg Actimmune human IFN-71b administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0738] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 tg INFERGEN consensus IFN-a administered subcutaneously qd or tiw; 100 g Actimmune human IFN-71b administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.

[0739] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a administered subcutaneously qd or tiw; and 50 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0740] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a administered subcutaneously qd or tiw; and 100 gg Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0741] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a administered subcutaneously qd or tiw; 25 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0742] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a administered subcutaneously qd or tiw; 200 gg Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0743] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 gg INFERGEN consensus IFN-a administered subcutaneously qd or tiw; and 25 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0744] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 g INFERGEN consensus IFN-a administered subcutaneously qd or tiw; and 200 g Actimmune human IFN-71b administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0745] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0746] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; 50 g Actimmune human IFN-71b administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0747] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; 100 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0748] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; and 50 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0749] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; and 100 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0750] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 .tg monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0751] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; 50 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0752] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; 100 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0753] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; and 50 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0754] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; and 100 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0755] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0756] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; 50 gg Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0757] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; 100 gg Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[0758] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; and 50 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0759] One embodiment provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days or qw; and 100 .tg Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[0760] Any of the above-described methods involving administering an NS3 inhibitor, a Type I interferon receptor agonist (e.g., an IFN-(x), and a Type II interferon receptor agonist (e.g., an IFN-y), may be augmented by administration of an effective amount of a TNF-a antagonist (e.g., a TNF-a antagonist other than pirfenidone or a pirfenidone analog). Exemplary, non-limiting TNF-a antagonists that are suitable for use in such combination therapies include ENBREL , REMICADE , and HUMIRATM.
[0761] One embodiment provides a method using an effective amount of ENBREL ; an effective amount of IFN-a; an effective amount of IFN-y, and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage ENBREL containing an amount of from about 0.1 g to about 23 mg per dose, from about 0.1 g to about I g, from about 1 tg to about 10 g, from about 10 gg to about 100 g, from about 100 gg to about 1 mg, from about I mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment.
[0762] One embodiment provides a method using an effective amount of REMICADE , an effective amount of IFN-a with or without an effective amount of IFN-y; and an effective amount of an NS3 inhibitor in the treatment of an HCV
infection in a patient, comprising administering to the patient a dosage of REMICADE
containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE , intravenously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment.
[0763] One embodiment provides a method using an effective amount of HUMIRATM, an effective amount of IFN-a; an effective amount of IFN-y; and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of HUMIRATM containing an amount of from about 0.1 gg to about 35 mg, from about 0.1 g to about 1 g, from about I g to about 10 g, from about 10 gg to about 100 g, from about 100 g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRATM, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment.
Combination therapies with pirfenidone [0764] In many embodiments, the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, an NS3 inhibitor compound, one or more interferon receptor agonist(s), and pirfenidone or pirfenidone analog are co-administered in the treatment methods of the embodiments. In certain embodiments, an NS3 inhibitor compound, a Type I interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered. In other embodiments, an NS3 inhibitor compound, a Type I interferon receptor agonist, a Type II interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered. Type I
interferon receptor agonists suitable for use herein include any IFN-a, such as interferon alfa-2a, interferon alfa-2b, interferon alfacon- 1, and PEGylated IFN-a's, such as peginterferon alfa-2a, peginterferon alfa-2b, and PEGylated consensus interferons, such as monoPEG (30 kD, linear)-ylated consensus interferon. Type II interferon receptor agonists suitable for use herein include any interferon-y.
[0765] Pirfenidone or a pirfenidone analog may be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
[0766] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally in one to five divided doses per day. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562;
5,518,729;
5,716,632; and 6,090,822.
[0767] One embodiment provides any of the above-described methods modified to include co-administering to the patient a therapeutically effective amount of pirfenidone or a pirfenidone analog for the duration of the desired course of NS3 inhibitor compound treatment.

Combination therapies with TN-F-(x antagonists [0768] In many embodiments, the methods provide for combination therapy comprising administering an effective amount of an NS3 inhibitor compound as described above, and an effective amount of TNF-a antagonist, in combination therapy for treatment of an HCV infection.
[0769] Effective dosages of a TNF-a antagonist range from 0.1 gg to 40 mg per dose, e.g., from about 0.1 g to about 0.5 g per dose, from about 0.5 gg to about 1.0 g per dose, from about 1.0 g per dose to about 5.0 gg per dose, from about 5.0 g to about 10 gg per dose, from about 10 gg to about 20 g per dose, from about 20 g per dose to about 30 gg per dose, from about 30 g per dose to about 40 g per dose, from about 40 gg per dose to about 50 g per dose, from about 50 g per dose to about 60 gg per dose, from about 60 g per dose to about 70 gg per dose, from about 70 g to about 80 g per dose, from about 80 gg per dose to about 100 gg per dose, from about 100 gg to about 150 gg per dose, from about 150 g to about 200 g per dose, from about 200 gg per dose to about 250 pg per dose, from about 250 gg to about 300 gg per dose, from about 300 gg to about 400 gg per dose, from about 400 g to about 500 g per dose, from about 500 g to about 600 g per dose, from about 600 g to about 700 gg per dose, from about 700 gg to about 800 g per dose, from about 800 g to about 900 gg per dose, from about 900 gg to about 1000 gg per dose, from about I mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.
[0770] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e.g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.
[0771] In many embodiments, a TNF-a antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about I month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist may be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.
[0772] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
[0773] A TNF-a antagonist and an NS3 inhibitor are generally administered in separate formulations. A TNF-a antagonist and an NS3 inhibitor may be administered substantially simultaneously, or within about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours, about 72 hours, about 4 days, about 7 days, or about 2 weeks of one another.
[0774] One embodiment provides a method using an effective amount of a TNF-a antagonist and an effective amount of an NS3 inhibitor in the treatment of an HCV
infection in a patient, comprising administering to the patient a dosage of a TNF-a antagonist containing an amount of from about 0.1 gg to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0775] One embodiment provides a method using an effective amount of ENBREL and an effective amount of an NS3 inhibitor in the treatment of an HCV
infection in a patient, comprising administering to the patient a dosage ENBREL
containing an amount of from about 0.1 gg to about 23 mg per dose, from about 0.1 g to about 1 g, from about 1 g to about 10 g, from about 10 g to about 100 g, from about 100 tg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0776] One embodiment provides a method using an effective amount of REMICADE and an effective amount of an NS3 inhibitor in the treatment of an HCV
infection in a patient, comprising administering to the patient a dosage of REMICADE
containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE , intravenously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0777] One embodiment provides a method using an effective amount of HUMIRATM and an effective amount of an NS3 inhibitor in the treatment of an HCV
infection in a patient, comprising administering to the patient a dosage of HUMIRATM

containing an amount of from about 0.1 g to about 35 mg, from about 0.1 .tg to about 1 g, from about I g to about 10 g, from about 10 g to about 100 g, from about 100 g to about I mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRATM, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.

Combination therapies with thymosin-a [0778] In many embodiments, the methods provide for combination therapy comprising administering an effective amount of an NS3 inhibitor compound as described above, and an effective amount of thymosin-a, in combination therapy for treatment of an HCV infection.
[0779] Effective dosages of thymosin-a range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In particular embodiments, thymosin-a is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
[0780] One embodiment provides a method using an effective amount of ZADAXINTM thymosin-a and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of ZADAXINTM containing an amount of from about 1.0 mg to about 1.6 mg per dose, subcutaneously twice per week for the desired duration of treatment with the NS3 inhibitor compound.

Combination therapies with a TNF-a antagonist and an interferon [0781] Some embodiments provide a method of treating an HCV infection in an individual having an HCV infection, the method comprising administering an effective amount of an NS3 inhibitor, and effective amount of a TNF-a antagonist, and an effective amount of one or more interferons.

[0782] One embodiment provides any of the above-described methods modified to use an effective amount of IFN-y and an effective amount of a TNF-a antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 g to about 300 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 gg to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0783] One embodiment provides any of the above-described methods modified to use an effective amount of IFN-y and an effective amount of a TNF-a antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of IFN-y containing an amount of about 10 g to about 100 gg of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0784] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-y and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a total weekly dosage of IFN-y containing an amount of about 30 g to about 1,000 g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0785] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-y and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a total weekly dosage of IFN-y containing an amount of about 100 g to about 300 g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0786] One embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and a TNF-a antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN containing an amount of about I g to about 30 g, of drug per dose of INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0787] One embodiment provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and a TNF-a antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN containing an amount of about I g to about 9 g, of drug per dose of INFERGEN , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0788] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-a and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 4 g to about 60 g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0789] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-a and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 18 g to about 24 g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 .ig to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0790] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of 1FN-a 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0791] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0792] Another embodiment provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0793] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYS PEGylated IFN-a2a and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS containing an amount of about 90 g to about 360 g, of drug per dose of PEGASYS , subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 gg to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0794] Another embodiment provides any of the above-described methods modified to use an effective amount of PEGASYS PEGylated IFN-a2a and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS containing an amount of about 180 g, of drug per dose of PEGASYS , subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0795] Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON containing an amount of about 0.75 g to about 3.0 gg of drug per kilogram of body weight per dose of PEG-INTRON , subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 g to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
[0796] Another embodiment provides any of the above-described methods modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and an effective amount of a TNF-a antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON containing an amount of about 1.5 .tg of drug per kilogram of body weight per dose of PEG-INTRON , subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF-a antagonist containing an amount of from about 0.1 .tg to about 40 mg per dose of a TNF-a antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.

Combination therapies with other antiviral agents [0797] Other agents such as inhibitors of HCV NS3 helicase are also attractive drugs for combinational therapy, and are contemplated for use in combination therapies described herein. Ribozymes such as HeptazymeTM and phosphorothioate oligonucleotides which are complementary to HCV protein sequences and which inhibit the expression of viral core proteins are also suitable for use in combination therapies described herein.
[0798] In some embodiments, the additional antiviral agent(s) is administered during the entire course of treatment with the NS3 inhibitor compound of the embodiments, and the beginning and end of the treatment periods coincide. In other embodiments, the additional antiviral agent(s) is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., treatment with the additional antiviral agent(s) begins before the NS3 inhibitor compound treatment begins and ends before the NS3 inhibitor compound treatment ends; treatment with the additional antiviral agent(s) begins after the NS3 inhibitor compound treatment begins and ends after the NS3 inhibitor compound treatment ends; treatment with the additional antiviral agent(s) begins after the NS3 inhibitor compound treatment begins and ends before the NS3 inhibitor compound treatment ends; or treatment with the additional antiviral agent(s) begins before the NS3 inhibitor compound treatment begins and ends after the NS3 inhibitor compound treatment ends.

[0799] The NS3 inhibitor compound may be administered together with (i.e., simultaneously in separate formulations; simultaneously in the same formulation;
administered in separate formulations and within about 48 hours, within about 36 hours, within about 24 hours, within about 16 hours, within about 12 hours, within about 8 hours, within about 4 hours, within about 2 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes or less) one or more additional antiviral agents.
[0800] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen may be modified to replace the subject IFN-a regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 .tg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS3 inhibitor compound.
[0801] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen may be modified to replace the subject IFN-a regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS3 inhibitor compound.
[0802] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen may be modified to replace the subject IFN-a regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS3 inhibitor compound.
[0803] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen may be modified to replace the subject IFN-a regimen with a regimen of INFERGEN interferon alfacon-1 comprising administering a dosage of INFERGEN
interferon alfacon-1 containing an amount of 9 g of drug per dose, subcutaneously once daily or three times per week for the desired treatment duration with an NS3 inhibitor compound.
[0804] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen may be modified to replace the subject ]FN-a regimen with a regimen of INFERGEN interferon alfacon-1 comprising administering a dosage of INFERGEN

interferon alfacon-1 containing an amount of 15 g of drug per dose, subcutaneously once daily or three times per week for the desired treatment duration with an NS3 inhibitor compound.
[0805] As non-limiting examples, any of the above-described methods featuring an IFN-y regimen may be modified to replace the subject IFN-y regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
[0806] As non-limiting examples, any of the above-described methods featuring an IFN-y regimen may be modified to replace the subject IFN-y regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
[0807] As non-limiting examples, any of the above-described methods featuring an IFN-y regimen may be modified to replace the subject IFN-y regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
[0808] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 .tg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0809] As non-limiting examples, any of the above-described methods featuring a TNF antagonist regimen may be modified to replace the subject TNF
antagonist regimen with a TNF antagonist regimen comprising administering a dosage of a TNF
antagonist selected from the group of. (a) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (c) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration with an NS3 inhibitor compound.
[0810] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0811] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0812] As non-limiting examples, any of the above-described methods featuring an IFN-a and 1FN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-y containing an amount of 100 gg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0813] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-7 combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 gg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-y containing an amount of 50 jig of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0814] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 gg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0815] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon- I containing an amount of 9 g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0816] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon- I containing an amount of 9.tg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 50 .tg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0817] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-7 containing an amount of 100 tg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0818] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 .tg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 25 tg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0819] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 gg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0820] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an 1FN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 .tg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0821] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 gg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration with an NS3 inhibitor compound.
[0822] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 50 .tg of drug per dose, subcutaneously three times per week;
for the desired treatment duration with an NS3 inhibitor compound.

[0823] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 gg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration with an NS3 inhibitor compound.
[0824] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 25 .tg of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0825] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon- I containing an amount of 15 g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0826] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen may be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon- I containing an amount of 15 gg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-'y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
[0827] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0828] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0829] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0830] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 150 gg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0831] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 200 gg of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-y containing an amount of 50 gg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0832] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG
(30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0833] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 25 gg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0834] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 50 p.g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.

[0835] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon- I containing an amount of 9 gg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 100 gg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0836] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-7 and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 gg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 25 gg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0837] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 gg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 50 gg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0838] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0839] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0840] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon- I containing an amount of 15 .tg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0841] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0842] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an 1FN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0843] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-I containing an amount of 15 g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0844] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0845] As non-limiting examples, any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen may be modified to replace the subject IFN-a and TNF antagonist combination regimen with an IFN-a and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.

[0846] As non-limiting examples, any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen may be modified to replace the subject IFN-a and TNF antagonist combination regimen with an IFN-(x and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0847] As non-limiting examples, any of the above-described methods featuring an IFN-(x and TNF antagonist combination regimen may be modified to replace the subject IFN-a and TNF antagonist combination regimen with an IFN-(x and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-(x containing an amount of 200 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0848] As non-limiting examples, any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen may be modified to replace the subject IFN-(x and TNF antagonist combination regimen with an IFN-a and TNF
antagonist combination regimen comprising: (a) administering a dosage of INFERGEN
interferon alfacon-1 containing an amount of 9 g of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF
antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.

[0849] As non-limiting examples, any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen may be modified to replace the subject IFN-a and TNF antagonist combination regimen with an IFN-a and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN
interferon alfacon-1 containing an amount of 15 gg of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0850] As non-limiting examples, any of the above-described methods featuring an IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-y and TNF antagonist combination regimen with an IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-y containing an amount of 25 gg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0851] As non-limiting examples, any of the above-described methods featuring an IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-y and TNF antagonist combination regimen with an IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-y containing an amount of 50 pg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week;
for the desired treatment duration with an NS3 inhibitor compound.
[0852] As non-limiting examples, any of the above-described methods featuring an IFN-y and TNF antagonist combination regimen may be modified to replace the subject IFN-y and TNF antagonist combination regimen with an IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
[0853] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a may be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 180 g of drug per dose, subcutaneously once weekly for the desired treatment duration with an NS3 inhibitor compound.
[0854] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a may be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 1.0 .tg to 1.5 g of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration with an inhibitor compound.
[0855] As non-limiting examples, any of the above-described methods may be modified to include administering a dosage of ribavirin containing an amount of 400 mg, 800 mg, 1000 mg or 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
[0856] As non-limiting examples, any of the above-described methods may be modified to include administering a dosage of ribavirin containing (i) an amount of 1000 mg of drug orally per day for patients having a body weight of less than 75 kg or (ii) an amount of 1200 mg of drug orally per day for patients having a body weight of greater than or equal to 75 kg, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
[0857] As non-limiting examples, any of the above-described methods may be modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.

[0858] As non-limiting examples, any of the above-described methods may be modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor regimen comprising administering a dosage of 0.1 mg to I ing of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.

[0859] As non-limiting examples, any of the above-described methods may be modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.

[0860] As non-limiting examples, any of the above-described methods may be modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.

[0861] As non-limiting examples, any of the above-described methods featuring an NS5B inhibitor regimen may be modified to replace the subject NSSB
inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
[0862] As non-limiting examples, any of the above-described methods featuring an NS5B inhibitor regimen may be modified to replace the subject NS5B
inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
[0863] As non-limiting examples, any of the above-described methods featuring an NS5B inhibitor regimen may be modified to replace the subject NS5B
inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.

[0864] As non-limiting examples, any of the above-described methods featuring .an NS5B inhibitor regimen may be modified to replace the subject NS5B
inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 10 ing to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.

Patient Identification [0865] In certain embodiments, the specific regimen of drug therapy used in treatment of the HCV patient is selected according to certain disease parameters exhibited by the patient, such as the initial viral load, genotype of the HCV infection in the patient, liver histology and/or stage of liver fibrosis in the patient.

[0866] Thus, some embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a treatment failure patient for a duration of 48 weeks.

[0867] Other embodiments provide any of the above-described methods for HCV in which the subject method is modified to treat a non-responder patient, where the patient receives a 48 week course of therapy.

[0868] Other embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a relapser patient, where the patient receives a 48 week course of therapy.

[0869] Other embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naive patient infected with HCV genotype 1, where the patient receives a 48 week course of therapy.
[0870] Other embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naive patient infected with HCV genotype 4, where the patient receives a 48 week course of therapy.
[0871] Other embodiments provide any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naive patient infected with HCV genotype 1, where the patient has a high viral load (HVL), where "HVL" refers to an HCV viral load of greater than 2 x 106 HCV genome copies per mL
serum, and where the patient receives a 48 week course of therapy.
[0872] One embodiment provide any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (l~ identifying a patient Iaving advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.

[0873] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.

[0874] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
[0875] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
[0876] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, ~J

or about 40'week to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.

[0877] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genie copies per ml of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.

[0878] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.

[0879] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
[0880] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 48 weeks.
[0881] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) a:,m if r' 'Fop ,1utl: ndf,= tlv,k:.._.:f..' X:t ::lradministering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.

[0882] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.

[0883] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.

[0884] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks.

[0885] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 or 4 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
[0886] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV

genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks.
[0887] Another embodiment provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks and up to about 48 weeks.
Subjects Suitable for Treatment [0888] Any of the above treatment regimens may be administered to individuals who have been diagnosed with an HCV infection. Individuals who are infected with HCV are identified as having HCV RNA in their blood, and/or having anti-HCV
antibody in their serum. Any of the above treatment regimens may be administered to individuals who have failed previous treatment for HCV infection ("treatment failure patients," including non-responders and relapsers).
[0889] Individuals who have been clinically diagnosed as infected with HCV
are of particular interest in many embodiments. Individuals who are infected with HCV are identified as having HCV RNA in their blood, and/or having anti-HCV antibody in their serum. Such individuals include anti-HCV ELISA-positive individuals, and individuals with a positive recombinant immunoblot assay (RIBA). Such individuals may also, but need not, have elevated serum ALT levels.
[0890] Individuals who are clinically diagnosed as infected with HCV include naive individuals (e.g., individuals not previously treated for HCV, particularly those who have not previously received IFN-(x-based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV ("treatment failure" patients).
Treatment failure patients include non-responders (i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFN-a monotherapy, a previous IFN-a and ribavirin combination therapy, or a previous pegylated IFN-a and ribavirin combination therapy); and relapsers (i.e., individuals who were previously treated for HCV, e.g., who received a previous IFN-(X monotherapy, a previous IFN-a and ribavirin combination therapy, or a previous pegylated IFN-a and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).
[0891] In particular embodiments of interest, individuals have an HCV titer of at least about 105, at least about 5 x 105, or at least about 106, or at least about 2 x 106, genome copies of HCV per milliliter of serum. The patient may be infected with any HCV
genotype (genotype 1, including la and lb, 2, 3, 4, 6, etc. and subtypes (e.g., 2a, 2b, 3a, etc.)), particularly a difficult to treat genotype such as HCV genotype 1 and particular HCV
subtypes and quasispecies.
[0892] Also of interest are HCV-positive individuals (as described above) who exhibit severe fibrosis or early cirrhosis (non-decompensated, Child's-Pugh class A or less), or more advanced cirrhosis (decompensated, Child's-Pugh class B or C) due to chronic HCV infection and who are viremic despite prior anti-viral treatment with IFN-a-based therapies or who cannot tolerate IFN-a-based therapies, or who have a contraindication to such therapies. In particular embodiments of interest, HCV-positive individuals with stage 3 or 4 liver fibrosis according to the METAVIR scoring system are suitable for treatment with the methods of the present embodiments. In other embodiments, individuals suitable for treatment with the methods of the embodiments are patients with decompensated cirrhosis with clinical manifestations, including patients with far-advanced liver cirrhosis, including those awaiting liver transplantation. In still other embodiments, individuals suitable for treatment with the methods of the embodiments include patients with milder degrees of fibrosis including those with early fibrosis (stages I
and 2 in the METAVIR, Ludwig, and Scheuer scoring systems; or stages 1, 2, or 3 in the Ishak scoring system.).

Preparation of Section A Viral Inhibitors [0893] Compounds of the general Formula I may be synthesized in the same general manner as described below for compounds of the general Formulas lI-XIX. The syntheses of various specific compounds of the general Formula I are described in the Examples below. Those skilled in the art will appreciate variations in the sequence and, further, will recognize variations in the appropriate reaction conditions from the analogous reactions shown or otherwise known which may be appropriately used in the processes described below to make the compounds of formula I.
[0894] The products of the reactions described herein are isolated by conventional means such as extraction, distillation, chromatography, and the like.
[0895] The salts of the compounds of formula described above are prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the compounds of formula I.

Preparation o 'Section B Viral inhibitors [0896] The meanings of the terms and structural names used within this section are the same as those in Section B above. Any references within this section to a particular number or label should be understood in the context of the corresponding numbering or labeling scheme used within this section or Section B above, rather than in the context of a possibly similar or identical numbering or labeling scheme used elsewhere herein, unless otherwise indicated.

[0897] The compounds of formulas II-X may be synthesized according to the methods described below.

Methodology Preparation of Compounds [0898] Two methods were used in preparing compounds with formulas II-X. In both methods, intermediates 1 and 4 were prepared according to the procedures disclosed in International Application PCT/CAOO/00353 (Publication No. WO 00/59929).
Intermediate 4 was also purchased from RSP Amino Acids.

Example 1-1: Synthesis of Compound # 101 (Compound AR00220042) by Method A:
OyN I i O
HO, O N O

H

A

Compound #101 (Compound AR00220042) Method A:

OH

OH BocN 2 I 1) CDI, DCM 0-- NRIR
HCI HZN
_~O + HATU, DIEA p O I p BocN +
p DMF p H 1 O I 2) RjR2NH BocN BocN II
O O 0 "'0 H 3 p H p O
1 2 1:1 (1R, 2S)/(1S, 2R) 1 ,';\I
(1R, 2S) (1S, 2R) O), NRi R2 O~NR1R2 NR1 Rz O
-0 Nolan's catalyst p 1) 4N HCl (dioxane) 0 N (30 mol%) O O
BocN 2) HATU, DIEA, DMF BocHW. O DCE, 50 C BocHN,. N O
N
p H O BocHN,, O 0 H 0 p H
p OH 1 _ -(1R, 2S) 4 P
LiOH-H20 O N HOB
THF:MeOH:H20 BocHN,,. ' O
(2:1:1) O H~

Step 1: Synthesis of 2S-(1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3) OH
OH
HCI'H2N + BocN 2,.
0 BocN HATU, DIEA
DMF p H O
HO O

1:1 (1R, 2S)/(1S, 2R) [0899] To a flask charged with ethyl-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropyl carboxylate (1, 1.0 g, 5.2 mmol), trans-N-(tert-Butoxycarbonyl)-4-hydroxy-L-proline (2, 1.3 g, 1.1 equiv), and HATU (2.7 g, 1.1 equiv) were added 30 mL
DMF to make a solution. It was cooled to 0 oC in an ice-water bath, followed by slow addition of a solution of DIEA (4.4 mL, 4 equiv) in DMF (15 mL) while stirring. The reaction was allowed to warm up to rt and stirred overnight [0900] After 16 h, the reaction was complete as monitored by HPLC. It was diluted with EtOAc (100 mL), washed with water (3 x 40 mL), sat. NaHCO3 (2 x 40 mL), and brine (2 x 40 mL), then dried over Na2SO4 and concentrated down to give a dark copper colored" oil. Tli'e 'crude was purified on silica gel (eluent:
acetone/hexanes 3:7), giving pure 3 as tan foamy powder (770 mg, 32 Step 2: Syntheses of 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1-tert-butoxycarbonyl-5-(1R-ethoxycarbonyl-2S-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3R-yl ester (5), and 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1-tert-butoxycarbonyl-5-(1S-ethoxycarbonyl-2R-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3R-yl ester (6) OH
BocN I 1) N_j L_/N O_(N O \\
0 NI ,,r0 2 O
H O 2) I c H BocN BocN ~2 ,,, v 0 N~~ 1 O 0 14 'r0 3 DCM, rt H O H O

(1 R, 2S) 6 (IS, 2R) [0901] The dipeptide 3 (300 mg, 0.81 mmol) was dissolved in DCM (8 mL), followed by addition of CDI (163 mg, 1.2 equiv) in one portion. The reaction was stirred at rt overnight. After 15 h, the reaction was complete as monitored by TLC
(DCM/MeOH
9:1). 1,2,3,4-tetrahydroisoquinoline (0.32 mL, 3 equiv) was added to the reaction portion-wise, and the reaction was stirred at rt for overnight.

[0902] After 22h, TLC showed reaction complete. The reaction was diluted with DCM (15 mL) and washed with IN aq. HCl (15 mL), brine (15 mL), dried (Na2SO4), and concentrated down. The crude was purified on silica gel (eluent:
DCM/Et2O/acetone 30:10:1). The top spot isolated (5) was white foamy powder (169 mg, 40 %), and the bottom spot (6) was white solid (156 mg, 38 %). MS m/e 550 (M++Na).

Step 3: Synthesis of 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1-(2S-tert-butoxycarbonylamino-non-8-enoyl)-5-(1R-ethoxycarbonyl-2S-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3R-yl ester (7) O
O
O
N O HN,, 0 OH 1) 4N HCI (dioxane) O O
BocN O I + 2) HATU, DIEA, DMF o `H,'' N
O
O N' N' O H
O Ol H

[0903] The top isomer 5 (118 mg, 0.22 mmol) was dissolved in 4N HCl (dioxane, 8 mL) and left at rt for 90 min to remove the BOC protective group.
It was then concentrated down, taken up in acetonitrile and concentrated down again twice.
To this light brownish residue was added 4 (66.8 mg, 1.1 equiv) and HATU (93.5 mg, 1.1 equiv), followed by 2 mL DMF under nitrogen. The reaction was cooled on ice-water bath for 15 min, after which a 0.5 mL DMF solution of DIEA (0.13 mL, 4 equiv) was added to the reaction drop-wise while stirring. The ice bath was left to slowly rise to rt and the reaction stirred for overnight.

[0904] After 24h, the reaction has turned dark brownish. Its aliquot TLC shows reaction complete. The reaction was diluted with EtOAc (30 mL) and washed with water (3 x 15 mL), sat. NaHCO3 (2 x 15 mL), brine (15 mL), dried (Na2SO4), and concentrated to give 7 as an orange oily residue (156 mg). It was directly used in the next step without further purification. MS 1n/e 703 (M++Na).

Step 4: Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo [14.3Ø0 4'6]nonadec-7-ene-4-carboxylic acid ethyl ester (8) \ N N

O
Y J

O )Lb O OYNO N O
O Cy3P
H/ O (30 mol%) N Isf, H O DCE, 50 C OO
O H

109.05i The crude 7 (135 mg, 0.2 mmol) was dissolved in 20 mL DriSolve DCE
to make a solution, followed by addition of the Nolan's catalyst (5 mg, 0.3 equiv) at rt under nitrogen. The solution turned purplish. The reaction was put on a pre-heated oil bath (50 C) and stirred for overnight.

[0906] After 10 h, the reaction had turned dark brownish. TLC (DCM/EtOAc 1:1) showed clean conversion to a new spot with slightly lower Rf. The reaction was concentrated down and purified on silica gel (eluent: DCM/EtOAc gradient from 5:1 to 2:1), giving product 8 as a tan foamy powder (75 ing, 58 %). MS m/e 653.1 (M++1).

Step 5: Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tent-Butoxycarbonylamino-18-(3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo [14.3Ø0 4'6]nonadec-7-ene-4-carboxylic acid (Compound# 101) O N I/ 0y N
~~
O l i O O N HOB
O O
\\ N O=0 UGH-H20 W.
N 2 THF:MeOH:H2O O H
O H
(2:1:1) 8 Compound# 101 [0907] The macrocyclic ester 8 (60 mg, 0.092 mmol) was dissolved in 0.9 mL
of a mixed solvent (THF/MeOH/H20 2:1:1), followed by addition of LiOH-H20 (23 mg, 6 equiv). The mixture was stirred at rt for overnight. After 18h, TLC (DCM/MeOH
9:1) showed a clean new spot with a lower Rf. The reaction was concentrated down to almost dryness and partitioned between 1N aq. HCl (15 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The organic layers were combined, dried over Na2SO4 and concentrated down, giving compound # 101 as a light brownish foamy powder (50 mg, 87 %). 1H NMR (CD3OD, 400 MHz) 51.20-1.67 (m, 21H), 1.70-1.83 (m, 1H), 1.88-2.10 (m, 1H), 2.12-2.58 (m, 4H), 2.82 (m, 2H), 3.60-3.80 (m, 2H), 3.86 (m, 1H), 4.20 (m, 1H), 4.35 (m, 1H), 4.54 (s, 7H), 4.58 (m, 3H), 5.29-5.41 (m, 2H), 5.57 (m, 1H), 7.0-7.24 (m, 4H). MS m/e 625.1 (M++1).

Example 1-la:

OyN
O
H O N HO
N,,, O
O
;
O H, Compound AR00220122 [0908] (1S, 4S, 6R, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4-dihydro-1 H-is oquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo [
14.3Ø0 4,6]nonadec-7-ene-4-carboxylic acid (Compound AR00220122) was prepared similarly according to procedures described in Example 1-1, substituting compound 5 with 6 in Step 3. MS m/e 625 (M++l).

Example 1-2: Synthesis of Compound# 101 (Compound AR00220042) by Method B:
Method B:

OH OH pH
HCI=H2N + HATU, DIEA BocN 2 1) 4N HCI (dioxane) 0 N
BocN DMF O 2) HATU, DIEA, DMF BocHN,.
O O
/Pv) N1 O N O
HO 0 H 0 BocHN, 0 (1R, 2S) 11 OH

OH OY
Nolan's catalyst or Hoveyda's Catalyst (8 %) 0 0 N \O 1) CDI, DCM O
BocHNi,. = N 0`=0 DCE, 50 C 0 Hmv 2) R1R2NH BocHN ,.
0 N>
H

O
LiOH-H20 0 N HOBO
BocHN,,. a THF:MeOH:H20 (2:1:1) 0 H
II

Compound' 1`01 was also prepared according to the above procedure.
The synthesis of the macrocyclic intennediate 10 described here is similar to that described in International Application PCT/CAOO/00353 (Publication No. WO 00/59929).

Step 1: Synthesis of 2S-(1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (3) OH
OH II
31 HCI=HZN + BocN
O O BocN HATU, DIEA 7, o 0\ DMF O
H O

1:1 (1R, 2S)/(1S, 2R) [0910] To a flask charged with ethyl-(1R, 2S)/(1S, 2R)-l-amino-2-vinylcyclopropyl carboxylate (1, 1.0 g, 5.2 mmol), trans-N-(test-Butoxycarbonyl)-4-hydroxy-L-proline (2, 1.3 g, 1.1 equiv), and HATU (2.7 g, 1.1 equiv) were added 30 mL
DMF to make a solution. It was cooled to 0 C in an ice-water bath, followed by slow addition of a solution of DIEA (4.4 mL, 4 equiv) in DMF (15 mL) while stirring. The reaction was allowed to warm up to rt and stirred overnight.

[0911] After 16 h, the reaction was complete as monitored by HPLC. It was diluted with EtOAc (100 mL), washed with water (3 x 40 mL), sat. NaHCO3 (2 x 40 mL), and brine (2 x 40 mL), then dried over Na2SO4 and concentrated down to give a dark copper colored oil. The crude was purified on silica gel (eluent:
acetone/hexanes 3:7), giving pure 3 as tan foamy powder (770 mg, 32 %).

Step 2: Synthesis of 1R-{[1-(2S-tert-Butoxycarbonylamino-non-8-enoyl)-4R-hydroxy-pyrrolidine-2S-carbonyl]-amino}-2S-vinyl-cyclopropanecarboxylic acid ethyl ester (9) OH OH
I 1) 4N HCI (dioxane) O
BocN BocHN':. N
O 2) HATU, DIEA, DMF N O
O H O O H
O BOCHN, O
OH

[0912] Compound 3 (2.85 g, 7.7 mmol) was dissolved in 10 mL 4N HCl (dioxane) and left at rt for 90 min to remove the Boc protective group. It was then concentrated down, taken up in acetonitrile and concentrated down again twice.
To this light brownish residue was added 4 (2.2 g, 8.1 mmol) and HATU (3.2 g, 8.5 minol), followed by 80 mL DMF under nitrogen. The reaction was cooled on ice-water bath for 15 min, after which a 5 mL DMF solution of DIEA (5.4 mL, 30.9 mmol) was added to the reaction drop-wise while stirring. The ice bath was left to slowly rise to rt and the reaction stirred for overnight.

[0913] After 18h, TLC showed reaction complete. The reaction was diluted with EtOAc (300 mL) and washed with water (3 x 150 mL), sat. NaHCO3 (2 x 150 mL), brine (150 mL), dried (Na2SO4), and solvent removed. The crude was purified by silica gel flash chromatography on Biotage 40M (eluent = 3 % to 5 % MeOH in DCM) to give 9 as a brownish foamy solid (3.5 g, 87 %).

Step 3: Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø0 4'6]nonadec-7-ene-4-carboxylic acid ethyl ester (10) OH
O I OH
N Nolan's catalyst N
BocHN .. or Hoveyda's Catalyst (5 to 30 %) BocHN .. O
O

DCE, 50 C

[0914] Compound 9 (2.6 g, 5.0 mmol) was dissolved in 500 mL DriSolve DCE
in a 1 L round-bottomed flask to make a solution. It was degassed by bubbling nitrogen through for 1 h. Then the Hoveyda catalyst (0.25 equiv) was added at rt under nitrogen.
The reaction was put on a pre-heated oil bath (50 C) and stirred for overnight. After 16 h, the reaction had turned dark brownish. TLC (DCM/EtOAc 1:1) showed clean conversion to a new spot with slightly lower Rf. The reaction was concentrated down and purified on silica gel (Biotage 40 M, eluent = DCM/EtOAc gradient from 1:1 to 1:2), giving product 10 as a tan foamy powder (0.64 g, 52 %). 1H NMR (CDC13, 400 MHz) 8 1.21 (t, J =
7.0 Hz, 3H), 1.43 (s, 9H), 1.20-1.50 (m, 6H), 1.53-1.68 (m, 2H), 1.83-1.96 (m, 2H), 1.98-2.28 (m, 4H), 2.60 (m, 1H), 3.13 (brs, I H), 3.68 (m, I H), 3.94 (m, I H), 4.01-4.19 (m, 2H), 4.48 (m, 1H), 4.56 (brs, 1H), 4.79 (m, 1H), 5.26 (t, J= 9.4 Hz, 1H), 5.36 (d, J= 7.8 Hz, 1H), 5.53 (m, 1H), 7.19 (brs, I H). MS m/e 494.0 (M++1).

Step 4: Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4-dihydro-IH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo [14.3Ø0 4,6]nonadec-7-ene-4-carboxylic acid ethyl ester (11) OH O
N O)\__O 1) CDI, DCM O
BocHN,,. = N OHO
O IN ~ 2) BocHN?~.
i NH O H
ZZ

[0915] The macrocyclic intermediate 10 (110 mg, 0.22 mmol) was dissolved in DCM (2.2 mL), followed by addition of CDI (45 mg, 0.27 minol) in one portion.
The reaction was stirred at rt overnight. After 15 h, the reaction was complete as monitored by TLC (DCM/MeOH 9:1). 1,2,3,4-tetrahydroisoquinoline (0.14 mL, 1.1 mmol) was added to the reaction drop-wise, and the reaction was stirred at rt for overnight.
After 22h, TLC
showed reaction complete. The reaction was diluted with DCM (6 mL) and washed with 1N aq. HCl (2 x 2 mL), sat. sodium bicarbonate (2 mL), brine (2 mL), dried (Na2SO4), and concentrated down. The crude was purified on silica gel (Biotage 40S, eluent:
2 to 4 %
MeOH in DCM), giving 11 as a pale yellowish foamy powder (131 mg, 90 %).

Step 5: Compound 11 was hydrolyzed in the same fashion as described in the Step 5 of Example 1-1 to give compound# 101.

[0916] The following compounds were also prepared according to Method B
described above, with 1,2,3,4-tetrahydroisoquinoline being substituted by various other secondary amines. Most of these amines were either purchased from commercial sources, or are known literature compounds, therefore were prepared using the procedures listed here (1. Stokker, G E. Tetrahedron Lett. 1996, 37(31), 5453-5456. 2. Chan, N
W.
Bioorganic & Medicinal Chemistry 2000, 8, 2085-2094. 3. Vecchietti, V. et al, J. Med.
Chem. 1991, 34, 2624-2633.) For those amine inputs that were not directly prepared according to literature procedures, or the specific input has not been reported in literature before at our best knowledge, their syntheses are given within each example.

Example 1-3:

N
O=~
O
O
H N \--OH
O~N,,.

~(O O H
Compound AR00226824 [0917] (1S, 4R, 6S, 14S, 18R)- 14-tert-Butoxycarbonylamino- 18-(6,7-dimethoxy-3,4-dihydro- IH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3 Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00226824) was synthesized according to Method B, except 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. MS m/e 585.2 (M++1-100).

Example 1-4:

N N
O=~ H
O
O O
H N ~--OH
N., O~(0 O H~
Compound AR00226825 [0918] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-2,15-dioxo-18-(1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00226825) was synthesized according to Method B, except 2,3,4,9-Tetrahydro-IH-b-carboline was used in Step 4 instead. MS m/e 564.2 (M++ I-100).

Example 1-5:

OY N
O
O~N1 O H~
H N O
..

H
O

Compound AR00291871 [0919] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-l8-(1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04' 6]nonadec-7-ene-4-carboxylic acid (compound AR00291871) was synthesized according to Method B, except 2,3-Dihydro-lH-isoindole was used in Step 4 instead. 'H NMR (CDC13, 500 MHz) 6 1.21-1.44 (m, 8H), 1.32 (s, 9H), 1.54-1.62 (m, 2H), 1.78-1.88 (m, 2H), 2.04-2.13 (m, 1H), 2.16-2.23 (m, 1H), 2.24-2.36 (m, 2H), 2.66-2.74 (m, 1H), 3.87-3.90 (m, 1H), 4.15 (d, J = 11.0 Hz, 1H), 4.37-4.43 (m, 1H), 4.61-4.77 (m, 5H), 5.18 (t, J = 10.3 Hz, 1H), 5.24-5.31 (m, 1H), 5.40-5.45 (m, 1H), 5.58-5.66 (m, 1H), 7.11-7.30 (m, 4H). MS m/e 611.0 (M++l).
Example 1-6:

OON I /
O
O HO
~No. N O
O
~(O O H~
Compound AR00291875 [0920] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(2,3-dihydro-indole- l-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04' 6]nonadec-7-ene-4-carboxylic acid (compound AR00291875) was synthesized according to Method B, except 2,3-Dihydro-lH-indole was used in Step 4 instead. MS m/e 610.9 (M++1).

Example 1-7:

OyN I /
O F F
0\` O N O -F
,.OH
Ol_ W.

O H
Compound AR00294382 [0921] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00294382) was synthesized according to Method B, except 8-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. MS m/e 693.0 (M+) Example 1-8:
F F
F
O"~r N
O
O O O
N \\-OH
O N~
H
Compound AR00294383 [0922] (IS, 4R, 6S, 14S, 18R)-14-tert-B utoxycarbonylamino-2,15-dioxo-18-(6-trifluoromethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00294383) was synthesized according to Method B, except 6-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. 1H NMR (500 MHz, CDC13): S 7.46-7.38 (m, 2H), 7.26-7.18 (m, 1H), 6.98 (s, 1H), 5.62 (q, 1H), 5.42 (s, 1H), 5.21-5.15 (m, 2H), 4.78-4.60 (m, 3H), 4.40 (s, 1H), 4.16-4.00 (m, 1H), 3.92-3.81 (m, 1H), 3.80-3.60 (m, 2H), 3.00-2.85 (m, 2H), 2.72-2.64 (br s, 1H), 2.40-1.18 (m, 20H). MS: We 693.0 (M+).

Example 1-9:

F
O"~' N
O
O
N 0%l--OH
N4>
H

Compound AR00294384 [0923] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5-fluoro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00294384) was synthesized according to Method B, except 5-fluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. 1H NMR (500 MHz, CDC13): 8 7.19-7.11 (m, 1H), 7.05 (m, 1H), 6.91 (t, 2H), 5.62 (q, iH), 5.40 (s, 1H), 5.24 (d, 1H), 5.20 (t, 1H), 4.78 (s, 1H), 4.64-4.56 (m, 2H), 4.42 (s, 1H), 4.12-4.02 (m, 1H), 3.92-3.81 (m, 1H), 3.78-3.61 (m, 2H), 2.84-2.80 (m, 2H), 2.74-2.64 (m, 1H), 2.36-2.18 (m, 2H), 1.91-1.81 (m, 2H), 1.64-1.54 (m, 2H), 1.48-1.10 (m, 15H). MS: m/e 643.0 (M+) Example 1-10:

OyN I /
O
O
O O
N -OH
O)HS,.
O N4>
H

Compound AR00301745 [0924] (1S, 4R, 6S, 14S, 18R)-18-(5-Amino-3,4-dihydro-IH-isoquinoline-2-carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00301745) was synthesized according to Method B, except 5-amino-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. MS: m/e 640.1 (M+) Example 1-11:

OyN I NH2 \`H O N ~-OH
O Not~-H
[0925] Compound AR00301749 [0926] (1S, 4R, 6S, 14S, 18R)-18-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00301749) was synthesized according to Method B, except 7-amino-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. MS: We 640.1 (M+), 641.1 (M++1) Example 1-12:

O
O"k N S
-NH
N

~ AOyN N~ O
OH
N
H
Compound AR00304000 [0927] (1 S, 4R, 6S, 14S, 18R)- 14-tert-Butoxycarbonylamino-2,15-dioxo- 18-(2-phenylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304000) was synthesized according to Method B, except Phenyl-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine was used in Step 4 instead. MS m/e 721.2 (M-1).

Example 1-13:

O.
N I a CI
O

O O O
N \\--OH
H

Compound AR00304062 [0928] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(7-chloro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304062) was synthesized according to Method B, except 7-Chloro-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. MS
mle 659.0 (M+), 661.0 (M++2) Example 1-14:
F
OYN I
O
O\\\\ O N O`\-OH
Ol'H,,. Y
N
H
Compound AR00304063 [0929] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-fluoro-3.4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304063) was synthesized according to Method B, except 6-fluoro-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. MS
m/e 643.0 (M+), 644.0 (M++1) Example 1-15:

N
O=( O
O
O
HN'" N -OH
O 0 0 H~

Compound AR00304065 [0930] (1 S, 4R, 6S, 14S, 18R)- 14-tert-Butoxycarbonylamino-18-(4,4-spirocyclobutyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304065) was synthesized according to Method B, except 4,4-siprocyclobutyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. 1H NMR (400 MHz, d6-acetone) S 7.99 (d, 1H), 7:5'7.7:66(, Y'I ,' 7.2'7'(t, 'lH), 7.09-7.22 (m, 2H), 5.99 (bs, 1H), 5.56 (dd, 1H), 5.42 (bs, 1H), 5.19-5.30 (m, 1H), 4.52-4.70 (in, 1H), 4.27-4.42 (m, I H), 4.17-4.27 (in, 1H), 3.91 (dd, 1H), 3.63-3.82 (m, 2H), 2.22-2.51 (m, 6H), 1.93-2.20 (m, 3H), 1.79-1.91 (m, 1H), 1.52-1.66 (m, 1H), 1.16-1.50 (in, 19H). MS in/z 665.1 (M++1) Example 1-15a:

Preparation of 4,4-siprocyclobutyl-1,2,3,4-tetrahydro-isoquinoline:
LiAIH4 McOCOCI H
NC THE H,N,_~ TEA, THF McOUN
A B O
PPA LiAIH4 C O D

[0931] A: To a solution of 1-phenyl-l-cyclopropane carbonitrile (2.00 g, 12.7 mmol) in 100 ml THE was added a 1.0 M solution of LiAlH (19.1 ml, 19.1 mmol) dropwise at r.t. The reaction was stirred at r.t. for 15 hours, then quenched slowly at OC with 10 ml H2O and then 10 ml l.ON NaOH and stirred at r.t. for 1.5 hours. The solution was filtered, and the THE was removed by rotary evaporation. The aqueous was extracted with EtOAc, and the organic extract was washed with H2O and brine, dried over Na2SO4, and concentrated to give 0.70 g (34%) of a clear oil which was used in the next step without further purification.

[0932] B: To a solution of C-(1-Phenyl-cyclobutyl)-inethylamine (0.70 g, 4.34 mmol) and TEA (0.67 ml, 4.78 mmol) in 40 ml THE at 0 C was added methyl chloroformate dropwise. The reaction was stirred at r.t. for 15 hours. The next day water and EtOAc were added and the organic layer was separated and washed with 1N
HCl and brine, dried over Na2SO4, concentrated to an oil, and used directly in the next step without further purification.

[0933] C: A mixture of (1-Phenyl-cyclobutylmethyl)-carbamic acid methyl ester (0.95 g, 4.34 mmol) and PPA (20ml) were added to a sand bath preheated to 150 C.
After 30 minutes the reaction was cooled to room temperature (r.t.). After cooling, water was added dropwise and the solution was extracted twice with DCM. The organic extracts were washed with brine, dried over Na2SO4, and concentrated to a clear oil which was used directly in the in the next step without further purification.
[0934] D: To a solution of the 3,4-dihydro-2H-isoquinolin-l-one (0.406 g, 2.17 mmol) in 20 ml THE at 0 C was added a 1.0 M solution of LiA1H (3.26 ml, 3.26 mmol) dropwise. The reaction was allowed to warm to r.t. and was stirred for 15 hours, then quenched slowly at 0 C with 5 ml H2O and then 5 ml 1.ON NaOH and stirred at r.t. for 1.5 hours. The solution was filtered, and the THE was removed by rotary evaporation. The aqueous was extracted with EtOAc, and the organic extract was washed with H2O
and brine, dried over Na2SO4, and concentrated to give 0.21 g (56%) of a clear oil which was used in the next step without further purification.

Example 1-16:

N
O=( O
O
O
HNC,. N ~-OH
00 O H' Compound AR00304066 [0935] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304066) was synthesized according to Method B, except 4,4-Dimethyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. 'H NMR (400 MHz, d6-acetone) b 7.98 (d, 1H), 7.39 (bs, 1H), 7.09-7.24 (m, 3H), 5.99 (bs, 1H), 5.57 (dd, 1H), 5.37-5.46 (bs, 1H), 5.24 (dd, IH), 4.55-4.69 (m, 1H), 4.26-4.36 (m, 1H), 4.16-4.26 (m, 1H), 3.90 (dd, IH), 3.40-3.49 (m, 1H), 2.28-2.50 (m, 4H), 1.98-2.09 ( 2H), 1.79-1.92 (m, 1H), 1.52-1.65 (m, 3H), 1.16-1.51 (m, 22H). MS m/z 653.0 (M++1) Example 1-16a:

HN

[0936] 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline was prepared following the experimental of steps A through D in Example 1-15a, 2-Methyl-2-phenyl-propionitrile (prepared according to Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc.
2000, 122, 712-713) was converted to the title compound.

Example 1-17:

N
O~

O
O
HNt,. N -OH
TN

Compound AR00304067 [0937] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4-methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304067) was synthesized according to Method B, except 4-methyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. 1H
NMR (400 MHz, d6-acetone) 6 7.93-8.03 (m, 1H), 7.04-7.28 (m, 4H), 6.02 (bs, 1H), 5.56 (dd, 1H), 5.40 (m, 1H), 5.23 (dd, 1H), 4.66-4.85 (m, 1H), 4.54-4.64 (m, 1H), 4.34-4.54 (m, 1H), 4.17-4.34 (m, 1H), 3.91 (dd, 1H), 3.57-3.78 (m, 1H), 3.42-3.57 (m, 1H), 2.26-2.52 (m, 4H), 1.96-2.09 (m, 2.0), 1.77-1.92 (m, 1.0), 1.50-1.64 (m, 3.0), 1.13-1.50 (m, 17h). MS m/z 639.0 (M++1) Example 1-17a:

HN
[0938] 4-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 2-phenyl-propylamine according to Grunewald, G. L.; Sall, D. J.; Monn, J. A. J. Med.
Chem. 1988, 31, 433-444.

Example 1-18:

oAN s >--NH
N

~OO~N N, 0 OH
H

Compound AR00304103 [0939] (1 S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino- I 8-(2-tert-butylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304103) was synthesized according to Method B, except tert-Butyl-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine was used in Step 4 instead. MS We 731.2 (M++ 1).

Example 1-19:

ON S -NH
OH
AO'N N, 0 H

Compound AR00304154 [0940] (IS, 4R, 6S, 145, 18R)-18-(2-Amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304154) was synthesized according to Method B, except 4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine was used in Step 4 instead. MS m/e 675.1 (M++1).

Example 1-20:

O-'- N 3 v ' N
~OOTN O N" 0 OH
N
H

Compound AR00304158 [0941] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (compound AR00304158) was synthesized according to Method B, except 2-Methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine was used in Step 4 instead. MS m/e 546.2 (M++1-100).

Example 1-21:
O
ON N
ON N O
O
OH
H

Compound AR00304183 [0942] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-l8-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304183) was synthesized according to Method B, except 5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidine was used in Step 4 instead. MS m/e 625.2 (M-1).

Example 1-22:

O~N
O
~H O N HO
/ N,,O
O
H
O

Compound AR00312023 [0943] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4-dihydro-l H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadecane-4-carboxylic acid (Compound AR00312023) was synthesized according to Method B, except that the ring-closing metathesis product 10 from step 3 was further reduced with H2 / Rh-A1203 before the next coupling step (WO 0059929, p.p. 76-77). MS m/e 625.3 (M-1).

Example 1-23:
O
0-1-N I \

_0OH
O
H

Compound AR00314578 [0944] (1S, 4R, 6S, 14S, 18R)-18-(6-Amino-3,4-dihydro-lH-isoquinoline-2-carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00314578) was synthesized according to Method B, except 1,2,3,4-Tetrahydro-isoquinolin-6-ylamine was used in Step 4 instead. MS (POS ESI) m/z 540.2 [parent, (M++1)-100 (Boc group)].

Example 1-24:

,>-NH
O)~N S
N
0'N N O
OH
N
H

Compound AR00314685 [0945] (1S, 4R, 6S, 14S, 18R)-18-(2-Acetylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00314685) was synthesized according to Method B, except N-(4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-acetamide was used in Step 4 instead. MS We 589.2 (M++1-100).

Example 1-25:

1~ N

O
O
H N \\-OH
O

H
O

Compound AR00315997 [0946] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5-dimethylamino-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00315997) was synthesized according to Method B, except Dimethyl-(1,2,3,4-tetrahydro-isoquinolin-5-yl)-amine (Example 1-25a) was used in Step 4 instead. MS We 668.0 (M+).

Example 1-25a NMe2 bOH
[0947] The synthesis of dimethyl-(1,2,3,4-tetrahydro-isoquinolin-5-yl)-amine is described in the following scheme:
1) Boc2O, NaOH
NH2 2) NaH, Mel NMe2 3) TFA, DCM
\ \
/ NH I / NH
[0948] To a solution of 5-aminotetrahydroisoquinoline (3.68 g, 24.8 mmol) in 1,4-dioxane (100 mL) was added 3 N NaOH (8.27 mL, 24.8 mmol). After cooling to 0 C, (Boc)20 (5.42 g, 24.8 mmol) in 1,4-dioxane (10 mL) was added drop-wise and stirred for overnight at room temperature. The reaction mixture was poured into water and extracted with EtOAc (2x). The combined organic layers was washed with sat. aq. NaHCO3 solution, water, and brine, then dried and concentrated. The residue was purified by silica gel column chromatography to give 5.44 g (88%) of the desired Boc-protected product as a white solid.
[0949] To a solution of the product from the previous step described above (0.2 g, 0.81 mmol) in THE (5 mL) was added NaH at 0 T. After 15 minutes, CH3I was added and the stirring continued for overnight at room temperature. After completion the reaction mixture was quenched with ice water, extracted with EtOAc (25 mL), dried (Na2SO4) and concentrated. The Boc group was removed with 60% TFA-DCM (2 mL) at 0 C to give 110 mg (77.5%) of the final product as a light greenish solid. MS: 177.1 (MH+).

Example 1-26:

ci O. N
O
O
O
!~H N ~--OH
O N,,.

H
O

Compound AR00315998 [0950] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5-chloro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00315998) was synthesized according to Method B, except 5-Chloro-2,3-dihydro-lH-isoindole was used in Step 4 instead. 1H NMR (400 MHz, CDC13):
S 7.24-7.02 (m, 3H), 6.82 (s, 1H), 5.68-5.51 (m, 1H), 5.36 (s, 1H), 5.11-4.96 (m, 2H), 4.67-4.44 (m, 5H), 4:29-4.20 (m, 1H),4.20-4.11(m, 1H), 3.82-3.74 (m, 1H), 2.69-2.55 (m, 1H), 2.31-2.15 (m, 1H), 2.14-2.06 (m, 1H), 2.03 (s, 1H), 2.01-1.86 (m, 1H), 1.86-1.24 (m, 11H), 1.22 (s, 9H). MS: m/e 644.9 (M+), 646.9 (M++2) Example 1-27:

OY N
O
O
H N \\-OH
O
O No.
N
H
Compound AR00315999 [0951] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5,6-dichloro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00315999) was synthesized according to Method B, except 5,6-Dichloro-2,3-dihydro-lH-isoindole was used in Step 4 instead. 'H
NMR

(400 MHz, CDC13): S 7.29 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 5.57-5.50 (m, 1H), 5.33 (s, 1H), 5.23-5.09 (m, 2H), 4.73-4.65 (m, 1H), 4.64-4.48 (m, 5H), 4.33-4.29 (m, 1H), 4.11-4.02 (m, 1H), 3.82-3.74 (m, 1H), 2.73-2.61 (m, 1H), 2.29-2.08 (m, 3H), 2.01 (s, 1H), 1.83-1.65 (m, 2H), 1.63-1.46 (m, 2H), 1.40-1.12 (m, 15H). MS: m/e 678.9 (M+), 681 (M++2) Example 1-28:

bN' O=<

O
H N O
NI.- -OH
O H
Compound AR00320122 [0952] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4R-methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320122) was synthesized according to Method B, except 4R-Methyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead.
1H NMR (400 MHz, CD3OD) 8 7.02-7.24 (m, 3H), 5.59 (dd, 1H), 5.30-5.44 (m, 2H), 4.66-4.81 (m, 1H), 4.14-4.64 (m, 3H), 3.83-3.92 (m, 1H), 3.58-3.81 (m, 1H), 3.44-3.56 (m, 1H), 2.86-3.86 (m, 1H), 2.23-2.58 (m, 4H), 1.87-2.13 (m, 2H), 1.70-1.87 (m, 1H), 1.50-1.70 (m, 3H), 1.07-1.51 (m, 19H), 0.80-0.96 (m, 2H). MS m/z 639.0 (M++1) Example 1-29:

0\-llj N
O=<

O
N O
OyN,,.-OH
O H
Compound AR00320123 [0953] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4S-methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø046]

nonadec-7-ene-4-carboxylic acid (Compound AR00320123) was synthesized according to Method B, except 4S-Methyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. 1H
NMR (400 MHz, CD3OD) 8 7.01-7.23 (m, 3H), 5.58 (dd, 1H), 5.32-5.45 (m, 2H), 4.66-4.82 (m, 1H), 4.12-4.64 (m, 3H), 3.86-3.94 (m, 1H), 3.52-3.74 (m, 1H), 3.43-3.56 (m, 1H), 2.88-3.85 (m, 1H), 2.24-2.60 (m, 4H), 1.87-2.15 (m, 2H), 1.71-1.87 (m, 1H), 1.52-1.70 (m, 3H), 1.07-1.52 (m, 19H), 0.80-0.96 (m, 2H). MS m/z 639.0 (M++1) Example 1-30:

T NO-O=<
O
O
N,. N OOH
O t~
Compound AR00320576 [0954] (IS, 4R, 6S, 14S, 18R)-14-tert-B utoxycarbonylamino- l 8-[4-(2-methoxy-phenyl)-piperidine-1-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04' 6]nonadec-7-ene-4-carboxylic acid (Compound AR00320576) was synthesized according to Method B, except 4-(2-Methoxy-phenyl)-piperidine was used in Step 4 instead. MS m/e 583.3 (M++1-100).
Example 1-31:
O O\
N

H
H N O
O '10 (:~
OYN,,. OH
O H

Compound AR00320577 [0955] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-methoxy-1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320577) was synthesized according to Method B, except 6-Methoxy-2,3,4,9-tetrahydro-IH-b-carboline was used in Step 4 instead. MS We 594.2 (M++1-100).

Example 1-32:

O No OAN I \
~OAO~N N" O
OH
N
H
Compound AR00301383 [0956] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-2,15-dioxo-18-(1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00301383) was synthesized according to Method B, except 1-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead. lH NMR (500 MHz, CD3OD) S 7.33 - 7.24 (m, 4H), 7.20 (br s, IH), 6.61 (br s, IH), 5.75 - 5.52 (m, 2H), 5.50 - 5.33 (m, 2H), 4.63 - 4.43 (m, 2H), 4.42 - 4.07 (m, 4H), 3.96 (br s, I H), 3.67 - 3.11 (m, 5H), 3.06 -2.88 (m, 2 H), 2.86 - 2.74 (m, 2 H), 2.56 - 2.35 (m, 3H), 2.23 (q, 1H), 2.04 - 1.90 (m, 2H), 1.89 - 1.52 (m, IOH), 1.51 - 1.32 (m, 12H); MS (POS APCI) m/z 722.3 (M++1).

Example 1-33:

oo OAN I \
~O OTN O H O
N N,' OH
H

Compound AR00333842 [0957] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-methoxy- l -methoxymethyl-3,4-dihydro-IH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333842) was synthesized according to the procedures described in Example 1-2, except that 6-methoxy-l-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS (APCI-): m/z 697.2 (M-1).

Example 1-34:
F
N

Of NO
OH
OA N=, O
H
Compound AR00365349 [0958] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-l8-(5-fluoro-l-methoxymethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00365349) was synthesized according to the procedures described in Example 1-2, except that 5-fluoro-l-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS (APCI-): m/z 685.3 (M-1).

Example 1-35:

O
O~N I ~
~OAO~N O H O
OH
N
H
Compound AR00333224 [0959] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(1-dimethylaminomethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333224) was synthesized according to the procedures described in Example 1-2, except that dimethyl-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-amine (synthesized according to Example 1-35a) was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS
(APCI+): mlz 582.3 (MH+-Boc).

Example 1-35a:

~
HN I \

[0960] Dimethyl-(1,2,3,4-tetrahydro-isoquinolin-l-ylmethyl)-amine was synthesized by a similar fashion as shown in Example 3-76a, except that in Step 1, phenethylamine was used to replace 2-(3-methoxy-phenyl)-ethylamine, and that in the first part of Step 3, dimethyl-amine was used to replace sodium methoxide as the nucleophile.
The crude product was used directly in the next coupling step without further purification.
Example 1-36:
ro O NJ
O-kN

O
O
` ON O N%
JJJ OH
H

Compound AR00333225 [0961] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(1-morpholin-4-ylmethyl-3,4-dihydro- I H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333225) was synthesized according to the procedures described in Example 1-2, except that 1-morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to Example 1-36a) was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS (APCI-):
m/z 722.3 (M-1).

Example 1-36a:

O

HN I

[0962] 1 -Morpholin-4-ylmethyl- 1,2,3,4-tetrahydro-isoquinoline was synthesized by a similar fashion as shown in Example 3-76a, except that in Step 1, phenethylamine was used to replace 2-(3-methoxy-phenyl)-ethylamine, and that in the first part of Step 3, morpholin was used to replace sodium methoxide as the nucleophile. The crude product was used directly in the next coupling step without further purification.

Example 1-37:

O
O' N

OO N H O
N,' OH
XO'`N O
H
Compound AR00333248 [0963] (1S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-methoxy-l-piperidin-1-ylmethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333248) was synthesized according to the procedures described in Example 1-2, except that 6-methoxy-l-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to Example 1-37a) was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS
(APCI-):
m/z 750.4 (M- 1).

Example 1-37a:

ND
HN

[0964] 6-Methoxy-l-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was synthesized by a similar fashion as shown in Example 3-76a, except that in the first part of Step 3, piperidine was used to replace sodium methoxide as the nucleophile.
The crude product was used directly in the next coupling step without further purification.

Example 1-38:

Or N

O
OAO:N NH , OH
N
H
Compound AR00333276 [0965] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(6-methoxy- t -morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333276) was synthesized according to the procedures described in Example 1-2, except that 6-methoxy-l-morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to Example 1-38a) was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead. MS
(APCI-):
m/z 750.3 (M-1).

Example I -38a:
r o N.J
HN
O"
[0966] 6-Methoxy- l -morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was synthesized by a similar fashion as shown in Example 3-76a, except that in the first part of Step 3, morpholin was used to replace sodium methoxide as the nucleophile. The crude product was used directly in the next coupling step without further purification.

Example 1-39:

O & O'er OO N H O
OA N N OH
- = ~ O
H
Compound AR00333277 [0967] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(1-dimethylaminomethyl-6-methoxy-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00333277) was synthesized according to the procedures described in Example 1-2, except that (6-methoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-dimethyl-amine (synthesized according to Example 1-39a) was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 instead.
MS (APCI+): m/z 712.3 (MH+).

Example 1-39a:

N~
HN I \

[0968] 6-Methoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-dimethyl-amine was synthesized by a similar fashion as shown in Example 3-76a, except that in the first part of Step 3, dimethylamine was used to replace sodium methoxide as the nucleophile. The crude product was used directly in the next coupling step without further purification.

Example 1-40:

F
N
O:--,-O
_~'O/X 0. N H O
~'J( N'' OH
N O
H

Compound AR00365369 [0969] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00365369) was synthesized according to the procedures described in Example 1-2, except that 4-fluoro-2,3-dihydro-1H-isoindole (synthesized according to Example 3-55a) was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 instead. 'H NMR (500 MHz, DMSO) 8 12.21 (br s, 1 H), 8.66 (br s, 1 H), 7.35 (q, 1 H), 7.19 (d, 1 H), 7.11 (q, 2 H), 7.03 (br s, I H), 5.51 (q, I H), 5.33 - 5.21 (m, 2 H), 4.66 (s, 4 H), 4.22 (q, I H), 4.24 (t, I H), 3.99 - 3.89 (m, 1 H), 3.73 - 3.64 (m, I H), 2.65 - 2.55 (m, 1 H), 2.28 - 2.08 (m, 3 H), 1.77 - 1.61 (m, 2 H), 1.54 - 1.42 (m, l H), 1.42 -1.03 (m, 16 H);
MS (APCI-): m/z 627.3 (M-1).

Example 1-41 oNS

N

'o O~ N H O
N
A OH
N o H
Compound AR00371946 [0970] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-[5-(2-morpholin-4-yl-ethoxy)-1,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[ I4.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00371946) was synthesized according to the procedures described in Example 1-2, except that 5-(2-Morpholin-4-yl-ethoxy)-2,3-dihydro-1 H-isoindole (prepared according to the procedures described in J. Med. Chem. 2002, Vol. 45, No. 26, 5771, preparation method D, and in Bioorg. Med. Chem. Lett. 11 (2001) 685-688. For the N-Boc protected amine input: 'H
NMR (500 MHz, CDC13) b 7.13 (dd, 1H), 6.85 - 6.74 (m, 2H), 4.61 (t, 4H), 4.10 (t, 2H), 3.73 (t, 4H), 2.81 (t, 2H), 2.61 - 2.54 (m, 4H), 1.51 (s, 9H); MS (APCI+): mlz 349.1 (M+1)) was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 instead. MS
(APCI+): m/z 640.3 [(M+1)-Boc].

Example 1-42 N-N
o j ,N N O
OH
N O
H
Compound AR00371947 [0971] (1 S, 4R, 6S, 14S, 18R)- 14-tert-Butoxycarbonylamino- 18-[5-(2-dimethylamino-ethoxy)- 1,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00371947) was synthesized according to the procedures described in Example 1-2, except that [2-(2,3-Dihydro-IH-isoindol-5-yloxy)-ethyl]-dimethyl-amine (prepared according to the procedures described in J. Med. Chem. 2002, Vol. 45, No. 26, 5771, preparation method D, and in Bioorg. Med. Chem. Lett. 11 (2001) 685-688. For the N-Boc protected amine input: 'H
NMR (500 MHz, CDC13) S 7.14 (dd, 1H), 6.88 - 6.76 (m, 2H), 4.61 (t, 4H), 4.04 (t, 2H), 2.72 (t, 2H), 2.34 (s, 6H), 1.50 (s, 9H); MS (APCI+): m/z 307.1 (M+1)) was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 instead. MS (APCI+): m/z 698.2 (M+1).

Example 1-43 HN-~
O

N
O--~-O
O O~- N N, 0 O-kN O OH
H

Compound AR00371948 [0972] (1 S, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-[5-(2-isopropylamino-ethoxy)-1,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00371948) was synthesized according to the procedures described in Example 1-2, except that [2-(2,3-Dihydro- I H-isoindol-5-yloxy)-ethyll-isopropyl-amine (prepared according to the procedures described in J. Med. Chem. 2002, Vol. 45, No. 26, 5771, preparation method D, and in Bioorg. Med. Chem. Lett. 11 (2001) 685-688. For the N-Boc protected amine input: 'H
NMR (500 MHz, CDC13) b 7.13 (dd, IH), 6.86 - 6.75 (m, 2H), 4.62 (t, 4H), 4.06 (t, 2H), 2.99 (t, 2H), 2.88 (septuplet, 1H), 1.62 (br s, 1H), 1.51 (s, 9H), 1.10 (d, 6H); MS (APCI+):
m/z 321.2 (M+ 1)) was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 instead. MS
(APCI-): m/z 710.3 (M-1).

Preparation of Compounds with General Structure III

O N O~ 4N HCI (dioxane) O N O R3X N O~
BocHN,,. O e HZN,,. O R3HN,,. O
N"> HCl O N
O H _ O H H
X= OC(O)CI, NCO, COCI ]

la O
O
LiOH-H20 N HOBO
R3HN,,.
THE/MeOH/H2O O N
III

[0973] Compounds with general structure II were prepared according to the general scheme shown above. A compound with structure la was first removed of its Boc protective group, followed by nucleophillic attack of the amino group on an electrophile, to form a carbamate, amide, or urea.

Example 2-1:

OyN I i O
O
H N HOBO
O-~ N,,.
O O
H~

Compound AR002473 10 Step 1: Preparation of (1S, 4R, 6S, 14S, 18R)-14-Amino-18-(3,4-dihydro-iH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø0 4'6]nonadec-7-ene-4-carboxylic acid ethyl ester.

OYN I / I \
OYN
O
O 4N HCI (Dioxane) ~=O _ O O
05-H ,,, N HZN,,. N ~O
O H HCI O H v [0974] The -Boc protected starting material (102 mg, 0.16 mmol) was dissolved in 6 mL 4N HCl (dioxane), and left at rt for 90 min. HPLC showed complete removal of the Boc protective group. The reaction mixture was then concentrated down, taken up in acetonitrile and concentrated down again twice. The resulting light brownish foamy powder was carried out to the next step.

Step 2: Preparation of (1S, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid ethyl ester.

OyN I

O O O O
H2N,,. N ~=0 ~J~OyCI THF, TEA ~H,,, N
O m HCI O H O O H I~

[0975] To a solution of cyclopentanol (42 mg, 0.48 mmol) in THE (16 mL), a toluene solution of phosgene (0.42 mL, 1.9 M, 0.80 mmol) was added drop-wise.
The mixture was stirred at rt for 2 h to form the cyclopentyl chloroformate reagent. The reaction was then concentrated down to about half the volume. It was then diluted with DCM to the original volume, and concentrated down again to half the volume, in order to completely remove excess phosgene. This solution of the cyclopentyl chloroformate was further diluted with THE (16 mL), cooled to 0 C, and added to the solid residue (0.16 mmol) from Step 1 above at 0 C. TEA (0.11 mL, 0.81 mmol) was then added to the reaction mixture, and the reaction was stirred at 0 C for 2 h. The reaction was complete by HPLC. It was concentrated down, taken up in EtOAc (15 mL), and then washed with water, sat. sodium bicarbonate, water, and brine (10 mL each), dried over Na2SO4 and concentrated down. The crude yellowish thick oil residue was purified by flash chromatography on Biotage 40S (eluent = hexanes/EtOAc 1:1), giving the desired product as a white crispy foamy powder (65.2 mg, 63 %). MS (MH+ 665.2) Step 3: Preparation of (1S, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-(3,4-dihydro-iH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00247310).

OI OyN I /
N I /
O
p O O LiOH, THF/MeOH/H2O O\\`` O N HO
N ~p !~N ,,O
p~H,,. p H
0 /-H H~
N
O H

[0976] Followed the same hydrolysis procedures as in Step 5 of Example 1-1.
[0977] The following compounds were also prepared following the same procedures as aforementioned in Example 2-1, with either the cyclopentyl chloroformate being substituted by other electrophiles, and/or the P2-tetrahydroisoquinoline being substituted by other amine inputs as illustrated in Step 4 of Method B in Example 1-2.

Example 2-2:

N
O=<
O
O

Compound AR00294376 [0978] (iS, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-lH-isoquinoline-2-carbonyloxy)-14-methoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04' 6]nonadec-7-ene-4-carboxylic acid (Compound AR00294376) was synthesized according to the procedures described in Example 2-1, except that methyl chloroformate was used in Step 2 instead.
Example 2-3:

F
(:p N
O=<
O
O
H N O
O~N,,.-OH
O O H
Compound AR00304074 [0979] (1S, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-18-(5-fluoro-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304074) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 5-Fluoro-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4 of Example 1-2. MS m/e 583.2 (M++1).

Example 2-4:

N
O~ F F F
O
O
H O
N ~'-OH
O O H
Compound AR00304075 [0980] (IS, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304075) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4 of Example 1-2. MS
m/e 705.1 (M++ 1).

Example 2-5:

N
O==<
p O O`\
N~,. N Y-OH
O O H~
Compound AR00304076 [0981] (IS, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-18-(1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304076) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-lH-isoindole was used instead in Step 4 of Example 1-2. MS m/e 623.2 (M++ 1).

Example 2-6:

N
O O
H N O
OH
O
O H

Compound AR00304125 [0982] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-lH-isoquinoline-2-carbonyloxy)-14-(2-fluoro-ethoxycarbonylamino)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304125) was synthesized according to the procedures described in Example 2-1, except that 2-fluoroethanol was used to form the chloroformate reagent in Step 2 instead of cyclopentanol. MS m/e 615.1 (M++ 1).

Example 2-7:

N
O=<
O
O
O
O~H N ~OH
O~ O O TN

Compound AR00304126 [0983] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-14-(tetrahydro-furan-3S-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304126) was synthesized according to the procedures described in Example 2-1, except that tetrahydro-furan-3S-ol was used to form the chioroformate reagent in Step 2 instead of cyclopentanol. MS
m/e 639.2 (M++1).

Example 2-8:

N
O=<
O
O
O
OC)O"rW. N OH
O O N
H
Compound AR00304127 [0984] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-IH-isoquinoline-2-carbonyloxy)-2,15-dioxo-14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304127) was synthesized according to the procedures described in Example 2-1, except that tetrahydro-furan-3R-ol was used to form the chloroformate reagent in Step 2 instead of cyclopentanol. MS
m/e 639.2 (M++1).

Example 2-9:

N
O=<
O
O
W. N O\\--OH
~O
O O O H~
Compound AR00320002 [0985] (IS, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-lH-isoquinoline-2-carbonyloxy)-2,15-dioxo-14-(tetrahydro-pyran-4-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320002) was synthesized according to the procedures described in Example 2-1, except that tetrahydro-pyran-4-ol was used to form the chloroformate reagent in Step 2 instead of cyclopentanol. MS
m/e 653.2 (M++1).

Example 2-10:
it N
O=~
O
O O
H N ~--OH
00 O O H~
Compound AR00320074 [0986] (1S, 4R, 6S, 14S, 18R)-18-(1,3-Dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320074) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-lH-isoindole was used instead in Step 4 of Example 1-2, and that tetrahydro-furan-3R-ol was used to form the chloroformate reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS
m/e 625.2 (M++ 1).

Example 2-11:

N
o=
O

H N -OH

O H O O lI

Compound AR00320075 [0987] (IS, 4R, 6S, 14S, 18R)-18-(1,3-Dihydro-isoindole-2-carbonyloxy)-2,15-dioxo- l4-(tetrahydro-furan-3S-yloxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320075) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-1H-isoindole was used instead in Step 4 of Example 1-2, and that tetrahydro-furan-3S-ol was used to form the chloroformate reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS m/e 625.2 (M++1).

Example 2-12:
i N
o=
O
O O
H N \-OH
F~ W.

O O H
Compound AR00320076 [0988] (1 S,4R,6S, 14S, 18R)- 18-(1,3-Dihydro-isoindole-2-carbonyloxy)-2,15-dioxo- 14-(2-fluoro-ethoxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320076) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-1H-isoindole was used instead in Step 4 of Example 1-2, and that 2-fluoroethanol was used to form the chloroformate reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS m/e 601.1 (M++1).

Example 2-13:

N
O=
O

H N \~--OH
O-1~N ,, O O O H~
Compound AR00320077 [0989] (IS, 4R, 6S, 14S, 18R)-18-(1,3-Dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-14-(tetrahydro-pyran-4-yloxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320077) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-]H-isoindole was used instead in Step 4 of Example 1-2, and that tetrahydro-pyran-4-ol was used to form the chloroformate reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS m/e 601.1 (M++
1).

Example 2-14:

O.-Y N
O
OO O
O N-OH
~H
O H
Compound AR00320445 [0990] (1S, 4R, 6S, 14S, 18R)-18-(5,6-Dichloro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320445) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used instead in Step 4 of Example 1-2, and that tetrahydro-furan-3R-ol was used to form the chloroformate reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS: m/e 693.0 (M+), 695.1 (M++2).

Example 2-15:

r (-N CI
OY N
O

O N,.. N Z~--OH
N">
H

Compound AR00320448 [0991] (IS, 4R, 6S, 14S, 18R)- 18-(5-Chloro- 1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo- 14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3 Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320448) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 5-dichloro-2,3-dihydro-lH-isoindole was used instead in Step 4 of Example 1-2, and that tetrahydro-furan-3R-ol was used to form the chloroformate reagent in Step 2 of Example 2-1 instead of cyclopentanol. 1H NMR (500 MHz, CD3OD): S 7.38 (s, 1H), 7.32-7.28 (m, 2H), 7.22 (d, 1H), 7.10 (br s, 1H), 5.56-5.50 (q, 1H), 5.42-5.38 (t, 1H), 5.35 (br s, 1H), 4.80-4.48 (m, 6H), 4.44 (m, 1H), 4.16 (d, 1H), 3.84 (dd, 1H), 3.78-3.69 (m, 1H), 3.68-3.60 (m, 1H), 3.50 (t, 1H), 2.55-2.36 (m, 3H), 2.21-2.12 (m, 1H), 1.98-1.85 (m, 1H), 1.72-1.62 (m, 2H), 1.61-1.51 (m, 2H), 1.50-1.20 (m, 9H). MS: We 659.1 (M+), 661.1 (M+2) Example 2-16:

O

O N.. N Z~--OH

[0992] Synthesis of (1S, 4R, 6S, 14S, 18R)-14-(Cyclopentanecarbonyl-amino)-18-(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR248689) [0993] Cyclopentyl carboxylic acid was first loaded on PS-TFP resin (purchased from Argonaut Technologies) to form an active ester. The activated ester on resin (26 mg, 1.16 mmol/g, 0.03 mmol) was swelled in 0.5 mL chloroform first, followed by addition of MP-carbonate resin (purchased from Argonaut Technologies, 300 mg, 2.5 mmol/g, 0.75 mmol). To this resin mixture was then added 0.5 M chloroform solution of the macrocyclic material (15 mg, 0.02 mmol), and the reaction was shaken for overnight at it The reaction was complete by HPLC after 16h. It was then filtered and concentrated down, giving clean N-acylated product. It was then hydrolyzed following the same hydrolysis procedures as in Step 5 of Example 1-1, giving the desired product AR248689 as a white solid (12.5 mg, 88 %). MS (APCI+): m/z 621.3 (MH+).

Example 2-17:

O
O
O H N O~--OH
O N~
H

Compound AR00248687 [0994] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-1H-isoquinoline-2-carbonyloxy)-14-(2,2-dimethyl-propionylamino)-2,15-dioxo-3,16-diaza-tricycio[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00248687) was synthesized following the same procedures as described in Example 2-16, except that tert-butyl carboxylic acid was first loaded on PS-TFP resin instead. MS (APCI+):
m/z 609.3 (MH+).

Example 2-18:

O\/N
O
O O H N O\-OH

0 N~
H
Compound AR00248688 [0995] (1 S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro- I H-isoquinoline-2-carbonyloxy)-14-isobutyrylamino-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00248688) was synthesized following the same procedures as escri e in Example 2-16, except that isopropyl carboxylic acid was first loaded on PS-TFP resin instead. MS (APCI+): m/z 595.3 (MH).

Example 2-19:

N
O==( O
H O N \~-OH
Boc-N-~-I Nmm H O O H

Compound AR00298989 Synthesis of (1S, 4R, 6S, 14S, 18R)-14-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-18-(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR298989) N O N
C (~P
O O r 1) Boc N O \\ O
O O O O O
N \\-OEt ~~ H N \--OH
HZN,,. N,,.
O H~ DCM, rt Boc-N O H'>
2) LIOH

[0996] 14-Amino-l8-(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04,6]nonadec-7-ene-4-carboxylic acid ethyl ester (120 mg, 217 umol) and N-a-t-Boc-L-valine N-hydroxysuccinamide ester (96 mg, 300 umol) were stirred together in 1.1 mL dichloromethane for 14 hours. The solvent was removed in vacuo and 1 mL each of water and ethyl acetate were added. The phases were separated and the aqueous layer was washed twice with 500 uL of ethyl acetate. The combined organics were dried over MgSO4 and the solvents removed in vacuo to provide the desired compound as a white solid (132 mg, 81%). MS na/z 752.2 (MH+).

Example 2-20:

N
O:=<
O
O
O \~ H N 0 N,,. -OH
C i H O O H
N =
Compound AR00301338 [0997] (IS, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-1 H-isoquinoline-2-carbonyloxy)-14- (3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino }-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00301338) was synthesized following the same procedures as described in Example 2-19, except that 3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butyric acid 2,5-dioxo-pyrrolidin-l-yl ester was used to replace N-a-t-B oc-L-valine N-hydroxysuccinamide ester instead. MS m/e 730.3 (M++1).
Example 2-21:

O=<
O
O N,,. N ~-OH
- H O
&-~
O
N

Compound AR00304072 [0998] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-1 H-isoquinoline-2-carbonyloxy)-14-{ 2-[(6-dimethylamino-pyridine-3-carbonyl)-amino]-3-methyl-butyrylamino }-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304072) was synthesized following the same procedures as described in Example 2-19, except that 2-[(6-Dimethylamino-pyridine-3-carbonyl)-amino]-3-methyl-butyric acid 2,5-dioxo-pyrrolidin-l-yl ester was used to replace N-a-t-Boc-L-valine N-hydroxysuccinamide ester instead. 'H NMR (CD3OD, 500 MHz): 6 8.69 (s, 1 H), 8.46 (s, 1 H), 8.37-8.39 (m, 1 H), 8.14-8.21 (m, 2 H), 7.07-7.18 (m, 5 H), 5.63 (q, I H), 5.36-5.42 (m, 2 H), 4.49-4.56 (m, 3 H), 4.42-4.45 (m, 1 H), 4.31-4.32 (m, 1 H), 3.92-3.95 (m, 1 H), 3.65-3.72 (m, 2 H), 2.85-2.91 (m, 2 H), 2.33-2.55 (m, 4 H), 1.93-2.03 (m, 3 H), 1.61-1.68 (m, 3 H), 1.27-1.52 (m, 12 H), 0.86-0.96 (m, 8 H). MS We 770.4 (M-1).

Example 2-22:

N
O--X
O
O
W. N O)- OH
O H

O O
Compound AR00304073 [0999] (IS, 4R, 6S, 14S, 18R)- 18-(3,4-Dihydro- IH-isoquinoline-2-carbonyloxy)- 14-{ 3-methyl-2-[(pyridine-3-carbonyl)-amino]-butyrylamino }-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304073) was synthesized following the same procedures as described in Example 2-19, except that 3-Methyl-2-[(pyridine-3-carbonyl)-amino]-butyric acid 2,5-dioxo-pyrrolidin-1-yl ester was used to replace N-a-t-Boc-L-valine N-hydroxysuccinamide ester instead. MS m/e 729.2 (M++1).
Example 2-23:

N
O=( O
H N O
N,.. ZLOH

Compound AR00298990 [1000] (IS, 4R, 6S, 14S, 18R)-14-(2-Amino-3-methyl-butyrylamino)-18-(3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04,6]nonadec-7-ene-4-carboxylic acid (Compound AR00298990) was prepared by following the same procedures as the Step I of Example 2-1. MS We 624.2 (M++1).

Example-12-2`4:"`

N
O-( O
O
NON,,. N \LOH

O O H

Compound AR00294378 Synthesis of (1S, 4R, 6S, 14S, 18R)-14-(3-Cyclopentyl-ureido)-18-(3,4-dihydro-lH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo [14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR294378) cp ~/N
O O NCO O-\
O
O DIEA, DCM O O
O
H2Ni,. N \\--OEt H N,., N \\-OH
2) UGH Nom( [1001] 14-Amino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[ 14.3Ø04,6]nonadec-7-ene-4-carboxylic acid ethyl ester hydrochloride salt (49 mg, 74 umol), diisopropylethylamine (29 mg, 222 umol), and cyclopentyl isocyanate (25 mg, 222 umol) were taken up in 375 uL
dichloromethane and stirred at 19 C for 1 hour. The reaction was loaded directly onto a C18 flash column and eluted with water/acetonitrile (10 to 100 %) containing 0.1% TFA to provide the title product as a white solid (42 mg, 77%). MS m/z 732.2 (MH+).

Example 2-25:

N
O
O
H H N O
~N-f N,. OH

O O
Compound AR00294377 [1002] (1S, 4R, 6S, 14S, 18R)-14-(3-tert-Butyl-ureido)-18-(3,4-dihydro-lH-isoquinoline-2-carbonyloxy)-2, l 5-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00294377) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that tert-butyl isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24 procedures. MS We 624.1 (M++1).

Example 2-26:
F
( :p N
O=<
O
O
H H N O
N"~ NJ,. -OH
O O H

Compound AR00304077 [1003] (IS, 4R, 6S, 14S, 18R)-14-(3-Cyclopentyl-ureido)-18-(5-fluoro-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304077) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 5-Fluoro-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
MS m/e 654.2 (M++ 1).

Example 2-27:

F
O= F F
O
O
H O
NN~,. N OH
O O H

Compound AR00304078 [1004] (IS, 4R, 6S, 14S, 18R)-14-(3-Cyclopentyl-ureido)-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-I H-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304078) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. MS m/e 704.1 (M++1).

Example 2-28:

PN
O=~
O
O
O
H N \\--OH
NON
O O H
Compound AR00304079 [1005] (IS, 4R, 6S, 14S, 18R)-14-(3-Cyclopentyl-ureido)-18-(1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00304079) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 2,3-dihydro-IH-isoindole was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. MS m/e 622.2 (M++1).
Example 2-29:

O=~
O
O O
H N ~-OH
NON,õ
O O N'00>
Compound AR00320078 [1006] (1S, 4R, 6S, 14S, 18R)-14-(3-tert-Butyl-ureido)-18-(1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320078) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 2,3-dihydro-1 H-isoindole was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that tert-butyl isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24 procedures. MS
m/e 610.1 (M++1).

Example 2-30:

O~N I /
O
O O`\
H W. -OH
O O N
H
Compound AR00320221 [1007] (1S, 4R, 6S, 14S, 18R)-18-(3,4-Dihydro-lH-isoquinoline-2-carbonyloxy)-2,15-dioxo-l4-[3-(tetrahydro-furan-3-yl)-ureido]-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320221) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 3-isocyanato-tetrahydro-furan was used to replace cyclopentyl isocyanate in the Example 2-24 procedures. MS m/e 638.2 (M++ 1).

Example 2-31:

CI
~- a~xl~
OY N
O

N `\
H Y-OH
W.

H
Compound AR00320449 [1008] (1S, 4R, 6S, 14S, 18R)-14-(3-tert-Butyl-ureido)-18-(5-chloro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04' 6]nonadec-7-ene-4-carboxylic acid (Compound AR00320449) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 5-chloro-2,3-dihydro- I H-isoindole was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that tert-butyl isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24 procedures. 'H
NMR (500 MHz, CD3OD): S 7.34 (s, 1H), 7.28-7.25 (m, 2H), 7.24 (s, 1H), 7.20 (s, 1H), 5.51 (m, 2H), 5.40 (s, 1H), 4.73-4.60 (m, 3H), 4.53 (t, 1H), 4.38 (d, 1H), 4.28 (d, 1H), 3.98 (dd, 1H), 2.43 (m, 2H), 2.38-2.30 (m, 1H), 2.12-2.00 (m, 2H), 1.81-1.70 (m, 1H), 1.64-1.56 (m, 3H), 1.48-1.20 (m, 8H), 1.18 (s, 9H). MS: m/e 644.0 (M+), 645.9 (M++2) Example 2-32:

CI
OYN
O
O O
N `\
JAN,.. Y--OH
H
H O N~
H
Compound AR00320450 [1009] (IS, 4R, 6S, 14S, 18R)-14-(3-tert-Butyl-ureido)-18-(5,6-dichloro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00320450) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that tert-butyl isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24 procedures. 1H NMR (500 MHz,CD3OD): S 7.50 (s, 1H), 7.38 (s, 1H), 5.56 (q, 1H), 5.42-5.38 (m, 2H), 4.72-4.61 (m, 4H), 4.55 (t, 1H), 4.34 (dd, 1H), 4.28 (d, 1H), 3.92 (dd, 1H), 2.45-2.32 (m, 2H), 2.32-2.18 (m, 1H), 2.08-2.00 (m, 1H), 1.75-1.68 (m, 1H), 1.63-1.54 (m, 3H), 1.50-1.22 (m, 8H), 1.18 (s, 9H). MS: We 678.0 (M+), 680.0 (M++2).

Example 2-33 F
iO ? N

aJN 0 N H O
OH
O
H
Compound AR00365381 [1010] (IS, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-18-(5-fluoro-1-methoxymethyl-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-ene-4-carboxylic acid (Compound AR00365381) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 5-fluoro-l-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 of Example 1-2 instead. MS (APCI-):
m/z 697.4 (M-1).

Preparation of Compounds with General Structure IV

P p 0 0 HO 1. CDI, DMF 0 O 0`S-R3 N O N NH
R4HN,,. 2. R3SO2NH2 R4HN~,.
H~ H

III IV

1f(11l ,.,Co'm p"oun"ds"' with general structure IV were prepared according to the [
scheme shown above (1. Khan et al, Bioorg. & Med. Chem. Lett., 1997, 7 (23), 3017-3022.
2. International Application PCT/US02/39926, WO 03/053349).

Example 3-1:

O~N
O O
O O O
\ NH
O H

O
H

Compound AR00261408 Synthesis of (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3Ø04'6] nonadec-7-en-18-yl ester (AR00261408) O N I/ O OC
O O O`Q
O O HO 1. CDI, DMF, 40 C
O -~I
\\\\ N \O 2. DBU, 40 C N NH
~`NO. O N,,.
O H O1, ,O H NII:~-[1012] The macrocyclic acid compound# 101 (7 mg, 0.011 mmol) was dissolved in 0.1 mL DMF, followed by addition of CDI (1.8 mg, 0.011 minol).
The mixture was stirred in a 40 C oil bath for 1 h. Then cyclopropylsulfonamide (2.0 mg, 0.017 mmol) was added to the reaction, followed by DBU (1.7 mg, 0.011 mmol). The reaction was stirred at 40 C for overnight. After 14h, LCMS showed reaction complete.
The reaction was cooled to rt, partitioned between 2 mL EA and 2 mL 5 % HC1 (aq).
The organic layer was washed with water, bicarb (2 mL ea), then dried (Na2SO4).
The crude was flashed on Biotage 12M (eluent = DCM:MeOH 20:1), giving AR00261408 (4.2 mg, 52 %) 1H NMR (CDC13, 500 MHz): 6 0.80-2.10 (m, 25H), 2.20-2.27 (m, 1H), 2.37-2.59 (m, 3H), 2.84 (m, 1H), 3.60-3.70 (m, 1H), 3.82-3.90 (m, 1H), 4.20-4.30 (m, 2H), 4.45-4.70 (m, 5H), 2H), 5.74 (m, 1H), 6.74 (m, 1H), 7.0-7.23 (m, 4H). MS
m/e 728.0 (M++H).

Example 3-2:

O~N
O
O O

N
O\\ \ NH
O HIS.
N">
O H

Compound AR00261407 [1013] 1S, 4R, 6S, 145, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarb onyl amino-2,15 -dioxo-4-(propane-2-sulfonylamino carbonyl)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00261407) was synthesized according to the procedures described in Example 3-1, except that isopropyl sulfonamide was used to replace cyclopropyl sulfonamide in the coupling step. MS m/e 728.4 (M-1).
Example 3-3:

OYN
O
O
' O O
N O \~-NiH
O H1,.
O H
Compound AR00254906 [1014] 1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-methanesulfonylamino carb onyl-2,15 -dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00254906) was synthesized according to the procedures described in Example 3-1, except that methyl sulfonamide was used to replace cyclopropyl sulfonamide in the coupling step. 1H NMR (CDC13, 500 MHz):
1.20-1.52 (m, 16H), 1.54-1.98 (m, 5H), 2.20-2.30 (m, 1H), 2.38-2.46 (m, 1H), 2.47-2.59 (m, 3H), 2.84 (m, 1H), 3.18 (s, 3H), 3.56-3.70 (m, 1H), 3.82-3.90 (m, 1H), 4.22-4.33 (m, 2H), 4.47-4.69 (m, 4H), 4.90-5.10 (m, 2H), 5.47 (brs, I H), 5.74 (m, 1H), 6.74 (m, I H), 7.03-7.23 (m, 4H). MS m/e 701.9 (M), 602.2 (parent, MH+-Boc group).

Example 3-4:

O'Y N 01 O O
O O O O, i DH,,. H
qO
Compound AR00261409 [1015] (IS, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-(butane- l-sulfonylaminocarbonyl)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00261409) was synthesized according to the procedures described in Example 3-1, except that n-butyl sulfonamide was used to replace cyclopropyl sulfonamide in the coupling step. 1H NMR (CDC13, 500 MHz):
80.80-1.03 (m, 7H), 1.20-2.10 (m, 22H), 2.20-2.60 (m, 4H), 2.84 (m, 1H), 3.20 (m, I H), 3.44 (m, 1H), 3.65 (m, IH), 3.80-3.95 (m, 1H), 4.20-4.34 (m, 2H), 4.50-4.65 (m, 4H), 4.95-5.05 (m, 1H), 5.30-5.39 (m, 1H), 5.44-5.49 (m, 1H), 5.74 (m, 1H), 6.74 (m, 1H), 7.0-7.23 (m, 4H). MS We 743.3 (M+, APCI-).

Example 3-5:

OON I /
O
O O O O`SO
- N ~-NH
O N,,.

H
Compound AR00282131 [1016] (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00282131) was synthesized according to the procedures described in Examples 2-1 and 3-1. MS
We 738.4 (M-1).

Example 3-6:

O.Y N
O
O
O O O`\ O` S
H N Y NH
W.

H
Compound AR00294381 [1017] (1S, 4R, 6S, 14S, 18R)-1,3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00294381) was synthesized according to the procedures described in Examples 1-5 and 3-1. 'H NMR (CDC13, MHz): 8 0.89-2.08 (m, 25H), 2.21-2.28 (m, 1H), 2.41-2.49 (m, 1H), 2.51-2.61 (m, 2H), 2.91 (m, 1H), 3.83 (m, 1H), 4.21 (m, 1H), 4.40 (d, J = 11.7 Hz, 1H), 4.53-4.80 (m, 5H), 4.95-5.04 (m, 2H), 5.47 (brs, 1H), 5.72 (m, 1H), 6.77 (m, 1H), 7.16 (m, 1H), 7.23-7.31 (m, 3H). MS
m/e 712.3 (APCI-, M-H).

Example 3-7:
F
Oy O
O O O S
N O=-<
OHi,. H
N
H
Compound AR00298996 [1018] (IS, 4R, 6S, 14S, 18R)-5-Fluoro-3,4-dihydro-IH-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00298996) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 5-Fluoro-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 'H NMR (400 MHz, CDCl3): 810.05 (s, 1H), 8.12 (s, IH), 7.04 (s, 1H), 6.84-6.73 (m, 2H), 6.70 (s, 1H), 5.65 (q, IH), 5.40 (s, IH), 4.59 (m, 2H), 4.54-4.40 (m, 3H), 4.30-4.10 (m, 2H), 3.82-3.74 (m, 1H), 3.72-3.51 (m, 2H), 2.92-2.68 (m, 3H), 2.55-2.30 (m, 3H), 2.21-2.15 (m, 1H), 2.00-1.60 (m, 3H), 1.40-0.75 (m, 18H). MS:
m/e 746.0 (M+).

Example 3-8:

O,~, N I /
F F
O O~NH F
N

~ O O
H

Compound AR00298997 [1019] (1S, 4R, 6S, 14S, 18R)-8-Trifluoromethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound AR00298997) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 'H NMR (500 MHz, CD3OD): S 7.55 (dd, 1H), 7.42 (dd, IH), 7.35 (t, 1H), 5.71-5.61 (m, 1H), 5.40 (m, 1H), 4.60 (s, 1H), 4.52 (m, 1H), 4.42 (m, 1H), 4.15 (m, IH), 3.91 (m, IH), 3.78-3.62 (m, 2H), 3.00-2.82 (m, 3H), 2.58-2.52 (m, 3H), 2.51-2.32 (m, 2H), 1.86-1.56 (m, 3H), 1.41 (m, 2H), 1.32-1.21 (m, 5H), 1.04-0.98 (m, 14H).
MS: m/e 795.9 (M+).

Example 3-9:

Y O
O
O O N O 0_S-<
W. N

H
O

Compound AR00301746 [1020] (1S, 4R, 6S, 14S, 18R)-7-Chloro-3,4-dihydro-lH-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04' 6]nonadec-7-en-18-yl ester (Compound AR00301746) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 7-chloro-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 'H NMR (400 MHz, CDC13): 6 10.10 (s, 1H), 7.08 (d, 1H), 7.02-6.96 (m, 2H), 6.60 (d, 1H), 5.64 (q, 1H), 5.40 (s,1H), 4.92-4.41 (m, 2H), 4.55-4.40 (m, 3H), 4.28-4.12 (m, 2H), 3.82-3.75 (m, 1H), 3.65-3.46 (m, 3H), 2.88-2.80 (m, 1H), 2.78-2.56 (m, 2H), 2.52-2.42 (m, 1H), 2.38-2.30 (m, 1H), 2.21-2.12 (q, 1H), 1.82-1.74 (m, 2H), 1.45-1.12 (m, 16H), 1.10-0.98 (m, 2H), 0.90-0.75 (m, 2H). MS m/e 761.9 (M+) Example 3-10:
F F
F
OYN I /
O
O O O O,S
~~Nr,. NH
N
H
Compound AR00301747 [10211 (IS, 4R, 6S, 14S, 18R)-6-Trifluoromethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00301747) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 1H NMR (500MHz, CD3OD): S 7.44 (m, 2H), 7.38-7.30 (m, I H), 7.28-7.24 (m, I H), 5.65 (q, 1H), 5.40 (m, 1H), 5.08 (m, I H), 4.56 (brs, 2H), 4.60-4.50 (m, 1H), 4.48 (m, 1H), 4.15 (d, 1H), 3.88 (d, 1H), 3.75-3.67 (m, 2H), 2.93-2.82 (m, 3H), 2.66-2.54 (m, 1H), 2.52-2.44 (m, 1H), 2.42-2.40 (m, 2H), 1.91-1.76 (m, 2H), 1.74-1.70 (dd, I H), 1.64-1.58 (m, I H), 1.54-1.36 (m, 4H), 1.34-1.25 (m, 12H), 1.50-1.20 (m, 2H), 1.00-0.70 (m, 1H), 0.52-0.34 (m, 1H). MS: m/e 795.9 (M+) Example 3-11:

Y N I /
O
\\\\ 0 l_N,,o N ~V -S-<

H N H

H

Compound AR00301751 [1022] (1S, 4R, 6S, 145, 18R)-6-Fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound AR00301751) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 6-fluoro-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 'H NMR (500 MHz, CD3OD): S 7.21-7.02 (m, 1H), 6.92 (m, 2H), 6.92 (m, 2H), 5.68 (q, 1H), 5.40 (m, 1H), 5.08 (t, 1H), 4.58 (m, 2H), 4.45 (m, 1H), 4.12 (d, 1H), 3.88 (d, 1H), 3.78-3.60 (m, 3H), 2.86-2.72 (m, 3H), 2.71-2.61 (m, 1H), 2.52-2.42 (m, 1H), 2.41-2.34 (m, 1H), 1.88-1.76 (m, 2H), 1.74-1.70 (m, 1H), 1.64-1.58 (m, 1H), 1.56-1.38 (m, 2H), 1.37-1.24 (m, 14H), 1.13-1.04 (m, 2H), 1.02-0.89 (m, 1H), 0.88-0.82 (m, 1H). MS:
m/e 746.0 (M+). MS m/e 757.2 (M++1).

Example 3-12:
F
N
O~
O

H O
NW. N )---N
H

Compound AR00304080 [1023] (IS, 4R, 6S, 14S, 18R)-5-Fluoro-3,4-dihydro-IH-isoquinoline-2-carboxylic acid 14-(3-cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound AR00304080) was synthesized according to the procedures described in Examples 1-2, 2-24 and 3-1, except that 5-fluoro- 1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2.

Example 3-13:

N F
O=< F F
p H O $RS
NOH S--'q O O H-tl~
Compound AR00304081 [1024] (1S, 4R, 6S, 14S, 18R)-8-Trifluoromethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid 14-(3-cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00304081) was synthesized according to the procedures described in Examples 1-2, 2-24 and 3-1, except that 8-trifluoromethyl- 1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. MS m/e 807.2 (M++1).

Example 3-14:

PN
O~
O O
O O "'S-<
HN~õ N -NFi N
O O H
Compound AR00304082 [1025] (1S, 4R, 6S, 14S, 18R)-1,3-Dihydro-isoindole-2-carboxylic acid 14-(3-cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound AR00304082) was synthesized according to the procedures described in Examples 1-2, 2-24 and 3-1, except 2,3-Dihydro-1H-isoindole was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
MS We 725.2 (M++1).

Example 3-15:

N
O=<
O

H
O W. N N
F H
O O H~
Compound AR00304161 [1026] (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14-(2-fluoro-ethoxycarbonylamino)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00304161) was synthesized according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 2-fluoroethanol was used to form the chloroformate reagent in Step 2 of Example 2-1, instead of cyclopentanol. MS m/e 718.1 (M++1).

Example 3-16:

N
O=( O
O O OO
H
ONt, N '-N'S
H
O O H
Compound AR00304162 [1027] (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydro-furan-3-yloxycarbonylamino)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00304162) was synthesized according to the procedures described in Examples 1-2, 2-1 and 3-1, except that tetrahydro-furan-3S-ol was used to form the chloroformate reagent in Step 2 of Example 2-1, instead of cyclopentanol. MS m/e 742.1 (M++1).

Example 3-17:

N
O=<
H p O OO
NH
p^.., O O H~
Compound AR00304163 [1028] (IS, 4R, 6S, 14S, 18R)-3,4-Dihydro-IH-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydro-furan-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00304163) was synthesized according to the procedures described in Examples 1-2, 2-1 and 3-1, except that tetrahydro-furan-3R-ol was used to form the chloroformate reagent in Step 2 of Example 2-1, instead of cyclopentanol. 'H NMR (d6-Benzene, 500 MHz):
S 10.53 (s, I H), 6.78-6.96 (m, 4 H), 5.83-5.90 (m, 1 H), 5.66 (q, 1 H), 5.18-5.21 (m, I H), 5.13 (brs, I H), 5.04 (brs, 1 H), 4.41-4.87 (m, 3 H), 3.85-4.05 (m, 4 H), 3.67-3.74 (m, I
H), 3.46-3.53 (m, 3 H), 3.23-3.34 (m, 1 H), 2.80-2.85 (m, 1 H), 2.34-2.59 (m, 4 H), 1.84-1.99 (m, 4 H), 0.98-1.60 (m, 14 H), 0.42-0.47 (m, 1 H), 0.27-0.32 (m, I H). MS m/e 741.2 (M-1).

Example 3-18:

p O--'- N S
/>--NH
N

N, pAN H'S
H

Compound AR00311814 [1029] (IS, 4R, 6S, 14S, 18R)-2-Phenylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-en-18-yI ester (Compound AR00311814) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that phenyl-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. MS We 826.2 (M+1).

Example 3-19:

O NDI
O-'-N

O O
N,, 0 O N NHS O
H X
Compound AR00311815 [1030] (1 S, 4R, 6S, 14S, 18R)-1-Piperidin-1-ylmethyl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-en-18-yI ester (Compound AR00311815) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 1-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
'H NMR (500 MHz, CD3OD) 8 8.94 (d, IH), 7.59 (s, 1H), 7.31 - 7.23 (m, 3H), 7.22 - 7.15 (m, 2H), 5.74-5.64 (m, 2H), 5.47 (br s, 1H), 5.06 (t, 1H), 4.54 (dt, 1H), 4.40 - 4.17 (m, 4H), 4.11 - 4.04 (m, 111), 3.96 - 3.88 (m, 1H), 3.75 - 3.40 (m, 5H), 3.14 - 2.32 (m, 7H), 2.05 (dd, IH), 1.99 - 1.68 (m, 5H), 1.65 - 0.95 (m, 24H); MS (POS ESI) m/z 825.4 (M+).

Example 3-20:

N
O=<
O
O
N O
HN. \\-NH
O0 O H~
Compound AR00312024 [1031] (1S, 4R, 6S, 14S, 18R)-4,4-Spirocyclobutyl-3,4-dihydro-IH-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound AR00312024) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 4,4-spirocyclobutyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 'H NMR (400 MHz, CD3OD) &7.54-7.60 (m, 1H), 7.26 (dd, 1H), 6.97-7.21 (m, 1H), 5.66 (dd, 1H), 5.37-5.48 (m, 1H), 5.11 (dd, 1H), 4.58 (s, 2H), 4.39 (t, 3H), 4.11-4.26 (m, 1H), 3.77-3.96 (m, 1H), 3.87 (t, 311), 3.60-3.70 (m, 1H), 2.83-2.93 (m, 1H), 2.23-2.68 (m, 6H), 1.70-2.23 (m, 7H), 1.18-1.69 (m, 18H), 0.81-1.12 (m, 3H). MS m/z 767.9 (M++1) Example 3-21:

O=<
O
O O
O
HNC,. N -NH
Compound AR00312025 [10321 (IS, 4R, 6S, 14S, 18R)-4,4-Dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound AR00312025) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 4,4-dmethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 'H NMR (400 MHz, CD3OD) S 7.31-7.40 (m, 1H), 6.97-7.23 (m, 3H), 5.67 (dd, 1H), 5.34-5.49 (m, 1H), 5.09 (dd, 1H), 4.64 (s, 1H), 4.50-4.61 (m, 1H), 4.33-4.44 (m, 3H), 4.11-4.24 (m, 1.0), 3.82-3.95 (m, 3H), 3.36-3.55 (m, 2H), 2.84-2.94 (m, 1H), 2.25-2.69 (m, 4H), 1.68-2.24 (m, 4H), 1.15-1.68 (m, 23H), 0.81-1.15 (m, 3H).
MS m/z 756.0 (M++1) Example 3-22:

N
O=<
O O
O
HNC,. N -NH
Compound AR00312026 [1033] (IS, 4R, 6S, 145, 18R)-4-Methyl-3,4-dihydro-IH-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-7-en-18-y1 ester (Compound AR00312026) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 4-methyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. 'H NMR (400 MHz, CD3OD) S 7.76 (s, 1H), 6.98-7.24 (m, 3H), 5.67 (dd, 1H), 5.2-5.51 (m, 1H), 5.04-5.15 (dd, 1H), 4.28-4.63 (m, 5H), 4.10-4.24 (m, 1H), 3.81-3.96 (m, 3H), 3.37-3.78 (m, 2H), 2.83-3.06 (m, 2H), 2.54-2.71 (m, 1H), 2.25-2.54 (m, 3H), 1.69-1.94 (m, 3H), 1.16-1.69 (m, 20H), 0.81-1.15 (3H). MS m/z 742.0 (M++1) Example 3-23:

N
O=<
p O O
H N O
.O-If N,,, '-NH
OD O O H
Compound AR00314635 [1034] (IS, 4R, 6S, 14S, 18R)-4,4-Spirocyclobutyl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-(tetrahydro-furan-3-yloxycarbonylamino)-3,16-diaza-tricyclo[
14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00314635) was synthesized according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 4,4-spirocyclobutyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and tetrahydro-furan-3R-ol was used to replace cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. 'H NMR (500 MHz, CD2CI2) S 10.24-10.29 (s, 1H), 7.49-7.55 (m, 1H), 7.24 (dd, 1H), 7.14 (dd, 1H), 7.04 (dd, 1H), 6.81 (d 1H), 5.71 (dd, 1H), 4.95 (dd, 1H), 4.90 (bs, 1H), 4.48-4.59 (m, 3H), 4.17-4.30 (m, 2H), 3.51-3.74 (m, 3H), 3.51-3.72 (6H), 2.80-2.86 (m, 1H), 2.36-2.54 (m, 3H), 2.10-2.33 (m, 411), 1.80-2.10 (m, 6H), 1.24-1.80 (m, 7H), 0.65-1.24 (m, l OH). MS m/z 741.2 (M++ 1) Example 3-24:

N
O=<
O
H O O OAS
O~N~,. N NH
O~ O O H' Compound AR00314654 [1035] (1S, 4R, 6S, 14S, 18R)-4,4-Dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydro-furan-3S-yloxycarbonylamino)-3,16-diaza-tricyclo[ 14.3 Ø046]nonadec-7-en-18-yl ester (Compound AR00314654) was synthesized according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and tetrahydro-furan-3S-ol was used to replace cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. 'H NMR
(500 MHz, CD2C12) S 8.51-8.64 (bs, 1H), 7.26-7.36 (m, 1H), 7.09-7.19 (m, 2H), 6.98-7.08 (m, 1H), 5.70 (dd, 1H), 4.95 (dd, 111), 4.83 (d, 1H), 4.44-4.72 (m, 3H), 4.17-4.30 (m, 2H), 3.25-3.91 (m, 911), 2.80-2.86 (m, 1H), 2.35-2.55 (m, 4H), 2.13-2.34 (m, 4H), 1.91-2.07 (m, 2H), 1.80-1.90 (m, 2H), 1.66-1.80 (m, 2H), 1.51-1.63 (m, 2H), 1.30-1.51 (m, 2H), 0.96-1.15 (m, 3H), 0.65-0.95 (m, 9H). MS m/z 770.1 (M++1) Example 3-25:

N
O=~
H H O 0 p~,S
NH
O p H

Compound AR00314656 [1036] (1S, 4R, 6S, 14S, 18R)-4-Methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-(3-tert-butyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3Ø04'6]nonadec-7-en-18-yl ester (Compound AR00314656) was synthesized according to the procedures described in Examples 1-2, 2-24 and 3-1, except that 4-methyl-1,2,3,4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and t-butyl isocyanate was used to replace cyclopentyl isocyanate in Example 2-24. 1H NMR (500 MHz, CD2CI2) 6 7.60-7.72 (m, 1H), 7.06-7.48 (m, 4H), 5.73 (dd, 111), 5.39-5.48 (m 1H), 5.18-5.27 (bs 1H), 4.98 (dd, 1H), 4.79-4.90 (bs, 1H), 4.30-4.72 (m, 4H), 3.40-3.77 (m, 5H), 2.97 (d, 1H), 2.83-2.90 (m, 1H), 2.37-2.58 (m, 3H), 2.17-2.30 (dt, 1H), 2.22-2.35 (dt, 1H), 1.97-2.07 (m, 1H), 1.82-1.95 (m, 2H), 1.68-1.79 (m, 1H), 1.55-1.66 (m, 2H), 1.05-1.55 (m, 15H), 0.83-0.98 (m, 3H). MS m/z 741.2 (M++1) Example 3-26:

O-YN I /
O

) N,,. N Z~-NH
O
H

H
Compound AR00314719 [1037] (1S, 4R, 6S, 14S, 18R)-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ 14.3Ø04'6]nonadec-18-yl ester (Compound AR00314719) was synthesized DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

THIS IS VOLUME OF _2 NOTE: For additional volumes please contact the Canadian Patent Office.

Claims (255)

1. A compound having the Formula I:
or a pharmaceutically acceptable salt thereof, 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, pyridyl, pyrimidyl, 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, naphthyl, 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, naphthyl, 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, C4-20 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 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 C1-6 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 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;
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; 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 tetrahydropyran ring linked through the C4 position of the tetrahydropyran 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 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 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, 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 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 NR1a R1b is a three- to six- membered alkyl cyclic 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 NR1a R1b 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 R1a 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 0, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 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, or 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 pyridyl, pyrimidyl, 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, with respect to Formula II, III, and IV:
(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, pyridyl, pyrimidyl, 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, (CH2)n NR6R7, O(CH2)n NR6R7, or O(CH2)n R9 where R9 is imidazolyl or pyrazolyl; said thienyl, pyrimidyl, 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, 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, pyridyl, 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 C1-6 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, 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;

(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 tetrahydropyran ring linked through the C4 position of the tetrahydropyran 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, C1-6 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, 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, 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, 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 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, 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 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, 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; 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, 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, 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, C4-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, or 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 pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
(qq) 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; and (rr) Z is a fused or appended aryl or heteroaryl ring system.

2. The compound or salt thereof of Claim 1, wherein the core ring is:

3. The compound or salt thereof of Claim 1, wherein the core ring is:

4. The compound or salt thereof of Claim 1, wherein the core ring is:

5. The compound or salt thereof of Claim 1 of the formula Ia:

6. The compound or salt thereof of Claim 1 of the formula Ib:

7. The compound or salt thereof of Claim 1 of the formula Ic:

8. The compound or salt thereof of Claim 1 of the formula Id:

9. The compound or salt thereof of Claim 1 of the formula Ie:

10. The compound or salt thereof of Claim 1 of the formula If:

11. The compound or salt thereof of Claim 1 of the formula Ig:

12. The compound or salt thereof of Claim 1 of the formula Ih:

13. The compound or salt thereof of Claim 1 of the formula Ii:

14. The compound or salt thereof of Claim 1 of the formula Ij:

15. The compound or salt thereof of Claim 1 of the formula Iz:

16. The compound or salt thereof of any one of Claims 1 to 15, wherein Y is sulfonimide of the formula -C(O)NHS(O)2R9, where R9 is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, and NR1a R1b, wherein R1a and R1b are each independently H, C1-6 alkyl, or C3-7 cycloalkyl.

17. The compound or salt thereof of any one of Claims 1 to 16, wherein the C13-C14 double bond is cis.

18. The compound or salt thereof of any one of Claims 1 to 16, wherein the C13-C14 double bond is trans.

19. A pharmaceutical composition comprising:
a) the compound or salt thereof of any one of Claims 1 to 18; and b) a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of Claim 19 in a formulation free of any alcohol and any poly-ol.

21. The pharmaceutical composition of Claim 20, wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).

22. The pharmaceutical composition of Claim 19 in an aqueous formulation free of any excipient that reduces polarity in the aqueous formulation.

23. The pharmaceutical composition of any one of Claims 19 to 22 in a tablet formulation.

24. The pharmaceutical composition of any one of Claims 19 to 22 in a caplet formulation.

25. The pharmaceutical composition of any one of Claims 19 to 22 in a capsule formulation.

26. Use of the compound or salt thereof of any one of Claims 1 to 18 for treating a hepatitis C virus infection in an individual.

27. Use of the compound or salt thereof of any one of Claims 1 to 18 for preparation of a medicament for treating a hepatitis C virus infection in an individual.

28. The use of Claim 26 or 27, wherein the compound is for achieving a sustained viral response.

29. The use of Claim 26, 27 or 28, wherein the compound is for use with a nucleoside analog.

30. The use of Claim 29, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

31. The use of any one of Claims 26 to 30, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

32. The use of any one of Claims 26 to 31, wherein the compound is for use with thymosin-.alpha..

33. The use of Claim 32, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

34. The use of any one of Claims 26 to 33, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

35. The use of Claim 34, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µ about 300 µ

36. The use of any one of Claims 26 to 35, wherein the compound is for use with interferon-alpha (IFN-.alpha.).

37. The use of Claim 36, wherein the IFN-.alpha.oPEG (30 kD, linear)-ylated consensus IFN-.alpha.ministration at a dosing interval of every 8 days to every 14 days.

38. The use of Claim 36, wherein the IFN-.alpha. is monoPEG(30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

39. The use of Claim 36, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

40. The use of any one of Claims 26 to 39, wherein the compound is for use with 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.

41. Use of the compound or salt thereof of any one of Claims 1 to 18 for treating liver fibrosis in an individual.

42. Use of the compound or salt thereof of any one of Claims 1 to 18 for preparation of a medicament for treating liver fibrosis in an individual.

43. The use of Claim 41 or 42, wherein the compound is for use with a nucleoside analog.

44. The use of Claim 43, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

45. The use of any one of Claims 41 to 44, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

46. The use of any one of Claims 41 to 45, wherein the compound is for use with thymosin-.alpha..

47. The use of Claim 46, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

48. The use of any one of Claims 41 to 47, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

49. The use of Claim 48, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µg to about 300 µg.

50. The use of any one of Claims 41 to 49, wherein the compound is for use with interferon-alpha (IFN-.alpha.).

51. The use of Claim 50, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of every 8 days to every 14 days.

52. The use of Claim 50, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

53. The use of Claim 50, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

54. The use of any one of Claims 41 to 53, wherein the compound is for use with 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.

55. Use of the compound or salt thereof of any one of Claims 1 to 18 for increasing liver function because of a hepatitis C virus infection.

56. Use of the compound or salt thereof of any one of Claims 1 to 18 for preparation of a medicament for increasing liver function because of a hepatitis C virus infection.

57. The use of Claim 55 or 56, wherein the compound is for use with a nucleoside analog.

58. The use of Claim 57, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

59. The use of any one of Claims 55 to 58, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

60. The use of any one of Claims 55 to 59, wherein the compound is for use with thymosin-.alpha..

61. The use of Claim 60, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

62. The use of any one of Claims 55 to 61, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

63. The use of Claim 62, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µg to about 300 µg.

64. The use of any one of Claims 55 to 63, wherein the compound is for use with interferon-alpha (IFN-.alpha.).

65. The use of Claim 64, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of every 8 days to every 14 days.

66. The use of Claim 64, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

67. The use of Claim 64, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

68. The use of any one of Claims 55 to 67, wherein the compound is for use with 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:

or a pharmaceutically acceptable salt thereof, 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 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 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 NR1a R1b is a three- to six- membered alkyl cyclic 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 NR1a R1b 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) V is selected from O, S, or NH;
(c) 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, C4-10 alkylcycloalkyl, or C1-6 alkyl optionally substituted with up to 5 fluoro;

(d) R2 is a bicyclic amine with the structure of wherein R21 and R22 are each independently H, halo, cyano, nitro, hydroxy, C1-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, pyridyl, pyrimidyl, 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, pyrimidyl, 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, pyridyl, 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-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, 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, 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, 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 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-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, 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, 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, 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 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 C4-10 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 fluoro, or C1-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or 10 aryl, in the definition of R20 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 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;
or R2 is R2a R2b 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, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR2c R2d, 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 NR2c R2d, 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 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;
(e) 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;
(f) R5 is H, C1-6 alkyl, C(O)NR6R7, C(S)NR6R7, C(O)R8, C(O)OR8, or S(O)2R8;
(g) 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 (h) the dashed line represents an optional double bond.

70. The compound of Claim 1 having the Formula XII:
XII
or a pharmaceutically acceptable salt thereof, 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;
or NR1a R1b is a three- to six- membered alkyl cyclic 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-tetrahydrofuryl;
(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, 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 1 having the Formula XIII:

or a pharmaceutically acceptable salt thereof, 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 R10 is H;
or NR1a R1b is a three- to six- membered alkyl cyclic 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-tetrahydrofuryl;
and (f) the dashed line represents an optional double bond.

72. The compound of Claim 1 having the Formula XIV:

or a pharmaceutically acceptable salt thereof, 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 a group consisting of:

wherein R1c is H;
or NR1a R1b is a three- to six- membered alkyl cyclic 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) R2a is C6 or C10 aryl optionally substituted with up to three NR2c R2d, 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;
(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. A pharmaceutical composition comprising:
a) the compound or salt thereof of any one of Claims 69 to 72; and b) a pharmaceutically acceptable carrier.

74. The pharmaceutical composition of Claim 73 in a formulation free of any alcohol and any poly-ol.

75. The pharmaceutical composition of Claim 74, wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).

76. The pharmaceutical composition of Claim 73 in an aqueous formulation free of any excipient that reduces polarity in the aqueous formulation.

77. The pharmaceutical composition of any one of Claims 73 to 76 in a tablet formulation.

78. The pharmaceutical composition of any one of Claims 73 to 76 in a caplet formulation.

79. The pharmaceutical composition of any one of Claims 73 to 76 in a capsule formulation.

80. Use of the compound or salt thereof of any one of Claims 69 to 72 for treating a hepatitis C virus infection in an individual.

81. Use of the compound or salt thereof of any one of Claims 69 to 72 for preparation of a medicament for treating a hepatitis C virus infection in an individual.

82. The use of Claim 80 or 81, wherein the compound is for achieving a sustained viral response.

83. The use of Claim 80 or 82, wherein the compound is for use with a nucleoside analog.

84. The use of Claim 83, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

85. The use of any one of Claims 80 to 84, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

86. The use of any one of Claims 80 to 84, wherein the compound is for use with thymosin-.alpha..

87. The use of Claim 86, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

88. The use of any one of Claims 80 to 87, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

89. The use of Claim 88, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µg to about 300 µg.

90. The use of any one of Claims 80 to 89, wherein the compound is for use with interferon-alpha(IFN-.alpha.).

91. The use of Claim 90, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of every 8 days to every 14 days.

92. The use of Claim 90, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

93. The use of Claim 90, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

94. The use of any one of Claims 80 to 93, wherein the compound is for use with 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.

95. Use of the compound or salt thereof of any one of Claims 69 to 72 for treating liver fibrosis in an individual.

96. Use of the compound or salt thereof of any one of Claims 69 to 72 for preparation of a medicament for treating liver fibrosis in an individual.

97. The use of Claim 95 or 96, wherein the compound is for use with a nucleoside analog.

98. The use of Claim 97, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

99. The use of any one of Claims 95 to 98, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

100. The use of any one of Claims 95 to 99, wherein the compound is for use with thymosin-.alpha..

101. The use of Claim 100, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

102. The use of any one of Claims 95 to 101, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

103. The use of Claim 102, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µg to about 300 µg.

104. The use of any one of Claims 95 to 103, wherein the compound is for use with interferon-alpha (IFN-.alpha.).

105. The use of Claim 104, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of every 8 days to every 14 days.

106. The method of Claim 104, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

107. The use of Claim 104, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

108. The use of any one of Claims 95 to 107, wherein the compound is for use with 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.

109. Use of the compound or salt thereof of any one of Claims 69 to 72 for increasing liver function because of a hepatitis C virus infection.

110. Use of the compound or salt thereof of any one of Claims 69 to 72 for preparation of a medicament for increasing liver function because of a hepatitis C virus infection.

111. The use of Claim 109 or 110, wherein the compound is for use with a nucleoside analog.

112. The use of Claim 111, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

113. The use of any one of Claims 109 to 112, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

114. The use of any one of Claims 109 to 113, wherein the compound is for use with thymosin-.alpha..

115. The use of Claim 114, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

116. The use of any one of Claims 109 to 115, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

117. The use of Claim 116, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µg to about 300 µg.

118. The use of any one of Claims 109 to 117, wherein the compound is for use with interferon-alpha (IFN-.alpha.).

119. The use of Claim 118, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of every 8 days to every 14 days.

120. The use of Claim 118, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

121. The use of Claim 118, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

122. The use of any one of Claims 109 to 121, wherein the compound is for use with 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, naphthyl, 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, naphthyl, 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, 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;
(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 or salt thereof of Claim 123, wherein R1 is phenyl, benzothiazole, benzothiophene, benzofuran, or benzimidazole, each optionally substituted with up to 1-2 NR5R6, halo, cyano, nitro, 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, 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;

R3 is H;
R4 is C1-6 alkyl, C(O)NR5R6, C(S)NR5R6, C(O)R, 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 or salt thereof 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, 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, 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 or salt thereof of Claim 123, 124 or 125; 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 any one of Claims 126 to 129 in a tablet formulation.

131. The pharmaceutical composition of any one of Claims 126 to 129 in a caplet formulation.

132. The pharmaceutical composition of any one of Claims 126 to 129 in a capsule formulation.

133. Use of the compound or salt thereof of Claim 123, 124 or 125 for treating a hepatitis C virus infection in an individual.

134. Use of the compound or salt thereof of Claim 123, 124 or 125 for preparation of a medicament for treating a hepatitis C virus infection in an individual.

135. The use of Claim 133 or 134, wherein the compound is for achieving a sustained viral response.

136. The use of Claim 133, 134 or 135, wherein the compound is for use with a nucleoside analog.

137. The use of Claim 136, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

138. The use of any one of Claims 133 to 137, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

139. The use of any one of Claims 133 to 138, wherein the compound is for use with thymosin-.alpha..

140. The use of Claim 139, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

141. The use of any one of Claims 133 to 140, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

142. The use of Claim 141, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µg to about 300 µg.

143. The use of any one of Claims 133 to 142, wherein the compound is for use with interferon-alpha (IFN-.alpha.).

144. The use of Claim 143, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of every 8 days to every 14 days.

145. The use of Claim 143, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

146. The use of Claim 143, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

147. The use of any one of Claims 133 to 146, wherein the compound is for use with 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.

148. Use of the compound or salt thereof of Claim 123, 124 or 125 for treating liver fibrosis in an individual.

149. Use of the compound or salt thereof of Claim 123, 124 or 125 for preparation of a medicament for treating liver fibrosis in an individual.

150. The use of Claim 148 or 149, wherein the compound is for use with a nucleoside analog.

151. The use of Claim 150, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

152. The use of any one of Claims 148 to 151, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

153. The use of any one of Claims 148 to 152, wherein the compound is for use with thymosin-.alpha..

154. The use of Claim 153, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

155. The use of any one of Claims 148 to 154, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

156. The use of Claim 155, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µg to about 300 µg.

157. The use of any one of Claims 148 to 156, wherein the compound is for use with interferon-alpha (IFN-.alpha.).

158. The use of Claim 157, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of every 8 days to every 14 days.

159. The use of Claim 157, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

160. The use of Claim 157, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

161. The use of any one of Claims 148 to 160, wherein the compound is for use with 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.

162. Use of the compound or salt thereof of claim 123, 124 or 125 for increasing liver function because of a hepatitis C virus infection.

163. Use of the compound or salt thereof of claim 123, 124 or 125 for preparation of a medicament for increasing liver function because of a hepatitis C virus infection.

164. The use of Claim 162 or 163, wherein the compound is for use with a nucleoside analog.

165. The use of Claim 164, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

166. The use of any one of Claims 162 to 165, wherein the compound is for use with a NS5B RNA-dependent RNA polymerase inhibitor.

167. The use of any one of Claims 162 to 166, wherein the compound is for use with thymosin-.alpha..

168. The use of Claim 167, wherein the thymosin-.alpha. is for administration subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

169. The use of any one of Claims 162 to 168, wherein the compound is for use with interferon-gamma (IFN-.gamma.).

170. The use of Claim 169, wherein the IFN-.gamma. is for administration subcutaneously in an amount of from about 10 µg to about 300 µg.

171. The use of any one of Claims 162 to 170, wherein the compound is for use with interferon-.alpha (IFN-.alpha.).

172. The use of Claim 171, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of every 8 days to every 14 days.

173. The use of Claim 171, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration at a dosing interval of once every 7 days.

174. The use of Claim 171, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

175. The use of any one of Claims 162 to 174, wherein the compound is for use with 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.

176. A compound of the formula:

or a pharmaceutically acceptable salt thereof, 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, G1y58, 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, Va178, 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, 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; 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 tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
with the proviso that the compound does not include a compound having the Formula II, III, or IV:

wherein, with respect to Formula II, III, and IV:
(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, pyridyl, pyrimidyl, 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 (CH2)n NR6R7, O(CH2)n NR6R7, or O(CH2)n R9 where R9 is imidazolyl or pyrazolyl; said thienyl, pyrimidyl, 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, 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, pyridyl, 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 C1-6 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, 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;
(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 tetrahydropyran ring linked through the C4 position of the tetrahydropyran 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, C1-6 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, 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, 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, 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 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, 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 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, C3-7 cycloalkyl, C4-lo 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, 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, 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, C4-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, or 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 pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
(qq) 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; and (rr) Z is a fused or appended aryl or heteroaryl ring system;
with the proviso that the compound does not include a compound having the formula:

177. The compound or salt thereof of Claim 176 of the formula

178. The compound or salt thereof of Claim 176 of the formula

179. The compound or salt thereof of Claim 176, 177 or 178, in which L
consists of from 2 to 5 atoms.

180. The compound or salt thereof of Claim 176, 177 or 178, in which L
comprises a -W-C(=V)- group, where V and W are each individually selected from O, S or NH.

181. The compound or salt thereof of Claim 176, 177 or 178, in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.

182. The compound or salt thereof of Claim 176, 177 or 178, wherein L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of nitrogen, hydrogen and sulfur.

183. The compound or salt thereof of any one of Claims 176 to 182 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.

184. The compound or salt thereof of Claim 179 in which L is selected from the group consisting of -OCH2- and -NHCH2-.

185. The compound or salt thereof of Claim 179 in which L is selected from the group consisting of -CH=CH- and -C.ident.C-.

186. The compound or salt thereof of Claim 179 in which L is selected from the group consisting of -SCH2-, -SO2-, and -CH2SO-.

187. The compound or salt thereof of Claim 179 in which L is selected from the group consising of -WC(=V)-NH- and -WC(=V)-O-, where V and W are each individually selected from O, S or NH.

188. The compound or salt thereof of any one of Claims 176 to 186, wherein the C13-C14 double bond is cis.

189. The compound or salt thereof of any one of Claims 176 to 186, wherein the C13-C14 double bond is trans.

190. The compound or salt thereof of any one of Claims 176 to 189, wherein P2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle.

191. The compound or salt thereof of anyone of Claims 176 to 189, in which P2 is

192. A compound having the formula:
or a pharmaceutically acceptable salt thereof, 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, pyridyl, pyrimidyl, 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, naphthyl, 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, naphthyl, 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 C1-6 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 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;
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; 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 tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
Y is COOR9, wherein R9 is C1-6 alkyl;
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, C4-10 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, or 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 pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
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; and with the proviso that the compound does not include a compound having the formula

193. The compound or salt thereof of Claim 192 of the formula:

194. A compound having the formula:

or a pharmaceutically acceptable salt thereof, 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 C1-6 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 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;
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; 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 tetrahydropyran ring linked through the C4 position of the tetrahydropyran ring;
Y is a sulfonimide of the formula -C(O)NHS(O)2R9;
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;

V is selected from OH, SH, or NH2;
the dashed line represents an optional double bond;
R21 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, 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 pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy,or thiophenoxy;
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; and with the proviso that the compound does not include a compound having the formula:

195. The compound or salt thereof of Claim 194 of the formula or a pharmaceutically acceptable salt thereof.

196. The compound or salt thereof of Claim 194 or 195, wherein Y is a sulfonimide of the formula -C(O)NHS(O)2R9, and wherein V is selected from OH and NH2.

197. A compound having the formula:

or a pharmaceutically acceptable salt thereof, 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, pyridyl, pyrimidyl, 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, naphthyl, 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, naphthyl, 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 C1-6 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 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;
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; 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 tetrahydropyran ring linked through the C4 position of the tetrahydropyran 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, C3-7 cycloalkyl, or C1-3 alkoxy, or Y is a carboxylic acid;
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, or 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 pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy,or thiophenoxy;
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; and with the proviso that the compound does not include a compound having the formula:

198. The compound or salt thereof of Claim 1 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;
or NR1aR1b is a three- to six- membered alkyl cyclic 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-tetrahydrofuryl;
(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, 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.

199. The compound or salt thereof of Claim 1 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;
or NR1a R1b is a three- to six- membered alkyl cyclic 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-tetrahydrofuryl;

and (f) the dashed line represents an optional double bond.

200. The compound or salt thereof of Claim 1 having the Formula XIV:
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 a group consisting of:

wherein R1c is H;
or NR1a R1b is a three- to six- membered alkyl cyclic 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) R2a is C6 or C10 aryl optionally substituted with up to three NR2c R2d, 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;
(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.

201. The compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity for use in the treatment of a hepatitis C virus infection in an individual.

202. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity for the treatment of a hepatitis C virus infection in an individual.

203. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity in the preparation of a medicament for the treatment of a hepatitis C
virus infection in an individual.

204. The use of Claim 202 or 203, wherein the treatment achieves a sustained viral response.

205. The use of Claim 202, 203 or 204, wherein the use further comprises use of a nucleoside analog.

206. The use of Claim 205, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

207. The use of any one of Claims 202 to 206, wherein the use further comprises use of a NS5B RNA-dependent RNA polymerase inhibitor.

208. The use of any one of Claims 202 to 207, wherein the use further comprises use of thymosin-.alpha..

209. The use of Claim 208, wherein the thymosin-.alpha. is for subcutaneous delivery twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

210. The use of any one of Claims 202 to 209, wherein the use further comprises use of interferon-gamma (IFN-.gamma.).

211. The use of Claim 210, wherein the IFN-.gamma. is for subcutaneous delivery in an amount of from about 10 µg to about 300 µg.

212. The use of any one of Claims 202 to 211, wherein the use further comprises use of interferon-alpha (IFN-.alpha.).

213. The use of Claim 212, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration in a dosing interval of every 8 days to every 14 days.

214. The use of Claim 212, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration in a dosing interval of once every 7 days.

215. The use of Claim 212, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

216. The use of any one of Claims 202 to 215, wherein the use further comprises use 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.

217. The compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity for use in the treatment of liver fibrosis in an individual.

218. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity for the treatment of liver fibrosis in an individual.

219. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity in the preparation of a medicament for the treatment of liver fibrosis in an individual.

220. The use of Claim 218 or 219, wherein the use further comprises use of a nucleoside analog.

221. The use of Claim 220, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

222. The use of any one of Claims 218 to 221, wherein the use further comprises use of a NS5B RNA-dependent RNA polymerase inhibitor.

223. The use of any one of Claims 218 to 222, wherein the use further comprises use of thymosin-.alpha..

224. The use of Claim 223, wherein the thymosin-.alpha. is for subcutaneous delivery twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

225. The use of any one of Claims 218 to 224, wherein the use further comprises use of interferon-gamma (IFN-.gamma.).

226. The use of Claim 225, wherein the IFN-.gamma. is for subcutaneous delivery in an amount of from about 10 µg to about 300 µg.

227. The use of any one of Claims 218 to 226, wherein the use further comprises use of interferon-alpha (IFN-.alpha.).

228. The use of Claim 227, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN- .alpha. for administration in a dosing interval of every 8 days to every 14 days.

229. The use of Claim 227, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration in a dosing interval of once every 7 days.

230. The use of Claim 227, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

231. The use of any one of Claims 218 to 230, wherein the use further comprises use 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.

232. The compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity for use in increasing liver function in an individual having a hepatitis C virus infection.

233. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity for increasing liver function in an individual having a hepatitis C virus infection.

234. Use of the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity in the preparation of a medicament for the increasing liver function in an individual having a hepatitis C virus infection.

235. The use of Claim 233 or 234, wherein the use further comprises use of a nucleoside analog.

236. The use of Claim 235, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

237. The use of any one of Claims 233 to 236, wherein the use further comprises use of a NS5B RNA-dependent RNA polymerase inhibitor.

238. The use of any one of Claims 233 to 237, wherein the use further comprises use of thymosin-.alpha..

239. The use of Claim 238, wherein the thymosin-.alpha. is for subcutaneous delivery twice weekly in an amount of from about 1.0 mg to about 1.6 mg.

240. The use of any one of Claims 233 to 239, wherein the use further comprises use of interferon-gamma (IFN-.gamma.).

241. The use of Claim 240, wherein the IFN-.gamma. is for subcutaneous delivery in an amount of from about 10 µg to about 300 µg.

242. The use of any one of Claims 223 to 241, wherein the use further comprises use of interferon-alpha (IFN-.alpha.).

243. The use of Claim 242, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration in a dosing interval of every 8 days to every 14 days.

244. The use of Claim 242, wherein the IFN-.alpha. is monoPEG (30 kD, linear)-ylated consensus IFN-.alpha. for administration in a dosing interval of once every 7 days.

245. The use of Claim 242, wherein the IFN-.alpha. is INFERGEN consensus IFN-.alpha..

246. The use of any one of Claims 233 to 245, wherein the use further comprises use 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.

247. A pharmaceutical composition for curative or prophylactic treatment of a hepatitis C virus infection, comprising the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

248. The pharmaceutical composition of any one of Claims 19 to 25, 73 to 79 and 126 to 132, for curative or prophylactic treatment of a hepatitis C virus infection.

249. A commercial package containing, as active pharmaceutical ingredient, the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, together with instructions for its use for curative or prophylactic treatment of a hepatitis C virus infection in an animal.

250. A pharmaceutical composition for curative or prophylactic treatment of liver fibrosis, comprising the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

251. The pharmaceutical composition of any one of Claims 19 to 25, 73 to 79 and 126 to 132, for curative or prophylactic treatment of liver fibrosis.

252. A commercial package containing, as active pharmaceutical ingredient, the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, together with instructions for its use for the curative or prophylactic treatment of liver fibrosis in an animal.

253. A pharmaceutical composition for increasing liver function in an individual having a hepatitis C virus infection, comprising the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

254. The pharmaceutical composition of any one of Claims 19 to 25, 73 to 79 and 126 to 132, for increasing liver function in an individual having a hepatitis C virus infection.

255. A commercial package containing, as active pharmaceutical ingredient, the compound of any one of Claims 1 to 18, 69 to 72, 123 to 125, and 176 to 200, or a pharmaceutically acceptable salt thereof, together with instructions for its use for increasing liver function in an individual having a hepatitis C virus infection in an animal.