MXPA06011268A

MXPA06011268A - Macrocyclic compounds as inhibitors of viral replication

Info

Publication number: MXPA06011268A
Application number: MXPA/A/2006/011268A
Authority: MX
Inventors: M Blatt Lawrence; J Stengel Peter; L Kennedy April; W Andrews Steven; Jiang Yutong; R Madduru Machender; T Woodard Benjamin; M Wenglowsky Steven; R Condroski Kevin; A Doherty George; A Josey John
Original assignee: W Andrews Steven; M Blatt Lawrence; R Condroski Kevin; A Doherty George; Intermune Inc; Jiang Yutong; A Josey John; L Kennedy April; R Madduru Machender; J Stengel Peter; M Wenglowsky Steven; T Woodard Benjamin
Priority date: 2004-03-30
Filing date: 2006-09-29
Publication date: 2007-04-20

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

MACROCYCLICAL COMPOUNDS AS INHIBITORS OF THE VIRAL REPLICATION Reference to related applications [0001] The present application is a partial continuation of the United States Patent Application No. 11 / 064,445, filed on February 23, 2005, which is a continuation of PCT / US04 / 33970, filed on October 13, 2004, which claims priority benefit under the 35 U.S.C. § 119 (e) for the United States Provisional Patent Application No. 60 / 511,541, filed October 14, 2003 and the United States Provisional Patent Application No. 60 / 612,460, filed September 22, 2004; the present application also claims the priority benefit for the United States Provisional Patent Application? o. 60 / 612,381, filed on September 22, 2004; Provisional United States Patent Application? 60 / 562,418, filed April 14, 2004; and the United States Provisional Patent Application No. 60 / 558,161, filed on March 30, 2004; all of which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION Field of the invention [0002] The present invention relates to compounds, processes for their synthesis, pharmaceutical compositions and methods for the treatment of flaviviral infections, such as infection by hepatitis C virus (HCV). In particular, the present invention provides novel peptide analogs, pharmaceutical compositions containing said analogs and methods for using those analogs in the treatment of flaviviral infection. Description of the Related Art [0003] Infection with hepatitis C virus (HCV) is the most common chronic hematogenous infection in the United States. While the number of new infections has declined, the burden of chronic infection is substantial, with the Centers for Disease Control estimating 3.9 million (1.8%) people infected in the United States. Chronic liver disease ranks tenth among the leading causes of death in adults in the United States, and is the cause of approximately 25,000 deaths annually, equivalent to approximately 1% of deaths from all causes. Studies indicate that approximately 40% of chronic liver diseases are related to HCV, which yields an estimated total of 8,000 - 10,000 deaths per year. Terminal liver disease associated with HCV is the most frequent indication for liver transplantation in adults.

[0004] The antiviral therapy of chronic hepatitis C registered a rapid evolution in the last decade, with significant advances in the effectiveness of the treatment. However, even with combination therapy using peginterferon alfa plus ribavirin, 40% to 50% of patients fail treatment, that is, they are non-responders or relapsers. These patients currently lack an effective therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis diagnosed by biopsy are at significant risk of developing complications of advanced liver disease, including ascites, jaundice, varicose hemorrhages, encephalopathy, and progressive liver failure, as well as a marked increase in the risk of carcinoma. hepatocellular [0005] The high prevalence of chronic HCV infection has important public health consequences due to 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 between the end of the 1960s and the beginning of the 1980s there was a significant increase in the rate of new infections- by HCV, particularly among people between 20 and 40 years of age. It is estimated that the number of people with long-standing HCV infection, of 20 years or more, could increase to more than four times between 1990 and 2015, from 750,000 to more than 3 million. The percentage increase among infected people between 30 and 40 years of age would be even greater. As the risk of chronic liver disease due to HCV is related to the duration of infection, progressively increasing the risk of cirrhosis in infected persons for more than 20 years, this increase in the number of people with prolonged HCV infection can be accompanied by a substantial increase of morbidity and mortality due to cirrhosis in patients who became infected between the years 1965-1985. [0006] HCV is an enveloped positive strand RNA virus of the Flaviviridae family. The genome of the single chain of AR? of HCV is approximately 9500 nucleotides in length and has an open reading frame (ORF) that codes for a single large polyprotein of about 3000 amino acids. In infected cells, this protein is cleaved at multiple sites by cellular and viral proteases, producing the structural and non-structural proteins (? S) of the virus. In the case of HCV, the generation of mature non-structural proteins (? S2,? S3,? S4,? S4A,? S4B,? S5A and? S5B) is carried out by two viral proteases. The first viral protease cleaves at the? S2-? S3 junction of the polyprotein. The second viral protease is the serine protease contained in the N-terminal region of NS3 (referred to herein as "NS3 protease"). The NS3 protease mediates all subsequent cleavage events at sites downstream from the position of NS3 in the polyprotein (i.e., sites located between the C terminus of NS3 and the C terminus of the polyprotein). The NS3 protease exhibits activity both in the cis form, in the cleavage site NS3-NS4, and in the trans form, in the remaining sites NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. It is believed that the NS4A protein performs multiple functions, acting as a cofactor of the NS3 protease and possibly collaborating in the localization of the NS3 membrane and other components of the viral replicase. Apparently, the formation of the complex between NS3 and NS4A is necessary for the processing of events mediated by NS3 and increases the proteolytic efficiency in all sites recognized by NS3. The NS3 protease also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is an RNA-dependent RNA polymerase that participates in the replication of HCV RNA. Literature [0007] ETAVIR (1994) Hepatology 20: 15-20; Brunt (2000) Hepatol. 31: 241-246; Alpini (1997) J. Hepatol. 27: 371-380; Baroni et al. (1996) Hepatol. 23: 1189-1199; Czaja et al. (1989) Hepatol. 10: 795-800; Grossman et al. (1998) J. Gastroenterol. Hepatol. 13: 1058-1060; Rockey and Chung (1994) J. Invest. Med. 42: 660-670; Sakaida et al. (1998). "Hepatol. 28: 471-479; Shi et al. (1997) Proc. Nati Acad. Sci. USES 94: 10663-10668; Baroni et al. (1999) Liver 19: 212-219; Lortat-Jacob et al. (1997) < J. Hepatol. 26: 894-903; Llorent et al. (1996) J. Hepatol. 24: 555-563; U.S. Patent No. 5,082,659; European Patent Application EP 294,160; U.S. Patent No. 4,806,347; Balish et al. (1992) "Infect. Diseases 166: 1401-1403; Katayama et al. (2001)". Viral Hepati tis 8: 180-185; U.S. Patent No. 5,082,659; U.S. Patent No. 5,190,751; U.S. Patent No. 4,806,347; Wandl et al. (1992) Br. J. Haematol. 81: 516-519; European Patent Application No. 294,160; Canadian Patent No. 1,321,348; European Patent Application No. 276,120; Wandl et al. (1992) Sem. Oncol. 19: 88-94; Balish et al. (1992) J. Infectious Diseases 166: 1401-1403; Van Dijk et al. (1994) Jzit. J. "Cancer 56: 262-268; Sundmacher et al. (1987) Current Eye Res. 6: 273-276; U.S. Patents Nros. 6,172,046; 6,245,740; 5,824,784; 5,372,808; 5,980,884; publications of international patent application WO 96/21468; WO 96/11953; WO 00/59929; WO 00/66623; WO2003 / 064416; WO2003 / 064455; WO2003 / 064456; WO 97/06804; WO 98/17679; WO 98/22496; WO 97/43310; WO 98/46597; WO 98/46630; WO 99/07733; WO 99/07734, WO 00/09543; WO 00/09558; WO 99/38888; WO 99/64442; WO 99/50230; WO 95/33764; Torre et al. (2001) J. Med. Virol. 64: 455-459; Bekkering et al. (2001). "Hepatol 34: 435-440; Zeuzem et al. (2001) Gastroenterol. 120: 1438-1447; Zeuzem (1999) J. Hepatol. 31: 61-64; Keeffe and Hollinger (1997) Hepatol. 26: 101S-107S; Wills (1990) Clin. Pharmacokinet. 19: 390-399; Heathcote et al. (2000) New Engl. J. Med. 343: 1673-1680; Husa and Husova (2001) Bratisl. Lek Listy 102: 248-252; Glue et al. (2000) Clin. Pharmacol. 68: 556-567; Bailón et al. (2001) Bioconj. Chem. 12: 195-202; and Neumann et al. (2001) Science 282: 103; Zalipsky (1995) Adv. Drug Delivery Reviews S. 16, 157-182; Mann et al. (2001) Lancet 358: 958-965; Zeuzem et al. (2000) New Engl. J. Med. 343: 1666-1672; U.S. Patent Nos. 5,633,388; 5,866,684; 6,018,020; 5,869,253; 6,608,027; 5,985,265; 5,908,121; 6,177,074; 5,985,263; 5,711,944; 5,382,657; and 5,908,121; Osborn et al. (2002) J. "Pharmacol. Exp. Therap 303: 540-548; Sheppard et al. (2003) Nat. Immunol. 4: 63-68; Chang et al. (1999) Nat. Biotechnol. 17: 793- 797; Adolf (1995) Multiple Sclerosis 1 Suppl 1: S44-S47; Chu et al-, Tet. Lett. (1996), 7229-7232; Ninth Conference on Antiviral Research, Urabandai, Fukyshima, Japan (1996) (Antiviral Research, (1996), 30: 1, A23 (abstract 19)), Steinkuhler et al., Biochem., 37: 8899-8905, Ingallinella et al., Biochem., 37: 8906- 8914. Summary of the invention [ 0008] The embodiments provide a compound having the Formula I:

[0009] where: [0010] Q is a central ring that is selected from:

[0011] Where the central ring can be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl, substituted C? _6 alkyl, C? _6 alkoxy, substituted C? .e. Alkoxy, Cs or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulfur, sulfoxide, sulfone, amino, alkoxyamino, acyloxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, cyclobutyl spirocyclic, cyclopentyl spirocyclic, or cyclohexyl spirocyclic, [0012] or Q is R1 -R2 / wherein R1 is C ?, 6 alkyl, C3-7 cycloalkyl, C_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 benzyl midazole, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C-? 0 alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-C? _6 alkyl, or Ci-6 alkyl optionally substituted with up to 5 fluoro, C? _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, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_ alkenyl, C? -6 alkoxy, hydroxy-C? -6 alkyl, C ? -6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; [0013] R4 is H, C? _6 alkyl, C3-7 cycloalkyl, C4-? 0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl , C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C6_6 alkoxy, hydroxy-C6_6 alkyl, C6 alkyl optionally substituted with up to 5 fluoro, or C6_6 alkoxy optionally substituted with up to 5 fluoro; [0014] R5 is H, d-e alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR21NH (CO) R22; [0015] R6 and R7 are each independently H, C? -6 alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2.6 alkenyl, hydroxy-C6-6 alkyl, C6-6 alkyl optionally substituted with up to 5 fluoro, or C6-6 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 C? _6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R8 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2.s alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl , C? -6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [0017] Y is a sulfonimide of the formula -C (0) NHS (0) 2R9, where R9 is C? _6 alkyl, C3-7 cycloalkyl, or C4_ a or alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl, or R9 is Cs 010 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? .6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, C2_6 alkenyl, C6-6alkoxy, hydroxy-C6-6alkyl, or C6-6alkyl optionally substituted with up to 5 fluoro, C6-6alkoxy optionally substituted with up to 5 fluoro; or R9 is an optionally substituted Cl-6 alkyl with up to 5 fluoro groups, NR6R7, NRlaRlb, or (CO) OH, or R9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C? -6 alkoxy; or Y is a carboxylic acid or a salt, solvate or prodrug acceptable for pharmaceutical use thereof; [0018] where Rla and Rlb are each independently H, C? Alkyl, C3_7 cycloalkyl, or C_? Alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, C? _6 alkoxy, amido, or phenyl, [0019] or Rl and Rlb are each independently H and C6 0 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C-e alkyl, C3_7 cycloalkyl, C4-? or alkylcycloalkyl , C2_6 alkenyl, C?, 6 alkoxy, hydroxy-C? -6 alkyl, C? -S alkyl optionally substituted with up to 5 fluoro, or C? -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 heterocyclic molecule, saturated or unsaturated, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, [0021] or NRlaRlb is a secondary cycloalkyl amine from three to six members, which optionally has one to three heteroatoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C? -6 alkoxy, amido, or phenyl, [0022] or NRlaRlb is a heteroaryl selected from the group consisting of:

[0023] where R c is H, halo, C? -6 alkyl, C3-6 cycloalkyl, C? -e alkoxy, C3_6 cycloalkoxy, N02, N (Rld) 2, NH (CO) RI ?, or NH (CO) ) NHRld, where each Rld is independently H, C? -6 alkyl, or C3-6 cycloalkyl, [0024] or RXc is NH (CO) ORle, where Rle is C? _6 alkyl or C3_6 cycloalkyl; [0025] p = 0 or 1; [0026] V is selected from 0, S, or NH; [0027] 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, C? _6 alkyl, C3.7 cycloalkyl, C? 0 alkylcycloalkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro; [0028] the hyphen lines represent a further double bond; [0029] R21 is C? _6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_ cycloalkyl, C4_10 alkylcycloalkyl, C2-6 alkenyl, C? _6 alkoxy, hydroxy-C? alkyl , or C? .6 alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and [0030] R22 is C? -6 alkyl, C3_7 cycloalkyl, or C4-? 0 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl; with the proviso that the compound having the Formula I does not comprise 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: II III IV [0032] wherein: [0033] a) R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C6-6 alkyl, C3-7 cycloalkyl, C4_ or alkylcycloalkyl, C2_6 alkenyl, C. ? alkoxy, hydroxy-C6-6alkyl, or C6-6alkyl optionally substituted with up to 5 fluoro, C6-alkoxy optionally substituted with up to 5 fluoro, C6 or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl , phenoxy, thiophenoxy, S (0) 2 NR6R7, NHC (0) NR6R7, NHC (S) NR6R7, C (0) NR6R7, NR6R7, C (0) R8, C (0) OR8, NHC (0) R8,? HC (0) OR8, SOmR8,? HS (0) 2R8, CHn? R6R7, OCHn? R6R7, or 0CHnR9 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, C? -6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy , hydroxy-C? _6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or L-6 alkoxy optionally substituted with up to 5 fluoro; said C6 0 i0 aryl, pyridal, phenoxy and thiophenoxy in the definition of R1 and R2 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2.s alkenyl , CX-6 alkoxy, hydroxy-Ci-g alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; [0034] b) m = 0, 1, or 2; [0035] c) R4 is H, C? -6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl , C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2-e alkenyl, C? _6 alkoxy, hydroxy-C? -6 alkyl, C? ~6 alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; [0036] d) R5 is H, C6.6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR21NH (CO) R22; [0037] e) R6 and R7 are each independently H,? -e alkyl, C3-7 cycloalkyl, C? 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Ca-6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, C2.6 alkenyl, hydroxyL6 alkyl, or C6.6 alkyl optionally substituted with up to 5 fluoro, C6-6 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) R is C? _6 alkyl, C3_7 cycloalkyl, or C4 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R8 is Cs 010 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C6-6 alkoxy, hydroxy-C? -S alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? -6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [0039] g) Y is a sulfonimide of the formula C (O) NHS (0) 2R9, where R9 is C? -6 alkyl, C3_7 cycloalkyl, or C-? Or alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C6-alkoxy, or phenyl, or R9 is C6 or the aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6 alkyl, C3-7 cycloalkyl, C4_x0 alkylcycloalkyl, C2-6 alkenyl, C_6 alkoxy, hydroxy-C? Alkyl, or C? -6 alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; or R9 is an optionally substituted Cl-6 alkyl 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 C?, 6 alkoxy; or Y is a carboxylic acid or a salt, solvate or prodrug acceptable for pharmaceutical use thereof; [0040] h) R10 and R11 are each independently H, C? Alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C6 or aryl, hydroxy-C? _6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro , (CH2) nNR6R7, (CH2) nC (0) OR14 where R14 is H, C? -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, C? _6 alkoxy, or phenyl; or R14 is C5010 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? .s alkoxy, hydroxy-C? _6 alkyl, C ? 6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; said C5 0 10 aryl, in the definition of R10 and R11 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C -6 alkoxy, hydroxy-C? -6 alkyl, Ca-6 alkyl optionally substituted with up to 5 fluoro, or C? _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; [0041] i) p = 0 or 1; [0042] j) R12 and R13 are each independently H, Ci_6 alkyl, C3.7 cycloalkyl, C4_a0 alkylcycloalkyl, Cs 0 10 aryl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, (CH2) ) nNR6R7, (CH2) nC (O) OR14 where R14 is H, C6-6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C ? 6 alkoxy, or phenyl; or R14 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_s alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, - 6 optionally substituted alkyl with up to 5 fluoro, or C6-alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-C? -6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or Ci-s 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 C? _6 alkyl optionally substituted with (CH2) nOR8; [0043] k) R20 is H, Ca_6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, C6 or aryl, hydroxy-C? -6 alkyl, C?, 6 alkyl optionally substituted with up to 5 fluoro, or (CH2) nNR6R7, ( CH2) nC (0) OR14 where R14 is H, C? _ Alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? -S-alkoxy , or phenyl; or R14 is C6 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_ or alkylcycloalkyl, C2_6 alkenyl, C6_6 alkoxy, hydroxy-C6_6 alkyl, Ca_6 alkyl optionally substituted with up to 5 fluoro, or C? _e alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2.6 alkenyl, C? _6 alkoxy, hydroxy -C? -6 alkyl, or C? _s alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; [0044] 1) n = 1-4; [0045] m) V is selected from O, S, or NH; [0046] n) when V is O or S, it is selected from O, NR15, or CR15; when it is NH, it is selected from NR15 or CR15, where R15 is H, C? _6 alkyl, C3.7 cycloalkyl, C_? alkylcycloalkyl, or C? -6 alkyl optionally substituted with up to 5 fluoro; [0047] or) the dashed line represents a further double bond, - [0048] p) R21 is C? Alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C? .e alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 0 i0 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C.ao alkylcycloalkyl, C2_6 alkenyl, C6.6 alkoxy, hydroxy C5 alkyl , C? -5 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 C? -6 alkyl, C3-7 cycloalkyl, C.10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl. [0050] The embodiments provide a compound having Formula XI: XI [0051] where: [0052] a) R -ola "y, pRlb" s_o_n each independently H, C? -6 alkyl, C3-7 cycloalkyl, or C4_10 alkylcycloalkyl, all of which are optionally substituted from one to three sometimes with halo, cyano, nitro, C? _6 alkoxy, amido, or phenyl; [0053] or Rla and Rlb are each independently H and C6 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C? 6 alkoxy, hydroxy-C? -6 alkyl, C? Alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; [0054] or Rla and Rlb are each independently H or heterocycle, which is a five, six or seven membered heterocyclic molecule, saturated or unsaturated, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; [0055] or NRlaRlb is a three to six membered cycloalkyl secondary amine, optionally having one to three heteroatoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C?, 6 alkoxy, amido, or phenyl; [0056] or NRlaRlb is a heteroaryl selected from the group consisting of:

[0057] where Rlc is H, halo, C? _6 alkyl, C3.6 cycloalkyl, C? -6 alkoxy, C3_6 cycloalkoxy, N02, N (Rld) 2, NH (CO) Rld, or NH (C0) NHRld, wherein each Rld is independently H, C? -6 alkyl, or C3-5 cycloalkyl; [0058] or Rlc is NH (CO) ORle where Rle is C? _6 alkyl, or C3-6 cycloalkyl; [0059] b) W is O or NH; [0060] c) V is selected from O, S, or NH; [0061] d) when V is O or S, W is selected from O, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C? -6 alkyl, C3_7 cycloalkyl, C.10 alkylcycloalkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro; [0062] e) Q is a bicyclic secondary amine with the structure:

[0063] wherein R21 and R22 are each independently H, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C? Or alkylcycloalkyl, C2-6 alkenyl, C? .6 alkoxy, hydroxy-C? 6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? -6 alkoxy optionally substituted with up to 5 fluoro, C6 or? Or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S ( 0) 2? RsR7,? HC (0)? R6R7,? HC (S)? RSR7, C (0)? R6R7,? RSR7, C (0) R8, C (0) OR8,? HC (0) R8 ,? HC (0) 0R8, SOmR8 (m = 0, 1 or 2), or? HS (0) 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, C?, 6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? .6 alkoxy, hydroxy-C? -6 alkyl, -β alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; said C6 0 10 aryl, pyridal, phenoxy and thiophenoxy in the definition of R21 and R22 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C5.5 alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro; [0064] wherein R10 and R11 are each independently H, C? _6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C6 0? Or aryl, hydroxy-C? _6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, or (CH2) nC (O) OR14 where R14 is H, C? 6 alkyl, C3-7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R14 is C60 x or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6 alkyl, C3_7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2.6 alkenyl, C? _6 alkoxy, hydroxy-C? -6 alkyl, C? .6 alkyl optionally substituted with up to 5 fluoro, Ci_ alkoxy optionally substituted with up to 5 fluoro; said Cs 0 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? .6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, C2_6 alkenyl, CX-g alkoxy, hydroxy-Ci -alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C6-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; [0065] where p = 0 or 1; [0066] wherein R12 and R13 are each independently H, C_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C6 0? Or aryl, hydroxy-Cx_g alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, (CH2) nC (0) OR14 where R is H, C? -6 alkyl, C3_7 cycloalkyl, -4-10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R14 is Cg 0? 0 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, Cx_e alkyl optionally substituted with up to 5 fluoro, C6-6 alkoxy optionally substituted with up to 5 fluoro; said Ce 0 10 aryl, in the definition of R 12 and R 13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, C2.6 alkenyl, C? .6 alkoxy, hydroxy -C? _g alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or C-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] where R20 is H, C? -6 alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, C6 0 aryl, hydroxy-Cx-alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, or (CH2) nC (0) OR14 where R14 is H, C? -6 alkyl, C3-7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R14 is Cg or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_s alkenyl, C? _6 alkoxy, hydroxy-Cx-g alkyl C, optionally substituted alkyl with up to 5 fluoro, or C6-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6.6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C6_6 alkoxy, hydroxy -C? _g alkyl, C? _g alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; [0068] where n = 0-4; [0069] where R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2.6 alkenyl, hydroxy-C? _6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or Re 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, where [0071] R is C? _6 alkyl, C3_7 cycloalkyl, 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 NR2cR2d, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C? s alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? -e alkoxy optionally substituted with up to 5 fluoro, - [0072] 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 NR2cR2, hal or, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C? -5 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? alkoxy optionally substituted with up to 5 fluoro; [0073] said Rc and Rd are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _g alkyl, C3_7 cycloalkyl, C-? Or alkylcycloalkyl, C2-g alkenyl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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; [0074] f) R4 is H, C? .6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3- 7-cycloalkyl, C4.10 alkylcycloalkyl, C2.6 alkenyl, Cg alkoxy, hydroxy-Ci-g alkyl, C? _e alkyl optionally substituted with up to 5 fluoro, or C? -S alkoxy optionally substituted with up to 5 fluoro; [0075] g) R5 is H, d-g alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) 0R8, or S (0) 2R8; [0076] h) R8 is C? -g alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, Ca_g alkoxy, or phenyl; or R8 is Cs 010 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy C? alkyl, Ca_6 optionally substituted alkyl with up to 5 fluoro, or C? -g alkoxy optionally substituted with up to 5 fluoro; and [0077] i) the dashed line represents an additional double binding. [0078] The embodiments provide a compound having Formula XVIII: XVIII [0079] wherein [0080] a) R1 is C? -e alkyl, C3.7 cycloalkyl, C4_? 0 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, Cx-alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_s alkenyl, C6_6alkoxy, hydroxy-dg alkyl, Cx_g alkyl optionally substituted with up to 5 fluoro, or C_s 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, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR5R6, halo, cyano, nitro, hydroxy, C? _ 6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, d-6 alkoxy, hydroxy-d-6 alkyl, d_6 alkyl optionally substituted with up to 5 fluoro, or d_6 alkoxy optionally substituted with up to 5 fluoro; [0082] c) R3 is H, C? Β alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl , C2_6 alkenyl, C6_6alkoxy, hydroxy-C6_6alkyl, d_6alkyl optionally substituted with up to 5 fluoro, or d_g_alkoxy optionally substituted with up to 5 fluoro; [0083] d) R4 is d-e alkyl, C (0) NR5R6, C (S) NR5R6, C (0) R7, C (0) OR7, or S (0) 2R7; [0084] e) R5 and R6 are each independently H, d_g alkyl, C3_7 cycloalkyl, C4-? 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, d_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, hydroxy-dg alkyl, or d-6 alkyl optionally substituted with up to 5 fluoro, C6_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 d_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, -β alkoxy, or phenyl; or R7 is C6 010 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, alkyl d, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, d_e alkoxy, hydroxy-6 alkyl, C6_6 optionally substituted alkyl with up to 5 fluoro, or C? -alkoxy optionally substituted with up to 5 fluoro; [0086] g) R8 is C? -3 alkyl, C3_ cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or Cx_3 alkoxy; and [0087] h) the dashed line represents a double additional ligature; [0088] or a salt acceptable for pharmaceutical use thereof. [0089] The embodiments provide a compound of the formula: 11 [0090] wherein: [0091] a) Z is a group configured to be linked through a hydrogen bond to an NS3 protease unit of His57 imidazole and to be hydrogen bonded to a nitrogen atom of Glyl37 of a protease NS3, - [0092] b) Pi 'is a group configured to form a non-polar interaction with at least one pocket unit SI' of Ns3 protease selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Fe43; [0093] c) L is a linking group consisting of between 1 and 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 is positioned by L to form a non-polar interaction with at least one S2 pocket unit of NS3 protease selected from the group consisting of His57, Argl55, Val78, Asp79, Gln80 and Asp81; [0095] e) the line of dashes represents a further double binding, - [0096] f) R5 is selected from the group consisting of H, C (0) NR6R7 and C (0) OR8; [0097] g) R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? alkyl, d-6 alkyl optionally substituted with up to 5 fluoro, optionally substituted C 1 -g alkoxy 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 C? -6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R8 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, d-? alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? _alkoxy optionally substituted with up to 5 fluoro; or R8 is Ci-g alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; with the proviso that the compound does not comprise a compound having the Formula II, III, or IV as defined. [0099] The embodiments provide a compound having the formula: [0100] wherein: [0101] R4 is H, d_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, d-ß alkyl, C3.7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-Ci-s alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _g alkoxy optionally substituted with up to 5 fluoro; [0102] R5 is Ci-g alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR1NH (CO) R22; [0103] R6 and R7 are each independently H, d-6 alkyl, C3_7 cycloalkyl, C_? Alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, d_6 alkyl, C3_7 cycloalkyl , C4_? Or alkylcycloalkyl, C2_s alkenyl, hydroxyCi-g alkyl, C? _ Alkyl optionally substituted with up to 5 fluoro, or d-6alkoxy 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 C? _g alkyl, C3.7 cycloalkyl, C_? Alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _g alkoxy, or phenyl; or R8 is C6 0? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, d-ß alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_g alkenyl, Ci-g alkoxy, hydroxy-dg alkyl, d -6 alkyl optionally substituted with up to 5 fluoro, or C? -S alkoxy optionally substituted with up to 5 fluoro; or R8 is Ca-6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [0105] Y is a sulfonimide of the formula - C (0) NHS (0) 2R9, where R9 is d_3 alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, Cx_3 alkyl, C3_7 cycloalkyl, or Cx_3 alkoxy, or Y is a carboxylic acid [0106] p = 0 or 1; [0107] V is selected from OH, SH, or NH2; [0108] the line of dashes represents a double additional ligature;

[0109] R21 is Ci-g alkyl, C3-.7 cycloalkyl, C4-10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? -g alkoxy, cycloalkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2.6 alkenyl, dg alkoxy, hydroxy-C6-6 alkyl, d- β-alkyl optionally substituted with up to 5 fluoro, C-alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and [0110] R22 is C? _6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, Cx_g alkyl optionally substituted with up to 5 fluoro, or phenyl. [0111] The embodiments provide a compound having the formula: w

[0112] where: [0113] Q is a central ring that is selected from:

[0114] wherein the central ring can be substituted or unsubstituted H, halo, cyano, nitro, hydroxy, alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-dg alkyl, C? _6 alkyl , substituted C? -6 alkyl, d-.beta.-alkoxy, substituted d-.beta.-alkoxy, Cs. 0-aryl, pyrid, pyrimid, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, acyloxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, cyclopropyl, spirocyclic, cyclobutyl, spirocyclic, cyclopentyl, spirocyclic, or cyclohexyl, spirocyclic, [0115] or Q is R ^ R2, where R1 is d- βalkyl, C 3-7 cycloalkyl, C 4 - α 0 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, Ci-β alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2 ~ alkenyl, C? -6 alkoxy, hydroxy-C? g alkyl, C ? 6 alkyl optionally substituted with up to 5 fluoro, or C? -g 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, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_s alkenyl, d-6 alkoxy, hydroxy-Ci-g alkyl, C? _d alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; [0116] R4 is H, Ci-g alkyl, C3-7 cycloalkyl, C_10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, d_g alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2.6 alkenyl, d-6 alkoxy, hydroxy-C? -6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or C? -g alkoxy optionally substituted with up to 5 fluoro, - [ 0117] R5 is C? Alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) 0R8, S (0) 2R8, O (C0) CHR21NH (C0) R22; [0118] R6 and R7 are each independently H, C? _ 6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, d_6 alkyl, C3-7 cycloalkyl, C4_ao alkylcycloalkyl, C2-6 alkenyl, hydroxy-d6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or d-6alkoxy 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 d-alquilo alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? -S alkoxy, or phenyl; or R8 is C6 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -5 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2-6 alkenyl, d-6 alkoxy, hydroxy-Ci-g alkyl , d-β alkyl optionally substituted with up to 5 fluoro, or d-β alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring, - [0120] Y is COOR9, where R9 is Ci-e alkyl; or Y is a sulfonimide of the formula -C (O) NHS (0) 2R9, wherein R9 is d -3 alkyl, C3.7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C ? _3 alkyl, C3_7 cycloalkyl, or C? ~ 3 alkoxy, or Y is a carboxylic acid [0121] p = 0 or 1; [0122] V and W are each individually selected from 0, S, or NH; [0123] the line of dashes represents a double additional ligature; [0124] R21 is C? _6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, d-?? alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3-7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, d-6 alkoxy, hydroxy-C? _6 alkyl , d-6 alkyl optionally substituted with up to 5 fluoro, C6-6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and [0125] R22 is d_g alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _g alkyl optionally substituted with up to 5 fluoro, or phenyl .

[0126] Embodiments provide pharmaceutical compositions comprising preferred compounds and vehicles acceptable for pharmaceutical use. [0127] The embodiments provide a method of treating infection with the virus of hematitis C in an individual, wherein the method comprises administering to the individual an effective amount of the preferred compounds. [0128] The embodiments provide a method of increasing liver function in an individual, wherein the method comprises administering to the individual an effective amount of the preferred compounds. [0129] The embodiments provide the method of increasing the liver function in an individual having an infection with the hepatitis C virus, wherein the method comprises administering to the individual an effective amount of the preferred compounds. [0130] The chemical formulas representing the compounds described herein also represent acceptable salts for pharmaceutical use, solvates, esters, and prodrug derivatives thereof. Detailed Description of the Preferred Embodiment Definitions [0131] As used herein, the term "liver fibrosis", which is used herein interchangeably with "liver fibrosis," refers to the growth of scar tissue in the liver that may occur in the liver. the context of an infection such as chronic hepatitis. [0132] The terms "individual", "host", "subject", and "patient" are used interchangeably herein, and refer to a mammal, which includes, but is not limited to, primates, including apes and humans . [0133] As used herein, the term "liver function" refers to the normal function of the liver, which includes, but is not limited to, a synthetic function, including, but not limited to, the synthesis of proteins such as serum proteins (eg, albumin, coagulation factors, alkaline phosphatase, aminotransferases (eg, alanine transaminase, aspartate transaminase), 5'-nucleosidase, β-glutaminyltranspeptidase, etc.), bilirubin synthesis, cholesterol synthesis, and acid synthesis biliary a metabolic hepatic function, which includes, but is not limited to, carbohydrate metabolism, amino acid and ammonium metabolism, hormonal metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, which includes splenic and portal hemodynamics; and the related thing. [0134] As used herein, the terms "HCV NS3 protease inhibitor" and "NS3 protease inhibitor" refer to any agent that inhibits the protease activity of the HCV NS3 / NS4 complex. Unless specifically stated, the term "NS3 inhibitor" is used interchangeably with the terms "HCV NS3 protease inhibitor" and "NS3 protease inhibitor". [0135] As used herein, the term "polyol" or "poly-ol" denotes a carbohydrate that includes at least two hydroxyls attached to carbon atoms, and includes sugars, (reducing and non-reducing sugars), alcoholic sugars and acid sugars. Examples of polyols include alcoholic sugars such as mannitol and trehalose, and polyethers. A "reducing sugar" is one that contains a hemiacetal group that can reduce metal ions or react covalently with lysine or another amino group of proteins, and a "non-reducing sugar" is one that does not have these properties of a reducing sugar. Example of reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose and glucose. Among non-reducing sugars, sucrose, trehalose, sorbose, melezitose, and raffinose are included. Mannitol, xylitol, erythritol, treitol, sorbitol and glycerol are examples of alcoholic sugars. As acidic sugars, these include L-gluconate and metal salts. [0136] The term "polyether" as used herein, denotes a carbohydrate containing at least three ether linkages. Other functional groups may be included among the polyethers. Polyethers include polyethylene glycol (PEG). [0137] The term "sustained viral response" (SVR; also called "sustained response" or "durable response"), as used herein, refers to the response of an individual to a treatment regimen for HCV infection, in terms of serum HCV titre. Generally, a "sustained viral response" refers to HCV RNA that is not detectable (eg less than about 500, less than about 200 or less than about 100 copies of the genome per milliliter of serum) in the patient's serum during 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 after cessation of treatment. [0138] "Patients with treatment failure "as used herein, it generally refers to patients infected with HCV who have failed in the response to therapy for HCV, (called" non-responders ") or who have initially responded to previous therapy, but in whom the The therapeutic response was not sustained (so-called "relapses"). Previous therapy can usually include treatment with monotherapy with IFN-a or c-therapy. ombinada with IFN-cü, where the combined therapy can include administration of IF? -c. and an antiviral agent such as ribavirin. [0139] As used herein, the terms "treatment", "treated" and the like, refer to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or its symptoms and / or may be therapeutic in terms of a partial or complete cure for a disease and / or an adverse effect attributable to the disease. "Treatment", as used herein, covers any treatment of the disease in a mammal, particularly a human, and includes: (a) preventing the occurrence of the disease in a subject which may be predisposed to the disease but which it has not been diagnosed as having it; (b) the inhibition of the disease, for example the arrest of its development; and (c) relief of the disease, for example causing a regression of the disease. [0140] The terms "individual", "host", "subject", and "patient" are used interchangeably herein, and refer to a mammal, which includes, but is not limited to, murines, apes, humans, animal farm mammals, sport mammal animals, and mammal pets.

[0141] As used herein, the term "pirfenidone" refers to 5-methyl-l-phenyl-2- (1H) -pyridone. As used herein, the term "pirfenidone analogue" refers to any compound of Formula I, IIA or IIB in the section entitled "Pirfenidone and its Analogs" below. A "specific pirfenidone analog", and all its grammatical variants, refer to, and are limited to, each and every one of the pirfenidone analogues shown in Table 1 in the section entitled "Pirfenidone and its Analogs" which is below. [0142] As used herein, the term "Interferon Type I receptor agonist" refers to any ligand of natural origin or unnatural origin of the Type I human interferon receptor, which binds to, and causes a signal translation through the receiver. Interferon Type I receptor agonists include interferons, including interferons of natural origin, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, mixed interferons; antibodies specific for an interferon receptor; non-peptide chemical agonists; and similar. [0143] As used herein, the term "interferon Type II receptor agonist" refers to any ligand of the Type II receptor of human interferon, of natural origin or of unnatural origin, which is linked to, and which causes a signal translation through the receiver. Type II interferon receptor agonists include interferon-? native human, species of IFN-? recombinant, glycosylated species of IF? - ?, PEGylated species of IF? - ?, modified species or variants of IF? - ?, IF fusion proteins? - ?, receptor-specific agonist antibodies, non-peptide agonists, and the like . [0144] As used herein, the term "interferon Type III receptor agonist" refers to any receptor a ligand a. of human IL-28, of natural origin or of non-natural origin ("IL-28R"), whose amino acid sequence is described by Sheppard, et al., infra., which is linked to, and which causes a signal translation through the receiver. [0145] As used herein, the term "interferon receptor agonist" refers to any interferon Type I receptor agonist, interferon Type II receptor agonist, or interferon Type III receptor agonist. [0146] The term "dosing event" as used herein, refers to the administration of an antiviral agent to a patient in need, which may eventually encompass one or more discharges of an antiviral agent from a delivery device. drug. Therefore, the term "dose event", as used herein, includes, but is not limited to, the implementation of a continuous delivery device, (e.g., a pump or other controlled injectable delivery system); a simple subcutaneous injection followed by the implementation of a continuous administration system. [0147] "Continuous administration" as used herein, (e.g. in the context of "continuous administration of a substance to a tissue") has the meaning of referring to the movement of the drug from the administration site, e.g. a tissue in a form that provides an administration of a desired amount of substance within the tissue, for a selected period of time, wherein approximately the same amount of drug is received by the patient each minute during the selected period of time. [0148] ] "Controlled discharge" as used herein, (e.g. in the context of "controlled drug release") encompasses substrate discharge (e.g., a Type I or Type III interferon receptor agonist, e.g. -a) at a selected or controlled speed in some way, the interval, and / or the quantity, which is not substantially influenced by the environment of use., but not necessarily limited to, substantially continuous administration, and administration following a pattern (eg, intermittent administration over a period of time that is interrupted by regular or irregular time intervals). [0149] "Following a pattern" or "temporary" as used in the context of drug administration, encompasses the administration of the drug following a pattern, generally a substantially regular pattern, over a preselected period of time (for example, an injection). of bolus). Drug administration "following a pattern" or "temporary" encompasses drug administration at a rate or range of increasing, decreasing, substantially constant, or pulsatile rates (eg, amount of drug per unit time, or volume of drug formulation) per unit of time), and subsequently covers an administration that is continuous or substantially continuous, or chronic. [0150] The term "controlled drug delivery device" encompasses any device where the administration (eg, the rate, time of discharge) of a drug or other desired substance that is contained in it is controlled by or determined by the device in if same, I am substantially influenced by the environment of use, or discharge at a rate that is reproducible within the environment of use. [0151] By "substantially continuous" as used, for example, in the context of "infusion" "substantially continuous" or "substantially continuous administration" is understood as the administration of the drug in a manner that is substantially uninterrupted during a preselected drug administration period, wherein the amount of drug received by the patient during any 8-hour interval in the period preselected never falls to zero.Moreover, "substantially continuous" drug administration can also encompass to drug administration at a substantially constant speed or range of speeds (eg, amount of drug per unit time, or volume of drug formulation per unit time) which is substantially uninterrupted for a preselected period of time. [0152] "Substantially steady state" as used in the context of a biological parameter that can vary as a function of time, is understood as the biological parameter that exhibits a substantially constant value over time, such as the area under the curve defined by the value of the biological parameter as a function of time during any 8 hour period during the time course (AUCdhr), and which is not more than about 20% above or about 20% below, and preferably, not more than about 15% above and about 15% below, and more preferably not more than 10% above and 10% below the average area under the curve of the biological parameter over a period of 8 hours over the course of time ( AUC8hr). The average AUC8hr is defined as the quotient (q) of the area under the curve of the biological parameter during the complete course of time (AUCotal), divided by the number of 8-hour intervals in the total time (total / 3 days), this is q = (AUCtotal) / (total / 3dias). For example, in the context of a serum concentration of a drug, the serum concentration of the drug is maintained in a substantially stationary state over the course of time when the area under the curve of the drug's serum concentration over time, during any period of 8 hours during the course of time (AUCdhr) is not more than about 20% above and 20% below the average area under the curve of the serum concentration of the drug , during a period of 8 hours in the course of time (Average AUCdhr), that is, the AUCdhr is not more than 20% higher or 20% lower than the average AUC8hr for the serum concentration of the drug over time. [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 covalently linked to another electronegative atom (such as oxygen, nitrogen, sulfur or halogen). See, for example, Stryer et al, "Biochemistry", Fifth Edition 2002, Freeman & Co. N. Y. Typically, the hydrogen bond is between a hydrogen atom and two unshared electrons from another atom. A hydrogen bond between hydrogen and an electronegative atom bound to hydrogen non-covalently can be present when the hydrogen atom is at a distance of about 2.5 angstrom to 3.8 angstrom from the non-covalently bonded electronegative atom, and the angle formed by the three atoms (electronegative atom covalently bonded to hydrogen, hydrogen, and electronegative atom bound non-covalently to hydrogen) deviate from the IdO degrees by approximately 45 ° or less. The distance between the hydrogen atom and the electronegative atom bound non-covalently to hydrogen can be called "length of the hydrogen bond" and the angle formed by the three atoms (electronegative atom covalently bound to hydrogen, hydrogen, and electronegative atom bound non-covalently to the hydrogen) can be named as "hydrogen bond angle". In some cases, stronger hydrogen bonds are formed when the hydrogen bond length is shorter; therefore, in some cases, the lengths of the hydrogen bonds may be in a range of about 2.7 angstrom to about 3.6 angstroms, to about 2.9 angstroms to 3.4 angstroms. In some cases stronger hydrogen bonds are formed when the angle is closer to linearity; therefore, in some cases, hydrogen bond angles can deviate from 180 degrees by approximately 25 degrees or less, or by approximately 10 degrees or less. [154] As used herein, "non-polar interactions" refers to the proximity of non-polar molecules, or proximity of molecules or species with low polarity, sufficient for van der Waals interactions between molecules and / or enough to exclude polar molecules of solvent such as water molecules. See, for example Stryer et. to the. "Biochemistry", Fifth Edition 2002, Freeman & Co. N. Y. Typically, the distance between atoms (excluding hydrogen atoms) of interacting non-polar species may be in the range of about 2.9 angstroms to about 6 angstroms. In some cases, the space that separates interacting non-polar species is less than the space that would accommodate a water molecule. As used herein, a non-polar or low polarity species refers to species with low dipole moment (typically dipolar moments less than the depilatory moment of the OH bond of the water and the? -H link?) And / or species that they are not typically present in hydrogen bonds or electrostatic interactions. Examples of species with low polarity are alkyl, alkenyl, and unsubstituted aryl species.

[155] As used herein, an NS3 pocket protease SI 'refers to an NS3 protease molecule that interacts with the amino acid positioned at a distance residue towards the C terminus of the cleavage site of the olive substrate polypeptide by the NS3 protease (for example, NS3 protease molecules that interact with amino acid S in the substrate polypeptide DLEWT-STWVLV). Examples of species include, but are not limited to, peptide backbone atoms or the side chains of the amino acids Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Phe43, see Yao et al. Structure 1999, 7, 1353. [0156] As used herein, an NS3 pocket protease S2, refers to an NS3 protease molecule that interacts with the amino acid positioned at two residues toward termination? of the cleavage site of a substrate polypeptide cleaved by the protease S3 (for example the protease molecules S3 that interact with the amino acid V in the substrate polypeptide DLEWTSTWVLV). Examples of these species include, but are not limited to, peptide backbone atoms or side chains of amino acids His57, Argl55, Val7d, Asp79, Gln80 and Aspdl, see Yao. et. al., Structure 1999, 7, 1353. [0157] As used herein, a first residue "positioned by" a second residue refers to the spatial orientation of the first residue that is determined by the properties of the second residue at which the first atom or residue is covalently bound. For example, a phenyl carbon can position an oxygen atom attached to the phenyl carbon in a spatial position such that the oxygen atom forms a hydrogen bond with a hydroxyl residue in an active NS3 site. [0158] Before the embodiments are subsequently described, it should be understood that this invention is not limited to the particular embodiments described, as they may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing only the particular embodiments, and does not intend to be limiting. [0159] Where ranges of values are provided, it is understood that each intermediate value, up to one tenth of the lower limit unit unless the context clearly dictates otherwise, the upper and lower limits of the range and all other established value or intermediate in that established range is encompassed by the realizations. The upper and lower values of these smaller ranges can be included independently in the smaller ranges and are also encompassed within the embodiments, subject to any limits specifically excluded from the established range. Where the established range includes one or both limits, the ranges that exclude both limits are also included in the embodiments. [0160] Unless defined otherwise, all the technical and scientific terms used herein have the same meaning as commonly understood by someone of ordinary knowledge in the art, to whom the embodiments belong. Although any method or material similar or equivalent to those described herein may also be used in the practice or testing of embodiments, preferred methods and materials are now described. All publications mentioned herein are incorporated as references to expose and describe the methods and / or materials in connection with which the publications are cited. [0161] It should be noted that as here and in the appended claims the singular forms "a", "and", and "the" include plural referents, unless the context clearly dictates otherwise. Thus, for example, in reference to "one method" a plurality of such methods is included and in reference to "a dose" reference is included to one or more doses and equivalents thereof known to those skilled in the art, so forth . [0162] The publications mentioned herein are provided only by virtue of their publication date prior to the filing date of the present invention. Nothing expressed herein should be construed as an admission that the present invention does not have priority rights over said publication by a prior date of invention. In addition, the publication dates provided may be different from those of the actual publications, which must be confirmed independently. [0163] The embodiments provide compounds of Formula I -XIX, as well as pharmaceutical compositions and formulations comprising any compound of Formula I-XIX. A treated compound is useful for the treatment of flaviviral infection, such as infection with HCV and other disorders, as discussed below. Compositions [0164] Several embodiments of compositions are described below. To facilitate the discussion, the description of these embodiments is divided into Sections A, B, C, D and E. Several terms that may be defined within a particular Section are understood to apply within that Section, and also apply in wherever reference is made to that particular Section. Likewise, any reference, within a section, to a particular numbering or marking should be understood as in the context of the corresponding numbering or marking scheme used within that Section, rather than in the context of a numbering or dialing scheme possibly similar or identical used in an unrelated Section, unless indicated. Section A [0165] The embodiments of Section A provide compounds having the general Formula I: 11 I [0166] where: [0167] Q is a c: entral ring that is selected from

[0168] wherein the central ring may be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_ alkylcycloalkyl, C2_6 alkenyl, d-.beta.-alkoxy, hydroxy-C? G alkyl, d_6 alkyl, substituted d-β alkyl, d-6 alkoxy, substituted d-β alkoxy, C 6 0 aryl, pyrid, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamido, urea, thiourea, amido, keto , carboxyl, carbamyl, sulfur, sulfoxide, sulfone, amino, alkoxyamino, acyloxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, [0169] or Q is R ^ 2, where R1 is d -6 alkyl, C3.7 cycloalkyl, C-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 benzimide zol, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C? -6 alkyl, C3-7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2-g alkenyl, d-.beta.-alkoxy, hydroxy-C? -6 alkyl, or C? -g alkyl optionally substituted with up to 5 fluoro, or C? _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, C? _6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, C_6 alkenyl, d-6 alkoxy, hydroxy-C? -6 alkyl, C? The alkyl optionally substituted with up to 5 fluoro, or d_6 alkoxy optionally substituted with up to 5 fluoro;

[0170] R4 is H, C? _6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3 .7 cycloalkyl, C4.10 alkylcycloalkyl, C_6 alkenyl, d-6 alkoxy, hydroxy-dg alkyl, Ci-g alkyl optionally substituted with up to 5 fluoro, or Ci-g alkoxy optionally substituted with up to 5 fluoro; [0171] R5 is H, C? -6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR21NH (CO R22; [0172] R6 and R7 are each independently H, d-6 alkyl, C3-7 cycloalkyl, C4_10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci-g alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, C2.s alkenyl, hydroxy-Ci-g alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? ~ 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 Ca_6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R8 is Cg 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci-g alkyl, C3-7 cycloalkyl, C_10 alkylcycloalkyl, C2-g alkenyl, d-6 alkoxy, hydroxy-alkyl, d_s alkyl optionally substituted with up to 5 fluoro, or d-β alkoxy optionally substituted with up to 5 fluoro; or R8 is d-S alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [0174] Y is a sulfonimide of the formula -C (0) NHS (0) 2R9, where R9 is C? -6 alkyl, C3_7 cycloalkyl, or C_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, d_g alkoxy, or phenyl, or R9 is C6 0 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, d-alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C_g alkenyl, d-βalkoxy, hydroxy-Cα-6alkyl, or d-6alkyl optionally substituted with up to 5 fluoro, C? _alkoxy optionally substituted with up to 5 fluoro; or R9 is a Cl-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 with halo, cyano, nitro, hydroxyl, or C? _6 alkoxy; or Y is a carboxylic acid or a salt, solvate or prodrug acceptable for pharmaceutical use thereof;

[0175] where Rla and Rlb are each independently H, d_6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, d_6 alkoxy, amido , or phenyl, [0176] or Rla and Rlb are each independently H and Cg or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, d_g alkyl, C3-7 cycloalkyl, d-x or alkylcycloalkyl , C2-g alkenyl, d-6 alkoxy, hydroxy-C? Alkyl, C? -alkyl optionally substituted with up to 5 fluoro, or dg alkoxy optionally substituted with up to 5 fluoro, [0177] or Rla and Rlb are each independently H, heterocycle, which is a five, six or seven membered heterocyclic molecule, saturated or unsaturated, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, [0178] or NRlaRlb is a cycloalkyl secondary amine of three to six members, which optional has one to three heteroatoms incorporated into the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, C? -6 alkoxy, amido, or phenyl, [0179] or? RlRlb is a heteroaryl which is select from the group consisting of:

[0180] where Rlc is H, halo, alkyl, C3-5 cycloalkyl, C6-6 alkoxy, C3-S cycloalkoxy, N02, N (Rld) 2, NH (C0) Rld, or NH (C0) NHRld, where each Rld is independently H, d-6 alkyl, or C3-6 cycloalkyl, [0181] or Rlc is NH (CO) ORle, where Rle is C? -6 alkyl or C3-6 cycloalkyl; [0182] p = 0 or 1; [0183] V is selected from 0, S, or NH; [0184] when V is O or S, it is selected from 0, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C6-6alkyl, C3_7 cycloalkyl, C_10alkylcycloalkyl, or d -6alkyl optionally substituted with up to 5 fluoro; [0185] the hyphen lines represent a double additional ligature; [0186] R21 is d-β alkyl, C3.7 cycloalkyl, C4_ alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C_6 alkoxy, C6-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or the aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, or C? -6 alkyl optionally substituted with up to 5 fluoro, C? _ alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and [0187] R22 is alkyl, C3_7 cycloalkyl, or C4-? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl. [0188] In preferred embodiments, the embodiments of Section A provide compounds having the general Formula I, wherein the central ring is

[0189] In preferred embodiments, the embodiments of Section A provide compounds having the general Formula I, wherein the central ring is

[0190]. In preferred embodiments, the embodiments of Section A provide compounds having the general Formula I, wherein the central ring is

[0191] In preferred embodiments, the embodiments of Section A provide compounds that have the general formula la: [0192] In preferred embodiments, the embodiments of the compounds that have the General Formula Ib

[0193] In preferred embodiments, embodiments of Section A provide compounds that have Q The general formula reads: [0194] In the preferred embodiments, the embodiments of Section A provide compounds that have Id the General Formula Id:

[0195] In preferred embodiments, the embodiments of Section A provide compounds having Q w The general formula is: [0196] In the preferred embodiments, embodiments of Section A provide compounds having / Q 11 the General Formula If:

[0197] In the preferred embodiments, embodiments of Section A provide compounds having / Q ig General Formula Ig: [0198] In preferred embodiments, embodiments of Section A provide compounds having the general formula Ih:

[0199] In the preferred embodiments, the embodiments of Section A provide compounds that have n General Formula Ii: [0200] In preferred embodiments, the embodiments of Section A provide compounds having the General Formula Ij

[0201] In preferred embodiments, the embodiments of Section A provide compounds having Q w General Formula Iz: [0202] In preferred embodiments, embodiments of Section A provide compounds having the general Formula I, wherein Y is sulfonimide of the formula -C (O) NHS (O) 2R9, wherein R9 is selects from the group consisting of C? -6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, and NRlaRlb, where RI and Rlb are each independently H, C? _g alkyl, or C3_7 cycloalkyl. [0203] In preferred embodiments, the embodiments of Section A provide compounds having the general Formula I, wherein the C13-C14 double bond is cis. [0204] In preferred embodiments, the embodiments of Section A provide compounds having the general Formula I, wherein the C13-C14 double bond is trans. [0205] In some embodiments, the compounds of general Formula I do not include the compounds disclosed in PCT / US04 / 33970. For example, in some 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] The embodiments of Section B provide c: II III IV [0207] wherein: [0208] R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2-g alkenyl, C ? 6 alkoxy, hydroxy-C? -6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, d-β alkoxy optionally substituted with up to 5 fluoro, C6 or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (0) 2NR6R7, NHC (0) NR6R7, NHC (S) NR6R7, C (0) NR6R7, NR6R7, C (0) R8, C (0) OR8, NHC (O) R8, NHC (O) OR8, SOmR8, NHS (O) 2R8, CHnNR6R7, OCHnNR6R7, or OCHnR9 wherein 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, d-6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, CX-g alkoxy, hydroxy ~ d_g alkyl, d_6 alkyl optionally substituted with up to 5 fluoro, or Ci-g alkoxy optionally substituted with up to 5 fluoro; said Cs 0 10 aryl, pyridal, phenoxy and thiophenoxy in the definition of R1 and R2 are optionally substituted by up to three halo, cyano, nitro, hydroxy, d6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Ci g alkoxy, hydroxy-Ci-g alkyl, d-6 alkyl optionally substituted with up to 5 fluoro, or C? _alkoxy optionally substituted with up to 5 fluoro; [0209] m = 0, 1, or 2; [0210] R4 is H, d_6 alkyl, C3_7 cycloalkyl, C_? 0 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -g alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxyC_6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _s alkoxy optionally substituted with up to 5 fluoro, - [0211] R5 is H, d- 6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR21NH (CO) R22; [0212] R6 and R7 are each independently H, d- 6 alkyl, C3_7 cycloalkyl, C-? 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2.6 alkenyl, hydroxy-C? _6 alkyl, or dg alkyl optionally substituted with up to 5 fluoro, C? _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 d-6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, d_g alkoxy, or phenyl; or R8 is C6 0? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _g alkyl, C3_7 cycloalkyl, C4-? 0 • alkylcycloalkyl, C2_6 alkenyl, C6-alkoxy, hydroxy-C1-alkyl, or Ca_g alkyl optionally substituted with up to 5 fluoro, C6-alkoxy optionally substituted with up to 5 fluoro; or R8 is d_g alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [0214] Y is a sulfonimide of the formula -C (O) NHS (0) 2R9, where R9 is C? -6 alkyl, C3_7 cycloalkyl, or C4_? Or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _g alkoxy, or phenyl, or R9 is C6_? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _g alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl , C2-6 alkenyl, C6-6alkoxy, hydroxy-d-6alkyl, or Ci-βalkyl optionally substituted with up to 5 fluoro, Ci-βalkoxy optionally substituted with up to 5 fluoro; or R9 is an optionally substituted Cl-6 alkyl 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 C? _g alkoxy; or Y is a carboxylic acid or a salt, solvate or prodrug acceptable for pharmaceutical use thereof; [0215] R10 and R11 are each independently H, C? -6 alkyl, C3.7 cycloalkyl, C-10 alkylcycloalkyl, Cg 0 aryl, hydroxy-C? G alkyl, d-6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, (CH2) nC (0) OR14 where R14 is H, C? _g alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro , hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 Q 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, d-β alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2-alkenyl, C6-6 alkoxy, hydroxy-d-6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or Ci-g alkoxy optionally substituted with up to 5 fluoro; said C6 0 or aryl, in the definition of R10 and R11 is optionally substituted by up to three halo, cyano, nitro, hydroxy, dg alkyl, C3_7 cycloalkyl, C_? 0 alkylcycloalkyl, C2_6 alkenyl, d-6 alkoxy, hydroxy-C ? 6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or Ci-g 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; [0216] p = 0 or 1; [0217] R12 and R13 are each independently H, C? -g alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C6 010 aryl, hydroxyCi-g alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, (CH2) ) nNR6R7, (CH2) nC (O) OR14 where R14 is H, Cx-g alkyl, C3-7 cycloalkyl, C4-? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _g alkoxy, or phenyl; or R14 is Cg 0 which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxyCi_g alkyl C6-6alkyl optionally substituted with up to 5 fluoro, or Ci-galkoxy optionally substituted with up to 5 fluoro; said C6 0 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci-g alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, C6_6 alkoxy, hydroxy C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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 -6 alkyl optionally substituted with (CH2) nOR8; [0218] is H, C? _s alkyl, C3.7 cycloalkyl, C4. 10 alkylcycloalkyl, Cs 0 10 aryl, hydroxy-Ci-g alkyl, d-β alkyl optionally substituted with up to 5 fluoro, or (CH 2) n NR 6 R 7, (CH 2) n C (0) OR 14 where R 14 is H, d-β alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C6-6 alkoxy, or phenyl; or R14 is Cg 010 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, d-alquilo alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, C _ alkoxy, hydroxy-Ci-g alkyl, C ? 6 alkyl optionally substituted with up to 5 fluoro, or Ci-g alkoxy optionally substituted with up to 5 fluoro; said C6 0 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2-6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, or d-β alkyl optionally substituted with up to 5 fluoro, Ci-g alkoxy optionally substituted with up to 5 fluoro; [0219] n = 1-4; [0220] V is selected from O, S, or NH; [0221] when V is O or S, W is selected from O, NR15, or CR15; when V is NH, it is selected from NR15 or CR15, where it is H, C? alkyl, C3.7 cycloalkyl, C4. 10 alkylcycloalkyl, or Ca_6 alkyl optionally substituted with up to 5 fluoro; [0222] the line of dashes represents a double additional ligature; [0223] R is C? _6 alkyl, C3_7 cycloalkyl, C4_ alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, Ci-? Alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci-β alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2 ~ 6 alkenyl, C? -6 alkoxy, hydroxy-C ? -6 alkyl, C? _g 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 [0224] R is d_6 alkyl, C3.7 cycloalkyl, nC4_-1: 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _g alkyl optionally substituted with up to 5 fluoro, or phenyl. [0225] The embodiments of Section B provide compounds having the general Formula II, 11 II [0226] wherein: [0227] R1 is H, halo, cyano, nitro, hydroxy, d-β alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2-6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C-alkoxy optionally substituted with up to 5 fluoro; [0228] R2 is H, OCHnNR6R7, OCHnR16, halo, cyano, nitro, hydroxy, Ci-g alkyl, C3.7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2_6 alkenyl, Ci-e alkoxy, hydroxy-C? _6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; said R6 and R7 in the definition of R2 each being independently H, d-6 alkyl, C3_7 cycloalkyl, or C4_? or 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 (0) NR6R7 or C (0) OR8, said R6 and R7 in the definition of R5 each being independently H, d-e alkyl, C3_7 cycloalkyl, or C4-10 alkylcycloalkyl; [0232] R8 is Ci-e alkyl, C3.7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [0233] Y is a sulfonimide of the formula - C (0) NHS (0) 2R9, where R9 is C? -6 alkyl, C3_7 cycloalkyl, or C4_? Or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, C? _6 alkoxy, or phenyl; [0234] R10, R11, R12 and R13 are H; [0235] p = 0 or 1; [0236] V = 0; and [0237] is selected from 0, NH, or CH2. [0238] In preferred embodiments, embodiments of Section B provide compounds having general Formulas II, III, and IV, wherein p may be 0. In preferred embodiments, embodiments of Section B provide compounds having General Formulas II, III, and IV, wherein p may be 1. [0239] In preferred embodiments, embodiments of Section B provide compounds having general Formulas II, III, and IV, wherein 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, the embodiments of Section B provide compounds having general Formulas II, III, and IV, wherein neither R1 nor R2 is H. In some embodiments, p is 0. In other embodiments, p is 1. [0241] In preferred embodiments, embodiments of Section B provide compounds having general Formulas II, III, and IV, where R2 is 0CHnNR6R7 or 0CHnR 16 [0242] In preferred embodiments, the embodiments of Section B provide compounds having general Formulas II, III, and IV wherein R9 is C? -6 alkyl, C3-7 cycloalkyl, or C4-? 0 alkylcycloalkyl, all which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, Ci-g alkoxy, or phenyl. [0243] In preferred embodiments, the embodiments of Section B provide compounds having the general formulas II, III, and IV wherein R9 is C6 or the aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C, alkyl, C3-7 cycloalkyl, C-? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, dg alkyl optionally substituted with up to 5 fluoro, or d-.beta.-alkoxy optionally substituted with up to 5. fluoro. [0244] In preferred embodiments, the embodiments of Section B provide compounds having general Formulas II, III, and IV wherein R9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C? _6 alkoxy. [0245] In preferred embodiments, the embodiments of Section B provide compounds having general Formulas II, III, and IV wherein R9 is an optionally substituted Cl-6 alkyl with up to 5 fluoro groups, NR6R7, or (CO ) OH. [0246] In preferred embodiments, the embodiments of Section B provide compounds having general Formulas II, III, and IV wherein the dashed line in Formula (II), (III), or (IV) represents a linkage simple. [0247] The embodiments of Section B provide compounds having the general Formula II: II [0248] wherein: [0249] R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, Ci-g alkyl, C3-7 cycloalkyl, C_ or alkylcycloalkyl, C2-6 alkenyl, C? -6alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, C6-6alkoxy optionally substituted with up to 5 fluoro, C6 or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (0) 2NR6R7, NHC (0) NR6R7, NHC (S) NR6R7, C (0)? R6R7,? R6R7, C (0) R8, C (0) 0R8,? HC (0 R8,? HC (0) 0R8, SOmR8,? HS (0) 2R8, OCHn? R6R7, or OCHnR16 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, C6-6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? -6 alkoxy optionally substituted with up to 5 fluoro; said Cg 0 the aryl, pyridal, phenoxy, and thiophenoxy in the definition of R1 and R2 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C-? 0 alkylcycloalkyl, d-b alkenyl, d-6alkoxy, hydroxy-C? -6alkyl, C? _6alkyl optionally substituted with up to 5 fluoro, or C? -6alkoxy optionally substituted with up to 5 fluoro; [0250] m = 0, 1, or 2;

[0251] R4 is H, C? -6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_x0 alkylcycloalkyl, C2-6 alkenyl, C? alkoxy, hydroxyCi-g alkyl, d-6 alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; [0252] R5 is H, C? _6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR21NH (CO) R22; [0253] R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4-? or alkylcycloalkyl, C2-6 alkenyl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? -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 C? -6 alkyl, C3-7 cycloalkyl, or C_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, d-6 alkoxy, or phenyl; or R8 is C6 0 i0 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_ alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _ Alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or Rs is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [0255] Y is a sulfonimide of the formula -C (0) NHS (0) 2R9, where R9 is C? _6 alkyl, C3-7 cycloalkyl, C_20 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo , cyano, nitro, hydroxy, C6-6alkoxy, or phenyl, or R9 is C6 or the aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_s alkenyl, C6-6alkoxy, hydroxy-C6-6alkyl, C1-galkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro, or R9 is an a Cl-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 C6-alkoxy; or Y is a carboxylic acid or a salt, solvate or prodrug acceptable for pharmaceutical use thereof;

[0256] R10 and R11 are each independently H, dg alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, Cs 0 i0 aryl, hydroxy-C? G alkyl, C_6 alkyl optionally substituted with up to 5 fluoro, (CH2) ) nNR6R7, or (CH2) nC (O) OR14 where R is H, C? _6 alkyl, C3.7 cycloalkyl, a or alkylcycloalkyl, all of which are optionally substituted one to three times with halo, cyano, nitro, hydroxy, C? _g alkoxy, or phenyl; or R14 is C6 0? 0 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_ cycloalkyl, C4_? 0 alkylcycloalkyl, C2-6 alkenyl, C? -6 alkoxy, hydroxy C? _6 alkyl, d-6 alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; said Cs 0 aryl, in the definition of R10 and R11 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _g alkyl, C3.7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, C? alkoxy, hydroxy-Ci-g alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or C? _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; [0257] p = 0 O 1; [0258] R12 and R13 are each independently H, C? -6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C6 010 aryl, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, or (CH2) nC (O) OR14 where R14 is H, C-6 alkyl, C3-7 cycloalkyl, C_? Alkylcycloalkyl, all of which are optionally substituted between one and three times with halo , cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R14 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4-? or alkylcycloalkyl, C2_6 alkenyl, C6-alkoxy, hydroxy-Ci-β alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Ci-g alkyl, C3_7 cycloalkyl, C-? 0 alkylcycloalkyl, C2.6 alkenyl, Ci-g alkoxy , hydroxy-Ci-g alkyl, d-6 alkyl optionally substituted with up to 5 fluoro, or C? s 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 C C _alkyl optionally substituted with (CH2) nOR8; [0259] R20 is H, C? -6 alkyl, C3.7 cycloalkyl, C4-? 0 alkylcycloalkyl, C6 or aryl, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, (CH2) ) nNR6R7, or (CH2) C (O) 0Rxi where R14 is H, C? _6 alkyl, C3_7 cycloalkyl, C4-? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy , C? -6 alkoxy, or phenyl; or R14 is Ce or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-d_6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_s alkenyl, C? _6 alkoxy, hydroxy-C ? 6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or C? -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 O or S, W is selected from O,? R15, or CR15; when V is? H, it is selected from? R15 or CR15, where R is H, C? -6 alkyl, C3_7 cycloalkyl, alkylcycloalkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro; [0263] the line of dashes represents a double additional ligature;

[0264] R21 is C? _6 alkyl, C3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 0 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-C6_6 alkyl, C? .6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and [0265] R is C? _6 alkyl, C3_7 cycloalkyl, alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl . [0266] The embodiments of Section B provide compounds having the general Formula lia: 11 Ha [0267] wherein: [0268] R1 and R2 are each independently H, halo, cyano, hydroxy, C? _3 alkyl, or C? -3 alkoxy; [0269] R5 is H, C (0) NR6R7, C (0) R8, or C (0) 0R8; [0270] R6 and R7 are each independently H, Ci-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl; [0271] R8 is C? -6 alkyl, C3-7 cycloalkyl, C4? 0 alkylcycloalkyl, or 3-tetrahydrofuryl. [0272] Y is a sulfonimide of the formula -C (0) NHS (0) 2R9, where R9 is Cx_3 alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C? _3 alkyl, C3_7 cycloalkyl, or C? _3 alkoxy, or Y is a carboxylic acid or a pharmaceutically acceptable salt, solvate or prodrug thereof;

[0273] R10 and R11 are each independently H or C_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 O or NH; and [0275] the dashed line represents a double additional ligature. [0276] The embodiments of Section B provide compounds that have l l Illa: Illa [0277] wherein: [0278] R1 and R2 are each independently H, halo, cyano, hydroxy, C? -3 alkyl, or C? -3 alkoxy; [0279] R4 is H; [0280] R5 is H, C (0) NR6R7, C (0) R8, or C (0) 0R8; [0281] R8 is C? -6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, or 3-tetrahydrofuryl.

[0282] Y is a sulfonimide of the formula -C (O) NHS (O) 2R9, where R9 is C? -3 alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, d_3 alkyl, C3-7 cycloalkyl, or C? _3 alkoxy, or Y is a carboxylic acid or a pharmaceutically acceptable salt, solvate or prodrug thereof; [0283] is selected from O or NH; and [0284] the dashed line represents an additional double binding. [0285] The embodiments of Section B provide compounds having the general Formula Hb: Hb [0286] wherein: [0287] R1 and R2 are each independently H, halo, cyano, hydroxy, C? _3 alkyl, or d-3 alkoxy; [0288] R5 is H, C (0) OR8 or C (0) NHR8;

[0289] R is C? _6 alkyl, C5-6 cycloalkyl, or 3-tetrahydrofuryl; [0290] R9 is d_3 alkyl, C3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? -3 alkyl, or C? -3 alkoxy; [0291] R10 and R11 are each independently H or C? _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] is selected from 0 or NH; and [0293] the dashed line represents an additional double binding. [0294] The embodiments of Section B provide compounds that IHb [0295] wherein: [0296] R1 and R2 are each independently H, halo, cyano, hydroxy, C? _3 alkyl, or C? _3 alkoxy; [0297] R5 is H, C (O) OR8 or C (0) NHR8; [0298] R8 is C? -6 alkyl, C5-6 cycloalkyl, or 3-tetrahydrofuryl; [0299] R9 is C? _3 alkyl, C3.5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or Cx_3 alkoxy; [0300] R10 and R11 are each independently H, CX-3 alkyl, or C4_5 cycloalkyl; [0301] W is selected from 0 or NH; and [0302] the dashed line represents an additional double binding. [0303] The embodiments of Section B provide compounds having the general formula He:

[0304] wherein: [0305] R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C? _3 alkyl, or d-3 alkoxy; [0306] R5 is H, C (O) OR8 or C (0) NHR8; [0307] R8 is C? -6 alkyl or C5_6 cycloalkyl; [0308] R9 is C? _3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? -3 alkyl, or C? -3 alkoxy; (e) R10 and R11 are each independently H or C? _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 line of dashes represents a double additional ligature. [0309] The embodiments of Section B provide compounds having the general Formula lile: IIIc [0310] wherein: [0311] R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C? _3 alkyl, or C? -3 alkoxy; [0312] R5 is H, C (0) 0R8 or C (0) NHR8; [0313] R8 is C? _6 alkyl or C5_6 cycloalkyl; [0314] R9 is C? _3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or C? -3 alkoxy; and [0315] the dashed line represents a double additional ligature. [0316] The embodiments of Section B provide compounds having the general Formula IHd: 11 IHd [0317] where: [0318] R > 1, y-tR? 2 are each independently H, halo, cyano, hydroxy, Cx_3 alkyl, or C? -3 alkoxy; [0319] R4 is H; [0320] R5 is H, C (0) NR6R7, C (0) R8, or C (0) OR8;

[0321] R8 is C? _g alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, or 3-tetrahydrofuryl; [0322] Y is a sulfonimide of the formula -C (O) NHS (O) 2R9, where R9 is d -3 alkyl, C3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy , C? _3 alkyl, C3_7 cycloalkyl, or C? -3 alkoxy, or Y is a carboxylic acid or a pharmaceutically acceptable salt, solvate or prodrug thereof; [0323] R10 and R11 are each independently H or C? _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] R is H, C? _6 alkyl, C3_7 cycloalkyl, C4 alkylcycloalkyl, C6 or aryl, hydroxy-C? -6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, or (CH2) nC (0) 0R14 where R14 is H, C? _6 alkyl, C3-7 cycloalkyl, or C4_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R is aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_g alkenyl, C? -6 alkoxy, hydroxy-C? _6 alkyl, C ? 6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _s alkoxy , hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; [0325] W is selected from O or NH; and [0326] the dashed line represents an additional double binding. [0327] The embodiments of Section B provide compounds having the general Formula IVa: or IVa [0328] wherein: [0329] R1 and R2 are each independently H, halo, cyano, hydroxy, C? _3 alkyl, or C? .3 alkoxy; [0330] R4 is H; [0331] R5 is H, C (0) NR6R7, C (0) R8, or C (0) 0R8;

[0332] R8 is Ca_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-tetrahydrofuryl; [0333] Y is a sulfonimide of the formula C (O) NHS (0) 2R9, where R9 is C? -3 alkyl, C3.7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy , C? _3 alkyl, C3_7 cycloalkyl, or C? _3 alkoxy, or Y is a carboxylic acid or a pharmaceutically acceptable salt, solvate or prodrug thereof, - [0334] R10 and R11 are each independently H or d_3 alkyl, or R10 and R11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; [0335] R is H, C? _6 alkyl, C3-7 cycloalkyl, C4_3 alkylcycloalkyl, C6 or? Or aryl, hydroxy-Ci-g alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, and (CH2) nC (O) OR14 where R14 is H, d_6 alkyl, C3.7 cycloalkyl, or C4_? Or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro , hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C-6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-d_6 alkyl, C ? 6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; said C6 or? aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2.6 alkenyl, C? _s alkoxy , hydroxy-C? -6 alkyl, or C? -6 alkyl optionally substituted with up to 5 fluoro, C? -6 alkoxy optionally substituted with up to 5 fluoro; [0336] is selected from O or NH; [0337] the line of dashes represents a double additional ligature; and [0338] where Z is a fused or added aryl heteroaryl ring system. Section C [0339] The embodiments of Section C provide compounds having the general Formula XI.

XI

[0340] where: [0341] Rla and Rlb are each independently H, C? -6 alkyl, C3_7 cycloalkyl, or C4-? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, d-.beta.-alkoxy, amido, or phenyl; [0342] or R1 and R1b are each independently H or C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, d-β alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C6-alkoxy, hydroxy-d-alkyl, Ci-g-alkyl optionally substituted with up to 5-fluoro, or C6-alkoxy optionally substituted with up to 5-fluoro; [0343] or Rla and Rlb are each independently H or heterocycle, which is a five, six or seven membered heterocyclic molecule, saturated or unsaturated, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; [0344] or NRlaRlb is a three to six membered cycloalkyl secondary amine, optionally having one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, Ci-g alkoxy , amido, or phenyl; [0345] or NR ^ R113 is a heteroaryl selected from the group consisting of: "N ^. And ^ • ^> ^ -R1c, 1c, and \ =? C .1c

[0346] where Rac is H, halo, C? -6 alkyl, C3_6 cycloalkyl, C? _6 alkoxy, C3-6 cycloalkoxy, N02, N (Rld) 2, NH (CO) Rld, or NH (CO) NHRld, wherein each Rld is independently H, C? -6 alkyl, or C3-.6 cycloalkyl; [0347] or Rlc is NH (CO) ORle where Rle is d-β alkyl or C 3-6 cycloalkyl; [0348] W is O or NH; [0349] V is selected from O, S, or NH; [0350] 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, C? _6 alkyl, C3-7 cycloalkyl, C-? 0 alkylcycloalkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro; [0351] R2 is a bicyclic secondary amine with the structure:

[0352] where R21 and R22 are each independently H, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_? cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-C? -6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro, C6 or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (0) 2NR6R7, NHC (0) NR6R7, NHC (S) NR5R7, C (0)? RsR7,? R6R7, C (0) R8, C (0) OR8,? HC (0) R8,? HC (0) OR8, SOmR8 (m = 0, lo 2), or? HS (0) 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, alkyl, C3_7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2_e alkenyl, Ca_6 alkoxy, hydroxy -Cx-g alkyl, Cx-g alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; said C6 or? or aryl, pyridal, phenoxy, and thiophenoxy in the definition of R21 and R22 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C6-6alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro; [0353] wherein R10 and R11 are each independently H, Ca_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, Cg 0 10 aryl, hydroxy-C? -6 alkyl, or C_6 alkyl optionally substituted with up to 5 fluoro, ( CH ^ n? R '7, or (CH2) nC (0) OR14 where R14 is H, d-6 alkyl, C3.7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C6-6alkoxy, or phenyl, or R is CeO or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C6_ alkoxy, hydroxyCi_g_ alkyl, or Ci_g alkyl optionally substituted with up to 5 fluoro, C_g_alkoxy optionally substituted with up to 5 fluoro, said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _g alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-Ci-g al chyl, C? _g alkyl optionally substituted with up to 5 fluoro, or C? -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; [0354] where p = 0 or 1; [0355] wherein R12 and R13 are each independently H, C? -6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C6 or? Or aryl, hydroxy-C? -6 alkyl, d-e alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, (CH2) nC (0) OR14 where R14 is H, d-alquilo alkyl, C3_7 cycloalkyl, C4_ 0 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy , C-alkoxy, or phenyl; or R14 is Cg 0 which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-C? _6 alkyl C6-6 alkyl optionally substituted with up to 5 fluoro, C6-alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3-7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2_6 alkenyl, C? 6 alkoxy, hydroxy-C? -6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or C? -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] where R20 is H, C? -6 alkyl, C3-7 cycloalkyl, C4_? Or alkylcycloalkyl, C6 or aryl, hydroxy-C? -6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, (CH2) nC (0) OR14 where R14 is H, C? _6 alkyl, C3.7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro , hydroxy, Ci-g alkoxy, or phenyl; or R14 is C6 0 x or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C2.6 alkenyl, C6-6 alkoxy, hydroxy-C6-6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, Ci-g alkoxy optionally substituted with up to 5 fluoro; said C6 0 10 aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3.7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C6-6 alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C1-6alkoxy optionally substituted with up to 5 fluoro; [0357] where n = 0-4; [0358] where R6 and R7 are each independently H, C1-6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Ca_6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, C2_e alkenyl, hydroxy-C6-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C6-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 RaR2b when W = NH and V = O, where [0360] R a is C? _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 NR2cR2d, halo, cyano, nitro, hydroxy , C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2.6 alkenyl, C? -6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? _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, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole , or benzimidazole, each optionally substituted with up to three NRcR2d, halo, cyano, nitro, hydroxy, C? -6 alkyl, C3.7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-C ? 6 alkyl, or C? ~? Alkyl optionally substituted with up to 5 fluoro, C? -6 alkoxy optionally substituted with up to 5 fluoro; [0362] said R2c and R2d are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl , C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-Ci-alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or d-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; [0363] R4 is H, C? _6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl , C2_6 alkenyl, C6-alkoxy, hydroxy-C6-6 alkyl, C6-6 alkyl optionally substituted with up to 5 fluoro, or d-6alkoxy optionally substituted with up to 5 fluoro; [0364] R5 is H, d_6 alkyl, C (0) NR6R7, C (S) R6R7, C (0) R8, C (0) 0R8, or S (0) 2R8; [0365] R8 is C? _6 alkyl, C3.7 cycloalkyl, or C4-10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R8 is Cs 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4-? 0 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C? Alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro, and [0366] the dashed line represents an additional double bond. [0367] The embodiments of Section C provide compounds having the general Formula XII.

XII

[0368] where: [0369] Rla and Rlb are each independently H, C? -6 alkyl, C3_7 cycloalkyl, or C? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, C? _6 alkoxy, amido, or phenyl; [0370] or Rla and Rlb are each independently H or heteroaryl selected from the group consisting of:

[0371] where Rlc is H, halo, d_6 alkyl, C3-6 cycloalkyl, C? _6 alkoxy, C3-6 cycloalkoxy, N0, N (Rld) 2, NH (CO) Rld, or? H (C0)? HRld , wherein each Rld is independently H, C? _6 alkyl, or C3_g cycloalkyl;

[0372] or NRlaR?: B is a three to six membered cycloalkyl secondary amine, optionally having one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, Cx_g alkoxy, amido, or phenyl; [0373] R21 and R22 are each independently H, halo, cyano, hydroxy, d-3 alkyl, or C1-3 alkoxy; [0374] R5 is H, C (0) NR6R7, C (0) R8, or C (0) OR8; [0375] Rs and R7 are each independently H, Cx_6 alkyl, C3.7 cycloalkyl, C4_10 alkylcycloalkyl, or phenyl; [0376] R8 is C? _6 alkyl, C3.7 cycloalkyl, C4_? Or alkylcycloalkyl, or 3-tetrahydrofuryl; [0377] R10 and R11 are each independently H, halo, or C? -3 alkyl, or R10 and R11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; [0378] R12 and R13 are each independently H, halo, C? -6 alkyl, C3_7 cycloalkyl, C_ or alkyl alkylcycloalkyl, C6 or? Or aryl, hydroxy-Cx_6 alkyl, or C_g alkyl optionally substituted with up to 5 halo atoms , - and [0379] the line of dashes represents a double additional ligature. [0380] The embodiments of Section C provide compounds having the general Formula XIII.

[0381] where: [0382] Rla and Rlb are each independently H, d_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, C? -6 alkoxy, amido, or phenyl; [0383] or Rla and Rlb are each independently H or heteroaryl selected from the group consisting of:

[0384] where Rlc is H, halo, alkyl, C3.6 cycloalkyl, Cx_g alkoxy, C3-6 cycloalkoxy, N0, N (Rld) 2, NH (C0) Rld, or NH (CO) NHRld, where each Rld is independently H, C? -6 alkyl, or C3.6 cycloalkyl;

[0385] or NRlaRlb is a three to six membered cycloalkyl secondary amine, which optionally has one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, Cx-6 alkoxy , amido or phenyl, - [0386] R21 and R22 are each independently H, halo, cyano, hydroxy, Cx-3 alkyl, or C? -3 alkoxy; [0387] R5 is H, C (0) NR6R7, C (0) R8, or C (0) OR8; [0388] Rs and R7 are each independently H, Ci-6 alkyl, C3. cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl; [0389] R8 is C? -6 alkyl, C3-7 cycloalkyl, C4_10 alkylcycloalkyl, or 3-tetrahydrofuryl; and [0390] the dashed line represents a double additional ligature. [0391] The embodiments of Section C provide compounds having the general Formula XIV.

XIV

[0392] where: [0393] Rla and Rlb are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, C? -6 alkoxy, amido, or phenyl; [0394] or Rla and Rlb are each independently H or heteroaryl selected from the group consisting of:

[0395] where Rlc is H, halo, C? _6 alkyl, C3_s cycloalkyl, C? -6 alkoxy, C3_6 cycloalkoxy, N02, N (Rld) 2, NH (C0) Rld, or NH (C0) NHRld, where each Rld is independently H, C? _6 alkyl, or C3_6 cycloalkyl; [0396] or NRlaRlb is a three to six membered cycloalkyl secondary amine, optionally having one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, C? _6 alkoxy , amido, or phenyl; [0397] R2a is optionally substituted C6 or Cxo aryl with up to three NR2cR2d, halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_ cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; [0398] said R2c and R2d are each independently H, C? _6 alkyl, C3-7 cycloalkyl, C-? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C ? 6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? _6 alkyl, C? .6 alkyl optionally substituted with up to 5 fluoro, or d-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; [0399] or R2a is a five or six membered unsaturated heteroaryl, or said defined heteroaryl fused to another cycle whether this heterocycle or any other cycle, - [0400] R5 is H, C (0) NR6R7, C (0) R8 , or C (0) 0R8; [0401] R6 and R7 are each independently H, d_6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, or phenyl; [0402] R8 is Ci-g alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl, or 3-tetrahydrofuryl; and [0403] the dashed line represents a double additional ligature. [0404] The embodiments of Section C provide compounds having the general Formula XV. 11 XV

[0405] wherein: [0406] R1 and R2 are each independently H, halo, cyano, hydroxy, d-3 alkyl, or C? -3 alkoxy, - [0407] R5 is H, C (O) OR8 or C (0) NHR8; [0408] R8 is Ci-g alkyl, C5_g cycloalkyl, or 3-tetrahydrofuryl, - [0409] R9 is CX-3 alkyl, C3_5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or C_3 alkoxy; [0410] R10 and R11 are each independently H, C? _3 alkyl, or C_5 cycloalkyl; [0411] is selected from O or NH; and [0412] the dashed line represents a double additional ligature. [0413] The embodiments of Section C provide compounds having the general Formula XVI. 11 XVI

[0414] where: [0415] R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C? _3 alkyl, or CX-3 alkoxy; [0416] R5 is H, C (0) OR8 or C (0) NHR8; [0417] R8 is C? -6 alkyl or C5_6 cycloalkyl; [0418] R9 is Cx_3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or C? _3 alkoxy;

[0419] R and R are each independently H or C? _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 a double additional ligature. [0421] The embodiments of Section C provide compounds having the general Formula XVII.

XVII

[0422] wherein: [0423] R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C? _3 alkyl, or C? -3 alkoxy; [0424] R5 is H, C (0) OR8 or C (0) NHR8; [0425] R8 is C? _6 alkyl or C5-6 cycloalkyl;

[0426] R9 is CX-3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, d-3 alkyl, or Cx_3 alkoxy; and [0427] the dashed line represents a double additional ligature.

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

[0429] wherein: [0430] R1 is Cx_6 alkyl, C3_7 cycloalkyl, C4_X0 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, Cx_6 alkyl, C3.7 cycloalkyl, C4-10 alkylcycloalkyl, C-6 alkenyl , Cx.6 alkoxy, hydroxy-Cx6 alkyl, C6-6 alkyl optionally substituted with up to 5 fluoro, or C6-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, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole , or benzimidazole, each optionally substituted with up to three NR5R6, halo, cyano, nitro, hydroxy, alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, C2_6 alkenyl, Ci-β alkoxy, hydroxy-C? -6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; [0432] R3 is H, d_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, CX-ß alkyl, C3.7 cycloalkyl, C4_0 alkylcycloalkyl, C2 .6 alkenyl, C6-6alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro; [0433] R4 is d-alquilo alkyl, C (0) NR R R6, C (S) NR5R6, C (0) R7, C (0) OR7, or S (0) 2R7;

[0434] R5 and R6 are each independently H, d-6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? _6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, or C? _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 C? _5 alkyl, C3-7 cycloalkyl, or C4_0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R7 is C6 0 x0 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_g alkyl, C3_7 cycloalkyl, C_ or alkylcycloalkyl, C2_6 alkenyl, CX-6 alkoxy, hydroxy-C6_6 alkyl, d_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, C3_4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or C1-3 alkoxy; and [0437] the dashed line represents a double additional ligature.

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

[0439] where: [0440] Z is a group configured to bind through a hydrogen to a His57 imidazole unit of the NS3 protease and bind via a hydrogen bond to a nitrogen atom of a Glyl37 unit of NS3 protease; [0441] Pl 'is a group configured to form a non-polar interaction with at least one pocket unit SI' of Ns3 protease selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Fe43; [0442] L is a linking group consisting of between 1 and 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 is positioned by L to form a non-polar interaction with at least one S2 pocket unit of NS3 protease selected from the group consisting of His57, Argl55, Val78, Asp79, GlndO and Asp81; [0444] the line of dashes represents a double additional ligature; [0445] R5 is selected from the group consisting of C (0) NR6R7 and C (0) 0R8; [0446] R6 and R7 are each independently H, d_6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl , C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? _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 C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? alkoxy, or phenyl; or R8 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2-6 alkenyl, Ci-g alkoxy, hydroxy-CX- 6alkyl, CX-6alkyl optionally substituted with up to 5 fluoro, Cx-6alkoxy optionally substituted with up to 5 fluoro; or R8 is Cx_6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring. [0448] As used herein, "hydrogen bonding" or "hydrogen bonding" refers to an attractive force between an electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a hydrogen atom which is covalently bound to another electronegative atom (such as oxygen, nitrogen, sulfur or halogen). See, for example, Stryer et. to the. "Biochemistry", fifth edition 2002, Freeman & Co. N. Y. Typically, hydrogen bonding is between a hydrogen atom and two unshared electrons from another atom. A hydrogen bonding between hydrogen and an electronegative atom bound to hydrogen in a non-covalent manner can be present when the hydrogen atom is at a distance between about 2.5 Angstrom and about 3.8 Angstrom from the electronegative atom attached in a manner non-covalent, and the angle formed by the three atoms (electronegative atom covalently linked to hydrogen, hydrogen, and electronegative atom non-covalently bound to the electronegative atom) deviates from the 180 degrees by approximately 45 degrees or less. The distance between the hydrogen atom and the non-covalently bonded electronegative atom can be referred to here as the "length of hydrogen bonding", and the angle formed by the three atoms (electronegative atom covalently bonded to hydrogen, hydrogen, and electronegative atom non-covalently bonded to the electronegative atom) can be referred to herein as the "angle of hydrogen bonding". In some cases, stronger hydrogen bridge bonds are formed when the length of the hydrogen bridge junction is shorter; thus, in some cases, the length of the hydrogen bridge junctions can vary within the range between about 2.7 Angstrom and about 3.9 Angstrom, or between about 2.9 Angstrom and about 3.9 Angstrom. In some cases, the strongest hydrogen bridge bonds are formed when the angle of hydrogen bonding is closer to linearity; thus, in some cases, the angles of hydrogen bridge junctions can deviate from 180 degrees by approximately 25 degrees or less, or by approximately 10 degrees or less.

[0449] As used herein, no polar interaction refers to the proximity of non-polar molecules or units, or to the proximity of molecules or units with low polarity, sufficient for van der Waals interaction between units and / or sufficient to exclude polar solvent molecules such as water molecules. See, for example, Stryer et. to the. "Biochemistry", fifth edition 2002, Freeman & Co. N. Y. Typically, the distance between the atoms (excluding the hydrogen atoms) of the non-polar units that interact may vary within the range between about 2.9 Angstrom and about 6 Angstrom. In some cases, the distance separating the non-polar units that interact is less than the distance a water molecule could accommodate. As used herein, a non-polar unit or a unit with low polarity refers to units with low dipole moments (typically dipole moments less than the dipole moment of the OH bonds of H20 and NH of the H3 bonds) and / or the units that are not typically present in hydrogen bonding or electrostatic interactions. Examples of units with low polarity are alkyl, alkenyl, and unsubstituted aryl units. [0450] As used herein, a pocket unit SI 'of protease? S3 refers to a unit of the protease? S3 which interacts with the amino acid located at a C-terminal residue of the cleavage site of the polypeptide substrate cleaved by the protease NS3 (for example, the NS3 protease units that interact with the amino acid S in the substrate polypeptide DLEWT-STWVLV). Examples of such type of units include, but are not limited to, amino acid atoms Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Fe43 of the peptide backbone or side chains, see Yao. Et. al., Structure 1999, 7, 1353. [0451] As used herein, an S2 pocket unit of the NS3 protease refers to a unit of the NS3 protease that interacts with the amino acid located at two residues? -terminals from the site of cleavage of the substrate polypeptide cleaved by the protease S3 (for example, the units of the protease S3 that interact with amino acid V in the substrate polypeptide DLEWT-STWVLV). An example of such a unit type includes, but is not limited to, amino acid atoms His57, Argl55, Val78, Asp79, GlndO and Aspdl of the peptide backbone or side chains, see Yao. Et. al., Structure 1999, 7, 1353. [0452] As used herein, a first unit "located next" to another second unit refers to the spatial orientation of a first unit as can be determined by the properties of a second unit to which the first atom or unit is covalently bound. For example, a carbon of a phenyl can put an oxygen atom attached to the carbon of the phenyl at a spatial position such that the oxygen atom is bound through a hydrogen bonding with an hydroxyl unit at an active NS3 site. [0453] Compounds containing units configured to interact with particular regions, particular amino acid residues, or particular atoms of the NS3 protease are also provided here. Some compounds provided herein contain one or more units configured to form a hydrogen bond with the NS3 protease in a particular region, amino acid residue, or atom. Some compounds provided herein contain one or more units configured to form a non-polar interaction with the NS3 protease in a particular region, amino acid residue, or atom. For example, the compound with General Formula XIX may contain one or more units that form a hydrogen bonding with an atom of a peptide of the main chain or side chain unit located in the pocket of the NS3 protease that binds to the substrate. In another example, the compound with General Formula XIX may contain one or more units that form non-polar interactions with atoms of the main chain or side chain of the peptide or atoms located in the pocket of the NS3 protease that binds to the substrate . In the compound of formula XIX, the line cut between the carbons 13 and 14 can be a simple union or a double union. [0454] According to figure in the compound with the general Formula XIX, Z can be configured to form a hydrogen bonding with an atom of a peptide of the main chain or side chain unit located in the pocket of the NS3 protease that it binds to the substrate, which includes, but is not limited to, the imidazole unit of His57 of the NS3 protease and the Glyl37 nitrogen atom of the NS3 protease. In some cases, Z can be configured to form a hydrogen bonding both with the imidazole unit of His57 of the NS3 protease and with the nitrogen atom of Glyl37 of the NS3 protease. [0455] The Pl 'group of the compound with the general Formula XIX can be configured to form a non-polar interaction with the atoms of the main chain or the side chain of the peptide or with the atoms located in the pocket of the NS3 protease that binds to the substrate, including, but not limited to, the amino acid residues that form the SI pocket of the NS3 protease. For example, the group Pl 'can form a non-polar interaction with at least one amino acid selected from Lysl36, Glyl37, Serl39, His57, Gly5d, Gln41, Ser42, and Fe43. [0456] The P2 group of the compound of the general Formula XIX can be configured to form a non-polar interaction with the atoms of the main chain or the side chain of the peptide or with the atoms located in the pocket of the NS3 protease that is binds to the substrate, including, but not limited to, the amino acid residues that form pocket S2 of the NS3 protease. For example, the P2 group can form a non-polar interaction with at least one amino acid selected from His57, Argl55, Val7d, Asp79, GlndO and Aspdl. The P2 group can also be configured to form a hydrogen bonding with the atoms of the main chain or the side chain of the peptide or with the atoms located in the pocket of the protease S3 that binds to the substrate, which include but without limitation, the amino acid residues that form the S2 pocket of the NS3 protease. For example, the P2 group can form a hydrogen bonding with at least one amino acid selected from His57, Argl55, Val78, Asp79, Gln80 and Aspdl. In some cases, P2 can form both a non-polar interaction and a hydrogen bonding with the peptide backbone or with side chain units or atoms located in the pocket of the NS3 protease that binds to the substrate, where said amino acids they are selected among His57, Argl55, Val78, Asp79, GlndO and Aspdl. Said hydrogen bonding and without polar interactions can occur with the same amino acid residue or with other amino acid residues in pocket S2 of the protease S3. 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 group P2 is determined by connector L. For example, P2 may be located near connector L to form a non-polar interaction with the atoms of the main chain or side chain of the peptide or with the atoms located in the pocket of the NS3 protease that binds to the substrate, including, but not limited to, the amino acid residues that form pocket S2 of the NS3 protease. For example, the P2 group can be located close to L to form a non-polar interaction with at least one amino acid selected from His57, Argl55, Val78, Asp79, GlndO and Aspdl. In another example, P2 may be located near the L-connector to form a hydrogen bonding with the atoms of the main chain or the side chain of the peptide or with the atoms located in the pocket of the NS3 protease that binds to the substrate , which include, but not limited to, the amino acid residues that form the S2 pocket of the NS3 protease. For example, the P2 group can be located close to L to form a hydrogen bonding with at least one amino acid selected from His57, Argl55, Val78, Asp79, Gln80 and Aspdl. In some cases, P2 may be positioned to form both a non-polar interaction and a hydrogen bonding with a principal chain or side chain atom of the peptide or with atoms located in the pocket of the NS3 protease that binds to the substrate, such as for example an amino acid selected from His57, Argl55, Val7d, Asp79, GlndO and Aspdl. Said hydrogen bonding and without polar interactions can occur with the same amino acid residue or with other amino acid residues in pocket S2 of the NS3 protease. [0458] As contained in the compound of the general Formula XIX, L can be a linking group linking P2 to the heterocyclic backbone of the compound of formula XIX. The L-linker can contain any of a variety of atoms and units suitable for placing P2 in the pocket of the NS3 protease that binds to the substrate. In one embodiment, L may contain between 1 and 5 atoms that are selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. In another embodiment, L may contain between 2 and 5 atoms which are selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. For example, L can contain a group with the formula -W-C (= V) -, where V and W are each individually selected from 0, S or? H. A specific example of groups for L includes, but is not limited to, ester, amide, carbamate, thioester, and thioamide. [0459] The compound of formula XIX may also contain a group R5, where the group R5 may contain a carboxyl unit. Examples of carboxyl units of R5 include C (0) NR6R7 and C (O) OR8 where R6 and R7 are each independently H, C? -6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? -6 alkyl, d_6 alkyl optionally substituted with up to 5 fluoro, C? _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 wherein R is C? -6 alkyl, C3_7 cycloalkyl, C_-xx alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R8 is C6 0 x0 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _g alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C? _s alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring [0460] In some embodiments, several linkages of the compound of formula XIX may have a particular chirality. [0461] The embodiments of Section E provide compounds where the C13-C14 double bond is cis. The embodiments of Section E provide compounds where the C13-C14 double bond is trans. [0462] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XIX, wherein L consists of between 2 and 5 atoms. [0463] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XIX, wherein L comprises a group -W- C (= V) -, where V and W are each individually selected from O , S or NH. [0464] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XIX, wherein L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.

[0465] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XIX, wherein P2 is also positioned by L to form a hydrogen bridge interaction with at least one S2 pocket unit of NS3 protease selected from the group consisting of His57, Argl55, Val78, Asp79, Gln80 and Aspdl. [0466] In preferred embodiments, embodiments of Section E provide compounds having the formula XlXa:

[0467] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXa, wherein L consists of between 2 and 5 atoms. [0468] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXa, wherein L comprises a group -WC (= V) -, where V and W are each individually selected from O, S , or NH. [0469] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXa, wherein L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide. [0470] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXa, wherein P2 is also positioned by L to form a hydrogen bridge interaction with at least one S2 pocket unit of NS3 protease selected from the group consisting of His57, Argl55, Val7d, Asp79, GlndO and Aspdl. [0471] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XIX, wherein P2 is

[0472] In preferred embodiments, embodiments of Section E provide compounds having the formula XlXb: 10 XlXb

[0473] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXb, wherein L consists of between 2 and 5 atoms. [0474] In preferred embodiments, embodiments of Section E provide compounds having the general Formula XlXb, wherein L comprises a group -W- C (= V) -, where V and W are each individually selected from O , S, or NH. [0475] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXb, wherein L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide. [0476] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXb, wherein P2 is also positioned by L to form a hydrogen bridge interaction with at least one S2 pocket unit of NS3 protease selected from the group consisting of His57, Argl55, Val7d, Asp79, Gln80 and Aspdl. [0477] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXb, wherein the C13-C14 double bond is cis. [0478] In preferred embodiments, the embodiments of Section E provide compounds having the general Formula XlXb, wherein the C13-C14 double bond is trans. [0479] Compounds of the formula XIX can be prepared in the same general form as the compounds of the formulas I-XVII. [0480] In some embodiments, the compounds of General Formula XIX do not include the compounds disclosed in PCT / US04 / 33970. For example, in some 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 and other derivatives thereof. A pharmaceutical composition of the invention comprises a compound of the invention and an excipient suitable for pharmaceutical use. A large variety of excipients suitable for pharmaceutical use are known in the art, so they do not need to be discussed in detail here. Suitable excipients for pharmaceutical use have been widely described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, &; Wiikins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., Eds., 7th ed. , Lippincott, Williams, & Wiikins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., Eds., 3rd ed. Amer. Pharmaceutical Assoc. [0482] Suitable excipients for pharmaceutical use, such as vehicles, adjuvants, transporters or diluents, are readily accessible to the public. In addition, auxiliary substances suitable for pharmaceutical use, such as pH regulating agents or buffers, agents for the regulation of tonicity, stabilizers, wetting agents and the like, are easily accessible to the public. Further examples of embodiments of pharmaceutical compositions and methods for their preparation are described in more detail below.

Inhibition of the enzymatic activity of a flavivirus [0483] In many embodiments, a compound of the invention inhibits the enzymatic activity of a flavivirus. Whether a compound of the invention inhibits a flavivirus or not can be easily determined using any known method. Flaviviral infections include those caused by flaviviruses, including, but not limited to, hepatitis C virus, West Nile fever virus, GB virus virus, Japanese encephalitis, dengue virus and fever virus. yellow. In many embodiments, a compound of the invention inhibits the enzymatic activity of the protease S3 of a hepatitis C virus (HCV). It can be easily determined whether or not a compound of the invention inhibits HCVγS3 using any known method. Typical methods include determining whether a polyprotein of HCV or another polypeptide comprising a recognition site? S3 is or is not ovated by? S3 in the presence of the agent. In many embodiments, a compound of the invention inhibits the enzymatic activity of the S3 at least about 10%, at least about 15%, at least about 20%, at least about 25%, at less 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 in about 90%, or more, compared to the enzymatic activity of NS3 in the absence of the compound. [0484] In many embodiments, a compound of the invention inhibits the enzymatic activity of a NS3 HCV protease with an IC50 of less than about 50 μM, e.g. ex. , a compound of the invention inhibits the enzymatic activity of a NS3 HCV protease with an IC50 of less than about 40 μM, less than about 25 μM, less than about 10 μM, less than about 1 μM, less than about of 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 compound of the invention inhibits viral replication of HCV. For example, a compound of the invention inhibits viral replication of HCV 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 Viral replication of HCV in the absence of the compound. Whether a compound of the invention inhibits viral replication of HCV or not can be determined using methods known in the art, including an in vitro viral replication assay. Treatment of a flaviviral infection [0486] The methods and compositions described herein are generally useful in the treatment of a flaviviral infection. [0487] It can be determined whether a method of the invention is effective or not to treat a flaviviral infection by measuring the reduction of viral load, the reduction of time to seroconversion (virus not detectable in the patient's serum), the increase in the sustained viral response rate to therapy, the reduction of morbidity or mortality in clinical outcomes, or through some other indicator of disease response. [0488] In general, an effective amount of a compound of the formulas I-XIX and, optionally, one or more additional antiviral agents, is an amount that is effective in reducing viral load or achieving a sustained viral response to therapy . [0489] It can be determined whether a method of the invention is effective or not to treat a flaviviral infection by measuring the viral load, or by measuring a parameter associated with a flaviviral infection, including but not limited to, liver fibrosis, increased levels of serum transaminases and necroinflammatory activity in the liver. Liver fibrosis indicators are discussed in detail later. [0490] The method includes administering an effective amount of a compound of the 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 the formulas I-XIX and, optionally, one or more additional viral agents, is an amount that is effective to reduce the viral titers to undetectable levels, e.g. ex. , to about 1000, to about 5000, to about 500 to about 1000 or to about 100 to about 500 copies of genome / ml of serum. In some embodiments, an effective amount of a compound of the formulas I-XIX and, optionally, one or more additional viral agents, is an amount that is effective to reduce the viral load to less than 100 copies of genome / ml of serum . [0491] In some embodiments, an effective amount of a compound of the formulas I-XIX and, optionally, of one or more additional viral agents, is an amount that is effective to achieve a reduction of 1.5-log; 2-log; 2,5-log; 3-log; 3,5-log; 4-log; 4.5-log or 5-log of the viral titer in the individual's serum. [0492] In many embodiments, an effective amount of a compound of the formulas I-XIX, and, optionally, one or more additional viral agents, is an amount that is effective to achieve a sustained viral response, e.g. ex. , no detectable HCV RNA is found (eg, less than about 500, less than about 400, less than about 200, or less than about 100 copies of genome per milliliter of serum) in the patient's serum during 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 after the interruption of therapy. [0493] As noted above, it can be determined whether or not a method of the invention is effective to treat a flaviviral infection by measuring a parameter associated with a flaviviral infection, such as liver fibrosis. Methods to determine the degree of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of hepatic fibrosis indicates the extent of hepatic fibrosis. [0494] As an illustrative example, serum alanine aminotransferase (ALT) levels are measured using standard techniques. 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 viral 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 the formulas I-XIX and, optionally, of one or more additional viral agents, is an amount that is effective to reduce the serum level of a hepatic fibrosis marker in at least about the 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 0%, or more, in comparison with the level of the marker in an untreated individual or in an individual treated with placebo. Methods for measuring serum markers include immunological methods, e.g. ex. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays and the like, using an antibody specific for a given serum marker. [0496] In many embodiments, an effective amount of a compound of the formulas I-XIX and an additional antiviral agent is a synergistic amount. As used herein, a "synergistic combination" or "synergistic amount" of a compound of the formulas I-XIX and of an additional antiviral agent is a combined dose that is more effective in the therapeutic or prophylactic treatment of an infection by HCV that the incremental improvement in treatment outcome can be predicted or expected from the mere sum of (i) the therapeutic or prophylactic benefit of the compound of formulas I-XIX administered in the same dose as monotherapy and (ii) the benefit Therapeutic or prophylactic of the additional antiviral agent administered in the same dose as monotherapy. [0497] In some embodiments, a selected amount of a compound of the 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 the formulas I -XIX and / or the selected amount of the additional antiviral agent is ineffective when used as monotherapy for the disease. Therefore, the embodiments encompass (1) regimens in which a selected amount of the additional antiviral agent potentiates the therapeutic benefit of a selected amount of the compound of the formulas I-XIX when used in combination therapy for a disease, wherein the selected amount of the additional antiviral agent does not provide therapeutic benefit when used as monotherapy for the disease (2) regimes in which a selected amount of the compound of the formulas I-XIX enhances the therapeutic benefit of a selected amount of the agent additional antiviral when used in combination therapy for a disease, wherein the selected amount of the compound of the formulas I-XIX does not provide therapeutic benefit when used as monotherapy for the disease and (3) regimes 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, wherein each of the selected amounts of the compound of formulas I-XIX and the additional antiviral agent, respectively, do not provide therapeutic benefit when used as monoterap ia for the disease. As used herein, a "synergistically effective amount" of a compound of the formulas I-XIX and an additional antiviral agent, and their grammatical equivalents, shall be understood to include any regimen encompassed by any of the items (l) - (3) precedents Treatment of a hepatitis virus infection [0498] The methods and compositions described herein are, in general, useful in the treatment of an HCV infection.

[0499] It can be determined whether a method of the invention is effective or not to treat an HCV infection by a reduction in viral load, a reduction of time to seroconversion (virus not detectable in the patient's serum), an increase of the sustained viral response rate to therapy, a reduction in morbidity or mortality in clinical outcomes or by some other indicator of disease response. [0500] In general, an effective amount of a compound of the formulas I-XIX and, optionally, of one or more additional viral agents, is an amount that is effective in reducing viral load or achieving sustained viral response to therapy. [0501] It can be determined whether or not a method of the invention is effective for treating an HCV infection by measuring viral load or measuring a parameter associated with HCV infection, including, but not limited to, liver fibrosis, increased levels of serum transaminase and necroinflammatory activity in the liver. Liver fibrosis indicators are discussed in detail later. [0502] The method includes administering an effective amount of a compound of the 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 the formulas I-XIX and, optionally, one or more additional viral agents, is an amount that is effective to reduce the viral titers to undetectable levels, e.g. ex. , to about 1000 to about 5000, to about 500 to about 1000 or to about 100 to about 500 copies of genome / ml of serum. In some embodiments, an effective amount of a compound of the formulas I-XIX and, optionally, one or more additional viral agents, is an amount that is effective to reduce the viral load to less than 100 copies of genome / ml of serum . [0503] In some embodiments, an effective amount of a compound of the formulas I-XIX and, optionally, of one or more additional viral agents, is an amount that is effective to achieve a reduction of 1.5-log; 2-log; 2,5-log; 3 -log; 3,5-log; 4-log; 4.5-log or 5-log of the viral titer in the individual's serum. [0504] In many embodiments, an effective amount of a compound of the formulas I-XIX and, optionally, of one or more additional viral agents, is an amount that is effective to achieve a sustained viral response, e.g. ex. , HCV undetectable RNA (eg, less than about 500, less than about 400, less than about 200, or less than about 100 copies of genome per milliliter of serum) in the patient's serum during a period of at least about one month, of at least about two months, of at least about three months, of at least about four months, of at least about five months, or of at least about six months thereafter to the interruption of therapy. [0505] As noted above, it can be determined whether a method of the invention is effective or not to treat an HCV infection by measuring a parameter associated with HCV infection, such as liver fibrosis. Methods to determine the degree 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 an example by way of illustration, serum alanine aminotransferase (ALT) levels are measured, using standard methods. 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 the formulas I-XIX, and optionally, one or more additional viral 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 the formulas I-XIX and, optionally, of one or more additional viral agents, is an amount that is effective to reduce the serum level of a hepatic fibrosis marker 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 less 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 in an individual treated with placebo . Methods for measuring serum markers include immunological methods, e.g. ex. , enzyme-linked immunosorbent assays (ELISA), radioimmunoassays and the like, using an antibody specific for a given serum marker. [0508] In many embodiments, an effective amount of a compound of the formulas I-XIX and of an additional antiviral agent is a synergistic amount. As used herein, a "synergistic combination" or "synergistic amount" of a compound of the formulas I-XIX and of an additional antiviral agent is a combined dose that is more effective in the therapeutic or prophylactic treatment of an infection by HCV that the incremental improvement in treatment outcome can be predicted or expected from the mere sum of (i) the therapeutic or prophylactic benefit of the compound of formulas I-XIX administered in the same dose as monotherapy and (ii) the benefit Therapeutic or prophylactic of the additional antiviral agent administered in the same dose as monotherapy. [0509] In some embodiments, a selected amount of a compound of the 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 the formulas I -XIX and / or the selected amount of the additional antiviral agent is ineffective when used as monotherapy for the disease. Therefore, the embodiments encompass (1) regimens in which a selected amount of the additional antiviral agent potentiates the therapeutic benefit of a selected amount of the compound of the formulas I-XIX when used in combination therapy for a disease, wherein the amount The selected additional antiviral agent does not provide therapeutic benefit when used as monotherapy for the disease (2) regimes in which a selected amount of the compound of the formulas I-XIX enhances the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, wherein the selected amount of the compound of the formulas I-XIX does not provide therapeutic benefit when used as monotherapy for the disease and (3) regimes in which a selected amount of the compound of formula I and a selected amount of the additional antiviral agent provide a bene Therapeutic use when used in combination therapy for a disease, wherein each of the selected amounts of the compound of the formulas I-XIX and the additional antiviral agent, respectively, does not provide therapeutic benefit when used as monotherapy for the disease. As used herein, a "synergistically effective amount" of a compound of the formulas I-XIX and an additional antiviral agent, and their grammatical equivalents, shall be understood to include any regimen encompassed by any of the items (l) - (3) precedents Treatment of fibrosis [0510] The embodiments provide methods for treating hepatic fibrosis (including forms of liver fibrosis resulting from or associated with HCV infection) which, generally, include administering a therapeutic amount of a compound of formulas I-XIX and, optionally, of one or more additional viral agents. The effective amounts of compounds of the formulas I-XIX, with and without one or more additional antiviral agents, as well as the administration regimens, are discussed below.

[0511] Whether treatment with a compound of the formulas I-XIX and, optionally, with one or more additional viral agents, is or is not effective in reducing liver fibrosis is determined by any number of well-established techniques for measuring liver fibrosis and liver function. The reduction of hepatic fibrosis is determined by analyzing a liver biopsy. A liver biopsy analysis involves evaluating two main components: necroinflammation, evaluated by "grade", as a measure of the severity and activity of the disease in progress, and lesions of fibrosis and parenchymal or vascular remodeling, evaluated as " stadium ", which reflect the long-term progression of the disease. See, p. ex. , Brunt (2000) Hepatol. 31: 241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on the examination of the liver biopsy, a score is assigned. There is a series of standardized scoring systems that provide a quantitative assessment of the degree and severity of fibrosis. They include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak score scales. [0512] The METAVIR scale is based on the analysis of various characteristics of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (lobular and lobular necrosis, acidophilic retraction and vacuolar degeneration); inflammation (inflammation of the portal tract, portal lymphoid accumulations and distribution of portal inflammation); alterations of the bile ducts and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall activity of the disease). The definitions of each stage of the METAVIR scale are the following: score: 0, without fibrosis; score: 1, star enlargement of the portal tract but without formation of partitions; score: 2, enlargement of the portal tract with formation of few partitions; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis. [0513] The Knodell scale, also called the Hepatitis Activity Index, classifies the samples based on scores in four histological categories: I. Periportal necrosis and / or anastomotic necrosis; II. Intralobular degeneration and focal necrosis; III. Inflammation portal; and IV. Fibrosis. In the Knodell stadium system, the scores are as follows: score: 0, without fibrosis; score: 1, mild fibrosis (portal fibrous expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (anastomotic fibrosis); and score: 4, cirrhosis. The higher the score, the greater the severity of the liver tissue damage. Knodell (1981) Hepatol. 1: 431 [0514] On the Scheuer scale the scores are as follows: score: 0, without fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal partitions or portals-portals, but with preserved architecture; score: 3, fibrosis with alteration of the architecture, but without apparent cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13: 372. [0515] The Ishak scale is described in Ishak (1995) J. Hepatol. 22: 696-699. Stage 0, without 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 anastomosis (P-P); Stage 4, fibrous expansion of portal areas with marked anastomoses (P-P) as well as central-portals (P-C); Stage 5, marked anastomosis (P-P and / or P-C) with occasional nodules (incomplete cirrhosis); Stage 6, cirrhosis, probable or definite. [0516] The benefit of antifibrotic therapy can also be measured and evaluated using the Child-Pugh scale, which comprises a multicomponent scoring system based on abnormalities of serum bilirubin level, serum albumin level, prothrombin time, presence and severity of ascites and presence and severity of encephalopathy. Based on the presence and severity of the abnormality of these parameters, patients can be classified into 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 the formula I and optionally, of one or more additional viral agents, is an amount that produces a variation of one unit or more in the stage of fibrosis, based on liver biopsies before and after therapy. In particular embodiments, a therapeutically effective amount of a compound of the formulas I-XIX and, optionally, of one or more additional viral agents, reduces hepatic fibrosis in at least one unit in the scales METAVIR, Knodell, Scheuer, Ludwig, or Ishak. [0518] To evaluate the efficacy of the treatment with a compound of the formulas I-XIX, secondary or indirect liver function indices can also be used. Also, semiautomatized computerized morphometric evaluations of the quantitative degree of hepatic fibrosis based on collagen-specific staining and / or serum hepatic fibrosis markers can be measured as an indication of the effectiveness of a method of treatment of the invention. Secondary liver function indices include, but are not limited to, transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and Child-Pugh score assessment. [0519] An effective amount of a compound of the formulas I-XIX, and, optionally, of one or more additional viral agents, is an amount that is effective to increase a liver function index by at least about 10%, at less around 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 liver function of an untreated individual or of an individual treated with placebo. Those skilled in the art will readily be able to measure such liver function indices using standard methods, many of which are commercially available and are routinely used in clinical settings. [0520] Liver markers of hepatic fibrosis can also be measured as an indication of the efficacy of a method of treatment of the invention. The 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 the formulas I-XIX and, optionally, of one or more additional viral agents, is an amount that is effective to reduce the serum level of a hepatic fibrosis marker in at least about the 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 with the level of the marker in an untreated individual or an individual treated with placebo. Those skilled in the art will readily be able to measure such serum liver fibrosis markers using standard methods, many of which are commercially available and used routinely in clinical settings. Methods to measure serum markers include immunological methods, p. ex. , immunosorbent assays linked to an enzyme (ELISA), radioimmunoassays and the like, using an antibody specific for a given serum marker.

[0522] Quantitative liver function reserve tests may be used to evaluate the efficacy of treatment with an interferon and pirfenidone receptor agonist (or a pirfenidone analogue). These include: indocyanine green clearance (ICG), galactose clearance (GEC), aminopyrin test in the expired air (ABT), antipyrine clearance, clearance of monoethylglycine-xylidide (MEG-X), and debugging caffeine. [0523] As used herein, a "complication associated with cirrhosis of the liver" refers to a disorder that is a sequela of a decompensated liver disease, which occurs subsequently and as a result of the development of a hepatic fibrosis and includes, without limiting character, development of ascites, hemorrhages due to esophageal varices, portal hypertension, jaundice, progressive liver failure, encephalopathy, hepatocellular carcinoma, liver failure that requires liver transplantation and mortality due to liver disease. [0524] A therapeutically effective amount of a compound of the formulas I-XIX, and, optionally, of one or more additional viral agents, is an amount that is effective to reduce the incidence (e.g., the likelihood that a develop individual) 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 around 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least around 75%, or at least about 80%, or more, compared to an untreated individual or an individual treated with placebo. [0525] Whether treatment with a compound of the formulas I-XIX and, optionally, with one or more additional viral agents, is or is not effective in reducing the incidence of a disorder associated with cirrhosis of the liver can be easily determined by the experts in art. [0526] The reduction of liver fibrosis increases the function of the liver. Thus, the embodiments provide methods for enhancing liver function that, in general, include the administration of a therapeutically effective amount of a compound of the formulas I-XIX and, optionally, one or more additional viral agents. Liver functions include, but are not limited to, the synthesis of proteins, such as serum proteins (eg, albumin, coagulation factors, alkaline phosphatase, aminotransferases (eg, alanine transaminase, aspartate transaminase) , 5'-nucleosidase, β-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol and synthesis of bile acids; the metabolic function of the liver, including, but not limited to, the metabolism of carbohydrates, the metabolism of amino acids and ammonia, the metabolism of hormones and the metabolism of lipids; the detoxification of exogenous drugs; hemodynamic function, including splanchnic and portal hemodynamics, and the like. [0527] Those skilled in the art can readily assess whether a liver function is increased or not by using well-established liver function tests. The synthesis of markers of liver function, such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like can be assessed by measuring the level of these markers in serum, using standard immunological and enzymatic methods. Splanchnic circulation and portal hemodynamics can be measured with a catheter to determine pressure and / or portal resistance using standard methods. The metabolic functions can be measured by measuring the level of ammonia in the serum. [0528] It can be determined whether or not the serum proteins normally secreted by the liver are within normal values by dosing the levels of said proteins, using standard immunological and enzymatic methods. Those skilled in the art know the normal limits of said serum proteins. The following are examples with illustrative character. The normal level of alanine transaminase is around 45 IU per milliliter of serum. The normal limits of aspartate transaminase are from about 5 to about 40 units per liter of serum. Bilirubin is dosed using standard methods. Normal bilirubin levels are usually less than about 1.2 mg / dL. Serum albumin levels are dosed using standard methods. Normal serum albumin levels are between about 35 to about 55 g / l. The prolongation of prothrombin time is measured using standard methods. The normal prothrombin time is less than about 4 seconds longer than the control. [0529] A therapeutically effective amount of a compound of the formulas I-XIX and, optionally, of one or more additional viral agents, is one that is effective to increase liver function in and 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 the formulas I-XIX and, optionally, of one or more additional viral agents, is an amount effective to reduce the elevated level of a serum marker of liver function by at least about 10%. %, at least around 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 serum level of the liver function marker to its normal limits. A therapeutically effective amount of a compound of the formulas I-XIX and, optionally, of one or more additional viral 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 its normal limits. Type I interferon receptor agonists [0530] In any of the methods described above, in some embodiments a Type I interferon receptor agonist is administered. The Type I interferon receptor agonist includes an IFN-a; an IFN- / 3; an IFN-tau; an IFN- ?; agonist antibodies specific for a Type I interferon receptor and any other Type I interferon receptor agonist, including non-polypeptide agonists. Interferon-Alpha [0531] Any known IFN-CÜ can be used in the embodiments. The term "interferon-alpha" as used herein refers to a family of related polypeptides that inhibit viral replication and cell proliferation and modulate the immune response. The term "IFN-a" includes IFN-a. natural; synthetic IFN-a; IFN-a derivatives (e.g., pegylated alpha interferon, glycosylated IFN-O, and the like); and IFN-o analogues; natural or synthetic; essentially, any IF? -a that has antiviral properties like those described for the IF? -a natural. [0532] Suitable alpha interferons include, but are not limited to, natural? A (including, but not limited to, natural IF? -a2a, IF? -a2b); recombinant interferon alfa-2b, such as interferon Intron-A, available from Schering Corporation, Kenilworth,? .J .; recombinant interferon alfa-2a, such as the interferon Roferon, available from Hoffmann-La Roche,? utley,?. J.; recombinant alpha-2C interferon, such as interferon alpha 2 Berofor, available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn. , - interferon alfa-nl, a purified mixture of natural alpha interferons, such as Sumiferon, available from Sumitomo, Japan or as Wellferon interferon alfa-nl (I? S), available from Glaxo-Wellcome Ltd., London, Great Britain; and interferon alfa-n3, a mixture of natural alpha interferons manufactured by Interferon Sciences and available from Purdue Frederick Co., Norwalk, Conn. , under the trade name of Alferon. [0533] The term "IFN-a." it also covers the IFN-c. of consensus. The consensus IFN-a (also called "CIFN" and "IFN-con" and "consensus interferon") includes, but is not limited to, the amino acid sequences designated as IF? -conl, IF? -con2 and IF? - con3, which are disclosed in U.S. Patent Nos. 4,695,623 and 4,897,471; and consensus interferon as defined by the determination of a consensus sequence of natural alpha interferons (e.g., Infergen®, InterMune, Inc., Brisbane, Calif.). IFN-conl is the consensus interferon agent in the product Infergen® alfacon-1. The Infergen® consensus interferon product is referred to herein by its trade name (Infergen®) or by its generic name (interferon alfacon-1). The DNA sequences encoding IFN-con can be synthesized in the manner described in the aforementioned patents or with other standard methods. Of particular interest is the use of the CIFN. [0534] Also suitable for use in the embodiments are fusion polypeptides comprising an IFN-G! and a heterologous polypeptide. The fusion polypeptides IFN-O! Suitable include, but are not limited to, Albuferon-alpha ™ (a fusion product of albumin and IFN-a; Human Genome Sciences; see, p. ex. , Osborn et al. (2002) J. Pharmacol. Exp. Therap. 303: 540-548). Also suitable for use in the embodiments herein are the forms of IFN-cf with gene-shuffled. See., P. ex. , Masci et al. (2003) Curr. Oncol. Rep. 5: 108-113. Pegylated IFN-alpha [0535] The term "IF? -a." it also encompasses derivatives of IF? -a that are obtained (eg, by chemical modification) to alter certain properties, such as serum half-life. Therefore, the term "IF? -a" includes glycosylated IF? -C? IF? -o; derivative with polyethylene glycol ("IF? -o; pegylated"); and similar. The IF? -a pegilado and the methods to obtain it are treated, p. ex. , in U.S. Patent Nos. 5,382,657; 5,981,709 and 5,951,974. The IFN-Q! pegylated encompasses conjugates with PEG and any of the IFN-CÜ molecules described above, including, but not limited to, PEG conjugated with interferon alfa-2a (Roferon, Hoffman La-Roche, Nutley, NJ), interferon alpha 2b (Intron, Schering -Plough, Madison, NJ), interferon alfa-2c (Berofor Alfa, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon, as defined by determination of a consensus sequence of natural alpha interferons (Infergen®, InterMune, Inc., Brisbane, Calif.). [0536] Any of the aforementioned IFN-QI polypeptides can be modified with one or more polyethylene glycol fractions, ie, 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 spliced IF? -aP? Contains a PEG moiety on only one amino acid. In other embodiments, the IF? -a. PEGylated contains a PEG fraction in two or more amino acids, p. ex. , IFN-a contains a PEG fraction linked to two, three, four, five, six, seven, eight, nine or ten different amino acid residues. [0537] IF? -a may be directly coupled to PEG (ie, without a linking group) through an amino group, a sulfhydryl group, an hydroxyl group or a carboxyl group. [0538] In some embodiments, the PEGylated IF? -a is PEGylated at an amino (? -terminal) terminus of the IF? -CÜ polypeptide or in its vicinity, e.g. ex. , the PEG fraction is conjugated to the IF? -a polypeptide at one or more amino acid residues from amino acid 1 to amino acid 4, or from amino acid 5 to about 10. [0539] In other embodiments, IF? -a PEGylated is PEGylated at one more amino acid residue from about 10 to about 28. [0540] In other embodiments, the IF? -a. PEGylated is PEGylated at the carboxyl (C-terminal) end of the IFN-c polypeptide. or in its vicinity, p. ex. , in one or more residues from amino acids 156-166, or from amino acids 150 to 155. [0541] In other embodiments, the PEGylated IFN-ce is PEGylated at one more amino acid residue from amino acids 100-114. [0542] Derivation with polyethylene glycol of the amino acid residues in the domains of the binding site of the receptor and / or the active site of the IFN-a protein, or in its vicinity, can alter the functioning of these domains. In certain embodiments, amino acids in which PEGylation should be avoided include the amino acid residues from amino acids 30 to amino acids 40; and the amino acid residues from amino acids 113 to amino acids 149. [0543] In some embodiments, PEG is linked to IFN-a. by means of a liaison group. The linking group is any biocompatible linking group, where "biocompatible" indicates that the compound or group is non-toxic and can be used in vitro or in vivo without causing injury, malaise, disease or death. The PEG may be linked to the linking group, for example, by means of an ether linkage, an ester linkage, a thiol linkage or an amide linkage. Biocompatible linkage groups include, without limitation, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, an 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 nitrophenyl group (including , for example, nitrophenyl carbonate (? PC) or trichlorophenyl carbonate (TPC)), a trisylate 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 preparing activated steamed PEGs succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) are described in U.S. Pat. 5,672,662 (Harris, et al.) And in WO 97/03106. [0545] Methods for attaching a PEG to an IF? -a polypeptide are known in the art and any known method can be used. See, for example, 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,? And, Chapter 21 (1992); United States Patent? 5,965,265; United States Patent? 5,672,662 (Harris, et al.) And WO 97/03106.

[0546] PEGylated IFN-a and the methods for preparing it are discussed, e.g. ex. , in U.S. Patent Nos. 5,382,657; 5,981,709; 5,985,265; and 5,951,974. IF-a PEGylated encompasses PEG conjugates and any of the IFN-a molecules. previously described, including, but not limited to, PEG conjugated with interferon alfa-2a (Roferon, Hoffman LaRoche, Nutley, N.J.), where the PEGylated Roferon is called Pegasys (Hoffman LaRoche); interferon alfa 2b (Intron, Schering-Plow, Madison, N.J.), where the PEGylated Intron is called PEG-Intron (Schering-Plow); interferon alfa-2c (Berofor Alfa, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as defined by determination of a consensus sequence of natural alpha interferons (Infergen®, InterMune, Inc., Brisbane, Calif.), where the PEGylated Infergen is called PEG-Infergen. [0547] In many embodiments, PEG is a monometoxyPEG molecule that reacts with primary amine groups in the IFN-O !. polypeptide. Methods for modifying polypeptides with monoethoxy PEG by means of reductive alkylation are known in the art. See, p. ex. , Chamow et al. (1994) Bioconj. Chem. 5: 133-140. [0548] In an example by way of illustration, PEG is linked to IFN-a. through a SPA link group. The SPA esters of PEG, and the methods for preparing them, are described in U.S. Patent No. 5,672,662.

The SPA bonds provide the link for the free amine groups in the IFN-a polypeptide. [0549] For example, a PEG molecule is fixed covalently by means of a linkage comprising an amide linkage between a propionyl group of the PEG moiety and the epsilon amino group of a surface lysine residue in IFN-a; polypeptide. Said ligature can be formed, e.g. ex. , by condensation of an activated ester of a-methoxy, omega propanoic acid of PEG (mPEGspa). [0550] As an example by way of illustration, a preferred monoPEGylated CIFN conjugate for use herein has a linear PEG fraction of about 30 kD fixed by means of a covalent bond to the CIFN polypeptide, where the covalent bond is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface lysine residue in the CIFN polypeptide, where the surface lysine residue is chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, or lis165, and the amide bond is formed by condensation of an activated ester of α-methoxy, omega propanoic acid with PEG. Polyethylene glycol [0551] Polyethylene glycol suitable for conjugation with an IFN-c polypeptide is soluble in water at room temperature and has the general formula R (0-CH2-CH2) nO-R, where R is hydrogen or a protective group, such as an alkyl or alkanol group, and where n is an integer between 1 and 1000. When R is a protecting group, it generally has from 1 to 8 carbons. [0552] In many embodiments, the PEG has at least one hydroxyl group, e.g. ex. , a terminal hydroxyl group, an hydroxyl group that is modified to generate a functional group that is reactive with an amino group, e.g. ex. , an amino-epsilon group of a lysine residue, a free amino group in 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, the PEG is derived to be reactive with free carboxyl groups of the IFN-a polypeptide, e.g. ex. , the free carboxyl group at the carboxyl terminus of the IFN-a polypeptide. Suitable P? G derivatives which 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 (eg, PEG-NH-NH2). [0554] In other embodiments, a derivation of the PEG is made to comprise a terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives. Due to the reactive nature of the acidic, the selectivity of certain amino groups is obtained over others. For example, -SH exhibits sufficient ability to be released from the group by reacting with the N-terminal amino group under suitable pH conditions, so that the e-amino groups of the lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions under suitable pH conditions cause some of the accessible lysine residues to react selectively. [0555] In other embodiments, the PEG comprises a reactive ester, such as an N-hydroxy succinimidate at the end of the PEG chain. Said PEG molecule containing N-hydroxysuccinimidate reacts with selective amino groups under particular pH conditions, such as neutral 6.5-7.5. For example, the N-terminal amino groups can be selectively modified under neutral pH conditions. However, if the reactivity of the reagent is extreme, accessible -NH2 groups of lysine can also react. [0556] The PEG can be directly conjugated with the IFN-QÍ polypeptide, or through a linker. In some embodiments, a binding element is added to the IFN-ce polypeptide, forming an IFN-a polypeptide modified by the linkage. These link elements provide various functions, e.g. ex. , reactive groups such as sulfhydryl, amino or carboxyl groups for coupling a reactive PEG to the IFN-a polypeptide modified by the linkage.

[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. Patent No. 5,643,575, "PEG star" ["star-PEG 's"] and PEG multi-arm, such as those described in the Shearwater Polymers catalog. , Inc. "Polyethilenglycol Derivatives 1997-1998." The star PEGs are described in the art, including, p. ex. , in U.S. Patent No. 6,046,305. [0558] PEG is generally used with a molecular weight in the range ranging from about 2 kDa to about 100 kDa, where the term "around," in the context of PEG, indicates that in polyethylene glycol preparations some molecules will weigh more and some less than the nominal molecular weight. For example, the PEG suitable for conjugation with IFN-a. it has a molecular weight ranging 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 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. Preparation of PEG-IFN-a conjugates. [0559] As discussed above, the PEG moiety can be fixed, directly or by means of a binding element to an amino acid residue in or near the N-terminus, internally, or in the C-terminus or in its vicinity of the IFN-a. polypeptide. The conjugation can be carried out in solution or in solid phase. N-terminal linkage [0560] Methods for fixing a PEG fraction to an amino acid residue at or near the N-terminus of an IFN-a polypeptide. they are known in the art. See, p. ex. , U.S. Patent No. 5,985,265. [0561] In some embodiments, known methods are used to selectively obtain a chemically modified IFN-CÜ at the N-terminus. For example, a method for protein modification by reductive alkylation, which exploits the differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available to make the derivative in a particular protein can be used. Under the appropriate reaction conditions, the substantially selective derivation of the protein at the N-terminus with a polymer containing a carbonyl group is obtained. The reaction is carried out at a pH which makes it possible to take advantage of the pKa differences between the e-amino groups of the lysine residues and that of the c-amino group of the N-terminal residue of the protein. By means of said selective derivatization of a PEG fraction with IFN-a, it is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of IFN-a and no significant modification of other reactive groups, such as groups, occurs. amino of the side chain of lysine. C-terminal ligation [0562] The specific coupling procedures for? -terminal such as those described in the U.S. Patent? 5,985,265 supply predominantly monoPEGylated products. However, purification procedures designed to remove excess reagents and minor PEGylated products remove the N-terminal blocked polypeptides. In terms of therapy, these processes lead to significant increases in production costs. For example, the analysis of the structure of the well-characterized amino acid sequence in the CIF? Infergen® Alfacon-1 reveals that the cut is approximately 5% at the carboxyl terminus and, therefore, there is only one major C-terminal sequence. Therefore, in some embodiments the PEGylated IFN-ci is not used in the α -terminal, but instead the PEGylated IFN-α polypeptide in the C-terminus. [0563] Accordingly, the effective approach for synthesis and for therapy to obtain the PEGylated mono Infergen product is projected as follows: [0564] A reactive PEG can be prepared that is selective for the C-terminus, with or without spacers For example, modified polyethylene glycol can be used as the starting material as methyl ether at one end and with an amino function at the other end. [0565] The preparation or preparation of a water-soluble carbodiimide can be carried out as a condensing agent. The coupling of IF? -a (eg, Infergen® Alfacon-1 CIF? Or consensus interferon) with a carbodiimide as a condensation reagent is generally carried out in an aqueous medium with a suitable buffer solution at an optimum pH for capture the amide bond. A high molecular weight PEG can be added covalently to the protein to increase molecular weight. [0566] The selected reagents will depend on the optimization studies of the process. An illustrative example of a suitable reagent is EDAC, or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide. The water solubility of the EDAC allows direct addition to the reaction, without the need for prior dissolution in an organic solvent. The excess reagent and the isourea formed as a by-product of the cross-linking reaction are water-soluble and can be easily 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, due to the labile nature of the reagent. Most synthetic protocols in the literature suggest that the optimal reaction medium is in a pH range between 4.7 and 6.0. In any case, the condensation reactions proceed without significant losses in the yields up to a pH of 7.5. Water can be used as a solvent. In view of the contemplated use for Infergen, the medium will preferably be buffer solution of sulfonic acid 2- (N-morpholino) ethane pretitled at a pH between 4.7 and 6.0. In any case, 0.1 M phosphate can also be used at pH 7-7.5 since the product is in the same buffer solution. The relationship between PEG amine and the IFN-a molecule. it is optimized in such a way that the C-terminal carboxylic residue (s) are selectively PEGylated to give one or more PEGylated derivatives. [0567] Although the use of the PEG amine was mentioned above by its name or structure, said derivatives are only by way of example, and other groups can also be used, such as hydrazine derivatives, such as in the PEG-NH-NH2, which is also will condense with the carboxyl group of the IFN-a protein. In addition to the aqueous phase, the reactions can also be carried out in the solid phase. The polyethylene glycol can be selected from a list of compounds of molecular weight ranging from 300-40000. The choice of the various polyethylene glycols will also be determined by the coupling efficiency and the biological yield of the purified derivative in vitro and in vivo, i.e. circulation times, antiviral effects, etc. [0568] Additionally, suitable spacers can be added to the C-terminus of the protein. The spacers can have reactive groups, such as SH, NH2 or COOH to couple with the appropriate reactive PEG to deliver high molecular weight IFN-a derivatives. A combined methodology in solid phase / solution for the preparation of PEGylated interferons in C-terminal can be projected. For example, the C-terminus of IF? -a is extended on a solid phase using a Gli-Gli-Cis-NH2 spacer and then monopegylated in solution using activated dithiopyridyl PEG reagents of suitable molecular weights. As the coupling in the C-terminal is independent of the block in the N-terminal, the projected process and its products will be beneficial in terms of costs (not a third of the protein is wasted as in the N-terminal pegylation methods) and contributing to the economics of the therapy to treat viral infections. [0569] There may be a more reactive carboxyl group of amino acid residues in another part of the molecule so that it reacts with the reactive PEG and leads to monopegylation at the site or leads to multiple pegylations in addition to the -COOH group at the C-terminus of the IFN-Q !. It is projected that these reactions will be minimal at best, due to the steric freedom at the C-terminal end of the molecule and the steric hindrance imposed by carbodiimides and reactive PEGs as in branched-chain molecules. Therefore, the preferred mode of PEG modification for Infergen and the like are said proteins, native or expressed in a host system, which may be blocked to varying degrees N-terminations to increase efficiencies and maintain higher biological activity in vivo. [0570] Another method to obtain PEGylation at C-terminal is as follows. The selectivity of C-terminal PEGylation is obtained with a sterically hindered reagent that excludes reactions at the carboxyl residues, hidden in the helices or internally in the IFN-a. For example, such a reagent could be a branched chain PEG of ~ 40kD molecular weight, and this agent could be synthesized as follows: [0571] OH3C- (CH2CH20) n-CH2CH2NH2 + glutamic acid, ie HOCO -CH2CH2CH (NH2) -COOH is condensed with a suitable agent, e.g. ex. , dicyclohexyl carbodiimide or water-soluble EDC to supply the branched-chain PEG agent 0H3C- (CH2CH20) n -CH2CH2NHCOCH (NH2) CH2OCH3- (CH2CH20) n -CH2CH2NHC0CH2. or II H3C -? - (CH2CH2?) n -CH2CH2NH2-. { - HO C-CH2CH2CH-C00H ' CHNH2 EDAC T H3C -? - (CH2CH2?) N -CH2CH2NH-C? CHNH2 (CH2) 2 H3C -? - (CH2CH2?) "- CH2CH2NH-C?

[0572] This reagent can be used in excess to couple the amino group with the free and flexible carboxyl group of IFN-a. to form in peptide bond. [0573] If desired, the PEGylated IFN-a is separated from the IFN-a; Non-PEGylated using any known method, including, but not limited to, ion exchange chromatography, gel chromatography, and combinations thereof. For example, when the PEG-IFN-a conjugate; Is it an IF? -Q! monoPEGylated, the products are separated first with ion-exchange chromatography to obtain material with the characteristic charge of the monoPEGylated material (there can be presence of another mui-PEGylated material with the same apparent charge), and then the monoPEGylated materials are separated with gel chromatography . IFN-Qf monoPEG (30 kD, linear) -ylated [0574] IF? -a; PEGylated suitable for use in embodiments includes a consensus interferon molecule (CIF?) MonoPEGylated formed by a single CIF polypeptide? and a single polyethylene glycol (PEG) fraction, where the PEG fraction is linear and has a molecular weight of about 30 kD and is directly or indirectly linked via a stable covalent bond to the? -terminal residue of the CIFN polypeptide or to a lysine residue of the CIFN polypeptide. In some embodiments, the IF? -a monoPEG (30 kD, linear) -ylated is a monopeptide (30 kD, linear) -IF consensus IFN-a. [0575] In some embodiments, the PEG moiety is linked to the alpha amino group of the? -terminal residue of the CIF polypeptide? or to the epsilon-amino group of a lysine residue of the CIF polypeptide ?. In other embodiments, the linkage consists of an amide linkage between the PEG moiety and the alpha amino group of the? -terminal residue or of the epsilon amino group of the lysine residue in the CIF polypeptide ?. In other embodiments, the linkage consists of an amide linkage between a propionyl group of the PEG moiety and the alpha amino group of the? -terminal residue or of the epsilon amino group of the lysine residue in the CIFN polypeptide. In further embodiments, the amide bond is formed by condensation of an activated ester of an alpha-methoxy, omega-propanoic acid of the PEG moiety and the alpha amino group of the N-terminal residue or of the epsilon amino group of the lysine residue in the polypeptide CIFN, thus forming a hydrolytically stable bond between the PEG fraction 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 CIF ?. In still other embodiments, the ligation is formed by an amide bond between the PEG moiety and the alpha amino group of the? -terminal residue in the CIF polypeptide ?. In still other embodiments, the ligation is formed by an amide bond between a propionyl group of the PEG moiety and the alpha amino group of the? -terminal residue in the CIF polypeptide ?. In further embodiments, the amide bond is formed by condensation of an activated ester of an alpha-methoxy, omega-propanoic acid with the PEG moiety and the alpha-amino group of the? -terminal residue in the CIF polypeptide ?. [0577] In some embodiments, the PEG fraction is linked to a lysine residue in the CIF ?. In other embodiments, the PEG moiety is linked to the epsilon amino group of a lysine residue in the CIFN polypeptide. In still other embodiments, the ligation consists of an amide bond between the PEG moiety and the epsilon amino group of the lysine group in the CIFN polypeptide. In still other embodiments, the ligation consists of an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of the lysine group on the CIFN polypeptide. In further embodiments, the amide bond is formed by condensation of an activated ester of alpha-methoxy acid, omega-propanoic with the PEG fraction and the epsilon amino group of the lysine residue in the CIFN polypeptide. [0578] In some embodiments, the PEG moiety is bound to a surface lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon amino group of the surface lysine residue in the CIFN polypeptide. In still other embodiments, the ligation consists of an amide bond between the PEG moiety and the epsilon amino group of the surface lysine residue in the CIFN polypeptide. In still other embodiments, the ligation consists of an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of the surface lysine residue in the CIFN polypeptide. In further embodiments, the amide bond is formed by condensation of an activated ester of alpha-methoxy, omega-propanoic acid from the PEG fraction and the epsilon amino group of the surface lysine residue in the CIFN polypeptide. [0579] In some embodiments, the PEG moiety is linked to a lysine chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon amino group of a lysine chosen from lys31, lys50, lys71, lys84, lys121, lys122, lysl4, lys135, and lys165 of the CIFN polypeptide. In other embodiments, the ligation consists of an amide bond between the PEG moiety and the epsilon amino group of the lysine residue chosen in the CIFN polypeptide. In still other embodiments, the ligation consists of an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of the lysine residue chosen in the CIFN polypeptide. In further embodiments, the amide bond is formed by condensation of an activated ester of alpha-methoxy, omega propanoic acid from the PEG fraction and the epsilon amino group of the lysine residue chosen in the CIF ?. [0580] In some embodiments, the PEG moiety is linked to a lysine chosen from lis121, lis134, lis135, and lis155 of the CIF? Polypeptide. In other embodiments, the PEG moiety is linked to the epsilon amino group of a lysine chosen from lis121, lis134, lis135, and lis165 of the CIF? Polypeptide. In still other embodiments, the ligation consists of an amide bond between the PEG moiety and the epsilon amino group of the lysine residue chosen in the CIFN polypeptide. In still other embodiments, the ligation consists of an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of the lysine residue chosen in the CIFN polypeptide. In further embodiments, the amide bond is formed by condensation of an activated ester of alpha-methoxy, omega propanoic acid from the PEG fraction and the epsilon amino group of the lysine residue chosen in the CIFN polypeptide. [0581] In connection with the monopegylated CIFN molecules described above, the invention contemplates embodiments of each of said molecules where the CIFN polypeptide is chosen from interferon alpha-cona, interferon alpha-con2, and interferon alpha-con3, whose amino acid sequences in the CIFN polypeptides are disclosed in U.S. Patent No. 4,695,623. Populations of IFN-a [0582] In addition, any of the methods of the embodiments may employ a PEGylated IFN-ce composition comprising a population of monoPEGylated IFNa molecules, wherein the population is composed of one or more species of monoPEGylated IFNce molecules. described above. The composition of the invention comprises a population of modified IFN-α 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 in a first amino acid residue; and at least one second IFN-a polypeptide. linked to a PEG molecule in a second amino acid residue, where the first and second IFN-a polypeptides are the same or different, and where 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 amino acid sequence of the second IF? -a polypeptide. As an example by way of illustration, a composition of the invention comprises a population of IF? -a polypeptides. modified, population composed of an IF? -a polypeptide. bound at its amino terminus to a linear PEG molecule; and an IFN-α polypeptide linked to a linear molecule of PEG in a lysine residue. [0584] Generally, a given species of modified IFN-o¿ represents between about 0.5% up to about 99.5% of the total population of IFN-Q polypeptide molecules! monoPEGylated in a population, p. ex. , a certain species of IF? -a. modified represents about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, around from 25%, around 30%, around 35%, around 40%, around 45%, around 50%, around 55%, around 60%, around 65%, around 70%, around 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5% of the total population of IFN-a polypeptide molecules. monoPEGilado in a population. In some embodiments, a composition of the invention comprises a population of monoPEGylated IFN-a polypeptides, population comprising at least about 70%, at least about d%, at least about 90%, at least about 95%, or at least about 99% of IFN-CÜ polypeptides linked to PEG at the same site, e.g. ex. , in the N-terminal amino acid. [0585] In particular embodiments of interest, a composition of the invention comprises a population of monoPEGylated CIFN molecules, population consisting of one or more species of molecules, wherein each species of molecules is characterized by a single bound, direct or unbound CIFN polypeptide. indirectly with a covalent ligation, to a single linear PEG fraction of about 30 kD molecular weight, and where the ligation is to a lysine residue in the CIFN polypeptide, or to the N-terminal amino acid residue of the CIFN polypeptide.

[0586] The amino acid residue to which the PEG is fixed is in many embodiments the N-terminal amino acid residue. In other embodiments, the PEG moiety is fixed (directly or via a linker) to a surface lysine residue. In further embodiments, the PEG moiety is fixed (directly or via a linker) to a lysine residue selected from lis31, lys50, lysl7, lys84, lys121, lys122, lys134, lys135, and lys165 of the CIFN polypeptide. In yet other embodiments, the PEG moiety is fixed (directly or via a linker) to a lysine residue chosen from lis121, lis134, lis135, and lis155 of the CIFN polypeptide. [0587] As an example, a composition of the invention comprises a population of monoPEGylated CIFN molecules, composed of a first species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to the N-terminal amino acid residue of a first CIFN polypeptide, and a second species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, wherein the first and second CIFN polypeptides are the same or different. A composition of the invention may further comprise at least one additional species of monoPEGylated CIFN polypeptide molecules, characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the ligation site in each additional species of monopolated CIFN polypeptide It is not the same as the ligation site in any of the other species. In all the species of this example, the PEG fraction is a linear PEG fraction having an average molecular weight of about 30 kD. [0588] In connection with each of the populations of monoPEGylated CIFN molecules described above, composed of a first species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to the N-terminal amino acid residue of a first CIF? Polypeptide. and a second species of CIF polypeptide molecules? monoPEGylated characterized by a PEG fraction linked to a first surface lysine residue of a second CIFN polypeptide, where the first and second CIF? They are the same or they are different. A composition of the invention may further comprise at least one additional species of CIF polypeptide molecules. monoPEGylated characterized by a PEG moiety linked to a surface lysine residue in the CIF? polypeptide, where the location of the ligation site in each additional species of monoPEGylated CIFN polypeptide is not the same as the location of the ligation site in any of the other species . In all the species of this example, the PEG fraction is a linear PEG fraction having an average molecular weight of about 30 kD.

[0589] In another example, a composition of the invention comprises a population of monoPEGylated CIFN molecules, composed of a first species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to the N-terminal amino acid residue of a first CIFN polypeptide , and a second species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a first lysine residue selected from lis31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and lys? 5 in a second CIFN polypeptide, where the first and the second CIFN polypeptides are the same or different. A composition of the invention may further comprise a third species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a second lysine residue selected from lys31, lys50, lys71, lys84, lys121, lys122, lysl4, lysl5, and lysl5 in a third CIF? polypeptide where the third CIF? is the same or different from the first and second CIF polypeptides, where the second lysine residue is located at a position in the amino acid sequence of the third CIF polypeptide? which is not the same as the position of the first lysine residue in the amino acid sequence of the second CIF polypeptide ?. A composition of the invention may also comprise at least one additional species of CIF polypeptide molecules. monoPEGylated characterized by a PEG fraction linked to lis31, lis50, lis71, lis84, lis121, lis122, lis134, lis135, and lis155, where the location of the binding site in each additional species of monoPEGylated CIFN polypeptide is not the same as the location of the binding site in any of the other species . In all the species of this example, the PEG fraction is a linear PEG fraction having an average molecular weight of about 30 kD. [0590] In another example, a composition of the invention comprises a population of monoPEGylated CIFN molecules, composed of a first species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to the N-terminal amino acid residue of a first CIFN polypeptide , and a second species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a first lysine residue selected from lis121, lis134, lis135, and lis165 in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or They are different . A composition of the invention may further comprise a third species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a second lysine residue selected from lis121, lis134, lis135, and lis165 in a third CIFN polypeptide, wherein the third CIFN polypeptide is the same or different from the first and the second CIFN polypeptide, where the second lysine residue is located at a position in the amino acid sequence of the third CIFN polypeptide which is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition of the invention may further comprise at least one additional species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a lis121, lis134, lis135, or lis155, where the location of the binding site in each additional CIFN polypeptide species monoPEGylated is not the same as the location of the binding site in any of the other species. In all the species of this example, the PEG fraction is a linear PEG fraction having an average molecular weight of about 30 kD. [0591] In another illustrative example, a composition of the invention comprises a population of CIF? monoPEGylated, composed of a first species of CIF polypeptide molecules? monoPEGylated characterized by a PEG fraction linked to a first lysine residue in a first CIF polypeptide?; and a second species of CIF polypeptide molecules? monoPEGylated characterized by a PEG moiety linked to a second lysine residue in a second CIF? polypeptide, wherein the first and second CIFN polypeptides are the same or different, and wherein the first lysine is located at a position in the amino acid sequence of the first CIF polypeptide? which is not the same as the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition of the invention may further comprise at least one additional species of monoPEGylated CIFN molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the ligation site in each additional species of monoPEGylated CIFN polypeptide is not the same as the location of the ligature site in any of the other species. In all the species of this example, the PEG fraction is a linear PEG fraction having an average molecular weight of about 30 kD. [0592] In another illustrative example, a composition of the invention comprises a population of monoPEGylated CIFN molecules, composed of a first species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a first lysine residue chosen from lis31, lis50, lis71, lis84, lis121, lis122, lis134, lis135, and lis1S5 in a first CIFN polypeptide; and a second species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a second lysine residue chosen from lys31, lys50, lys71, lys84, lys121, lys122, lys134, lys135, and liss165 in a second CIFN polypeptide, where the former and the second CIFN polypeptide are the same or different, and wherein the second lysine residue is located at 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 also comprise at least one additional species of monoPEGylated CIFN polypeptide molecules linked to a lys31, lys50, lys71, lys84, lys121, lys122, lysl4, lys135, or lysl5, where the location of the ligation site in each additional species of CIPP monoPEGylated polypeptide is not the same as the location of the binding site in any of the other species. In all the species of this example, the PEG fraction is a linear PEG fraction having an average molecular weight of about 30 kD. [0593] In another example by way of illustration, a composition of the invention comprises a population of monoPEGylated CIFN molecules, composed of a first species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a first lysine residue chosen from lis121, lis134, lis135, and lis165 in a first CIFN polypeptide; and a second species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a second lysine residue chosen from lis121, lis134, lis135, and lis165 in a second CIEN polypeptide, where the first and second CIFN polypeptides are the same or are different, and where the second lysine residue is located at 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 species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to lis121, lis134, lis135, or lis165, where the location of the ligation site in each additional species of monoPEGylated CIFN polypeptide is not same as the location of the binding site in any of the other species. In all the species of this example, the PEG fraction is a linear PEG fraction having an average molecular weight of about 30 kD. [0594] In another example by way of illustration, a composition of the invention comprises a population of monoPEGylated CIFN molecules, composed of a first species of monoPEGylated CIFN polypeptide molecules characterized by a PEG moiety linked to a first surface lysine residue in a first CIFN polypeptide; and a second species of CIF polypeptide molecules? monoPEGylated characterized by a PEG moiety linked to a second surface lysine residue in a second CIF? polypeptide, wherein the first and second CIFN polypeptides are the same or different, and wherein the first surface lysine is located at a position in the sequence of amino acids of the first C1F polypeptide? which is not the same as the position of the second surface lysine residue in the amino acid sequence of the CIFN polypeptide. A composition of the invention may further comprise at least one additional species of monoPEGylated CIFN molecules characterized by a PEG moiety bound to a surface lysine residue in the CIFN polypeptide, where the location of the ligation site in each additional species of monoPEGylated CIFN polypeptide is not it is the same as the location of the binding site in any of the other species. In all the species of this example, the PEG fraction is a linear PEG fraction having an average molecular weight of about 30 kD. [0595] In connection with each of the populations of monoPEGylated CIFN molecules described above, the invention contemplates embodiments in which the molecules of each of said populations comprise a CIFN polypeptide chosen from interferon alf -conx, interferon alpha-con, and interferon alfa-con3. [0596] Certain embodiments also exhibit a product that is obtained by the process of reacting a CIFN polypeptide with a succinimidyl alpha-methoxy ester, omega-propionyl poly (ethylene glycol) (mPEGspa) which is linear and has a molecular weight around of 30 kD, where the reactants are initially present in a molar ratio of about 1: 1 to about 1: 5 CIFN: mPEGspa, and where the reaction is carried out 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 in a molar ratio of about 1: 3 CIFN-.mPEGspa and the reaction is carried out at a pH of about d. In another embodiment in which the product is generated by a staging procedure necessary for toxicological and clinical investigations, the reagents are initially present in a molar ratio of 1: 2 CIFN: mPEGspa and the reaction is carried out at a pH of around 8.0. [0597] In connection with the above-described product process, the invention contemplates embodiments in which the reactive CIFN is chosen between interferon alpha-coni, interferon alpha-con2, and interferon alpha-con3. IFN-jS [0598] The term interferon-beta ("IFN- / 3") includes natural IFN- / 3 polypeptides; unnatural IFN-jβ polypeptides and natural or unnatural IF? - / 3 analogues that retain antiviral activity of a natural or unnatural IF? - / 3 mother. [0599] Any of a variety of beta interferons can be administered by the method of continuous administration of the embodiments herein. Suitable beta interferons include, but are not limited to, natural IF? IF? - / 3la, p. ex. , Avonex® (Biogen, Inc.), and Rebif® (Serono, SA); IF? - / 3lb (Betaseron®; Berlex); and similar.

[0600] The formulation of IFN-jβ 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. It is also appropriate to use an IF? - / S consensus. [0601] IFβ-β polypeptides can be produced by any known method. The DNA sequences encoding IF? - / 3 can be synthesized using standard methods. In many embodiments, IF? - / 3 polypeptides are products of the expression of sequences made from AD? transformed or passed on in bacterial hosts, p. e. , E. coli, or in eukaryotic host cells (eg, yeast, mammalian cells, such as CHO cells, and the like). In these embodiments, the IF? - / 3 is "recombinant IF? - / 3". When the host cell is a bacterial host cell, the IF? -jS is modified to include a? -terminal methionine. [0602] It should be understood that the IF? - / 3 as described herein may comprise one or more modified amino acid residues, e.g. ex. , glycosylations, chemical modifications and the like. IF? -tau [0603] The term interferon-tau includes natural IF? -tau polypeptides, unnatural IF? -tau polypeptides and natural or unnatural IF? -tau analogues that retain the antiviral activity of a natural mother IFN-tau or not natural.

[0604] Suitable interferons tau include, without limitation, natural IFN-tau; Tauferon® (Pepgen Corp.); and similar. [0605] IFN-tau may comprise an amino acid sequence as set forth in any of GenBank Access Nos. P15696; P5682d; P56632; P56629; P56831; Q29429; Q28595; Q28594; S0d072; Q0d071; Q0d070; Q06053; P56830; P2dl69; P2dl72; and P2dl71. The sequence of any known IFN-tau polypeptide can be altered in various ways known in the art in order to generate certain changes of the sequence. A variant of the polypeptide will usually be substantially similar to the sequences provided herein, that is, it will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. Sequence changes can 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. ex. , acetylation or carboxylation; changes in the sequence of amino acids that introduce or remove a glycosylation site; changes in the amino acid sequence make the protein susceptible to PEGylation; and similar. Modifications of glycosylation, e.g. ex. , those performed by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in subsequent processing steps, e.g. ex. , exposing the polypeptide to enzymes that affect glycosylation, such as glycosylating enzymes or deglicosylating mammals. Also included are sequences that have phosphorylated amino acid residues, e.g. ex. , 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. It is also appropriate to use a consensus IFN-tau. [0608] The IFN-tau polypeptides can be produced by any known method. The DNA sequences encoding IFN-tau can be synthesized using standard methods. In many embodiments, the IFN-tau polypeptides are products of expression of sequences made of transformed or transfected DNAs in bacterial hosts, e.g. ex. , E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and similar). In these embodiments, IFN-tau is "recombinant IFN-tau". When the host cell is a bacterial host cell, the IFN-tau is modified to include 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. ex. , glycosylations, chemical modifications and the like. IFN-? [0610] The term interferon-omega ("IFN-?") Includes IFN-α polypeptides natural, IFN-polypeptides? unnatural and analogous IFN-? natural or unnatural that preserve the antiviral activity of an IFN-? mother natural or not natural. [0611] Any omega interferon can be administered by the method of continuous administration of the embodiments herein. IFN-? suitable include, without limitation, IFN-? natural IFN-? recombinants, p. ex. , Biomed 510 (BioMedicines); and similar. [0612] The IFN-? it may comprise an amino acid sequence as set forth in GenBank Access No. NP_002168 or AAA70091. The sequence of any IFN-α polypeptide known can be altered in various ways known in the art in order to generate certain changes of the sequence. A variant of the polypeptide will usually be substantially similar to the sequences provided herein, that is, it will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. Sequence changes can 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. ex. , acetylation or carboxylation; changes in the sequence of amino acids that introduce or remove a glycosylation site; changes in the amino acid sequence make the protein susceptible to PEGylation; and similar. Modifications of glycosylation, e.g. ex. , those performed by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in subsequent processing steps, e.g. ex. , exposing the polypeptide to enzymes that affect glycosylation, such as glycosylating enzymes or deglicosylating mammals. Also included are sequences that have phosphorylated amino acid residues, e.g. ex. , phosphotyrosine, phosphoserine or phosphothreonine. [0614] The formulation of IFN-? it 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. It is also appropriate to use an IFN-? of consensus. [0615] IFN-α polypeptides they can be produced by any known method. The DNA sequences that encode IFN-? they can be synthesized using standard methods. In many embodiments, the IFN-α polypeptides are products of the expression of sequences made of DNA transformed or passed on in bacterial hosts, e.g. ex. , E. coli, or in eukaryotic host cells (eg, yeast, mammalian cells, such as CHO cells, and the like). In these embodiments, the IF? -? is "IF? -? recombinant." When the host cell is a bacterial host cell, the IF? -? is modified to include a methionine? -terminal. [0616] It should be understood that the IF? -? as described herein may comprise one or more modified amino acid residues, e.g. ex. , glycosylations, chemical modifications and the like. Type III Interferon Receptor Agonists [0617] In any of the methods described above, the interferon receptor agonist is in some embodiments a type III interferon receptor agonist (eg, "an interferon agonist Type III") . Type III interferon agonists include an IL-2db polypeptide; and an IL-28a polypeptide; and an IL-29 polypeptide; specific antibody to type III interferon receptor; and any other Type III interferon receptor agonist, including non-polypeptide agonists. [0618] IL-28A, IL-28B and IL-29 (collectively referred to herein as "Type III Interferons" or "Type III IFNs") are described in Sheppard et al. (2003) Nature 4: 63-68. Each polypeptide is linked to a heterodimeric receptor consisting of a β-chain IL-10 receptor and an IL-28 a receptor. Sheppard et al. (2003), supra. The amino acid sequence of IL-26A, IL-26B and IL-29 are found under Access Nos. GenBank NP_742150, NP_742151, and NP_742152, respectively. [0619] The amino acid sequence of an IFN Type III polypeptide can be modified in various ways known in the art to generate determined changes in the sequence. A variant of the polypeptide will usually be substantially similar to the sequences provided herein, that is, it will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. Sequence changes can be substitutions, insertions or deletions. The scanning of mutations that systematically introduce alanine or other residues can be used to determine the key amino acids. The substitutions of interest of specific amino acids 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. ex. , acetylation or carboxylation; changes in the sequence of amino acids that introduce or remove a glycosylation site; changes in the amino acid sequence make the protein susceptible to PEGylation; and similar. Modifications of glycosylation, e.g. ex. , those performed by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in subsequent processing steps, e.g. ex. , exposing the polypeptide to enzymes that affect glycosylation, such as glycosylating enzymes or deglicosylating mammals. Also included are sequences that have phosphorylated amino acid residues, e.g. ex. , phosphotyrosine, phosphoserine or phosphothreonine. [0621] Polypeptides that were modified using ordinary chemical techniques are included in the embodiments in order to increase their resistance to proteolytic degradation, optimize their solubility properties or render them more suitable as therapeutic agents. For example, the backbone of the peptide can be cyclized to improve stability (see Friedler et al (2000) J. Biol. Chem. 275: 23783-23789). Analogs that include residues that are not natural L-amino acids, e.g. ex. , D-amino acids or synthetic non-natural amino acids. The protein can be PEGylated to improve its stability. The polypeptides can be fused to albumin. [0622] The polypeptides can be prepared by in vitro synthesis, using conventional methods known in the art, by recombinant methods, or can be isolated from induced cells or natural producers of the protein. The particular sequence and mode of preparation will be determined by convenience, economic factors, degree of purity required and similar parameters. If desired, various groups can be introduced into the polypeptide during synthesis or during expression, which allow for ligation to other molecules or to a surface. Thus, cysteines can be used to make thioethers, histidines for ligation to a metal ion complex, carboxyl groups to form amides or esters, amino groups to form amides, and the like. Type II Interferon Receptor Agonists [0623] Type II interferon receptor agonists include any natural or non-natural type II human interferon receptor ligand that binds and causes transduction of the signal via the receptor. Type II interferon receptor agonists comprise interferons, including natural interferons, modified interferons, synthetic interferons, PEGylated interferons, fusion proteins comprising an interferon and a heterologous protein, mixed interferons; specific antibody for an interferon receptor; non-peptide chemical agonists; and similar. [0624] A specific example of a Type II interferon receptor agonist is IFN-? and the variants of it. While embodiments of the present exemplify the use of an IFN-α polypeptide, it will be readily apparent that any Type II interferon receptor agonist can be used in a method of the invention. Interferon-Gama [0625] Nucleic acid sequences encoding IFN-D polypeptides can be consulted in public databases, p. ex. , Genbank, magazines, etc. While various IFN-0 mammalian polypeptides are of interest, human protein will generally be used for the treatment of human diseases. The coding sequence of human IFN-D can be found in Genbank, accession numbers X13274; V00543; and? M_000619. The corresponding genomic sequence can be found in Genbank, access 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-α lb (Actimmune®, human interferon) in a 140 amino acid single chain polypeptide. It is done with recombinant techniques in E. coli and is not glycosylated. Rinderknecht et al. (1984) J. Biol. Chem. 259: 6790-6797. The IF? -? recombinant which is discussed in U.S. Pat. 6,497,871 is also suitable for use herein. [0627] The IF? -? to be used in the methods of the embodiments herein may be any of the IF? -? natural, IF? -? recombinants and derivatives thereof, as long as they have IF? -? activity, particularly IF activity? -? human. The IF? -? human exhibits the antiviral and antiproliferative properties characteristic of interferons, as well as a number of other immunomodulatory actions, as is known in the art. While the IFN-? is based on the sequences mentioned above, protein production and proteolytic processing can result in processing variants thereof. The unprocessed sequence provided by Gray et al., Supra, consists of 166 amino acids (aa). While originally it was believed that the IF? -? The recombinant produced in E. coli had 146 amino acids, (starting at amino acid 20), then it was found that the natural human IF? -D is cleaved after residue 23, producing a protein of 143 aa, or 144 aa if the Methionine terminal is present, as required for expression in bacteria. During purification, the mature protein can be further cleaved at the C terminus after radiation 162 (with reference to the sequence of Gray et al.), Giving rise to a protein of 139 amino acids, or of 140 amino acids if methionine is present. from the initial end, p. ex. , if it is required for bacterial expression. The? -terminal methionine is an artifact encoded by the AUG signal of "initiation" of translational mRNA which, in the particular case of expression in E. coli, is not outside the process. In other microbial systems or eukaryotic expression systems, methionine can be removed. [0628] For use in the methods of the invention, any of the IF? -? Peptides can be used. natural, and the modifications and variants thereof, or a combination of one or more peptides. The IFN-D peptides of interest include fragments, and may be variously truncated at the carboxyl terminus relative to the entire sequence. Said fragments continue to exhibit the characteristic properties of human interferon gamma, as long as amino acids 24 to around 149 are present (numbering from the residues of the unprocessed polypeptide). Foreign sequences can be replaced by the amino acid sequence after amino acid 155 without loss of activity. See, for example, U.S. Patent No. 5,690,925. The fractions of IFN-? natural include molecules that range variously 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 possessing activity IFN-7 can be used in the methods of the present invention. [0629] The amino acid sequence an IFN-α polypeptide it can be modified in various ways known in the art to generate certain changes in the sequence. A variant of the polypeptide will usually be substantially similar to the sequences provided herein, that is, it will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. Sequence changes can be substitutions, insertions or deletions. The scanning of mutations that systematically introduce alanine or other residues can be used to determine the key amino acids. The substitutions of interest of specific amino acids 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. ex. , acetylation or carboxylation; changes in the sequence of amino acids that introduce or remove a glycosylation site; changes in the amino acid sequence make the protein susceptible to PEGylation; and similar. One embodiment contemplates the use of variants of the IFN-? with one or more non-natural glycosylation and / or PEGylation sites that are genetically engineered to deliver glycosylated and / or PEGylated polypeptides with reduced serum clearance, such as the IFN- polypeptide variants and described in International Patent Publication No WO 01/36001. Modifications of glycosylation, e.g. ex. , those performed by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in subsequent processing steps, e.g. ex. , exposing the polypeptide to enzymes that affect glycosylation, such as glycosylating enzymes or deglicosylating mammals. Also included are sequences that have phosphorylated amino acid residues, e.g. ex. , phosphotyrosine, phosphoserine or phosphothreonine. [0631] Polypeptides that were modified using ordinary chemical techniques are included in the embodiments in order to increase their resistance to proteolytic degradation, optimize their solubility properties or render them more suitable as therapeutic agents. For example, the backbone of the peptide can be cyclized to improve stability (see Friedler et al (2000) J. Biol. Chern ^ 275: 23783-23789). Analogs that include residues that are not natural L-amino acids, e.g. ex. , D-amino acids or synthetic non-natural amino acids. The protein can be PEGylated to improve its stability. The polypeptides can be fused to albumin. [0632] The polypeptides can be prepared by in vitro synthesis, using conventional methods known in the art, by recombinant methods, or they can be isolated from induced cells or natural producers of the protein. The particular sequence and mode of preparation will be determined by convenience, economic factors, degree of purity required and similar parameters. If desired, various groups can be introduced into the polypeptide during synthesis or during expression, which allow for ligation to other molecules or to a surface. Thus, cysteines can be used to make thioethers, histidines for ligation to a metal ion complex, carboxyl groups to form amides or esters, amino groups to form amides, and the like. [0633] The polypeptides can also be isolated and purified according to conventional methods of recombinant synthesis. A lysate of the expression host can be prepared and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography or other purification technique. For the most part, the compositions to be 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 the contaminants related to the method of preparation of the product and its purification. Usually, the percentages are calculated on the total protein. Pirfenidone and analogues thereof [0634] Pirfenidone (5-methyl-1-phenyl-2- (1H) -pyridone) and specific analogs of pirfenidone are disclosed for the treatment of fibrotic frames. A "fibrotic picture" is one susceptible to treatment by administration of a compound having antifibrotic action. Pirfenidone Pirfenidone analogues I IIA IIB Descriptions of the substituents RX / R2, X [0635] Rx: carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alkyl (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furiol, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like. [0636] Rx may further include substitutions in 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, carbocyclic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl, and the like. [0638] X: can be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring. The substituents can be the same or different. The substituents may include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl, and the like.

[0639] The substituents may themselves be, optionally, substituted with 1-3 substituents of 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

[0641] U.S. Patent Nos. 3,974,281; 3,839,346; 4,042,699; 4,052,509; 5,310,562; 5.51d.729; 5,716,632; and 6,090,822 describe methods for the synthesis and formulation of pirfenidone and pirfenidone-specific analogs in pharmaceutical compositions suitable for use in the methods of the embodiments herein. Thymosin-a [0642] Thymosin-a (Zadaxin ™, available from SciClone Pharmaceuticals, Inc., San Mateo, CA) is a synthetic form of thymosin alpha 1, a hormone found naturally in the circulation and synthesized by the body. scam. Thymosin-o increases the activity of T cells and NK cells. Zadaxin ™, formulated for subcutaneous injection, is a sterile and purified lyophilized preparation of chemically synthesized alpha 1 thymosin, identical to human alpha 1 thymosin. Thymosin alpha 1 is an acetylated polypeptide with the following sequence: Ac - Ser - Asp - Ala - Ala - Val - Asp - Thr - Ser - Ser - Glu - lie - Thr - Thr - Lys - Asp - Leu - Lys - Glu - Lys - Lys - Glu - Val - Val - Glu - Glu - Ala - Glu - Asn - OH, and has a molecular weight of 3,108 daltons. The lyophilized preparation contains 1.6 mg of synthetic thymosin-a, 50 mg of mannitol, and sodium phosphate buffer to adjust the pH to 6.8. Ribavirin [0643] Ribavirin, l- / 3-D-ribofuranosyl-lH-l, 2,4-triazole-3-carboxamide, is a nucleoside analogue available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., And is described in the Merck Index, composed No. 6199, Eleventh Edition. Its manufacture and formulation are described in U.S. Patent No. 4,211,771. Embodiments also contemplate the use of ribavirin derivatives (see, e.g., U.S. Patent No. 6. 277.d30). Ribavirin can be administered orally in capsules or tablets. Of course, as they are available, other routes of ribavirin administration are contemplated, such as nasal spray, transdermal, suppositories, sustained release forms, etc. Any form of administration will be useful as long as the appropriate doses are administered without destroying the active principle. [0644] Ribavirin is generally administered in an amount ranging from about 400 mg to about 1200 mg, between about 600 mg to about 1000 mg, or between about 700 to about 900 mg daily. In some embodiments, ribavirin is administered throughout the course of therapy with the NS3 inhibitor. Levovirin [0645] Levovirin is the L-enantiomer of ribavirin, and has the property of increasing a Thl-type immune response with respect to a Th2-type immune response. Levovirin is manufactured by ICN Pharmaceuticals. [0646] Levovirin has the following structure: Viramidine [0647] Viramidine is a 3-carboxamidine derivative of ribavirin, and acts as a prodrug of ribavirin. Adenosine deaminase converts it to ribavirin efficiently. [0648] Viramidine has the following structure: Nucleoside analogs [0649] Nucleoside analogs that are suitable for use in a subject combination therapy include, without limitation, ribavirin, levovirin, viramidine, isatoribine, an L-ribofuranosyl nucleoside as disclosed in U.S. Pat. 5,559,101 and encompassed by Formula I of U.S. Patent No. 5,559,101 (e.g., L- -L-ribofuranosyluracil, 1- / 3-L-ribofuranosyl-5-fluorouracil, I- / 3 -L-ribofuranosilcitosina, 9-, 6-L-ribofuranosiladenina, 9- / 3-L-ribofuranosilhipoxanthina, 9-jd-L-ribofuranosilguanina, 9- -L-ribofuranosil-6-thioguanina, 2-amino-a: ~ L -ribofuranyl [1 ', 2' .- 4, 5] oxazoline, O2, 0 -anhydro-1-aL-ribofuranosyluracil, 1-aL-ribofuranosiluracil, 1- (2,3,5-tri-O-benzoyl-a -ribofuranosyl) -4-thiouracil, 1-aL-ribofuranosylcytosine, la-ribofuranosyl-4-thiouracil, 1-aL-ribof ranosyl-5-fluorouracil, 2-amino-β-L-arabinofuran [1 ', 2': 4 , 5] oxazoline, 02,02-anhydro- / 3-L-arabinofuranosiluracil or, 2 '-deoxy- / 3-L-uridine, 3'5'-Di-0-benzoyl-2'-deoxy-4-thio-L-uridine, 2'-deoxy- / 3-L-cytidine, 2 '-deoxy-fS-L-4-thiouridine, 2' -deoxy-5-L-thymidine, 2'-deoxy-3-L-5-fluorouridine, 2 ', 3' -dideoxy-jd-L-uridine , 2'-deoxy- / 3-L-5-fluorouridine, and 2'-deoxy-jS-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 1 of U.S. Patent Publication No. 2002/0058635; a nucleoside analogue as disclosed in WO 01/90121 A2 (Idenix); a nucleoside analogue as disclosed in WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.); a nucleoside analogue as disclosed in WO 02/057287 A2 or WO 02/057425 A2 (both Merck / lsis); etc. TNF Antagonists [0650] In some embodiments, a method of the invention comprises administering an effective amount of an NS3 inhibitor and an effective amount of an α-factor antagonist. of tumor necrosis (TNF-a.). Antagonists of TNF-α that are suitable for use herein include agents that decrease the level of synthesis of TNF-α;, agents that block or inhibit the binding of TNF-α to a TNF-α receptor (FNTR), and agents that block or inhibit the transduction of the signal mediated by FNTR. Unless expressly specified otherwise, it will be understood that any reference to an "TNF-a antagonist" or "TNF antagonist" means herein an antagonist of TNF-α; different from pirfenidone or a pirfenidone analog. [0651] As used herein, the terms "FNT polypeptide receptor" and "FNTR polypeptide" refer to polypeptides derived from the FNTR (of any species) that are capable of binding to TNF. Two different cell surface FNTRs have been described: Type II FNTR (or p75 FNTR or FNTRII) and Type I FNTR (or p55 FNTR or FNTRI). The full-length mature human pFNRF is a glycoprotein with a molecular weight of approximately 75-80 kiloDaltons (kD). The full-length mature human pFNRF is a glycoprotein with a molecular weight of about 55-60kD. Examples of FNTR polypeptides are derived from Type I FNTR and / or Type II FNTR. Soluble FNTR includes the p75 FNTR polypeptide; FNTR p75 fusions with heterologous fusion partners, for example, the Fc portion of an immunoglobulin. [0652] An FNTR polypeptide can be an intact FNTR or an appropriate fragment of the FNTR. U.S. Patent No. 5,605,690 provides examples of FNTR polypeptides, including FNTR soluble polypeptides, which are suitable for use in the embodiments herein. In many embodiments, the FNTR polypeptide comprises an extracellular domain of the FNTR. In some embodiments, the FNTR polypeptide is a fusion polypeptide comprising an extracellular domain of the FNTR linked to a constant domain of an immunoglobulin molecule. In other embodiments, the FNTR polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 FNTR bound to a constant domain of an IgG1 molecule. In some embodiments, when administration to humans is contemplated, an Ig is used for fusion proteins that is human, e.g., human IgGl. [0653] Monovalent and multivalent forms of FNTR polypeptides can be used in the embodiments of the present invention. Multivalent forms of FNTR polypeptides possess more than one binding site for F? T. In some embodiments, the F? TR is a bivalent, or dimeric, form of the F? TR. For example, as described in the United States Patent? 5,605,690 and in Mohler et al., 1993, J. Immunol. , 151: 1548-1561, a chimeric polypeptide antibody with extracellular F? TR domains substituted for the variable domains of one of the heavy or light immunoglobulin chains or both could provide a F? TR polypeptide for the embodiments of the invention. I presented. In general, when the cells produce a chimeric FNTR polypeptide: antibody with these characteristics, it forms a bivalent molecule through disulfide bridge junctions between the immunoglobulin domains. A chimeric FNTR polypeptide-antibody with these characteristics is called FNTR: Fc. [0654] In one embodiment, a method of the invention includes administering an effective amount of the soluble ENBREL® FNTR. ENBREL® is a dimeric fusion protein that consists of the extracellular portion that binds to the human FNTR ligand of 75 kiloDalton (p75) bound to the Fc portion of human IgGl. The Fc component of ENBREL® contains the CH2 domain, the CH3 domain and the hinge region, but not the CH1 domain of IgG1. ENBREL® is produced in a mammalian 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). "Immunol., 151: 1546-1561; U.S. Patent No. 5,395,760; and U.S. Patent No. 5,605,690. [0655] Also suitable for use are monoclonal antibodies that bind to FNT-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 sequence of amino acids, etc. See, for example, WO 90/10077, WO 90/04036, and WO 92/02190. Appropriate monoclonal antibodies include antibody fragments, such as for example Fv, F (ab ') 2 and Fab; synthetics, artificial antibodies, antibodies obtained by phage display, etc. [0656] Examples of monoclonal antibodies that are appropriate include Infliximab (REMICADE®, Centocor) and Adalimumab (HUMIRA ™, Abbott) REMICADE® is a chimeric monoclonal antibody to anti-TNF-a. which includes about 25% of a mouse amino acid sequence and about 75% of a human amino acid sequence. REMICADE® comprises a variable region of a mouse monoclonal anti-TNF-α antibody fused to the constant region of a human IgG1. Elliott et al. (1993) Arthritis Rheum. 36: 1661-1690; Elliott et al. (1994) Lancet 344: 1105-1110; Baert et al. (1999) Gastroenterology 116: 22-28. HUMIRA ™ is a full-length, human IgGl monoclonal antibody that was identified using phage display technology. Piascik (2003) J ". Am. Pharm. Assoc. 43: 327-328. [0657] In the term" TNF antagonist ", stress-inhibited protein kinase (SAPK) inhibitors are also included, and therefore are suitable for use in a method of the invention SAPK inhibitors are known in the art, and include, but are not limited to, 2-alkyl imidazoles which are disclosed in U.S. Patent No. 6,548,520; 1,4,5 which are 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 which are disclosed in U.S. Published Patent Application No. 2003/0073632, pyridyl imidazole compounds disclosed in U.S. Patent No. 6,268.0d9, and heteroaryl aminobenzophenones disclosed in U.S. Pat. No. 6,432,962, the compounds which are also interesting are also which are 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 that are activated in response to stress stimuli. SAPKs include, but are not limited to, p38 kinases (Lee et al. (1994) Nature 372: 739) and N-terminal c-jun (JNK). [0658] Methods for evaluating TNF antagonist activity are known in the art and are given here as an example. For example, TNF antagonist activity can be evaluated with a competitive cell-based binding assay. In an assay with these characteristics, radiolabeled TNF is mixed with TNF antagonist diluted in series and cells expressing F? TR bound to cell membrane. The portions of the suspension are centrifuged to separate the free F? T from the bound and the amount of radioactivity in the free and bound fractions is determined. The antagonist activity of F? T is analyzed by the inhibition of F? T binding to the cells in the presence of the F? T antagonist. [0659] As another example, one can analyze the ability to neutralize the in vitro activity of the F? T of the F? T antagonists in a bioassay using cells susceptible to the cytotoxic activity of F? T as target cells. In such an assay, target cells, cultured with F? T, are treated with different amounts of F? T antagonist and subsequently cytolysis is examined. The antagonist activity of F? T is analyzed by decreasing the cytolysis of the target cells induced by F? T in the presence of the F? T antagonist. S5B Inhibitors [0660] Some embodiments provide a method comprising 'administering an effective amount of a subject S3 inhibitor and an effective amount of a non-structural inhibitor of HCV protein-5 (NS5; RNA-dependent RNA polymerase) to a HCV patient who needs them. Suitable αS5B 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 the International Patent Applications Nos. PCT / CA02 / 01127, PCT / CA02 / 01128, and PCT / CA02 / 01129, all filed 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, for example, JTK-003 (Japan Tobacco); a dinucleotide analogue as disclosed in Zhong et al. (2003) Antimicrob. Agents Chemother. 47: 2674-2681; a benzothiadiazine compound as disclosed in Dhanak et al. (2002) J. Biol. Chem. 277 (41): 38322-7; an NS5B inhibitor as disclosed in WO 02/100646 Al or WO 02/100651 A2 (both Shire); an inhibitor of NS5B as disclosed in WO 01/85172 Al or WO 02/098424 Al (both by Glaxo Smith Kline); an inhibitor of NS5B as disclosed in WO 00/06529 or WO 02/06246 Al (both of Merck); an NS5B inhibitor as disclosed in WO 03/000254 (Japan Tobacco); an inhibitor of NS5B as disclosed in EP 1 256,628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan Tobacco), -tecetera. [0661] In many embodiments, NS5 inhibitors that are specific inhibitors of NS5, for example, inhibitors of NS5 which inhibit RNA-dependent RNA polymerase? S5 and which lack significant inhibitory effects towards other NS5 inhibitors, are of particular interest.

RNA polymerases dependent on AR? and towards AR? polymerases dependent on AD ?. Additional antiviral agents [0662] Other additional antiviral therapeutics that can be administered in cnation with a subject compound inhibitor of S3 include, without limitation, inhibitors of inosine monophosphate dehydrogenase (IMPDH); ribozymes that are complementary to viral nucleotide sequences; inhibitors of antisense non-coding RNA; etc. IMPDH Inhibitors [0663] IMPDH inhibitors that are suitable for use in a subject cnation therapy include, but are not limited to, VX-497 (Tetrahydrofuran-3-yl ester of acid (S) -N-3 - [3- (3-methoxy-4-oxazol-5-ylphenyl) ureido] benzylcarbamic); Vértex Pharmaceuticals; see, for example, Markland et al. (2000) Antimicrob. Agents Chemother. 44: 859-666); ribavirin; levovirin (Ribapharm; see, for example, Watson (2002) Curr. Opin. Investig. Drugs 3 (5): 680-3); viramidine (Ribapharm); etc. Ribozyme and Antisense [0664] The antiviral ribozyme and antisense agents that are suitable for use in a subject cnation therapy include, but are not limited to, ISIS 14803 (ISIS Pharmaceuticals / Elan Corporation, see, e.g., Witherell (2001) Curr. Opin. Investigation Drugs 2 (11) .1523-9); Heptazyme ™, - etcetera. [0665] In some embodiments, an additional antiviral agent is administered throughout the course of treatment with NS3 inhibitor compound. In other embodiments, an additional antiviral agent is administered over a period of time that overlaps with that of the NS3 inhibitor compound treatment, for example, treatment with additional antiviral agent may begin before treatment with inhibitory compound of NS3 and finish before the end of treatment with NS3 inhibitor compound; treatment with additional antiviral agent may begin after treatment with NS3 inhibitor compound begins and terminate after treatment with NS3 inhibitor compound is terminated, - treatment with additional antiviral agent may begin after treatment with inhibitor compound of NS3 begins. NS3 and finish before the end of treatment with NS3 inhibitor compound; or treatment with additional antiviral agent may begin before treatment with NS3 inhibitor compound begins and terminate after treatment with NS3 inhibitor compound is terminated. Dosages, Formulations, and Routes of Administration [0666] In the methods of the invention, the active agent (s) (e.g., compound of formula I, and, optionally, one or more additional viral agents) can be administered to the host using any convenient means capable of resulting in the therapeutic effect desired. Thus, the agent can be incorporated into a variety of formulations for therapeutic administration. More particularly, the agents of the embodiments herein may be formulated into pharmaceutical compositions by cnation with suitable vehicles or diluents acceptable for pharmaceutical use, and may be formulated into preparations in solid, semisolid, liquid or gaseous forms, such as Examples are tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols. Formulations [0667] The active agent (s) discussed above can be formulated using reagents and methods that are well known. The compositions are provided in formulation with acceptable excipient (s) for pharmaceutical use. A wide variety of acceptable excipients for pharmaceutical use are known in the art and it is not necessary to expose them here in detail. Acceptable excipients for pharmaceutical use have been extensively described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20th edition, Lippincott, Williams, &; Wiikins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., Eds., 7th ed. , Lippincott, Williams, & Wiikins; and Handbook of Pharmaceutical Excipients (2000) A. H. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc. [0668] The public can easily obtain acceptable excipients for pharmaceutical use, such as vehicles, adjuvants, vehicles or diluents. Moreover, the public can easily obtain acceptable auxiliary substances for pharmaceutical use, such as, for example, pH adjusting agents and pH buffers, tonicity adjusting agents, stabilizers, wetting agents and so on. [0669] In some embodiments, an agent is formulated in an aqueous buffer solution. Aqueous buffer solutions which are suitable include, but are not limited to, buffer solutions of pH to acetate, succinate, citrate, and phosphate with forces ranging from 5mM to 100mM. In some embodiments, the aqueous buffer solution includes reagents that provide an isotonic solution. Such reagents include, but are not limited to, sodium chloride; and sugars for example, mannitol, dextrose, sucrose, and so on. In some embodiments, the aqueous buffer solution further includes a nonionic surfactant such as polysorbate 20 or 80. Optionally, the formulations may also include a preservative. Suitable preservatives include, without limitation, a benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the formulation is stored at approximately 4 ° C. The formulations can also be lyophilized, in which case they generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, mannitol, and the like. Freeze-dried formulations can be stored for long periods of time, even at ambient temperatures. [0670] As such, the administration of the agents can be achieved in different ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc. administration. In many embodiments, administration is by bolus injection, eg, subcutaneous injection of a bolus, intramuscular injection of a bolus, and the like. [0671] The pharmaceutical compositions of the embodiments herein may be administered orally, parenterally or by an implanted reservoir. Oral or injection administration is preferred. [0672] Subcutaneous administration of a pharmaceutical composition of the embodiments herein is achieved using standard methods and devices, for example, needle and syringe, a catheter delivery system for subcutaneous injection, and so on. See, for example, U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017.32d. A combination of a catheter for subcutaneous injection and a device for administering a pharmaceutical composition of the embodiments to a patient through the catheter is referred to herein as "a catheter delivery system for subcutaneous injection". In many embodiments, subcutaneous administration is accomplished by administration of a bolus using needle and syringe. [0673] In 'pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or may also be used alone or in an appropriate association, as well as in combination with other compounds having pharmaceutical activity. The following methods and excipients are given as an example only and are by no means limiting. [0674] For oral preparations, the agents may be used alone or in combination with appropriate additives for making tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch.; with binders, such as for example crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatin; with disintegrants, such as, for example, corn starch, potato starch or sodium carboxymethyl cellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, pH buffering agents, wetting agents, preservatives and flavoring agents. [0675] Agents can be formulated into injection preparations by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as in vegetable or other similar oils, glycerides of synthetic aliphatic acids, 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] In addition, the agents can be formed into suppositories by mixing them with a variety of bases such as emulsified bases or water soluble bases. The compounds of the embodiments herein can be administered rectally by a suppository. The suppository may include carriers such as cocoa butter, carbowax and polyethylene glycols, which melt at body temperature, although they are solid at room temperature.

[0677] Dosage unit forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided where each unit dosage, eg, teaspoonful, spoonful, tablet or suppository, contains a predetermined amount of the composition which contains one or more inhibitors. Similarly, the dosage unit forms for injection or intravenous administration may comprise the inhibitor (s) in a composition as a solution in sterile water, normal saline, or other vehicle acceptable for pharmaceutical use. [0678] As used herein, the term "unit dosage form" refers to physically discrete units suitable as dosage units for human and animal subjects, wherein each unit contains a predetermined amount of the compounds of the embodiments in a quantity sufficient to produce the desired effect in association with a diluent, vehicle or vehicle acceptable for pharmaceutical use. The specifications for the novel dosage unit forms of the embodiments herein depend on the particular compound employed and the effect to be achieved, and on the pharmacodynamics associated with each compound in the host.

[0679] The public can easily obtain acceptable excipients for pharmaceutical use, such as vehicles, adjuvants, vehicles or diluents. Moreover, the public can easily obtain acceptable auxiliary substances for pharmaceutical use, such as, for example, pH adjusting agents and pH buffers, tonicity adjusting agents, stabilizers, wetting agents and so on. Other antiviral agents [0680] As set forth above, in some embodiments a method of the invention is carried out by administering an NS3 inhibitor which is a compound of the formulas I-XIX, and optionally one or more agent (s) additional antiviral (s). [0681] In some embodiments, the method further includes administering one or more interferon receptor agonist (s). The interferon receptor agonists were described above. [0682] In other embodiments, the method further includes the administration of pirfenidone or a pirfenidone analog. Pirfenidone and pirfenidone analogs were 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 azidothymidine (AZT) (zidovudine), and analogs and derivatives thereof; 2 ', 3'-dideoxyinosine (DDI) (didanosine), and analogs and derivatives thereof; 2 ', 3' -dideoxycytidine (DDC) (dideoxycytidine), and analogues and derivatives thereof; 2 '3,' -dideshydro-2 ', 3' -dideoxythymidine (D4T) (stavudine), and analogues and derivatives thereof; combivir; abacavir; adefovir dipoxil; cidofovir; ribavirin; ribavirin analogues; etc. [0684] In some embodiments, the method further includes the administration of ribavirin. Ribavirin, 1-jS-D-ribofuranosyl-lH-1, 2,4-triazole-3-carboxamide, which can be obtained from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., Is described in the Merck Index, eleventh edition, as compound No. 8199. Its manufacture and formulation is described in U.S. Patent No. 4,211,771. The embodiments also contemplate the use of ribavirin derivatives (see, for example, U.S. Patent No. 6,277,830). Ribavirin can be administered orally in the form of capsules or tablets, or in the same form of administration or in a different form and by the same route or by a different route than the interferon receptor agonist. Of course, other types of administration of both drugs are contemplated, as they are available, as for example by nasal spray, transdermal, intravenous, by suppository, by means of a sustained release dosage form, etc. Any form of administration will serve as long as the correct dosages are given without destroying the active ingredient. [0685] In some embodiments, an additional antiviral agent is administered throughout the course of treatment with NS3 inhibitor compound. In other embodiments, an additional antiviral agent is administered over a period of time that overlaps with that of the treatment with the S3 inhibitor compound, for example, treatment with additional antiviral agent may begin before beginning treatment with inhibitory compound. of? S3 and finish before the end of the treatment with compound inhibitor of? S3; treatment with additional antiviral agent may begin after treatment with the S3 inhibitor compound begins and terminate after the treatment with the S3 inhibitor compound has ended; treatment with additional antiviral agent may begin after treatment with the S3 inhibitor compound begins and terminate before treatment with the S3 inhibitor compound is terminated; or treatment with additional antiviral agent may begin before beginning treatment with the S3 inhibitor compound and terminate after treatment with the S3 inhibitor compound has ended.

[0686] The NS3 inhibitor compounds of the embodiments are suitable for use in formulations that require good water solubility. For example, the compounds of the embodiments can be used in sugar free formulations alcohols and polyols, such as for example sugar trihydric or higher alcohols, for example, glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol, and free from other alcohols, such as for example propylene glycol and poly (ethylene glycol) (PEG), or other agents that are 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, wherein said capsule, tablet or caplet formulation provides adequate bioavailability due to the high water solubility of the compound. In some embodiments, the solubility of the subject compound allows administration of dosages equal to or greater than 1 mg drug compound / kg body weight of the patient. Methods of Treatment Monotherapies [0687] The NS3 inhibitor compound of the embodiments can be used in an acute or chronic therapy for HCV disease. In many embodiments, the NS3 inhibitor compound is administered for a period of between about 1 day and about 7 days, or between about 1 week and about 2 weeks, or between about 2 weeks and about 3 weeks, or between about 3 weeks and about 4 weeks, or between about 1 month and about 2 months, or between about 3 months and about 4 months, or between about 4 months and about 6 months, or between about 6 months and about 8 months, or between about 8 months and approximately 12 months, or for at least one year, and may be administered for longer periods of time. The NS3 inhibitor compound can be administered 5 times a day, 4 times a day, three times a day, twice a day, every day, every other day, twice a week, three times a week, every week, a week , three times a month, or once a month. In other embodiments, the NS3 inhibitor compound is administered as a continuous infusion. [068d] In many embodiments, an NS3 inhibitor compound of the embodiments is administered orally. [0689] With respect to the methods previously described for treating HCV disease in a patient, an NS3 inhibitor compound of the embodiments can be administered to the patient at a dosage of between about 0.01 mg and about 100 mg / kg of body weight of the patient per day, in between 1 and 5 divided doses per day. In some embodiments, the NS3 inhibitor compound is administered at a dosage of between about 0.5 mg and about 75 mg / kg of body weight of the patient per day, in between 1 and 5 divided doses per day. [0690] The amount of active ingredient that can be combined with carrier materials to produce a dosage form can vary depending on the host to be treated and the particular mode of administration. A typical pharmaceutical preparation may contain between about 5% and about 95% active ingredient (w / w). In other embodiments, the pharmaceutical preparation may contain between about 20% and about 80% active ingredient. [0691] Those skilled in the art will readily appreciate that the dosage levels may vary depending on the specific NS3 inhibitor compound, the severity of the symptoms and the subject's susceptibility to side effects. Preferred dosages of a given NS3 inhibitor compound can be readily determined by those skilled in the art, employing 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 an NS3 inhibitor compound are administered. For example, an NS3 inhibitor compound is administered once a month, twice a month, three times a month, week by means (qow), once a week (qw), twice a week (biw), three times per week (tiw), four times a week, five times a week, six times a week, every other day (qod), every day (qd), twice a day (qid), or three times a day (tid) , for a period of time ranging from about one day to about one week, between about two weeks and about four weeks, between about one month and about two months, between about two months and about four months, between about four months and about six months, between approximately six months and approximately eight months, between approximately eight months and approximately 1 year, between approximately 1 year and approximately 2 years, or between approximately 2 years and approximately 4 years, or more. Combination Therapies with Ribavirin [0693] In some embodiments, the methods provide combination therapies comprising the administration of an NS3 inhibitor compound as previously described, and an effective amount of ribavirin. Ribavirin can be administered in dosages of approximately 400 mg, approximately 800 mg, approximately 1000 mg, or approximately 1200 mg per day.

[0694] An embodiment provides any of the methods previously described, modified to include co-administration to the patient of an effective amount for the therapeutic use of ribavirin, for the duration of the desired course of treatment with an NS3 inhibitor compound. [0695] Another embodiment provides any of the methods previously described, modified to include co-administration to the patient of between about 800 mg and about 1200 mg of ribavirin orally per day, while the desired course of treatment with an inhibitory compound of? S3. [0696] Another embodiment provides any of the methods previously described, modified to include co-administration to the patient of (a) 1000 mg ribavirin orally per day if the patient has a body weight less than 75 kg or (b) 1200 mg of 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 2 doses for the duration of the desired course of treatment with an inhibitor compound of? S3. Levovirin combination therapies [0697] In some embodiments, the methods provide a combination therapy comprising administering an αS3 inhibitor compound as previously described, and an effective amount of levovirin. Levovirin is generally administered in an amount ranging from about 30 mg to about 60 mg, between about 60 mg and about 125 mg, between about 125 mg and about 200 mg, between about 200 mg and about 300 mg, between about 300 mg and about 400 mg, between about 400 mg and about 1200 mg, between about 600 mg and about 1000 mg, or about 700 and about 900 mg per day, or about 10 mg / kg of body weight per day. In some embodiments, levovirin is administered orally at dosages of about 400, about 800, about 1000, or about 1200 mg per day, for the duration of the desired course of treatment with the NS3 inhibitor compound. Combination Therapies with Viramidine [0698] In some embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as previously described, and an effective amount of viramidine. Viramidine is generally administered in an amount, ranging from about 30 mg to about 60 mg, between about 60 mg and about 125 mg, between about 125 mg and about 200 mg, between about 200 mg and about 300 mg, between about 300 mg and about 400 mg, between about 400 mg and about 1200 mg, between about 600 mg and about 1000 mg, or between about 700 and about 900 mg per day, or about 10 mg / kg of body weight per day. In some embodiments, viramidine is administered orally in dosages of about 800, or about 1600 mg per day, for the duration of the desired course of treatment with the NS3 inhibitor compound. Combination therapies with thymosin-a; [0699] In some embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as previously described, and an effective amount of thymosin-a. Thymosin-a (Zadaxin ™) is usually administered by subcutaneous injection. Thymosin-a. can be administered tid, bid, qd, qod, bi, tiw, qw, qow, three times a month, once a month, substantially continuously, or continuously for the duration of the desired course of treatment with the NS3 inhibitor compound . In many embodiments, thymosin-a is administered twice a week, while the desired course of treatment with the NS3 inhibitor compound lasts. [0700] Effective dosages of thymosin-a vary between approximately 0, 5 mg and about 5 mg, for example, between about 0.5 mg and about 1.0 mg, between about 1.0 mg and about 1.5 mg, between about 1.5 mg and about 2.0 mg, between about 2.0 mg and about 2.5 mg, between about 2.5 mg and about 3.0 mg, between about 3.0 mg and about 3.5 mg, between about 3.5 mg and about 4.0 mg, between about 4.0 mg and about 4.5 mg, or between about 4.5 mg and about 5.0 mg. In particular embodiments, thymosin-a. it is administered in dosages that contain an amount of 1.0 mg or 1.6 mg.

[0701] Thymosin-a! it can be administered for a period of time ranging from about one day to about one week, between about two weeks and about four weeks, between about one month and about two months, between about two months and about four months, between about four months and approximately six months, between approximately six months and approximately eight months, between approximately eight months and approximately 1 year, between approximately 1 year and approximately 2 years, or between approximately 2 years and approximately 4 years, or more. In one embodiment, the thymosin-a. is administered for the duration of the desired course of treatment with the NS3 inhibitor compound. Combination Therapies with Interferon (or Inteferons) [0702] In many embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as previously described, and an effective amount of an interferon receptor agonist. In some embodiments, a compound of formula I and an interferon type I or III receptor agonist are co-administered in the methods of treatment of the embodiments. Type I interferon receptor agonists suitable for use in this documentation include any interferon-c (IFN-OI). In certain embodiments, interferon-a; It is an interferon-a. PEGylated In other determined embodiments, interferon-a. it is a consensus interferon, such as interferon alfacon-1 INFERGEN®. In still other embodiments, interferon-a; it is a monoPEG (30 kD, linear) -type consensus interferon. [0703] The effective dosages of an IFN-c. they vary between about 3 μg and about 27 μg, between about 3 MU and about 10 MU, between about 90 μg and about 180 μg, or between about 18 μg and about 90 μg. Effective IFN-a dosages of Infergen® consensus include about 3 μg, about 6 μg, about 9 μg, about 12 μg, about 15 μg, about 18 μg, about 21 μg, about 24 μg, about 27 μg, or about 30 μg of drug per dose. The effective dosages of IFN-a; 2a and IFN-a; 2b vary between 3 million units (MU) and 10 MU per dose. Effective dosages of PEGASYS® IFN-α; 2a PEGylated contain an amount between about 90 μg and 270 μg, or about 180 μg of drug per dose. Effective dosages of PEGylated IFN-α; 2b PEG-INTRON® contain an amount of between about 0.5 μg and 3.0 μg of drug per kg of body weight per dose. The effective dosages of PEGylated consensus interferon (PEG-CIFN) contain an amount of between about 18 9 and about 90 μg, or between about 27 μg and about 60 μg, or about 45 μg of CIF amino acid? per dose of PEG-CIF ?. The effective dosages of CIF? monoPEG (30 kD, linear) -ylated contain an amount between about 45 μg and about 270 μg, or between about 60 μg and about 180 μg, or between about 90 μg and about 120 μg of drug per dose. The IF? -c. It can be administered daily, every other day, once a week, three times a week, every other week, three times a month, once a month, 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 between about 1 day and about 7 days, or between about 1 week. and about 2 weeks, or between about 2 weeks and about 3 weeks, or between about 3 weeks and about 4 weeks, or between about 1 month and about 2 months, or between about 3 months and about 4 months, or between approximately 4 months and approximately 6 months, or between approximately 6 months and approximately 8 months, or between approximately 8 months and approximately 12 months, or at least once a year, and may be administered for longer periods of time. Dosage regimens may include administrations tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or monthly. Some embodiments provide any of the methods previously described, where the desired dosage of IFN-a is administered to the patient subcutaneously, through a bolus injection qd, qod, tiw, biw, qw, qow, three times a month, or monthly, or administered to the patient subcutaneously daily using a substantially continuous or continuous administration, while the desired treatment lasts. Other embodiments provide any of the previously described methods, wherein the desired dosage of PEGylated IFN-a (PEG-IF? -a) is administered.;) the patient subcutaneously through a bolus administration qw, qow, three times a month, or monthly, while the desired treatment lasts.

[0705] In other embodiments, an NS3 inhibitor compound and a Type II interferon receptor agonist are co-administered in the methods of treatment of the embodiments. Type II interferon receptor agonists appropriate for use in this documentation include any interferon-? (IFN-?). [0706] The effective dosages of IFN-? they may vary between about 0.5 μg / m2 and about 500 μg / m2, commonly between about 1.5 μg / m2 and 200 μg / m2, depending on the size of the patient. This activity is based on international units of 106 (U) per 50 μg of protein. The IFN-? it can be administered daily, every other day, three times a week, or substantially continuously or continuously. [0707] In specific embodiments of interest, the IFN-? it is administered to an individual in an individual dosage form of between about 25 μg and about 500 μg, between about 50 μg and about 400 μg, or between about 100 μg and about 300 μg. In particular embodiments of interest, the dose is approximately 200 μg of IFN- ?. In many embodiments of interest, IFN-β lb is administered. [0708] When the dosage is 200 μg of IFN-α per dose, the amount of IFN-? by body weight (assuming a range of body weights of between approximately 45 kg and approximately 135 kg) is in the range of between approximately 4.4 μg IFN-? per kg of body weight and approximately 1.4dg of IFN-? per kg of body weight. [0709] The surface area of an individual subject generally varies between approximately 1.33 m2 and approximately 2.50 m2. Accordingly, in many embodiments, the dosage of IFN-7 ranges from about 150 μg / m2 to about 20 μg / m2. For example, a dosage of IFN-? ranges from about 20 μg / m2 to about 30 μg / m2, between about 30 μg / m2 and about 40 μg / m2, between about 40 μg / m2 and about 50 μg / m2, between about 50 μg / m2 and about 60 μg / m2, between about 60 μg / m2 and about 70 μg / m2, between about 70 μg / m2 and about 80 μg / m2, between about 80 μg / m2 and about 90 μg / m2, between about 90 μg / m2 and about 100 μg / m2, between approximately 100 μg / m2 and approximately 110 μg / m2, between approximately 110 μg / m2 and approximately 120 μg / m2, between approximately 120 μg / m2 and approximately 130 μg / m2, between approximately 130 μg / m2 and about 140 μg / m2, or between about 140 μg / m2 and about 150 μg / m2. In some embodiments, the dosage groups vary between about 25 μg / m2 and about 100 μg / m2. In other embodiments, the dosage groups vary between about 25 μg / m2 and about 50 μg / m2. [0710] In some embodiments, an Interferon Type I or Type III receptor agonist is administered in a first dosage regimen, followed by a second dosage regimen. The first dosage regimen of a Type I or Type III interferon receptor agonist (also known as an "induction regimen") generally comprises the administration of a higher dosage of Type I or Type III interferon receptor agonist. For example, in the case of IFN-a; Infergen® consensus (CIFN), the first dosage regimen comprises the administration of CIFN at a rate of approximately 9 μg, approximately 15 μg, approximately 18 μg, or between approximately 27 μg. The first dosage regimen may comprise a single dosing event, or at least two or more dosing events. The first dosage regimen of the Type I or Type III interferon receptor agonist can be administered daily, day by month, three times a week, week by month, three times a month, once a month, 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, where this period of time may be at least about 4 weeks, at least about d weeks, or at least about 12 weeks. [0712] The second dosage regimen of the Type I or Type III interferon receptor agonist (also known as the "maintenance regimen") generally comprises the administration of a minor amount of the Type I or Type III interferon receptor agonist. For example, in the case of CIFN, the second dosage regimen comprises administration of CIFN at a dose of at least about 3 μg, at least about 9 μg, at least about 15 μg, or at least about ld μg. The second dosage regimen may comprise a single dosing event, or at least two or more dosing events. [0713] The second dosage regimen of the Type I or Type III interferon receptor agonist can be administered daily, day by month, three times a week, week by month, three times a month, once a month, substantially continuously or continuous [0714] In some embodiments, when administering an "induction" / "maintenance" dosing regimen of a Type I or Type III interferon receptor agonist, a "priming" dose of an interferon receptor agonist is included. Type II (for example, IFN-?). In these embodiments, IFN-? for a period of time between about 1 day and about 14 days, between about 2 days and about 10 days, or between about 3 days and about 7 days, before the start of treatment with the type I interferon receptor agonist or type III. This period of time is known as the "priming" phase. [0715] In some of these embodiments, the administration of the Type II interferon receptor agonist is continued during the desired treatment period with the Type I or Type III interferon receptor agonist. In other embodiments, treatment with the Type II interferon receptor agonist is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist. In these embodiments, the total treatment time with the Type II interferon receptor agonist (including the "priming" phase) is between about 2 days and about 30 days, between about 4 days and about 25 days, between about 8 days. days and approximately 20 days, between approximately 10 days and approximately 18 days, or between approximately 12 days and approximately 16 days. In still other embodiments, treatment with the Type II interferon receptor agonist is interrupted once treatment with the Type I or Type III interferon receptor agonist begins.

[0716] In other embodiments, the Type I or Type III interferon receptor agonist is administered in a single dosage regimen. For example, in the case of CIFN, the dose of CIFN is generally in a range of between about 3 μg and about 15 μg, or between about 9 μg and about 15 μg. The dose of type I or type III interferon receptor agonist is usually administered daily, every other day, three times a week, a week in a row, three times a month, once a month, or in a substantially continuous manner. The dose of the Type I or Type III interferon receptor agonist is administered for a period of time which may be, for example, between at least about 24 weeks and at least about 48 weeks, or longer. [0717] In some embodiments, when a single dosage regimen of a Type I or Type III interferon receptor agonist is administered, a "priming" dose of a type II interferon receptor agonist is included. (for example, IFN-?). In these embodiments, the IFN-? it is administered for a period of time between approximately 1 day and approximately 14 days, between approximately 2 days and approximately 10 days, or between approximately 3 days and approximately 7 days, before beginning treatment with the interferon type I interferon receptor or Type III This period of time is known as the "priming" phase. In some of these embodiments, treatment with the Type II interferon receptor agonist is continued during the entire treatment period with the Type I or Type III interferon receptor agonist. In other embodiments, treatment with the Type II interferon receptor agonist is terminated before the end of treatment with the Type I or Type III interferon receptor agonist. In these embodiments, the total treatment time with the Type II interferon receptor agonist (including the "priming" phase) is between about 2 days and about 30 days, between about 4 days and about 25 days, between about 8 days and approximately 20 days, between approximately 10 days and approximately 18 days, or between approximately 12 days and approximately 16 days. In still other embodiments, treatment with the Type II interferon receptor agonist is interrupted once treatment with the Type I or Type III interferon receptor agonist begins. [0718] In other embodiments, an NS3 inhibitor compound, an interferon type I or III receptor agonist, and a Type II interferon receptor agonist are co-administered for the duration of the desired treatment in the methods of the embodiments. In some embodiments, an NS3 inhibitor compound, an interferon-a;, and an interferon-? while the desired treatment lasts in the methods of the embodiments. [0719] Some embodiments provide methods for using an amount of a Type I or Type III interferon receptor agonist, an Type II interferon receptor agonist, and an NS3 inhibitor compound, effective for the treatment of an HCV infection in a patient. In some embodiments, the embodiments provide methods for using an effective amount of an IFN-CÜ, IFN-β, and an NS 3 inhibitor compound in the treatment of an HCV infection in a patient. One embodiment provides a method for using an effective amount of an IFN-a; consensus, an IFN-? and an? S3 inhibitor compound in the treatment of an HCV infection in a patient. [0720] In general, an effective amount of a consensus interferon (CIF?) And an IF? -? suitable for use in the methods of embodiments with a dosage ratio of 1 μg CIF ?: 10 μg of IF? - ?, where the CIF? and the IFN-? they are non-PEGylated and non-glycosylated species. [0721] An embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-a; I? FERGE? ® consensus and an IF? -7 in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of I? FERGE? ® containing an amount of between about 1 μg and about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qo, three times a month, once a month, or daily, substantially continuously or continuously, in combination with a dosage of IFN -? which contains an amount of between about 10 9 and about 300 μg of drug per dose of IFN- ?, subcutaneously qd, qod, tiw, biw, qw, qo, three times a month, once a month, or daily, in a substantially continuous or continuous manner, while the desired treatment lasts with a? S3 inhibitor compound. [0722] Another embodiment provides any of the methods previously described, modified to use an effective amount of an IF? -ce consensus I? FERGE? ® and an IF? - ?, in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of I? FERGE? ® containing an amount of between about 1 μg and about 9 μg of drug per dose of I? FERGE? ®, subcutaneously qd, qod, tiw, biw, qw, qow , three times a month, once a month, or daily, substantially continuously or continuously, in combination with an IF dosage? which contains an amount of between about 10 g and about 100 μg of drug per dose of IF? - ?, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily, in substantially continuous or continuous form, while the desired treatment lasts with an NS3 inhibitor compound. [0723] Another embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-c. INFERGEN® consensus and an IFN- ?, in the treatment of a viral infection in a patient, comprising administering to the patient a dosage of INFERGEN® containing an amount of between approximately 1 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily, substantially continuously or continuously, in combination with a dosage of IFN-? which contains an amount of between about 10 μg and about 50 μg of drug per dose of IFN- ?, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily, in substantially continuous or continuous form, while the desired treatment lasts with an NS3 inhibitor compound. [0724] Another embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-a consensus INFERGEN® and an IFN-β, in the treatment of a viral infection in a patient, comprising administering to the patient a dosage of INFERGEN® containing an amount of between approximately 9 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily, in substantially continuous or continuous form, in combination with a dosage of IFN-? which contains an amount of between about 90 μg and about 100 μg of drug per dose of IF? - ?, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily , in a substantially continuous or continuous manner, while the desired treatment lasts with an inhibitor compound of? S3. [0725] Another embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-c. I? FERGE? ® consensus and an IF? - ?, in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of I? F? RGE? ® containing an amount of between about 30 μg of drug per dose of I? FERG? ®, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily, substantially continuously or continuously, in combination with a dosage of IF? -? which contains an amount of between about 200 μg and about 300 μg of drug per dose of IF? -7, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily , in a substantially continuous or continuous manner, while the desired treatment lasts with an inhibitor compound of? S3.

[0726] Another embodiment provides any of the methods previously described, modified to use an effective amount of a consensus PEGylated IFN-a and an IF? -? in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of a consensus PEGylated IFN-a (PEG-CIF?) containing an amount of between about 4 μg and about 60 μg of CIF amino acid weight? per dose of PEG-CIF ?, subcutaneously qw, qow, three times a month, or once a month, in combination with a weekly total dosage of IFN-? which contains an amount of between about 30 μg and about 1000 μg of drug per week, in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, for the duration of the desired treatment with a compound inhibitor of? S3. [0727] Another embodiment provides any of the methods previously described, modified to use an effective amount of an IF? -a. P? Gilado consensus and an IF? -? in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of an IF? -a; P? Gilad consensus (PEG-CIF?) Containing an amount of between about 18 μg and about 24 μg of CIF amino acid weight? per dose of PEG-CIF ?, subcutaneously qw, qow, three times a month, or once a month, in combination with a weekly total dosage of IF? -? containing an amount of between about 100 μg and about 300 μg of drug per week, in divided doses administered subcutaneously qd, qod, tiw, biw, or in substantially continuous or continuous form, for the duration of the desired treatment with an inhibitory compound of NS3. [0728] In general, an effective amount of IFN-a; 2a or 2b or 2c and IFN-? suitable for use in the methods of the embodiments is provided with a dosage ratio of 1 million units (MU) IFN-a 2a or 2b or 2c: 30 μg of IFN- ?, where the IFN-a; 2a or 2b or 2c and IFN-? they are non-PEGylated and non-glycosylated species. [0729] Another embodiment provides any of the methods previously described, modified to use an effective amount of IFN-a; 2a or 2b or 2c and IFN-? in the treatment of a viral infection in a patient, comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount between about 1 MU and about 20 MU of drug per dose of IFN-a. 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or daily, in substantially continuous or continuous form, in combination with a dosage of IFN-7 containing an amount of between about 30 μg and about 600 μg of drug per dose of IFN- ?, subcutaneously qd, qod, tiw, biw, or daily, in a substantially continuous or continuous manner, while the desired treatment lasts with an NS3-inhibiting compound. [0730] Another embodiment provides any of the methods previously described, modified to use an effective amount of IFN-a 2a or 2b or 2c and IF? -? in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of IF? -a. 2a, 2b or 2c containing a quantity of about 3 MU of drug per dose of IF? -CÜ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or daily, substantially continuously or continuously, in combination with a dosage of IFN-? which contains an amount of between about 100 μg of drug per dose of IFN- ?, subcutaneously qd, qod, tiw, biw, or daily, in a substantially continuous or continuous manner, while the desired treatment lasts with an inhibitory compound of? S3. [0731] Another embodiment provides any of the methods previously described, modified to use an effective amount of IF? -c. 2a or 2b or 2c and IF? -? in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of IF? -a; 2a, 2b or 2c that contains an amount between approximately 10 MU of drug per dose of IF? -a; 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or daily, substantially continuously or continuously, in combination with a dosage of IF? -? which contains an amount of between about 300 μg of drug per dose of IFN- ?, subcutaneously qd, qod, tiw, biw, or daily, substantially continuously or continuously, for the duration of the desired treatment with an NS3 inhibitor compound . [0732] Another embodiment provides any of the methods previously described, modified to use an effective amount of a PEGASYS® PEGylated IFN-α; 2a and an IFN-β, in the treatment of a viral infection in a patient, comprising administering to the patient a patient dosing PEGASYS® containing an amount between about 90 μg and about 360 μg of drug per dose of PEGASYS®, subcutaneously qw, qow, three times a month, or once a month, in combination with a dosage weekly total of IFN-? containing an amount of between about 30 μg and about 1000 μg of drug per week, administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered in substantially continuous or continuous form, for the duration of the desired treatment with a NS3 inhibitor compound. [0733] Another embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-α; 2a PEGylated PγGASYS® and an IFN-β, in the treatment of a viral infection in a patient, comprising administer to the patient a dosage of PEGASYS® containing an amount of approximately 180 μg of drug per dose of PEGASYS®, subcutaneously qw, qow, three times a month, or once a month, in combination with a total weekly dosage of IFN-? containing an amount of between about 100 μg and about 300 μg of drug per week, administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the duration of the desired treatment with a NS3 inhibitor compound. [0734] Another embodiment provides any of the methods previously described, modified to use an effective amount of a PEGylated PEG-I? TRO? ® IFN-a.2b and an IFN-? In the treatment of a viral infection in a patient , which comprises administering to the patient a dosage of PEG-I? TRO? ® containing an amount between about 0.75 μg and about 3.0 μg of drug per kilogram of body weight per dose of PEG-I? TRO? , subcutaneously qw, qow, three times a month, or once a month, in combination with a total weekly dosage of IFN-? containing an amount of between about 30 μg and about 1000 μg of drug per week, administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered in substantially continuous or continuous form, for the duration of the desired treatment with a inhibitor compound of? S3.

[0735] Another embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-α; 2b Pγ Gilated PγG-INTRON® and an IFN-β, in the treatment of a viral infection in a patient, comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 1.5 μg of drug per kilogram of body weight per dose of P? G-INTRON®, subcutaneously qw, qow, three times per month, or once a month, in combination with a total weekly dosage of IFN-? containing an amount of between about 100 μg and about 300 μg of drug per week, administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the duration of the desired treatment with a NS3 inhibitor compound. [0736] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering from an HCV infection of an effective amount of an NS3 inhibitor, - and a regimen of 9 μg of IFN-a; Consensus INF? RG? N®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor, - and a regimen of 9 μg of IFN-a; consensus INF? RG? N®, administered subcutaneously qd or tiw; 50 μg of IFN-? Lb human Actimmune®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a 9 μg IFN-a consensus I? FERG? ® regimen, administered subcutaneously qd or tiw; 100 μg of human IFN-? Lb Actimmune®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a 9 μg IFN-a consensus INFERGEN® regimen, administered subcutaneously qd or tiw; and 50 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks. [0740] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 9 μg IFN-ce consensus INFERGEN®, administered subcutaneously qd or tiw; and 100 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks. [0741] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor, - and a regimen of 9 μg of IFN-a; Consensus INFERG? N®, administered subcutaneously qd or tiw; 25 μg of IFN-? Lb human Actimmune®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor, and a 9 μg consensus IFN-CÜ regimen. INF? RG? N®, administered subcutaneously qd or tiw; 200 μg of IFN-? Lb human Actimmune®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a 9 μg IFN-a regimen; consensus INF? RG? N®, administered subcutaneously qd or tiw; and 25 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks. [0744] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a 9 μg IFN-a consensus INFERGEN® regimen, administered subcutaneously qd or tiw; and 200 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks. [0745] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering from an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 100 μg of IFN-a; consensus monoPEG (30 kD, linear) -ylated, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 100 μg consensus IFN-a monoPγG (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; 50 μg of IFN-lb human Actimmune®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering from an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 100 μg of IFN-a. consensus monoPEG (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; 100 μg of human IFN-? Lb Actimmune®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor.; and a regimen of 100 μg of IFN-a; consensus monoP? G (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; and 50 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks.

[0749] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering from an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 100 μg consensus IFN-a monoPγG (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; and 100 μg of IF? - lb human Actimmune®, administered subcutaneously tiw, where the duration of the therapy is 4d weeks. [0750] An embodiment provides any of the methods previously described, modified so that it comprises administration to an individual suffering an HCV infection of an effective amount of a? S3 inhibitor; and a regimen of 150 μg of IF? -ce consensus monoP? G (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw, and ribavirin, administered orally qd, where the duration of the therapy is of 4d 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] An embodiment provides any of the methods previously described, modified so that it comprises administration to an individual suffering from an HCV infection of an effective amount of an? S3 inhibitor; and a regimen of 150 μg IF? -a. consensus monoP? G (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; 50 μg of IFN-? Lb human Actimmune®, administered subcutaneously tiw; and ribavirin, administered orally qd, where the duration of therapy is 4d 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 150 μg of IFN-a; consensus monoPEG (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; 100 μg of human IFN-? Lb Actimmune®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 150 μg of IFN-a; consensus monoP? G (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; and 50 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks. [0754] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering from an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 150 μg of IFN-CÜ consensus monoPEG (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; and 100 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks. [0755] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 200 μg of IFN-a; consensus monoPEG (30 kD, linear) -ylated, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor.; and a 200 μg regimen of IFN-a consensus monoPγG (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; 50 μg of IFN-lb human Actimmune®, 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] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering from an HCV infection of an effective amount of an? S3 inhibitor, and a regimen of 200? G IF? - a consensus monoP? G (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; 100 μg of IF? -? Lb human Actimmune®, 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] An embodiment provides any of the methods previously described, modified so that it comprises administration to an individual suffering from an HCV infection of an effective amount of an? S3 inhibitor; and a regimen of 200 μg of IF? -a; consensus monoPEG (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; and 50 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks. [0759] An embodiment provides any of the methods previously described, modified to include administration to an individual suffering an HCV infection of an effective amount of an NS3 inhibitor; and a regimen of 200 μg of IFN-a; consensus monoPEG (30 kD, linear) -ylated, administered subcutaneously every 10 days or qw; and 100 μg of human IFN-β lb Actimmune®, administered subcutaneously tiw, where the duration of therapy is 48 weeks. [0760] Any of the previously described methods comprising the administration of an NS3 inhibitor, a Type I interferon receptor agonist (eg, an IFN-a;), and a Type II interferon receptor agonist (for example, an IFN-α) can be increased by administering an effective amount of a TNF-α antagonist; (for example, a TNF-a antagonist, other than pirfenidone or a pirfenidone analog). Non-limiting examples of TNF-a antagonists; which are appropriate for use in these combination therapies include? NBRBL®, RBMICAD? ®, and HUMIRA ™. [0761] One embodiment provides a method for using an effective amount of? NBRBL®; an effective amount of IFN-a;; an effective amount of IFN- ?; and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient an ENBRBL® dosage containing an amount of between about 0.1 μg and about 23 mg per dose, between about 0.1 μg and about 1 μg, between about 1 μg and about 10 μg, between about 10 μg and about 100 μg, between about 100 μg and about 1 mg, between about 1 mg and about 5 mg, between about 5 mg and about about 10 mg, between about 10 mg and about 15 mg, between about 15 mg and about 20 mg, or between about 20 mg and about 23 mg of? NBRBL®, subcutaneously qd, qod, tiw, biw, qw, qow , three times a month, once a month, or once a month, or daily, in a substantially continuous or continuous manner, while the desired treatment lasts. [0762] One embodiment provides a method for using an effective amount of REMICADE®, an effective amount of IFN-ci with or without an effective amount of IFN-α; and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, which comprises administering to the patient a dosage of R? MICADE® containing an amount of between about 0.1 mg / kg and about 4, 5 mg / kg, between about 0.1 mg / kg and about 0.5 mg / kg, between about 0.5 mg / kg and about 1.0 mg / kg, between about 1.0 mg / kg and about 1 , 5 mg / kg, between about 1.5 mg / kg and about 2.0 mg / kg, between about 2.0 mg / kg and about 2.5 mg / kg, between about 2.5 mg / kg and about 3.0 mg / kg, between about 3.0 mg / kg and about 3.5 mg / kg, between about 3.5 mg / kg and about 4.0 mg / kg, or between about 4.0 mg / kg and about 4.5 mg / kg per dose of REMICADE®, intravenously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or once a month, or daily, in form substantially continuous a or continuous, while the desired treatment lasts. [0763] One embodiment provides a method for using an effective amount of HUMIRA ™, an effective amount of IFN-a; an effective amount of IFN- ?; 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 HUMIRA ™ containing an amount of between about 0.1 μg and. about 35 mg, between about 0.1 μg and about 1 μg, between about 1 μg and about 10 μg, between about 10 μg and about 100 μg, between about 100 μg and about 1 mg, between about 1 mg and about 5 mg , between about 5 mg and about 10 mg, between about 10 mg and about 15 mg, between about 15 mg and about 20 mg, between about 20 mg and about 25 mg, between about 25 mg and about 30 mg, or between about 30 mg and approximately 35 mg per dose of a HUMIRA ™, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or once a month, or daily, substantially continuous or continuous, while the desired treatment lasts. Combination Therapies with Pirfenidone [0764] In many embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as previously described, and an effective amount of pirfenidone or a pirfenidone analogue. In some embodiments, an NS3 inhibitor compound, one or more interferon receptor agonists, and pirfenidone or a pirfenidone analog are co-administered in the methods of treatment of the embodiments. In certain embodiments, an NS3 inhibitor compound, an interferon type I receptor agonist, and pirfenidone (or a pirfenidone analog) is co-administered. In other embodiments, an NS3 inhibitor compound, an interferon type I receptor agonist, an interferon type II receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered. Type I interferon receptor agonists appropriate for use in this documentation include any selected from IFN-a;, such as interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, and IFN-c. PEGylated, such as PEGylated interferon alfa-2a, PEGylated interferon alfa-2b, and PEGylated consensus interferons, such as monoPEG consensus (30 kD, linear) -ylated interferon. Type II interferon receptor agonists appropriate for use in this documentation include any interferon-? . [0765] Pirfenidone or pirfenidone analog can be administered once a month, twice a month, three times a month, once a week, twice a week, three times a week, four times a week, five times a week. week, six times a week, daily, or in divided daily doses ranging from once a day 5 times a day, for a period of time ranging from about a day to about a week, between about two weeks and about four weeks , between about one month and about two months, between about two months and about four months, between about four months and about six months, between about six months and about eight months, between about eight months and about one year, between about one year and approximately 2 years, or between approximately 2 years and approximately 4 years, or more.

[0766] Effective dosages of pirfenidone or a specific pirfenidone analog include a dosage based on weight in the range of between about 5 mg / kg / day and about 125 mg / kg / day, or a fixed dosage of between about 400 mg and approximately 3600 mg per day, or between approximately 800 mg and approximately 2400 mg per day, or between approximately 1000 mg and approximately 1800 mg per day, or between approximately 1200 mg and approximately 1600 mg per day, administered orally in between a and 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. Patent Nos. 5310562, 5518729, 5716632 and 6090822. [0767] One embodiment provides any of the methods previously described, modified to include a co-administration to the patient of an effective amount for the therapeutic use of pirfenidone or a pirfenidone analog, while the desired course of treatment with the NS3 inhibitor compound lasts. Combination therapies with TNF-a antagonists; [0768] In many embodiments, the methods provide a combination therapy comprising administering an effective amount of an NS3 inhibitor compound as previously described, and an effective amount of a TNF-a antagonist; combination for the treatment of an HCV infection. [0769] Effective dosages of a TNF-α antagonist! they vary between 0.1 μg to 40 mg per dose, for example, between about 0.1 μg and about 0.5 μg per dose, between about 0.5 μg and about 1.0 μg per dose, between about 1.0 μg per dose and approximately 5.0 μg per dose, between approximately 5.0 and approximately 10 μg per dose, between approximately 10 μg and approximately 20 μg per dose, between approximately 20 μg per dose and approximately 30 μg per dose, between approximately 30 μg per dose and approximately 40 μg per dose, between about 40 μg per dose and about 50 μg per dose, between about 50 μg per dose and about 60 μg per dose, between about 60 μg per dose and about 70 μg per dose, between about 70 μg and about 80 μg per dose, between about 80 μg per dose and about 100 μg per dose, between about 100 μg and about 150 μg per dose, between about 150 μg and about 200 μg per dose, between about 200 μg per dose and about 250 μg per dose, between about 250 μg and about 300 μg per dose, between about 300 μg and about 400 μg per dose, between about 400 μg and about 500 μg per dose, between about 500 μg and about 600 μg per dose, between about 600 μg and about 700 μg per dose, between about 700 μg and about 800 μg per dose, between about 800 μg and about 900 μg per dose, between about 900 μg and about 1000 μg per dose, between about 1 mg and about 10 mg per dose, between about 10 μM and about 15 mg per dose, between about 15 mg and about 20 mg per dose, between about 20 mg and about 25 mg per dose, between approximately 25 mg and approximately 30 mg per dose, between approximately 30 mg and about 35 mg per dose, or between about 35 mg and about 40 mg per dose. [0770] In some embodiments, effective dosages of a TNF-a antagonist; they are expressed as mg / kg of body weight. In these embodiments, the effective dosages of a TNF-a antagonist; are between about 0.1 mg / kg of body weight and about 10 mg / kg of body weight, for example, between about 0.1 mg / kg of body weight and about 0, 5 mg / kg of body weight, between about 0.5 mg / kg of body weight and about 1.0 mg / kg of body weight, between about 1.0 mg / kg of body weight and about 2.5 mg / kg. kg of body weight, between about 2.5 mg / kg of body weight and about 5.0 mg / kg of body weight, between about 5.0 mg / kg of body weight and about 7.5 mg / kg of body weight , or between about 7.5 mg / kg of body weight and about 10 mg / kg of body weight. [0771]? In many embodiments, a TNF-a antagonist; it is administered for a period of between about 1 day and about 7 days, or between about 1 week and about 2 weeks, or between about 2 weeks and about 3 weeks, or between about 3 weeks and about 4 weeks, or between about 1 month and about 2 months, or between about 3 months and about 4 months, or between about 4 months and about 6 months, or between about 6 months and about d months, or between about 8 months and about 12 months, or at least a year , and can be administered for longer periods of time. The TNF-a antagonist; can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times a month, once a month, substantially continuously, or continuously. [0772] In many embodiments, multiple doses of a TNF-a antagonist are administered; . For example, a T? F-a antagonist is administered. once a month, twice a month, three times a month, every other week (qow), once a week (qw), twice a week (biw), three times a week (tiw), four times a week , five times a week, six times a week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, for a period of time ranging from about one day to about one week, between about two weeks and about four weeks, between about one month and about two months, between about two months and about four months, between about four months and about six months months, between approximately six months and approximately eight months, between approximately eight months and approximately 1 year, between approximately 1 year and approximately 2 years, or between approximately 2 years and approximately 4 years, or more. [0773] In general, a TNF-a antagonist is administered; and an NS3 inhibitor in separate formulations. A TNF-a antagonist can be administered; and an NS3 inhibitor in substantially simultaneous or with a separation of 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, approximately 4 days, approximately 7 days, or between approximately 2 weeks. [0774] One embodiment provides a method for 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 between about 0.1 μg and about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound. [0775] One embodiment provides a method for using an effective amount of E? BRBL® and an effective amount of an? S3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a B? BRBL dosage. ® containing an amount of between about 0.1 μg and about 23 mg per dose, between about 0.1 μg and about 1 μg, between about 1 μg and about 10 μg, between about 10 μg and about 100 μg, between about 100 μg and about 1 mg, between about 1 mg and about 5 mg, between about 5 mg and about 10 mg, between about 10 mg and about 15 mg, between about 15 mg and about 20 mg, or between about 20 mg and about 23 mg of? NBRBL®, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or once every other month, or daily, in a substantially continuous or continuous manner, while the desired treatment lasts with an NS3 inhibitor compound. [0776] One embodiment provides a method for using an effective amount of REMICADB® 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 R? MICAD? ® containing an amount of between about 0.1 mg / kg and about 4.5 mg / kg, between about 0.1 mg / kg and about 0.5 mg / kg, between about 0.5 mg / kg and about 1 , 0 mg / kg, between about 1.0 mg / kg and about 1.5 mg / kg, between about 1.5 mg / kg and about 2.0 mg / kg, between about 2.0 mg / kg and about 2.5 mg / kg, between about 2.5 mg / kg and about 3.0 mg / kg, between about 3.0 mg / kg and about 3.5 mg / kg, between about 3.5 mg / kg and about 4.0 mg / kg, or between about 4.0 mg / kg and about 4.5 mg / kg per dose of R? MICAD? ®, intravenously qd, qod, tiw, biw, qw, qow, three times a month, a once per month, or once per month, or daily, substantially continuously or continuously, for the duration of the desired treatment with an NS3 inhibitor compound. [0777] One embodiment provides a method for using an effective amount of HUMIRA ™ 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 HUMIRA ™ containing a amount between about 0.1 μg and about 35 mg, between about 0.1 μg and about 1 μg, between about 1 μg and about 10 μg, between about 10 μg and about 100 μg, between about 100 μg and about 1 mg , between about 1 mg and about 5 mg, between about 5 mg and about 10 mg, between about 10 mg and about 15 mg, between about 15 mg and about 20 mg, between about 20 mg and about 25 mg, between about 25 mg and about 30 mg, or between about 30 mg and about 35 mg per dose of a HUMIRA ™, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or once a month, or daily, substantially continuously or continuously, for the duration of the desired treatment with an NS3 inhibitor compound. Combination therapies with thymosin-a; [077d] In many embodiments, the methods provide a combination therapy comprising the administration of an effective amount of an NS3 inhibitor compound as previously described, and an effective amount of thymosin-a;, in a combination therapy for the treatment of an HCV infection. [0779] The effective dosages of thymosin-a; they vary between about 0.5 mg and about 5 mg, for example, between about 0.5 mg and about 1.0 mg, between about 1.0 mg and about 1.5 mg, between about 1.5 mg and about 2 mg. , 0 mg, between about 2.0 mg and about 2.5 mg, between about 2.5 mg and about 3.0 mg, between about 3.0 mg and about 3.5 mg, between about 3.5 mg and about 4.0 mg, between about 4.0 mg and about 4.5 mg, or between about 4.5 mg and about 5.0 mg. ? n particular realizations, thymosin-a; it is administered in dosages that contain an amount of 1.0 mg or 1.6 mg. [0780] One embodiment provides a method for using an effective amount of thymosin-a; ZADAXIN ™ and an effective amount of an? S3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of ZADAXI? ™ containing an amount of between about 1.0 mg and about 1, 6 mg per dose, subcutaneously twice a week, for the duration of the desired treatment with the NS3 inhibitor compound. Combination therapies with a TNF-a antagonist; and an interferon [0781] Some embodiments provide a method for treating an HCV infection in an individual suffering an HCV infection, wherein the method comprises administering an effective amount of an NS3 inhibitor, an effective amount of a TNF- antagonist. a., and an effective amount of one or more interferons. [0782] An embodiment provides any of the methods previously described, modified to use an effective amount of IFN-? and an effective amount of a TNF-a antagonist; in the treatment of an HCV infection in a patient, which comprises administering to the patient a dosage of IFN-α. containing an amount of between about 10 μg and about 300 μg of drug per dose of IFN- ?, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily, in substantially continuous or continuous form, in combination with a dosage of a TNF-α antagonist containing an amount between about 0.1 μg and about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod , tiw, or biw, or daily, in a substantially continuous or continuous manner, while the desired treatment lasts with an NS3 inhibitor compound. [0783] An embodiment provides any of the methods previously described, modified to use an effective amount of IFN-? and an effective amount of a TNF-a antagonist; in the treatment of an HCV infection in a patient, which comprises administering to the patient a dosage of IFN-α. which contains an amount of between about 10 μg and about 100 μg of drug per dose of IF? - ?, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily , in substantially continuous or continuous form, in combination with a dosage of a T? Fa antagonist; which contains an amount of between about 0.1 μg and about 40 mg per dose of a T-Fa antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an? S3 inhibitor compound. [0784] Another embodiment provides any of the methods previously described, modified to use an effective amount of IF? -? and an effective amount of a T? F-a antagonist; in the treatment of a viral infection in a patient, which comprises administering to the patient a total weekly dosage of IF? -? containing an amount of between about 30 μg and about 1000 μg 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 an antagonist of TNF-a; containing an amount of between about 0.1 μg and about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound. [0785] Another embodiment provides any of the methods previously described, modified to use an effective amount of IFN-? and an effective amount of a TNF-a antagonist; in the treatment of a viral infection in a patient, which comprises administering to the patient a total weekly dosage of IFN-α. containing an amount of between about 100 μg and about 300 μg 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 an antagonist of TNF-a; containing an amount of between about 0.1 μg and about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound.

[0786] An embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-a; INFERG ® consensus and a TNF-cü antagonist in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of INFERGEN® containing an amount of between about 1 μg and about 30 μg of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily, substantially continuously or continuously, in combination with a dosage of a TNF antagonist -to; containing an amount of between about 0.1 μg and about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound. [0787] An embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-a; INFERG? consensus and a TNF-a antagonist; in the treatment of a HCV infection in a patient, which comprises administering to the patient a dosage of INF? RGEN® containing an amount between about 1 μg and about 9 μg of drug per dose of INFERG? N, subcutaneously qd, qod, tiw, biw, qw, qow, three times a month, once a month, or daily, substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist; which contains an amount between about 0.1 μg and about 40 mg per dose of a TNF-a !, antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound. [0788] Another embodiment provides any of the methods previously described, modified to use an effective amount of an IFN-a; PEGylated consensus and an effective amount of a TNF-a antagonist; in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of a consensus PEGylated IFN-a (PEG-CIF?) containing an amount of between about 4 μg and about 60 μg of CIF amino acid weight? per dose of PEG-CIF ?, subcutaneously qw, qow, three times a month, or once a month, in combination with a dosage of a TNF-a antagonist; which contains an amount of between about 0.1 μg and about 40 mg per dose of a T? Fa! antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an? S3 inhibitor compound. [0789] Another embodiment provides any of the methods previously described, modified to use an effective amount of a consensus PEGylated IFN-α and an effective amount of a TNF-α antagonist! in the treatment of a viral infection in a patient, comprising administering to the patient a dosage of an IFN-a; PEGylated consensus (PEG-CIEN) containing an amount of between approximately 18 M and approximately 24 μg of amino acid weight CIFN per dose of PEG-CIF ?, subcutaneously qw, qow, three times a month, or once a month , in combination with a dosage of a T? Fa antagonist! which contains an amount of between about 0.1 μg and about 40 mg per dose of a T-Fa antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an? S3 inhibitor compound. [0790] Another embodiment provides any of the methods previously described, modified to use an effective amount of IFN-c. 2a or 2b or 2c and an effective amount of a T? F-a antagonist; in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of IF? -CÜ 2a, 2b or 2c containing an amount of between approximately 1 MU and approximately 20 MU of drug per dose of IF? -a; 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or daily, substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist; containing an amount of between about 0.1 μg and about 40 mg per dose of a TNF-α antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound. [0791] Another embodiment provides any of the methods previously described, modified to use an effective amount of IF? -c. 2a or 2b or 2c and an effective amount of a T? F-C? Antagonist in the treatment of a viral infection in a patient, comprising administering to the patient a dosage of IF? -a? 2a, 2b or 2c containing an amount of between about 3 MU of drug per dose of IF? -CÜ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or daily, substantially continuously or continuously, in combination with a dosage of a T? Fa antagonist; which contains an amount between about 0.1 μg and about 40 mg per dose of a TNF-a !, antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an? S3 inhibitor compound. [0792] Another embodiment provides any of the methods previously described, modified to use an effective amount of IFN-c. 2a or 2b or 2c and an effective amount of a TNF-a antagonist! in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of IFN-a; 2a, 2b or 2c containing an amount of between about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or daily, substantially continuously or continuously, in combination with a dosage of a TNF-a antagonist; which contains an amount between about 0.1 μg and about 40 mg per dose of a T? F-C? antagonist, subcutaneously qd, qod, tiw, or biw, or daily, in substantially continuous or continuous form, while the desired treatment lasts with an inhibitor compound of? S3. [0793] Another embodiment provides any of the methods previously described, modified to use an effective amount of PEGASYS® PEGylated IF? -a; 2a and an effective amount of a T? F-a antagonist; in the treatment of a viral infection in a patient, comprising administering to the patient a dosage of PEGASYS® containing an amount between about 90 μg and about 360 μg of drug per dose of P? GASYS®, subcutaneously qw, qow , three times a month, or once a month, in combination with a dosage of a T? Fa antagonist; which contains an amount of between about 0.1 μg and about 40 mg per dose of a T-Fa antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an? S3 inhibitor compound.

[0794] Another embodiment provides any of the methods previously described, modified to use an effective amount of PEGASYS® PEGylated IFN-α 2a and an effective amount of a TNF-α antagonist; in the treatment of a viral infection in a patient, comprising administering to the patient a dosage of PEGASYS® containing an amount of approximately 180 μg of drug per dose of PEGASYS®, subcutaneously qw, qow, three times a month, or once a month, in combination with a dosage of a TNF-a antagonist! containing an amount of between about 0.1 g and about 40 mg per dose of a TNF-a !, antagonist subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound. [0795] Another embodiment provides any of the methods previously described, modified to use an effective amount of a PEGylated IFN-α; 2b PEG-INTRON® and an effective amount of a TNF-α antagonist; in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of P? G-INTRON® containing an amount of between about 0.75 μg and about 3.0 μg of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times a month, or once a month, in combination with a dosage of a TNF-a antagonist; which contains an amount between about 0.1 μg and about 40 mg per dose of a TNF-a !, antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound. [0796] Another embodiment provides any of the methods previously described, modified to use an effective amount of a PEGylated IFN-α; 2b PβG-INTRON® and an effective amount of a TNF-α antagonist; in the treatment of a viral infection in a patient, which comprises administering to the patient a dosage of P? G-INTRON® containing an amount of about 1.5 μg of drug per kilogram of body weight per dose of P? G-INTRON ®, subcutaneously qw, qow, three times a month, or once a month, in combination with a dosage of a TNF-a antagonist; which contains an amount between about 0.1 μg and about 40 mg per dose of a TNF-a !, antagonist, subcutaneously qd, qod, tiw, or biw, or daily, substantially continuously or continuously, while it lasts the desired treatment with an NS3 inhibitor compound. Combination Therapies with Other Antiviral Agents [0797] Other agents, such as inhibitors of the HCV NS3 helicase, are also attractive drugs for combination therapies, and are contemplated for use in the combination therapies described in this documentation. Ribozymes, such as Heptazyme ™, 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 the combination therapies described herein. [0798] In some embodiments, additional antiviral agents are administered during the course of complete 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 agents are administered for a period of time that overlaps with that of the treatment with the NS3 inhibitor compound, eg, treatment with the additional antiviral agent (s) begins before the start of treatment with the antiviral agent. NS3 inhibitor compound and terminates before the end of treatment with the NS3 inhibitor compound; treatment with additional antiviral agents begins after the start of treatment with the NS3 inhibitor compound and ends after the end of treatment with the NS3 inhibitor compound; treatment with additional antiviral agents begins after the start of treatment with the NS3 inhibitor compound and terminates before the end of treatment with the NS3 inhibitor compound; or treatment with additional antiviral agents begins before the start of treatment with the NS3 inhibitor compound and ends after the end of treatment with the NS3 inhibitor compound. [0799] The NS3 inhibitor compound can be administered together with (i.e., simultaneously in separate formulations, simultaneously in the same formulation, administered in separate formulations and with a separation of 46 hours, with a separation of 36 hours, with a separation of 24 hours, with a separation of 16 hours, with a separation of 12 hours, with a separation of 8 hours, with a separation of 4 hours, with a separation of 2 hours, with a separation of 1 hour, with a separation of 30 minutes, or with a separation of 15 minutes or less) one or more additional antiviral agents. [0800] As non-limiting examples, any of the previously described methods comprising a regimen with IF? -a;, can be modified to replace the regimen with IF? -a mentioned by an IF regimen? -a; consensus monoPEG (30 kD, linear) -ylated, which comprises administering a dosage of an IF? -a; consensus monoPEG (30 kD, linear) -ylated that contains an amount of 100 μg of drug per dose, subcutaneously, once a week, once every day, or once every 10 days, while the desired treatment lasts an inhibitor compound of? S3.

[OdOl] By way of non-limiting examples, any of the previously described methods comprising a regime with IFN-c- can be modified to replace the regime with IFN-Q! mentioned by a regimen of IF? -a consensus monoPEG (30 kD, linear) -ilated, which comprises administering a dosage of an IF? -a consensus monoPEG (30 kD, linear) -late containing an amount of 150 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days, for the duration of the desired treatment with an inhibitor compound of? S3. [0802] By way of non-limiting examples, any of the previously described methods comprising a regimen with IF? -a;, may be modified to replace the regimen with IF? -cü mentioned by a monoPEG consensus IFN-a regimen (30). kD, linear) -ylated, which comprises administering a monopeptide (30 kD, linear) IFN-a consensus dosage that contains an amount of 200 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days, while the desired treatment lasts with an inhibitor compound of? S3. [0803] By way of non-limiting examples, any of the previously described methods comprising a regimen with IF? -a can be modified to replace the regimen with IFN-a mentioned by a regimen of Inferieron alfacon-1 INFERG ?? ®, which comprises administering a dosage of Interferon alfacon-1 INFERG? N® containing an amount of 9 μg of drug per dose, subcutaneously once a day or three times a week, while the desired treatment lasts with an NS3 inhibitor compound . [0804] By way of non-limiting examples, any of the previously described methods comprising a regimen with IFN-ar, can be modified to replace the regimen with IF? -O! mentioned by an Interferon alfacon-1 I? F? RG? ® regimen, which comprises administering a dosage of Inferieron alfacon-1 I? F? RGE? ® containing an amount of 15 μg of drug per dose, subcutaneously once a day or three times a week, while the desired treatment lasts with an inhibitor compound of? S3. [0805] By way of non-limiting examples, can any of the previously described methods comprising a regimen with IF? - ?, be modified to replace the regimen with IF? -? mentioned by an IF regimen? - ?, which comprises administering a dosage of IF? -? which contains an amount of 25 μg of drug per dose, subcutaneously three times a week, for the duration of the desired treatment with an inhibitor compound of? S3. [0806] As non-limiting examples, can any of the previously described methods comprising a regimen with IF? - ?, be modified to replace the regimen with IF? -? mentioned by an IF regimen - ?, which comprises administering a dosage of IFN-? containing an amount of 50 μg of drug per dose, subcutaneously three times a week, for the duration of the desired treatment with an NS3 inhibitor compound. [0807] As non-limiting examples, any of the previously described methods comprising a regimen with IFN-α can be modified to replace the regimen with IFN-? mentioned by an IFN-? regimen, which comprises administering a dosage of IFN-? containing an amount of 100 μg of drug per dose, subcutaneously three times a week, for the duration of the desired treatment with an NS3 inhibitor compound. [0808] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a can be modified; and IFN- ?, to replace the combination regimen with IFN-o; and IFN-? for a combination regimen with IFN-a; and IFN- ?, which comprises: (a) administering a dosage of an IFN-a; consensus monoPEG (30 kD, linear) -ylated that contains an amount of 100 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-? containing an amount of 50 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound.

[0809] By way of non-limiting examples, any of the previously described methods comprising a regimen with a TNF antagonist, can be modified to replace the regimen with a TNF antagonist mentioned by a regimen with a TNF antagonist, which comprises administering a dosage of a TNF antagonist selected from the group consisting of: (a) etanercept in an amount of 25 mg of drug per dose subcutaneously twice a week, (b) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenous dose 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 a week or once every 2 weeks; while the desired treatment lasts with an inhibitor compound of? S3. [0810] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IF? -a can be modified; and IF? - ?, to replace the combination regimen with IFN-c. and IFN-? by a combination regimen with IFN-a and IF? - ?, which comprises: (a) administering a dosage of an IF? -a consensus monoPEG (30 kD, linear) -ylated containing an amount of 100 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days; and (b) administer a dosage of IF? -? containing an amount of 100 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0811] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a and IF? - ?, can be modified to replace the combination regimen with IFN-a; and IFN-? by a combination regimen with iFN-a and IF? - ?, which comprises: (a) administering a dosage of an IF? -a consensus monoPEG (30 kD, linear) - containing a quantity of 150 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days; and (b) administer a dosage of IF? -? containing an amount of 50 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an inhibitor compound of? S3. [0812] As non-limiting examples, any of the previously described methods comprising a combination regimen with IF? -CÜ and IFN- ?, can be modified to replace the combination regimen with IF? -x and IFN-? by a combination regimen with IF? -ae IF? - ?, which comprises: (a) administering a dosage of a monopeptide (30 kD, linear) IFN-a consensus that contains an amount of 150 μg of drug per dose , subcutaneously, once a week, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-7 containing an amount of 100 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0813] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a can be modified; and IFN- ?, to replace the combination regimen with IFN-c. and IFN-? by a combination regimen with IFN-a and IFN-α, comprising: (a) administering a dosage of a consensus monopeptide (30 kD, linear) IFN-a IFN-a containing an amount of 200 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days; and (b) administer a dosage of IF? -? containing an amount of 50 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an inhibitor compound of? S3. [0814] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IF? -a and IF? - ?, can be modified to replace the combination regimen with IF? -c. and IF? -? by a combination regimen with IFN-a and IF? - ?, which comprises: (a) administering a dosage of an IF? -C. consensus monoP? G (30 kD, linear) -ylated containing a quantity of 200 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN-? containing an amount of 100 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0815] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a! Can be modified. and IFN- ?, to replace the combination regimen with IFN- and IFN-? for a combination regimen with IFN-a; and IFN- ?, which comprises: (a) administering a dosage of Interferon alfacon-1 INFERG? N® containing an amount of 9 μg of drug per dose, subcutaneously three times a week; and (b) administering a dosage of IFN-? containing an amount of 25 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0816] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a can be modified; and IFN- ?, to replace the combination regimen with IFN-a; and IFN-? for a combination regimen with IFN-a; and IFN- ?, which comprises: (a) administering a dosage of Inferron alfacon-1 INFERG? N® containing an amount of 9 μg of drug per dose, subcutaneously three times a week; and (b) administering a dosage of IFN-? containing an amount of 50 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0817] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a and IF? - ?, can be modified to replace the combination regimen with IF? -a and IFN-? by a combination regimen with IFN-a and IF? - ?, comprising.- (a) administering a dosage of Inferieron alfacon-1 I? FERG ?? ® containing an amount of 9 μg of drug per dose, via subcutaneous three times a week; and (b) administer a dosage of IF? -? containing an amount of 100 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an inhibitor compound of? S3. [0818] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IF? -a can be modified; and IFN- ?, to replace the combination regimen with IFN-a; and IFN-? for a combination regimen with IF? -c. and IFN- ?, which comprises: (a) administering a dosage of Inferido-1 INFERGE? ® containing an amount of 9 μg of drug per dose, subcutaneously once a day; and (b) administer a dosage of IFN-? containing an amount of 25 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0819] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a can be modified; and IFN- ?, to replace the combination regimen with IFN-a; and IFN-? for a combination regimen with IFN-a; and IFN- ?, which comprises: (a) administering a dosage of Inferon-1 INFERG? N® containing an amount of 9 μg of drug per dose, subcutaneously once a day; and (b) administer a dosage of IFN-? which contains a quantity of 50 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0820] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a! Can be modified. and IFN- ?, to replace the combination regimen with IFN-a; and IFN-7 by a combination regimen with IFN-a; and IFN- ?, which comprises: (a) administering a dosage of Inferieron alíacon-1 INFERGEN® containing an amount of 9 μg of drug per dose, subcutaneously once a day; and (b) administer a dosage of IFN-? containing an amount of 100 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0821] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a and IFN-α can be modified to replace the combination regimen with IFN-c. and IFN-? by a combination regimen with lFN-a and IF? - ?, which comprises: (a) administering a dosage of Inferieron alfacon-1 I? FERG? ® containing an amount of 15 μg of drug per dose, subcutaneously three times per week; and (b) administer a dosage of IF? -? containing an amount of 25 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an inhibitor compound of? S3. [0822] As non-limiting examples, can any of the previously described methods comprising a combination regimen with IF? -a and IF? - ?, be modified to replace the combination regimen with IFN-a and IF? -? by a combination regimen with IF? -a; and IF? - ?, which comprises: (a) administering a dosage of Inferon aliacon-1 I? F? RG ?? ® containing an amount of 15 μg of drug per dose, subcutaneously three times a week; and (b) administer a dosage of IF? -? containing an amount of 50 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0823] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a can be modified; and IFN- ?, to replace the combination regimen with IFN-tx and IF? -? by a combination regimen with IFN-a and IF? - ?, comprising: (a) administering a dosage of Inferieron alfacon-1 I? F? RGE? ® containing an amount of 15 μg of drug per dose, via subcutaneous three times a week; and (b) administer a dosage of IF? -? containing an amount of 100 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an inhibitor compound of? S3. [0824] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IF? -a can be modified; and IF? - ?, to replace the combination regime with IF? -a; and IF? -? for a combination regimen with IF? -c. and IF? -7, comprising: (a) administering a dosage of Interferon alfacon-1 I? FERG? ® containing an amount of 15 μg of drug per dose, subcutaneously once a day; and (b) administer a dosage of IF? -? containing an amount of 25 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0825] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a and IFN-α can be modified to replace the combination regimen with IFN-a and IFN-7 by a regimen of combination with IF? -a; and IF? - ?, which comprises: (a) administering a dosage of Interferon alfacon-1 I? FERGE? ® containing an amount of 15 μg of drug per dose, subcutaneously once a day; and (b) administer a dosage of IF? -? containing an amount of 50 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an inhibitor compound of? S3. [0826] By way of non-limiting examples, any of the previously described methods comprising a combination regimen with IFN-a can be modified; and IF? - ?, to replace the combination regimen with IFN-ar and IFN-7 by a combination regimen with IF? -ae IF? -7, which comprises: (a) administering a dosage of Interferon alfacon-1 I ? F? RGE? ® containing a quantity of 15 μg of drug per dose, subcutaneously once a day; and (b) administering a dosage of IF? -7 containing an amount of 100 μg of drug per dose, subcutaneously three times a week; while the desired treatment lasts with an NS3 inhibitor compound. [0827] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-a, IFN-7 and a T? F antagonist, can be modified to replace the combination regimen of IF? - a, IF? -7 and a T? F antagonist mentioned by a combination regimen of IF? -a, IF? -7 and a TNF antagonist, comprising: (a) administering a dosage of an IF? -a consensus monoPEG (30 kD, linear) -ylated that contains an amount of 100 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days; (b) administering a dosage of IF? -7 containing an amount of 100 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously in weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an inhibitor compound of? S3. [0828] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-a, IFN-7 and a T? F antagonist, can be modified to replace the IFN-c combination regimen . , IF? -7 and a T? F antagonist mentioned by a combination regimen of IF? -ce, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of an IFN-O ! consensus monoPEG (30 kD, linear) -ylated that contains an amount of 100 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-7 containing an amount of 50 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously in weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an inhibitor compound of? S3. [0829] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IF? -a :, IFN-7 and a T? F antagonist, can be modified to replace the IF combination regimen. ? -O! IF? -7 and a TNF antagonist mentioned by a combination regimen of IF? -a;, IF? -7 and a TNF antagonist, comprising: (a) administering a dosage of an IFN- a consensus monoPEG (30 kD, linear) -ylated that contains an amount of 150 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days, - (b) administer a dosage of IFN-7 containing an amount of 50 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an NS3 inhibitor compound. [0d30] By way of non-limiting examples, can any of the previously described methods comprising a combination regimen of IFN-a, IF? -7 and a T? F antagonist be modified to replace the combination regimen of IF? -O !, IF? -7 and a T? F antagonist mentioned by a combination regimen of IF? -a, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of a IF? -a; consensus monoPEG (30 kD, linear) -ylated containing an amount of 150 μg of drug per dose, subcutaneously, once a week, once every day, or once every 10 days; (b) administering a dosage of IFN-7 containing an amount of 100 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every d weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an NS3 inhibitor compound. [0831] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IEN-a, IFN-7 and a TNF antagonist, can be modified to replace the combination regimen of IFN-O !, IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-a, IFN-7 and a TNF antagonist, comprising: (a) administering a dosage of an IFN-a; consensus monoPEG (30 kD, linear) -ylated that contains a quantity of 200 μg of drug per dose, subcutaneously, once a week, once every day, or once every 10 days, - (b) administer a dosage of IFN-7 containing an amount of 50 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an NS3 inhibitor compound. [0832] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-CÜ, IFN-7 and a TNF antagonist, can be modified to replace the combination regimen of IFN-α;, IFN-7 and a TNF antagonist mentioned by a combination regimen of IF? -ce, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of an IF? -o! consensus monoPEG (30 kD, linear) -ylated containing a quantity of 200 μg of drug per dose, subcutaneously, once a week, once every 8 days, or once every 10 days; (b) administering a dosage of IF? -7 containing an amount of 100 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter; or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an NS3 inhibitor compound. [0833] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-α;, IFN-7 and a TNF antagonist, can be modified to replace the combination regimen of IFN-O! , IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-a;, IFN-7 and a T? F antagonist, comprising: (a) administering a dosage of Inferiorialyl-1 I? FERGE? ® that contains an amount of 9 μg of drug per dose, subcutaneously three times a week; (b) administering a dosage of IF? -7 containing an amount of 25 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously at weeks 0, 2, and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once per week; while the desired treatment lasts with an inhibitor compound of? S3. [0834] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-α;, IFN-7 and a TNF antagonist, can be modified to replace the IFN-a combination regimen, IFN-7 and a TNF antagonist mentioned by a combination regimen of IF? -CÜ, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of Inferiorialy-1 I? FERGE? ® that contains an amount of 9 μg of drug per dose, subcutaneously three times a week; (b) administering a dosage of IF? -7 containing an amount of 50 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously at weeks 0, 2, and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0835] As non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-a, IF? -7 and a T? F antagonist, can be modified to replace the combination regimen of IF? -c., IF? -7 and a T? F antagonist mentioned by a combination regimen of IFN-c. , IF? -? and a T? F antagonist, comprising: (a) administering a dosage of Interferon alfacon-1 INFERG? N® containing an amount of 9 μg of drug per dose, subcutaneously three times a week; (b) administer a dosage of IFN-? containing an amount of 100 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2, and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0836] As non-limiting examples, any of the previously described methods comprising a combination regimen of IF? -a;, IF? -7 and a T? F antagonist, can be modified to replace the combination regimen of IF? -7 and a T? F antagonist mentioned by a combination regimen of IF? -CÜ, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of They injected alíacon-1 I? F? RG ?? ® containing an amount of 9 μg of drug per dose, subcutaneously once a day; (b) administering a dosage of IF? -7 containing an amount of 25 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a 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 per subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0837] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-α;, IFN-7 and a TNF antagonist, can be modified to replace the IFN-c combination regimen. , IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-a !, IFN-7 and a TNF antagonist, comprising: (a) administering a dosage of Interferon alfacon-1 INFERGEN® containing an amount of 9 μg of drug per dose, subcutaneously once a day; (b) administering a dosage of IFN-7 containing an amount of 50 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a 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 per subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0838] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-α;, IFN-7 and a TNF antagonist can be modified to replace the combination regimen of IFN-α! , IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-a;, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of Inferior Allycon-1 I? FERGE ? ® containing a quantity of 9 μg of drug per dose, subcutaneously once a day; (b) administering a dosage of IF? -7 containing an amount of 100 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously in weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an inhibitor compound of? S3. [0839] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-c-, IFN-7 and a TNF antagonist, can be modified to replace the combination regimen of IFN-CÜ, IFN-7 and a T? F antagonist mentioned by a combination regimen of IF? -a, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of Interferon alfacon-1 I? F? RG ?? ® containing an amount of 15 μg of drug per dose, subcutaneously three times a week; (b) administering a dosage of IFN-7 containing an amount of 25 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously at weeks 0, 2, and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once per week; while the desired treatment lasts with an inhibitor compound of? S3. [0840] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IF? -a;, IF? -7 and a T? F antagonist, can be modified to replace the combination regimen of IF? -O! IF? -7 and a TNF antagonist mentioned by a combination regimen of IF? -a;, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of Interferon alfacon-1 INFERG? N® containing a quantity of 15 μg of drug per dose, subcutaneously three times a week; (b) administering a dosage of IFN-7 containing an amount of 50 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2, and 6, and every d weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0641] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-a can be modified.;, IFN-7 and a TNF antagonist, to replace the combination regimen of IFN-O !, IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-a;, IFN-7 and an antagonist of TNF, which comprises: (a) administering a dosage of Inferido-1 INF? RG? N® containing an amount of 15 μg of drug per dose, subcutaneously three times a week; (b) administering a dosage of IFN-7 containing an amount of 100 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2, and 6, and every d weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0d42] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-a, IFN-7 and a TNF antagonist, can be modified to replace the combination regimen of IFN-O !, IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-cü, IFN-7 and a TNF antagonist, comprising: (a) administering a dosage of Interferon alfacon-1 INFERG? N® containing an amount of 15 μg of drug per dose, subcutaneously once a day; (b) administering a dosage of IFN-7 containing an amount of 25 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a 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 per subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0843] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-α;, IFN-7 and a TNF antagonist, can be modified to replace the combination regimen of IFN-α! , IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-CÜ, IFN-7 and a TNF antagonist, which comprises: (a) administering a dosage of Inferior Aliacon-1 INFERG? N® containing a amount of 15 μg of drug per dose, subcutaneously once a day; (b) administering a dosage of IFN-7 containing an amount of 50 μg 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 a 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 per subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0844] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-cü, IF? -7 and a T? F antagonist, can be modified to replace the combination regimen of IF? -a, IF? -7 and a T? F antagonist mentioned by a combination regimen of IF? -CÜ, IF? -7 and a T? F antagonist, comprising: (a) administering a dosage of Interferon alfacon -1 I? FERG ?? ® containing an amount of 15 μg of drug per dose, subcutaneously once a day; (b) administering a dosage of IF? -7 containing an amount of 100 μg of drug per dose, subcutaneously three times a week; and (c) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously in weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an inhibitor compound of? S3. [0845] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN- and a T? F antagonist, to replace the combination regimen of IF? -and a T-antagonist can be modified. F mentioned by a combination regimen of IF? -and a T? F antagonist, comprising: (a) administering a dosage of an IF? -a consensus monoPEG (30 kD, linear) -ylated containing a quantity of 100 μg of drug per dose, subcutaneously, once a week, 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 a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an NS3 inhibitor compound. [0846] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-ce and a TNF antagonist can be modified to replace the combination regimen of IFN-a and a TNF antagonist mentioned for a combination regimen of IFN-a; and a TNF antagonist, comprising: (a) administering a monopeptide (30 kD, linear) IFN-a consensus dosage containing an amount of 150 μg of drug per dose, subcutaneously, once a week , once every day, 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 a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every d weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an NS3 inhibitor compound. [0847] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-a can be modified; and a TNF antagonist, to replace the IFN-c combination regimen. and a T? F antagonist mentioned by a combination regimen of IF? -c. and a T? F antagonist, comprising: (a) administer a dosage of an IFP - monoPEG consensus (30 kD, linear) - containing a quantity of 200 μg of drug per dose, subcutaneously, once a week, once every 8 days, or a 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 a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an inhibitor compound of? S3.

[0848] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-a can be modified; and a T? F antagonist, to replace the combination regimen of IFN-a; and a T? F antagonist mentioned by a combination regimen of IF? -a; and a T? F antagonist, comprising: (a) administering a dosage of Inferiorialy-1 I? FERG? ® containing an amount of 9 μg of drug per dose, subcutaneously once a day or three times per week; and (b) administering a dosage of a T? F antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of weight intravenously in weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an inhibitor compound of? S3. [0849] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-a can be modified; and a T? F antagonist, to replace the combination regimen of IF? -a; and a T? F antagonist mentioned by a combination regimen of IF? -a; and a T? F antagonist, comprising: (a) administering a dosage of Inferon alfacon-1 INFERGEN® containing an amount of 15 μg of drug per dose, subcutaneously once a day or three times a week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an NS3 inhibitor compound. [0850] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-7 and a TNF antagonist, can be modified to replace the combination regimen of IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-7 and a TNF antagonist, comprising: (a) administering a dosage of IFN-7 containing an amount of 25 μg of drug per dose, subcutaneously three times a week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a 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 per subcutaneously, once a week or once per week; while the desired treatment lasts with an NS3 inhibitor compound. [0851] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-7 and a TNF antagonist, can be modified to replace the combination regimen of IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-7 and a TNF antagonist, comprising: (a) administering a dosage of IFN-7 containing an amount of 50 μg of drug per dose, subcutaneously three times a week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every d weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an NS3 inhibitor compound. [0d52] By way of non-limiting examples, any of the previously described methods comprising a combination regimen of IFN-7 and a TNF antagonist can be modified to replace the combination regimen of IFN-7 and a TNF antagonist mentioned by a combination regimen of IFN-7 and a TNF antagonist, comprising: (a) administering a dosage of IFN-7 containing an amount of 100 μg 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 a week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per intravenously at weeks 0, 2 and 6, and every d weeks thereafter, or (iii) adalimumab in an amount of 40 mg subcutaneously, once a week or once a week in the medium; while the desired treatment lasts with an inhibitor compound of? S3. [0853] By way of non-limiting examples, any of the previously described methods that include an IF regimen may be modified; consensus monoPEG (30 kD, linear) -ylated to replace the IF regimen? -a consensus monoPEG (30 kD, linear) -named mentioned by a regimen of interferon alfa-2a PEGilado, which comprises administering a dosage of interferon alfa-2a Spray containing an amount of 180 μg of drug per dose, subcutaneously, once a week, while the desired treatment lasts with an inhibitor compound of? S3. [0654] By way of non-limiting examples, any of the previously described methods including an IF regimen can be modified; consensus monoP? G (30 kD, linear) -ylated, to replace the IFN-c regimen. consensus monoP? G (30 kD, linear) -ylated mentioned by a PEGylated interferon alpha-2b regimen, which comprises administering a dosage of interferon alfa-2b P? Gilado containing an amount of between 1.0 μg and 1.5 μg of drug per kilogram of body weight per dose, subcutaneously once or twice a week, while the desired treatment lasts with an inhibitor compound of? S3. [0855] By way of non-limiting examples, any of the previously described methods can be modified to include the administration of a ribavirin dosage 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, while the desired treatment lasts with an inhibitor compound of? S3. [0856] By way of non-limiting examples, any of the previously described methods may be modified to include the administration of a ribavirin dosage containing (i) an amount of 1000 mg of drug orally per day for patients with a weight body weight less than 75 kg or (ii) an amount of 1200 mg of oral drug per day for patients with a body weight of greater than or equal to 75 kg, optionally in two or more divided doses per day, while the treatment lasts desired with an? S3 inhibitor compound.

[0857] By way of non-limiting examples, any of the previously described methods for replacing the regimen with the NS3 inhibitor mentioned by a regimen with an NS3 inhibitor, which comprises administering a dosage of between 0.01 mg and , 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, while the desired treatment lasts with the NS3 inhibitor compound. [0858] By way of non-limiting examples, any of the previously described methods for replacing the regimen with the NS3 inhibitor mentioned by a regimen with an NS3 inhibitor, which comprises administering a dosage of between 0.1 mg and 1, can be modified. mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, while the desired treatment lasts with the inhibitory compound of NS3. [0859] By way of non-limiting examples, any of the previously described methods for replacing the regimen with the NS3 inhibitor mentioned by a regimen with an NS3 inhibitor, comprising administering a dosage of between 1 mg and 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, while the desired treatment lasts with the NS3 inhibitor compound. [0860] By way of non-limiting examples, any of the previously described methods for replacing the regimen with the NS3 inhibitor mentioned by a regimen with an NS3 inhibitor, comprising administering a dosage of between 10 mg and 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, while the desired treatment lasts with the NS3 inhibitor compound. [0861] By way of non-limiting examples, any of the previously described methods comprising a regimen with an NS5B inhibitor, can be modified to replace the regimen with a NS5B inhibitor mentioned by a regimen with an NS5B inhibitor, which comprises administering a dosage of between 0.01 mg and 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, while the desired treatment lasts with an NS3 inhibitor compound. [0862] By way of non-limiting examples, any of the previously described methods comprising a regimen with an NS5B inhibitor, can be modified to replace the regimen with a NS5B inhibitor mentioned by a regimen with an NS5B inhibitor, which comprises administering a dosage of between 0.1 mg and 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, while the desired treatment lasts with an NS3 inhibitor compound. [0863] By way of non-limiting examples, any of the previously described methods comprising a regimen with an NS5B inhibitor, can be modified to replace the regimen with an NS5B inhibitor mentioned by a regimen with an NS5B inhibitor, which comprises administering a dosage of between 1 mg and 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, while the desired treatment lasts with an NS3-inhibiting compound. [0864] As non-limiting examples, any of the previously described methods comprising a regimen with an NS5B inhibitor, can be modified to replace the regimen with a NS5B inhibitor mentioned by a regimen with an NS5B inhibitor, which comprises administering a dosage of between 10 mg and 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, while the desired treatment lasts with an inhibitory compound of NS3. Patient Identification [0865] Bn certain embodiments, the specific drug therapy regimen used in the treatment of the patient with HCV is selected according to certain parameters of the disease exhibited by the patient, such as the initial viral load, genotype of infection with HCV in the patient, liver histology and / or stage of hepatic fibrosis in the patient. [0866] In this way, some embodiments provide any of the methods described above for the treatment of HCV infection in which the exposed method is modified to treat a patient who failed treatment for 48 weeks. [0867] Other embodiments provide any of the methods described above for HCV in which the exposed method is modified to treat an unresponsive patient, where the patient receives therapy during the course of 48 weeks. [0868] Other embodiments provide any of the methods described above for the treatment of infection with HCV in which the exposed method is modified to treat a patient with relapse, where the patient receives a therapy during the course of 4d weeks. [0869] Other embodiments provide any of the methods described above for the treatment of infection with HCV in which the exposed method is modified to treat a patient who had not been treated with HCV genotype 1, where the patient receives a therapy during the course of 48 weeks. [0870] Other embodiments provide any of the methods described above for the treatment of infection with HCV in which the exposed method is modified to treat a patient who had not been treated with HCV genotype 4, where the patient receives a therapy during the course of 48 weeks. [0871] Other embodiments provide any of the methods described above for the treatment of infection with HCV in which the exposed method is modified to treat a patient who had not been treated with HCV genotype 1, where the patient has a high viral load (HVL), where "HVL" refers to a viral load of HCV greater than 2 x 106 copies of the HCV genome per milliliter of serum, and where the patient receives a therapy during the course of 4d weeks. [0872] An embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is "modified to include the steps of (1) identifying a patient who has an advanced or severe stage of liver fibrosis. measured according to the Knodell scale of 3 or 4 and then (2) administering the drug therapy of the exposed method to the patient for a period of time between about 24 weeks and about 60 weeks, or between about 30 weeks and about one year, or between about 36 weeks and about 50 weeks, or between about 40 weeks and about 4d 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 4d weeks, or at least about 60 weeks. [0873] Another embodiment provides any of the methods described in for the treatment of an infection with HCV, where the exposed method is modified to include the steps of (1) identifying a patient who has an advanced or severe stage of liver fibrosis measured according to the Knodell scale of 3 or 4 and then ( 2) administer to the patient the drug therapy of the method set forth for a period of time between about 40 weeks and about 50 weeks, or about 4d weeks. [0874] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to include the steps of (1) identifying a patient who has an infection with HCV genotype 1 and an initial viral load greater than 2 million copies of the viral genome per milliliter of patient serum and then (2) administer to the patient the drug therapy of the exposed method for a period of time between about 24 weeks and about 60 weeks, or between about 30 weeks and about one year, or between about 36 weeks and about 50 weeks, or between about 40 weeks and about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks. weeks, or at least approximately 40 weeks, or at least approximately 48 weeks, or at least approximately 60 weeks. [0875] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to include the steps of (1) identifying a patient who has an infection with HCV genotype 1 and an initial viral load greater than 2 million copies of the viral genome per milliliter of patient serum and then (2) administering the drug therapy of the exposed method to the patient for a period of time between about 40 weeks and about 50 weeks, or approximately 48 weeks.

[0876] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to include the steps of (1 > identifying a patient who has an infection with HCV genotype 1 and an initial viral load greater than 2 million copies of the viral genome per milliliter of patient serum and an early or absent liver fibrosis stage of 0, 1, or 2 measured according to the Knodell scale and then (2) administered to the patient drug therapy of the method set forth for a period of time between about 24 weeks and about 60 weeks, or between about 30 weeks and about one year, or between about 36 weeks and about 50 weeks, or between about 40 weeks and about 48 weeks; 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 approximately 48 weeks, or at least approximately 60 weeks. [0877] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to include the steps of (1) identifying a patient who has an infection with HCV genotype 1 and an initial viral load greater than 2 million copies of the viral genome per milliliter of patient's serum and an early or absent liver fibrosis stage of 0, 1, or 2 measured according to the Knodell scale and then (2) administer to the patient the drug therapy of the method set forth for a period of time between about 40 weeks and about 50 weeks, or about 48 weeks. [0878] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to include the steps of (1) identifying a patient who has an infection with HCV genotype 1 and an initial viral load less than or equal to 2 million copies of the viral genome per milliliter of the patient's serum and then (2) administer to the patient the drug therapy of the method set forth for a period of time between about 20 weeks and about 50 weeks , or between about 24 weeks and about 48 weeks, or between about 30 weeks and 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 methods described above for the treatment of an infection with HCV, where the method set forth is modified to include the steps of (1) identifying a patient who has an infection with HCV genotype 1 and an initial viral load less than or equal to 2 million copies of the viral genome per milliliter of the patient's serum and then (2) administering the drug therapy of the exposed method to the patient for a period of time between about 20 weeks and about 24 weeks . [0880] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to include the steps of (1) identifying a patient who has an infection with HCV genotype 1 and an initial viral load less than or equal to 2 million copies of the viral genome per milliliter of the patient's serum and then (2) administer to the patient the drug therapy of the exposed method for a period of time between about 24 weeks and about 48 weeks . [0881] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to include the steps of (1) identifying a patient who has an infection with genotypes 2 or 3 of HCV and then (2) administering the drug therapy of the exposed method to the patient for a period of time between about 24 weeks and about 60 weeks, or between about 30 weeks and about one year, or between about 36 weeks and about 50 weeks, or between about 40 weeks and about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks. weeks, or at least approximately 40 weeks, or at least approximately 48 weeks, or at least approximately 60 weeks. [0882] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to ude the steps of (1) identifying a patient who has an infection with genotypes 2 or 3 of HCV and then (2) administering the drug therapy of the exposed method to the patient for a period of time between about 20 weeks and about 50 weeks, or between about 24 weeks and about 48 weeks, or between about 30 weeks and 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 methods described above for the treatment of an infection with HCV, where the method set forth is modified to ude the steps of (1) identifying a patient who has an infection with genotypes 2 or 3 of HCV and then (2) administering the drug therapy of the exposed method to the patient for a period of time between about 20 weeks and about 24 weeks. [0884] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to ude the steps of (1) identifying a patient who has an infection with genotypes 2 or 3 of HCV and then (2) administer to the patient the drug therapy of the exposed method over a period of time of at least about 24 weeks. [0885] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to ude the steps of (1) identifying a patient who has an infection with genotypes 1 or 4 of HCV and then (2) administering the drug therapy of the exposed method to the patient for a period of time between about 24 weeks and about 60 weeks, or between about 30 weeks and about one year, or between about 36 weeks and about 50 weeks , or between about 40 weeks and 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 methods described above for the treatment of an infection with HCV, where the method set forth is modified to ude the steps of (1) identifying a patient having an HCV infection characterized by any of the HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering the drug therapy of the exposed method to the patient for a period of time between about 20 weeks and about 50 weeks. [0887] Another embodiment provides any of the methods described above for the treatment of an infection with HCV, where the method set forth is modified to ude the steps of (1) identifying a patient who has an HCV infection characterized by any of the HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering the drug therapy of the exposed method to the patient for a period of time of at least about 24 weeks and up to about 4d weeks. Subjects Eligible for Treatment [0888] Any of the above treatment regimens should be administered to individuals who have been diagnosed with HCV infection. Individuals infected with HCV are identified as having an HCV RNA in their blood, and / or for possessing an anti-HCV antibody in its serum. Any of the above treatment regimens should be administered to individuals who have failed previous treatments for HCV infection ("patients in whom treatment failed," including those who do not respond and those who relapse). [0889] Individuals who have been diagnosed with an infection with HCV are of particular interest in many embodiments. Individuals who are infected with HCV are identified as having an HCV RNA in their blood, and / or possessing an anti-HCV antibody in their serum. Such individuals include ELISA-positive individuals to anti-HCV, and individuals with a positive recombinant immunoblot (RIBA) assay. Such individuals may also, but not necessarily, have elevated serum ALT levels. [0890] Individuals with a clinical diagnosis of infection with HCV include individuals who had not been treated (eg, individuals who had not previously been treated for HCV, particularly those who had not previously received a therapy based on HCV). IFN-a and / or ribavirin) and individuals who failed previous treatments for HCV ("patients in whom treatment failed"). Patients in whom treatment failed include those who do not respond (eg, individuals in whom the HCV titer was not significantly or sufficiently reduced by a prior treatment with HCV, eg, previous monotherapy with IFN-c., A previous combination therapy of IFN-a; and ribavirin, or a previous combination therapy of pegylated IFN-a and ribavirin); and those with relapses (eg, individuals who had been previously treated against HCV, eg, those who had received previous monotherapy with IFN-a;, a previous combination therapy of IFN-c. ribavirin, or a previous combination therapy of pegylated IFN-CÜ and ribavirin, whose HCV titre decreased, and then increased). [0891] In particular embodiments, individuals have an HCV titer of at least about 105, at least about 5 x 10 5, or at least about 106, or at least about 2 x 10e copies of the HCV genome per milliliter of serum. The patient may be infected with any genotype of HCV (genotype 1, including the and Ib, 2, 3, 4, 6, etc. and subtypes (eg, 2a, 2b, 3a, etc.)), in particular with a difficult-to-treat genotype such as the HCV 1 genotype and particular HCV sub-types and quasispecies. [0892] HCV-positive individuals (as described above) who show severe fibrosis or early cirrhosis (not decompensated, Child-Pugh class A or less), or more advanced cirrhosis (decompensated, class B or C) are also of interest. of Child-Pugh) due to a chronic infection with HCV and that are viraemic in spite of a previous antiviral treatment with therapies based on IFN-a; or that they can not tolerate therapies based on IFN-a;, or that they have contraindicated said therapies. In particular embodiments of interest, HCV-positive individuals with liver fibrosis in a step 3 or 4 according to the M? TAVIR measurement system are suitable for treatment with the methods of the present embodiments. In other embodiments, the individuals fit for treatment with the methods of the embodiments are patients with decompensated cirrhosis with clinical manifestations, including patients with highly advanced liver cirrhosis, including those awaiting a liver transplant. In yet other embodiments, individuals fit for treatment with the methods of embodiments include patients with milder degrees of fibrosis including those with early fibrosis (stages 1 and 2 in the METAVIR, Ludwig, and Scheuer measurement systems) or stages. 1, 2, or 3 in the Ishak measurement system). Preparation of the viral inhibitors of Section A [0893] The compounds of the general Formula I can be synthesized in the same general manner as described below for the compounds of the general formulas II-XIX. The syntheses of the various specific compounds of general Formula I are described in the following Examples. Those skilled in the art will appreciate variations in the sequence and will also recognize variations in the appropriate reaction conditions of the analogous reactions that arise or are known from other sources, which can be used appropriately in the processes described below for preparing 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 the preceding formulas are prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the compounds of formula I. Preparation of the viral inhibitors of Section B [0896] The meanings of the structural terms and names used in this Section are the same as in Section B above. Any reference in this Section to a particular number or identification must be understood in the context of the corresponding identification numbering or scheme used in this Section or in Section B above, and not in the context of similar or identical numbering or identification. that could appear elsewhere in this documentation, unless otherwise indicated .. [0897] Compounds of Formulas II-X can be synthesized according to the methods described below. Methodology Preparation of the Compounds [0898] Two methods were used to prepare the compounds with Formulas II-X. In both methods, intermediates 1 and 4 were prepared according to the procedures described in International Patent Application PCT / CA00 / 00353 (Publication No. WO 00/59929). Intermediary 4 was also purchased from RSP Amino Acids.

Example 1-1: Synthesis of compound # 101 (Compound Compound # 101 (Compound AR00220042) Method A: Step 1: Synthesis of (3) 2S- (1-? -toxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4i? -hydroxy-pyrroli-1-carboxylic acid tert-butylester 1: 1 (1R, 2S.) / (1S, 2R) [0899] In a vessel loaded with ethyl- (IR, 2S) / (1, 2R) -l-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) was added 30 mL DMF to prepare a solution, cooled to 0 ° C in a water and ice bath, followed by the slow addition of a DIEA solution (4.4 mL, 4 equiv) in DMF ( 15 mL) with stirring The reaction was allowed to take room temperature and stirred overnight [0900] After 16 h, the reaction was complete, as indicated by HPLC, diluted with EtOAc (100 mL), it was washed with water (3 x 40 mL), saturated NaHCO 3 (2 x 40 mL), and brine (2 x 40 mL), then dried over Na 2 SO and concentrated to give a dark copper oil. silica gel (eluent: acetone / hexanes 3: 7), to give pure 3 as a roasted foamy powder (770 mg, 32 %). Step 2: Synthesis of l-tert-butoxycarbonyl-5- (R-ethoxycarbonyl-25-vinyl-cyclopropylcarbamoyl) -pyrroli3R-1 -3,4-Dihydro-li-isoquinoline-2-carboxylic acid ester ( 5), and l-tert-butoxycarbonyl-5- (SS-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -pyrroli3R-yl ester of 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid (6) (1R, 2S) 6 (1S.2R) [0901] Dipeptide 3 (300 mg, 0.61 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 room temperature overnight. After 15 h, the reaction was complete, as indicated by TLC (DCM / MeOH 9: 1). 1, 2,3, 4-tetrahydroisoquinoline (0.32 mL, 3 equiv) was added to the reaction portionwise, and the reaction was stirred at room temperature overnight. [0902] After 22h, the TLC showed the completion of the reaction. The reaction was diluted with DCM (15 mL) and washed with aq. 1 N (15 mL), brine (15 mL), dried (Na 2 SO), and concentrated. The crude was purified on silica gel (eluent: DCM / Et2? / Acetone 30: 10: 1). The isolated upper spot (5) was a white foamy powder (169 mg, 40%), and the lower spot (6) was a white solid (156 mg, 38%). MS m / e 550 (M + + Na). Step 3: Synthesis of 1- (2S-tert-butoxycarbonylamino-non-8-enoyl) -5- (lR-ethoxycarbonyl-2S-vinyl-cyclopropylcarbamoyl) -pyrroli3R-1-ester of 3,4-Dihydro acid -lii-isoquinoline-2-carboxylic acid (7)

[0903] Top isomer 5 (118 mg, 0.22 mmol) was dissolved in 4N HCl (dioxane, 8 mL) and left at room temperature for 90 min to remove the BOC protecting group. It was then concentrated, taken up in acetonitrile and concentrated again twice. To this light brown 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 in a water-ice bath for 15 min, after a solution of 0.5 ml in DMF of DIBA (0.13 mL, 4 equiv) was added to the reaction by dropwise dripping. The ice bath was allowed to slowly take the room temperature the reaction was stirred overnight. [0904] After 24h, the reaction turned dark brown. Your aliquot TLC indicates that the reaction is complete. The reaction was diluted with? TOAc (30 mL) and washed with water (3 x 15 mL), sat. NaHCO 3 (2 x 15 mL), brine (15 mL), dried (Na 2 SO 4), and concentrated to give the reaction mixture. as an oily orange residue (156 mg). It was used directly in the next step without further purification. MS m / e 703 (M + + Na). Step 4: Synthesis of acid ethyl ester (SS, AR, 6S, 14S, 18R) -14-tert-Butoxycarbonylamino-18- (3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2, 15- dioxo-3, 16-diaza-tricyclo [14.3.0.0 4,6] nonadec-7-en-4-carboxylic (8) [0905] Crude 7 (135 mg, 0.2 mmol) was dissolved in 20 mL DriSolve DCE to prepare a solution, followed by addition of Nolan catalyst (5 mg, 0.3 equiv) at room temperature under nitrogen. The solution became bruised. The reaction was introduced into a preheated oil bath (50 C) and stirred overnight. [0906] After 10 h, the reaction turned dark brownish. TLC (DCM / EtOAc 1: 1) showed a clean conversion for a new point with a slightly low Rf. The reaction was concentrated and purified on silica gel (eluent: DCM / EtOAc 5: 1 to 2: 1), yielding product 8 as a roaster frothy powder (75 mg, 58%). MS m / e 653.1 (M ++ l). Step 5: Synthesis of acid (SS, 4R, 6S, 14S, 18R) -14-tert-Butoxycarbonylamino-18- (3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 4.6] nonadec-7-en-4-carboxylic (Compound # 101) 8 ^^^ SS? J [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 room temperature overnight. After 18h, TLC (DCM / MeOH 9: 1) showed a new clean point with a low Rf. The reaction was concentrated to near dryness and partitioned between aq HCl. 1 N (15 mL) and DCM (20 mL). The organic layer was extracted with DCM (2 x 10 mL). The organic layers were combined, dried over Na 2 SO 4 and concentrated to give compound # 101 as a light brown foamy powder (50 mg, 87%). XH NMR (CD3OD, 400 MHz) D.1.20-1, 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 ++ l). Example 1-the: Compound AR00220122 [0908] Acid (SS, AS, 6R, 1A, 18R) -14-tert-Butoxycarbonylamino-ld- (3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2,15-dioxo- 3, 16-diaza-tricyclo [14.3.0.0 4.6] nonadec-7-en-4-carboxylic acid (Compound AR.00220122) according to the 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:

[0909] Bl compound # 101 was also prepared according to the above procedure. The synthesis of the macrocyclic intermediate 10 described herein is similar to that described in the international application PCT / CA00 / 00353 (Publication No. WO 00/59929). Step 1: Synthesis of 2S- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4K-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (3) 1: 1 (1R, 2S) / (1S, 2R) [0910] To a vessel loaded with ethyl- (1R, 2S) / (1S, 2R) -l-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) 30 mL DMF was added to prepare a solution. It was cooled to 0 ° C in a water and ice bath, followed by the slow addition of a solution of DI? A (4.4 mL, 4 equiv) in DMF (15 mL) with stirring. The reaction was allowed to take room temperature and stirred overnight. [0911] After 16 h, the reaction was complete, as indicated by HPLC. It was diluted with? TOAc (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 to give an Dark copper oil. The crude was purified on silica gel (eluent: acetone / hexanes 3: 7), to give pure 3 as a roasted foamy powder (770 mg, 32%).

S). Step 2: Synthesis of ethyl ester of lR- acid. { [1- (2S-tert-Butoxycarboniland.no-non-8-enoyl) -AR-hydroxy-pyrrolidine-2S-carbonyl] -amino} -2S-vinyl-cycle? Ropanecarboxílico (9)

[0912] Compound 3 (2.85 g, 7.7 mmol) was dissolved in 10 mL 4N HCl (dioxane) and left at room temperature for 90 min to remove the BOC protecting group. It was then concentrated, taken up in acetonitrile and concentrated again twice. To this light brown residue was added 4 (2.2 g, 8.1 mmol) and HATU (3.2 g, 8.5 mmol), followed by 80 mL DMF under nitrogen. The reaction was cooled in a water-ice bath for 15 min, after 5 mL of a DMF solution of DIEA (5.4 mL, 30.9 mmol) was added to the drop reaction with stirring. The ice bath was allowed to slowly take the room temperature and the reaction was stirred overnight. [0913] After Idh, the TLC showed the completion of the reaction. The reaction was diluted with EtOAc (300 mL) and washed with water (3 x 150 mL), sat. NaHCO 3 (2 x 150 mL), brine (150 mL), dried (Na 2 SO), and the solvent was removed. The crude was purified by flash chromatography on silica gel in Biotage 40M (eluent = 3% to 5% MeOH in DCM) to give 9 as a brownish frothy solid (3.5 g, d7%). Step 3: Synthesis of acid ethyl ester (S, AR, 6S, 1A, 18R) -14-tert-Butoxycarbonylamino-18-hydroxy-2/15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 4 ' 6] nonadec-7-en-4-carboxylic acid (10)

[0914] Compound 9 (2.6 g, 5.0 mmol) was dissolved in 500 mL DriSolve DCB in a 1 L round bottom flask to prepare a solution. It was degassed by bubbling nitrogen for 1 h. Then the Hoveyda catalyst (0.25 equiv) was added at room temperature under nitrogen. The reaction was introduced into a preheated oil bath (50 C) and stirred overnight. After 16 h, the reaction turned dark brownish. TLC (DCM / EtOAc 1: 1) showed a clean conversion for a new point with a slightly low Rf. The reaction was concentrated and purified on silica gel (Biotage 40 M, eluent = DCM / EtOAc gradient from 1: 1 to 1: 2), yielding the product 10 as a roaster frothy powder (0.64 g, 52%). XH NMR (CDC13, 400 MHz) Dl, 21 (t, J = 7.0 Hz, 3H), 1.43 (s, 9H), 1.20-1.50 (m, 6H), 1.53-1.66 ( m, 2H), l, d3-l, 96 (m, 2H), 1.98-2.28 (m, 4H), 2.60 (m, 1H), 3.13 (brs, 1H), 3 , 68 (m, 1H), 3.94 (m, 1H), 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, 1H). MS m / e 494.0 (M ++ l). Step 4: Synthesis of acid ethyl ester (SS, 412, SS, 14S, 18.R) -14-tert-Butoxycarbonylamino-18- (3, A-dihydro-1H-isoquinoline-2-carbonyloxy) -2, 15 -dioxo-3,16-diaza-tricyclo [14.3.0.0, 6] nonadec-7-en-4-carboxylic acid (11) [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 mmol) in one portion. The reaction was stirred at room temperature overnight. After 15 h, the reaction was complete, as indicated by TLC (DCM / MeOH 9: 1). 1, 2, 3, 4-tetrahydroisoquinoline (0.14 mL, 1.1 mmol) was added to the reaction by dropping, and the reaction was stirred at room temperature overnight. After 22 h, the TLC showed the completion of the reaction. The reaction was diluted with DCM (6 mL) and washed with aq. IN (2 x 2 mL), saturated sodium bicarbonate (2 mL), brine (2 mL), dried (Na2SO4), and concentrated. The crude was purified on silica gel (Biotage 40S, eluent: 2 to 4% MeOH in DCM), giving 11 as a pale yellow foamy powder (131 mg, 90 %) - Step 5: Compound 11 was hydrolyzed in the same manner as described in step 5 of Example 1-1 to give compound # 101. [0916] The following examples were also prepared according to Method B described above, with 1, 2, 3, 4-tetrahydroisoquinoline substituted with several other secondary amines. Most of these secondary amines were purchased from commercial sources, or are compounds known in the literature, therefore they were prepared using the procedures listed herein. (1. Stokker, G E. Tetrahedron Lett, 1996, 37 (31), 5453-5456. 2. Chan, N W. Bioorganic & cinal Chemistry 2000, 8, 2085-2094. 3. Vecchietti, V. et al, J. Chem. 1991, 34, 2624-2633.) For those amine inputs that were not prepared directly according to Literature, or that to our knowledge has not been previously reported in the literature, its syntheses are given in each example.

Compound AR00226824 [0917] Acid, AR, 6S, 1A, 18R) -14-tert-Butoxycarbonylamino-18- (6,7-dimethoxy-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2 was synthesized , 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (compound ARO0226824) according to Method B, except that 6,7-dimethoxy- 1,2,3,4-tetrahydro-isoquinoline in Step _ MS m / e 585.2 (M + + 1-100).

Compound AR00226825 [0918] 1S, AR, 6S, 1AS, 18R) -14- tert-Butoxycarbonylamino-2, 15-dioxo-18- (1,3,4,9-tetrahydro-b-carboline-2-acid was synthesized. carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 4,6] nonadec-7-en-4-carboxylic acid (compound AR00226825) according to Method B, except that 2,3,4,9- Tetrahydro-lH-b-carboline in Step ^ MS m / e 564.2 (M ++ l- 100).

Compound AR00291871 [0919] 1S, AR, 6S, 1AS, 18R) -14-tert-Butoxycarbonylamino-ld- (1,3-dihydro-isoindol-2-carbonyloxy) -2,15-dioxo-3, 16 acid was synthesized -diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (compound AR00291871) according to Method B, except that 2,3-Dihydro-lH-isoindole was used in Step 4 ^ XH NMR (CDC13, 500 MHz) D. 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).

Compound AR00291875 [0920] 1S, AR, 6S, 1AS, 1812) -14- tert-Butoxycarbonylamino-18- (2,3-dihydro-indole-l-carbonyloxy) -2, 15-dioxo-3, 16 acid was synthesized -diaza-tricyclo [14.3.0.0 4.6] nonadec-7-en-4-carboxylic acid (compound AR00291875) according to Method B, except that 2,3-Dihydro-1H-indole was used in Step 4 ^ MS m / e 610.9 (M ++ l).

Compound AR00294382 [0921] Acid, AR, 6S, 1A, 18R) -14- tert-Butoxycarbonylamino-2, 15-dioxo-ld- (8-trifluoromethyl-3, 4-dihydro-1H-isoquinolin-2- was synthesized. carbonyloxy) -3,16-diazatricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (compound ARO0294382) according to Method B, except that 8-Trifluoromethyl-1,2 was used, 3,4-tetrahydro-isoquinoline in Step 4 ^ MS m / e 693.0 (M +) Compound ARO0294383 [0922] 1S, AR, 6S, 1AS, 18R) -14-tert-Butoxycarbonylamino-2, 15-dioxo-ld- (6-trifluoromethyl-3,4-dihydro-lH-isoquinolin-2-acid was synthesized carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (compound AR00294383) according to Method B, except that 6-trifluoromethyl-1,2,2 was used, 3,4-tetrahydro-isoquinoline in Step A? XH NMR (500 MHz, CDCl3): D..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 (, 2H), 4.7d-4.60 (m, 3H), 4.40 (s, 1H), 4.16-4.00 (m, 1H), 3.92-3.81 (m, 1H), 3.80-3.60 (, 2H), 3.00-2.85 (, 2H), 2.72-2.64 (br s, 1H), 2.40-1.18 (m, 20H). MS: m / e 693.0 (M +). Compound AR00294384 [0923] Acid, AR, 6S, 1AS, 18R) -14-tert-Butoxycarbonylamino-18- (5-fluoro-3) was synthesized, 4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 4'5] nonadec-7-en-4-carboxylic acid (compound AR00294384) in accordance with Method B, except that 5-fluoromethyl-l, 2,3,4-tetrahydro-isoquinoline was used in Step 4_ ^ XH NMR (500 MHz, CDC13): D.7, 19-7.11 (m, 1H), 7.05 (m, 1H), 6.91 (t, 2H), 5.62 (q, 1H), 5.40 (s, 1H), 5.24 (d, 1H), 5, 20 (t, 1H), 4.7d (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), 2.64-2.60 (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. m, 15H). MS: m / e 643.0 (M +) Bj. 1-10: Compound ARO0301745 [0924] Acid, AR, 6S, 1A, 18R) -Id- (5-Amino-3,4-dihydro-lH was synthesized -isoquinolin-2-carbonyloxy) -14-tert-butoxycarbonylamino-2, 15-dioxo-3,16-diaza-tricyclo [14.3.0.0 '6] nonadec-7-en-4-carboxylic acid (compound AR00301745) according to Method B, except that 5-amino-1, 2, 3, 4-tetrahydro-isoquinoline was used in Step 4_: MS: m / e 640.1 (M +)

[0925] Compound AR00301749 [0926] ISS, 4R, 6S, 14S, 18R) -16- (7-Amino-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -14-tert-butoxycarbonylamino acid was synthesized. 2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 4, 6] nonadec-7-en-4-carboxylic acid (compound AR00301749) according to Method B, except that 7-amino-1 was used , 2, 3, 4-tetrahydro-isoquinoline in Step 4_j_ MS: m / e 640.1 (M +), 641.1 (M ++ l) Compound AR00304000 [0927] Acid, AR, 6S, 1AS was synthesized , 18R) -14- tert-Butoxycarbonylamino-2, 15-dioxo-18- (2-phenylamino-6,7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carbonyloxy) -3,16- diazatricyclo [14.3.0. O 4,6] nonadec-7-en-4-carboxylic acid (compound ARO0304000) according to Method B, except that Phenyl- (4,5,6,7-tetrahydro-thiazolo [5, 4-c] pyridine was used. -2-yl) -amine in Step 4 ^ MS m / e 721.2 (Ml).

Compound ARO0304062 [0928] 1S, AR, SS, 1AS, 18R) -14-tert-Butoxycarbonylamino-18- (7-chloro-3,4-dihydro-lH-isoquinolin-2-carbonyloxy) -2, 15 acid was synthesized -dioxo-3, 16-diaza-tricyclo [14.3.0.0 4, ß] nonadec-7-en-4-carboxylic (compound ARO0304062) according to Method B, except that 7-Chloro-1,2 was used, 3,4-tetrahydro-isoquinoline in Step 4 ^ MS m / e 659.0 (M +), 661.0 (M ++ 2) Compound ARO0304063 [0929] 1S, AR, 6S, 1AS, 18R) -14- tert-Butoxycarbonylamino-18- (6-fluoro-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2, 15 acid was synthesized -dioxo-3, 16-diazatricyclo [14.3.0.0 '6] nonadec-7-en-4-carboxylic acid (compound AR00304063) according to Method B, except that 6-fluoro-2,3 was used , 4-tetrahydro-isoquinoline in Step A MS m / e 643.0 (M +), 644.0 (M ++ l) Compound ARO0304065 [0930] 1S, AR, 6S, 1AS, 18R) -14-tert-Butoxycarbonylamino-18- (4, 4-spironocyclobutyl-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2 was synthesized , 15-dioxo-3, 16-diazatricyclo [14.3.0.04, e] nonadec-7-en-carboxylic acid (compound ARO0304065) according to Method B, except that 4, 4-siprocyclobutyl-1 was used, 2, 3, 4-tetrahydro-isoquinoline in Step 4 ^ XH NMR (400 MHz, d6-acetone) 0.7.99 (d, 1H), 7.57-7.66 (m, 1H), 7.27 ( t, 1H), 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 (m, 1H), 4.27-4.42 (m, 1H), 4.17-4.27 (m, 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 (m, 19H). MS m / z 665.1 (M ++ 1) Example 1-15a: Preparation of 4,4-siprocyclobutyl-1,2,3,4-tetrahydro-isoquinoline:

[0931] A: To a solution of 1-phenyl-1-cyclopropane carbonitrile (2.00 g, 12.7 mmol) in 100 mL THF was added a 1.0 M solution of LiAlH (19.1 mL, 19, 1 mmol) by dripping at room temperature. The reaction was stirred at room temperature for 15 hours, then cooled slowly to 0 ° C with 10 ml H20 and then with 10 ml 1.0N NaOH and stirred at room temperature for 1.5 hours. The solution was filtered, and the THF was removed by rotary evaporation. The aqueous layer was extracted with EtOAc, and the organic extract was washed with H20 and brine, dried over Na2SO4, and concentrated to give 0.70 g (34%) of a limpid oil which was used in the next step without purification additional . [0932] B: To a solution of C- (1-Phenyl-cyclobutyl) -methylamine (0.70 g, 4.34 mmol) and TEA (0.67 mL, 4.78 mmol) in 40 mL THF at 0 ° C Methyl chloroformate was added dropwise. The reaction was stirred at room temperature for 15 hours. The next day water and EtOAc were added and the organic layer was separated and washed with IN HCl and brine, dried over Na 2 SO 4, concentrated in an oil, and used directly in the next step without further purification. [0933] C: A mixture of methyl (1-phenyl-cyclobutylmethyl) -carbamic acid methyl ester (0.95 g, 4.34 mmol) and PPA (20 ml) were added to a preheated sand bath at 150 ° C. After 30 minutes the reaction was cooled to room temperature. 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 in a limpid oil which was used directly in the next step without further purification. [0934] D: To a solution of 3,4-dihydro-2H-isoquinolin-1-one (0.406 g, 2.17 mmol) in 20 ml THF at 0 ° C was added a 1.0 M solution of LiAlH (3.26 ml, 3.26 mmol) per drop. The reaction was allowed to take room temperature and stirred for 15 hours, then cooled slowly to 0 ° C with 5 ml H20 and then with 5 ml 1.0N NaOH and stirred at room temperature for 1.5 hours. The solution was filtered, and the THF was removed by rotary evaporation. The aqueous layer was extracted with? TOAc, and the organic extract was washed with H20 and brine, dried over Na2SO4, and concentrated to give 0.21 g (56%) of a limpid oil which was used in the next step without further purification. .

Compound AR00304066 [0935] Acidic acid, AR, 6S, 1AS, 18R) -14-tert-Butoxycarbonylamino-ld- (4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2 was synthesized , 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 '6] nonadec-7-en-4-carboxylic (compound ARO0 04066) according to Method B, except that 4,4-dimethyl- 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 ^ _ XH NMR (400 MHz, ds-acetone) 0.7.98 (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, 1H), 4, 55-4.69 (m, 1H), 4.26-4.36 (m, 1H), 4.16-4.26 (m, 1H), 3.90 (dd, 1H), 3.40- 3.49 (m, 1H), 2.2d-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 ++ l)? Example l-16a:

[0936] 4,4-dimethyl-l, 2,3,4-tetrahydroisoquinoline was prepared following the experiments of steps A to D in the Example l-15a, 2-Methyl-2-phenyl-propionitrile (prepared according to Carón, S.; Vázquez, E .; Wojcik, J. M. J. Am.

Chem. Soc. 2000, 122, 712-713) became the title compound.

Compound AR00304067 [0937] lfl, AR, 6S, 1AS, 18R) -14-tert-Butoxycarbonylamino-18- (4-methyl-3,4-dihydro-1H-iso-quinolin-2-carbonyloxy) -2 acid was synthesized, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (compound AR00304067) according to Method B, except that 4-methyl-1, 2 was used , 3,4-tetrahydro-isoquinoline in Step 4 ^ XH NMR (400 MHz, ds-acetone) 0.7.93-8.03 (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 ++ l) Example l-17a:

[0938] 4-Methyl-1,2,4-tetrahydroisoquinoline was prepared from 2-phenyl-propylamine according to Grunewald, G. L.; I left, D. J.; Monn, J. A. " Med. Chem. 198d, 31, 433-444.

Compound AR00304103 [0939] Acidic acid, AR, 6S, 1AS, 18R) -14-tert-Butoxycarbonylamino-ld- (2-tert-butylamino-6,7-dihydro-4H-thiazolo [5, 4-c] was synthesized pyridine-5-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 4, s] nonadec-7-en-4-carboxylic acid (compound AR00304103) according to Method B, except that tert -Butyl- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c] pyridin-2-yl) -amine was used in Step 4 MS m / e 731.2 (M ++ l).

Compound AR00304154 [0940] acid, S, AR, 6S, 1A, 18R) -18- (2-Amino-6,7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carbonyloxy) -14- tert-butoxycarbonylamino-2, 15-dioxo-3,16-diazatricyclo [14.3.0.04, s] nonadec-7-en-4-carboxylic acid (compound ARO 0304154) was synthesized according to Method B, except that 4, 5, 6, 7-Tetrahydro-thiazolo [5, 4-c] pyridin-2-ylamine was used in Step 4 ^ MS m / e 675, 1 (M ++ l).

Compound AR00304158 [0941] 1S, AR, 6S, 1AS, 1822) -14-tert-Butoxycarbonylamino-18- (2-methyl-6,7-dihydro-4H-thiazolo [5, 4-c] pyridine- acid was synthesized- 5-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.04'6] nonadec-7-en-4-carboxylic (compound AR00304158) according to Method B, except that 2-Methyl-4,5,6,7,7-tetrahydro-thiazolo [5, -c] pyridine was used in Step 4_ MS m / e 546.2 (M ++ l-100).

Compound AR00304183 [0942] 1S, AR, 6S, 1AS, 182?) -14- tert-Butoxycarbonylamino-18- (7,8-dihydro-5H-pyrido [4, 3-d] pyrimidine-6-carbonyloxy acid was synthesized) ) -2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic (Compound ARO0304183) according to Method B, except that 5, 6 , 7, 8-Tetrahydro-pyrido [4, 3-d] pyrimidine in Step 4_ / MS m / e 625.2 (Ml).

Compound ARO0312023 [0943] 1S, AR, SS, 14S, 1822) -14-tert-Butoxycarbonylamino-18- (3, 4-dihydro-lH-isoquinoline-2-carbonyloxy) -2, 15-dioxo-3 acid was synthesized , 16-diaza-tricyclo [14.3.0.0 4.6] nonadecane-4-carboxylic acid (Compound AR00312023) according to Method B, except that the ring closing metathesis product 10 from step 3 was further reduced with H2 / Rh- Al203 before the next coupling step (WO 0059929, pp. 76-77). MS m / e 625.3 (M-1).

Compound ARO0314578 [0944] ISS acid, 422, SS, XAS, 1822) -18- (6-Amino-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -14-tert-butoxycarbonylamino-2, was synthesized. -dioxo-3, 16-diaza-tricyclo [14.3.0.04'6] nonadec-7-en-4-carboxylic acid (Compound ARO0314578) according to Method B, except that l, 2,3,4-tetrahydrochloride was used -isoquinolin-6-ylamine in Step 4 ^ MS (POS ESI) m / z 540.2 [precursor, (M ++ l) -100 (Boc group)].

Compound ARO0314685 [0945] Acid 15, 422, SS, 1AS, 1822) -18- (2-Acetylamino-6,7-dihydro-4H-thiazolo [5, 4-c] iridine-5-carbonyloxy) -14 was synthesized. -tert-butoxycarbonylamino-2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound AR00314665) according to Method B, except that N- (4, 5, 6, 7-Tetrahydro-thiazolo [5, 4-c] pyridine was used -2-il) -acetamide in Step 4 ^ MS m / e 5d9.2 (M ++ l-100).

Compound ARO0315997 [0946] Acid 15, 422, 65, 145, 1822) -14-tert-Butoxycarbonylamino-18- (5-dimethylamino-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2, 15 was synthesized -dioxo-3, 16-diaza-tricyclo [14.3.0.04'6] nonadec-7-en-4-carboxylic (Compound AR00315997) was synthesized according to Method B, except that Dimethyl- (1, 2, 3, 4-tetrahydro-isoquinolin-5-yl) -amine (Example l-25a) was used in Step 4 ^ MS m / e 668.0 (M +).

[0947] The synthesis of dimethyl- (1, 2, 3, 4-tetrahydro-isoquinolin-5-yl) -amine is described in the following scheme: [0948] To a solution of 5-aminotetrahydroisoquinoline (3.68 g, 24.8 mmol) in 1,4-dioxane (100 mL) was added 3 N NaOH (6.27 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 dropwise and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with EtOAc. (2x) The combined organic layers were washed and washed with sat. ac. of NaHC03 solution, water, and brine, then dried and combined. The residue was purified with silica gel chromatography to give 5.44 g (88%) of the 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 THF (5 mL) was added NaH at 0 ° C. After 15 minutes, CH3I was added and the stirring continued overnight at room temperature. After completion of the reaction mixture, it was cooled with ice water, extracted with EtOAc (25 mL), dried (Na2SO) 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: Compound AR00315996 [0950] Acid 15, 422, 65, 145, 1822) -14- tert-Butoxycarbonylamino-18- (5-chloro-l, 3-dihydro-isoindol-2-carbonyloxy) - was synthesized - 2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 4, s] nonadec-7-en-4-carboxylic acid (Compound AR00315998) according to Method B, except that 5-Chloro-2 was used , 3-dihydro-lH-isoindole in Step 4 ^ XH NMR (400 MHz, CDC13): 0. 7.24-7.02 (m, 3H), 6, d2 (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) Compound ARO0315999 [0951] Acid 15, 422, SS, 145, 1822) -14- tert-Butoxycarbonylamino-18- (5,6-dichloro-l, 3-dihydroisoindole-2-carbonyloxy) -2, 15 was synthesized. -dioxo-3, 16-diazatricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (Compound AR00315999) according to Method B, except that 5,6-Dichloro-2 was used, 3-dihydro-lH-isoindole in Step 4 ^ XH NMR (400 MHz, CDC13): 0. 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, 64-4.4d (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) Compound AR00320122 [0952] Acid 15, 422, SS, 145, 1822) -14-tert-butoxycarbonylamino-18- (422-methyl-3, 4-dihydro-1H-isoquinoline-2-carbonyloxy) -2, 15 was synthesized. -dioxo-3, 16-diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (Compound AR00320122) according to Method B, except that 422-Methyl-1,2,2 was used, 3,4-tetrahydro-isoquinoline in Step 4 ^ XH NMR (400 MHz, CD30D) 0.7.02-7.24 (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 ++ l) Compound AR00320123 [0953] Acid 15, 422, SS, 145, 1822) -14-tert-butoxycarbonylamino-18- (45-methyl-3, 4-dihydro-lH-isoquinoline-2-carbonyloxy) -2, 15 was synthesized -dioxo-3, 16-diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (Compound AR00320123) according to Method B, except that 45-Methyl-1,2,2 was used, 3,4-tetrahydro-isoquinoline in Step 4 ^ "" "H NMR (400 MHz, CD3OD) 0.7, 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 (, 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 ++ l) Compound AR00320576 [0954] Acid 15, 422, 6S, 14S, 1822) -14- tert-Butoxycarbonylamino was synthesized -18- [4- (2-methoxy-phenyl) -piperidine-1-carbonyloxy] -2, 15-dioxo-3,16-diaza-tricyclo [14.3.0.0 4, s] nonadec-7-en-4- carboxylic acid (Compound AR00320576) according to Method B, except that 4- (2-Methoxyphenyl) -piperidine was used in Step 4 ^ MS m / e 583.3 (M ++ l-100).

Compound ARO0320577 [0955] Acid 15, 422, 6S, 145, 1822) -14-tert-Butoxycarbonylamino-18- (6-methoxy-1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy acid was synthesized. ) -2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0. O 4,6] nonadec-7-en-4-carboxylic acid (Compound ARO0320577) according to Method B, except that 6-Methoxy-2,3,4,9-tetrahydro-lH-b-carboline was used in Step 4 ^ MS m / e 594, 2 (MX-1-lOO).

Compound ARO0301383 [0956] Acid 15, 422, SS, 145, 1822) -14-tert-butoxycarbonylamino-2, 15-dioxo-18- (1-piperidin-1-ylmethyl-3,4-dihydro-1H- was synthesized. isoquinoline-2-carbonyloxy) -3,16-diaza-tricyclo [14.3.0.04'6] nonadec-7-en-4-carboxylic acid (Compound ARO0301383) according to Method B, except that 1-Piperidin-1 was used -ylmethyl-1,2,3,4-tetrahydro-isoquinoline in the Step 4 ^ XH NMR (500 MHz, CD3OD) 0.7.33-7.24 (m, 4H), 7.20 (br s, 1H), 6.61 (br s, 1H), 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, 1 H), 3.67 - 3.11 (m, 5H), 3.06 - 2, dd (m, 2 H), 2.86 - 2.74 (m, 2 H), 2, 56-2.35 (m, 3H), 2.23 (g, 1H), 2.04-1.90 (m, 2H), 1.89-1.52 (m, 10H), 1.51- 1.32 (m, 12H); MS (POS APCI) m / z 722.3 (M ++ l). Example 1-33: Compound AR00333d42 [0957] Acid 15, 422, SS, 145, 1822) -14-tert-Butoxycarbonylamino-18- (6-methoxy-1-methoxymethyl-3,4-dihydro-lH-isoquinoline was synthesized. -2-carbonyloxy) -2, 15-dioxo-3,16-diaza-tricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound ARO0333842) according to the procedures described in Example 1-2, except that 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydrochloride isoquinolinium was used in replacement of 1,2,3,4-Tetrahydro-isoquinoline in Step 4_-MS (APCI-): m / z 697.2 (Ml).

Compound AR00365349 [0958] Acid 15, 422, 65, 14S, 1622) -14-tert-Butoxycarbonylamino-18- (5-fluoro-l-methoxymethyl-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) was synthesized) -2, 15-dioxo-3, 16-diazatricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound ARO0365349) according to the procedures described in Example 1-2, except that 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydrochloride isoquinolinium was used in replacement of 1,2,3,4-Tetrahydro-isoquinoline in Step 4 ^ MS (APCI-): m / z 685.3 (Ml).

Compound AR00333224 [0959] Acid 15, 422, SS, 145, 1822) -14-tert-Butoxycarbonylamino-18- (1-dimethylaminomethyl-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2, 15 was synthesized. -dioxo-3, 16-diaza-tricyclo [14.3.0. O 4,6] nonadec-7-en-4-carboxylic acid (Compound AR00333224) 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 l-35a) was used in replacement of 1, 2,3, 4-Tetrahydro-isoquinoline in Step 4. MS (APCI +): m / z 582.3 (MH + -Boc). Bj emplo l ~ 35a.- "0 [0960] Dimethyl- (1,2, 3,4-tetrahydro-isoquinolin-1-ylmethyl) -amine was synthesized in a manner similar to that shown in Example 3-76a, except that in Step 1, Phenethylamine was used to replace 2- (3-methoxy-phenyl) -ethylamine, and in the first part of Step 3, dimethyl amine was used to replace sodium methoxide as a nucleophile. next coupling step without further purification.

Compound AR00333225 [0961] Acid 15, 422, 65, 145, 1822) -14-tert-Butoxycarbonylamino-18- (l-morpholin-4-ylmethyl-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) was synthesized -2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound AR00333225) according to the procedures described in Example 1-2, except that l-morpholin-4-ylmethyl-l, 2, 3,4-tetrahydro- isoquinoline (synthesized according to Example l-36a) in replacement of 1, 2, 3, 4-Tetrahydro-isoquinoline in Step 4. MS (APCI-): m / z 722.3 (Ml). Example 1-36a: [0962] l-Morpholin-4-ylmethyl-l, 2, 3, 4-tetrahydro-isoquinoline was synthesized in a manner similar to that shown in Example 3-76a, except that in Step 1, phenethylamine was used to replace 2- (3-methoxy-phenyl) -ethylamine, and in the first part of Step 3, morpholino was used to replace sodium methoxide as a nucleophile. The crude product was used directly in the next coupling step without further purification.

Compound ARO0333248 [0963] Acid 15, 422, 6S, 145, 1822) -14-tert-Butoxycarbonylamino-18- (6-methoxy-1-piperidin-1-ylmethyl-3, -dihydro-1H-isoquinoline-2 was synthesized. -carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound AR00333248) according to the procedures described in Example 1-2, except that 6-methoxy-1-piperidin-1-ylmethyl-1, 2, 3 was used, 4-tetrahydro-isoquinoline (synthesized according to Example 1-37a) in replacement of 1,2,3,4-Tetrahydro-isoquinoline in Step 4. MS (APCI-): m / z 750.4 (Ml).

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

Compound AR00333276 [0965] Acid 15, 422, 65, 145, 1822) -14-tert-butoxycarbonylamino-18- (6-methoxy-l-morpholin-4-ylmethyl-3,4-dihydro-lH-isoquinoline- was synthesized. 2-carbonyloxy) -2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0. O 4,6] nonadec-7-en-4-carboxylic acid (Compound .AR00333276) according to the procedures described in Example 1-2, except that 6-methoxy-1-morpholin-4-ylmethyl-1,2,3 was used , 4-tetrahydro-isoquinoline (synthesized according to Example 1-38a) in replacement of 1,2,3,4-Tetrahydro-isoquinoline in Step 4 ^ MS (APCI-): m / z 750.3 (Ml) ). synthesized 6-methoxy-l-morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline in a manner similar to that shown in Example 3-76a, except that in the first part of Step 3, used morpholine in replacement of sodium methoxide as a nucleophile. The crude product was used directly in the next coupling step without further purification.

Compound AR00333277 [0967] ISS, 422, 6S, 145, 1822) -14-tert-Butoxycarbonylamino-18- (1-dimethylaminomethyl-6-methoxy-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) acid was synthesized) -2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0. O4.6] nonadec- -en-4-carboxylic acid (Compound AR00333277) according to the procedures described in Example 1-2, except that (6-methoxy-1,2,3- tetrahydro-isoquinoline-1- was used. ilmethyl) -dimethyl-amine (synthesized according to Example 1-39a) in replacement of 1,2,3,4-Tetrahydro-isoquinoline in Step 4_. MS (APCI +): m / z 712.3 (MH +). Example 1-39a:

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

Compound ARO0365369 [0969] Acid 15, 422, 65, 145, 1822) -14- tert-Butoxycarbonylamino-18- (4-fluoro-1,3-dihydro-isoindol-2-carbonyloxy) -2, 15-dioxo was synthesized -3,16 diazatricyclo [14.3.0. O4.6] nonadec-7-en-4-carboxylic (Compound AR00365369) according to the procedures described in the Example 1-2, except that 4-fluoro-2, 3-dihydro-lH-isoindole was used (synthesized according to Example 3-55a) in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 ^ XH NMR (500 MHz, DMSO) 0.12.21 (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, 1 H), 5.51 (q, 1 H), 5.33-5.21 (m, 2 H), 4.66 (s, 4 H), 4.22 (q, 1 H), 4.24 (t, 1 H), 3.99 - 3.89 (m, 1 H), 3.73 - 3.64 (m, 1 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, 1 H), 1.42-1.03 (m, 16 H); MS (APCI-): m / z 627.3 (M-1).

Compound ARO0371946 [0970] Acid 15, 422, SS, XAS, 1822) -14- tert-Butoxycarbonylamino-18- [5- (2-morpholin-4-yl-ethoxy) -1,3-dihydro-isoindol- was synthesized. 2-carbonyloxy] -2, 15-dioxo-3, 16-diazatricyclo [14.3.0. O4.6] nonadec-7-en-4-carboxylic (Compound AR00371946) according to the procedures described in the Bj emplo 1-2, except that 5- (2-Morpholin-4-yl-ethoxy) -2,3-dihydro-1H-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) 665-688. For the amine introduced protected by N-Boc: aH NMR (500 MHz, CDC13) O..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 +): m / z 349.1 (M + l)) was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step A? MS (APCI +): m / z 640.3 [(M + l) -Boc].

Compound AR00371947 [0971] Acid 15, 422, SS, XAS, 1822) -14- tert-Butoxycarbonylamino-18- [5- (2-dimethylamino-ethoxy) -1,3-dihydro-isoindol-2-carbonyloxy] was synthesized] -2, 15-dioxo-3, 16-diazatricyclo [14.3.0. O4.6] nonadec-7-en-4-carboxylic (Compound AR00371947) according to the procedures described in the Bj emplo 1-2, except that [2- (2, 3-Dihydro-lH-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 amine introduced protected by N-Boc: "? RMN (500 MHz, CDC13) D. 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 + l)) was used to replace 1,2,3,4-tetrahydro-isoquinoline in Step 4 ^ MS (APCI +): m / z 698.2 (M + 1).

Compound AR00371948 [0972] Acid 15, 422, 65, 145, 1822) -14- tert-Butoxycarbonylamino-18- [5- (2-isopropylamino-ethoxy) -1,3-dihydro-isoindol-2-carbonyloxy] was synthesized] -2, 15-dioxo-3, 16-diazatricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound ARO0371948) according to the procedures described in Example 1-2, except that [2- (2,3-Dihydro-lH-isoindol-5-yloxy) - ethyl] -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 -668.For the introduced amine protected by N-Boc: XH NMR (500 MHz, CDC13) 0..7.13 (dd, 1H), 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 + l)) was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4A MS (APCI -): m / z 710.3 (Ml). Preparation of Compounds with general structure III 973] Compounds with general structure II were prepared according to the general scheme described. First of removed a compound with structure that of its protective group Boc, followed by the nucleophilic attack of the amino group on an electrophile, to form a carbamate, amide, or urea.

Compound AR00247310 Step 1: Preparation of ethyl ester of acid (15, 422, 65, 14S, 1822) -14-Amino-18- (3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2, 15-dioxo -3,16-diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid.

[0974] The initial protected N-Boc material was dissolved (102 mg, 0.16 mmol) in 6 mL 4N HCl (dioxane), and left at room temperature for 90 min. HPLC exhibited complete removal of the BOC protecting group. Then the reaction mixture was concentrated, taken up in acetonitrile and concentrated again twice. The resulting light brownish foamy powder was taken to the next step. Step 2: Preparation of ethyl ester of acid (IS, 422, 6S, 145, 1822) -14-Cyclopentyloxycarbonylamino-18- (3,4-dihydro-1H-isoquinolin-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid.

[0975] To a solution of cyclopentanol (42 mg, 0.48 mmol) in THF (16 mL), a phosgene solution of toluene (0.42 mL, 1.9 M, 0.80 mmol) was added dropwise. . The mixture was stirred at room temperature for 2 h to form the cyclopentyl chloroformate reagent. Then the reaction concentrated to about half the volume. It was diluted with DCM to the original volume, and it was again concentrated to half the volume, in order to completely remove the excess of pho- nogen. This solution of cyclopentyl chloroformate was further diluted with THF (16 mL), cooled to 0 ° C, and added to the solid residue (0.16 mmol) from Step 1 above at 0 ° C. Then TEA (0.11 mL, 0.81 mmol) was added to the reaction mixture, and the reaction was stirred at 0 ° C for 2 h. The reaction was completed by HPLC. It was concentrated, taken up in EtOAc (15 mL), and then washed with water, sat. of sodium bicarbonate, water, and brine (10 mL each), dried over Na2SO and concentrated. 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 brittle foamy powder (65.2 mg, 63%). MS (MH + 665.2) Step 3: Preparation of acid (1S, 422, 6S, 145, 1822) -14- Cyclopentyloxycarbonylamino.no-18- (3,4-dihydro-lH-isoajuinolin-2-carbonyloxy) -2 , 15-dioxo-3,16-diazatricyclo [14.3.0.04'5] nonadec-7-en-4-carboxylic (Compound

[0976] Followed by the same hydrolysis procedures of Step 5 of Example 1-1. [0977] The following examples were also prepared following the same procedures mentioned above in Example 2-1, with either replacing the cyclopentyl chloroformate with other electrolytes, and / or replacing the P2-tetrahydroisoquinoline with other amine inserts as it is illustrated in Step 4 of Method B in Example 1-2. Example 2-2: Compound AR00294376 [0978] Acid 15, 422, SS, XAS, 1822) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14-methoxycarbonylamino-2, 15-dioxo-3, 16 was synthesized -diaza-tricyclo [14.3.0.0 4.6] nonadec-7-en-4-carboxylic acid (Compound AR00294376) according to the procedures described in Example 2-1, except that methyl chloroformate was used in Step 2 ^ Compound AR00304074 [0979] IS acid, 422, 6S, 145, 1822) -14-Cyclopentyloxycarbonylamino-18- (5-fluoro-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2,15-dioxo was synthesized -3,16-diaza-tricyclo [14.3.0.0 '6] nonadec-7-en-4-carboxylic acid (Compound AR00304074) according to the procedures described in? Examples 1-2 and 2-1, except that 5-Fluoro-l , 2, 3, 4-tetrahydro-isoquinoline was used in Step 4 of Example 1-2. MS m / e 5d3.2 (M ++ l).

Compound AR00304075 [0980] Acid 15, 422, SS, XAS, 1822 was synthesized) -14- Cyclopentyloxycarbonylamino-2, 15-dioxo-18- (d-trifluoromethyl-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -3,16-diazatricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (Compound ARO0304075) according to the procedures described in Examples 1-2 and 2-1, except that 8-trifluoromethyl-1 , 2, 3, 4-tetrahydro-isoquinoline was used in Step 4 of Example 1-2. MS m / e 705.1 (M ++ 1).

Compound JAR00304076 - -

[0981] IS acid was synthesized, 422, 6S, 14S, 1822) -14- Cyclopentyloxycarbonylamino-18- (1,3-dihydro-isoindol-2-carbonyloxy) -2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0, 6] nonadec-7-en-4-carboxylic acid (Compound AR00304076) according to the procedures described in examples 1-2 and 2-1, except that 2,3-Dihydro-1H-isoindole was used in the Step 4 of Example 1-2. MS m / e 623.2 (M ++ l). Example 2-6 Compound ARO0304125 [0982] Examplel5, 422, 65, 145, 1822) -18- (3,4-Dihydro-lH-isoquinoline-2-carbonyloxy) -14- (2-fluoro-ethoxycarbonylamino) -2,15-dioxo- 3,16-diaza-tricyclo [14.3.0.0 4'6] nonadec-7-en-4-carboxylic acid (Compound AR00304125) according to the procedures described in Example 2-1, except that 2-fluoroethanol was used to form the chloroformate reagent in Step 2 of cyclopentanol. MS m / e 615.1 (M ++ l). Example 2-7: Compound AR00304126 [0983] Acid 15, 42 ?, 65, 145, 1822) -18- (3,4-Dihydro-lH-isoquinoline-2-carbonyloxy) -2,15-dioxo- was synthesized. 14- (tetrahydro-furan-3S-iloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0. O4'6] nonadec-7-en-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 chloroformate reagent in Step 2 of cyclopentanol. MS m / e 639.2 (M ++ l).

Compound ARO0304127 [0984] Acid 15, 422, SS, XAS, 1822) -18- (3,4-Dihydro-lH-isoquinoline-2-carbonyloxy) -2,15-dioxo-14- (tetrahydrofuran) was synthesized. 322-ioxycarbonylamino) -3,16-diaza-tricyclo [14.3 .0. 04'6] nonadec-7-en-4-carboxylic acid (Compound AR00304127) according to the procedures described in Example 2-1, except that tetrahydro-furan-322-ol was used to form the chloroformate reagent in Step 2 of cyclopentanol . MS m / e 639.2 (M ++ l).

Compound ARO0320002 [0985] Acid 15, 422, SS, XAS, 1822) -18- (3,4-Dihydro-lH-isoquinolin-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-pyran) was synthesized. 4-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound ARO0320002) 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 of Cyclopentanol MS m / e 653.2 (M ++ l).

Compound AR00320074 [0986] Acid 15, 422, 6S, 14S, 1622) -18- (1,3-Dihydro-isoindol-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-furan-322-) was synthesized. iloxycarbonylamino) -3,16-diazatricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound ARO0320074) according to the procedures described in examples 1- 2 and 2-1, except that 2,3-Dihydro-1H-isoindole was used in Step 4 of Example 1-2, and except that tetrahydro-furan-322-ol was used to form the chloroformate reagent in Step 2 of Example 2-1 of cyclopentanol. MS m / e 625.2 (M ++ l).

Compound AR00320075 [0987] Acid 15, 422, 6S, XAS, 1822) -18- (1, 3-Dihydro-isoindol-2-carbonyloxy) -2,15-dioxo-14- (tetrahydrofuran-35- was synthesized. iloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0. O 4,6] nonadec-7-en-4-carboxylic acid (Compound AR00320075) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-lH-isoindole was used in Step 4 of Example 1-2, and except that tetrahydrofuran-35-ol was used to form the chloroformate reagent in Step 2 of Example 2 -1 of cyclopentanol. MS m / e 625, 2 (M ++ l).

Compound ARO0320076 [0988] Acid 15, 422, 65, 145, 1822) -18- (1,3-Dihydro-isoindol-2-carbonyloxy) -2,15-dioxo-14- (tetrahydrofuran-35-) was synthesized. iloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0. O 4,6] nonadec-7-en-4-carboxylic acid (Compound AR00320076) according to the procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-1H-isoindole was used in Step 4 of Example 1-2, and except that 2-fluoroethanol was used to form the chloroformate reagent in Step 2 of Example 2-1 of cyclopentanol. MS m / e 601.1 (M ++ l).

Compound AR00320077 [0989] Acid 15, 42 ?, SS, XAS, 182?) Was synthesized -18- (1,3-Dihydro-isoindol-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-pyran- 4-ioxycarbonylamino) -3,16-diazatricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound AR00320077) according to the procedures described in Examples 1-2 and 2-1, except that 2,3-Dihydro-lH-isoindole was used in Step 4 of Example 1-2, and except that tetrahydro-pyran-4-ol was used to form the chloroformate reagent in Step 2 of Example 2-1 of cyclopentanol. MS m / e 601.1 (M ++ l).

Compound AR00320445 [0990] Acid 15, 42 ?, SS, XAS, 1822) -18- (5,6-Dichloro-l, 3-dihydro-isoindol-2-carbonyloxy) -2,15-dioxo-14- was synthesized. (tetrahydro-furan-32? -yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0, s] nonadec-7-en-4-carboxylic acid (Compound AR00320445) according to the procedures described in Examples 1-2 and 2- 1, except that 5,6-dichloro-2,3-dihydro-lH-isoindole was used in Step 4 of Example 1-2, and except that tetrahydro-furan-32? -ol was used to form the chloroformate reagent in Step 2 of? j employs 2-1 cyclopentanol. MS: m / e 693, 0 (M +), 695, 1 (M ++ 2).

Compound AR00320448 [0991] Acid 15, 42 ?, 65, 145, 1822) -18- (5-Chloro-1,3-dihydro-isoindol-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro) was synthesized. -furan-32? -yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0. O 4,6] nonadec-7-en-4-carboxylic acid (Compound AR00320448) according to the procedures described in examples 1-2 and 2-1, except that 5-dichloro-2,3-dihydro-1H-isoindole was used in Step 4 of Example 1-2, and except that tetrahydro-furan-32? -ol was used to form the chloroformate reagent in Step 2 of Example 2-1 of cyclopentanol. XR NMR (500 MHz, CD30D): 0..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: m / e 659.1 (M +), 661.1 (M ++ 2) Example 2-16: AR00248669 [0992] Synthesis of acid (15, 42 ?, SS, XAS, 182?) -14- ( Cyclopentanecarbonyl-amino) -18- (3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0. O 4,6] nonadec-7-en-4-carboxylic acid (Compound AR248669) [0993] Cyclopentyl carboxylic acid is first charged to PS-TFP resin (purchased from Argonaut Technologies) to form an active ester. The activated ester was swollen in resin (26 mg, 1.16 mmol / g, 0.03 mmol) in first in 0.5 mL of chloroform, followed by addition of carbonate resin MP (purchased from Argonaut Technologies, 300 mg, 2.5 mmol / g, 0.75 mmol). To this resin was then added 0.5 M chloroform solution of the macrocyclic material (15 mg, 0.02 mmol), and the reaction was stirred overnight at room temperature. The reaction was completed by HPLC after 16h. It was then filtered and concentrated, giving an N-acylated product. It was then hydrolyzed following the same hydrolysis procedures as in Step 5 of Example 1-1, giving the desired product AR24d689 as a white solid (12.5 mg, 88%). MS (APCI +): m / z 621.3 (MH +).

Compound AR00248687 [0994] Acid 15, 42 ?, 65, 145, 182?) -18- (3,4-Dihydro-lH-isoquinoline-2-carbonyloxy) -14- (2, 2-dimethyl-propionylamino) was synthesized -2, 15-dioxo-3, 16-diazatricyclo [14.3.0. O4'6] nonadec-7-en-4-carboxylic (Compound AR00248687) following the same procedure as described in Example 2-16, except that tert-butyl carboxylic acid was first loaded into PS-TFP resin. MS (APCI +): m / z 609.3 (MH +).

Compound AR00248688 [0995] 15, 42? 6S, XAS, 182?) -18- (3,4-Dihydro-lH-isoquinoline-2-carbonyloxy) -14-isobutyrylamino-2, 15-dioxo-3 was synthesized. , 16-diaza-tricycle [14.3.0. O4'6] nonadec-7-en-4-carboxylic acid (Compound AR00248686) following the same procedure as described in the Example in Example 2-16, except that first isopropyl carboxylic acid was loaded on PS-TFP ^ MS resin (APCI + ): m / z 595.3 (MH +).

Compound ARO 0298969 Synthesis of acid (IS, 422, 65, 145, 1822) - 14- (2-tert-Butoxycarbonylamino-3-methyl-butyrylamino) -18- (3, -dihydro-1H-isoquinoline-2-carbonyloxy) ) -2, 15-dioxo-3, 16-diaza-tricyclo [14.3 .0. O4'6] nonadec-7-en-4-carboxylic (Compound

[0996] Ethyl ester of 14-Amino-18- (3,4-dihydro-lH-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3] was stirred together. 0 04, 6] nonadec-7-en-4-carboxylic acid (120 mg, 217 umol) and N-0-t-Boc-L-valine ester N-hydroxysuccinamide (96 mg, 300 umol) in 1.1 mL dichloromethane for 14 hours. The solvent was removed in vacuo and 1 mL 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 MgSO4 were dried and the solvents removed in vacuo to provide the desired compound as a white solid (132 mg, 81%). MS m / z 752.2 (MH +).

Compound ARO0301338 [0997] Acid 15, 422, SS, XAS, 182?) -18- (3,4-Dihydro-lH-isoquinoline-2-carbonyloxy) -14- was synthesized. { 3-methyl-2- [(pyrazine-2-carbonyl) -amino] -butyrylamino} -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.04'6] nonadec-7-en-4-carboxylic acid (Compound AR00301338) following the same procedure as that described in Example 2-19, except that used 2,5-dioxo-pyrrolidin-1-yl ester of 3-methyl-2- [(pyrazine-2-carbonyl) -amino] -butyric acid in replacement of N-0-t-Boc-L-aline ? -hydroxysuccinamide. MS m / e 730.3 (M ++ l). Example 2-21: Compound ARO0304072 [0998] Acid (15, 42 ?, 65, 145, 182?) -18- (3,4-Dihydro-lH-isoquinoline-2-carbonyloxy) -14- was synthesized. { 2- [(6-dimethylamino-pyridine-3-carbonyl) -amino] -3-methyl-butyrylamino} -2, 15-dioxo-3, 16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-4-carboxylic (Compound AR00304072) following the same procedures as those described in Example 2-19, except that 2- [(6-Dimethylamino-pyridine-3-carbonyl) - 2,5-dioxo-pyrrolidin-1-yl ester was used amino] -3-methyl-butyric in replacement of N-hydroxysuccinamide ester of N-0-t-Boc-L-valine. ^ "H NMR (CD30D, 500 MHz): 0.8.69 (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, 1 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, d H). MS m / e 770.4 (M-1). Example 2-22: Compound ARO0304073 [0999] The acid (15, 42 ?, 65, 145, 182?) -18- (3,4-Dihydro-1H-isoquinolin-2-carbonyloxy) -14- was synthesized. { 3-methyl-2- [(pyridine-3-carbonyl) -amino] -butyrylamino} -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04,6] nonadec-7-en-4-carboxylic acid (Compound AR00304073) following the same procedures as those described in Example 2 -19, except that 2-5-dioxo-pyrrolidin-1-yl ester of 3-Methyl-2- [(pyridin-3-carbonyl) -amino] -butyric acid was used in replacement of N-hydroxysuccinamide ester of N- 0- t-Boc-L-valine. MS m / e 729.2 (M ++ l). Example 2-23: Compound AR00298990 [1000] The acid (15, 42? 6S, XAS, 182?) -14- (2-Amino-3-methyl-butyrylamino) -18- (3,4-dihydro-lH-isoquinoline-) was prepared. 2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14, 3.0, O4'6] nonadec-7-en-4-carboxylic (Compound 298990) following the same procedures as in Step 1 of Example 2-1, MS m / e 624.2 (M ++ l). Example 2-24: Compound ARO0294378 Synthesis of acid (1S, 422, 6S, 145, 1822) -14- (3-Cyclopentyl-ureido) -18- (3,4-dihydro-lH-isoquinolin-2-carbonyloxy) -2, 15-dioxo -3,16-diaza-tricyclo [14,3, 0, 04,6] nonadec-7-en-4-carb

[1001] Hydrochloride salt of 14-Amino-2, 15-dioxo-18- (8-trifluoromethyl-3, 4-dihydro-1H-isoquinoline-2-carbonyloxy) -3,16-diazahic acid ethyl ester was collected. tricyclo [14,3, 0, 04, 6] nonadec-7-en-4-carboxylic acid (49 mg, 74 umol), diisopropylethylamine (29 mg, 222 umol), and cyclopentyl isocyanate (25 mg, 222 umol) in 375 uL of 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 give the title product as a white solid (42 mg, 77%). MS m / z 732.2 (MH +). Example 2-25: Compound AR00294377 [1002] The acid was synthesized 15, 42 ?, 65, 145, 182?) -14- (3-tert-Butyl-ureido) -18- (3, 4-dihydro-lH-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14, 3.0, 04'6] nonadec-7-en-4-carboxylic acid (Compound AR00294377 ) according to the procedures described in Examples 1-2 and 2-24, except that tert-butyl isocyanate was used in place of cyclopentyl isocyanate in the procedures of Example 2-24. MS m / e 624.1 (M ++ l). Example 2-26: Compound ARO0304077 [1003] The acid was synthesized 15, 42 ?, 65, 14S, 182?) -14- (3-Cyclopentyl-ureido) -18- (5-fluoro-3,4-dihydro) lH-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-4-carboxylic acid (Compound AR00304077) according to the described procedures in Examples 1-2 and 2-24, except that 5-Fluoro-1, 2, 3, 4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of the Example 1-2, MS m / e 654.2 (M ++ l). Example 2 -27: Compound ARO0304078 [1004] The acid was synthesized 15, 42 ?, 65, 145, 182?) -14- (3-Cyclopentyl-ureido) -2, 15-dioxo-18- (d-trifluoromethyl-3,4-dihydro) -lH-isoquinoline-2-carbonyloxy) -3,16-diaza-tricyclo [14,3, 0, 04, s] nonadec-7-en-4-carboxylic acid (Compound AR0030407d) according to the procedures described in Examples 1- 2 and 2-24, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, MS m / e 704.1 (M ++ l). Example 2-28: Compound AR00304079 [1005] Acid 15, 42? 6S, XAS, 182?) -14- (3-Cyclopentyl-ureido) -18- (1,3-dihydro-isoindol-2-carbonyloxy) -2 was synthesized, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-4-carboxylic acid (Compound AR00304079) according to the procedures described in examples 1-2 and 2-24 , except that 2, 3-dihydro-1H-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, MS m / e 622.2 (M ++ l ). Example 2-29: Compound ARO0320078 [1006] Acid 15, 42 ?, 65, 14S, 182?) -14- (3-tert-Butyl-ureido) -18- (1,3-dihydro-isoindole) was synthesized 2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14, 3.0, O4'6] nonadec-7-en-4-carboxylic acid (Compound AR00320078) according to the procedures described in Examples 1 -2 and 2-24, except that 2,3-dihydro-lH-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that isocyanate was used of tert-butyl in replacement of cyclopentyl isocyanate in the procedures of Example 2-24. MS m / e 610.1 (M ++ l). Example 2-30: Compound AR00320221 [1007] Acid 15, 42 ?, 65, 145, 182?) -ld- (3,4-Dihydro-lH-isoquinoline-2-carbonyloxy) -2,15-dioxo-14- [3 was synthesized - (tetrahydro-furan-3-yl) -ureido] -3,16-diaza-tricyclo [14, 3.0, O4,6] nonadec-7-en-4-carboxylic (Compound 7AR00320221) according to the procedures described in Examples 1-2 and 2-24, except that 3-isocyanato-tetrahydrofuran was used in replacement of cyclopentyl isocyanate in the procedures of Example 2-24. MS m / e 638.2 (M ++ l).

Example 2-31: Compound AR00320449 [1008] Acid 15, 4i ?, 6S, 14S, 182?) -14- (3-tert-Butyl-ureido) -18- (5-chloro-1,3-dihydro-isoindol-2) was synthesized -carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, s] nonadec-7-en-4-carboxylic acid (Compound AR00320449) according to the procedures described in Examples 1 2 and 2-24, except that 5-chloro-2,3-dihydro-lH-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that Tert-butyl isocyanate was substituted for cyclopentyl isocyanate in the procedures of Example 2-24. X H NMR (500 MHz, CD30D): 0. 7.34 (s, 1 H), 7.28-7.25 (m, 2 H), 7.24 (s, 1 H), 7.20 (s, 1 H) , 5.51 (, 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: Compound AR00320450 [1009] Acid 15, 42 ?, 65, 14S, 1822) -14- (3-tert-Butyl-ureido) -18- (5,6-dichloro-l, 3-dihydro-isoindole) was synthesized. 2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-4-carboxylic acid (Compound AR00320450) according to the procedures described in Examples 1 -2 and 2-24, except that 5,6-dichloro-2,3-dihydro-lH-isoindole was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that tert-butyl isocyanate was used in replacement of cyclopentyl isocyanate in the procedures of Example 2-24. X H NMR (500 MHz, CD 3 OD): O. 7.50 (s, 1 H), 7.38 (s, 1 H), 5.56 (q, 1 H), 5.42-5.38 (m, 2 H) , 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: m / e 678.0 (M +), 680.0 (M ++ 2). Example 2-33 Compound AR00365381 [1010] The acid was synthesized 15, 42 ?, 65, 145, 182?) -14-Cyclopentyloxycarbonylamino-18- (5-fluoro-l-methoxymethyl-3,4-dihydro-lH-isoquinoline-2-carbonyloxy) ) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-4-carboxylic acid (Compound AR00365381) according to the procedures described in examples 1-2 and 2-1, except that 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of? Example 1-2. MS (APCI-): m / z 697.4 (M-1). Preparation of Compounds with general structure IV

[1011] Compounds 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: Compound AR00261408 Synthesis of 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14.3,0,04,6] nonadec-7-en-18-yl ester of acid (1S, 422, 6S, 14S, 1822) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid

[1012] Compound number 101 of macricyclic acid (7 mg, 0.011 mmol) was dissolved in 0.1 mL DMF, followed by the addition of CDI (1.8 mg, 0.011 mmol). The mixture was stirred in an oil bath at 40 C for 1 hour. Cyclopropylsulfonamide (2.0 mg, 0.017 mmol) was then added to the reaction, followed by DBU (1.7 mg, 0.011 mmol). The reaction was stirred at 40 C overnight. After 14 h, the LCMS showed the complete reaction. The reaction was cooled to room temperature, partitioning between 2 mL EA and 2 mL 5% HCl (aq). The organic layer was washed with water, bicarb (2 mL ea), then dried (Na2SO). The crude product was evaporated instantaneously in Biotage 12M (eluent = DCM: MeOH 20: 1), to give AR00261408 (4.2 mg, 52%) 2H NMR (CDC13, 500 MHz): D.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), 4.95-5.05. (m, 2H), 5.30-5.48 (m, 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: Compound AR00261407 [1013] 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (propan-2-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-ld-il acid ester 15, 42 ?, 65, 145, 162?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00261407) according to the procedures described in Example 3-1, except that isopropyl sulfonamide was used in replacement of cyclopropyl sulfonamide in the coupling step. MS m / e 728.4 (M-1). Example 3-3: Compound AR00254906 [1014] 14-tert-Butoxycarbonylamino-4-methanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04,6] nonadec-7-en-18-yl was synthesized 15, 42? 6S, 14S, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid ester (Compound AR00254906) according to the procedures described in Example 3-1, except that methyl sulfonamide was used in replacement of cyclopropyl sulfonamide in the coupling step. a H NMR (CDC13, 500 MHz): 0.1.20-1.52 (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, 1H), 5.74 (m, 1H), 6.74 (m, 1H), 7.03-7.23 (m, 4H). MS m / e 701.9 (M *), 602.2 (progenitor, MH + -Boc group). Example 3-4: Compound AR00261409 [1015] 4- (Butan-1-sulfonylaminocarbonyl) -14-tert-butoxycarbonylamino-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04 'was synthesized 6] nonadec-7-en-ld-yl ester of acid 15, 42 ?, 65, 145, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00261409) according to the procedures described in Example 3-1, except that n-butyl sulfonamide was used in replacement of cyclopropyl sulfonamide in the coupling step. XH NMR (CDC13, 500 MHz): 0.080-1, 03 (m, 7H), 1.20-2.10 (m, 22H), 2.20-2.60 (m, 4H), 2.84 (m, 1H), 3.20 (m, 1H), 3.44 (m, 1H), 3.65 (m, 1H), 3.80-3.95 (m, 1H), 4.20-4.34 (m, 2H), 4.50-4.65 (m, 4H), 4.95-5.05 (m, 1H), .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 m / e 743, 3 (M +, APCI-). ? jmplo 3 -5: Compound AR00282131 [1016] 14-Cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, e] nonadec-7-en-18-yl ester of the 15, 42 ?, 65, 145, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00282131) according to the procedures described in examples 2-1 and 3-1, MS m / e 738.4 (Ml). Example 3-6: Compound AR00294381 [1017] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized acid ester 15, 42? 6S, 14S, 1822) -1,3-Dihydro-isoindol-2-carboxylic acid (Compound AR00294381) according to the procedures described in Examples 1-5 and 3-1,? NMR (CDC13, 500 MHz): D.0,89-2, 08 (m, 25H), 2.21-2.28 (m, 1H), 2.41-2.49 (, 1H), 2, 51-2.61 (m, 2H), 2.91 (m, 1H), 3.83 (m, 1H), 4.21 (m, 1H), 4.40 (d, «7 = 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 (, 1H), 7.16 (, 1H), 7.23-7.31 (m, 3H). MS m / e 712.3 (APCI-, M-H). Example 3-7: Compound ARO0298996 [1018] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized en-18-yl ester, 42? 65, 145, 182?) -5-Fluoro-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00298996) according to the procedures described in the? 1-2 and 3-1, except that 5-Fluoro-1, 2,3,4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1 2, XH NMR (400 MHz, CDC13): D.10.05 (s, 1H), 8.12 (s, 1H), 7.04 (s, 1H), 6.84-6.73 (m, 2H), 6.70 (s, 1H), 5.65 (q, 1H), 5.40 (s, 1H), 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 (, 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: Compound AR00298997 [1019] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04,6] nonadec-7-en-ld-il was synthesized 15, 42? 6S, 14S, 182?) -d-Trifluoromethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid ester (Compound AR00298997) according to the procedures described in examples 1-2 and 3 -1, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, XH NMR ( 500 MHz, CD3OD): 0.7.55 (dd, 1H), 7.42 (dd, 1H), 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, 1H), 3.91 (m, 1H), 3.78-3.62 (m, 2H), 3.00-2.82 (m, 3H), 2.5d-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: Compound AR00301746 [1020] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14.3, 0, 0] nonadec-7-en-18-yl was synthesized ES ester, 42? SS, XAS, 182?) -7-Chloro-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00301746) according to the procedures described in examples 1-2 and 3 -1, except that 7-chloro-l, 2,3,4-tetrahydro-isoquinoline was used in replacement of 1, 2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, ^ H NMR ( 400 MHz, CDC13): D.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, lH), 4.92-4.41 (m, 2H), 4.55-4.40 (m, 3H), 4.28-4.12 ( m, 2H), 3.62-3.75 (m, 1H), 3.65-3.46 (m, 3H), 2.8d-2, d0 (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 +)? J 3-10 Compound AR00301747 [1021] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04'6] nonadec-7-en-18-yl was synthesized acid ester 15, 42 ?, 65, 14S, 182?) -6-Trifluoromethyl-3,4-dihydro-lH-isoquinolin-2-carboxylic acid (Compound AR00301747) according to the procedures described in examples 1-2 and 3 -1, except that 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, E NMR (500MHz) , CD3OD): 0.7.44 (, 2H), 7.38-7.30 (m, 1H), 7.28-7.24 (m, 1H), 5.65 (q, 1H), 5.40 (m, 1H), 5.08 (m, 1H), 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, 1H), 1.64-1.58 (m, 1H), 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: Compound ARO0301751 [1022] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, s] nonadec-7-en-ld-il was synthesized acid ester 15, 42? SS, XAS, 182?) -6-Fluoro-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00301751) according to the procedures described in Examples 1-2 and 3- 1, except that 6-fluoro-1,2,3,4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, ^ H NMR (500 MHz, CD3OD): 0.7.21-7.02 (m, 1H), 6.92 (m, 2H), 6.92 (, 2H), 5.66 (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 (, 1H), 2 , 41-2.34 (m, 1H), 1.86-1.76 (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 ++ l). Example 3-12: Compound AR00304080 [1023] 14- (3-Cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14,3, 0, O4,6] nonadec-7-en was synthesized -18-yl ester, 42 ?, 65, 145, 1822) -5-Fluoro-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00304080) according to the procedures described in the? 2, 2-24 and 3-1, except that 5-fluoro-1,2,3,4-tetrahydro-isoquinoline was used in replacement of 1,2,4-tetrahydro-isoquinoline in Step 4 of the Example 1-2, Example 3-13: Compound AR00304081 [1024] 14- (3-cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14.3, 0] was synthesized , 0, s] nonadec-7-en-18-yl ester, 1S, 42 ?, SS, XAS, 182?) -8-Trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (Compound AR00304081 ) 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 in replacement of 1, 2, 3, 4 -tetr ahydro-isoquinoline in Step 4 of Example 1-2, MS m / e 807.2 (M ++ l). Example 3-14: Compound ARO 0304082 [1025] 14- (3-Cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14, 3, 0, 04, 6] nonadec-7 was synthesized en-18-yl ester of the acid 15, 42 ?, 6S, XAS, 182?) -l, 3-Dihydro-isoindol-2-carboxylic acid (Compound AR00304082) according to the procedures described in examples 1-2, 2-24 and 3-1, except that 2,3-Dihydro-IH-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro- isoquinoline in Step 4 of Example 1-2, MS m / e 725.2 (M ++ l). Example 3-15: Compound AR00304161 [1026] 4-Cyclopropanesulfonylaminocarbonyl-14- (2-fluoro-ethoxycarbonylamino) -2,1-dioxo-3,16-diaza-tricyclo [14, 3, 0, 4'6] nonadec-7-en was synthesized -18-yl, 42? 6S, 14S, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid ester (Compound AR00304161) 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, in replacement of cyclopentanol. MS m / e 718.1 (M ++ l). Example 3-16: Compound ARO0304162 [1027] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (tetrahydro-furan-3-yloxycarbonylamino) -3,16-diaza-tricyclo [14,3, 0, O4] was synthesized '6] nonadec-7-en-18-yl ester of 15, 42? 6S, 14S, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound ARO0304162) according to the procedures described in Examples 1-2, 2-1 and 3-1, except that tetrahydro-furan-35-ol was used to form the chloroformate reagent in Step 2 of Example 2-1, replacing cyclopentanol. MS m / e 742.1 (M ++ 1). Example 3 - 17: Compound ARO0304163 [1028] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (tetrahydro-furan-32? -yloxycarbonylamino) -3,16-diaza-tricyclo [14,3, 0, 04,6] was synthesized nonadec- 7-en-18-yl ester of the acid 15, 42 ?, SS, XAS, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00304163) according to the procedures described in Examples 1-2 , 2-1 and 3-1, except that tetrahydro-furan-32? -ol was used to form the chloroformate reagent in Step 2 of Example 2-1, in replacement of cyclopentanol. XH NMR (d6-Benzene, 500 MHz): D.10.53 (s, 1 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, 1 H), 5.13 (brs, 1 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, 1 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, 1 H). MS m / e 741.2 (M-1). Example 3-18 Compound AR00311814 [1029] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized acid ester 15, 42 ?, 65, 14S, 182?) -2-Phenylamino-6,7-dihydro-4H-thiazolo [5, 4-c] pyridine-5-carboxylic acid (Compound AR00311814) 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 in replacement of 1, 2, 3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, MS m / e 826.2 (M ++ 1). Example 3-19: Compound AR00311815 [1030] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 0] s-nonadec-7-en-18-yl was synthesized acid ester 15, 42? SS, XAS, 182?) -l-Piperidin-l-ylmethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00311815) according to the procedures described in Examples 1- 2 and 3-1, except that l-Piperidin-l-ylmethyl-l, 2,3,4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1 -2, XH NMR (500 MHz, CD3OD) 0.8.94 (d, 1H), 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, 1H), 3.96 -3.88 (m, 1H), 3.75-3.40 (m, 5H), 3, 14-2.32 (, 7H), 2.05 (dd, 1H), 1.99-1.68 (m, 5H), 1.65-0.95 (m, 24H); MS (POS ESI) m / z 825, 4 (M +). Example 3 -20: Compound AR00312024 [1031] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0, 04.6] nonadec-7 was synthesized -in-18-yl ester of IS, 42 ?, SS, XAS, 1822) -4,4-spirocyclobutyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (Compound AR00312024) 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 in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, 1 H NMR (400 MHz, CD3OD) 0..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, 3H), 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: Compound AR00312025 [1032] 14-Tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04's] nonadec-7-en-18-yl ester was synthesized acid 15, 422, SS, XAS, 1822) -4,4-Dimethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00312025) according to the procedures described in Examples 1-2 and 3-1, except that 4,4-dimethyl-l, 2,3,4-tetrahydro-isoquinoline was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, 1 H NMR (400 MHz , CD3OD) D. 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 ++ l)? Example 3-22: Compound AR00312026 [1033] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized acid ester 15, 4R, 6S, 145, 1822) -4-Methyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00312026) according to the procedures described in Examples 1-2 and 3-1, except that 4-methyl-1, 2, 3, 4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, E NMR (400 MHz, CD30D ) 0. 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: Compound AR00314635 [1034] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (tetrahydro-furan-3-yloxycarbonylamino) -3,16-diaza-tricyclo [14, 3, 0, 04'6] nonadec-7 was synthesized -in-18-yl ester of 15, 422, 6S, XAS, 182?) -4,4-spirocyclobutyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00314635) according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 4,4-spirocyclobutyl-l, 2,3,4-tetrahydro-isoquinoline was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in the Step 4 of Example 1-2, and tetrahydro-furan-32? -ol was used in replacement of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. ^ H NMR (500 MHz, CD2C12) 0.10, 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 (d1H), 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, 4H), 1.80-2.10 (m, 6H), 1 , 24-1.80 (m, 7H), 0.65-1.24 (m, 10H). MS m / z 741.2 (M ++ 1) Example 3-24: Compound AR00314654 [1035] 4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (tetrahydro-furan-35-yloxycarbonylamino) -3,16 was synthesized -diaza-tricyclo [14.3, 0, O4'6] nonadec-7-en-18-yl ester of acid 15, 42 ?, 65, 145, 182?) -4, 4-Dimethyl-3, 4 ~ dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00314654) according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 4,4-dimethyl-l, 2,3,4- tetrahydro-isoquinoline in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and tetrahydro-furan-35-ol was used in replacement of cyclopentanol in Step 2 of Example 2 -1 to form the chloroformate reagent. XH NMR (500 MHz, CD2C12) 0.8.51-8.64 (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, 1H), 4.83 (d, 1H), 4.44-4.72 (m, 3H), 4.17-4.30 (m, 2H), 3.25-3.91 (m, 9H), 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 (, 2H), 0.96-1.15 (m, 3H), 0.65-0.95 (m, 9H). MS m / z 770, 1 (M ++ 1) Example 3 -25: Compound AR00314656 [1036] 14- (3-tert-Butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3 was synthesized, 16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl ester of acid 15, 42 ?, 65, 145, 182?) -4-Methyl-3,4-dihydro -lH-isoquinoline-2-carboxylic acid (Compound AR00314656) 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 in replacement of 1, 2, 3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and t-butyl isocyanate was used in replacement of cyclopentyl isocyanate in Example 2-24, XH NMR (500 MHz , CD2C12) 0.7, 60-7.72 (m, 1H), 7.06-7.48 (m, 4H), 5.73 (dd, 1H), 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: Compound AR00314719 [1037] 14-Tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14] was synthesized. , 3, 0, 0, 6] nonadec-18-yl ester of acid 15, 42 ?, 65, 145, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00314719) according to the procedures described in Examples 1-22 and 3-1, MS m / e 630.2 (M ++ l-100). Example 3-27: Compound AR00320001 [1038] 14- (3-tert-Butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-yl ester of 15, 42 ?, 65, 14S, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320001) according to the procedures described in Examples 1-2, 2-24 and 3-1, except that t-butyl isocyanate was used in replacement of cyclopentyl isocyanate in Example 2-24, MS m / e 725.7 (Ml). Example 3-28: 'Compound AR00320073 [1039] 4-Cyclopropanesulfonylaminocarbonyl-14- (2-fluoro-ethoxycarbonylamino) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'5] nonadec-7 was synthesized en-18-yl ester, 15, 42 ?, SS, XAS, 182?) -l, 3-Dihydro-isoindole-2-carboxylic acid (Compound AR00320073) according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 2,3-dihydro-lH-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and 2-fluoroethanol was used as a replacement. of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. MS m / e 704.0 (M ++ l). Example 3-29: Compound AR00320079 [1040] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (tetrahydro-furan-3-yloxycarbonylamino) -3,16-diaza-tricyclo [14,3, 0, O4'6] nonadec-7 was synthesized -in-18-yl ester of IS, 42 ?, 65, 145, 1822) -1, 3-Dihydro-isoindol-2-carboxylic acid (Compound 7AR00320079) according to the procedures described in examples 1-2, 2- 1 and 3-1, except that 2,3-dihydro-lH-isoindole was used in replacement of 1, 2,3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and tetrahydro-furan was used -32? -ol in replacement of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. MS m / e 728.1 (M ++ l). Example 3-30: Compound AR00320080 [1041] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (tetrahydro-uran-35-yloxycarbonylamino) -3,16-diaza-tricyclo [14,3, 0, 04, s] nonadec-7 was synthesized -in-18-yl ester, 15, 42 ?, SS, XAS, 182?) -l, 3-Dihydro-isoindol-2-carboxylic acid (Compound AR00320080) according to the procedures described in Examples 1-2, 2- 1 and 3-1, except that 2,3-dihydro-lH-isoindole was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and tetrahydrofuran was used. 35-ol in replacement of cyclopentanol in Step 2 of Example 2-1 to form the reactive chloroformate. MS m / e 728.1 (M ++ l). Example 3-31: Compound ARO0320081 [1042] 4-Cyclopropansulinoylaminocarbonyl-2, 15-dioxo-14- (tetrahydro-pyran-4-yloxycarbonylamino) -3,16-diaza-tricyclo [14, 3, 0, O4,6] nonadec-7 was synthesized -in-18-yl ester of the acid 15, 42 ?, SS, XAS, 1822) -1, 3-Dihydro-isoindol-2-carboxylic acid (Compound AR00320081) according to the procedures described in examples 1-2, 2- 1 and 3-1, except that 2,3-dihydro-lH-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and tetrahydro-pyran was used. -4-ol in replacement of cyclopentanol in Step 2 of Example 2-1 to form the reactive chloroformate. MS m / e 742.1 (M ++ 1). Example 3-32 Compound AR00320082 [1043] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (tetrahydro-pyran-4-yloxycarbonylamino) -3,16-diaza-tricyclo [14, 3, 0, O4,6] nonadec-7 was synthesized -in-18-yl ester of 15, 422, 65, 145, 1822) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320082) according to the procedures described in examples 1-2, 2 -1 and 3-1, except that tetrahydro-pyran-4-ol was used in replacement of cyclopentanol in Step 2 of Example 2-1 to form the reactive chloroformate. MS m / e 756.1 (M ++ l). Example 3-33: Compound ARO0320119 [1044] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized en-18-yl ester of acid 15, 42 ?, SS, XAS, 182?) -5-Chloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00320119) according to the procedures described in Examples 1-2 and 3-1, except that 5-chloro-2,3-dihydro-lH-isoindole was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, XH NMR (500 MHz, CD3OD) : .0. 7.36 (s, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.12-7.20 (m, 1H), 6 , 64 (br s, 1H), 5.72-5.64 (m, 1H), 5.41 (s, 1H), 5.14-5.04 (m, 1H), 4.80-4, 62 (m, 2H), 4.61-4.56 (t, 1H), 4.54-4.48 (m, 1H), 4.10 (d, 1H), 3.85 (d, 1H) , 2.90 (m, 1H), 2.65 (br s, 1H), 2.54-2.48 (m, 1H), 2.46-2.32 (m, 2H), 1.91- 1.72 (m, 2H), 1.64-1.56 (m, 2H), 1.56-1.21 (m, 8H), 1.18 (s, 9H), 1.12-1, 05 (m, 1H) 1.00 (m, 1H), 0.94-0.82 (m, 2H). MS m / e 747.9 (M +) Example 3-34: Compound AR00320120 [1045] 14-Tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14.3, 0.04'6] nonadec-7-en-18-yl ester of acid 15, 42 ?, SS, XAS, 182?) -5-Dimethylamino-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound ARO0320120) according to the procedures described in Examples 1-2 and 3-1, except that dimethyl- (1,2,3,4-tetrahydro-isoquinolin-5-yl) -amine (Example l-25a) was used instead. of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, XH NMR (400 MHz, CDC13): 0.10.08 (s, 1H), 7.13-7.05 (m , 1H), 6.88-6.81 (d, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 6.61-6.53 (s, 1H), 5, 71-5.60 (q, 1H), 5.40 (s, 1H), 5.00-4.88 (m, 2H), 4.55-4.38 (m, 3H), 4.24- 4.16 (m, 2H), 3.88-3.77 (d, 1H), 3.64-3.41 (m, 3H), 2.91-2.69 (m, 3H), 2, 61 (s, 6H), 2.53-2.41 (m, 2H), 2.40-2.39 (m, 1H), 2.22-2.11 (m, 1H), 1.89- 1.72 (m, 1H), 1.61-1.22 (m, 10H), 1.18 (s, 9H), 1.09- 0.97 (m, 2H), 0.91-0.76 (m, 2H). MS: 771.1 (M +), 772.1 (M ++ 1), 773.1 (M ++ 2) Example 3-35: Compound ARO0320121 [1046] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl- was synthesized 2, 15-dioxo-3, 16-diaza-tricyclo [14, 3.0, 04.6] nonadec-7-en-18-yl ester of 1S, 42 ?, SS, XAS, 182?) -5 , 6-Dichloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00320121) according to the procedures described in examples 1-2 and 3-1, except that 5,6-Dichloro-2, 3- was used. dihydro-1H-isoindole in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, "? NMR (500 MHz, CD30D): 0.7.52 (s, 1H), 7 , 38 (s, 1H), 6.61 (br s, 1H), 5.72-5.65 (q, 1H), 5.40 (s, 1H), 5.08 (t, 1H), 4 , 78-4.62 (m, 3H), 4.63-4.57 (t, 1H), 4.50 (d, 1H), 4.20 (d, 1H), 3.65 (d, 1H) ), 2.90 (m, 1H), 2.55 (m, 1H), 2.52-2.45 (m, 1H), 2.46-2.31 (m, 2H), 1.91- 1.75 (m, 3H), 1.67-1.60 (, 1H), 1.58-1.25 (m, 8H), 1.18 (s, 9H), 1.12-1.05 (m, 2H), 1.04-0.81 (m, 2H) MS: m / e 781.9 (M +)? Example 3-36: Compound AR 00320220 [1047] 14- (3-tert-Butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3.0, 04'6] nonadec-7 was synthesized en-18-yl ester of acid 15, 42 ?, SS, XAS, 182?) -l, 3-Dihydro-isoindole-2-carboxylic acid (Compound AR00320220) according to the procedures described in examples 1-2, 2-24 and 3-1, except that 2,3-Dihydro-lH-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro- isoquinoline in Step 4 of Example 1-2, and that t-butyl isocyanate was substituted for cyclopentyl isocyanate in Example 2-24, MS m / e 713.1 (M ++ 1). Example 3-37: Compound AR00320222 [1048] 4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- [3- (tetrahydro-furan-3-yl) -ureido] -3,16-diaza-tricyclo [14, 3, 0, 04] was synthesized , e] nonadec-7-en-18-yl ester of IS, 42 ?, SS, XAS, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound ARO0320222) according to the procedures described in Examples 1-2, 2-24 and 3-1, except that 3-isocyanate-tetrahydrofuran was used in replacement of cyclopentyl isocyanate in Example 2-24, MS m / e 740.8 (M ++ l ). Example 3-38: Compound AR00320403 [1049] 14- (3-cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3.0, 04'6] nonadec-7-en was synthesized -18-yl, 42, 65, 145, 182?) -3, 4-Dihydro-lH-isoquinoline-2-carboxylic acid ester (Compound AR00320403) according to the procedures described in Examples 1-2, 2- 24 and 3-1, MS m / e 739.2 (M ++ l). Example 3-39: Compound AR00320446 [1050] 14- (3-tert-Butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14.3.0, 04 '] was synthesized 6] nonadec-7-en-18-yl ester of acid 15, 42 ?, 65, 145, 182?) -5-Chloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00320446) according to the described procedures in Examples 1-2, 2-24 and 3-1, except that 5-chloro-2,3-Dihydro-lH-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that t-butyl isocyanate was used in replacement of cyclopentyl isocyanate in Example 2-24, XH NMR (500 MHz, CD30D): 0.7.35 (s, 1H), 7.28 ( s, 1H), 7.26 (s, 1H), 7.02 (s, 1H), 7.18 (s, 1H), 5.65-5.72 (q, 1H), 5.45 (s) , 1H), 5.06 (t, 1H), 4.74-4.60 (m, 4H), 4.56 (t, 1H), 4.46 (m, 1H), 4.22 (d, 1H), 3.87-3.91 (dd, 1H), 2.86-2.94 (m, 1H), 2.65-2.54 (m, 1H), 2.52-2.45 (m. m, 1H), 2.42-2.34 (m, 2H), 1.92-1.83 (m, 1H), 1.78-1.70 (m, 2H), 1.62-1, 56 (m, 1H), 1.54-3.92 ( , 4H), 1.39-1.23 (m, 7H), 1.12 (s, 9H), 1.02-0.98 (m, 1H), 0.94-0.86 (m, 1H) ). MS: m / e 747, 1 (M +), 749, 1 (M ++ 2) Example 3 -40: Compound AR00320447 [1051] 14- (3-tert-butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl- was synthesized 2, 15-dioxo-3, 16-diaza-tricyclo [14, 3, 0.04's] nonadec-7-en-18-yl ester of 1S, 42? 6S, XAS, 182?) -5, 6 -Dichloro-l, 3-dihydro-isoindol-2-carboxylic acid (Compound AR00320447) according to the procedures described in Examples 1-2, 2-24 and 3-1, except that 5,6-dichloro-2,3 was used -Dihydro-lH-isoindole in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and that t-butyl isocyanate was used in place of cyclopentyl isocyanate in Example 2- 24, MS: m / e 781.1 (M +). 783.1 (M ++ 2) Example 3-41: Compound AR00320506 [1052] 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 0,6] nonadec-7-en-18-yl ester of the acid 15, 42 ?, SS, XAS, 182?) - 1-Piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (Compound AR00320506) according to the procedures described in examples 1-2 , 2-1 and 3-1, except that l-Piperidin-l-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, MS (POS ESI) m / z 837.4 (M +). Example 3-42: Compound AR00320547 [1053] 4-Benzenesulfonylaminocarbonyl-14-tert-butoxycarbonylamino-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, O4'6] nonadec-7-en-18-yl was synthesized acid ester 15, 42 ?, 65, 14S, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320547) according to the procedures described in Examples 1-2 and 3-1, except that benzenesulfonamide was used in replacement of cyclopropylsulfonamide in the coupling step of Example 3-1, MS m / e 762.3 (M-1). Example 3-43: Compound AR00320548 [1054] 14-Tert-butoxycarbonylamino-4- (4-methoxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3, 04.04] was synthesized. 6] nonadec-7-en-18-yl ester of acid 15, 42 ?, SS, XAS, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320548) according to the procedures described in Examples 1-2 and 3-1, except that 4-methoxy-benzenesulfonamide was used in replacement of cyclopropylsulfonamide in the coupling step of Example 3-1, MS m / e 792.3 (Ml). Example 3-44: Compound AR00320549 [1055] 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (toluene-4-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-yl ester of 15, 42 ?, 65, 145, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320549) according to the procedures described in Examples 1-2 and 3-1, except that 4-methyl-benzenesulfonamide was used in replacement of cyclopropylsulfonamide in the coupling step of Example 3-1, MS m / e 776.3 (M ++ 1). Example 3-45: Compound AR00320556 [1056] 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'5] nonadec-7-en-18-yl ester of the 15, 42 ?, 65, 145, 182?) -l-Piperidin-12? -methyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320556) according to the procedures described in Examples 1-2 , 2-1 and 3-1, except that l-Piperidin-12? -methyl-l, 2, 3, 4-tetrahydro-isoquinoline was used in replacement of 1,2,3,4-tetrahydro-isoquinoline in Step 4, Example 1-2, XH NMR (500 MHz, CD3OD) 0.8.99 (br s, 1H), 7.34 -7.13 (m, 6H), 5.75-5.65 (m, 2H) ), 5.44 (br s, 1H), 5.06 (t, 1H), 4.60 (t, 1H), 4.51 (d, 1H), 4.44 - 4.16 (m, 2H) ), 4.12 -3.97 (m, 2H), 3.86 (d, 1H), 3.75-3.38 (m, 2H), 3.07 (t, 2H), 2.96 - 2.86 (, 1H), 2.78 (d, 1H), 2.66 (br s, 1H), 2.56-2.26 (m, 3H), 2.06 (d, 1H), 1 , 99-1.66 (m, 10H), 1.65-1.21 (m, 18H), 1.15-0.95 (m, 3H); MS (ESI POS) m / z 837.4 (M +). Example 3-46: Compound ARO0320557 [1057] 14-Cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl ester of the 15, 42? SS, XAS, 182?) -l-Piperidin-15-ylmethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320557) according to the procedures described in examples 1-2 , 2-1 and 3-1, except that l-Piperidin-15-ylmethyl-l, 2, 3, 4-tetrahydro-isoquinoline was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2, ^ H NMR (500 MHz, CD3OD) D.7.32-7.14 (m, 6H), 6.87 (br s, 1H), 5.72-5.60 (m, 2H), 5.47-5.39 (m, 1H), 5.11 (br s, 1H), 4.58 (t, 1H) 4.53 - 3.86 (m, 8H), 3.67 - 3.40 (m, 2H), 3.08 - 2.85 (m, 1H), 2.78 (d, 1H), 2.65-2.24 (m, 4H), 2.10-2.22 (m, 27H), 1.19 (dt, 1H), 1.10-1.02 (m, 2H), 1.01-0.93 (m, 1H), 0.89 (q, 1H); MS (ESI POS) m / z 837.4 (M +). Example 3-47: Compound JAR00320574 [1058] 14- (3-cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] was synthesized nonadec-7-en-18-yl ester of 15, 42 ?, 65, 14S, 182?) -5-Chloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00320574) according to the procedures described in Examples 1-2, 2-24 and 3-1, except that 5-chloro-2,3-Dihydro-lH-isoindole was used in replacement of 1, 2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, MS -. m / e 759.1 (M +), 761.1 (M ++ 2) Example 3 -48; Compound AR00320575 [1059] 14- (3-cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en was synthesized -18-yl ester of the acid 15, 42 ?, 65, 145, 182?) -5,6-Dichloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00320575) according to the procedures described in the? -2, 2-24 and 3-1, except that 5,6-dichloro-2,3-Dihydro-lH-isoindole was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline in Step 4 of? Example 1-2, MS: m / e 793.1 (M +)? Example 3-49: Compound AR00320578 [1060] 4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (2,2,2-trifluoro-ethoxycarbonylamino) -3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec was synthesized -7-en-18-yl ester of the acid 15, 42? 6S, 14S, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320578) according to the procedures described in Examples 1- 2, 2-1 and 3-1, except that 2,2, 2-trifluoro-ethanol was used in replacement of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. MS m / e 754, 0 (M ++ l). Example 3-50: Compound AR00320579 [1061] 4-Cyclopropanesulfonylaminocarbonyl-14- (2,2-difluoro-ethoxycarbonylamino) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0, 04, 6] nonadec-7-en-18-yl ester of the acid 15, 42 ?, 65, 145, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320579) according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 2,2-Difluoro-ethanol was used in replacement of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. MS m / e 736.0 (M ++ l). Example 3-51: Compound AR00320580 [1062] 4-Cyclopropanesulfonylaminocarbonyl-14- (2-fluoro-l-fluoromethyl-ethoxycarbonylamino) -2,15-dioxo-3,16-diaza-tricyclo [14,3, O, O 4,6] nonadec was synthesized -7-en-18-yl ester of the acid 15, 42 ?, SS, XAS, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320580) according to the procedures described in Examples 1- 2, 2-1 and 3-1, except that 1,3-Difluoro-propan-2-ol was used in replacement of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. MS m / e 750.1 (M ++ l). Example 3-52: Compound AR00320581 [1063] 4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (2,2,2-trifluoro-1-methyl-ethoxycarbonylamino) -3,16-diaza-tricyclo [14,3, 0, O4] was synthesized , 6] nonadec-7-en-18-yl ester of acid 15, 42 ?, SS, XAS, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320581) according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 1, 1, 1-Trifluoro-propan-2-ol was used in replacement of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. MS m / e 768.1 (M ++ l). Example 3-53: Compound AR00320582 [1064] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (2,2,2-trifluoro-1,1-dimethyl-ethoxycarbonylamino) -3,16-diaza-tricyclo [ 14,3, 0, 04, s] nonadec-7-en-18-yl ester of acid 15, 42? 6S, XAS, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00320582) according to the procedures described in Examples 1-2, 2-1 and 3-1, except that 1, 1, 1-Trifluoro-2-methyl-propan-2-ol was used in replacement of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent. MS m / e 782.1 (M ++ 1). Example 3-54: Compound AR00324375 [1065] 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04,6] nonadec-18-yl ester of acid 15, 42 was synthesized ?, SS, 14S, 182?) -3,4-Dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00324375) according to the procedures described in examples 1-22, 2-1 and 3-1, MS m / e 740.5 (M ++ l). Example 3-55 Compound AR00334191 [1066] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, 6] nonadec-7-en-18-yl was synthesized acid ester 15, 422, 65, 145, 1822) -4-Fluoro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00334191) according to the procedures described in examples 1-2 and 3-1, except that in Step 4 of Example 1-2, 4-Fluoro-2, 3-dihydro-lH-isoindole was used as substitution for 1,2,3,4-tetrahydro-isoquinoline. X H NMR (500 MHz, d6-acetone) D.10.70 (br s, 1 H), 8.34 (d, 1 H), 7.39-7.33 (m, 1 H), 7.20 (d, 1 H), 7.10-7.02 (m, 2 H), 6.13 (d, 1 H), 5.70 (q, 1 H), 5.44 (br s, 1 H) ), 4.99 (t, 1H), 4.78-4.59 (m, 5 H), 4.18-4.08 (m, 1 H), 3.88-3.81 (m, 1) H), 2.86 - 2.78 (m, 3 H), 2.71 - 2.60 (m, 1 H), 2.52 - 2.35 (m, 3 H), 1.92 - 1 , 81 (m, 2 H), 1.75 (t, 1 H), 1.61-1.14 (m, 17 H), 1.04-0.95 (m, 2 H); - APCI MS m / z 730.4 (M-l).

Example 3 -55a [1067] 4-Fluoro-2,3-dihydro-lH-isoindole used in Example 3-55 was prepared in the following two steps: [1068] Step 1:

[1069] The best result is obtained when the starting material is poured 0.5 M in formamide and heated at 125 ° C for 1 to 5 h depending on the scale. The starting material is not soluble in formamide until the temperature is > 60 ° C. At the end of the reaction that is monitored by LC / MS (apcinag), the heat is removed and the volume of the water reaction is added 3 times. The reaction can then be warmed to room temperature and stirred until a pale yellow precipitate forms. The yellow solid product was filtered and washed with water before being dried overnight to give yields between 70-77%. [1070] Step 2:

[1071] 4 equivalents of 1 M BH3-THF were added to the starting material in a round bottom flask by dripping using an additional funnel to form a golden solution which upon heating and stirring turns copper. The reaction was then heated to reflux for 18 h. [1072] The reaction is then cooled to room temperature (rt) and then to 0 ° C in an ice bath. 4 equivalents of MeOH are added dropwise and the ice bath is removed, then the reaction can be warmed to room temperature. The color of the reaction darkens during this heating process. Then, 6 N HCl was added dropwise at room temperature until paper f shows the reaction to be acidic and the reaction was refluxed (63 ° C) for 1 h. The reaction was then cooled to room temperature. At this point the reaction was concentrated and washed with Et20 (2x) and DCM (2x). The aqueous layer is then brought to f = 11 with NaOH pellets. More water was added and the aqueous layer was extracted with ether (4x). The combined extracts were dried over α2S0 and concentrated to give a light tan oil product, which was used directly. The recovery of the dough is always slightly higher than the theoretical but the material is used raw like this to give >; 80% performance in the next step. Example 3-56 Compound AR00333833 [1073] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04, 6] nonadec-18- was synthesized 15, 422, 65, 14S, 1822) -l, 3-Dihydro-isoindole-2-carboxylic acid ester (Compound AR00333833) according to Examples 1-2 and 3-1, except that in the steps of Example 1 -2 analogue, 2, 3-Dihydro-1H-isoindole was used in Step 4 and the ring closure metathesis product 10 of Step 3 of Example 1-2 was further reduced with H2 / Rh-Al03 before the next step coupling according to a method of the literature (WO 0059929, pp. 76-77). XH NMR (400 MHz, CD3SOCD3) 0.11.11 (s, 1H), 8.89 (s, 1H), 7.16-7.29 (m, 4H), 6.95 (d, 1H), 5, 25 (bs, 1H), 4.50-4.60 (bs, 4H), 4.40 (dd, 1H), 4.23 (d, 1H), 3.93 (m, 1H), 3.68 (d, 1H), 2.92 (m, 1H), 2.32 (dd, 1H), 2.11 (m.1H), 1.40-1.68 (m, 2H), 0.92- 1.40 (m, 19H). MS m / z 717.0 (M + 1). Example 3-57 Compound AR00334286 [1074] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14.3.0, 04.6] nonadec-7 was synthesized en-18-yl ester of the acid 15, 42 ?, SS, XAS, 182?) -5-Amino-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00334286) according to the procedures shown in the following scheme .

[1075] Step 1, Synthesis of the ethyl ester of the acid (15, 42? SS, XAS, 182?) -14-tert-Butoxycarbonylamino-2, 15-dioxo-18-triisopropylsilanyloxy-3,16-diaza-tricyclo [ 14.3, 0, O4.6] nonadec-7-en-4-carboxylic acid. To a solution of the free hydroxymalecrocycle intermediate (compound 10 of Example 1-2, 5.0 g, 10.1 mmol) in DriSolve DCM (30 ml) was added imidazole (827 mg, 1.2 equiv) and TIPSC1 (2, 15 g, 1.1 equiv). The reaction mixture was stirred at room temperature for 18 h. TLC (5% MeOH-DCM) shows a considerable amount of SM still remaining. More imidazole (410 mg), TIPSCl (1 g) and DMAP were added to this reaction mixture. (121 mg). After stirring overnight, the reaction mixture shows a small amount of SM left over. The reaction mixture was washed with water (2 x 25 ml). The combined aqueous layers were again washed with DCM (25 ml). The combined aqueous layers were dried and concentrated to give a light yellowish oil. The crude material was used in the next step without further purification. [1076] Step 2, Synthesis of the acid (15, 42? 6S, XAS, 182?) -14-tert-Butoxycarbonylamino-2, 15-dioxo-18-triisopropylsilanyloxy-3,16-diaza-tricyclo [14.3] , 0, O4'6] nonadec-7-en-4-carboxylic acid. First, the SM ester from Step 1 was dissolved in a mixture of THF (20 ml) and MeOH (20 ml). Then LiOH-H0 (2.1 g, 50 mmol) in water (10 ml) was added to this mixture and stirred for 12 h at room temperature. LCMS showed the complete reaction. The reaction mixture was concentrated in almost dryness. The solid residue was then dissolved in 50 mL water, acidified with 2N HCl, and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO and concentrated. The crude material was used in the next step without further purification. [1077] Step 3, Synthesis of tert-butyl ester of acid (15, 42? 6S, XAS, 182?) - (4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-18-triisopropylsilanyloxy-3,16-diaza-tricyclo [14, 3, 0, 04'6] nonadec-7-en-14-yl) -carbamic. First, the SM acid from Step 2 above was dissolved in 25 mL of DriSolvel, 2-dichloroethane. CDI (2.2 g, 13.8 mmol) was added in one portion to this solution and the reaction was stirred 50 ° C for 3h. Then cyclopropyl sulfonamide was added (3.3 g, 27.5 mmol) to the reaction, followed by DBU (4.2 g, 27.5 mmol), and the reaction was stirred at 50 ° C for 4 h.

LCMS showed the complete reaction. Then, the reaction mixture was washed with water (2 x 50 mL), and the organic layer was dried (anhydrous Na 2 SO 4) and concentrated. The crude material was used in the next step without further purification. [1078] Step 4, Synthesis of tert-butyl ester of the acid (15, 42? SS, XAS, 182?) - (4-Cyclopropanesulfonylaminocarbonyl-18-hydroxy-2, 15-dioxo-3, 16-diaza-tricyclo [14,3, 0, 0, s] nonadec-7-en-14-yl) -carbamic. First the crude product from Step 3 above was dissolved in THF (40 mL). Then TBAF (3.6 g, 13.7 mmol, 1.5 equiv) was added to this solution and stirred for 2 h at room temperature. TLC showed the completion of the reaction. The reaction mixture was then concentrated to dryness, redissolved in EtOAc and washed with water. The organic layer was dried (anhydrous Na 2 SO 4) and concentrated. For purification, the crude product was dissolved in DCM (50 L) and washed with a 3N? AOH solution. The aqueous layer was neutralized with 2? HCl and extracted with DCM (2 x 25 mL). The combined organic layers were dried (Na2SO4) and concentrated to give a pure white solid (2.4 g, 46%). MS m / z (APCI +) 469.1 (MH + -Boc). [1079] Step 5, Synthesis of 14-tert -butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14,3, 0, 04'5] nonadec-7-en-18- The ester of the acid (15, 42? 6S, XAS, 182?) -5-Amino-1,3-dihydro-isoindole-2-carboxylic acid (Compound AR00334286). To a DCE solution of the product from Step 4 above (19 mg, 33 mmol) was added CDI (7 mg, 1.3 equiv), and the reaction was stirred at room temperature overnight. LCMS indicates complete reaction. Then 2, 3-Dihydro-lH-isoindol-5-ylamine (18 mg, 4 equiv) was added. After 4 h at room temperature, LCMS showed the complete reaction. The reaction mixture was loaded directly onto silica gel and eluted with 1 to 5% methanol / DCM. The pure product was isolated as a white solid. MS m / z (APCI +): 629.2 (MH + -Boc). Example 3-58 Compound AR00334385 [1080] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14.3.0, 04.6] nonadec-7-en-18-yl ester of the 1S, 42? 6S, 14S, 182?) -4-Amino-1,3-dihydro-isoindole-2-carboxylic acid (Compound AR00334385) was synthesized in a manner similar to that described in Example 3-57, substituting 2 , 3-Dihydro-lH-isoindol-5-ylamine in Step 5 with 2,3-Dihydro-lH-isoindol-4-ylamine. In addition, the purification of the final product was carried out in the reverse phase of column chromatography (eluent = 5 to 100% acetonitrile in water), yielding the final product as a beige foamy solid. MS m / z (APCI-): 728.2 (M +). Example 3-59 Compound AR00340479 [1081] 14-tert-Butoxycarbonylamino-2, 15-dioxo-4-trifluoromethanesulfonylaminocarbonyl-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized 15, 42? SS, XAS, 182?) -l, 3-Dihydro-isoindole-2-carboxylic acid ester (Compound AR00340479) according to the procedures described in Example 3-6, except that trifluoromethanesulfonamide was used in replacement of cyclopropanesulfonamide. X H NMR (400 MHz, d6-Acetone): 0. 7.98 (brs, 1 H), 7.23-7.35 (m, 4 H), 6.13 (brd, 1 H), 5.70 (q, 1 H), 5.44 (brs 1 H), 4.98-5.02 (m, 1 H), 4.61-4.72 (m, 5 H), 4.49 (d, 1 H), 4.16-4.18 (m, 1 H), 3.87-3.90 (m, 1 H), 2.57-2.59 (m, 2 H), 2.38- 2.51 (m, 2 H), 1.82-1.92 (m, 2 H), 1.72-1.79 (m, 2 H), 1.21-1.59 (m, 8 H) ), 1.21 (s, 9 H). MS m / z (APCI-): 741.1 (M +). Example 3-60 Compound AR00365387 [1082] 14-Tert-butoxycarbonylamino-4- (4-carboxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-yl ester of acid 15, 42 ?, SS, XAS, 182?) -l, 3-Dihydro-isoindol-2-carboxylic acid (Compound ARO0365387) according to the procedures described in Example 3-6, except that 4-sulfamoyl-benzoic acid was used in replacement of cyclopropanesulfonamide. MS m / z (APCI-): 792.3 (M-1). Example 3 -61 Compound AR00365388 [1083] 14-Tert-butoxycarbonylamino-4- (5-carboxy-2-chloro-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 0,6 was synthesized ] nonadec-7-en-18-yl ester of IS, 42? 6S, 145, 182?) -1, 3-Di- hydroxyisoindole-2-carboxylic acid (Compound AR00365388) according to the procedures described in Example 3-6, except that 4-chloro-3-sulfamoyl-benzoic acid was used in replacement of cyclopropanesulfonamide. MS m / z (APCI-): 826.2 (M-2). EXAMPLE 3-62 Compound AR00365425 [1084] 14-tert-Butoxycarbonylamino-4- (3-carboxy-4-methoxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0] was synthesized , 04'6] nonadec-7-en-18-yl ester of acid 15, 42? 6S, XAS, 1822) -1,3-Dihydro-isoindole-2-carboxylic acid (Compound AR00365425) according to the procedures described in Example 3-6, except that 2-methoxy-5-sulfamoyl-benzoic acid was used in replacement of cyclopropanesulfonamide. MS m / z (APCI-): 822.3 (M-1).

Compound ARO0365426 [1085] 14-tert-Butoxycarbonylamino-4- (5-carboxy-4-chloro-2-fluoro-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3.0] was synthesized , 0, s] nonadec-7-en-18-yl ester of the acid 15, 42? 6S, XAS, 1822) -1,3-Dihydro-isoindole-2-carboxylic acid (Compound AR00365426) according to the procedures described in Example 3-6, except that 2-chloro-4-fluoro-5-sulfamoyl-benzoic acid was used in replacement of cyclopropanesulfonamide. MS m / z (APCI-): 844.2 (M-2).

Compound AR00365572 [1086] 14-tert-Butoxycarbonylamino-4- (4-dimethylamino-benzenesulfonylaminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, s] nonadec-7 was synthesized -in-18-yl ester of acid 15, 422, SS, XAS, 182?) -1, 3-Dihydro-isoindol-2-carboxylic acid (Compound ARO0365572) according to the procedures described in Example 3-6, except that 4-dimethylamino-benzenesulfonamide was used in replacement of cyclopropanesulfonamide. MS m / z (APCI-): 791.3 (M-1).

Compound ARO0333801 [1087] 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (propan-2-sulphonylaminocarbonyl) -3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-yl acid ester 15, 42 ?, 65, 145, 182?) -l, 3-Dihydro-isoindole-2-carboxylic acid (Compound AR00333801) according to the procedures described in Example 3-6, except that propan-2-sulionic acid amide was used to replace cyclopropansulonamide. MS m / z (APCI-): 714.4 (M-1).

Compound AR00333802 [1088] 4-Benzenesulionylaminocarbonyl-14-tert-butoxycarbonylamino-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized 15, 42? 6S, 145, 18R) -1,3-Dihydro-isoindole-2-carboxylic acid ester (Compound JAR00333802) according to the procedures described in Example 3-6, except that benzenesulfonamide was used to replace cyclopropanesulfonamide. MS m / z (APCI-): 748.3 (M-1).

Example 3-67 Compound AR00333803

[1089] 14-tert-Butoxycarbonylamino-4-methanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diazatricyclo [14, 3, 0, 04, s] nonadec-7-en-18-yl ester of 15, 42 ?, 65, 14S, 182?) -l, 3-Dihydro-isoindol-2-carboxylic acid (Compound AR00333803) according to the procedures described in Example 3-6, except that methanesulfonamide was used in replacement of cyclopropanesulfonamide . MS m / z (APCI-): 686.4 (M-1).

Compound AR00334188 [1090] 14-Tert-butoxycarbonylamino-4- (5-chloro-thiophene-2-sulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04'5 was synthesized ] nonadec-7-en-18-yl, 42, 65, 145, 182?) -1, 3-Dihydro-isoindol-2-carboxylic acid ester (Compound AR00334188) according to the procedures described in Example 3- 6, except that 5-chloro-thiophene-2-sulfonic acid amide was used in replacement of cyclopropanesulfonamide. MS m / z (APCI-): 788.3 (M-2).

Compound AR00334247 [1091] was synthesized 4- (5-acetylamino- [1,3,4] thiadiazol-2-sulfonylaminocarbonyl) -14-tert-butoxycarbonylamino-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, O4'6] nonadec-7-en-18-yl ester, S, 4R, 6S, 14S, 18R) -1,3-Dihydro-isoindole-2-carboxylic acid (Compound AR00334247) according to the described procedures in Example 3-6, except that N- (5-sulfamoyl- [1,3,4] thiadiazol-2-yl) -acetamide was used in replacement of cyclopropanesulfonamide. XR NMR (400 MHz, d6-Acetone) .- D. 7.24-7.31 (m, 4 H), 5.96 (brd, 1 H), 5.42 (brs 1 H), 5.28 (m, 1 H), 5.15 (m, 1 H), 4.68 (m, 6 H), 4.49 (m, 1 H), 4.14 (m, 2 H), 2.60 (m, 1 H), 2.25-2.36 (m, 5 H), 1.70-2.19 (m, 8 H), 1.19-1.48 (m, 4 H), 1 , 30 (s, 9 H). MS m / z (APCI-): 813.3 (M-1).

Compound AR00334248 [1092] 14-tert-butoxycarbonylamino-4- (4-cyano-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-yl, 4R, 6S, 14S, 18R) -l, 3-Dihydro-isoindol-2-carboxylic acid ester (Compound AR00334248) according to the procedures described in Example 3-6, except that -cyano-benzenesulfonamide was used in replacement of cyclopropanesulfonamide. X H NMR (400 MHz, ds-Acetone): 0. 11.32 (brs, 1 H), 8.36 (brs, 1 H), 8.04-8.15 (m, 4 H), 7.22 -7.35 (m, 4 H), 6.12 (brd, 1 H), 5.47 (brs 1 H), 5.28 (q, 1 H), 4.60-4.72 (m, 5 H), 4.48-4.54 (m, 2 H), 4.14-4.17 (m, 1 H), 3.86-3.90 (m, 1 H), 2.37- 2.52 (m, 4 H), 1.72-1.85 (m, 2 H), 1.59-1.62 (m, 1 H), 1.20-1.55 (m, 8 H) ), 1.20 (s, 9 H). MS m / z (APCI-): 773.3 (M-1).

Example 3-71 Compound AR00334249 [1093] 14-Tert-butoxycarbonylamino-4- (4-nitro-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14,3, 0, O4 'was synthesized. 6] nonadec-7-en-18-yl ester of IS, 4R, 6S, 14S, 18R) -1,3-Dihydro-isoindol-2-carboxylic acid (Compound AR00334249) according to the procedures described in Example 3-6 , except that 4-nitro-benzenesulfonamide was used in replacement of cyclopropanesulfonamide. 1 H NMR (400 MHz, d6-Acetone): 0. 11.39 (brs, 1 H), 8.46 (d, 2 H), 8.35 (brs, 1 H), 8.23 (d, 2 H), 7.23-7.36 (m, 4 H), 6.11 (brd, 1 H), 5.47 (brs 1 H), 5.23 (q, 1 H), 4.59- 4.72 (m, 5 H), 4.49-4.54 (m, 2 H), 4.15 (m, 1 H), 3.86-3.90 (m, 1 H), 2, 40-2.53 (m, 4 H), 1.72-1.85 (m, 2 H), 1.59-1.62 (m, 1 H), 1.20-1.56 (m, 8 H), 1.20 (s, 9 H). MS m / z (APCI-): 793.3 (M-1).

Compound AR00334250 [1094] 14- Tert-butoxycarbonylamino-4- (4-chloro-benzenesulfonylaminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14, 3, 0, O4,6] nonadec-7 was synthesized -in-18-yl ester of IS, 4R, 6S, 14S, 18R) -1, 3-Dihydro-isoindol-2-carboxylic acid (Compound AR00334250) was synthesized according to the procedures described in Example 3-6, except that 4-chloro-benzenesulfonamide was used in replacement of cyclopropanesulfonamide. 1 HOUR NMR (400 MHz, ds-Acetone): 0.11.16 (brs, 1 H), 8.34 (brs, 1 H), 7.96 (d, 2 H), 7.65 (d, 2 H) ), 7.22-7.36 (m, 4 H), 6.13 (brd, 1 H), 5.46 (brs 1 H), 5.27 (q, 1 H), 4.59-4.71 (m, 5) H), 4.48-4.54 (m, 2 H), 4.14-4.18 (m, 1 H), 3.87-3.89 (m, 1 H), 2.35-2.52 (m, 4 H), 1.75-1.85 (m, 2 H), 1.58-1.61 (m, 1 H), 1.20-1.53 (m, 8 H), 1.20 (s, 9 H). MS m / z (APCI-): 782.3 (M-2).

Compound AR00334341 [1095] 14-tert-Butoxycarbonylamino-4- (4-methoxy-benzenesulfonylaminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-yl ester, S, 4R, 6S, 14S, 18R) -l, 3-Dihydro-isoindol-2-carboxylic acid (Compound AR00334341) according to the procedures described in Example 3-6, except that 4-methoxy-benzenesulfonamide was used in replacement of cyclopropanesulfonamide. X H NMR (400 MHz, d6-Acetone): 0. 8.26 (brs, 1 H), 7.84 (d, 2 H), 7.19-7.32 (m, 4 H), 7.05 (d, 2 H), 6.08 (brd, 1 H), 5.43 (brs) 1 H), 5.25 (q, 1 H), 4.55-4.67 (m, 5 H), 4.48 (q, 2 H), 4.10-4.14 (m, 1 H) ), 3.87 (s, 3 H), 3.82-3.87 (m, 1H), 2.29-2.47 (m, 4 H), 1.74-1.84 (m, 2 H), 1.51-1.55 (m, 1 H), 1.37-1.47 (m, 4 H), 1 20-1.32 (m, 5 H), 1.17 (s, 9 H). MS m / z (APCI-): 779.1 (M-1).

Compound AR00364266 [1096] 14-tert-Butoxycarbonylamino-4- (5-carboxy-l-methyl-lH-pyrrole-2-sulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3] was synthesized , 0, 04'6] nonadec-7-en-18-yl ester of IS, 4R, 6S, 14S, 18R) -1,3-Dihydro-isoindol-2-carboxylic acid (Compound AR00364266) according to the procedures described in Example 3-6, except that 1-methyl-5-sulfamoyl-1H-pyrrole-2-carboxylic acid was used in replacement of cyclopropanesulfonamide. XH NMR (400 MHz, d6-Acetone): D. 10.84 (brs, 1 H), 8.27 (brs, 1 H), 7.59 (d, 1 H), 7.24-7.35 (m, 4 H), 7.18 (d, 1 H), 6.10 (brd, 1 H), 5.50 (br, 1 H), 5.46 (m 1 H), 5.36 (q, 1 H) ), 4.59-4.71 (m, 6 H), 4.48 (d, 1 H), 4.13- 4.17 (m, 1 H), 4.00 (s, 3 H), 3.85-3.89 (m, 1H), 2.35-2.59 (m, 4 H), 1.71-1.90 (m, 2 H), 1.62-1.65 (m) , 1 H), 1.20-1.51 (m, 8 H), 1.20 (s, 9 H). MS m / z (APCI-): 795.4 (M-1).

Compound AR00365427 [1097] 14-tert-Butoxycarbonylamino-2, 15-dioxo-4- (thiophene-2-sulphonylaminocarbonyl) -3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-yl, 4R, 6S, 14S, 18R) -1, 3-Dihydro-isoindol-2-carboxylic acid ester (Compound AR00365427) according to the procedures described in Example 3-6, except that used thiophene-2-sulfonic acid amide in replacement of cyclopropanesulfonamide. MS m / z (APCI-): 754.4 (M-1).

Example 3-76 Compound AR00334339 [1098] 14-tert-butoxycarbonyl mino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diazatricyclo [14,3, 0, 04'6] nonadec-7-en-18- was synthesized IL, 4R, 6S, Idel 4S, 18R) -6-Methoxy-1-methoxymethyl-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid ester (Compound AR00334339) according to the procedures described in the Example 3-6, except that 6-methoxy-1-methoxymethyl-1,2,4,4-tetrahydro-isoquinoline (for synthesis see Example 3-76a) was used in replacement for 2,3-dihydro-1H-isoindole. MS m / z (APCI-): 800.5 (M-1).

[1099] The synthesis of 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride is shown in the following scheme: Step l Step 2 [1100] Step 1: Synthesis of 2-chloro- N- [2- (3-methoxyphenyl) -ethyl] -acetamide. The amine, 2- (3-methoxy-phenyl) -ethylamine, was taken as a 0.6 M solution in DCM, followed by addition of TEA (2 eq.). The mixture was cooled in an IPA / dry ice bath. When the reaction temperature reached -60 ° C, a solution of chloroacetyl chloride in DCM (2.6 M) was added dropwise so that the temperature was maintained below -60 ° C. After the addition was complete, the reaction was stirred at -60 ° C for 1 h. The reaction was then heated to -20 ° C and filtered on GF filter paper to remove part of the TEA-HCl salt. The filtrate was warmed to room temperature and transferred to a separatory funnel where it was washed with 1 N HCl (2x) and brine. The organic layer was dried over MgSO4 and concentrated to give dark purple solid. This crude product was used directly in the next step without further purification. [1101] Step 2: Synthesis of 1-chloromethyl-6-methoxy-3 chloride, 4-dihydro-isoquinolinio. Two equiv. Were boiled. of P05 (12.9 g) in xylenes (180 mL) as 0.25 M solution. The crude product from Step 1 above was also boiled first in xylenes (45 mL) to prepare a 0.5 M solution and was added dropwise through an addition funnel to the P205 solution. The mixture was stirred and heated to reflux per lh. The reaction was then cooled to room temperature and the xylenes were decanted at this point. The vessel was then placed in ice water and ice, water, ΔtOAc, and finally 4 M NaOH were added carefully until f >; 12, Reaction was maintained at < 25 ° C until reaching f = 12. The reaction was then extracted with? TOAc (3x) The combined organic extracts were dried over MgSO4 and concentrated to obtain a dark solution.

This was cooled in an ice bath while adding 400 mL of cold t20 followed by 100 mL of cold HCl /? t20. A precipitate formed and filtered, washing with? T20. The solid was immediately placed on high vacuum for two h to obtain the desired product as a colored foamy solid. This crude product was used directly in the next step without further purification. [1102] Step 3: Synthesis of 6-Methoxy-l-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride. The crude product from Step 2 above was added in one portion to T? A (5 equiv.) and Nal (0.1 equiv.) in MeOH at 0 ° C. Then 2.2 equiv. of NaOMe and the homogenous reaction turned cloudy.

The reaction was then stirred at 0 ° C for 1 h. LC / MS showed imine with completely free base. [1103] The reaction was then cooled again to 0 ° C in an ice bath and NaBH4 (1.5 equiv.) Was carefully added. The reaction was heated again to room temperature and stirred for 2 h. After the reaction was complete monitored by LC / MS, it was concentrated, treated with 1 N NaOH and extracted with? TOAc. The organic layer was dried over MgSO and concentrated. The resulting residue was taken up in MeOH and cooled in an ice bath. HCl gas was bubbled through it for 10 min. The reaction mixture was concentrated and redissolved in MeOH. After concentrating for the second time the reaction was placed under high vacuum overnight. The crude material was then triturated with? tOAc (3x) to obtain the product in the form of a foamy, brownish solid which rested in high vacuum overnight. This crude product was used directly in the next step without further purification. MS m / z (POSESI): 208.1 (MH +).

Example 3-77 Compound ARO0365193 [1104] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14, 3.0, 04.6] nonadec-7-en-18-yl was synthesized ester of IS, 4R, 6S, 14S, 18R) -5-Fluoro-l-methoxymethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00365193) according to the procedures described in Example 3-76 , except that 5-fluoro-l-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride (for synthesis see Example 3 -77a) was used to replace 6-methoxy-1-methoxymethyl-1-chloride, 2, 3, 4-tetrahydro-isoquinolinium XH NMR (500 MHz, CD3OD) 0.8.99 - 8.91 (m, 1H), 7.23 - 7.15 (m, 1H), 7.13 - 6.99 (m, 2H), 6.99-6.90 (m, 1H), 5.68 (q, 1H), 5.41 (br s, 1H), 5.35-5.21 (m, 1H) , 5.06 (t, 1H), 4.60-4.31 (m, 3H), 4.30-4.05 (m, 3H), 3.96-3.81 (m, 1H), 3 , 80- 3.56 (m, 3H), 3.35 (d, 3H), 2.98-2.30 (m, 9H), 1.91-1.68 (m, 4H), 1.64 - 0.95 (m, 16H); MS (APCI-) m / z 788.3 (M-1).

Example 3 -77a [1105] Synthesis of 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was performed in a manner similar to that shown in Example 3-76a, except that in Step 1, 2- (2-Fluoro-phenyl) -ethylamine was used in replacement of 2- (3-methoxy-phenyl) -ethylamine.

Compound ARO0365438 [1106] 14-tert-Butoxycarbonylamino-4- (4-carboxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04'6] nonadec-7 was synthesized -in-18-yl, 4R, 6S, 14S, 18R) -4-Fluoro-l, 3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00365438) according to the procedures described in Example 3-55, except that 4-sulfamoyl-benzoic acid was used in replacement of cyclopropanesulfonamide. XH-NMR (500 MHz, CD3OD) 0.8.92 (d, 1H), 8.25-8.19 (m, 1H), 8.15 (d, 2H), 8.04 (d, 2H), 7 , 36-7.27 (m, 1H), 7.14 (d, 1H), 7.05-6.95 (m, 2H), 5.42 (br s, 1H), 5.26 (q, 1H), 4.82 - 4.50 (m, 8H), 4.10 - 4.00 (m, 1H), 3.85 (d, 1H), 3.75 - 3.69 (m, 1H) , 2.60-2.39 (m, 4H), 2.26 (p, 2H), 1.89-1.84 (m, 1H), 1.81-1.05 (m, 15H); MS (APCI-): m / z 810.2 (M-1).

Compound ARO0340303 [1107] Synthesis of 14-. { 2-Cyclohexyl-2- [(pyrazine-2-carbonyl) -amino] -acetylamino} 4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04'6] nonadec-7-en-18-yl ester of 1S, 4R, 6S, 14S, 18R ) -4-Fluoro-l, 3-dihydro-isoindol-2-carboxylic acid (Compound AR00340303).

[1108] The starting material (AR00334191, Example 3-55, 10 mg, 13.7 mmol) was dissolved in 1 mL of 50% TFA (DCM) and stirred at room temperature for 1 h. The reaction mixture was then concentrated to dryness, taken up in acetonitrile and concentrated again. The previous process was repeated once more to eliminate any excess TFA. The resulting solid residue was then dissolved in DCE (137 OL), cooled to 0 ° C in an ice bath, followed by addition of the amino acid, cyclohexyl- [(pyrazin-2-carbonyl) -amino] -acetic acid (1 , 05 equiv), HATU (10 mg) and DIEA (4 drops). The mixture was allowed to slowly warm to room temperature and stir overnight. To work the reaction mixture was loaded directly onto a C-18 column and purified with reverse phase column chromatography, obtaining the desired compound as a white solid. MS (APCI-): m / z 876.1 (M-1).

Compound ARO0340122 [1109] 14- (2-Acetylamino-2-cyclohexyl-acetylamino) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, O4,6] nonadec was synthesized -7-en-18-yl ester, 1S, 4R, 6S, 14S, 18R) -4-Fluoro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00340122) according to the procedures described in Example 3 -79, except that acetylamino-cyclohexyl-acetic acid was used to replace cyclohexyl- [(pyrazine-2-carbonyl) -amino] -acetic acid. MS (APCI-): m / z 811.3 (M-1).

Compound AR00340156 [1110] Synthesis of 4-cyclopropanesulfonylaminocarbonyl-14- [2- (4-methoxy-phenyl) -acetylamino] -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6 ] nonadec-7-en-18-yl ester (ÍS, 4R, 6S, 14S, 18R) -4-Fluoro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00340156).

[1111] The starting material (AR00334191, Example 3-55, 10 mg, 13.7 Omol) was dissolved in 1 mL of 50% TFA (DCM) and stirred at room temperature for 1 h. The reaction mixture was then concentrated to dryness, taken up in acetonitrile and concentrated again. The previous process was repeated once more to eliminate any excess TFA. The resulting solid residue was then dissolved in DCE (137 OL), followed by addition of the acid chloride, (4-methoxy-phenyl) -acetyl chloride (2 g) and DI? A (4 g). The mixture was stirred at room temperature overnight. After completion, the reaction was loaded directly onto a C-18 Column and purified with reverse phase column chromatography. The compound was further purified on normal phase silica gel chromatography (eluent = 40%? TOAc / hexanes with 1% formic acid) to obtain the desired compound as a white solid. XH NMR (500 MHz, CD3OD) 0.7.33 (p, 1H), 7.15 (d, 1H), 7.05-6.92 (m, 3H), 6.65 (dd, 2H), 5, 68 (q, 1H), 5.40 (br s, 1H), 5.09 (t, 1H), 4.78-4.46 (m, 7H), 4.43-4.24 (m, 2H) ), 3.89 - 3.80 (m, 1H), 3.68 (d, 3H), 3.21 (d, 1H), 2.69-2.57 (m, 1H), 2.52 - 2.30 (m, 5H), 2.06-0.80 (m, 15H); MS (APCI-): m / z 778.3 (M-1) • Compound .ARO0340178 [1112] 4-Cyclopropanesulfonylaminocarbonyl-14- [2- (3-methoxy-phenyl) -acetylamino] -2,1-dioxo-3,16-diaza-tricyclo [14.3,0,0, 6] nonadec-7-en-18-yl ester of IS, 4R, 6S, 14S, 18R) -4-Fluoro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00340178) according to the procedures described in Example 3-81, except that (3-methoxy-phenyl) -acetyl chloride was used in replacement of (4-methoxy-phenyl) -acetyl chloride XH NMR (500 MHz , CD30D) 0.7.32 (p, 1H), 7.14 (d, 1H), 7.05-6.92 (m, 3H), 6.76-6.58 (m, 2H), 5.68 (q, 1H), 5.41 (br s, 1H), 5.09 (t, 1H), 4.76-4.46 (m, 7H), 4.43-4.26 (m, 2H), 3.91 - 3.82 (m, 1H), 3.69 (d, 3H), 2.94 - 2.85 (, 1H), 2.70-2.57 (m, 1H), 2.52-2.30 (m, 5H), 2.06-0.80 (m, 15H); MS (APCI-) m / z 778.3 (M-1).

Example 3-83 Compound AR00340188 [1113] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14-phenylacetylamino-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en- 18-yl, 4R, 6S, 14S, 18R) -4-Fluoro-l, 3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00340188) according to the procedures described in Example 3-81, except that phenylacetyl chloride was used in replacement of (4-methoxy-phenyl) -acetyl chloride MS (APCI-) m / z 748.4 (Ml).

Compound AR00334314 [1114] was synthesized 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diazatricyclo [14.3, 0, 04'6] nonadec-7-en-18-yl 1S, 4R, 6S, 14S, 18R) -5-Methoxy-1,3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00334314) according to the procedures described in Example 3-6, except that 5 -methoxy-2, 3-dihydro-1H-isoindol (prepared in a manner similar to that described in: JOC, Vol. 53, No. 22, 1988, pp. 5381-5383) in replacement for 2,3-dihydro-lH -isoindol. MS m / z (APCI-): 742.3 (M-1).

Compound AR00334399 [1115] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized 1S, 4R, 6S, 14S, 18R) -4,7-Difluoro-l, 3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00334399) according to the procedures described in Example 3-6, except that used 4,7-Difluoro-2, 3-dihydro-lH-isoindole (prepared in a manner similar to that described in: JOC, Vol. 53,? o. 22, 1988, pp.5381-5383) in replacement of 2, 3-dihydro-lH-isoindol. X H NMR (500 MHz, CD 3 OD) D .. 8.97 (s, 1 H), 6.99 - 6.85 (m, 2 H), 5.69 (q, 1 H), 5.42 (br s, 1 H ), 5.07 (t, 1H), 4.83-4.57 (m, 6H), 4.51 (d, 1H), 4.13-4.02 (m, 1H), 3.85 ( t, 1H), 2.94-2.86 (m, 1H), 2.73-2.59 (m, 1H), 2.55-2.28 (m, 4H), 1.89-1, 70 (m, 3H), 1.65-1.22 (m, 10H), 1.18-0.96 (m, 10H), MS m / z (APCI-): 746.1 (Ml).

Compound AR00338066 [1116] 14- (3-tert-Butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-yl ester, 1S, 4R, 6S, 14S, 18R) -4-Fluoro-l, 3-dihydro-isoindol-2-carboxylic acid (Compound AR00338066) according to the procedures described in Example 3-36, except that 4-fluoro-2,3-dihydro-lH-isoindole was used in replacement of 2,3-dihydro-lH-isoindole. XH NMR (500 MHz, CD3OD) 0.7.38-7.28 (m, 1H), 7.13 (d, 1H), 7.01 (p, 1H), 5.69 (q, 1H), 5.45 ( br s, 1H), 5.07 (t, 1H), 4.83-4.66 (m, 4H), 4.59 (q, 1 H), 4.49 (d, 1H), 4.37 - 4.17 (m, 2 H), 3.94 - 3.84 (m, 1 H), 3.72 (t, 1H), 2.95 - 2.87 (m, 1H), 2.68 - 2.29 (m, 5 H), 2.09 - 1.22 (m, 11 H), 1.12 - 0.95 (m, 12H); MS (APCI-): m / z 729.3 (M-1).

Compound AR00338070 [1117] 4-Cyclopropanesulfonylaminocarbonyl-14- (3, 3-dimethyl-butyrylamino) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, s] nonadec-7 was synthesized -in-18-yl ester of ÍS acid, 4R, 6S, 14S, 18R) -4-Fluoro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00338070) according to the procedures described in Example 3-81, except that 3,3-dimethyl chloride was used -butyryl in replacement of (4-methoxy-phenyl) -acetyl chloride MS (APCI-) m / z 728.3 (Ml). Example 3-88 Compound AR00338071 [1118] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (4, 4, 4-trifluoro-butyrylamino) -3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec was synthesized -7-en-18-yl ester, 1S, 4R, 6S, 14S, 18R) -4-Fluoro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00338071) according to the procedures described in Example 3 81, except that 4,4,4-trifluoro-butyryl chloride was used to replace (4-methoxy-phenyl) -acetyl chloride MS (APCI-) m / z 754.3 (Ml).

Compound ARO 0341649 [1119] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, O4,6] nonadec-7-en-18- was synthesized 15, 42? 65, 145, 182?) -5-Isopropylamino-l, 3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00341649) according to the procedures described in Example 3-6, except that used (2,3-Dihydro-lH-isoindol-5-yl) -isopropyl-amine (prepared in a manner similar to that described in: Org. Letters, 2003, Vol. 5, No. 6, 793-796,) in 2, 3-dihydro-1H-isoindol replacement. XR NMR (500 MHz, CD3OD) 0.8.94 (br d, 1H), 7.52 (s, 1H), 7.48 (d, 1H), 7.41-7.32 (m, 2H), 7 , 32-7.24 (m, 2H), 5.69 (q, 1H), 5.41 (br s, 1H), 5.07 (t, 1H), 4.82-4.66 (m, 3H), 4.60 (t, 1H), 4.52 (t, 1H), 4.08 (d, 1H), 3.85 (d, 1H), 3.80-3.68 (m, 1H) ), 2.94-2.87 (m, 1H), 2.71-2.59 (m, 1H), 2.55-2.45 (m, 1H), 2.45-2.30 (m) , 3H), 1.88-1.69 (m, 3H), 1.61 (t, 1H), 1.58-0.94 (m, 25H); MS (APCI-): m / z 770.1 (M-1) • Compound AR00364936 [1120] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized 1S, 42? SS, XAS, 182?) -5-Hydroxy-l, 3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00364936) according to the procedures described in Example 3-6, except that , 3-Dihydro-1H-isoindol-5-ol (prepared in a manner similar to that described in: JOC, Vol. 53, No. 22, 1988, pp. 5381-5383) was used in replacement of 2,3-dihydro -lH-isoindol. MS m / z (APCI-): 728.2 (M-1).

Compound AR00365083 [1121] It was synthesized 2- (14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en- 18-yl) ester 5-methyl ester of acid 15, 42? 6S, 145, 182?) -1,3-Dihydro-isoindol-2, 5-dicarboxylic acid (Compound ARO0365083) was synthesized according to the procedures described in? Example 3-57, except methyl ester of 2,3-dihydro-lH-isoindole-5-carboxylic acid was used (prepared as shown in Example 3-91a) in replacement of 2,3-dihydro-lH-isoindol-5-ylamine in Step 5: MS m / z (APCI +): 672.2 (MH + - Boc).

[1122] 2,3-Dihydro-lH-isoindol-5-carboxylic acid methyl ester was synthesized according to the following scheme:

[1123] A mixture of 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butylester (200 mg, 0.67 mmol), Pd (OAc) 2 (30 mg, 0.2 mg) was stirred. equiv), DPPP (55 mg, 0.2 equiv), TEA (0.93 mL, 10 equiv) and MeOH: DMSO (1: 1, 4 mL) for 16 h under CO (balloon) at 80 ° C. LC-MS and TLC (20% EtOAc-Hexane) showed that the reaction was complete. The reaction mixture was concentrated to remove MeOH and diluted with EtOAc (10 mL), and washed with water (2 x 25 mL). The organic layer was dried (Na 2 SO), concentrated and purified by silica gel column chromatography (eluent = 20%? TOAc-Hexane) to obtain 2-tert-butyl ester 5-methyl ester of 1,3-acid. pure dihydro-isoindol-2, 5-dicarboxylic acid (150 mg, 81%). MS (APCI +): m / z 178.1 (MH + -BOC). [1124] The above product was removed from the protecting group by treatment with 50% TFA-DCM per lh at 0 ° C-TA. The reaction mixture was concentrated to dryness, redissolved in DCM, and neutralized with sat. NaHCO 3 solution. The organic layer was separated, dried and concentrated to give the desired compound as free base, which was used directly in the next coupling step without further purification.

Compound ARO0333831 [1125] 14-Cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 0] s-nonadec-7-en-18-yl ester of the 1S, 4R, 6S, 14S, 18R) -1, 3-Dihydro-isoindol-2-carboxylic acid (Compound AR00333831) according to the procedures described in Example 3-5, except that 2,3-dihydro-lH-isoindole it was used in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline ^ 1HNMR (400 MHz, CD3OD): 0.7.36-7.22 (m, 3H), 7.21-7.16 (m, 1H) , 5.74- 5.60 (m, 1H), 5.40 (s, 1H), 5.20-5.03 (m, 1H), 4.80-4.54 (m, 6H), 4 , 38-4.28 (m, 1H), 4.18 (, 1H), 3.90-3.80 (m, 1H), 2.96-2.85 (m, 1H), 2.70- 2.31 (m, 4H), 1.92-0.98 (m, 24 H). MS m / z (APCI-): 724.4 (M-1).

Compound AR00340494 [1126] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04'6] nonadec-7-en-18-yl ester of the 15, 42 ?, 65, 145, 182?) -5-Morpholin-4-yl-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00340494) was synthesized according to the procedures described in Example 3-6 , except that 5-morpholin-4-yl-2, 3-dihydro-1H-isoindole (prepared in a manner similar to that described in: J. Org Chem. 2000, 65, 1144-1157) was used in replacement of 2. , 3-dihydro-lH-isoindol. XHNMR (400 MHz, DMSO-dd): 0.7, 80-7, 22 (m, 1H), 7.22-7.15 (m, 1H), 7.00-6.81 (m, 2H), 5 , 45- (m, 1H), 5.26 (m, 1H), 4.62-4.50 (m, 4H), 4.42 (m, 1H), 4.28-4.10 (m, 2H), 3.98 (m, 1H), 3.76 (m, 4H), 3.12 (m, 4H), 2.71-2.60 (m, 1H), 2.40-1.45 (m, 3H), 1.40-1.21 (m, 10H), 0.98-0.61 (m, 4H). MS m / z (APCI +): 699.2 (MH + -Boc).

Compound AR00365082 [1127] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04,6] nonadec-7-en-18-yl ester of the Acid 15, 42 ?, 65, 145, 182?) -5-Cyano-l, 3-dihydro-isoindol-2-carboxylic acid (Compound AR00365082) was synthesized according to the procedures described in Example 3-6, except that 2,3-dihydro-lH-isoindol-5-carbonitrile (prepared in a manner similar to that described in: J. Org. Chem. 1998, 63, 8224-8228) was used in replacement of 2,3-dihydro-lH-isoindole. MS m / z (APCI +): 639.1 (MH + -Boc).

Example 3-95 Compound ARO0365252 [1128] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, O4'5] nonadec-7-en-18-yl ester of 15, 42? SS, XAS, 182?) -5-? Tylcarbamoyl-l, 3-dihydro-isoindole-2-carboxylic acid (Compound ARO0365252) was synthesized according to the procedures of Compound AR00365083

[1129] The compound AR00365083 (70 mg, 91 μmol), the synthesis of which was described above in this documentation, was dissolved in a mixture of THF: MeOH (2: 1, 3 mL), followed by addition of aqueous solution 1 mL of LiOH- H20. The reaction was stirred by Ih at room temperature. LC-MS indicated complete hydrolysis, the reaction was allowed to continue for another 30 min before concentrating it, neutralizing it with 0.1N HCl and extracting it with 5 mL of EtOAc. The organic layer was dried (Na2SO), concentrated and purified on silica gel column chromatography (eluent = 5-7% MeOH-DCM) to obtain the hydrolysis product as a white solid. MS (APCI +): m / z 658.1 (MH + -Boc). [1130] The product from the previous step (23 mg, 30 μmol) was first dissolved in anhydrous DMF (2 mL), followed by addition of ethylamine (3 equiv), HOAT (3 equiv), and HATU (3 equiv) , and finally, DI? A (6 equiv) was added. The reaction mixture was stirred at room temperature overnight. LC-MS showed that the reaction was complete. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (2 x 10 mL). The organic layer was dried, concentrated and the crude product was purified by preparative TLKC. MS (APCI +): 685.2 (MH + -Boc).

Compound ARO0334218 [1131] 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diazatricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl ester of the 15, 42 ?, 65, 145, 182?) -5-Chloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound ARO0334218) according to the procedures described in Example 3-5, except that 5-chloro -2, 3-dihydro-lH-isoindol was used in replacement of 1,2,3,4-tetrahydro-isoquinoline _; _ XH NMR (400 MHz, CD3CN) D.7.55 (bs, 1H), 7, 19-7.33 (m, 3H), 5.63-5.73 (m, 2H), 5.27-5.34 (m, 1H), 4.98 (t, 1H), 4.52- 4.72 (m, 5H), 4.48 (t, 1H), 4.34-4.44 (m, 1H), 4.06-4.15 (m, 1H), 2.77-2, 90 (m, 2H), 2.54 (bs, 1H), 2.24-2.44 (m, 3H), 1.64-1.75 (m, 2H), 1.13-1.57 ( m, 18H), 0.91-1.09 (m, 4H). MS m / z 759.9 (M + l) Compound ARO0334220 [1132] 4-Cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-14- (tetrahydro-furan-3-yloxycarbonylamino) -3,16-diaza-tricyclo [14,3, 0, O4'6] nonadec-7 was synthesized -in-18-yl ester, 42 ?, 65, 145, 182?) -5-Chloro-1,3-dihydro-isoindol-2-carboxylic acid (Compound ARO0334220) according to the procedures described in Example 3- 16, except that 5-chloro-2,3-dihydro-lH-isoindole was used to replace 1, 2, 3, 4-tetrahydro-isoquinoline ^ XH NMR (400 MHz, CD3CN) 0.7.57 (bs, 1H) , 7.20-7.34 (m, 3H), 5.87-5.93 (m, 1H), 5.65 (q, 1H), 5.31 (bs, 1H), 5.23-5 , 29 (m, 1H), 4.98 (t, 1H), 4.44-4.71 (m, 5H), 4.29-4.39 (m, 1H), 4.07-4.18 (m, 1H), 3.70-3.87 (m, 4H), 3.61-3.70 (m, 1H), 3.44-3.55 (m, 2H), 3.30-3 , 42 (m, 1H), 2.76-2.89 (m, 2H), 2.54 (bs, 1H), 2.36-2.46 (m, 1H), 2.24-2.36 (m, 2H), 1.69-1.76 (m, 1H), 1.59-1.69 (m, 1H), 1.13-1.56 (m, 8H), 0.90-1 , 10 (m, 4H). MS m / z 762.0 (M + l) Compound AR00334222 [1133] 4-Cyclopropanesulfonylaminocarbonyl-14- (2-fluoro-ethoxycarbonylamino) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en was synthesized -18-yl ester of 15, 42? 6S, 14S, 182?) -5-Chloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00334222) according to the procedures described in Example 3-28, except that 5-chloro-2,3-dihydro-1H-isoindole was used in replacement of 2,3-dihydro-1H-isoindole; (400 MHz, CD3CN) 0.7.53 (bs, 1H), 7.20-7.33 (m, 3H), 5.93 (d, 1H), 5.67 (q, 1H), 5.32 ( bs, 1H), 4.93-5.05 (m, 1H), 4.52-4.72 (m, 5H), 4.47 (t, 1H), 4.39 (t, 1H), 4 , 25-4.36 (m, 2H), 4.12-4.25 (m, 2H), 3.65-3.96 (m, 2H), 2.76-2.89 (m, 2H) , 2.54 (bs, 1H), 2.22-2.44 (m, 3H), 1.67-1.76 (m, 1H), 1.13-1.60 (m, 10H), 0 , 91-1.13 (m, 4H) .. MS m / z 737.9 (M + l) Compound AR00334225 [1134] 4-Cyclopropanesulfonylaminocarbonyl-14- (3, 3-dimethyl-butyrylamino) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 was synthesized -in-18-il acid ester 15, 42? 6S, 145, 182?) -5-Chloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00334225) according to the procedures described in Example 3-81, except that 3,3-dimethylbutyryl chloride was used in replacement of (4-methoxy-phenyl) -acetyl chloride and that 5-chloro-2 , 3-dihydro-lH-isoindol was used in replacement of 4-fluoro-2,3-dihydro-lH-isoindol ^ XH NMR (400 MHz, CD3CN) 0.7.60 (bs, 1H), 7.15-7, 33 (m, 3H), 6.54-6.65 (m, 1H), 5.63-3.73 (m, 1H), 5.33 (bs, 1H), 4.93-5.02 ( m, 1H), 4.53-4.65 (m, 3H), 4.39-4.48 (m, 2H), 4.28-4.38 (m, 1H), 3.74-3, 83 (m, 2H), 2.77-2.89 (m, 1H), 2.54 (bs, 1H), 2.23-2.44 (m, 3H), 1.68-1.91 ( m, 4H), 1.12-1.54 (m, 11H), 0.91-1.11 (m, 4H), 0.76- 0.90 (m, 9H). MS m / z 746.2 (M + l) Compound AR00334226

[1135] 14- (2-Cyclopentyl-acetylamino) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18 was synthesized -15-acid ester, 42? 6S, XAS, 182?) -5-Chloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00334226) according to the procedures described in Example 3-81, except that cyclopentyl-acetyl chloride was used in replacement of (4-methoxy-phenyl) -acetyl chloride, and that 5-chloro-2, 3 was used. -dihydro-lH-isoindol in replacement of 4-fluoro-2,3-dihydro-lH-isoindol ^ XH NMR (400 MHz, CDC13) D.10.85 (bs, 1H), 6.95-7.30 ( m, 3H), 5.87-6.02 (m, 1H), 5.63-5.79 (m, 1H), 5.43-5.52 (m, 1H), 4.93-5, 08 (m, 1H), 4.52-4.85 (m, 5H), 4.31-4.52 (m, 1H), 3.79-3.95 (m, 1H), 3.60- 3.75 (m, 2H), 3.14 (q, 1H), 2.90 (bs, 1H), 2.37-2.63 (m, 3H), 2.14-2.29 (m, 1H), 1.73-2.12 (m, 6H), 1.16-1.74 (m, 13H), 0.96-1.16 (m, 4H), 0.68-0.96 ( m, 9H). MS m / z 758.2 (M + 1).

Compound AR00340173 [1136] 14-tert-Butoxycarbonylamino-4- (5-chloro-thiophene-2-sulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3, 04.04, d] was synthesized. ] nonadec-7-en-18-yl ester of acid 15, 42 ?, 65, 145, 182?) -5-Chloro-l, 3-dihydro-isoindole-2-carboxylic acid (Compound AR00340173) according to the procedures described in Example 3-6, except that 5-chloro-thiophene-2-sulfonic acid amide was used in replacement of cyclopropanesulfonamide, and that 5-chloro-2,3-dihydro-1H- isoindol was used in replacement of 2,3-dihydro-lH-isoindol ^ XH NMR (400 MHz, CD3CN) 0.8, 07 (d, 1H), 7.50 (d, 1H), 7.16-7.32 ( m, 3H), 6.98 (d, 1H), 5.86 (bs, 1H), 5.27-5.39 (m, 2H), 4.81-4.92 (m, 1H), 4 , 58-4.64 (m, 2H), 4.51-4.58 (m, 2H), 4.44 (t, 1H), 4.33 (d, 1H), 4.10-4.20 (m, 1H), 3.73-3.81 (m, 1H), 2.47 (bs, 1H), 2.16-2.41 (m, 3H), 1.63-1.77 (m , 2H), 1.47-1.57 (m, 2H), 1.07-1.47 (m, 17H). MS m / z 724.1 (M + 1-Boc) Compound ARO0340526 [1137] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized 1S, 42? 6S, 145, 182?) -5-Bromo-1,3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00340526) according to the procedures described in Example 3-6, except that it was used 5-bromo-2, 3-dihydro-lH-isoindol in replacement of 2,3-dihydro-lH-isoindol_¡_ XH NMR (400 MHz, CDC13) 0.10, 31 (bs, 1H), 7.36-7.44 (m, 1H), 6.99-7.32 (m, 3H), 5.70 (q, 1H), 5.42-5.49 (m, 1H), 5.06-5.13 (m, 1H), 4.99 (t, 1H), 4.52-4.78 (m, 5H), 4.32-4.44 (m, 1H), 4.16-4.27 (m, 1H), 3, 78-3.89 (m, 1H), 3.33-3.42 (m, 1H), 2.85-2.94 (m, 1H), 2.40-2.64 (m, 3H), 2.20-2.32 (m, 1H), 1.68-1.97 (m, 4H), 1.17-1.67 (m, 16H), 1.01-1.17 (m, 3H) ), 0.80-0.98 (m, 2H). MS m / z 694.0 (M + 1-Boc).

Compound AR00333462 [1138] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized acid ester 15, 42 ?, 65, 145, 182?) -42? -Methyl-3, 4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00333462) according to the procedures described in Example 3-1, except that 422-methyl-l, 2,3,4-tetrahydro-isoquinoline (prepared according to procedures similar to those of Example l-17a, except that enantiomerically pure starting material was used in place of racemic) in replacement of 1, 2, 3, 4-tetrahydro-isoquinoline ^ MS m / z 642.2 (M + 1-Boc).

Bj emplo 3-104 Compound ARO0333463 [1139] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diazatricyclo [14,3, 0, O4'6] nonadec-7-en-18-yl was synthesized acid ester 15, 42 ?, 65, 14S, 182?) -4S-Methyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid (Compound AR00333463) according to the procedures described in Example 3-1, except that 4S-methyl-1,2,3,4-tetrahydro-isoquinoline (prepared according to procedures similar to those of Example I-17a was used, except that enantiomerically pure starting material was used instead of racemic) as a replacement of 1, 2, 3, 4-tetrahydro-isoquinoline_¡_ MS m / z 642.2 (M + 1-Boc).

Example 3-105 Compound AR00345032 [1140] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04, 5] nonadec-7-en-18-yl was synthesized 15 acid ester, 42 ?, 65, 145, 182?) -5- [2- (Morpholine-4-carbonyloxy) -ethoxy] -1,3-dihydro-isoindole-2-carboxylic acid (Compound AR00345032) according to the procedures described in Example 3 -6, except that 2- (2,3-dihydro-lH-isoindol-5-yloxy) -ethyl ester of morpholine-4-carboxylic acid (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) in replacement of 2,3-dihydro-1H-isoindole.

MS (APCI-): m / z 885.4 (M-1).

Example 3-106 Compound AR00345075 [1141] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 0] s nonadec-7-en-18-yl was synthesized 15, 42? 6S, XAS, 182?) -5- (3-Morpholin-4-yl-propoxy) -1,3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00345075) according to the procedures described in Example 3-6, except that 5- (3-Morpholin-4-yl-propoxy) -2,3-dihydro-1H-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) in replacement of 2,3-dihydro-lH-isoindole; MS (APCI-): m / z 855.6 (M-1).

Example 3-107 Compound ARO0345090 [1142] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized acid ester 15, 42? SS, XAS, 182?) - 5- (2-Morpholin-4-yl-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid (Compound AR00345090) according to the procedures described in Example 3-6, except that 5- (2-Morpholin-4-yl-ethoxy) -2,3-dihydro-1H-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) in replacement of 2,3-dihydro-lH-isoindol. MS (APCI-): m / z 841.5 (M-1).

Example 3-108 Compound AR00345094 [1143] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04,6] nonadec-7-en-18-yl was synthesized acid ester 15, 42? SS, XAS, 182?) -5- (2-Isopropylamino-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid (Compound AR00345094) according to the procedures described in Example 3 -6, except that [2- (2, 3-Dihydro-lH-isoindol-5-yloxy) -ethyl] -isopropylamine (prepared according to the procedures described in J. Med. Chem. 2002, Vol. 45 was used. , No. 26, 5771, preparation method D, and in Bioorg, Med. Chem. Lett 11 (2001) 685-688) in replacement of 2,3-dihydro-lH-isoindolJ_MS (APCI-): m / z 813.5 (Ml).

Example 3-109 Compound AR00345095 [1144] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl ester of acid, S ?, 42 ?, 65, 14S, 182?) -5- (2-Dimethylamino-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid (Compound AR00345095) was synthesized according to the procedures described in Example 3 -6, except that [2 - (2,3-Dihydro-lH-isoindol-5-yloxy) -ethyl] -dimethyl-amine (prepared according to the procedures described in J. Med. Chem. 2002, Vol. 45 was used. , No. 26, 5771, preparation method D, and in Bioorg, Med. Chem. Lett.11 (2001) 685-688) in replacement of 2,3-dihydro-lH-isoindol ^ MS (APCI-): m / z 799.5 (M-l). ? jmplo 3-110 Compound ARO0345096 [1145] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl was synthesized 1S, 42? 65, 145, 182?) -5- (2-Imidazol-1-yl-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid ester (Compound AR00345096) according to the procedures described in Example 3-6, except that 5- (2-Imidazol-1-yl-ethoxy) -2,3-dihydro-lH-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) was used in replacement of 2,3-dihydro-lH-isoindol ^ MS (APCI-): m / z 822.5 (Ml).

Example 3-111 Compound ARO0364924 [1146] 14-Tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en was synthesized -18-yl acid ester, 42? 6S, 145, 182?) -5- (2-Pyrazol-1-yl-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid (Compound JAR00364924) according to procedures described in Example 3-6, except that 5- (2-pyrazol-1-yl-ethoxy) -2,3-dihydro-1H-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) was used in replacement of 2,3-dihydro-lH-isoindol ^ MS (APCI- ): m / z 742.1 [(M-100) +18].

Example 3-112 Compound AR00340495 [1147] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl ester of the 1S, 42? 6S, XAS, 182?) -5- (4-Methyl-piperazin-1-yl) -1,3-dihydro-isoindole-2-carboxylic acid (Compound AR00340495) was synthesized in a manner similar to described in Example 3-57, substituting 2, 3-Dihydro-lH-isoindol-5-ylamine in Step 5 with 5- (4-Methyl-piperazin-1-yl) -2,3-dihydro-lH- isoindol (prepared in a manner similar to that described in: J. Org Chem. 2000, 65, 1144-1157 XH-NMR (400 MHz, DMS0-ds): 7.72-7.40 (m, 1H), 7 , 22-7.05 (m, 1H), 6.95-6.70 (m, 2H), 5.55-5.45 (m, 1H), 5.35-5.22 (m, 2H) , 4.62-4.50 (m, 4H), 4.40 (m, 1H), 4.30-4.08 (m, 2H), 4.0-3.89 (m, 1H), 3 , 10 (m, 3H), 2.65 (m, 1H), 2.42 (m, 3H), 2.33-2.20 (m, 6H), 1.85-1.50 (m, 5H) ), 1.42-1.0 (, 14H), 0.82-0.55 (m, 4H), MS (APCI +): 712.3 (MH + - Boc) Example 3 -113 Compound ARO0365084 [1148] 2- (14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14,3, 0, 04,6] nonadec was synthesized -7-en-18-yl) acid ester 15, 42? 6S, 145, 182?) -1, 3-Dihydro-isoindol-2, 5-dicarboxylic (Compound ARO0365084) according to procedures similar to those described in Example 3-91, except that the product AR00365083 of such example was further hydrolyzed with LiOH in A mixture of THF-MeOH-H20 to obtain AR00365084, MS: 658 (M - Boc) Compound AR00364989 [1149] 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-18-yl ester of 15, 42 ?, 65, 145, 182?) -5- (2-Methyl-thiazol-4-yl) -1,3-dihydroisoindole-2-carboxylic acid (Compound AR00364989) was synthesized in a similar manner to described in Example 3-57, substituting 2,3-Dihydro-lH-isoindol-5-ylamine in Step 5 with 5- (2-Methyl-thiazol-4-yl) -2, 3-dihydro-lH-isoindole ^ XH NMR (400 MHz, CD3COCD3) D.10.69 (bs, 1H) 8.32 (bs, 1H), 7.94 (d, 1H) 7.88 (d, 1H) 7.70 (d, 1H) 7.34 (dd, 1H) 6.08-6.16 (m, 1H), 5.69 (q, 1H) 5.45 (bs, 1H) 5.00 (t, 1H) 4.58 -4.81 (m, 5H), 4.44-4.53 (m, 1H), 4.12-4.21 (m, 1H), 3.83-3.91 (m, 1H), 2 , 86-2.97 (m, 1H), 2.57-2.71 (m, 1H), 2.33-2.54 (m, 3H), 1.81-1.96 (m, 2H) , 1.75 (dd, 1H) 1.17-1.63 (m, 20H), 1.06-1.17 (m, 1H), 0.94-1.06 (m, 2H). MS m / z 711.2 (M + 1-100).

[1150] The synthesis of 5- (2-Methyl-thiazol-4-yl) -2,3-dihydro-lH-isoindole was prepared following the experiments of steps A to F in Example 3-115a, using thioacetamide in Step E ^ Example 3-115 Compound ARO0365019 [1151] 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14, 3.0, 04.6] nonadec-7-en-18-yl was synthesized ester of IS, 42? 6S, XAS, 182?) -5- (2-Isopropylamino-thiazol-4-yl) -1,3-dihydro-isoindol-2-carboxylic acid (Compound AR00365019) in a similar manner to described in Example 3-57, substituting 2, 3-Dihydro-lH-isoindol-5-ylamine in Step 5 with [4- (2,3-Dihydro-lH-isoindol-5-yl) -thiazole-2- il] -isopropyl-amine ^ XH NMR (400 MHz, CD3COCD3) D.10.69 (bs, 1H), 8.27-8.36 (m, 1H), 7.28-7.50 (m, 2H ) 7.01-7.20 (m, 1H), 6.08-6.15 (m, 1H), 5.70 (q, 1H) 4.45 (bs, 1H) 4.94-5.05 (m, 1H), 4.68-4.76 (m, 4H), 4.59-4.64 (m, 1H), 4.45-4.53 (m, 1H), 4.10-4, 20 (m, 1H), 3.81-3.90 (m, 1H) 3.65-3.76 (m, 1H), 2.86-2.98 (m, 1H), 2.63 (bs) , 1H), 2.32-2.54 (m, 3H), 1.80-1.94 (m, 2H), 1.70-1.79 (m, 1H) 1.05-1.65 (m. m, 19H) 0.95-1.05 (m, 2H). MS m / z 754.2 (M + l-100).

Example 3-115a

[1152] The synthesis of [4- (2,3-Dihydro-lH-isoindol-5-yl) -thiazol-2-yl] -isopropylamine is shown in the following scheme "0Et CIZn ^, PEt Br í 1 ) ffluLi T + BocN Pd (PPh3) 4 THF 2) ZnCI2 BA

[1153] A. T-BuLi (0.79 mL, 1.34 mmol) was added dropwise to a solution of 4 mL THF and 1 mL ethyl vinyl ether at -78 C. The solution was warmed to room temperature and stirred for 30 minutes. A 0.5 M solution of ZnCl 2 in THF (3.02 mL, 1.51 mmol) was added dropwise and the reaction was stirred at room temperature for 30 minutes. This mixture was used without further purification. [1154] B. A crude vinyl zinc species was cannulated from the passage to a solution of aryl bromide (0.200 g, 0.67 mmol) and Pd (PF3) (39 mg, 0.33 mmol) dissolved in THF under N2. . The reaction was heated to 50 ° C for 36 hours, and then filtered through a plug of Al203 with the aid of? TOAc and concentrated to give an oil which was used without further purification. [1155] C. The crude oil from step B was dissolved in THF (2 ml) and 1.0? HCl (2ml) and stirred for 1 hour. The reaction was taken up in BtOAc and separated, and the organic layer was washed with saturated aHC03 and brine, and dried over? A2S04 and concentrated in an orange oil. This oil was chromatographed with 5: 1 hex: EtOAc to obtain a white solid (95 mg, 54%) [1156] D. To a solution of 1.0 M LiHMDS (4.0 mL, 4.0 mmol) under 2 to -78 C, TMSC1 (3.38 mL, 26.6 mmol) was added dropwise. The ketone from step C in 3ml THF was added to this solution. The reaction was stirred at -78 ° C for 30 minutes and warmed to 0 ° C. PTTB (1.0g, 2.93 mmol) was added and the reaction was stirred for 30 minutes at 0 ° C, concentrating on a solid which was taken in? TOAc and water. The organic product was washed with water and brine, and dried over Na 2 SO 4 and concentrated, and the oil was purified with 5: 1 Hex: α tOAc to obtain a yellow solid (0.64 g, 71%). [1157] E. A slurry of bromoketone (75 mg, 0.22 mmol), Na 2 CO 3 (37 mg, 0.44 mmol) and 1-isopropyl thiourea (26 mg, 22 mmol) in? TOH was heated to reflux. 30 minutes. The reaction was taken up in? TOAc and separated, and the organic layer was washed with sat. NaHCO3. and brine, and dried over Na2SO4 and concentrated in a yellow oil. The oil was purified with 3: 1 Hex: MTBB to obtain a clear oil (77 mg, 97%). [1158] F. The Boc-amine of the step? it stirred in 4N HCl / dioxane (2.0 ml) for one hour and concentrated to a white solid. This solid was taken up in 0.1N HCl and washed with DCM.

The aqueous layer was basified with 1.0N NaOH and extracted with DCM, dried, and concentrated and used without further purification. Preparation of the intermediary Macrocyclic Aminoproline: Example 4-1: Synthesis of acid ethyl ester (SS, 422, 65, 145, 1822) -18-amino-14-er-butoxycarbonylamino-2, 15-dioxo-3,16-diaza -trip [14,3, 0, O4'6] nonadec-7-en-4-carboxylic 1. 5% Hoveyda 1st generation cat, ° ^ N- (H DCM, 40 ° C 2. TBAF.THF 50 ° C iá -OEt

[1159] AA a solution of (25,422) -4-amino-1- [benzyloxycarbonyl] pyrrolidine-2-methylcarboxylate hydrochloride (2.00 g, 2.34 mmol) in methylene chloride (25 ml) was added 2- (trimethylsilyl) ethyl p-nitrophenyl carbonate (1.98 g, 6.99 mmol) and triethylamine (1.81 mL, 13.34 mmol). The reaction was stirred for 3 days, placed on silica gel and the product was eluted with 40% EtOAc / hexanes to obtain a colorless oil. The oil was dissolved in methanol (20 ml) and stirred with 10% palladium on low carbon to hydrogen gas balloon. After stirring for 4 h, the reaction was filtered and concentrated. The resulting solid was dissolved in IN aqueous HCl (75 ml) and extracted with methylene chloride (75 ml). The aqueous layer was basified by the addition of sodium hydroxide and again extracted with methylene chloride (100 ml). Both organic extractions were combined, concentrated and the resulting residue was purified by silica gel chromatography eluting with 10% methanol / methylene chloride to obtain a brownish solid (1.29 g, 70%). LCMS = 289 (H +). [1160] B A solution of 4 (2?) - (2-trimethylsilylethyl carbonylamino) -pyrrolidine-2 (5) -carboxylic acid methyl ester (1.29 g, 4.50 mmol) was stirred overnight. (S) -tert-butoxycarbonylamino-non-8-enoic (1.22 g, 4.51 mmol), HATU (2.06 g, 5.41 mmol) and diisopropylethylamine (1.18 ml, 6.76 mmol) in dimethylformamide (10 ml). The reaction was diluted with ethyl acetate (150 ml), washed with IN aqueous HCl (2 x 100 ml), dried over magnesium sulfate and concentrated. Chromatography on silica gel allowed to obtain an oil which was stirred with lithium hydroxide (0.28 g, 6.76 mmol) in methanol (5 ml) for 2 h. The reaction was diluted with methylene chloride and washed with IN aqueous HCl, dried over magnesium sulfate and concentrated to give 1.2 g (49%) of the product. [1161] C A solution of 4N HCl / dioane (2.87 ml, 11.46 mmol) was added to l (2?) - tert-butoxycarbonylamino-2 (S) -vinyl-cyclopropanecarboxylic acid ethyl ester (0, 70 g, 2.75 mmol). After stirring for 2 h, the reaction was concentrated to obtain a solid. To this solid was added 1- (2 (5) -tert-butoxycarbonylamino-non-8-enoyl) -4 (2?) - (2-trimethylsilylethyl carbonylamino) -pyrrolidine-2 (S) -carboxylic acid (1.21). g, 2.29 mmol), HATU (1.05 g, 2.75 mmol) and diisopropylethylamine (1.60 mL, 9.17 mmol) and methylene chloride (10 mL) and the reaction was stirred for 18 h at room temperature. ambient . The reaction was placed on silica gel and eluted with a solution of 50% ethyl acetate / hexanes to obtain the product as a colorless oil (1.27 g, 83%). 665 (H +) [1162] D A solution of ethyl ester of 1- acid. { [1- (2 (5) -tert-butoxycarbonylamino-non-8-enoyl) -4 (2?) - (2-trimethylsilylethyl carbonylamino) -pyrrolidine-2 (5) -carbonyl] -amino} -2 (5) -vinyl-cyclopropan-1- (2?) -carboxylic acid (1.27 g, 1.91 mmol) in methylene chloride (195 ml) was degassed for 1 h by bubbling N2 through the solution. Dichloro (o-isopropoxyphenyl-methien) (tricyclohexylphosphine) ruthenium (II) (0.057 g, 0.096 mmol) was added and the reaction was stirred at 40 ° C for 16 h. The reaction was concentrated, placed on silica gel and eluted with 50% ethyl acetate / hexanes. The resulting oil was treated with TBAF (1.0 M in THF, 2.87 ml) and heated at 50 ° C for 4 h. The reaction was placed on silica gel and eluted with 20% methanol / methylene chloride to obtain a tan solid. (0.65 g, 69%). X H NMR (CDCl 3, 400 MHz): 0.1, 06-1, 66 (m, 17 H), 1.85-1.95 (m, 2H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 2.65-2.75 (M, 1H), 3.40 (m, 1H), 3.73-3.83 (m, 2H), 4.08-4.19 (m, 2H), 4.56 (m, 1H), 4.78 (d, J = 5.5 Hz, 1H), 5.20 (t, J = 8, l Hz , 1H), 5.34 (d, J = 8, 1 Hz, 1H), 5.47 (dt, J = 4.5, 10.8 Hz, 1H), 7.08 (s, 1H). 493 (H +). Preparation of Compounds with the general structure V Compound ARO 0287262 Synthesis of acid (15, 422, 6Sr 14S, 1822) -14- ert-butoxycarbonylamino-18 - [(3,4-dihydro-lH-isoquinoline-2-carbonyl) -amino] -2, 15-dioxo -3,16 -diaza-tricyclo [14, 3, 0, O4'6] nonadec-7-en-4-carboxylic (Compound

[1163] A solution of 3,4-dihydro-lH-isoquinoline-2-carbonyl chloride (0.030 g, 0.152 mmol), ethyl ester of the acid (15, 42? 65, 145, 182?) Was stirred together. 18-amino-14-tert-butoxycarbonylamino-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en-4-carboxylic acid (0.025 g, 0.050 mmol) , DI? A (0.027 ml, 0.153 mmol) and a catalytic amount of DMAP in methylene chloride (0.3 ml) for 18 h. The reaction was placed on silica gel and the product was eluted with 40% acetone / hexanes and isolated as a white solid. The solid was dissolved in methanol and treated with lithium hydroxide (0.011 g, 0.254 mmol) and 1 drop of water. After stirring for 5 h, the reaction was diluted with methylene chloride (30 ml), washed with IN aqueous HCl (30 ml), brine (30 ml), dried over magnesium sulfate and concentrated to give the compound of the title as a white solid. LCMS = 624 (MH +).

[1164] The following compound was also prepared with the procedure described in Example 5-1, substituting 1,3-dihydro-isoindol-2-carbonyl chloride for 3,4-dihydro-lH-isoquinolin-2-chloride. carbonyl LCMS = 610 (H +) Example 5-2: Compound AR00298980 [1165] 1S, 42?, 65, 145, 182?) -14-tert-Butoxycarbonylamino-18 - [(1,3-dihydro-isoindol-2-carbonyl) - amino] -2, 15-dioxo-3, 16-diaza-tricyclo [14, 3.0, O4'6] nonadec-7-en-4-carboxylic acid (Compound AR00298980) according to the procedures described in Example 5- 1, substituting 3,4-Dihydro-lH-isoquinolin-2-carbonyl chloride with 1,3-Dihydro-isoindol-2-carbonyl chloride MS m / e 608.2 (Ml).

Compound ARO0304160 [1166] Acid 15, 42 ?, 65, 145, 182?) -14-tert-Butoxycarbonylamino-18 - [(3,4-dihydro-2H-quinolin-1-carbonyl) -amino] -2 was prepared , 15-dioxo-3, 16-diaza-tricyclo [14, 3.0, 04'6] nonadec-7-en-4-carboxylic acid (Compound AR00304160) according to the procedures described in Table 5-1, substituting chloride of 3,4-Dihydro-lH-isoquinoline-2-carbonyl with 3,4-Dihydro-2H-quinoline-1-carbonyl chloride MS m / e 524.3 (M ++ l- 100).

Preparation of Compounds with the general structure VI Compound ARO0304010 [1167] Acid 15, 42? 6S, XAS, 182?) -14-tert-Butoxycarbonylamino-18 - [(3,4-dihydro-lH-isoquinoline-2-carbothioyl) -amino] -2 was prepared , 15-dioxo-3, 16-diaza-tricyclo [14, 3, 0, 0, s] nonadec-7-en-4-carboxylic (Compound AR00304010) using the same procedure described in Step 4 of Example 1-2, except that the carbonyl diimidazole was replaced by thiocarbonyl diimidazole. LCMS = 640 (H +). MS m / e 640.1 (M ++ l).

Preparation of Compounds with the general structure VII VII (X = C, S) Compound AR00287266 [1168] Ter-butylester of the acid (15, 42? 6S, XAS, 182?) - was prepared. { 4-Cyclopropanesulfonylaminocarbonyl-18 - [(3,4-dihydro-lH-isoquinoline-2-carbonyl) -amino] -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, O4'6] nonadec-7-en-14-il} -carbamic (Compound AR00287266) according to the same procedures described in Example 3-1, starting from the acid prepared according to the procedures described in Example 5-1, MS m / e 727.0 (M ++ l).

Example 7-2 Compound ARO0304008 [1169] Ter-butylester of acid 15, 42 ?, 6S, XAS, 182 was prepared -). { 4-Cyclopropanesulfonylaminocarbonyl-18 - [(1,3-dihydro-isoindol-2-carbonyl) -amino] -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, e] nonadec- 7-in-14-il} -carbamic (Compound AR00304008) according to the same procedures described in Example 3-1, starting from the acid prepared according to the procedures described in Example 5-2, MS m / e 613.2 (M ++ l-100).

Compound ARO0304014 [1170] [14- (3-Cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04'6] nonadec-7 was prepared en-18-yl] -amide of IS acid, 4R, 6S, 14S, 18R) -l, 3-Dihydro-isoindol-2-carboxylic acid (Compound AR00304014) according to the same procedures described in Example 2-24, starting with the acyl sulfonamide prepared according to the procedures described in Example 7-4, MS m / e 724.2 (M ++ l).

Compound AR00304012 [1171] Ter-butyl ester of IS acid, 42? 6S, XAS, 182 was prepared -). { 4-Cyclopropanesulfonylaminocarbonyl-18 - [(3,4-dihydro-lH-isoquinoline-2-carbothioyl) -amino] -2,15-dioxo-3,16-diaza-tricyclo [14.3, 0, O4.6] nonadec-7-en-14-il} -carbamic or (Compound AR00304012) according to the same procedures described in Example 3-1, starting with the acid prepared according to the procedures described in Example 6-1, MS m / e 743.0 (M ++ 1).

Example 7-5 AR00424775 [1172] 14-amino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diazatricyclo [14,3, 0, 04, e] nonadec-7-en-18-yl ester of the acid was synthesized 1S, 4R, 6S, 14S, 18R) -5-Fluoro-l-methoxymethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid, HCl salt (Compound AR00424775) taking AR00335293 (84 mg) in 0.5 mL of 4 M HCl / Dioxane and stirring at room temperature for 16 h. The reaction was then concentrated and taken up in acetonitrile by re-concentration. The hydrochloride salt was then dried overnight in a high vacuum pump to obtain the product as a white solid ester 80 mg. + APCI MS m / z 690.1 (M + 1).

AR00424874 [1173] 14-amino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, 6] nonadec-7-en-18-yl ester of 1S acid was synthesized , 4R, 6S, 14S, 18R) -4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid, HCl salt (Compound 7AR00424874) AR00334191 (98 mg) was taken in 0.5 mL of 4 M HCl / Dioxane and stirred at room temperature for 16 h. The reaction was then concentrated and taken back into acetonitrile by concentration. The hydrochloride salt was then dried overnight in a high vacuum pump to obtain the product as a white solid (89 mg). + APCI MS m / z 632.1 (M + 1). Example 8 Assay with NS3-NS4A Proteases NS3 Complex Formation with NS4A-2 [1174] Full length NS3 of E. coli or recombinant Baculovirus was diluted to 3.33 μM with assay buffer and the material was transferred to a Bppendorf tube and placed in a water bath in a refrigerator at 4 ° C. The appropriate amount of 8.3 M NS4A-2 in assay buffer was added to an equal volume of NS3 in step 2.1.1 (conversion factor - 3.8 mg / 272 μl assay buffer). The material was transferred to a ppendorf tube and then placed in a water bath in a refrigerator at 4 ° C. [1175] After equilibrating at 4 ° C, equal volumes of NS3 and NS4A-2 solutions were combined in a? Ppendorf tube, mixed gently with a manual pipettor and the mixture was incubated for 15 minutes in the water bath 4 ° C. The final concentrations in the mixture were 1.67 μM for NS3, 4.15 mM for NS4A-2 (a molar excess of 2485 times NS4A-2). [1176] After 15 minutes at 4 ° C, the? Ppendorf tube was removed with NS3 / NS4A-2 and placed in a water bath at room temperature for 10 minutes. Aliquots of appropriate volumes of NS3 / NS4A-2 were taken and stored at -80 ° C (NS3 of E. coli at 2 nM in the assay, aliquot of 25 μl, NS3 of BV at 3 nM in the assay, aliquot of 30 μl). Nonsense inhibition NS3 [1177] Step 2.2.5. The test compounds were dissolved to 10 mM in DMSO then diluted to 2.5 mM (1: 4) in DMSO. Typically, the compounds were added to a test plate at a concentration of 2.5 mM, an initial concentration of 50 microM being obtained after the dilution in the curve of the inhibition test. The compounds were serially diluted in assay buffer to provide test solutions at lower concentrations. [1178] Step 2.2.6. ? NS3 / NS4A-2 from E. coli was diluted to 4 nM NS3 (1: 417.5 of a stock solution 1.67 μM - 18 μl of stock solution 1.67 μM + 7497 μl of buffer assay) . [1179] BV NS3 / NS4A-2 was diluted to 6 nM NS3 (1: 278.3 of 1.67 μM stock solution - 24 μL of 1.67 μM stock solution + 6655 μL of assay buffer). [1180] Step 2.2.7. Using the multi-channel manual pipettor, and taking care not to introduce bubbles in the plate, 50 μl of assay buffer was added to cavities A01-H01 of a Costar black 96-cavity polypropylene storage plate. [1181] Step 2.2.8. Using the multi-channel manual pipettor, and taking care not to introduce bubbles in the plate, 50 μl of NS3 / NS4A-2 diluted from step 2.2.6 was added to cavities A02-H12 of the plate in step 2.2.7. [1182] Step 2.2.9. Using the multi-channel manual pipettor, and taking care not to introduce bubbles in the plate, 25 μl was transferred from the cavities of the drug dilution plate from step 2.2.5 to the corresponding cavities of the step assay plate. 2.2.8. The tips of the multi-channel pipettor were changed for each row of transferred compounds. [1183] Step 2.2.10. Using the manual multi-channel pipettor, and taking care not to introduce bubbles in the plate, the content of the cavities of the assay plate of step 2.2.9 was mixed by aspirating and releasing five times 35 μl of the 75 μl of each cavity. The tips of the multi-channel pipettor were changed for each row of mixed cavities. [1184] Step 2.2.11. The plate was covered with a lid for polystyrene plates and the plate from step 2.2.10 containing NS3 protease and test compounds was preincubated for 10 minutes at room temperature. [1185] While the plate from step 2.2.11 is preincubated, the RETS1 substrate was diluted in a 15 ml polypropylene centrifuge tube. The RETS1 substrate was diluted to 8 μM (1: 80.75 of 646 μM stock solution - 65 μl of 646 μM stock solution + 5184 μl of assay buffer). [1186] Once the pre-incubation of the plate from step 2.2.11 was completed, and using the multi-channel manual pipettor, 25 μl of substrate was added to all the wells of the plate. The contents of the cavities were quickly mixed, as in step 2.2.10, but by mixing 65 μl of the 100 μl contained in the cavities. [1187] The plate was read in kinetic mode with the SpectraMáx Gemini XS plate reader from Molecular Devices. Read settings: Reading time: 30 minutes, Interval: 36 seconds, Readings: 51,? Xcitation?: 335 nm,? Mission ?: 495 nm, Cut: 475 nm, Automatic mixing: off, Calibration: once, PMT : high, Readings / cavity: 6, Vmax pts: 21 or 28/51 depending on the extension of the linearity of the reaction. [1188] The IC 50 values were determined using a four-parameter curve fitting equation and converted to Ki values using the following Km: E. Coli full-length NS3: 2.03 μM full-length NS3 of BV : 1.74 μM where Ki = IC50 / (1+ [S] / Km)) Quantification by ELISA of the selectable marker protein, neomycin phosphotransferase II (NPTII) in the subgenomic replicon of HCV, GS4.3 [1189] The replicon subgenomic level of HCV (I377 / NS3 -3 ', Accession No. AJ242652), stably maintained in HuH-7 hepatoma cells, was created by Lohmann et al. Science 285: 110-113 (1999). The cell culture containing the replicon, called GS4.3, was obtained from Dr. Christoph Seeger of the Insti tute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania. [1190] GS4.3 cells were maintained at 37 ° C, C02 %, in DMEM (Gibco 11965-092) supplemented with L-glutamine 200 mM (100X) (Gibco25030-081), non-essential amino acids (? EAA) (Bio hittaker 13-114E), bovine fetal serum (FBS) (Hyclone SH3007.03) inactivated by heat (Hl) and geneticin 750 μg / ml (G418) (Gibco 10131-035). The cells were subdivided: 3 or 4 every 2-3 days. [1191] Twenty-four hours before the assay, GS4.3 cells were harvested, counted and plated in 96-well plates (Costar 3585) at 7500 cells / well in 100 μl of standard maintenance medium (above) and incubated under the conditions indicated previously. To start the assay, culture medium was removed, the cells were washed once with PBS (Gibco 10010-023) and 90 μl of assay medium was added (DMEM, L-glutamine, NEAA, Hl FBS 10%, without G418 ). The inhibitors were obtained as a 10X stock solution in assay medium, (3X dilutions from 10 μM to a final concentration of 56 pM, a final concentration of DMSO of 1%), 10 μl was added to duplicate the cavities, plates were shaken to mix and incubated as previously indicated for 72 h. [1192] A set of NPTII elements for ELISA from AGDIA, Inc. was obtained. { Compound direct ELISA test system for Neomycine Phosphotransf erase II, PSP 73000/4800). The instructions of the supplier were used, with some modifications. 10X PEB-1 lysis buffer was obtained which included 500 μM PMSF (Sigma P7626, 50 mM stock solution in isopropanol). After 72 h of incubation, the cells were washed once with PBS and 150 μl of PEB-1 was added with PMSF per well. The plates were shaken vigorously for 15 minutes at room temperature, then frozen at -70 ° C. The plates were thawed, the lysates were thoroughly mixed and 100 μl was applied to an NPTII Elisa plate. A standard curve was drawn. The lysates of the control cells treated with DMSO were pooled, serially diluted with PEB-1 with PMSF and applied to the cavities, in duplicate, of the ELISA plate, in a range of lysate initiation of 150 μl- 2.5 μl. In addition, 100 μl of buffer solution was applied only, in duplicate, as a blank. Plates were sealed and shaken gently at room temperature for 2 h. After incubation by capture, the plates were washed 5X with 300 μl with PBS-T (0.5% Tween-20, the PBS-T was supplied with the set of elements for ELISA). For detection, a dilution IX of enzyme-conjugated MRS-2 diluent (5X) was made in PBS-T, to which 1: 100 dilutions of enzyme conjugates A and B were added, according to the instructions. The plates were resealed and incubated with shaking, covered, at room temperature, for 2 h. The wash was then repeated and 100 μl of TMB substrate was added at room temperature.

After approximately 30 minutes of incubation (room temperature, stirring, covers), the reaction was stopped with 50 μl of 3 M sulfuric acid. Plates were read at 450 nm with a Versamax plate reader from Molecular Devices. [1193] The inhibitory effect was expressed as the percentage of control signal treated with DMSO, and the inhibition curves were calculated using a 4-parameter equation: y = A + ((BA) / (1+ ((C / x) ? D))), where C is the maximum average activity or EC50. EXAMPLES OF ACTIVITY: Where: A indicates an IC50 or EC50, as indicated, less than 50 μM B indicates an IC50 or BC50, as indicated, less than 10 μM C indicates an IC50 or? C50, as indicated, less than 1 μM and D indicates an IC50 or? C50, as indicated, less than 0.1 μM Table 2 Specificity assays [1194] When the compounds were evaluated in specificity assays, the compounds of Formula I were found to be selective in that they did not demonstrate significant inhibition for cathepsin B, chymotrypsin, thrombin or leukocyte elastase. Example 9: Pharmacokinetic Analysis of Compounds Methods [1195] The compounds were synthesized and initially evaluated for their potency (IC50) in a fluorogenic assay with the NS3 / 4 protease and the cell-based HCV replicon system previously described in Example 8. A pharmacokinetic analysis of plasma was then used in Rattus sp. after IV administration together with stability studies in hepatocytes and human liver microsomes (HLM) in vitro to direct the design of metabolically stable compounds from compounds with a < 20 nM. These first compounds were then optimized for the drug-like physical properties and administered orally in Rattus sp. in order to evaluate the concentrations in liver, heart and plasma. [1196] The compounds were evaluated for their liver clearance in time after a single oral dose of 3 mg / kg in rats. Additional toxicological evaluations were performed on rats with any of the compounds having a liver concentration 8 hours after administration that was at least 100 times higher than the concentration of said effective compound to inhibit 50% of the maximum inhibition in the assay with the replicon (? C50 replicon), using dosages of up to 30 mg / kg BID orally for seven days. Results [1197] Compounds AR294381, AR261408, AR333833 and AR334191 allowed to obtain EC50 values in replicon of approximately 2 nM and presented stability in vitro in incubation tests of rat, dog and human hepatocytes, being that said data would allow to predict low indices a moderate liver clearance. In addition, these compounds exhibited a high degree of selectivity against a panel of other serine proteases and no significant inhibition of the cytochrome P450 isoforms or the activity of hBRG channels even at the highest concentrations evaluated (10 μM). [1198] With the compounds AR294381, AR261408, AR333833 and AR334191, a single oral dose of 30 mg / kg in Rattus sp. liver concentrations were obtained 24 hours after the dose was administered which were at least 200 times more than their respective EC50 values in replicon. [1199] With the compound AR334191 heart and plasma levels were obtained up to two orders of magnitude lower, and were kinetically correlated with liver concentrations in the same animals. At a clinically more reasonable oral dose (3 mg / kg), with the compound AR334191 a liver concentration was obtained 8 hours after the dose was administered which was more than 100 times greater than the value of the C50 in replicon of the compound. After exposing compound AR334191 at a dosage of 30 mg / kg BID orally for 7 days, no mortality, change in weight or abnormalities in clinical chemistries were observed in the treated animals. Conclusion [1200] Potent, metabolically stable, orally available small molecules have been developed as inhibitors of the HCV NS3 protease. At moderate oral dosage levels (3 mg / kg) these compounds have high levels in the liver (100 times greater than their respective BC50 values in replicon) 8 hours after the dose is administered. Exposure in plasma and heart is up to two orders of magnitude lower than that observed in the liver, and such low concentrations minimize any potential systemic toxicological concern. [1201] Compound AR334191 showed no toxicity in Rattus sp. administered in doses for seven days at 30 mg / kg BID, which provides a margin of safety at least 10 times higher than the supposedly effective dose (3 mg / kg) with which liver concentrations are obtained 100 times greater than the value of the BC50 in replicon for said compound. Preparation of the viral inhibitors of Section C [1202] The meaning of the structural terms and names used in this section are the same as those used previously in Section C. All reference in this section to a particular number or label must be understood in the context of the corresponding numbering or labeling scheme used in this section or Section C above, instead of the context of a possibly similar or identical numbering or labeling scheme used elsewhere in the present, unless otherwise indicated. [1203] The compounds of formula XI-XVII can be synthesized according to the methods that will be described below. Methodology [1204] The NS3 inhibitors shown in Examples 1-35 were prepared according to the chemistry illustrated in Scheme 1. Intermediates Ethyl ester of 1 (2?) - tert-butoxycarbonylamino-2 (5) - vinyl-cyclopropanecarboxylic acid, 2- (5) -ter-jbutoxycarbonylamino-non-8-enoic acid and the macrocyclic hydroxy intermediate (Step C) were prepared in a similar manner as described in International Application PCT / CA00 / 00353 (Publication N) WO 00/59929). The 2 (5) -tert-J-butoxycarbonylamino-non-8-enoic acid was also obtained from RSP Amino Acids. Example 1: Synthesis of compound 101 Compound 101 Scheme 1 Step A: Synthesis of 25- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -422-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester. [1205] To a balloon loaded with ethyl- (12? 25) / (15, 22?) -l-amino-2-vinylcyclopropyl carboxylate (1.0 g, 5.2 mmol), trans-N- ( tert-butoxycarbonyl) -4-hydroxy-L-proline (1.3 g, 1.1 equiv) and HATU (2.7 g, 1.1 equiv) were added 30 ml of DMF to obtain a solution. It was cooled to 0 ° C in a bath of ice water, followed by the slow addition of a solution of DIEA (4.4 ml, 4 equiv) in DMF (15 ml) under stirring. The reaction was allowed to reach rt and stirred overnight. [1206] 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. NaHCO 3. (2 x 40 ml) and saline (2 x 40 ml), then dried over Na 2 SO 4 and concentrated to obtain a dark copper oil. The crude product was purified on silica gel (eluent: acetone / hexanes 3: 7), obtaining the desired pure product as a roasted fluffy powder (770 mg, 32%). Step B: Synthesis of 122- acid ethyl ester. { [1- (2S-tert-butoxycarbonylamino-non-8-enoyl) -422-hydroxy-pyrrolidine-25-carbonyl] -amino} -25-vinyl-cyclopropanecarboxylic acid [1207]? The dipeptide product from step A (2.85 g, 7.7 mmol) was dissolved in 10 ml of 4N HCl (dioxane) and left at rt for 90 min to remove the group Boc protector. It was then concentrated, taken up in acetonitrile and re-concentrated twice. To this light brown residue was added 2 (5) -tert-butoxycarbonylamino-non-8-enoic acid (2.2 g, 8.1 mmol) and HATU (3.2 g, 8.5 mmol), followed by 80 ml of DMF under nitrogen. The reaction was cooled on ice-water bath for 15 min, after which 5 ml of a solution of DMF in DIEA (5.4 ml, 30.9 mmol) was added to the reaction by drops under stirring. The ice bath was allowed to slowly reach rt and the reaction was stirred overnight. [1208] After 18 hours, the TLC showed that the reaction was complete. The reaction was diluted with EtOAc (300 mL) and washed with water (3 x 150 mL), sat. NaHCO 3. (2 x 150 ml), saline (150 ml), dried (Na 2 SO) and the solvent was removed. The crude product was purified by flash chromatography on silica gel with Biotage 40 M (eluent = 3% to 5% MeOH in DCM) to obtain the desired product as a brown fluffy solid (3.5 g, 87%). Step C: Synthesis of (1S, 422, 6S, 14S, 1822) -1-tert-butoxycarbonylamino-18-hydroxy-2, 15-dioxo-3,16-diaza-tricyclic acid ester [14,3, 0, 0 4.6] nonadec-7-en-4-carboxylic acid [1209] The product from step B (2.6 g, 5.0 mmol) was dissolved in 500 ml of DriSolve DCE in a 1 1 balloon to obtain a solution. It degassed by bubbling nitrogen through it for 1 h. Then the Hoveyda catalyst (0.25 equiv) was added at rt under nitrogen. The reaction was placed on a preheated oil bath (50 ° C) and stirred overnight. After 16 hs, the reaction had turned dark brown. TLC (DCM / EtOAc 1: 1) showed a clear conversion with a new spot with slightly lower Rf. The reaction was concentrated and purified over silica gel (Biotage 40 M, eluent = DCM / EtOAc gradient from 1: 1 to 1: 2), obtaining the desired product as a roasted fluffy powder (0.64 g, 52% ). X H NMR (CDCl 3, 400 MHz) 0.1.21 (t, J = 7.0 Hz, 3 H), 1.43 (s, 9 H), 1.20-1.50 (m, 6 H), 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, 1H), 3.68 (m, 1H), 3.94 (m, 1H), 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, 1H). MS m / z 494.0 (M ++ l). Step D: Synthesis of ethyl ester of (15, 422, 6S, 145, 1822) - 14-tert-butoxycarbonylamino-18- (1, 3-dihydro-isoindol-2-carbonyloxy) -2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.04.6] nonadec-7-en-4-carboxylic acid [1210] The macrocyclic product from step C (110 mg), 0.22 mmol) was dissolved in DCM (2.2 ml), followed by addition of CDI (45 mg, 0.27 mmol) 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). Isoindoline (0.12 ml, 1.1 mmol) was added to the reaction by droplets and the reaction was stirred at 40 ° C overnight. After 22 hours, the TLC showed that the reaction was complete. The reaction was cooled to rt, diluted with DCM (6 mL) and washed with aq. 1N (2 x 2 ml), sodium bicarbonate sat. (2 ml), saline (2 ml), dried (Na2SO4) and concentrated. The crude product was purified on silica gel (Biotage 4OS, eluent: 2 to 4% MeOH in DCM), yielding the desired product as a white powder (131 mg, 90%). Step E: Synthesis of acid (15, 422, 6S, 14S, 1822) - 14-tert-butoxycarbonylamino-18- (1, 3-dihydro-isoindol-2-carbonyloxy) -2,15-dioxo-3,16- diaza-tricyclo [14.3.0.0.4.6] nonadec-7-en-4-carboxylic acid. [1211] The macrocyclic ester product from step D (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 overnight. After 8 hours, the TLC (DCM / MeOH 9: 1) showed a new clear spot with a lower Rf. The reaction was concentrated almost to dryness and partitioned between IN HC 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 Na 2 SO and concentrated to obtain the desired product as a white fluffy powder (50 mg, 87%). XH NMR (CDC13, 500 MHz) 0. 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 = .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 / z 611.0 (M ++ l).

Step F: Synthesis of 14-tert-butoxycarbonylamino-4- (N, N-dimethylsulfonyl-a-norcarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04,6] nonadec 7-en-18-yl ester of the acid (SS, 422, 65, 14S, 1822) -1, 3-dihydro-isoindole-2-carboxylic acid (Compound 101) [1212] The macrocyclic acid product of step E ( mg, 0.066 mmol) was dissolved in 0.7 ml of DCE, followed by addition of CDI (13 mg, 0.079 mmol) in one portion. The mixture was stirred in an oil bath at 50 ° C for 2 h. TLC (10% methanol in dichloromethane) showed absence of the initial acidic material and a new stain with a much higher Rf. Then N, N-dimethylsulfamide (12 mg, 0.098 mmol, obtained from TCI) was added to the reaction, followed by DBU (15 mg, 0.098 mmol). Heating was continued at 50 ° C for 2 h, both TLC and LCMS showed that the reaction had been completed and that the product had formed. The reaction was concentrated and loaded directly onto a column of Biotage 40 S silica gel. It was purified by flash chromatography (eluent = ethyl acetate 40% in hexanes with formic acid 1%), yielding the desired product as a white solid ( 30 mg, 64%). MS m / z 715.5 (APCI-, M-1). [1213] The following compounds in Examples 2-35 were prepared according to procedures similar to those described above in Example 1, substituting N, N-dimethylsulfamide for other appropriate sulfonamides in Step F and / or substituting isoindoline for other amines instead. The sulfonamides used were obtained from commercial sources or were prepared through routes A or B described below in Scheme 2. Methods similar to those of Route A are described in the literature (eg Heteroatom Chemistry, 2001, 12 ( 1), 1-5). The sulfamollant reagent a in Route B was prepared according to a literature procedure (Winum, J-Y et al, Organic Letters, 2001, 3, 2241-2243). Route A: TFA H2N ° N C "Route B: Scheme 2 Synthesis of N-cyclopropylsulfamide

[1214] To a stirred solution of chlorosulfonyl isocyanate (1 ml, 11.5 mmol) in 20 ml of DriSolve DCM was added anhydrous t-butanol (1.1 ml, 1 equiv) at 0 ° C. After stirring for 90 min, the resulting solution of carbamatosulfamoyl chloride and 5 ml of TEA in 20 ml of DCM were added dropwise to a solution of cyclopropylamine (0.66 g, 1 equiv) in 25 ml of DCM and 3 ml of TEA. The reaction temperature was kept below 5 ° C during the addition. The ice bath was removed after the addition and the resulting mixture was stirred at rt for 3 h. [1215] 'The TLC (Hex / EA 1: 1) showed a large spot with a higher Rf. The LCMS showed that the product had been formed. The reaction mixture was then diluted with 100 ml of DCM and washed with 0.1 N HCl (2 x 200 ml) and saline (150 ml). The organic layer was dried over Na 2 SO 4 and concentrated, yielding the Boc-protected sulfamide as a light yellowish solid, 1.2 g. The XH-NMR showed that it was the desired product plus a small amount of impurities. The crude product was recrystallized from EA / Hex (rt at 0 ° C), obtaining 0.64 g of pure whitish crystalline product. XH NMR (CDC13, 400 MHz) 0.71-0.77 (m, 4 H), 1.51 (s, 9 H), 2.44 (m, 1 H), 5.58 (br s) , 1 H), 7.42 (br s, 1 H). MS m / z 234.7 (APCI-, M-1). [1216] To remove the Boc protecting group, the product from the previous step was dissolved in 10 ml of a 1: 1 (v / v) mixture of DCM: TFA and left at rt for 1 h. Then he concentrated on a rotovap and then a great vacuum. The thick oil solidified with a large vacuum, yielding the title product as a whitish solid. XH NMR (CDC13, 400 MHz) 0. 0.66-0.74 (m, 4 H), 2.57-2.58 (m, 1 H), 5.29 (br s, 2 H), 5 , 42 (br s, 1 H). Synthesis of pyrrolidinolsulfamide [1217] The title compound was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide above, substituting cyclopropylamine for pyrrolidine. For the title product protected with Boc: XH NMR (CDC13, 400 MHz) 0. 1.49 (s, 9H), 1.92-1.95 (m, 4 H), 3.48-3.52 ( m, 4 H), 7.02 (br s, 1 H). MS m / z 249 (APCI-, M-1).

[1218] The title compound was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide above, substituting cyclopropylamine for morpholine. For the title product protected with Boc: XH NMR (CDC13, 400 MHz) 0. 1.50 (s, 9 H), 3.39 (t, 4 H), 3.76 (t, 4 H), 7.18 (br s, 1 H). MS m / z 265 (APCI-, M-l)

[1219] The title compound was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide above, substituting cyclopropylamine for 2-amino thiazole. However, the Boc-protected intermediate was never isolated due to the loss of the protection group during the isolation and purification reaction and the following recrystallization steps. The title product was then isolated by silica gel column chromatography (Biotage 40 M, eluent = 5-10% MeOH in DCM). XH NMR (d6-DMSO, 400 MHz) 0. 6.52 (br s, 2 H), 6.75 (d, 1 H), 7.19 (d, 1 H), 12.1 (br s, 1 HOUR) . MS m / z 180 (BSI +, MH +). Synthesis of 4-methyl-piperizinsulfamide

[1220] The title compound was prepared according to Route B in Scheme 2. 4-methyl-piperizine was dissolved (0.15 g, 1.50 mmol) in 3 ml of DriSolve DCM in 10 ml RBF, followed by addition of the sulfamoylating reagent a (0.45 g, 1.50 mmol). After about 5 min of stirring the latter reagent gradually dissolved to obtain a clear and almost colorless solution. It was stirred at rt overnight. After 17 h, TLC showed that the reaction was complete (DCM: MeOH 9: 1 with TEA 1%). The reaction was concentrated and the resulting crude pinkish solid was subjected to flash chromatography on a Biotage 40 S silica gel column (eluent = DCM: MeOH 10: 1 with TEA 1%), yielding the title product protected with Boc as a white powder with basically quantitative performance. XH NMR (CDC13, 400 MHz) 0. 1.48 (s, 9 H), 2.33 (s, 3 H), 2.52 (t, 4 H), 3.43 (t, 4 H). MS m / z 278 (APCI-, M-1).

[1221] The Boc protecting group was then removed in the same manner as described in the synthesis of N-cyclopropylsulfamide and the resulting title product was used directly for the following coupling steps without further purification. Example 2 Compound 102 [1222]? L Compound 14-tert-butoxycarbonylamino-4- (N-cyclopropylsulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, O4'6] nonadec- 7-en-18-yl ester of the acid 15, 42? 6S, XAS, 182?) -l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in the Example 1, substituting N, N-dimethylsulfamide for N-cyclopropylsulfamide in Step F. MS m / z 728 (APCI-, Ml). Example 3: Compound 103 [1223]? L Compound 14-tert-butoxycarbonylamino-4- (pyrrolidinesulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, 0, O4'6] nonadec-7 iS, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid-18-yl ester was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide by pyrrolidinolsulfamide in Step F. MS m / z 742 (APCI-, Ml). Example 4: Compound 104 [1224] The compound 14-tert-butoxycarbonylamino-4- (morpholin-sulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en -I-ester, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid ester was synthesized according to the same procedures as described in Example 1, substituting N, N -dimethylsulfamide by morpholinolsulfamide in Step F. MS m / z 758 (APCI-, Ml). Example 5: Compound 105 [1225] The compound 14-tert-butoxycarbonylamino-4- (thiozol-2-ylaminosulfonylaminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14.3, 0, 04'6] ] nonadec-7-en-18-yl ester of the acid, S, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide for thiozoyl-2-ylaminosulfamide in Step F. XH NMR (400 MHz, d6-acetone) D. 1.15 (s, 9 H), 1.22-1.54 (m , 11 H), 1.60 (m, 1 H), 1.68-1.88 (m, 2 H), 2.35-2.45 (m, 3 H), 2.57 (, 1 H) ), 3.85 (m, 1 H), 4.15 (br d, 1 H), 4.48 (m, 1 H), 4.65 (m, 4 H), 4.74 (t, 1 H) ), 4.92 (t, 1 H), 5.43-5.52 (m, 2 H), 6.92 (d, 1H), 7.20-7.33 (m, 5 H), 8 , 18 (s, 1 H). MS m / z 770 (ESI-, M-1). Example 6: Compound 106 [1226] The compound 14-tert-butoxycarbonylamino-4- (N, N-dimethylsulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec -7-en-18-yl-ester of 1S acid, 4R, 6S, 14S, 18R) -5-fluoro-l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting isoindoline for 5-fluoroisoindoline in Step D XH NMR (400 MHz, CD3OD) D. 7.31 (q, 1H), 7.13 (d, 1H), 7.03-6.97 (m, 2H), 6.63 (br s, 1H ), 5.70 (q, 1H), 5.40 (br s, 1H), 5.07 (t, 1H), 4.78-4.51 (m, 7H), 4.10 - 4.02 (m, 1H), 3.83 (d, 1H), 2.84 (s, 6H), 2.73-2.64 (m, 1H), 2.55-2.47 (m, 1H), 2.43-2.29 (m, 3H), 1.84-1.67 (m, 4H), 1.64-1.57 (m, 2H), 1.13 (d, 9H), 0, 94-0.82 (m, 4H). MS m / z 733, 4 (APCI -, M-1). Example 7: Compound 107 [1227] The compound 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (N, N-dimethyl-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3, 0, 0, 63 nonadec 7-en-18-yl-ester of acid 15, 42 ?, 65, 145, 182?) -l-piperidin-l-ylmethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid was synthesized in accordance with the same procedures as described, in Example 1, substituting isoindoline for l-piperidin-l-ylmethyl-3,4-dihydro-1H-isoquinoline in Step D. XH NMR (400 MHz, CD3OD) 0. 7.32 -7.16 (m, 4H), 5.75-5.64 (m, 2H), 5.47 (br s, 1H), 5.05 (t, 1H), 4.52-4.45 ( m, 2H), 4.39 - 4.17 (m, 3H), 4.12 - 4.02 (m, 1H), 3.99 - 3.88 (m, 1H), 3.70 - 3, 38 (m, 6H), 3.14- 3.00 (m, 4H), 2.83 (d, 6H), 2.59-2.24 (m, 4H), 2.08-2.01 ( m, 2H), 1.98-1.65 (m, 10H), 1.63-1.51 (m, 4H), 1.23 (d, 9H), 0.92-0.84 (m, 1 HOUR) . MS m / z 826.6 (APCI-, M-1). Example 8: Compound 108 [1228]? L Compound 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (N-cyclopropyl-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14, 3, 0.0 '6] nonadec- 7-en-18-yl-ester of acid 15, 42? 6S, XAS, 182?) -l-piperidin-l-ylmethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid was synthesized in accordance with the same procedures as described in Example 1, substituting isoindoline for l-piperidin-l-ylmethyl-3,4-dihydro-1H-isoquinoline in Step D, and substituting N, N-dimethylsulfamide for N-cyclopropylsulfamide in the Step F. X H NMR (400 MHz, CD 3 OD) 0. 7.31 - 7.15 (m, 4 H), 5.75 - 5.58 (m, 2 H), 5.47 (br s, 1 H), 5 , 11 (t, 1H), 4.62 - 4.57 (m, 1H), 4.52-4.45 (m, 1H), 4.41 - 4.17 (m, 3H), 4.15 - 3.84 (m, 3H), 3.73 - 3.34 (m, 5H), 3.16 - 2.71 (m, 5H), 2.70 - 2.27 (m, 6H), 2 , 13-2.67 (m, 10H), 1.65-1.24 (m, 15H), 0.73-0.47 (m, 4H); MS m / z 838.4 (APCI-, M-1). Example 9: Compound 109 [1229]? l Compound 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (pyrrolidin-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14, 3.0, 04.6] nonadec-7-en-18-yl-ester of the acid 15, 42 ?, 65, 14S, 182?) -l-piperidin-l-ylmethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid was synthesized from according to the same procedures as described in Example 1, substituting isoindoline for l-piperidin-l-ylmethyl-3,4-dihydro-lH-isoquinoline in Step D and substituting N, N-dimethylsulfamide for pyrrolidinosulfamide in Step F XH NMR (400 MHz, CD3OD) D 8.94 (d, 1H), 7.31-7.16 (m, 4H), 5.75-5.62 (m, 2H), 5.48 (br. s, 1H), 5.08-4.99 (m, 1H), 4.66 -3.84 (m, 7H), 3.72-3.39 (m, 7H), 3.28-3, 20 (m, 2H), 3.17-2.25 (m, 10H), 2.12-1.99 (m, 2H), 1.98-1.66 (m, 11H), 1.64- 1.22 (m, 15H); . MS m / z 852.5 (APCI-, M-1). Example 10: Compound 110 [1230] The compound 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (morpholine-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3, 0.06] nonadec-7 en-18-yl ester of acid 15, 42? 6S, XAS, 182?) -l-piperidin-l-ylmethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid was synthesized according to the same procedures that were described in Example 1, substituting isoindoline for l-piperidin-l-ylmethyl-3,4-dihydro-lH-isoquinoline in Step D and substituting N, N-dimethylsulfamide for morpholinesulfonide in Step F. XH NMR ( 400 MHz, CD3OD) 0 7.33-7.14 (m, 4H), 5.78-5.63 (m, 2H), 5.47 (br s, 1H), 5.11 (t, 1H) , 4.63 - 3.84 (m, 7H), 3.74 - 3.36 (m, 9H), 3.29 - 3.19 (m, 3H), 3.16 - 2.14 (, 11H) ), 2.13-1.23 (m, 24H), 0.94-0.81 (m, 1H); . MS m / z 868.6 (APCI-, M-1). Example 11: Compound 111 [1231]? L Compound 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (pyrrolidin-1-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14,3, 0, 0, d] nonadec- 7-en-18-yl-ester of acid 15, 42? 6S, XAS, 182?) -1-morpholin-4-ylmethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid was synthesized in accordance with the same procedures as described in Example 1, substituting isoindoline for l-morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinoline in Step D and substituting N, N-dimethylsulfamide for pyrrolidinosulfamide in Step F. MS m / z 874.3 (APCI-, M + 18)? Step 12: Compound 112 [1232]? L Compound 14-tert-butoxycarbonylamino-2, 15-dioxo-4- (pyrrolidin-1-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.06] nonadec -7-en-18-yl ester of acid 15, 42 ?, 65, 145, 182?) - (2-morpholin-4-yl-l-phenyl-ethyl) -carbamic acid was synthesized according to the same procedures which were described in Example 1, substituting isoindoline for 2-morpholin-4-yl-l-phenylethylamine in Step D and substituting N, N-dimethylsulfamide for pyrrolidinosulfamide in Step F. MS m / z 828.3 (APCI-, Ml)? Jmplo 13: Compound 113 [1233]? L Compound 14-tert-butoxycarbonylamino-4- (N, N-dimethylsulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, 0, O4'6] nonadec-7-en-18-yl-ester of acid 15, 42 ?, SS, XAS, 182?) -5-chloro-l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as were described in Example 1, substituting isoindoline for 5-chloroisoindoline in Step D. MS m / z 651 (APCI +, M-Boc). Example 14: Compound 114 [1234] The compound 14-tert-butoxycarbonylamino-4- (N-cyclopropyl-sulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec -7-en-18-yl ester of acid 15, 42 ?, 65, 145, 182?) -5-chloro-l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting isoindoline for 5-chloroisoindoline in Step D and substituting N, N-dimethylsulfamide for N-cyclopropylsulfamide in Step F. MS m / z 663 (APCI +, M-Boc). Example 15: Compound 115 [1235] The compound 14-tert-butoxycarbonylamino-4- (pyrrolidin-sulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, O, O 4,6] nonadec-7 -in-18-yl ester of acid 15, 42 ?, 65, 145, 182?) -5-chloro-l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting isoindoline for 5-chloroisoindoline in Step D and substituting N, N-dimethylsulfamide for pyrrolidinosulfamide in Step F. MS m / z 677 (APCI +, M-Boc). Example 16: Compound 116 [1236] The compound 14-tert-butoxycarbonylamino-4 ~ (morpholin-sulfonyl-aminocarbonyl) -2, 15-dioxo-3,16-diaza-tricyclo [14.3.0, 04.6] nonadec-7 -in-18-yl ester of the acid 15, 42 ?, 6S, XAS, 182?) -5-chloro-l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting isoindoline for 5-chloroisoindoline in Step D and substituting N, N-dimethylsulfamide for morpholinesulfamide in Step F. MS m / z 693 (APCI +, M-Boc). Bj emplo 17: Compound 117 [1237] The compound 14-tert-butoxycarbonylamino-4- (azetidine-sulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6 ] nonadec-7-en-18-yl-ester of 1S, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindol-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide for azetidine-1-sulfonamide in Step F. XH ™ MR (400 MHz, ds-acetone) 0. 1.21 (s, 9 H), 1.28-1.54 ( m, 8 H), 1.59-1.63 (m, 1 H), 1.77-1.89 (m, 3 H), 2.38-2.42 (m, 1 H), 2, 46-2.52 (m, 2 H), 3.77 (t, 2 H), 3.84-3.94 (m, 3 H), 4.14-4.22 (m, 3 H), 4.50 (br d, 1 H), 4.61-4.72 (m, 5 H), 5.12 (t, 1 H), 5.44 (br s, 1 H), 5.78 (br. q, 1 H), 6.17 (br d, 1 H), 7.23-7.36 (m, 4 H), 8.38 (s, 1 H). MS m / z 727.4 (APCI-, M-1). Example 17a: o or [1238] The title compound, azetidin-1-sulfonamide, was prepared according to Route B in the Scheme 2. Azetidine (0.16 g, 2.8 mmol) was dissolved in 5.6 ml of DriSolve DCM in a 10 ml RBF, followed by addition of the sulfamoylating reagent a (0.85 g, 2.8 mmol) . After about 5 min of stirring the last reagent gradually dissolved to obtain a clear and almost colorless solution. It was stirred at rt overnight. After 17 h, TLC showed that the reaction was complete (DCM: MeOH 9: 1). The reaction was concentrated and the resulting crude white solid was subjected to flash chromatography on a Biotage 40 S silica gel column (eluent = MeOH / DCM 5 to 10%), yielding the title product protected with Boc in a basically quantitative yield . The product was initially a thick oil, which gradually solidified under high vacuum at night. XH NMR (CDC13, 400 MHz) 0. 1.52 (s, 9 H), 2.27 (m, 2 H), 4.15 (t, 4 H), 7.18 (br s, 1 H) . [1239] The product from the previous step (0.4 g, 2 mmol) was dissolved in 10 ml of a TFA / DCM mixture (1: 1 v / v) and left at rt for 2 h. Then the volatiles were removed. The resulting oily residue was treated with diethyl ether and filtered. The white powder product of the filtration was used for the coupling step without further purification. XH NMR (d6-Acetone, 400 MHz) 0. 2.12-2.19 (m, 2 H), 3.77 (t, 4 H), 6.05 (br s, 2 H). Example 18: Compound 118 [1240]? l Compound 14-tert-butoxycarbonylamino-4- (4-methylpiperazin-1-sulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3, 0, O4'6] nonadec-7-en-18-yl ester of IS, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as were described in Example 1, substituting N, N-dimethylsulfamide for 4-methylpiperazine-1-sulfonamide in Step F. XH NMR (400 MHz, ds-acetone) D. 1.21 (s, 9 H), 1 , 19- 1.58 (m, 9 H), 1.70-1.73 (m, 1 H), 1.85-1.88 (m, 2 H), 2.24 (s, 3 H), 2.36-2.48 (m, 7 H), 2.53 (m, 1 H), 3.24-3.29 (m, 4) H), 3.84-3.88 (m, 1 H), 4.14-4.18 (m, 1 H), 4.49 (br d, 1 H), 4.60-4.72 (m, 5 H), 5.04 (t, 1 H), 5.44 (br s, 1 H), 5.71 (q, 1 H), 6.16 (br d, 1 H), 7.23-7.36 (m, 4 H), 8.31 (s, 1 H). MS m / z 770.5 (APCI-, M-1). Example 19: Compound 119 [1241] The compound 14-tert-butoxycarbonylamino-4- (4- (2-trimethylsilylethoxycarbonyl) piperazine-1-sulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14.3, 0.04.6 nonadec-7-en-18-yl ester of the acid, S, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as were described in Example 1, substituting N, N-dimethylsulfamide for 4- (2-trimethylsilylethoxycarbonyl) piperazine-1-sulfonamide in Step F. XH NMR (400 MHz, d6-acetone) 0. 0.06 (s, 9H ), 0.94-0.98 (m, 2 H), 1.15 (s, 9 H), 1.17-1.50 (m, 8 H), 1.50-1.54 (m, 1 H), 1.65-1.68 (m, 1 H), 1.75-1.82 (m, 2 H), 2.30-2.44 (m, 3 H), 2.56- 2.68 (m, 1 H), 3.17-3.26 (m, 4 H), 3.44-3.47 (m, 4 H), 3.78-3.81 (m, 1 H) ), 4.08-4.14 (m, 3 H), 4.44 (br d, 1 H), 4.54-4.66 (m, 5 H), 4.98 (t, 1 H) , 5.38 (br s, 1 H), 5.56-5.63 (m, 1 H), 6.12 (br d, 1 H), 7.16-7.30 (m, 4 H), 8.26 (s, 1 H). MS m / z 901.3 (APCI-, Ml) Example 19a: [1242] The title compound, 4- (2-trimethylsilylethoxycarbonyl) piperazine-1-sulfonamide, was prepared according to Scheme 3 which is described below: Scheme 3

[1243] Step 1: Tert-butyl piperazine-1-carboxylate (1.0 g, 5.4 mmol) was dissolved in 10 ml of DriSolve DCM in a 50 ml RBF, followed by addition of the sulfamoylating reagent to (1.6 g, 5.4 mmol). After about 5 min of stirring the last reagent gradually dissolved to obtain a clear and almost colorless solution. It was stirred at rt overnight. After 17 h, TLC showed that the reaction was complete (DCM: MeOH 20: 1). The reaction was concentrated and the resulting crude white solid was subjected to flash chromatography on a Biotage 40 M silica gel column (eluent = 2% MeOH / DCM), yielding the Boc-protected product as a fluffy white solid. XH NMR (d6-acetone, 400 MHz) 0. 1.45 (s, 9 H), 1.46 (s, 9 H), 3.30-3.32 (m, 4 H), 3.48- 3.50 (m, 4 H). LCMS m / z 364.1 (APCI-, M-l).

[1244] Step 2: The product from step 1 above (0.90 g, 2.5 mmol) was dissolved in about 20 ml of a 1: 1 (v / v) mixture of TFA-DCM and left at rt for 2 hours Then he concentrated. The solid residue was taken in MeCN and re-concentrated, the unprotected product being obtained as a white fine powder. [1245] To this unprotected product was added 20 ml of DriSolve DCM, followed by 1 ml of T? A. To the resulting white suspension was added Teoc-succimate (0.70 g, 2.7 mmol) in one portion under stirring. The white suspension disappeared rapidly and the clear colorless solution was stirred at rt overnight. The reaction was then concentrated and purified by chromatography on silica (Biotage 40 S, eluent = Hex: BA 2: 1), obtaining the pure product as a white solid, 0.65 g (85%). XH NMR (d6-acetone, 400 MHz) 0. 0.06 (s, 9 H), 0.94-0.98 (m, 2 H), 3.01 (t, 4 H), 3.48 ( t, 4 H), 4.10-4.14 (m, 2 H), 6.03 (br s, 2 H). LCMS m / z 308.2 (APCI-, M-1). Example 20: Compound 120 [1246]? L Compound 14-tert-butoxycarbonylamino-4- (piperazin-1-sulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3, 0, 04'6] nonadec-7-en-18-yl-ester of 1S acid, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid was synthesized by removal of the protective group from the compound 119. Compound 119 (54.8 mg, 60.7 Omol) was first dissolved in 0.5 ml of DriSolve THF, followed by addition of a 1.0 M solution of TBAF THF (0.2 ml, 200 Omol). The reaction was heated in an oil bath at 60 ° C for 2 hrs and TLC showed that the reaction was complete. The reaction was purified by chromatography on silica (Biotage 12 M, eluent = 0 to 20% MeOH in DCM), obtaining the compound 120 as a white solid, 42.4 mg (92%). MS m / z 756.4 (APCI-, M-1). Bj emplo 21: Compound 121 [1247] The compound 14-tert-butoxycarbonylamino-4- (N-cyclopropylsulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04, s] nonadec-7 -in-18-yl ester of acid 15, 42 ?, 65, 145, 182?) -4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide for N-cyclopropylsulfamide in Step F. X H NMR (500 MHz, CD 3 OD) 0. 8.91 (d, 1 H), 7.32 (q, 1 H), 7.14 (d, 1H), 7.01 (t, 1H), 5.63 (q, 1H), 5.40 (br s, 1H), 5.13 (t, 1H), 4.80 - 4.68 (m, 4H), 4.61 (q, 1H), 4.56-4.49 (, 1H), 4.06 (t, 1H), 3.83 (br s, 1H), 3.72 ( p, 1H), 3.22 (p, 1H), 2.72-2.60 (m, 1H), 2.57-2.48 (m, 1H), 2.46-2.31 (m, 4H), 1.83-1.69 (m, 4H), 1.66-1.58 (m, 1H), 1.56-1.19 (, 5H), 1.13 (d, 9H), 0.71 - 0.51 (m, 4H). MS m / z 745.3 (APCI-, M-1). Example 22: Compound 122 [1248] The compound 14-tert-butoxycarbonylamino-4- (aminosulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7-en -18-yl ester of IS, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindol-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N - di-ethylsulfamide by sulfamide in Step F. MS m / z 688.2 (APCI-, Ml). ? jmplo 23 Compound 123 [1249]? L Compound 14-tert-butoxycarbonylamino-4- (N- (1-cyanocyclopropyl) aminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, O4] '6] nonadec-7-en-18-yl-ester of 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide for 1-cyanocyclopropylsulfamide in Step F. XH NMR (400 MHz, d6-acetone) D. 1.22 (s, 9 H), 1.20-1.55 ( m, 11 H), 1.58-1.61 (m, 1 H), 1.66-1.69 (m, 1H), 1.71-1.75 (m, 1 H), 1.81 -1.90 (m, 2 H), 2.42-2.48 (m, 3 H), 2.60-2.70 (m, 1 H), 3.84-3.88 (m, 1) H), 4.16-4.20 (m, 1 H), 4.48 (br d, 1 H), 4.58-4.71 (m, 5 H), 5.07 (t, 1 H) ), 5.44 (br s, 1 H), 5.62 (q, 1 H), 6.14 (br d, 1 H), 7.22-7.36 (m, 4 H), 7.88 (br s, 1 H), 8.20 (s, 1 H). MS m / z 752.3 (APCI-, Ml)? Jpha 23a: [1250]? The title compound, 1-cyanocyclopropylsulfamide, was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide ( Route A, Scheme 2), substituting cyclopropylamine for 1-aminociclopropanecarbonitrile hydrochloride. XH NMR (CDC13, 400 MHz) 0.141.44 (m, 2 H), 1.52-1.55 (, 2 H), 5.86 (br s, 2 H), 7, 19 (br s, 1 H). ? j 24 Compound 124 [1251] The compound 14-tert-butoxycarbonylamino-4- (cyclopropyl (l-methylpiperidin-4-yl) aminosulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14.3, , 04'6] nonadec-7-en-18-yl ester of IS, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide for cyclopropyl (l-methylpiperidin-4-yl) sulfamide in Step F. XH NMR (400 MHz, d6-acetone) 0.75-0.77 (m , 2 H), 0.96-1.01 (m, 2 H), 1.21 (s, 9 H), 1.20-1.57 (m, 7 H), 1.60-1.66 (m, 1 H), 1.71-1.74 (m, 1 H), 1.80-1.92 (m, 3 H), 1.97-2.06 (m, 1H), 2, 38-2.60 (m, 5 H), 2.68 (s, 3 H), 2.88-3.02 (m, 2H), 3.32-3.41 (m, 2 H), 3 , 90-3.96 (m, 2 H), 4.17-4.23 (m, 2 H), 4.41-4.47 (m, 2 H), 4.59-4.72 (m , 5 H), 5.10 (t, 1 H), 5.45 (br s, 1 H), 5.63-5.70 (m, 1 H), 6.11 (br d, 1H), 6.95 (s, 1 H), 7.19-7.35 (m, 4 H), 8.42 (s, 1 H). MS m / z 824.4 (APCI-, M-1). Example 24a:

[1252] The title compound, cyclopropyl (1-methylpiperidin-4-yl) sulfamide, was prepared in the same manner as that described in Example 17a, substituting azetidine for N-cyclopropyl-l-methylpiperidin-4-amine . XH NMR (d6-DMS0, 400 MHz) 0. 0.67-0.76 (m, 4 H), 1.93-1.97 (m, 2 H), 2.07-2.18 (m, 2 H), 2.22-2.26 (m, 1 H), 2.75 (s, 3 H), 2.96-3.05 (m, 2 H), 3.45-3.48 (m, 2 H). m, 2 H), 3.77-3.83 (m, 1 H), 6.93 (br s, 2 H), 9.78 (br s, 1 H). Example 25: Compound 125 [1253]? l Compound 14-tert-butoxycarbonylamino-4- (2-cyanoethyl (cyclopropyl) aminosulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14.3, 0, 04'6] nonadec-7-en-18-yl ester of the acid, S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as were described in Example 1, substituting N, N-dimethylsulfamide for 2-cyanoethyl (cyclopropyl) sulfamide in Step F. XH NMR (400 MHz, d6-acetone) D. 0.74-0.78 (m, 2 H), 0.98-1.01 (m, 2 H), 1.21 (s, 9 H), 1.20-1.54 (m, 7 H), 1.59-1.63 (m , 1 H), 1.74-1.77 (m, 1 H), 1.82-1.87 (m, 2 H), 2.41-2.65 (m, 6H), 2.79- 2.83 (m, 2H), 3.49-3.56 (m, 1 H), 3.84-3.88 (m, 1 H), 3.97-4.04 (m, 1 H) , 4.14-4.18 (m, 1 H), 4.50 (br d, 1 H), 4.60-4.72 (m, 5 H), 5.05 (t, 1 H), 5.45 (br s, 1 H), 5.68 (q, 1 H), 6.15 (br d, 1H), 7.22-7.36 (m, 4 H), 8.33 (s, 1 H). MS m / z 781.3 (APCI-, M). Example 25a:

[1254] The title compound, 2- cyanoethyl (cyclopropyl) sulfamide, was prepared in the same manner as that described in Example 17a, substituting azetidine for 3- (cyclopropylamino) propan-nitrile. XH NMR (d6-DMSO, 400 MHz) 0. 0.68-0.76 (m, 4 H), 2.36-2.37 (m, 1 H), 2.78 (t, 2 H), 3.35 (t, 2 H), 7.05 (br s, 2 H). Example 26: Compound 126 [1255]? L Compound 14-tert-butoxycarbonylamino-4- (?,? - diisopropylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04'6] n-S-7-en-18-yl ester of SS, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in the Example 1, substituting?,? - dimethylsulfamide for?,? - diisopropylsulfamide in Step F. XH? MR (400 MHz, d6-acetone) 0. 1.21 (s, 9 H), 1.25-1.53 ( m, 20 H), 1.68-1.71 (m, 1 H), 1.81-1.87 (m, 2 H), 2.38-2.45 (m, 3 H), 2, 56-2.68 (m, 1 H), 3.84-3.87 (m, 1 H), 3.94-4.01 (m, 2 H), 4.14-4.18 (m, 1 H), 4.47 (br d, 1 H), 4.58-4.68 (m, 5 H), 5.03 (t, 1 H), 5.44 (br s, 1 H), 5.62 (q, 1 H), 6.11 (br d, 1H), 7.23-7.36 (m, 4 H), 8.24 (s, 1 H), 10.29 (br s) , 1 HOUR) . MS m / z 772, 3 (APCI-, M). ? jmplo 26a:

[1256] The title compound, N, N-diisopropylsulfamide, was prepared in the same manner as that described in Example 17a, substituting azetidine for diisopropylamine. XH NMR (d6-acetone, 400 MHz) 0. 1.23 (d, 12 H), 3.70-3.77 (m, 2 H), 5.67 (br s, 2 H). Example 27: Compound 127 [1257]? L Compound 14-tert-butoxycarbonylamino-4- (phenylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14,3,0, 04, s] nonadec-7 1S, 4R, 6S, 14S, 18R) -1,3-Dihydro-isoindole-2-carboxylic acid ester-18-yl ester was synthesized according to the same procedures as described in Example 1, substituting N, N-di-ethylsulfamide by phenylsulfamide in Step F. XH NMR (400 MHz, d6-acetone) 0. 1.20 (s, 9 H), 1.20-1.50 (m, 8 H), 1.60-1.70 (m, 2 H), 1.78- 1.86 (m, 1 H), 2.30-2.44 (m, 4 H), 3.81-3.85 (m, 1 H), 4.12-4.17 (m, 1 H) ), 4.45 (br d, 1 H), 4.54-4.75 (m, 6 H), 5.28 (q, 1 H), 5.43 (br s, 1 H), 6, 11 (br d, 1 H), 7.14-7.35 (m, 9 H), 8.22 (s, 1 H), 8.97 (br s, 1 H), 10.80 (br s, 1 HOUR) . MS m / z 764.3 (APCI-, M). Example 27a:

[1258] The title compound, phenylsulfamide, was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), substituting cyclopropylamine for aniline. XH NMR (d6-DMSO, 400 MHz) 0. 6.95-6.98 (m, 1 H), 7.06 (br s, 2 H), 7.14-7.16 (m, 2 H) , 7.24-7.28 (m, 2 H), 9.46 (br s, 1 H). Example 28: Compound 128 [1259]? L Compound 14-tert-butoxycarbonylamino-4- (4-chlorophenylaminosulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec- 7-en-18-yl ester of the acid, S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindol-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide by 4-chlorophenylsulfamide in Step F. X H NMR (400 MHz, d6-acetone) O. 1.19 (s, 9 H), 1.18-1.51 (m, 8 H), 1.61-1.72 (m, 2 H), 1.76-1.87 (m, 1 H), 2.32-2.44 (m, 4) H), 3.82-3.86 (m, 1 H), 4.12-4.16 (m, 1 H), 4.45 (br d, 1 H), 4.54-4.72 ( m, 6 H), 5.28 (q, 1 H), 5.43 (br s, 1 H), 6.10 (br d, 1 H), 7.22-7.38 (m, 8 H) , 8.24 (s, 1 H). MS m / z 798.2 (APCI-, M). Example 28a:

[1260] The title compound, 4-chlorophenylsulfamide, was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), substituting cyclopropylamine for 4-chlorobenzenamine. XH NMR (d6-DMSO, 400 MHz) 0. 7.09-7.12 (m, 4 H), 7.27 (d, 2 H), 9.59 (br s, 1 H). Example 29: Compound 129 [1261]? L Compound 14-tert-butoxycarbonylamino-4- (4-methoxyphenylaminosulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec- 7-en-18-yl ester of 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide by 4-methoxyphenylsulfamide in Step F. XH? MR (400 MHz, d6-acetone) 0. 1.20 (s, 9 H), 1.18-1.54 (m, 8 H) , 1.64-1.87 (m, 3 H), 2.22-2.46 (m, 4 H), 3.80 (s, 3 H), 3.77-3.82 (m, 1 H), 4.14 (m, 1 H), 4.43 (br d, 1 H), 4.52-4.70 (m, 5 H), 4.88 (t, 1 H), 5, 40-5.50 (m, 2 H), 6.10 (br d, 1 H), 6.88-6.90 (d, 2 H), 7.18-7.35 (m, 6 H), 8.18 (s, 1 H). MS m / z 794.3 (APCI-, M). Example 29a:

[1262] The title compound, 4-methoxyphenylsulfamide, was prepared according to the same procedures as described for the synthesis of β-cyclopropylsulfide (Route A, Scheme 2), substituting cyclopropylamine for 4-methoxybenzenamine. XH ™ MR (d6-DMSO, 400 MHz) 0. 3.71 (s, 3 H), 6.85-6.87 (m, 4 H), 7.11 (d, 2 H), 9.01 (br s, 1 H). Example 30: Compound 130 [1263] The compound 14-tert-butoxycarbonylamino-4- (4-methylphenylaminosulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14, 3, 0, O4'6] nonadec-7 -in-18-yl ester of 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N , N-dimethylsulfamide by 4-methylphenylsulfamide in Step F. XH NMR (400 MHz, d6-acetone) 0. 1.20 (s, 9 H), 1.20-1.52 (m, 8 H), 1 , 60-1.74 (m, 2 H), 1.76-1.87 (m, 1 H), 2.26-2.42 (m, 4 H), 2.31 (s, 3 H) , 3.81-3.84 (m, 1 H), 4.14-4.17 (m, 1 H), 4.44 (br d, 1 H), 4.52-4.79 (m, 6 H), 5.32 (q, 1 H), 5.42 (br s, 1 H), 6.11 (br d, 1 H), 7.14-7.35 (m, 8 H), 8 , 20 (s, 1 H), 8.79 (br s, 1 H), 10.69 (br s, 1 H). MS m / z 778.2 (APCI-, M). Example 30a:

[1264] The title compound, 4-methylphenylsulfamide, was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), substituting cyclopropylamine for 4-methylbenzenamine. X H NMR (d 6 -DMSO, 400 MHz) 0. 2.18 (s, 3 H), 6.91 (s, 2 H), 7.01 (s, 4 H), 9.20 (s, 1 H) ). Example 31: Compound 131 [1265] The compound 14-tert-butoxycarbonylamino-4- (4-cyano-phenylaminosulfonyl-aminocarbonyl) -2,1-dioxo-3,16-diaza-tricyclo [14, 3.0, 04'6] nonadec-7 -I-S, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid ester was synthesized according to the same procedures as described in Example 1, substituting N , N-dimethylsulfamide by 4-cyanophenylsulfamide in Step F. XH? MR (400 MHz, d6-acetone) 0. 1.20 (s, 9 H), 1.18-1.53 (m, 8 H), 1.60-1.70 (m, 2 H), 1.76-1.87 (m, 1 H), 2.32-2.48 (m, 4 H), 3.85-3.88 (m. m, 1 H), 4.15-4.17 (m, 1 H), 4.46 (br d, 1 H), 4.57-4.71 (m, 6 H), 5.16 (q , 1 H), 5.46 (br s, 1 H), 6.10 (br d, 1 H), 7.24-7.35 (m, 4 H), 7.42 (d, 2 H), 7.76 (d, 2 H), 8.28 (s, 1 H). MS m / z 788.3 (APCI-, M-1). Example 31a:

[1266] The title compound, 4-cyanophenylsulfamide, was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), substituting cyclopropylamine for 4-aminobenzonitrile. XH NMR (d6-DMSO, 400 MHz) 0. 7.22 (d, 2 H), 7.40 (br s, 2 H), 7.70 (d, 2 H), 10.24 (br s, 1 HOUR) . Example 32: Compound 132 [1267] The compound 14-tert-butoxycarbonylamino-4- (4-trifluoromethylphenylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14,3, 0, 04'6] nonadec-7 -I-ester, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid ester was synthesized according to the same procedures as described in Example 1, substituting N , N-dimethylsulfamide by 4-trifluoromethylphenylsulfamide in Step F. XH NMR (400 MHz, d6-acetone) D. 1.19 (s, 9 H), 1.18-1.64 (m, 10 H), 1 , 82 (q, 1 H), 2.30-2.46 (m, 4 H), 3.84-3.87 (m, 1 H), 4.12-4.16 (m, 1 H), 4.47 (br d, 1 H), 4.57-4.71 (m, 6 H), 5.11 (q, 1 H), 5.45 (s, 1 H), 6.12 (br d, 1 H), 7.23-7.35 (m, 4 H), 7.45 (d, 2 H), 7.69 (d, 2 H) , 8.30 (s, 1 H), 9.53 (br s, 1 H), 11.06 (br s, 1 H). MS m / z 832.2 (APCI-, M).

Example 32a:

[1268] The title compound, 4-trifluoromethylphenylsulfamide, was prepared according to the same procedures as described for the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), substituting cyclopropylamine for 4- (trifluoromethyl) benzenamine. H NMR (d6-DMSO, 400 MHz) 0. 7.26-7.30 (m, 4 H), 7.59 (d, 2 H), .05 (br s, 1 H). Example 33: Compound 133 [1269] The compound 14-tert-butoxycarbonylamino-4- (cyclobutylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 0] nonadec-7-en -18-yl ester of 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N -dimethylsulfamide by cyclobutylsulfamide in Step F. XH NMR (400 MHz, ds-acetone) D. 1.21 (s, 9 H), 1.20-1.70 (m, 11 H), 1.80-1 , 90 (m, 2 H), 2.02-2.09 (m, 2 H), 2.21-2.30 (m, 2 H), 2.41-2.47 (m, 3 H) , 2.58-2.68 (m, 1 H), 3.75-3.87 (m, 2 H), 4.15-4.18 (m, 1 H), 4.47 (br d, 1 H), 4.57-4.72 (m, 5 H), .11 (t, 1 H), 5.44 (s, 1 H), 5.63 (q, 1 H), 6.14 (br d, 1H), 6.34 (br d, 1 H), 7.23-7.36 (m, 4 H), 8.18 (s, 1 H). MS m / z 741.4 (APCI-, M-1). Example 33a: N NH2 H [1270] The title compound, cyclobutylsulfamide, was prepared in the same manner as that described in Example 17a, substituting azetidine for cyclobutanamine. XH NMR (d6-DMSO, 400 MHz) 0. 1.20-1.60 (m, 2 H), 1.89-1.94 (m, 2 H), 2.14-2.21 (m, 2 H), 3.67 (m, 1 H), 6.42 (br s, 2 H), 6.82 (br s, 1 H). Example 34 Compound 134 [1271] The compound 14-tert-butoxycarbonylamino-4- (cyclopentylaminosulfonyl-aminocarbonyl) -2, 15-dioxo-3,16-diaza-tricyclo [14, 3, 0, O4'6] nonadec-7-en -18-yl ester of 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide by cyclopentylsulfamide in Step F. X H ™ MR (400 MHz, d6-acetone) 0. 1.21 (s, 9 H), 1.20-1.73 (m, 15 H), 1.87 -1.96 (m, 4 H), 2.41-2.49 (m, 3 H), 2.56-2.68 (m, 1 H), 3.55-3.60 (m, 1) H), 3.84-3.87 (m, 1 H), 4.15-4.18 (m, 1 H), 4.48 (br d, 1 H), 4.57-4.72 ( m, 5 H), 5.08 (t, 1 H), 5.44 (s, 1 H), 5.63 (q, 1 H), 6.15 (br d, 1H), 6.24 ( br d, 1 H), 7.23-7.35 (m, 4 H), 8.25 (s, 1 H), 10.25 (br s, 1 H). MS m / z 755.4 (APCI-, M-1). Example 34a:

[1272] The title compound, cyclopentylsulfamide, was prepared in the same manner as that described in Example 17a, substituting azetidine for cyclopentanamine. XH MR MR (d6-DMSO, 400 MHz) 0. 1.43-1.61 (m, 6 H), 1.80-1.83 (m, 2 H), 3.54 (m, 1 H) , 6.42 (br s, 3 H). Example 35: Compound 135 [1273] The compound 14-tert-butoxycarbonylamino-4- (cyclohexylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, O, 04, s] nonadec-7 iS, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindole-2-carboxylic acid-18-yl ester was synthesized according to the same procedures as described in Example 1, substituting N, N-dimethylsulfamide by cyclohexylsulfamide in Step F. XH? MR (400 MHz, dd-acetone) D. 1.21 (s, 9 H), 1.14-2.0 (m, 21 H), 2.41 -2.48 (m, 3 H), 2.57-2.67 (m, 1 H), 3.07-3.16 (, 1 H), 3.84-3.87 (m, 1 H) ), 4.15-4.19 (m, 1 H), 4.47 (br d, 1 H), 4.57-4.72 (m, 5 H), 5.08 (t, 1 H) , 5.44 (s, 1 H), 5.64 (q, 1 H), 6.13-6.17 (m, 2H), 7.23-7.36 (m, 4 H), 8, 23 (s, 1 H), 10.30 (br s, 1 H). MS m / z 769.4 (APCI-, M-1). [1274] Example 35a: Compound 136 Synthesis of 14-amino-4- (α, β-dimethylsulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14, 3, 0, 04, 6] nonadec-7-en- 18-yl ester of (1S, 4R, 6S, 14S, 18R) -l, 3-dihydro-isoindol-2-carboxylic acid, Salt HCl (Compound 136) [1275] Was synthesized by taking Compound 101 (79 mg) in 0.5 ml of 4 M HCl / Dioxane and stirred at rt for 16 h. The reaction was then concentrated and taken up in acetonitrile to re-concentrate it. The hydrochloride salt was then dried overnight with a large vacuum pump to obtain the product as a white solid (76 mg). + APCI MS m / z 617.1 (M + 1). Example 35b:

[1276] The title compound, cyclohexylsulfamide, was prepared in the same manner as that described in Example 17a, substituting azetidine for cyclohexanamine. XH NMR (ds-DMSO, 400 MHz) 0. 1.08-1.23 (m, 5 H), 1.50-1.54 (m, 1 H), 1.65-1.68 (m, 2 H), 1.86-1.89 (m, 2 H), 3.02 (m, 1 H), 6.40 (br s, 3 H). Example 36: NS3-NS4 Protease Assay NS3 Complex Formation with NS4A-2. [0001] [1277] The full-length NS3 was diluted E. coli or Recombinant Baculovirus up to 3.33 μM with assay buffer and the material was transferred to an Eppendorf-type tube which was placed in a water bath cooled to A ° C. The appropriate amount of NS4A-2 was added. achieve a concentration of 8.3 mM in assay buffer to equalize the volume of NS3 in step 2.1.1 (conversion factor - 3.8 mg / 272 μL assay buffer). The material was transferred to an Eppendorf tube and placed in a water bath cooled to 4o C. [1278] After arriving at the equilibrium at 4 ° C, equal volumes of the NS3 and NS4A-2 solution were combined in a? ppendorf type tube, were mixed gently with a manual pipettor, and the mixture was incubated for 15 minutes in the water bath at A ° C. The final concentrations in the mixture are 1.67 μM of NS3, 4.15 mM of NS4A-2. { 2485-fold in molar excess of NS A-2). [1279] After 15 minutes at 4 ° C, the tube with NS3 / NS4A-2 was removed and placed in a water bath at room temperature for 10 minutes. The? S3 /? S4A-2 was divided into aliquots of appropriate volumes and stored at -80 ° C (NS3 from E. coli run at 2 nM in the assay, aliquots from 25 μL.? S3 from BV to 3 nM in the assay, aliquots of 30 μL). Example 37:? S3 inhibition assay [1280] Step 2.2.5. The test compounds were dissolved to a concentration of 10 mM in DMSO and then diluted to a concentration of 2.5 mM (1: 4) in DMSO. Typically, the compounds were added to a test plate in a concentration of 2.5 mM, giving an initial concentration, after dilution, of 50 μM in the inhibition curve of the assay. Serial dilutions of the compounds in assay buffer were made to provide test solutions at lower concentrations. [1281] Step 2.2.6. The NS3 / NS4A-2 from E. coli was diluted to a concentration of 4nM of NS3 (1: 417, 5 of 1.67 μM of stock solution - 18 μL of 1.67 μM stock solution + 7497 μL of assay buffer). The NS3 / NS4A-2 from BV was diluted to a concentration of 6 nM of NS3 (1: 278.3 of 1.67 μM of stock solution - 24 μL of 1.67 μM of stock solution + 6655 μL of buffer solution of test) . [1282] Step 2.2.7. Using the multi-channel manual pipettor, and taking care not to introduce bubbles into the plate, 50 μL of assay buffer was added to the A01-H01 cavities of a Costar black polypropylene 96-well storage plate. [1283] Step 2.2.8. Using the multi-channel manual pipettor, and being careful not to introduce bubbles into the plate, 50 μL of NS3 / NS4A-2 from step 2.2.6 was added to cavities A02-H12 of the plate in step 2.2.7. [1284] Step 2.2.9. Using the multi-channel manual pipettor, and taking care not to introduce bubbles into the plate, 25 μL was transferred from the cavities of the drug dilution plate from step 2.2.5 to the corresponding cavities in the test plate of the Step 2.2.8. The tips of the multi-channel pipettor were changed before transferring each of the rows of compounds. [1285] Step 2.2.10. Using the manual multi-channel pipettor, and taking care not to introduce bubbles into the plate, the contents of the cavities of the assay plate of step 2.2.9 were mixed by aspirating and dispensing 35μL of the 75μL of each cavity, five times . The tips of the multi-channel pipettor were changed before mixing each of the rows of compounds. [1286] Step 2.2.11. The plate was covered with a cover for polystyrene plates, and the plate from step 2.2.10 containing the NS3 protease and the test compounds was preincubated for 10 minutes at room temperature. [1287] While the plate from step 2.2.11 was in preincubation, the RETS1 substrate was diluted in a 15 ml polypropylene centrifuge tube. The substrate R? TS1 was diluted to a concentration of 8 μM (1: 80.75 of 646 μM of stock solution - 65 μL of 646 μM of stock solution + 5184 μL of assay buffer). [1288] After the plate from step 2.2.11 had pre-incubated, and using the multi-channel manual pipettor, 25 μL of substrate was added to all the wells of the plate. Quickly, all the contents of the plate cavities were mixed, as in step 2.2.10, but mixing 65μL of the lOOμL contained in the cavities. [1289] The plate was read in the kinetic mode with the Molecular Devices SpectraMáx Gemini XS plate reader. Read settings: Reading time: 30 minutes, Interval: 36 seconds, Readings: 51,? Xcitation?: 335 nm,? Mission ?: 495 nm, Cut: 475 nm, Automatic mixing: off, Calibration: once, PMT : height, Readings / cavity: 6, Vmax pts: 21 or 28/51 depending on the length of the linearity of the reaction. [1290] The IC50 were determined using a four-parameter curve fitting equation, and then converted to Ki using the following Km: full length NS3 of E. coli - 2.03 μM full-length NS3 of BV-1, 74 μM where Ki = IC50 / (1+ [S] / Km)) Quantification by BLISA of the selectable marker protein, Neomycin phosphotransferase II (NPTII) in the subgenomic Replicon of HCV, GS4.3 [1291]? Subgenomic replicon of the HCV (I377 / NS3-3 ', Accession No. AJ242652), maintained stably in HuH-7 hepatoma cells, was created by Lohmann et al. Science 285: 110-113 (1999). The cell culture containing the replicon, designated GS4.3, was obtained from Dr. Christoph Seeger of the Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania. [1292] GS4.3 cells were maintained at 37 ° C, 5% C02, in DMβM (Gibco 11965-092) supplemented with 200mM L-glutamine (100X) (Gibco25030-081), non-essential amino acids (NEAA) (Bio hittaker 13-114E), Bovine Fetal Serum (FBS) (Hyclone SH3007.03) inactivated by heat (Hl) and 750 μg / ml of geneticin (G418) (Gibco 10131-035). The cells were subdivided 1: 3 or 1: 4 every 2-3 days. [1293] Twenty-four hours before the assay, GS4.3 cells were collected, counted and distributed in 96-well plates (Costar 3585) at 7500 cells / well in 100 μl of standard maintenance medium (above) and incubated in the conditions that were detailed above. To start the assay, the culture medium was removed, the cells were washed once with PBS (Gibco 10010-023) and 90 μl of Test Medium was added (DMEM, L-glutamine, NEAA, 10% HL FBS, no G418). Inhibitors were obtained as a 10X stock solution in Test Medium, (3 times more diluted from 10 μM to a final concentration of 56 pM, final concentration of DMSO of 1%), 10 μl was added to duplicate the cavities, they were oscillated the plates to mix them, and they were incubated in the same way as described above for 72h. [1294] A set of NPTII elements was obtained for Elisa from AGDIA, Inc. (Direct ELISA Test System for Compounds, for Neomycin Phosphotransferase II, PSP 73000/4800). The supplier's instructions were followed, with some modifications. The 10X lysis buffer solution of PEB-1 was obtained to include 500 μM of PMSF (Sigma P7626, 50 mM stock solution in isopropanol). After 72 hours of incubation, the cells were washed once with PBS and 150 μl of PBB-1 was added with PMSF in each well. The plates were shaken vigorously for 15 minutes, at room temperature, then they were frozen at -70 ° C. The plates were thawed, the lysates were thoroughly mixed, and 100 μl was applied to a Blisa NPTII plate. A standard curve was made. Aliquots were prepared from the lysates of control cells treated with DMSO, serial dilutions were made with P? B-1 and with PMSF, and were applied to the duplicate cavities of the BLISA plate, in a range of an initial lysate amount of 150 μl-2.5 μl. In addition, 100 μl of the buffer solution alone was duplicated as a blank. Plates were sealed and gently shaken at room temperature for 2 h. After the capture incubation, the plates were washed with 300μl of 5X PBS-T (0.5% T een-20, PBS-T were provided in the set of ELISA elements). For detection, a dilution of IX of the conjugate diluent of the enzyme MRS-2 (5X) was made in PBS-T, in which 1: 100 dilutions of the conjugates of enzyme A and B were added, as described in the instructions. The plates were sealed again and incubated with shaking, covered, at room temperature, for 2 h. The wash was then repeated and 100 μl of TMB substrate was added at room temperature. After approximately 30 minutes of incubation (room temperature, shaking, with coverage), the reaction was stopped with 50 μl of 3M sulfuric acid. Plates were read at 450 nm in a Molecular Devices Versmax plate reader. [1295] The inhibitory effect was expressed as a percentage of the control signal treated with DMSO, and the inhibition curves were calculated using a 4-parameter equation: y = A + ((BA) / (1+ ((C / x ) D))), where C is half the maximum activity or EC50. Examples of activity: Where: A indicates an IC50 or EC50 less than 1 μM and B indicates an IC50 or EC50 less than 0.1 μM Table 3 Example 38: "Specificity" [1296] When the compounds were tested in specificity assays, the compounds of Formula I were found to be selective in that they do not show significant inhibition in Cathepsin B, Chymotrypsin, Thrombin or Leukocyte Blastase . Example 39: Pharmacokinetic analysis of compounds [1297] Compounds were synthesized and initially evaluated for potency (IC50) in a fluorogenic NS3 / 4 protease assay and in a cell-based HCV replicon system in the same way in what was described above. Next, a pharmacokinetic analysis of plasma in Rattus sp. followed by administration of IV in conjunction with in vitro studies of human liver microsomes (HLM) and the stability of hepatocytes, to direct the design of metabolically stable compounds from compounds with < 20 nM of power. These determinations were later optimized further in terms of their physical properties, similar to those of drugs, and administered orally in 2? attus sp. to determine liver, heart and plasma concentrations. Methods [1298] Some compounds were initially synthesized and evaluated for potency (IC50) in a fluogenic assay of the NS3 / 4 protease and in a cell-based HCV replicon system, described in Example 8 which was find above. Next, the pharmacokinetic analysis of the plasma in Rattus sp. after administration of IV in conjunction with in vitro studies of human liver microsomes (HLM) and the stability of hepatocytes to direct the design of metabolically stable compounds from compounds with < 20 nM of power. These determinations were later optimized further in terms of their physical properties, similar to those of drugs, and administered orally in 2? Attus sp. to determine liver, heart and plasma concentrations. [1299] The compounds were evaluated for their liver cleanliness over time after a single oral dose of 3 mg / kg in rats. Additional toxicological determinations were made in rats for those compounds that showed a concentration, at 8 hours after administration, that was at least 100 times greater than the concentration of the compound that is effective to inhibit 50% of the maximum inhibition in the replicon assay (EC50 of the replicon), using oral doses of up to 30 mg / kg of the IDB for seven days. Results [1300] Compound AR334187 gave an EC50 value of the replicon of approximately 2 nM and exhibited in vitro stability in incubation assays in rat, dog and human hepatocytes, whose data would predict low to moderate liver cleansing rates. In addition, this compound showed a high degree of selectivity against a panel of other serine proteases, and no significant inhibition of Cytochrome P450 isoforms or channel activity h? RG, even at the highest concentrations evaluated (10 μM) . [1301] For the compound AR334187, a single oral dose of 30 mg / kg in 2? Attus sp. exhibited a concentration in the liver after 24 h from the dose that was at least 200 times greater than the EC50 value of the replicon of the compound. [1302] Compound AR334187 exhibited heart and plasma levels that were up to two orders of magnitude less than, and kinetically correlated with, hepatic concentrations in the same animals. Using a more reasonable oral dose in clinical terms (3 mg / kg), the compound AR334187 exhibited a concentration in the liver, at 8 hours after the dose, which was about 100 times greater than the EC50 value of the replicon of the compound. After exposure to compound AR334187 in an oral dosage of 30 mg / kg of IDB for 7 days, no mortality was observed, change in weight, or abnormalities in the clinical chemistries of the treated animals. Conclusion [1303] Potent, metabolically stable, and orally available, small molecules that act as inhibitors of the HCV NS3 protease have been developed. At modest oral dosage concentrations (3 mg / kg) these compounds exhibit high hepatic levels (100 times higher than their respective EC or replicon values) after 8 hours post-dose. Exposure to plasma and the heart is up to two orders of magnitude below that observed in the liver, and low concentrations of this type minimize any issue of potential systemic toxicology. [1304] Compound AR334187 did not exhibit toxicity in Rattus sp. when dosed for seven days at 30 mg / kg of the IDB, providing at least a safety margin of at least 10 times above the presumably effective dose (3 mg / kg), which shows liver concentrations with a 100-fold excess on the value of? C5o of the replicon of the compound. Preparation of the viral inhibitors of Section D [1305] The meanings of the terms and the names of the structures used in this section are the same as those used in Section D above. Any reference within this section that refers to a particular number or label must be understood in the context of the corresponding numbering or labeling scheme used within this section or in Section D above, and not in the context of a possibly similar or identical numbering or labeling scheme used elsewhere in the present, unless otherwise indicated. [1306] The compounds of formula XVIII can be synthesized according to the methods described below. [1307]? (2S, 4R) -4-Amino-l- [benzyloxycarbonyl] pyrrolidin-2-methylcarboxylate hydrochloride was available from Array Biopharma, 2 (S) -ter-butoxycarbonylamino-non-8-enoic acid and the ethyl ester of 1 (R) -ter-butoxycarbonylamino-2 (S) -inyl-cyclopropanecarboxylic acid were prepared according to the procedures described in International Application PCT / CA00 / 00353 (Publication No. WO 00/59929). Bl 2 (S) -ter-butoxycarbonylamino-non-8-enoic acid was also obtained from RSP Amino Acids. [1308] Two key intermediates A and B macrocyclic aminoprolins were used in the preparation of the NS3 inhibitors shown in examples 1-69. 1. Preparation of the Intermediate A Macrocyclic Aminoproline Asylsulfonamide [1309] Synthesis of tert-butylester of the acid (15, 42? 6S, XAS, 182?) - (18-amino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diazo-tricyclo [14.3.0.04.6] nonadec-7-in-14- Scheme 1 [1310] Step A. 2- (Trimethylsilyl) ethyl p-nitrophenylcarbonate (1.98 g, 6.99 mmol) and triethylamine were added. (1.81 ml, 13.34 mmol) was added to a solution of (2S, 4R) -4-amino-l- [benzyloxycarbonyl] pyrrolidin-2-methylcarboxylate hydrochloride (2.00 g, 2.34 mmol) in chloride methylene (25 ml). The reaction was stirred for 3 days, placed on a silica gel and the product eluted with EtOAc / hexanes 40% to give a colorless oil. The oil was dissolved in methanol (20 ml) and stirred with 10% palladium on carbon under a gaseous hydrogen balloon. After stirring for 4 h, the reaction was filtered and concentrated. The resulting solid was dissolved in 1N aqueous HCl (75 ml) and extracted with methylene chloride (75 ml). The aqueous layer was basified by the addition of sodium hydroxide and again extracted with methylene chloride (100 ml). Both organic extractions were combined, concentrated and the resulting residue purified by chromatography on silica gel eluting with 10% methanol / methylene chloride to give a brownish solid (1.29 g, 70%). LCMS = 289 (H +). [1311] Step B. A solution of 4 (2?) - (2-trimethylsilylethylcarbonylamino) -pyrrolidin-2 (5) -carboxylic acid methyl ester (1.29 g, 4.50 mmol), acid 2 ( 5) -ter-butoxycarbonylamino-non-8-enoic acid (1.22 g, 4.51 mmol), HATU (2.06 g, 5.41 mmol) and diisopropylethylamine (1.18 mL, 6.76 mmol) in dimethylformamide (10 ml) overnight. The reaction was diluted with ethyl acetate (150 ml), washed with an aqueous solution of IN HCl (2 x 100 ml), dried over magnesium sulfate and concentrated. Chromatography on silica gel gave an oil which was stirred with lithium hydroxide (0.28 g, 6.76 mmol) in methanol (5 ml) for 2 h. The reaction was diluted with methylene chloride and washed with IN aqueous HCl, dried over magnesium sulfate and concentrated to obtain 1.2 g (49%) of the product. [1312] Step C. A 4N solution of HCl / dioxane was added (2.87 ml, 11.46 mmol) was added to the ethyl ester of l (2?) - tert-butoxycarbonylamino-2- (5) -vinyl-cyclopropanecarboxylic acid (0.70 g, 2.75 mmol). After stirring for 2 h, the reaction was concentrated to give a solid. To this solid was added 1- (2 (5) -tert-butoxycarbonylamino-non-8-enoyl) -4 (2?) - (2-trimethylsilylethyl carbonylamino) -pyrrolidin-2 (S) -carboxylic acid (1.21 g, 2.29 mmol), HATU (1.05 g, 2.75 mmol) and diisopropylethylamine (1.60 mL, 9.17 mmol) and methylene chloride (10 mL), and the reaction was stirred for 18 h at room temperature. The reaction was placed on a silica gel and eluted with a 50% ethyl acetate / hexanes solution to give the product as an uncolored oil (1.27 g, 83%). 665 (H +) [1313] Step D. A solution of ethyl ester of l- was degassed. { [1- (2 (5) -ter-butoxycarbonylamin-non-8-enoyl) -4 (2?) - (2-trimethylsilylethylcarbonylamino) -pyrrolidin-2 (5) -carbonyl] -amino} -2 (5) -vinyl-cyclopropan-1- (2?) -carboxylic acid (2.57 g, 3.87 mmol) in methylene chloride (500 ml) for one hour by bubbling N2 through the solution . Dichloro (o-isopropoxyphenyl-methien) (tricyclohexylphosphine) ruthenium (II) (0.116 g, 0.193 mmol) was added and the reaction was stirred at 40 ° C for 16 h. The reaction was concentrated, placed on a silica gel and eluted with 50% ethyl acetate / hexanes to give the product (2.01 g, 3.16 mmol, 82%). 637.0 (H +). [1314] Step EA a solution of acid ethyl ester (SS, 42 ?, 65, 14S, 182?) - (14-tert-butoxycarbonylamino-2, 15-dioxo-18- (2-trimethylsilanyl-ethoxycarbonylamino) -3, 16-diazo-tricyclo [14.3.0.04, 6] nonadec-7-en-4-carboxylic acid (1.94 g, 3.04 mmol) in methanol / water 10: 1 (10 mL) was added hydroxide. lithium (1.02 g, 24.37 mmol) and the reaction was stirred at room temperature overnight The reaction was stopped by the addition of 1N HCl (50 ml) and extracted into methylene chloride (2 x 50 ml) The combined organic phases were washed with saline (50 ml), dried over magnesium sulfate and concentrated to give a solid (1)., 78 g, 2.92 mmol). A solution of this acid was heated together with carbonyl diimidazole (0.711 g, 4.39 mmol) in dichloroethane at 50 ° C. After 1 h, HPLC analysis indicated the presence of the starting material, whereby additional carbonyl diimidazole (0.1 g) was added. After an additional hour of stirring at 50 ° C, HPLC analysis indicated complete consumption of the starting material. A solution of cyclopropanesulfonyl chloride (0.46 g, 3.80 mmol) and DBU (0.57 g, 3.80 mmol) was added to the reaction and this was heated to 50 ° C. After 1 h, the reaction had not yet been completed, judging from the HPLC monitoring, so that 0.07 g of cyclopropylsulfonamide and 0.1 g of additional DBU were added. After stirring for an additional 30 minutes, the reaction was judged to be complete. The reaction was cooled, placed on a silica gel and the product was eluted with a gradient of methanol / DCM 3% to methanol / DCM 7.5% as a white solid. LCMS 710.5 (H-) [1315] Step F. A solution of 1 (0.80 g, 1.124 mmol) and tetrabutylammonium fluoride (1.0 M solution in THF, 1.4 ml) was stirred together at 50 ° C for 1 h. The reaction was cooled, placed on a silica gel and the product was eluted with a gradient of methanol / 5% DCM to methanol / 25% DCM as a white solid (0.51 g). LCMS = 568, (H +) 2. Preparation of the Macrocyclic Aminoproline Intermediate B Ester [1316] Synthesis of (15, 42 ?, 65, 145, 182?) -18-amino-14-tert-butoxycarbonylamino-2-ethyl ester. , 15-dioxo-3,16-diaza-tricyclo [14,3.0.04, s] nonadec-7-en-4-carboxylic acid.

B Route l Route 2 Scheme 3? j emplo 1 [1319] Synthesis of tert-butyl-ester acid (15, 42? 6S, XAS, 182?) -. { 18- [(3-chloro-benzo [b] thiophen-2-carbonyl) -amino] -4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.04.6] nonadec-7 en-14-il} -carbamic [1320] A solution of tert-butylester of the acid (SS, 42? 6S, XAS, 182?) - (18-amino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3, 16-diaza-tricyclo [ 14.3.0.04.6] nonadec-7-en-14-yl) -carbamic acid (0.254 g, 0.44 mmol), 3-chloro-benzo [b] thiophene-2-carbonyl chloride (0.124 g, 0.54 mmol) and DI? A (0.087 g, 0.67 mmol) was subjected to stirring in DCM at room temperature. After 1 h, the reaction was placed on silica gel and the product was eluted as a white solid using a gradient of methanol / 1% DCM to methanol / 5% DCM. XH NMR (CSDS, 400 MHz) 0.7.66-7.70 (m, 1H), 7.22-7.24 (m, 1H), 7.04-7.07 (m, 2H), 6.97 (t, 1H), 6.83 (bs, 1H), 5.61 (d, 1H), 5.18 (t, 1H), 5.05 (d, 1H), 4.48-4.50 ( b, 1H), 4.26 (t, 1H), 3.8-4.0 (m, 1H), 3.65-3.74 (m, 1H), 3.20-3.35 (M, 1H), 2.78-2.85 (M, 1H), 2.55-2.65 (m, 1H), 2.3-2.4 (m, 1H), 1.95-2.15 ( m, 2H), 1.75-1.85 (m, 1H), 1.20-1.40 (m, 16 H), 0.95-1.15 (m, 5H) 0.4-0, 5 (M, 1H), 0.25-0.35 (M, 1H); LCMS = 662 (H + -Boc) Examples 2-69 [1321] The following examples were made following one of the general procedures described for the synthesis of Example 1, substituting with acyl chloride or acid / HATU carboxylic acid suitable for 3-chloro-benzo [b] thiophene-2-carbonyl chloride, or through coupling procedures of similar amides and acyl sulfonamides, as described in Example 1 and in the synthesis of A, but by adopting in this case the route 2 of Scheme 3. Table 4 Assay of the protease NS3-NS4 Formation of the NS3 complex with NS4A-2. [1322] Full length NS3 of recombinant E. coli or Baculovirus was diluted to 3.33 μM with the assay buffer, and transferred to an Eppendorf tube which was placed in a water bath in a refrigerator at 4 ° C . The appropriate amount of NS4A-2 at a concentration of 8.3mM in assay buffer was added to an equivalent volume of NS3 in step 2.1.1 (conversion factor - 3.8mg / 272μL assay buffer). The material was transferred to an Eppendorf tube and placed in a water bath cooled to 4 ° C. [1323] Once equilibrated at 4 ° C, equal volumes of the NS3 and NS4A-2 solutions were combined in an Eppendorf tube, mixed gently with a manual pipettor, this solution was incubated for 15 minutes in the water bath 4 ° C. [1324] After 15 minutes at 4 ° C, the Eppendorf tube containing NS3 / NS4A-2 was fractionated into aliquots of appropriate volumes that were stored at -80 ° C (NS3 from E. coli to 2nM in the assay, aliquots at 25 μl NS3 of BV run at 3 nM in the assay, aliquots at 30 μl). NS3 inhibition assay. [1325] The test compounds were dissolved in DMSO to a concentration of 10 mM, and then diluted with DMSO to a concentration of 2.5 mM. As usual, the compounds were added to a test plate in a concentration of 2.5 mM, providing after dilution, an initial concentration of 50 μM in the inhibition curve of the assay. Serial dilutions were made in the assay buffer to provide analysis solutions at lower concentrations. [1326] NS3 / NS4A-2 was diluted from?. coli to a concentration of 4 nM NS3 (1: 417.5 of the 1.67μM reserve solution - 18μL of the 1.67μM reserve solution + 7497μL of the assay buffer). [1327] BV NS3 / NS4A-2 was diluted to a concentration of 6 nM NS3 (1: 278.3 of the 1.67μM stock solution - 24μL of the 1.67μM stock solution + 6655μL of the assay buffer). [1328] Add 50μL of the assay buffer to the cavities A01-H01 of a storage plate Cost of 96 cavities, in black polypropylene, using the manual multi-channel pipettor, and trying not to introduce bubbles in the plate. [1329] Add 50μL of NS3 / NS4A-2 diluted from step 2.2.6 to cavities A02-H12 of the plate in step 2.2.7, using the multi-channel pipettor, and trying not to introduce bubbles in the plate. [1330] Transfer 25 μL of the cavities of the drug dilution plate from step 2.2.5 to the corresponding cavities of the assay plate in step 2.2.8, using the manual multi-channel pipettor, and trying not to introduce bubbles in the plate. Change the pipette tips of the multi-channel pipettor for each row of transferred compounds. [1331] Mix the cavities of the assay plate from step 2.2.9 by aspirating and discharging 35μl of the 75μl present in each cavity five times, using the manual multi-channel pipettor, and trying not to introduce bubbles into the plate. Change the pipette tips of the multi-channel pipettor for each row of mixed cavities. [1332] Cover the plate with a cover for polystyrene plates and pre-incubate the plate from step 2.2.10 containing the NS3 protease and the test compounds, for 10 minutes at room temperature. [1333] While the plate in step 2.2.11 is pre-incubated, dilute the RETS1 substrate in a 15 ml centrifuge tube. [1334] Dilute the R? TS1 substrate to a concentration of 8 μM (1: 80.75 of the 646 μM stock solution - 65 μL of the 646 μM stock solution + 5184 μL of the assay buffer). [1335] Once the plate is already pre-incubated, add 25 μl of substrate to all the cavities of the plate, using the manual multi-channel pipettor. Quickly mix the plate as described in step 2.2.10, mixing 65 μl of the 100 μl present in the wells. [1336] Read the plate in kinetic mode on a Molecular Spectramax Gemini XS plate for reading plates. Reader setting: Reading time: 30 minutes, Interval: 36 seconds, Readings: 51,? Xcitation ?: 335nm,? Mission ?: 495nm, limit: 475nm, Automix: off, Calibrate: once, PMT: high, Readings / cavity: 6, Vmax pts: 21 or 28/51 depending on the extension of the linearity of the reaction. [1337] IC50: are determined using an equation of fit to a curve of four parameters, and are converted to Ki values using the following values of Km NS3 of total length of E. coli - 2.03 μM NS3 of total length of BV - 1.74 μM where Ki = IC50 / (1+ [S] / Km)) Examples of activity: Bn where: A indicates an IC50 of less than 10 μM B indicates an IC50 of less than 1 μM and C indicates an IC50 of less than 0.1 μM Table 5 Intermediates of the synthesis [1338] Some intermediaries of the synthesis schemes are contemplated within the embodiments. Below are examples of useful intermediaries.

[1339] A compound having the formula: 11 [1340] where: [1341] Q is a central ring that is selected from:

[1342] wherein the central ring may be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, C? Alkyl, C3_v cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-C? -6 alkyl , C? -6 alkyl, substituted C? -6 alkyl, C? -6 alkoxy, substituted? -6 alkoxy, C6 or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamido, urea , thiourea, amido, keto, carboxyl, carbamyl, sulfur, sulfoxide, sulfone, amino, alkoxyamino, acyloxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, [1343] or Q is Rx- R2, where R1 is C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzim dazol, each optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_e alkenyl, C? -6 alkoxy, hydroxy-C? _6 alkyl, C ? -alkyl optionally substituted with up to 5 fluoro, or C? _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, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, Cx_6 optionally substituted alkyl with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; [1344] R4 is H, C? -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, C? _6 alkyl, C3_7 cycloalkyl, C4_ 0 alkylcycloalkyl, C2_6 alkenyl, C_s alkoxy, hydroxyC_s alkyl, C_6_6 alkyl optionally substituted with up to 5 fluoro, or C_s alkoxy optionally substituted with up to 5 fluoro; [1345] R5 is C? -6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR21NH (CO) R22; [1346] R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? _6 alkyl, C? -6 alkyl optionally substituted with up to 5 fluoro, or Cx_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; [1347] R8 is C? _6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R8 is C6 or the aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, C2_6 alkenyl, C6_6 alkoxy, hydroxy-C6_6 alkyl, C! _6 alkyl optionally substituted with up to 5 fluoro, or C? -6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [1348] Y is COOR9, where R9 is C? _6 alkyl; [1349] p = 0 or 1; [1350] V is selected from O, S, or NH; [1351] when V is O or S, it is selected from O, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C? -6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl or C? _6 alkyl optionally substituted with up to 5 fluoro; [1352] the line of dashes represents a double additional ligature; [1353] R21 is C? _6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C? _6 optionally substituted alkyl with up to 5 fluoro, or phenyl; or R21 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _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 [1354] R22 is C? _6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro , or phenyl.

[1355] A compound having the formula: [1356] wherein: [1357] R4 is H, C? _6 alkyl, C3_7 cycloalkyl, C4 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; [1358] R5 is H, C? Alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR21NH (CO) R22; [1359] R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl , C3_7 cycloalkyl, C_? Or alkylcycloalkyl, C_6 alkenyl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or Cx_ 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; [1360] R8 is C? _6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R8 is C6 or the aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C ? 6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; [1361] Y is COOR9, where R9 is C? _s alkyl; [1362] p = 0 or 1; [1363] V is selected from OH, SH, or NH2; [1364] the line of dashes represents a double additional ligature; [1365] R21 is C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is Ce or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl C6-6alkyl optionally substituted with up to 5 fluoro, C6-6alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and [1366] is C? _6 alkyl, C3_7 cycloalkyl, C4_: alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl. Metabolites [1367] Some embodiments are metabolites of compounds of Formulas I-XIX. in some cases, the metabolites are themselves compounds of Formulas I-XIX. Below are examples of useful metabolites. [1368] The metabolites of the compounds of Formulas I-XIX can be identified by the following procedure: [1369] 1. Suspend Hepatocytes in supplemented KHB (Krebs-Henseleit Buffer af 7.3) at a density of approximately 2xl? 6 viable hepatocytes per ml.

[1370] 2. Prepare stock solutions (20μM) of ITMN-187 and ITMN-191 in KHB. [1371] 3. Add 50μl of ITMN-187 or ITMN-191 to 50μl of hepatocyte suspension in a 96-well polypropylene plate. The final substrate concentration is 10 μM (~7 μg / mL). [1372] 4. Incubate the plate at 37 ° C, 5% C? 2 with moisture saturation for 0 to 2 hours. [1373] 5. Finish the reaction with 100μl of acetonitrile and shake the plate at 700 rpm for 30 seconds. [1374] 6. Centrifuge the plates immediately in a centrifuge (1,500 x g) for 10 min to pellet with the denatured hepatocytes. [1375] 7. Transfer 180μl of supernatant to another plate. [1376] 8. Combine the content of the cavities, evaporate the solvent with N2 at 37 ° C, reconstitute the residue 75/25 water / acetonitrile, v / v and analyze by LC-MS / MS. [1377] Although the present invention has been described with reference to specific embodiments thereof, specialists will understand that various changes can be practiced and equivalents used therein without departing from the true spirit and scope of the invention. In addition, numerous modifications can be introduced to adapt it to specific situations, materials, compositions of materials, processes, step or steps of the process, to the object, spirit and scope of the present invention. It is intended to include all such modifications within the scope of the appended claims.

Claims

R IVINDICACION? S: 1.- A compound CARACT? CURLED BY? has the Formula I where: Q is a central ring that is selected from: where the central ring can be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C_6 alkenyl, C? _6 alkoxy, hydroxy C? alkyl, C? _6 alkyl , substituted C? _6 alkyl, C? _6 alkoxy, substituted C-6 alkoxy, C6 or? or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkoxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, cyclopropyl, spirocyclic, cyclobutyl, spirocyclic, cyclopentyl, spirocyclic, or cyclohexyl, spirocyclic, or Q is Rx-R2, where R1 is C6-6alkyl, C3_7 cycloalkyl, C4_? 0 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 u optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? _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, C? _6 alkyl, C3_7 cycloalkyl, C? or alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 optionally substituted alkyl with up to 5 fluoro, or C6-6 alkoxy optionally substituted with up to 5 fluoro; R4 is H, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C2_6 alkenyl, C6_6alkoxy, hydroxy-C6_6alkyl, C6_6alkyl optionally substituted with up to 5 fluoro, or C_6alkoxy optionally substituted with up to 5 fluoro; R5 is H, C? _6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) 0R8, S (0) 2R8, or (C0) CHR21NH (C0) R22; R6 and R7 are each independently H, C? Alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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 C? -6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, Cx_6 alkoxy, or phenyl; or R8 is C6 to x or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2-e alkenyl, C? 6 alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; Y is a sulfonimide of the formula -C (O) NHS (O) 2R9, where R9 is C? _6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano , nitro, hydroxy, C? _6 alkoxy, or phenyl, or R9 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? 6alkoxy, hydroxy-C? _6alkyl, or C? _6alkyl optionally substituted with up to 5 fluoro, C? _ealkoxy optionally substituted with up to 5 fluoro; or R9 is an optionally substituted Cl-6 alkyl with up to 5 fluoro groups, NR6R7, NR ^ R115, or (CO) OH, or R9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C? _6 alkoxy; or Y is a carboxylic acid or a salt, solvate or prodrug acceptable for pharmaceutical use thereof; where RXa and Rxb are each independently H, C? _6 alkyl, C3_7 cycloalkyl, or C_? or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, C? _6 alkoxy, amido , or phenyl, or RXa and Rxb are each independently H and C6 or? Or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, C6-6alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro, or RXa and Rxb are each independently H, heterocycle, which is a five, six or seven membered heterocyclic molecule, saturated or unsaturated, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or NRXaRxb is a three-membered cycloalkyl secondary amine to six members, which optionally has one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, C? _6 alkoxy, amido, or phenyl, or NRXRxb is a heteroaryl which is select from the group consisting of: Ric and ycrRic where Rlc is H, halo, C? _6 alkyl, C3_6 cycloalkyl, C? _6 alkoxy, C3_6 cycloalkoxy, N02, N (Rxd) 2, NH (CO) Rxd, or NH (CO) NHRxd, where each Rxd is independently H , C_6 alkyl, or C3_6 cycloalkyl, or RXc is NH (CO) ORXe, where RXe is C? _6 alkyl or C3_6 cycloalkyl; p = 0 or 1; V is selected from O, S, or NH; when V is O or S, W is selected from O, NR15, or CR15; when V is NH, it is selected between? R15 or CR15, where RX? is H, C? alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro; the hyphen lines represent a double additional ligature; is C? _6 alkyl, C3_7 cycloalkyl, alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-C? _6 alkyl, or C_6 alkyl optionally substituted with up to 5 fluoro, C6-6 alkoxy optionally substituted with up to 5 fluoro; or R2X is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and R22 is C? -6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C -6 alkyl optionally substituted with up to 5 fluoro, or phenyl; with the proviso that the compound of Formula I does not comprise a compound having Formula II, III, or IV: where: (aa) R x and R 2 are each independently H, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_10 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-C? _6 alkyl, or C6-6alkyl optionally substituted with up to 5 fluoro, C6-6alkoxy optionally substituted with up to 5 fluoro, C6O0o aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (0) NR6R7, NHC (0) NReR7, NHC (S) NR6R7, C (0) NR6R7, NR6R7, C (0) R8, C (0) OR8, NHC (0) R8, NHC (0) OR8, SOmR8, NHS (0) 2R8 , CHnNR6R7, OCHnNR6R7, or OCHnR9 wherein 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, C6-6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C2_6 alkenyl, Cx_d alkoxy , hydroxy-C? _6 alkyl, C? _ alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; said C6 or? or aryl, pyridal, phenoxy and thiophenoxy in the definition of Rx and R2 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C? Alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_ s alkoxy, hydroxy C? _6 alkyl, C? _ E optionally substituted alkyl with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; (bb) m = 0, 1, or 2; (ce) R4 is H, C_6 alkyl, C3_7 cycloalkyl, C4_ alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, C2_6 alkenyl, C6_6alkoxy, hydroxy-C6_6alkyl, C6_6alkyl optionally substituted with up to 5 fluoro, or C_6alkoxy optionally substituted with up to 5 fluoro; (dd) R5 is H, C? alkyl, C (0) NR6R7, C (S) NReR7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR2XNH (CO) R22; (ee) R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C_0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _g alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? -6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? _d 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 C? _6 alkyl, C3_7 cycloalkyl, or C_ or x alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? -6 alkoxy, or phenyl; or R8 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? _e alkoxy optionally substituted with up to 5 fluoro; or R8 is C? _s alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; (gg) Y is a sulfonimide of the formula -C (0) NHS (0) 2R9, where R9 is C? _6 alkyl, C3_7 cycloalkyl, or C4_? or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? s alkoxy, or phenyl, or R9 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _ alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl , C2_6 alkenyl, Ca_6alkoxy, hydroxy-C6_6alkyl, or C6_6alkyl optionally substituted with up to 5 fluoro, C6_6alkoxy optionally substituted with up to 5 fluoro; or R9 is an optionally substituted Cl-6 alkyl 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 C? _6 ' alkoxy; or Y is a carboxylic acid or a salt, solvate or prodrug acceptable for pharmaceutical use thereof; (hh.) Rxo and Rxx are each independently H, C? -6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C6 or? or aryl, hydroxy-C? _6 alkyl, C? 6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, (CH2) nC (0) 0R14 where R14 is H, C? _e alkyl, C3-7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C6 alkylcycloalkyl, C2-6 alkenyl, C6-6 alkoxy, hydroxy-C6-6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of Rxo and R1X is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy- C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or Rxo and RX1 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or Rxo and R11 combine as O; (ii) p = 0 or 1; (jj) R12 and R13 are each independently H, C? -6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C? or aryl, hydroxy C? alkyl, C? 6 optionally substituted alkyl with up to 5 fluoro, (CH2) nNR6R7, (CH2) nC (0) OR14 where R14 is H, C6-6 alkyl, C3_ 7-cycloalkyl, C_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_ cycloalkyl, C4_? 0 alkylcycloalkyl, C2_G alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2-6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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 C? _6 alkyl optionally substituted with (CH2) nOR8; (kk) R20 is H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C6 or aryl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or (CH2) nNR6R7, (CH2) nC (0) OR14 where R14 is H, C? _6 alkyl, C3_? cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxyCi-e alkyl, -alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? -6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? -6 alkoxy, hydroxy-C? _6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? _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, is selected from O, NR15, or CR15; when V is NH, W is selected from? R15 or CR15, where R15 is H, C? _6 alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, or C -6 alkyl optionally substituted with up to 5 fluoro; (oo) the dashed line represents an additional double binding; (pp) R2X is C? _6 alkyl, C3_7 cycloalkyl, C4-10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or RX is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and (qq) R22 is C? _6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
2. The compound of claim 1, CARACT? CURLED WHY? the central ring is The compound of claim 1, CARACT? CURLED WHY? the central ring is The compound of claim 1, CHARACTERIZED BECAUSE the central ring is 5. The compound of claim 1 CARACT? CURLED 10 11 WHY? has the formula: the 6. The compound of claim 1 CARACT? CURLED _ / Q v = < 10 11 Ib WHY? has the formula Ib 7. The compound of claim 1 CARACT? CURLED WHY? has the formula him: The compound of claim 1 CARACT? RIZADO or 10 WHY? has the formula Id: The compound of claim 1 CARACT? CURLED OR w WHY? has the formula him: 10. The compound of claim 1 CHARACTERIZED Q WHY? has the formula If: 11. The compound of claim 1 CHARACTERIZED / Q 10 11 ig BECAUSE it has the formula Ig: 12. The compound of claim 1 CHARACTERIZED _ / Q BECAUSE it has the formula Ih: 13 The compound of claim 1 CARACT? CURLED / Q WHY? has the formula Ii: 14. The compound of claim 1 CHARACTERIZED 10 11 BECAUSE he has the formula Ij 15. The compound of claim 1 CHARACTERIZED WHY? has the formula Iz: 16. The compound of claim 1, CHARACTERIZED BY AND is sulfonimide of the formula -C (O) NHS (O) 2R9, wherein R9 is selected from the group consisting of C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, and? RlaRlb, where R1 and Rxb are each independently H, C6-6 alkyl, or C3_7 cycloalkyl. 17. The compound of claim 2, CHARACTERIZED BECAUSE Y is sulfonimide of the formula -C (O) HS HS (O) 2R9, wherein R9 is selected from the group consisting of C? _6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl , and? RlaRXb, where RXa and Rxb are each independently H, C? _6 alkyl, or C3_7 cycloalkyl. 18. The compound of claim 3, CHARACTERIZED BECAUSE Y is sulfonimide of the formula -C (O) HS HS (O) 2R9, wherein R9 is selected from the group consisting of C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, and NR aR, where RXa and Rxb are each independently H, C? _6 alkyl, or C3_7 cycloalkyl. 19. The compound of claim 4, CHARACTERIZED BECAUSE Y is sulfonimide of the formula -C (O) NHS (O) 2R9, wherein R9 is selected from the group consisting of Ca_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, and N ^ 113 , wherein RXa and Rxb are each independently H, C? _6 alkyl, or C3_7 cycloalkyl. 20. The compound of claim 1, CHARACTERIZED BECAUSE the C13-C14 double bond is cis. 21. The compound of claim 1, CHARACTERIZED BECAUSE the C13-C14 double bond is trans. 22. A pharmaceutical composition CHARACTERIZED BECAUSE comprises: a) the compound of claim 1; and b) a vehicle acceptable for pharmaceutical use. 23. The pharmaceutical composition of claim 22 CHARACTERIZED BECAUSE it is in a formulation free of alcohols and polyols. 24. The pharmaceutical composition of claim 23, CHARACTERIZED WHY? the formulation is free of sugar alcohols and poly (ethylene glycol) (P? G). 25. The pharmaceutical composition of claim 22 CHARACTERIZED BECAUSE it is in an aqueous formulation free of any excipient that reduces the polarity in the aqueous formulation. 26. The pharmaceutical composition of claim 22 CHARACTERIZED BY? It is in a tablet formulation. 27. The pharmaceutical composition of claim 22 CARACT? RIZADA PORQU? It is in a capsule formulation. 28. The pharmaceutical composition of claim 22 CARACT? RIZADA PORQU? It is in a capsule formulation. 29. A method of treating infection with the virus of hematitis C in an individual, CARACT? RIZADO PORQU? comprises administering to the individual an effective amount of the compound of claim 1. 30. The method of claim 29, CHARACTERIZED BY WHY? a sustained viral response is achieved. 31. The method of claim 29, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of a nucleoside analogue. 32. The method of claim 31, CHARACTERIZED BECAUSE the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 33. The method of claim 29, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on NS 5B RNA. 34. The method of claim 29, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of thymosin-a .. 35. The method of claim 29, CHARACTERIZING WHY? thymosin-a is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 36. The method of claim 29, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ). 37. The method of claim 36, CHARACT? CURLED BECAUSE IFN-? it is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 38. The method of claim 29, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a.). 39. The method of claim 38, CARACT? RIZADO PORQU? IFN-a is IFN-OI monoP? G (30 kD, linear) -ylated consensus IFN-a. administered at an administration interval of every 8 days up to every 14 days. 40. The method of claim 38, CARACT? RIZADO PORQU? the IFN-a. is IFN-c. monoP? G (30 kD, linear) -elemented consensus administered at a one-time administration interval every 7 days. 41. The method of claim 38, CHARACTERIZED BECAUSE IFN-a is I? FERG ?? IF consensus? -a. 42. The method of claim 29, CHARACTERIZED BECAUSE it further comprises administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ' , 3 '-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 43. A method of increasing the liver function in an individual, CHARACTERIZED BECAUSE comprises administering to the individual an effective amount of the compound of claim 1. 44. The method of claim 43, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of a nucleoside analogue. 45. The method of claim 44, CHARACTERIZED BECAUSE the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 46. The method of claim 43, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on NS 5B RNA. 47. The method of claim 43, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of thymosin-a. 48. The method of claim 47, CHARACTERIZED BECAUSE the thymosin-a! it is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 49. The method of claim 43, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ). 50. The method of claim 49, CHARACTERIZED BECAUSE IFN-7 is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 51. The method of claim 43, CHARACTERIZING WHY? the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a). 52. The method of claim 51, CARACT? CURLING WHY? the IF? -a. is IF? -a. monoP? G (30 kD, linaar) -ylated consensus administered at an administration interval of every 8 days up to every 14 days. 53. The method of claim 51, CARACT? CURLING WHY? IFN-a is IF? -a monoP? G (30 kD, linaar) -ylated consensus administered at a one-time administration interval every 7 days. 54. The method of claim 51, CHARACTERIZED BECAUSE the IF? -a. is IF? -a; I? FERG ?? consensus 55. The method of claim 43, CHARACTERIZED BECAUSE it further comprises administering an effective amount of an agent selected from 3 '-azidothymidine, 2', 3'-dideoxyinosine, 2 ', 3'-dideoxycytidine, 2-, 3-didehydro-2' , 3 '-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 56. A method of increasing liver function in an individual who has an infection with the hepatitis C virus, CARACT? RIZADO PORQU? comprises administering to the individual an effective amount of the compound of claim 1. 57. The method of claim 56, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of a nucleoside analogue. 58. The method of claim 57, CHARACTERIZED BECAUSE the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 59. The method of claim 56, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on S 5B RNA. 60. Bl method of claim 56, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of thymosin-a !. 61. The method of claim 60, CARACT? RIZADO PORQU? the thymosin-a it is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 62. The method of claim 56, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ). 63. The method of claim 62, CARACT? RIZADO PORQU? the IF? -? it is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 64. The method of claim 56, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a.). 65. The method of claim 64, CHARACTERIZED BECAUSE the IF? -a; is IF? -a! monoPEG (30 kD, linaar) -ylated consensus administered at an administration interval of every 8 days up to every 14 days. 66. The method of claim 64, CHARACTERIZED BECAUSE the IF? -a; is IFN-a; monoP? G (30 kD, linaar) -ylated consensus administered at a one-time administration interval every 7 days. 67. The method of claim 64, CARACT? RIZADO PORQU? IFN-a is IFN-a INFERGEN consensus. 68. The method of claim 56, wherein it further comprises administering an effective amount of an agent selected from 3 '-azidothymidine, 2', 3'-dideoxyinosine, 2 ', 3'-dideoxycytidine, 2-, 3-didehydro-2. ', 3' -dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 69. A compound CHARACTERIZED BECAUSE it has the Formula XI: XI where: (a) RXa and Rlb are each independently H, C? -6 alkyl, C3_7 cycloalkyl, or C? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, C? -6 alkoxy, amido, or phenyl; or RXa and Rxb are each independently H and Ce or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy -C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or Ra and Rxb are each independently H or heterocycle, which is a five, six or seven membered heterocyclic molecule, saturated or unsaturated, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; or NRXaRxb is a three to six membered cycloalkyl secondary amine, optionally having one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, C? _6 alkoxy, amido, or phenyl; or NRXaRlb is a heteroaryl selected from the group consisting of: where Rlc is H, halo, C? _6 alkyl, C3-6 cycloalkyl, C? -6 alkoxy, C3-6 cycloalkoxy, N02, N (Rxd) 2, NH (CO) Rxd, or NH (CO) NHRxd, where each Rxd is independently H, C? _e alkyl, or C3-.6 cycloalkyl; or RXc is NH (CO) ORXe where RXe is C? _6 alkyl, or C3_6 cycloalkyl; (b) W is 0 or NH; (c) V is selected from O, S, or NH; (d) when V is O or S, it is selected from O, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or C? _e alkyl optionally substituted with up to 5 fluoro; (e) Q is a bicyclic secondary amine with the structure: where R¿ and R22 are each independently H, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro C 6 -alkoxy optionally substituted with up to 5 fluoro, C 6 or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (0) 2NR 6 R 7, NHC (0) NR 6 R 7, NHC (S) NR 6 R 7 , C (0) NR6R7, NRdR7, C (0) R8, C (0) OR8, NHC (0) R8, NHC (0) OR8, SOmR8 (m = 0, 1 or 2), or NHS (0) 2R8; said thienyl, pyrimidal, furanyl, thiazolyl and oxazolyl in the definition of R2X and R22 are optionally substituted by up to two halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, C? 6 alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, pyridal, phenoxy and thiophenoxy in the definition of R2X and R22 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro; where R10 and Rxx are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C6 or aryl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, ( CH2) nNR6R7, or (CH ^ nC OOR14 where R14 is H, C? _6 alkyl, C3_7 cycloalkyl, or C_? Alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C ? 6 alkoxy, or phenyl, or R14 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl Io, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-Ci- 6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or Rxo and RX1 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or Rxo and R1X are combined as 0; where p = 0 or 1; where R12 and R13 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C6 or aryl, hydroxy-C? _6 alkyl, Cx_6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNReR7, (CH2) nC (0) OR14 where R14 is H, C? alkyl, C3_ 7 cycloalkyl, or C_0 alkylcycloalkyl, all of which are optionally substituted one to three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, Ca_6 alkyl optionally substituted with up to 5 fluoro, C? _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, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy- C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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; where R is H, alkyl alkyl, C3_7 cycloalkyl, C4. Alkylcycloalkyl, C6 or α or aryl, hydroxy-C6-6 alkyl, CX6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNRsR7, or (CH2) nC (0) OR14 where R14 is H, C6-6 alkyl, C3-7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C.substituted optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_ or alkylcycloalkyl, C2-6 alkenyl, C6-6 alkoxy, hydroxy- C? _6 alkyl, C? -e alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; where n = 0-4; where Rs and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl , C4_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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 R2aR2b when W = NH and V = O, where R is C? _6 alkyl, C3_7 cycloalkyl, 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 NR2cR2d, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C_xo alkylcycloalkyl, C2_6 alkenyl, Cx_ 6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; R2b is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazol, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole , each optionally substituted with up to three NR2cR2d, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_Xo alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C_e alkyl optionally substituted with up to 5 fluoro, or C? _e alkoxy optionally substituted with up to 5 fluoro, said R2c and R2d are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C_ or alkyl alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C_ or x alkylcycloalkyl, C2_6 alkenyl, hydroxy-Cx_6 alkyl, Cx_6 alkyl optionally substituted with up to 5 fluoro, or Cx_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; (f) R4 is H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl , C2_6 alkenyl, C6_6alkoxy, hydroxy-C6_6alkyl, C6_6alkyl optionally substituted with up to 5 fluoro, or C_6alkoxy optionally substituted with up to 5 fluoro; (g) R5 is H, C? _6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, or S (0) 2R8; (h) R8 is C? -6 alkyl, C3_7 cycloalkyl, or C4_0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R8 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C4_x0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-Cx_e alkyl, C? _6 optionally substituted alkyl with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; and (i) the dashed line represents an additional double binding. 70. The compound of claim 69 CARACT? RIZADO PORQU? has Formula XII: XII where: (a) RXa and Rxb are each independently H, C? -6 alkyl, C3_7 cycloalkyl, or C_? alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, C ? -6 alkoxy, amido, or phenyl; or RXa and Rxb are each independently H or heteroaryl which is selected from the group consisting of: where RXc is H, halo, C? alkyl, C3-6 cycloalkyl, C? -6 alkoxy, C3-s cycloalkoxy, N02, N (Rxd) 2, NH (CO) Rxd, or NH (CO) NHRxd, where each Rxd is independently H, C? _6 alkyl, or C3_6 cycloalkyl; or NRXRxb is a three to six membered cycloalkyl secondary amine, optionally having one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, C? _6 alkoxy, amido, or phenyl; (b) RX and R22 are each independently H, halo, cyano, hydroxy, C? _3 alkyl, or C? _3 alkoxy; (c) Rs is H, C (0) NR6R7, C (0) R8, or C (0) OR8; (d) R6 and R7 are each independently H, C? -6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, or phenyl; (e) R8 is C? -6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or 3-tetrahydrofuryl; (f) Rxo and Rxx are each independently H, halo, C? _3 alkyl, or Rxo and Rxx 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, C? -6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C5 010 aryl, hydroxy-C? _6 alkyl, or C? _6 alkyl optionally substituted with up to 5 halo atoms; and (h) the line of dashes represents a double additional ligature. 71. The compound of claim 69 CHARACTERIZED BECAUSE it has Formula XIII: XIII where: (a) Rl and Rlb are each independently H, C? -6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, Cx-6 alkoxy, amido, or phenyl; or Rla and Rlb are each independently H or heteroaryl which is selected from the group consisting of: where R is H, halo, Cx_6 alkyl, C3_6 cycloalkyl, Cx_6 alkoxy, C3_6 cycloalkoxy, N02, N (Rld) 2, NH (CO) Rld, or NH (CO) NHRld, where each Rld is independently H, C? _6 alkyl, or C3_6 cycloalkyl; or NRlaRlb is a three to six membered cycloalkyl secondary amine, optionally having one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, Ca_6 alkoxy, amido, or phenyl; (b) R21 and R22 are each independently H, halo, cyano, hydroxy, C? _3 alkyl, or Cx_3 alkoxy; (c) Rs is H, C (0)? R6R7, C (0) R8, or C (0) OR8; (d) R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl; (e) R8 is C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or 3-tetrahydrofuryl; and (f) the line of dashes represents a double additional ligature. 72. The compound of claim 69 CHARACTERIZED BECAUSE it has Formula XIV: 11 10 XIV where: (a) Rla and Rlb are each independently H, C? _6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, C? _6 alkoxy, amido, or phenyl; or Rla and Rlb are each independently H or heteroaryl selected from a group consisting of: where Rlc is H, halo, C? _6 alkyl, C3_6 cycloalkyl, Ci-s alkoxy, C3-6 cycloalkoxy, N02, N (Rld) 2,? H (CO) Rld, or? H (CO)? HRld, where each Rld is independently H, C? alkyl, or C3_s cycloalkyl; or? RlaRlb is a three to six membered cycloalkyl secondary amine, optionally having one to three heteroatoms incorporated in the ring, and which is optionally substituted between one and three times with halo, cyano, nitro, C? _6 alkoxy, amido , or phenyl; (b) Q is C6 or Cio aryl optionally substituted with up to three? R2cR2d, halo, cyano, nitro, hydroxy, C1-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C_6 alkoxy, hydroxy-C? _6 alkyl or C 1-6 alkyl optionally substituted with up to 5 fluoro, C6-6 alkoxy optionally substituted with up to 5 fluoro; said R2a and R2d are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3- 7-cycloalkyl, C_? 0 alkylcycloalkyl, C2_e alkenyl, hydroxy-C? _6 alkyl, C_6 alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; or R2c and R2d are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; or R2a is an unsaturated heteroaryl of five or six members, or said defined heteroaryl fused to another cycle is this heterocycle or any other cycle; (c) R5 is H, C (0) NR6R7, C (0) R8, or C (0) OR8; (d) R6 and R7 are each independently H, Cx_6 alkyl, C3_7 cycloalkyl, C_ or alkylcycloalkyl, or phenyl; (e) R8 is C? _6 alkyl, C3_7 cycloalkyl, C_? 0 alkylcycloalkyl, or 3-tetrahydrofuryl; and (f) the line of dashes represents a double additional ligature. 73. The compound of claim 69 CHARACTERIZED BECAUSE it has the Formula XV: XV wherein: (a) R1 and R2 are each independently H, halo, cyano, hydroxy, C? _3 alkyl, or C? _3 alkoxy; (b) R5 is H, C (0) 0R8 or C (0) NHR8; (c) R8 is C? _6 alkyl, Cs_6 cycloalkyl, or 3-tetrahydrofuryl; (d) R9 is C? _3 alkyl, C3_5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Cx_3 alkyl, or C? _3 alkoxy; (e) R10 and R11 are each independently H, C? _3 alkyl, or C4_5 cycloalkyl; (f) is selected from 0 or NH; and (g) the line of dashes represents a double additional ligature. 74. The compound of claim 69 CHARACTERIZED BECAUSE it has Formula XVI: XVI wherein: (a) R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, C? _3 alkyl, or Cx_3 alkoxy; (b) R5 is H, C (0) OR8 or C (0) NHR8; (c) R8 is C? alkyl or C5_6 cycloalkyl; (d) R9 is C? _3 alkyl, C3_ cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Cx_3 alkyl, Cx_3 alkoxy; (e) R10 and R11 are each independently H, Cx-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 line of dashes represents a double additional ligature. 75. The compound of claim 69 CARACT? RIZADO PORQU? has Formula XVII: 10 11 XVII wherein: (a) R1 and R2 are each independently H, chloro, fluoro, cyano, hydroxy, Cx_3 alkyl, or Cx_3 alkoxy; (b) R5 is H, C (0) OR8 or C (0) NHR8; (c) R8 is Cx_6 alkyl or C5_6 cycloalkyl, - (d) R9 is Cx_3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or C? _3 alkoxy; and (e) the dashed line represents an additional double binding. 76. A pharmaceutical composition CARACTOR RIZADA PORQU? comprises: a) the compound of claim 69; and b) a vehicle acceptable for pharmaceutical use. 77. The pharmaceutical composition of claim 76 CARACT? RIZADA PORQU? It is found in a formulation free of alcohols and polyols. 78. The pharmaceutical composition of claim 77, CHARACTERIZED BECAUSE the formulation is free of sugar alcohols and and poly (ethylene glycol) (PEG). 79. The pharmaceutical composition of claim 76 CARACT? RIZADA PORQU? It is found in an aqueous formulation free of any excipient that reduces the polarity in the aqueous formulation. 80. The pharmaceutical composition of claim 76 CHARACTERIZED BECAUSE it is in a tablet formulation. 81. The pharmaceutical composition of claim 76 CHARACTERIZED BY? It is found in a capsule formulation. 82. The pharmaceutical composition of claim 76 CARACT? RIZADA PORQU? It is in a capsule formulation. 83. A method of treating infection with the virus of hematitis C in an individual, CHARACTERIZED BY WHAT? comprises administering to the individual an effective amount of the compound of claim 69. 84. The method of claim 83, CHARACTERIZADO PORQU? a sustained viral response is achieved. 85. The method of claim 83, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of a nucleoside analogue. 86. The method of claim 85, CHARACTERIZED BECAUSE the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 87. The method of claim 83, CHARACTERIZADO PORQU? the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on NS 5B RNA. 88. The method of claim 83, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of thymosin-a; 89. The method of claim 88, CARACT? RIZADO PORQU? thymosin-a is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 90. The method of claim 83, CHARACTERIZADO PORQU? the method further comprises administering to the individual an effective amount of interferon-gamma (IF? -?). 91. The method of claim 90, CARACT? RIZADO PORQU? the IF? -? it is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 92. The method of claim 83, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a). 93. The method of claim 92, CHARACTERIZED BECAUSE IFN-a is IFN-a; monoPEG (30 kD, linaar) -ylated consensus administered at an administration interval of every 8 days up to every 14 days. 94. The method of claim 92, CHARACT? CURLED BECAUSE IFN-ar is IF? -a. monoPEG (30 kD, linaar) -elived consensus administered at a one-time administration interval every 7 days. 95. The method of claim 92, CHARACTERIZED BECAUSE the IF? -a; is IF? -a. I? FERGE? consensus. 96 The method of claim 83, CHARACTERIZED BECAUSE further comprises administering an effective amount of an agent selected from 3 '-azidothymidine, 2', 3'-dideoxyinosine, 2 ', 3'-dideoxycytidine, 2-, 3-didehydro- 2 ', 3' -dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 97. A method of increasing the liver function in an individual, CHARACTERIZED BECAUSE comprises administering to the individual an effective amount of the compound of claim 69. 98. The method of claim 97, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of a nucleoside analogue. 99. The method of claim 98, CHARACTERIZED BY WHERE? the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 100. The method of claim 97, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on NS 5B RNA. 101. Bl method of claim 97, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of thymosin-a; 102. The method of claim 101, CHARACTERIZED BECAUSE thymosin-a; it is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 103. The method of claim 97, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ). 104. The method of claim 103, CARACT? RIZADO PORQU? IFN-? it is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 105. The method of claim 97, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a;). 106. The method of claim 105, CHARACTERIZED BECAUSE IFN-a; is IFN-a; monoPEG (30 kD, linaar) -ylated consensus administered at an administration interval of every 8 days up to every 14 days. 107. The method of claim 105, CARACT? RIZADO PORQU? IFN-a is IFN-a; monoPEG (30 kD, linaar) -elived consensus administered at a one-time administration interval every 7 days. 108. The method of claim 105, CARACT? RIZADO PORQU? the IFN-a; is IFN-c. I? F? RGE? consensus. 109. The method of claim 97, CHARACTERIZED BY further comprising administering an effective amount of an agent selected from 3 '-azidothymidine, 2', 3'-dideoxyinosine, 2 ', 3'-dideoxycytidine, 2-, 3-didehydro-2' , 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 110. A method of increasing the liver function in an individual who has an infection with the hepatitis C virus, CHARACTERIZADO PORQU? comprises administering to the individual an effective amount of the compound of claim 69. 111. The method of claim 110, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of a nucleoside analogue. 112. The method of claim 111, CHARACTERIZED BECAUSE the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 113. The method of claim 110, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on NS 5B RNA. 114. The method of claim 110, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of thymosin-a;. 115. The method of claim 114, CHARACTERIZING WHY? the thymosin-a; it is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 116. The method of claim 110, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-gamma (IF? -?). 117. The method of claim 116, CHARACTERIZED BECAUSE the IF? -? it is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 118. The method of claim 110, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a;). 119. The method of claim 118, CHARACTERIZED BECAUSE IFN-a. is IFN-a, monoPEG (30 kD, linaar) -ylated consensus administered at an administration interval of every 8 days up to every 14 days. 120. The method of claim 118, CHARACTERIZED BECAUSE IFN-c is IFN-CÜ monoPEG (30 kD, linaar) -ylated consensus administered at a one-time administration interval every 7 days. 121. The method of claim 118, CARACT? RIZADO PORQU? IFN-CÜ is IFN-a; INF? RG? N consensus. 122. The method of claim 110, CHARACTERIZED BY further comprising administering an effective amount of an agent selected from 3 '-azidothymidine, 2', 3'-dideoxyinosine, 2 ', 3'-dideoxycytidine, 2-, 3-didehydro-2' , 3 '-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 123. A compound CHARACTERIZED BECAUSE it has the Formula XVIII: XVIII wherein (a) R1 is C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 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 NR5R, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, C2_6 alkenyl, C ? 6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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, C? alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-Cx_6 alkyl, Cx_6 alkyl optionally substituted with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; (c) R3 is H, Cx-6 alkyl, C3_7 cycloalkyl, C4_X0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, CX-6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, C2-6 alkenyl , Cx_6 alkoxy, hydroxy-Cx_6 alkyl, Cx_6 alkyl optionally substituted with up to 5 fluoro, or Cx-6 alkoxy optionally substituted with up to 5 fluoro; (d) R4 is CX-6 alkyl, C (0) NR5R6, C (S) NR5R6, C (0) R7, C (0) 0R7, or S (0) 2R7; (E) R5 and Rd are each independently H, alkyl Cx_6, C3-7 cycloalkyl, alkylcycloalkyl C_xo or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, ? C 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C -6 alkyl, or C _6 alkyl optionally substituted with up to 5 fluoro, C -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 C _6 alkyl, C3_7 cycloalkyl, C 0 alkylcycloalkyl, all of which are optionally substituted one to three times with halo, cyano, nitro, hydroxy, C _6 alkoxy, or phenyl?; or R7 is C6 or aryl Io which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_ 6 alkoxy, hydroxy Cx_6 alkyl, CX-6 optionally substituted alkyl with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; (g) R8 is Cx_3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, Cx_3 alkyl, or CX-3 alkoxy; and (h) the dashed line represents an additional double bond; or an acceptable salt for pharmaceutical use thereof. 124. The compound of claim 123, CHARACTERIZED BECAUSE R1 is phenyl, benzothiazole, benzothiophene, benzofuran, or benzimidazole, each optionally substituted with up to 1-2 NR5R6, halo, cyano, nitro, hydroxy, Cx_2 alkyl, C3-7 cycloalkyl, C_ 0 alkylcycloalkyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl , C_6 alkenyl, C? _6 alkoxy, hydroxyC? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; R3 is H; R4 is C? _6 alkyl, C (0) NRR6, C (S) NR5R6, C (0) R7, C (0) OR7, or s (o) 2R7; R5 and R6 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C_ or alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to two halo, cyano, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C_? Or alkylcycloalkyl, C2_s alkenyl, hydroxy-C6-6alkyl, or C6-6alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy 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 C? _6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R7 is Cs or the aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C2_6 alkenyl, Cx_ alkoxy, hydroxy-C? _6 alkyl, C ? 6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; R8 is Cx_3 alkyl, C3_ cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or C? _3 alkoxy; and the line of dashes represents a double additional ligature. 125. The compound of claim 123, CHARACTERIZED BECAUSE R1 is phenyl, benzothiazole, or benzothiophene each optionally substituted with up to 1-2 halo, hydroxy, C? 2 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; R2 is H or phenyl optionally substituted with up to 1-2 halo, hydroxy, C? _3 alkyl, alkyl, or C? _3 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; R3 is H; R 4 is C 1-6 alkyl, C (0) NR 5 R 6, C (0) R 7, or C (0) OR 7; R5 is H and R6 is H, C? _6 alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to two halo, cyano, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C_ or alkyl alkylcycloalkyl, C2_6 alkenyl , hydroxy-C? _6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; R7 is C? _6 alkyl or C3_7 cycloalkyl, all of which are optionally substituted between one and three times with halo or phenyl; or R7 is C6 or aryl which is optionally substituted by up to one halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy- Cx_6 alkyl, or Cx_6 optionally substituted alkyl with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; R8 is Cx_3 alkyl, C3_4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C? _3 alkyl, or Cx_3 alkoxy; and the line of dashes represents a double additional ligature. 126. A pharmaceutical composition CHARACTERIZED BY WHAT? understands -. a) the compound of claim 123; and b) a vehicle acceptable for pharmaceutical use. 127. The pharmaceutical composition of claim 126 CHARACTERIZED BECAUSE it is in a free formulation of alcohols and polyols. 128. The pharmaceutical composition of claim 127, CHARACTERIZED BECAUSE the formulation is free of sugar alcohols and poly (ethylene glycol) (P? G). 129. The pharmaceutical composition of claim 126 CHARACTERIZED BECAUSE it is in an aqueous formulation free of any excipient that reduces the polarity in the aqueous formulation. 130. The pharmaceutical composition of claim 126 CARACT? RIZADA PORQU? It is found in a tablet formulation. 131. The pharmaceutical composition of claim 126 CARACT? RIZADA PORQU? It is found in a capsule formulation. 132. The pharmaceutical composition of claim 126 CARACT? RIZADA PORQU? It is in a capsule formulation. 133. A method of treating infection by the virus of hematitis C in an individual, CHARACTERIZED BECAUSE comprises administering to the individual an effective amount of the compound of claim 123. 134. The method of claim 133, CHARACTERIZED BECAUSE a sustained viral response is achieved. 135. The method of claim 133, CHARACTERIZING WHY? the method further comprises administering to the individual an effective amount of a nucleoside analogue. 136. The method of claim 135, CHARACTERIZED BECAUSE the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 137. The method of claim 133, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on? S 5B RNA. 138. The method of claim 133, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of thymosin-a;. 139. The method of claim 138, CHARACTERIZED BECAUSE the thymosin-a! it is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 140. The method of claim 133, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-gamma (IF? -?). 141. The method of claim 140, CHARACTERIZED BECAUSE IFN-? it is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 142. The method of claim 133, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-c.). 143. The method of claim 142, CHARACTERIZED BECAUSE the IF? -c. is IF? -c. monoPEG (30 kD, linaar) -ylated consensus administered at an administration interval of every 8 days up to every 14 days. 144. The method of claim 142, CARACT? RIZADO PORQU? the IFN-a. is IF? -a monoPEG (30 kD, linaar) -ylated consensus administered at a one-time administration interval every 7 days. 145. The method of claim 142, CHARACTERIZED BECAUSE the IF? -a; is IF? -c. I? FERG ?? consensus. 146. The method of claim 133, CHARACTERIZED WHY? further comprises administering an effective amount of an agent selected from 3 '-azidothymidine, 2', 3'-dideoxyinosine, 2 ', 3'-dideoxycytidine, 2-, 3-didehydro-2', 3'-dideoxythymidine, combivir, abacavir , adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 147. A method to increase the liver function in an individual, CARACT? RIZADO PORQU? comprises administering to the individual an effective amount of the compound of claim 123. 148. The method of claim 147, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of a nucleoside analogue. 149. The method of claim 148, CHARACTERIZED BECAUSE the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 150. The method of claim 147, CHARACTERIZING WHY? the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on NS 5B RNA. 151. The method of claim 147, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of thymosin-a; 152. The method of claim 151, CHARACTERIZED BECAUSE the thymosin-a; it is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 153. The method of claim 151, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ). 154. The method of claim 153, CARACT? RIZADO PORQU? the IF? -? it is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 155. The method of claim 147, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of interferon-alpha (IF? -a;). 156. The method of claim 155, CARACT? RIZADO PORQU? the IF? -a; is IF? -cf monoP? G (30 kD, linaar) -ylated consensus administered at an administration interval of every 8 days up to every 14 days. 157. The method of claim 155, CHARACTERIZED BECAUSE IFN-a; is IFN-a monoPEG (30 kD, linaar) -ylated consensus administered at a one-time administration interval every 7 days. 158. The method of claim 155, CHARACTERIZED BECAUSE IFN-a is IFN-a INFERG? N consensus. 159. The method of claim 147, CHARACTERIZED BECAUSE further comprises administering an effective amount of an agent selected from 3 '-azidothymidine, 2', 3'-dideoxyinosine, 2 ', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3' -dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 160. A method of increasing the liver function in an individual having a hepatitis C virus infection, CHARACTERIZED BECAUSE comprises administering to the individual an effective amount of the compound of claim 123. 161. The method of claim 160, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of a nucleoside analogue. 162. The method of claim 161, CHARACTERIZING WHY? the nucleoside analogue is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 163. The method of claim 160, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of an RNA polymerase inhibitor dependent on NS 5B RNA. 164. Bl method of claim 160, CARACT? RIZADO PORQU? the method further comprises administering to the individual an effective amount of thymosin-ce. 165. The method of claim 164, CARACT? RIZADO PORQU? thymosin-a is administered subcutaneously twice a week in an amount of from about 1.0 mg to about 1.6 mg. 166. The method of claim 164, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ). 167. The method of claim 166, CHARACTERIZED BECAUSE the IFN-? it is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 168. The method of claim 164, CHARACTERIZED BECAUSE the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-a;). 169. The method of claim 168, CHARACTERIZED BECAUSE IFN-a; is IFN-a; monoPEG (30 kD, linaar) -ylated consensus administered at an administration interval of every 8 days up to every 14 days. 170. The method of claim 169, CHARACTERIZED BECAUSE IFN-a; is IF? -a; monoPEG (30 kD, linaar) -elived consensus administered at a one-time administration interval every 7 days. 171. The method of claim 169, CHARACTERIZED BECAUSE the IF? -a; is IF? -a! I? FERG ?? consensus. 172. The method of claim 160, CARACT? RIZADO PORQU? further comprises administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir , adefovir dipoxil, cidofovir, and an inhibitor of inosine monophosphate dehydrogenase. 173. A compound of the formula: CHARACTERIZED WHY: (a) Z is a group configured to bind through a hydrogen to a His57 imidazole unit of the NS3 protease and to bind through a hydrogen to a nitrogen atom of NS3 protease Glyl37; (b) Pi 'is a group configured to form a non-polar interaction with at least one pocket unit SI' of Ns3 protease selected from the group consisting of Lysl36, Glyl37, Serl39, His57, Gly58, Gln41, Ser42, and Fe43; (c) L is a linking group consisting of between 1 and 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 is positioned by L to form a non-polar interaction with at least one S2 pocket unit of NS3 protease selected from the group consisting of His57, Argl55, Val78, Asp79, GlndO and Aspdl; (e) the line of dashes represents a double additional ligature; (f) R5, is selected from the group consisting of H, C (0) NR6R7 and C (0) OR8; (g) R6 and R7 are each independently H, C? -6 alkyl, C3_7 cycloalkyl, C4-? or alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C_6 alkenyl, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? _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 C? _6 alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C_6 alkoxy, or phenyl; or R8 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_X0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-Cx_6 alkyl, Cx_6 alkyl optionally substituted with up to 5 fluoro, Cx_6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; with the proviso that the compound does not comprise a compound having Formula II, III, or IV: II III IV where: (aa) R1 and R2 are each independently H, halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-Cx_6 alkyl, or C? Alkyl optionally substituted with up to 5 fluoro, C6-6 alkoxy optionally substituted with up to 5 fluoro, C6 or α or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (0) 2NR6R7, NHC ( 0) NR6R7, NHC (S) NR6R7, C (0) NR6R7, NR6R7, C (0) R8, C (0) OR8, NHC (0) R8, NHC (0) OR8, SOmR8, NHS (0) 2R8, CHnNR6R7, 0CHnNR6R7, or 0CHnR9 wherein 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, Cx_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy , hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, pyridal, phenoxy and thiophenoxy in the definition of R1 and R2 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C_6 alkyl, C3-7 cycloalkyl, C_10 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-Cx_6 alkyl, C6-6 alkyl optionally substituted with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; (bb) m = 0, 1, or 2; (ce) R4 is H, Cx-.6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_ or alkylcycloalkyl, C2_6 alkenyl, C6_6alkoxy, hydroxy-C6_6alkyl, C6_6alkyl optionally substituted with up to 5 fluoro, or C6_6alkoxy optionally substituted with up to 5 fluoro; (dd) R5 is H, C? _6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (CO) CHR21NH (CO) R22; (ee) R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? -6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? _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 C? _6 alkyl, C3_7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which they are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R8 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? alkyl, C3_7 cycloalkyl, C4-? or alkylcycloalkyl, C2_6 alkenyl, C? _ alkoxy, hydroxy-C? _6 alkyl, or C? _ E alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; (gg) Y is a sulfonimide of the formula -C (0) NHS (0) 2R9, where R9 is C? _6 alkyl, C3_7 cycloalkyl, or C4_? or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, Cx_6 alkoxy, or phenyl, or R9 is Cs or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Ca-6-alkoxy, hydroxy-C6-6 alkyl, or C-alkyl optionally substituted with up to 5 fluoro, C6-6 alkoxy optionally substituted with up to 5 fluoro; or R9 is a C6_6alkyl 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 C6_6alkoxy; or Y is a carboxylic acid or a salt, solvate or prodrug acceptable for pharmaceutical use thereof; (hlx) R10 and R11 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C60 aryl, hydroxy-C? _6 alkyl, Cx_ 6 alkyl optionally substituted with up to 5 fluoro, (CH2) nNR6R7, (CH2) nC (0) OR14 where R14 is H, C6-6 alkyl, C3-7 cycloalkyl, or C4_? 0 alkylcycloalkyl, all of which are optionally substituted one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 0? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl C, optionally substituted alkyl with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro, -dichoCe or aryl, in the definition of R10 and R11 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C6 or x or aryl, hydroxy-C? _6 alkyl, C? _ 6 optionally substituted alkyl with up to 5 fluoro, (CH2) nNR6R7, (CH2) nC (0) 0R14 where R14 is H, C6-6 alkyl, C3_ 7-cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R14 is C6 or the aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-Cx_6 alkyl, Cx_6 alkyl optionally substituted with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; said C6 or aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C ? 6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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 C? _6 alkyl optionally substituted with (CH2) nOR8; (kk) R20 is H, Cx_6 alkyl, C3_7 cycloalkyl, C4_xo alkylcycloalkyl, C6 or aryl, hydroxy-C5-5 alkyl, CX_6 alkyl optionally substituted with up to 5 fluoro, or (CH2) nNR6R7, (CH2) nC (0 ) OR 14 where R14 is H, C? Alkyl, C3_ 7 cycloalkyl, C4-x0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, Cx_6 alkoxy, or phenyl; or R14 is C6 or? or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C_Xo alkylcycloalkyl, C2_6 alkenyl, Cx_ s alkoxy, hydroxy-Cx_6 alkyl, Cx_6 alkyl optionally substituted with up to 5 fluoro, or Cx-6 alkoxy optionally substituted with up to 5 fluoro; said C6 or? aryl, in the definition of R12 and R13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2-6 alkenyl, C_6 alkoxy, hydroxy -C? _6 alkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, C? _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, it is selected from O, NR15, or CR15; when V is NH, it is selected from NR15 or CR15, where R15 is H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or C? _6 alkyl optionally substituted with up to 5 fluoro, - (oo) dashed line represents a double additional ligature; (pp) R21 is C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3-7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-CX-6 alkyl , Cx_6 alkyl optionally substituted with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and (qq) R22 is Cx_6 alkyl, C3_7 cycloalkyl, C4_Xo alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, Cx_6 alkyl optionally substituted with up to 5 fluoro, or phenyl. 174. The compound of claim 173 CARACT? RIZADO PORQU? L consists of between 2 and 5 atoms. 175. The compound of claim 173 CARACT? RIZADO PORQU? L comprises a group -W-C (= V) -, where V and each are individually selected from 0, S or NH. 176. The compound of claim 175 CHARACTERIZED BECAUSE L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide. 177. The compound of claim 175 CHARACTERIZED BECAUSE P2 is also positioned by L to form an interaction of a hydrogen bond with at least one S2 pocket unit of NS3 protease selected from the group consisting of His57, Argl55, Val78, Asp79, Gln80 and Asp81. 178. The compound of claim 175, CHARACTERIZADO PORQU? the double bond C13-C14 is cis. 179. The compound of claim 175, CHARACTERIZED BECAUSE the C13-C14 double bond is trans. 180 The compound of claim 175, CHARACTERIZED BECAUSE P2 is 181 The compound of claim 175 CHARACTERIZED BECAUSE it is of the formula 10 11 162. The compound of claim ldl CHARACTERIZED BECAUSE L consists of between 2 and 5 atoms. 183. The compound of claim 181 CHARACTERIZED BECAUSE L comprises a group -C (= V) -, where V and each are individually selected from O, S, or NH. 184. The compound of claim 181 CHARACTERIZED BECAUSE L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide. 185. The compound of claim 181 CHARACTERIZED BECAUSE P2 is also positioned by L to form an interaction of a hydrogen bond with at least one pocket unit S2 of NS3 protease selected from the group consisting of His57, Argl55, Val78, Asp79, Gln80 and Aspdl . 186. The compound of claim 181, CHARACTERIZED BECAUSE the C13-C14 double bond is cis. 187. The compound of claim 181, CHARACTERIZED BECAUSE the C13-C14 double bond is trans. 188. The compound of claim 173 CHARACTERIZED BECAUSE it is of the formula 10 189. The compound of claim 188 CHARACTERIZED BECAUSE L consists of between 2 and 5 atoms. 190. The compound of claim 188 CARACT? RIZADO PORQU? L comprises a group -W-C (= V) -, where V and each are individually selected from O, S, or NH. 191. The compound of claim 18d CHARACTER? RIZADO PORQU? L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide. 192. The compound of claim ldd CARACT? RIZADO PORQU? P2 is also positioned by L to form an interaction of a hydrogen bond with at least one S2 pocket unit of NS3 protease selected from the group consisting of His57, Argl55, Val78, Asp79, GlndO and Aspdl. 193. The compound of claim ldd, CARACT? RIZADO PORQU? the double bond C13-C14 is cis. 194. The compound of the claim ldd, CARACT? CURLED PORQU? the double bond C13-C14 is trans. 195. A compound CHARACTERIZED BECAUSE it has the formula: 10 11 where: Q is a central ring that is selected from: wherein the central ring may be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, Cx_6, C3_7 cycloalkyl, C4_xo alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl, substituted C? _6 alkyl, C? _6 alkoxy, substituted C? _6 alkoxy, C6 or? or aryl, piridal, pirimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, aciloxiheterociclilo, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic ciciohexilo, or Q is R1-R2, wherein R1 is C? _6 alkyl, C3_7 cycloalkyl , C4_? 0 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 one optionally substituted with up to three NR6R7, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, C? _s alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or Cx_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, Cx_6 alkyl, C3_7 cycloalkyl, C4_ x or alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; R4 is H, L_6 alkyl, C3_7 cycloalkyl, C4_x0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C_ or alkylcycloalkyl, C2_6 alkenyl, C ? 6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? -G alkoxy optionally substituted with up to 5 fluoro; R5 is C? _6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) 0R8, S (0) 2R8, or (CO) CHR21NH (CO) R22; R6 and R7 are each independently H, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_ 0 alkylcycloalkyl, C2_s alkenyl, hydroxy-C6-6 alkyl, C6-6 alkyl optionally substituted with up to 5 fluoro, or C6-6 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 C_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R8 is C6 s 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or Cx_6 alkoxy optionally substituted with up to 5 fluoro; or R8 is Cx_6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; Y is COOR9, where R9 is Cx_6 alkyl; p = 0 or 1; V is selected from O, S, or NH; when V is O or S, it is selected from O, NR15, or CR15; when V is NH, W is selected from NR15 or CR15, where R15 is H, Cx_6 alkyl, C3_7 cycloalkyl, C_ or alkylcycloalkyl or Cx_6 alkyl optionally substituted with up to 5 fluoro; the line of dashes represents a double additional ligature; R21 is C_6 alkyl, C3_7 cycloalkyl, C_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is C5 or x or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-C? _6 alkyl, Cx_6 optionally substituted alkyl with up to 5 fluoro, or C6-6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and R22 is C? _6 alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl. 196. The compound of claim 195 CHARACTERIZED BECAUSE it is of the formula 197. A compound CHARACTERIZED BY WHAT? has the formula: wherein: R4 is H, C? -6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C 1 or alkylcycloalkyl, C 2 6 alkenyl, C 6 alkoxy, hydroxy C 6 alkyl, C 6 alkyl optionally substituted with up to 5 fluoro, or C 6 alkoxy optionally substituted with up to 5 fluoro; R5 is Ci-s alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) 0R8, S (0) 2R8, or (CO) CHR21NH (CO) R22; R6 and R7 are each independently H, C? Alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C_? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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 C? _6 alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R8 is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-C? _6 alkyl, C ? 6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C6-6alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; Y is a sulfonimide of the formula -C (O) NHS (O) 2R9, where R9 is C? _3 alkyl, C3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C? _3 alkyl, C3_7 cycloalkyl, or C? _3 alkoxy, or Y is a carboxylic acid p = O or 1; V is selected from OH, SH, or NH2; the line of dashes represents a double additional ligature; R21 is C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, CX-6 alkoxy, C? _6 alkyl optionally substituted with up to 5 fluoro , or phenyl; or R is C6 or aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C_? alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl C6-6alkyl optionally substituted with up to 5 fluoro, C6-6alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and R22 is C? _6 alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl. 198. The compound of claim 197 CARACT? CURLED WHY? it is of the formula 199. The compound of claim 198, CHARACTERIZADO PORQU? Y is a sulfonimide of the formula -C (0) NHS (O) 2R9, where R9 is d_3 alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C? _3 alkyl, C3_7 cycloalkyl, or C? _3 alkoxy, and where V is selected from OH and NH2. 200. A compound CARACT? CURLED WHY? has the formula: where: Q is a central ring that is selected from: where the central ring can be unsubstituted or substituted with H, halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_0 alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy Ci_e alkyl, C? _6 alkyl substituted C_6 alkyl, C? _ alkoxy, substituted C? _6 alkoxy, C6 or aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamido, urea, thiourea, amido, keto, carboxyl, carbamyl , sulfide, sulfoxide, sulfone, amino, alkoxyamino, acyloxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, or Q is R1-R2, where R1 is C? _6 alkyl, C3_7 cycloalkyl, C_? 0 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, C? _6 alkyl, C3_7 cycloalkyl, C? 0 alkylcycloalkyl, C2_6 alkenyl, CX-6 alkoxy, hydroxy-C? _6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _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, C? _6 alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, C2_6 alkenyl, C? _6 alkoxy, hydroxy-C? _6 alkyl, C? alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; R4 is H, C6-6alkyl, C3-7 cycloalkyl, C4_xoalkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, Cx_6 alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, C2_6 alkenyl, C6-6alkoxy, hydroxy-C6-6alkyl, C6-6alkyl optionally substituted with up to 5 fluoro, or C6-6alkoxy optionally substituted with up to 5 fluoro; R5 is Cx_6 alkyl, C (0) NR6R7, C (S) NR6R7, C (0) R8, C (0) OR8, S (0) 2R8, or (C0) CHR21NH (C0) R22; R6 and R7 are each independently H, Cx_6 alkyl, C3-7 cycloalkyl, C4_X0 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_ cycloalkyl, C4? 0 alkylcycloalkyl, C2_6 alkenyl, hydroxy-C6_6alkyl, C6_6alkyl optionally substituted with up to 5 fluoro, or C_6alkoxy 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 C? _6 alkyl, C3_7 cycloalkyl, C4_? Or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, or phenyl; or R8 is Ce aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C6-6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2-6 alkenyl, C? 6 alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, or C? _6 alkoxy optionally substituted with up to 5 fluoro; or R8 is C? _6 alkyl optionally substituted with up to 5 fluoro groups; or R8 is a tetrahydrofuran ring attached through the C3 or C4 position of the tetrahydrofuran ring; or R8 is a tetrapyranyl ring attached through the C4 position of the tetrapyranyl ring; Y is COOR9, where R9 is C6-6alkyl; or Y is a sulfonimide of the formula -C (O) NHS (O) 2R9, where R9 is C3_3alkyl, C3_7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C3_3alkyl , C3_7 cycloalkyl, or Cx_3 alkoxy, or Y is a carboxylic acid p = 0 or 1; V and each one is selected individually between O, S, or NH; the dashed line represents a further double bond, - R21 is Cx_6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkoxy, C ? 6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R21 is Ce 0 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C? _6 alkyl, C3_7 cycloalkyl, C4_? 0 alkylcycloalkyl, C2_6 alkenyl, Cx_6 alkoxy, hydroxy-C? -6 alkyl, C? _6 alkyl optionally substituted with up to 5 fluoro, C? _6 alkoxy optionally substituted with up to 5 fluoro; or R21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and R22 is C? _6 alkyl, C3_7 cycloalkyl, C4_? or alkylcycloalkyl, all of which are optionally substituted between one and three times with halo, cyano, nitro, hydroxy, C? _6 alkyl optionally substituted with up to 5 fluoro, or phenyl. R? SUM? N D? THE INVENTION Various embodiments are provided with compounds of the General formulas I-XIX, as well as compositions, among which are included pharmaceutical compositions, which comprise a compound of the invention. The embodiments further provide methods of treatment, including methods of treating flaviviral infections, including infection by the hepatitis C virus and methods of treating liver fibrosis. The methods generally consist in the administration to an individual in need thereof, an effective amount of a compound or composition of the invention.