JP4950026B2 - Macrocyclic compounds as viral replication inhibitors - Google Patents

Description

  This application gives priority to U.S. Provisional Application No. 60/511541 filed on October 14, 2003 and U.S. Provisional Application No. 60/612460 filed on September 22, 2004. Filed on February 23, 2005, which is a continuation of PCT / US04 / 33970 filed on October 13, 2004, alleged under section 119 (e) (35 USC §119 (e)) US patent application Ser. No. 11/064445, which is a continuation-in-part of U.S. Patent Application No. 11/064445; this application is also a U.S. Provisional Application No. 60/612381 filed on September 22, 2004, on April 14, 2004. Claims priority to filed U.S. Provisional Application No. 60/562418 and U.S. Provisional Application No. 60/558161 filed March 30, 2004; all of which are hereby incorporated by reference in their entirety Is incorporated herein by reference.

  The present invention relates to compounds, methods for their synthesis, pharmaceutical compositions, and methods for treating flaviviruses such as hepatitis C virus (HCV) infection. Specifically, the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs, and methods of using such analogs in the treatment of flavivirus infections.

  Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States. Although the number of new infections has declined, the burden of chronic infection is considerable, and the US Centers for Disease Control and Prevention estimates that 3.9 million people (1.8%) are infected in the United States. Chronic liver disease is the 10th leading cause of death among adults in the United States, causing approximately 25,000 deaths annually, or accounting for approximately 1% of all deaths. Studies have shown that 40% of chronic liver diseases are related to HCV, resulting in an estimated 8,000-10,000 deaths. End-stage liver disease associated with HCV is the most common indication of liver transplantation in adults.

  Antiviral therapy for chronic hepatitis C has developed rapidly over the last decade, and considerable progress has been made in therapeutic efficacy. Nevertheless, even with combination therapy using PEGylated IFN-α + ribavirin, 40% to 50% of patients fail treatment, ie non-responders or relapsers. Such patients do not currently have another effective treatment option. In particular, patients with advanced fibrosis or cirrhosis following liver biopsy have significant risk of developing complications of advanced liver disease, including ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure As well as the risk of hepatocellular carcinoma.

  The high prevalence of chronic HCV infection has important public health implications for the future burden of the United States on chronic liver disease. Data from the National Health and Nutrition Survey (NHANES III) show that the proportion of new HCV infections has increased significantly between the late 1960s and the 1980s, especially among those aged 20-40 ing. The number of people with long-lasting HCV infection over 20 years is expected to quadruple between 1990 and 2015, ie 750,000 to 3 million. The increase in the proportion of people who have been infected for 30 or 40 years should be even greater. The risk of HCV-related chronic liver disease is related to the duration of infection, and since the risk of cirrhosis increases progressively in those who have been infected for more than 20 years, the number of people with this long-lasting HCV infection The increase will significantly increase morbidity and mortality associated with cirrhosis in patients infected between 1965 and 1985.

  HCV is a plus-strand RNA virus with a coat of the Flaviviridae family. The single-stranded HCV RNA genome is about 9500 nucleotides in length and has a unique open reading frame (ORF) that encodes a single large polyprotein consisting of about 3000 amino acids. In infected cells, this polyprotein is cleaved at several sites by cellular and viral proteases to produce viral structural and nonstructural (NS) proteins. In the case of HCV, two viral proteases produce mature nonstructural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B). The first viral protease cleaves the NS2-NS3 junction of the polyprotein. The second viral protease is a serine protease (referred to herein as “NS3 protease”) contained within the N-terminal region of NS3. NS3 protease mediates subsequent total cleavage events at a site downstream of the position of NS3 in the polyprotein (ie, the site located between the C-terminus of NS3 and the C-terminus of the polyprotein). NS3 protease is active in cis at the NS3-NS4 cleavage site and in trans at the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is thought to serve a number of functions as it acts as a cofactor for the NS3 protease and possibly assists in membrane localization of NS3 and other viral replicase components. Apparently, the formation of a complex between NS3 and NS4A is required for NS3-mediated processing events and appears to increase proteolytic efficiency at all sites recognized by NS3. NS3 protease also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is an RNA-dependent RNA polymerase involved in HCV RNA replication.

(Reference)
US Patent Provisional Application No. 60/511541 U.S. Provisional Application No. 60/612460 PCT / US04 / 33970 U.S. Patent Application No. 11/064445 US Provisional Patent Application No. 60/612381 U.S. Provisional Patent Application No. 60/562418 US Provisional Patent Application No. 60/558161 Stryer et al., “Biochemistry”, 5th edition, 2002, Freeman & Co. NY Yao et al., Structure 1999, 7, 1353 A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20th edition, Lippincott, Williams, & Wilkins `` Pharmaceutical Dosage Forms and Drug Delivery Systems '' (1999), HC Ansel et al., 7th edition, Lippincott, Williams, & Wilkins "Handbook of Pharmaceutical Excipients" (2000), edited by AH Kibbe et al., 3rd edition, Amer. Pharmaceutical Assoc. Brunt (2000), Hepatol. 31: 241-246 METAVIR (1994), Hepatology Volume 20: 15-20 pages Knodell (1981), Hepatol. Volume 1: 431 Scheuer (1991), J. Hepatol. 13: 372 Ishak (1995), J. Hepatol. 22: 696-699 U.S. Pat. No. 4,695,623 U.S. Pat.No. 4,897,471 Osborn et al. (2002) J. Pharmacol. Exp. Therap. 303: 540-548. Masci et al. (2003), Curr. Oncol. Rep. 5: 108-113 U.S. Patent No. 5382657 U.S. Patent No. 5981709 U.S. Patent No. 5951974 U.S. Pat. WO 97/03106 Park et al., Anticancer Res., Volume 1: 373-376 (1981) Zaplipsky and Lee, `` Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications '', edited by JM Harris, Plenum Press, New York, USA, Chapter 21 (1992) U.S. Pat. No. 5,985,265 Chamow et al. (1994) Bioconj. Chem. 5: 133-140 U.S. Patent No. 5643575 U.S. Pat.No. 6046305 Sheppard et al. (2003), Nature Volume 4: 63-68. Friedler et al. (2000), J. Biol. Chem. 275: 23783-23789 Gray et al. (1982) Nature 295: 501. Rinderknecht et al. (1984), JBC 259: 6790. U.S. Pat. U.S. Patent No. 5690925 International patent application WO 01/36001 U.S. Pat.No. 3,974281 U.S. Patent No. 3839346 U.S. Patent No. 4042699 U.S. Patent No. 4052509 U.S. Pat.No. 5,310,562 U.S. Pat.No. 5,587,729 U.S. Pat.No. 5,716,632 U.S. Patent No. 6090822 Merck Index, Compound No. 8199, 11th edition U.S. Pat. U.S. Pat. No. 6,277,830 U.S. Pat. U.S. Patent No. 6423695 US Patent Publication No. 2002/0058635 WO 01/90121 A2 WO 02/069903 A2 WO 02/057287 A2 WO 02/057425 A2 US Patent No. 5605690 Mohler et al., 1993, J. Immunol. 151: 1548-1561. Smith et al. (1990) Science 248: 1019-1023 U.S. Pat.No. 5,395,760 WO 90/10077 WO 90/04036 WO 92/02190 Elliott et al. (1993), Arthritis Rheum. 36: 1681-1690. Elliott et al. (1994), Lancet Vol. 344: 1105-1110 Baert et al. (1999), Gastroenterology 116: 22-28. Piascik (2003), J. Am. Pharm. Assoc. 43: 327-328 U.S. Patent No. 6548520 U.S. Patent No. 6489325 U.S. Pat. Published US Patent Application No. 2003/0073832 U.S. Patent No. 6288089 U.S. Patent No. 6432962 US Patent Application Publication No. 2003/0149041 U.S. Patent No. 6,214,854 Lee et al. (1994) Nature 372: 739. US Pat. No. 6,479,508 International Patent Application PCT / CA02 / 01127 PCT / CA02 / 01128 PCT / CA02 / 01129 U.S. Patent No. 6440985 WO 01/47883 Zhong et al. (2003), Antimicrob. Agents Chemother. 47: 2674-2681 Dhanak et al. (2002), J. Biol Chem. 277 (41): 38322-7. WO 02/100846 A1 WO 02/100851 A2 WO 01/85172 A1 WO 02/098424 A1 WO 00/06529 WO 02/06246 A1 WO 03/000254 EP 1 256628 A2 Markland et al. (2000) Antimicrob. Agents Chemother. 44: 859-866. Watson (2002), Curr Opin Investig Drugs Volume 3 (5): 680-3 pages U.S. Pat.No. 3,547,119 U.S. Pat.No. 4,755,173 U.S. Pat.No. 4531937 U.S. Pat.No. 4311137 US Patent No. 6017328 International patent application PCT / CA00 / 00353 (publication number WO00 / 59929) Stokker, G E., Tetrahedron Lett., 1996, 37 (31), 5453-5456 Chan, N W., Bioorganic & Medicinal Chemistry, 2000, 8, 2085-2094 Vecchietti, V. et al., J. Med. Chem., 1991, 34, 2624-2633 Caron, S .; Vazquez, E .; Wojcik, JM, J. Am. Chem. Soc., 2000, 122, 712-713 Grunewald, GL; Sall, DJ; Monn, JA, J.Med.Chem., 1988, 31, 433-444 J. Med. Chem., 2002, 45, 26, 5771 Bioorg.Med.Chem.Lett., 11 (2001) 685-688 Khan et al., Bioorg. & Med. Chem. Lett., 1997, 7 (23), 3017-3022 International Patent No. 03/053349 JOC, 53, 22, 1988, 5381-5383 Org.Letters, 2003, Volume 5, Issue 6, 793-796 J. Org. Chem., 2000, 65, 1144-1157 J. Org. Chem., 1998, 63, 8224-8228 Lohmann et al., Science, 285, 110-113, 1999 Heteroatom Chemistry, 12 (1), 1-5, 2001 Winum, JY et al., Organic Letters, Volume 3, pages 2421-2243, 2001

  Embodiments provide compounds having the following Formula I:

[In the above formula,
Q is a core ring selected from:

In the above formula, the core ring is unsubstituted or H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy -C _{1 to 6} alkyl, C _{1 to 6} alkyl, substituted C _{1 to 6} alkyl, C _{1 to 6} alkoxy, substituted C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl , Furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide, urea, thiourea, amide, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocycle, alkylamino, alkylcarboxy, Carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or B cyclic cyclohexyl by may be substituted;
Alternatively, Q is R ¹ -R ² and R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, 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 with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _{1- 6} alkyl or up to 5 substituents C _{1 to 6} a be optionally substituted with fluoro, Kill, may be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with up to 5 fluoro; R ² 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 up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. May be C _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is bonded through the C ₄ position of the tetrapyranyl ring. Is a tetrapyranyl ring;
Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ and R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl , All of which may be optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl, or R ⁹ may have up to 3 halo, cyano, nitro , Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or up to 5 good C _{1 to 6} alkyl which may be optionally substituted with fluoro, optionally optionally substituted with up to 5 substituents C _{1 to 6} alkoxy which may be optionally substituted with fluoro C _{6 or} be ₁₀ aryl; or R ⁹ is the highest 5 fluoro groups, NR ⁶ R ^7, an NR ^1a R ^1b, or (CO) optionally C _{1 to 6} alkyl which may be optionally substituted with OH,, or R ⁹ is halo, cyano, nitro, Is an aromatic heterocycle optionally substituted up to two times by hydroxyl or C _1-6 alkoxy; or Y is a carboxylic acid, or a pharmaceutically acceptable salt, solvate, or Is a prodrug;
R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C _1-6 Optionally substituted 1-3 times by alkoxy, amide, or phenyl,
Alternatively, R ^1a and R ^1b are each independently H, and up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, optionally by 5 fluoro hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy,
Alternatively, R ^1a and R ^1b are each independently H, a heterocyclic ring, which includes 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Or a 7-membered saturated or unsaturated heterocyclic molecule,
Alternatively, NR ^1a R ^1b is a 3-6 membered alicyclic secondary amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, Optionally substituted 1-3 times by C _1-6 alkoxy, amide, or phenyl,
Or NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

In the above formula, R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl,
Or R ^1c is NH (CO) OR ^1e and R ^1e is C _1-6 alkyl or C _3-6 cycloalkyl;
p = 0 or 1;
V is selected from O, S, or NH;
When V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy By, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or up to 5 fluoro C _1-6 alkyl optionally substituted, C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro Is aryl; Alternatively or R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, there oxazolyl, phenoxy, or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro Optionally substituted _C1-6 alkyl, or optionally substituted 1-3 times by phenyl;
However, a compound having Formula I does not include a compound having Formula II, III, or IV as defined below. ]

  Embodiments provide compounds having the following Formula II, III, or IV.

[In the above formula,
a) R ¹ and R ² are each independently H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, it is optionally substituted with up to 5 fluoro which may be C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, ^{_{thiophenoxy, S (O) 2 NR 6}} R 7, NHC (O) NR 6 R ⁷ , NHC (S) NR ⁶ R ⁷ , C (O) NR ⁶ R ⁷ , NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , NHC (O) R ⁸ , NHC (O ) OR ⁸ , SO _m R ⁸ , NHS (O) ₂ R ⁸ , CH _n NR ⁶ R ⁷ , OCH _n NR ⁶ R ⁷ , or OCH _n R ⁹ (R ⁹ is imidazolyl or pyrazolyl); Rules for R ¹ and R ² It said thienyl, Pirimi Jill, furanyl, thiazolyl, and oxazolyl are up to two halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl alkyl, C _{4 to 10} alkyl cycloalkyl alkyl, C of _2-6 alkenyl, C _{1 to 6} alkoxy, optionally by 5 fluoro hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, It may be optionally substituted with optionally C _{1 to 6} alkoxy optionally substituted by selection; the C _{6 or 10} aryl of R ¹ and R ² defined, pyridyl, phenoxy and thiophenoxy is best in three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydro Shi -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up to five which may _{C. 1 to} substituted optionally by fluoro, Optionally substituted by ₆ alkoxy;
b) m = 0, 1, or 2;
c) R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, wherein the phenyl or benzyl is a maximum of 3 halo, cyano , Nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 Optionally substituted by C _1-6 alkyl, optionally substituted by fluoro, or optionally substituted by C _1-6 alkoxy, optionally substituted by up to 5 fluoro ;
d) R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ or (CO) CHR ²¹ NH (CO) R ²² ;
e) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being at most 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl or up to 5 fluoro, Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy, optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
f) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of these by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 1-3 times; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, 5 C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, at the highest C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by fluoro; or R ⁸ is optionally substituted by up to 5 fluoro groups Is replaced with Be also good C _{1 to 6} alkyl; or R ⁸ is an tetrahydrofuran ring attached via a C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is, via the C ₄ position of Tetorapiraniru ring A bound tetrapyranyl ring;
g) Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ , where R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl All of which may be optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl, or R ⁹ may have up to 3 halo, cyano, , Nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or up to 5 C _1-6 alkyl optionally substituted by ₁ fluoro, optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro C _{6 or 10} aryl; or R ⁹ is the highest Or C _9-6 alkyl, NR ⁶ R ⁷ , or (CO) OH, optionally substituted by 5 fluoro groups, or R ⁹ is halo, cyano, nitro, hydroxyl, or C An aromatic heterocycle optionally substituted up to 2 times by _1-6 alkoxy; or Y is a carboxylic acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
h) R ¹⁰ and R ¹¹ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, or C _{4 to 10} alkylcycloalkyl), all of which halo, 1 to 3 cyano, nitro, hydroxy, C _{1 to 6} alkoxy or by phenyl, Optionally substituted once; or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, in up to 5 fluoro Which may be optionally substituted with optionally C _{1 to 6} alkoxy substituted optionally which may be C _{1 to 6} alkyl optionally substituted, or the best, by 5 fluoro What C _{6 or 10} aryl; said C _{6 or 10} aryl as defined for R ¹⁰ and R ¹¹ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or, Optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ¹⁰ and R ¹¹ together with the carbon to which they are attached. Become cyclopropi , Cyclobutyl, cyclopentyl, or cyclohexyl; or R ¹⁰ and R ¹¹ are combined as O;
i) p = 0 or 1;
j) R ¹² and R ¹³ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkyl cycloalkyl), 1-3 times all of which halo, cyano, nitro, hydroxy, C _{1 to 6} alkoxy or by phenyl, Optionally substituted; or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted with meaning selected C _{1 to 6} alkyl or up to 5 substituents C _{6 or} be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, It is ₁₀ aryl; wherein C _{6 or 10} aryl provisions of R ¹² and R ^13, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, _{C. 4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by C _1-6 alkoxy optionally substituted by 5 fluoro; or R ¹² and R ¹³ together with the carbon to which they are attached. Cyclopropyl, Si Forms chlorobutyl, cyclopentyl, or cyclohexyl; or R ¹² and R ¹³ are each independently C _1-6 alkyl optionally substituted by (CH ₂ ) _n OR ⁸ ;
k) R ²⁰ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, or (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _1-6 alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkyl cycloalkyl), all of which halo, cyano, nitro, hydroxy, C _{1 to 6} alkoxy or substituted optionally 1-3 times by phenyl, Or R ¹⁴ may be up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C ₆ alkoxy, hydroxy -C _1-6 alkyl, optionally substituted with up to 5 fluoro There be which may be C _{6 or 10} aryl optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with 5 fluoro also good C _{1 to 6} alkyl or up and; R Said C _{6 or 10} aryl as defined for ¹² and R ¹³ is a maximum of 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl optionally or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, by up to 5 fluoro, Optionally substituted by optionally substituted C _1-6 alkoxy;
l) n = 1-4;
m) V is selected from O, S, or NH;
n) when V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted by up to 5 fluoro;
o) The dashed line represents an optional double bond;
p) R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 Optionally substituted by fluoro of C _1-6 alkyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro optionally substituted with C _{1 to 6} alkyl or substituted optionally with up to 5 substituents C _{1 to 6} alkoxy which may be optionally substituted with fluoro C _6, by _or Oh in ₁₀ aryl ; Or R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, there oxazolyl, phenoxy, or thiophenoxy;
q) R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally selected by halo, cyano, nitro, hydroxy, up to 5 fluoro It may be optionally substituted 1 to 3 times with optionally substituted C _1-6 alkyl, or phenyl. ]

  Embodiments provide compounds having Formula XI.

[In the above formula,
a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C ₁ Optionally substituted 1-3 times by alkoxy- ₆ , amide, or phenyl;
Alternatively, R ^1a and R ^1b are each independently H, and up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, optionally by 5 fluoro hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy;
Alternatively, R ^1a and R ^1b are each independently H or a heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur Or a 7-membered, saturated or unsaturated heterocyclic molecule;
Alternatively, NR ^1a R ^1b is a 3-6 membered alicyclic secondary amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, Optionally substituted 1-3 times by C _1-6 alkoxy, amide, or phenyl;
Or NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

In the above formula, R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl;
Or R ^1c is NH (CO) OR ^1e and R ^1e is C _1-6 alkyl or C _3-6 cycloalkyl;
b) W is O or NH;
c) V is selected from O, S, or NH;
d) when V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted by up to 5 fluoro;
e) R ² is a bicyclic secondary amine having the structure:

In the above formula, R ²¹ and R ²² are each independently H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6. Alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkyl, up to 5 fluoro which may be C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, ^{_{thiophenoxy, S (O) 2 NR 6}} R 7, NHC (O) NR ⁶ R ⁷ , NHC (S) NR ⁶ R ⁷ , C (O) NR ⁶ R ⁷ , NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , NHC (O) R ⁸ , NHC ( _{^{O) oR 8, SO m R}} 8 (m = 0,1 or 2), or NHS (O) be ₂ R ^8; the thienyl, Pirimi Jill provisions of R ²¹ and R ^22, furanyl, thiazolyl, Contact Yo Fine oxazolyl is up to two halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up to five which may _{C. 1 to} substituted optionally by fluoro, may be optionally substituted with ₆ alkoxy; said C _{6 or 10} aryl provisions of R ²¹ and R ^22, pyridyl, phenoxy and thiophenoxy is up to three halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optional with up to 5 fluoro so Optionally substituted by C _1-6 alkyl, which may be substituted, or C _1-6 alkoxy, optionally substituted by up to 5 fluoro;
Wherein R ¹⁰ and R ¹¹ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl , C _1-6 alkyl, (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is optionally substituted with up to 5 fluoro H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl), which are all 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. May be optionally substituted three times; or R ¹⁴ may be up to three halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 C _1-6 alkyl optionally substituted by Luoro, C ₆ optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro C _{6 Or} C _{6 or 10} aryl as defined for R ¹² and R ¹³ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up, Optionally substituted by 5 fluoro and optionally substituted by C _1-6 alkoxy; or R ¹⁰ and R ¹¹ together with the carbon to which they are attached. Cyclop Pills, cyclobutyl, cyclopentyl or cyclohexyl to form,; or R ¹⁰ and R ¹¹ are coalesced as O;
Where p = 0 or 1;
Wherein R ¹² and R ¹³ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl C _1-6 alkyl, optionally substituted with up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H , C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl), which are all 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. May be optionally substituted three times; or R ¹⁴ may be up to three halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluors C _1-6 alkyl optionally substituted by b, optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro C _{6 Or} C _{6 or 10} aryl as defined for R ¹² and R ¹³ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up, Optionally substituted by 5 fluoro and optionally substituted by C _1-6 alkoxy; or R ¹² and R ¹³ together with the carbon to which they are attached. Cyclopropi To form cyclobutyl, cyclopentyl, or cyclohexyl;
Wherein R ²⁰ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl, optionally substituted by (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _1-6 alkyl All of which are optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl), C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl) Or R ¹⁴ may be up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl. , optionally by 5 fluoro C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, with the highest Optionally substituted C _{1 to 6} alkyl or up to 5 amino which may be C _{6 or 10} aryl optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, Yes; said C _{6 or 10} aryl as defined for R ¹² and R ¹³ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcyclo alkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up to five, Optionally substituted by C _1-6 alkoxy optionally substituted by fluoro;
Where n = 0-4;
In the formula, R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, and the phenyl has a maximum of 3 Halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by, or C _1-6 alkoxy, optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
Or R ² is R ^2a R ^2b when W = NH, V = O,
R ^2a is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, 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 up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally up to 5 fluoro Optionally substituted C _1-6 alkyl, or up to 5 fluoro Optionally substituted by C _1-6 alkoxy optionally substituted by;
R ^2b 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 up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, 5 fluoro up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, the good C _{1 to 6} alkoxy which may be optionally substituted with It may be substituted with meaning selected;
R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halos. , Cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, optional up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted, or C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ^2c And R ^2d together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
f) R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted C _1-6 alkyl, or optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy;
g) R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , or S (O ) ₂ R ⁸ ;
h) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of these by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 1-3 times; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, 5 C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by fluoro;
i) The dashed line represents an optional double bond. ]

  Embodiments include a compound having the formula XVIII:

[In the above formula,
a) R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, iso Oxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each up to 3 NR ⁵ R ⁶ , halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro good C _{1 to 6} alkyl optionally substituted by selection or up to 5 fluoro, Thus it may be optionally substituted with optionally C _{1 to 6} alkoxy substituted optionally;
b) R ² is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzo Thiophene, benzofuran, indole, or benzimidazole, each up to 3 NR ⁵ R ⁶ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, 5 C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by C _1-6 alkoxy optionally substituted by fluoro May be optionally substituted;
c) R ³ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted C _1-6 alkyl, or optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy;
d) R ⁴ is C _1-6 alkyl, C (O) NR ⁵ R ⁶ , C (S) NR ⁵ R ⁶ , C (O) R ⁷ , C (O) OR ⁷ , or S (O) ₂ R ⁷ ;
e) R ⁵ and R ⁶ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being at most 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl or up to 5 fluoro, Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy, optionally substituted by up to 5 fluoro; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
f) R ⁷ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Optionally substituted 3 times; or R ⁷ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcyclo alkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up to five, C _{6 or 10} aryl optionally substituted with C _1-6 alkoxy optionally substituted with fluoro;
g) R ⁸ is optionally substituted with C _1-3 alkyl, C _3-4 cycloalkyl, or up to 2 halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy. Optionally phenyl;
h) The dashed line represents an optional double bond],
Or a pharmaceutically acceptable salt thereof.

  Embodiments provide compounds of the formula:

[In the above formula,
a) Z is a group arranged to hydrogen bond to the NS3 protease His57 imidazole moiety and hydrogen bond to the NS3 protease Gly137 nitrogen atom;
b) P1 ′ is arranged so as to have nonpolar interaction with at least one NS3 protease S1 ′ pocket portion selected from the group consisting of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42, and Phe43 Radicals;
c) L is a linking group consisting of 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
d) P2 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocycle, and substituted heterocycle; P2 is His57, Arg155, Val78, Asp79, Gln80, And is positioned by L to have a nonpolar interaction with at least one NS3 protease S2 pocket portion selected from the group consisting of Asp81,
e) the dashed line represents an optional double bond;
f) R ⁵ is selected from the group consisting of H, C (O) NR ⁶ R ⁷ , and C (O) OR ⁸ ;
g) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being at most 3 By halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted C _1-6 alkyl, optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ And R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
h) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Optionally substituted 3 times; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcyclo alkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, up to 5 fluoro C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by; or R ⁸ is optionally substituted by up to 5 fluoro groups C _1-6 may be Or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring bonded through the C ₄ position of the tetrapyranyl ring. Is;
However, this compound does not include compounds having the formula II, III or IV. ]

  Embodiments provide compounds having the formula:

[In the above formula,
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ , Or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. May be C _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is bonded through the C ₄ position of the tetrapyranyl ring. Is a tetrapyranyl ring;
Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ , where R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl, or up to 2 halo, cyano, Nitro, hydroxy, C _1-3 alkyl, C _3-7 cycloalkyl, or phenyl optionally substituted by C _1-3 alkoxy, or Y is a carboxylic acid ;
V is selected from OH, SH, or NH ₂ ;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, _or C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro. Is aryl; Alternatively or R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, there oxazolyl, phenoxy, or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro. C _1-6 alkyl, which may optionally be substituted, or optionally substituted 1 to 3 times by phenyl. ]

  Embodiments provide compounds having the formula:

[In the above formula,
Q is a core ring selected from:

In the above formula, the core ring is unsubstituted or H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy -C _{1 to 6} alkyl, C _{1 to 6} alkyl, substituted C _{1 to 6} alkyl, C _{1 to 6} alkoxy, substituted C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl , Furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide, urea, thiourea, amide, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocycle, alkylamino, alkylcarboxy, Carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or B cyclic cyclohexyl by may be substituted;
Or Q is R ¹ -R ² and R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan , Thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl , up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or, May be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with 5 fluoro at high; R ² 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 with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 Alkyl, optionally substituted with up to 5 fluoro Optionally substituted by C _1-6 alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ , Or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. May be C _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is bonded through the C ₄ position of the tetrapyranyl ring. Is a tetrapyranyl ring;
Y is, R ⁹ is C _{1 to 6} alkyl, COOR ^9; or Y is the formula -C (O) NHS (O) sulfonimide is ₂ R ^9, R ⁹ is _{C. 1 to} Optionally substituted by ₃ alkyl, C _3-7 cycloalkyl, or up to 2 halo, cyano, nitro, hydroxy, C _1-3 alkyl, C _3-7 cycloalkyl, or C _1-3 alkoxy Optionally phenyl, or Y is a carboxylic acid ;
V and W are each independently selected from O, S, or NH;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro And yes Is or R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, there oxazolyl, phenoxy, or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro. Optionally substituted _C1-6 alkyl, or optionally substituted 1-3 times by phenyl].

  Embodiments provide a pharmaceutical composition comprising a preferred compound and a pharmaceutically acceptable carrier.

  Embodiments provide a method of treating hepatitis C virus infection in an individual comprising administering an effective amount of a preferred compound to the individual.

  Embodiments provide a method of treating liver fibrosis in an individual comprising administering an effective amount of a preferred compound to the individual.

  Embodiments provide a method for enhancing liver function in an individual infected with hepatitis C virus, comprising administering an effective amount of a preferred compound to the individual.

  The chemical formulas representing the compounds described herein also represent pharmaceutically acceptable salts, solvates, esters and prodrug derivatives thereof.

Definitions As used herein, the term “hepatic fibrosis” is used interchangeably herein with “liver fibrosis” and refers to the growth of scar tissue in the liver that can occur in chronic hepatitis infections. Point to.

  The terms “individual”, “host”, “subject”, and “patient” are used interchangeably herein and refer to mammals, including but not limited to primates, including apes and humans.

  As used herein, the term `` liver function '' includes, but is not limited to, serum proteins (e.g. albumin, clotting factor, alkaline phosphatase, aminotransferase (e.g. alanine transaminase, aspartate transaminase), 5'-nucleosidase, synthetic functions including synthesis of proteins such as γ-glutaminyl transpeptidase, bilirubin synthesis, cholesterol synthesis, and bile acid synthesis; including carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism It refers to the liver's standard functions including, but not limited to, liver metabolic functions; detoxification of foreign drugs; hemodynamic functions including visceral and portal hemodynamics.

  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 / NS4A complex. Unless otherwise indicated, the term “NS3 inhibitor” is used interchangeably with the terms “HCV NS3 protease inhibitor” and “NS3 protease inhibitor”.

  As used herein, the term “polyol” or “poly-ol” means a hydrocarbon containing at least two hydroxyls attached to a carbon atom, including sugars (reducing and non-reducing sugars), sugar alcohols, and Contains sugar acids. The polyol can also contain other functional groups. Examples of polyols include sugar alcohols such as mannitol and trehalose, and polyethers. A “reducing sugar” is a sugar that contains a hemiacetal group that can reduce metal ions or can covalently react with lysine and other amino groups in proteins. It is a sugar without these characteristics. Examples of reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose, and glucose. Non-reducing sugars include sucrose, trehalose, sorbose, meretitol, and raffinose. Mannitol, xylitol, erythritol, threitol, sorbitol, and glycerol are examples of sugar alcohols. For sugar acids, these include L-gluconate and its metal salts.

  As used herein, the term “polyether” means a hydrocarbon containing at least three ether linkages. The polyether can also contain other functional groups. Polyethers include polyethylene glycol (PEG).

  The term “persistent viral response” (also referred to as SVR, “persistent response” or “permanent response”) is used herein to refer to an individual's serum HCV titer relative to a treatment plan for HCV infection. Refers to a response. In general, a “sustained viral response” refers to a patient who has been on treatment for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months No detectable HCV RNA is found in the serum (eg, less than about 500, less than about 200, or less than about 100 genome replicas are found per milliliter of serum).

  “Treatment failure patient” as used herein generally refers to an HCV infected patient who has not responded to a previous HCV treatment (also referred to as a “non-responder”) or who initially responded to a previous treatment but whose treatment response Refers to HCV-infected patients (also called “responders”) who are not maintained. Previous treatment may generally include treatment with IFN-α monotherapy or IFN-α combination therapy, which may include administration of an antiviral agent such as IFN-α and ribavirin .

  As used herein, the terms “treatment”, “treating” and the like refer to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in that it completely or partially prevents the disease or symptom and / or partially or completely cures the adverse consequences caused by the disease and / or disease. And may be therapeutic. “Treatment” as used herein includes any treatment of disease in mammals, particularly humans, and (a) develops disease in a subject who may be predisposed to the disease but has not yet been diagnosed Such as preventing it from occurring, (b) suppressing the disease, ie preventing its progression, and (c) alleviating the disease, ie reversing the disease.

  The terms “individual”, “host”, “subject”, and “patient” are used interchangeably herein and include, but are not limited to, murine, ape, human, domestic mammal, competition mammal, and pet mammal. Refers to mammals including animals.

  As used herein, the term “pirfenidone” refers to 5-methyl-1-phenyl-2- (1H) -pyridone. As used herein, the term “pirfenidone analog” refers to any compound of formula I, IIA, or IIB in the following section whose title is “pirfenidone and its analogs”. “Specific pirfenidone analogs” and all grammatical variants thereof refer to the respective pirfenidone analogs and all pirfenidone analogs shown in Table 1 in the following section whose title is “Pirfenidone and its analogs”. Point to and be limited to them.

  As used herein, the term “type I interferon receptor agonist” refers to any naturally occurring or non-naturally occurring human type I interferon receptor ligand that binds to and causes signaling through the receptor. Point to. Type I interferon receptor agonists include naturally occurring interferons, modified interferons, synthetic interferons, PEGylated interferons, fusion proteins containing interferons and heterologous proteins, interferons including mixed interferons; specific for interferon receptors Antibodies; non-peptide chemical agonists and the like.

  As used herein, the term “type II interferon receptor agonist” refers to any naturally occurring or non-naturally occurring human type II interferon receptor ligand that binds to and causes signaling through the receptor. Point to. Type II interferon receptor agonists include natural human interferon γ, recombinant IFN-γ species, glycosylated IFN-γ species, PEGylated IFN-γ species, modified or variant IFN-γ species, IFN-γ fusion proteins, antibodies specific for this receptor, non-peptide agonists and the like are included.

  As used herein, the term “type III interferon receptor agonist” refers to any naturally occurring or non-naturally occurring human IL-28 receptor α that binds to and causes signaling through the receptor. ("IL-28R") refers to a ligand, the amino acid sequence of which is described in Sheppard et al.

  As used herein, the term “interferon receptor agonist” refers to any of type I interferon receptor agonists, type II interferon receptor agonists, or type III interferon receptor agonists.

  The term “administration event” as used herein refers to the administration of an antiviral agent to a patient in need thereof, and may include one or more releases of the antiviral agent from a drug metering device. Thus, the term “administration event” as used herein includes, but is not limited to, a sustained delivery system after installation of a sustained release device (e.g., a pump or other controlled injection system for injection) and a single subcutaneous injection. Including installation.

  `` Sustained delivery '' as used herein (for example, with respect to `` sustained delivery of a substance to a tissue '') delivers a desired amount of substance to a tissue over a selected time and during the selected time Means in a manner that allows the patient to receive approximately the same amount of drug per minute and that the drug moves to a delivery site, eg, tissue.

  `` Controlled release '' as used herein refers to a substance (e.g., with respect to `` controlled release of drug '') in which a substance (e.g., a type I or type III interferon receptor agonist such as IFN-α) is selected or otherwise Meaning release at a controlled rate, interval, and / or amount, with little influence from the environment of use. Thus, "controlled release" includes, but is not necessarily limited to, substantially sustained delivery and pattern delivery (e.g., intermittent delivery over a period of time with regular or irregular intervals). .

  “Pattern” or “temporal”, when used with respect to drug delivery, takes a drug over a pre-selected time (e.g., other than the time it takes, for example, a bulk injection), in a pattern, generally nearly regular. It is meant to include delivering in a pattern. `` Pattern '' or `` temporal '' drug delivery is an increasing trend, decreasing trend, nearly constant, or pulsatile rate or rate range (e.g., amount of drug per unit time or drug formulation volume per unit time). In addition to the delivery of other drugs, and also to include sustained or substantially sustained or prolonged delivery.

  The term `` controlled drug delivery device '' is any device in which the release (e.g., rate, release timing) of a drug or other desired substance contained therein is controlled or determined by the device itself, and its environment of use. It is meant to include those that are substantially unaffected by or that release at a reproducible rate within their environment of use.

  “Substantially sustained”, for example, when used with respect to “substantially sustained infusion” or “substantially sustained delivery”, is substantially interrupted during a preselected drug delivery period. Rather, it means that the amount of drug received by the patient is delivered so that it never becomes zero during any 8 hour interval during the preselected period. Also, “substantially sustained” drug delivery is a substantially constant preselected rate or rate range that is substantially uninterrupted during a preselected drug delivery period (eg, an amount of drug per unit time). Or drug delivery volume per unit time).

  “Substantially stable state” means that when used with respect to biological parameters that may vary with time, the biological parameter is an organism over time over any 8 hour period of time. The area under the curve (AUC8hr) defined by the value of the biological parameter does not exceed about 20% of the average area under the curve (AUC8hr average) over the course of 8 hours of the biological parameter or about 20% Means less than about 15%, preferably no more than about 15%, or no less than about 15%, more preferably no more than about 10% and no more than about 10%. The AUC8hr mean is the quotient (q) divided by the area under the curve over the time course of biological parameters (AUC total) divided by the number of 8 hour intervals in the time course (total 1/3 day), i.e. q = (AUC total) / (total 1/3 days). For example, for serum drug concentration, the area under the curve of serum drug concentration over time for any 8 hour over time (AUC8hr) is the area under the average curve for serum drug concentration over the course of 8 hours (AUC8hr average) Serum drug when the AUC8hr does not exceed 20% of the AUC8hr average during the time course of serum drug concentration or does not fall below 20%. The concentration remains substantially stable over time.

  As used herein, the term “hydrogen bond” refers to a hydrogen atom that is covalently bonded to an electronegative atom (oxygen, nitrogen, sulfur, halogen, etc.) and another electronegative atom (oxygen, nitrogen, sulfur, halogen, etc.). Refers to the attractive force between See, for example, Stryer et al., “Biochemistry”, 5th edition, 2002, Freeman & Co. N.Y. Usually, a hydrogen bond exists between a hydrogen atom and two unpaired electrons of another atom. A hydrogen atom is about 2.5 angstroms to about 3.8 angstroms from a non-covalent electronegative atom, and 3 atoms (non-covalent to electronegative atom, hydrogen, and electronegative atom covalently bonded to hydrogen) When the deviation from an angle of 180 degrees formed by (electronegative atom) is about 45 degrees or less, a hydrogen bond between a hydrogen atom and an electronegative atom that is not covalently bonded to the hydrogen atom is Can exist. The distance between a hydrogen atom and a non-covalent electronegative atom is sometimes referred to herein as the “hydrogen bond distance” and is 3 atoms (electronegative atom covalently bonded to hydrogen, hydrogen, And the angle formed by an electronegative atom that is non-covalently bonded to the electronegative atom) may be referred to herein as a “hydrogen bond angle”. Stronger hydrogen bonds may be formed when the hydrogen bond distance is shorter, for example, the hydrogen bond distance may be in the range of about 2.7 angstroms to about 3.6 angstroms, or about 2.9 angstroms to about 3.4 angstroms. Stronger hydrogen bonds may be formed when the hydrogen bond angle is closer to a straight line. For example, the deviation of the hydrogen bond angle from 180 degrees may be about 25 degrees or less, or about 10 degrees or less.

As used herein, “nonpolar interaction” refers to the proximity of a nonpolar molecule or moiety sufficient for van der Waals interactions between the moieties and / or sufficient to exclude polar solvent molecules such as water molecules, Alternatively, it refers to the proximity of a low polarity molecule or moiety. See, for example, Stryer et al., “Biochemistry”, 5th edition, 2002, Freeman & Co. NY. In general, the distance between atoms (excluding hydrogen atoms) of nonpolar interacting moieties may range from about 2.9 angstroms to about 6 angstroms. The space separating the nonpolar interaction portions may be smaller than the space containing water molecules. As used herein, a nonpolar portion or a low polarity portion is a portion having a low dipole moment (usually less than the dipole moment of the OH bond of H ₂ O and the NH bond of NH ₃ ) and / or It refers to a moiety that does not normally exist in hydrogen bonding or electrostatic interaction. Examples of low polarity moieties include alkyl, alkenyl, and unsubstituted aryl moieties.

  As used herein, NS3 protease S1 ′ pocket portion refers to an NS3 protease portion that interacts with an amino acid located at one C-terminal residue of a polypeptide substrate cleavage site cleaved by NS3 protease (e.g., polypeptide substrate DLEVVT). -Refers to the NS3 protease moiety that interacts with amino acid S in STWVLV). Examples of such moieties include, but are not limited to, peptide backbone atoms or side chain moiety atoms of amino acids Lys136, G1y137, Ser139, His57, G1y58, G1n41, Ser42, and Phe43. See Yao et al., Structure 1999, 7, 1353.

  As used herein, NS3 protease S2 pocket moiety refers to an NS3 protease moiety that interacts with an amino acid located at two N-terminal residues of a polypeptide substrate cleavage site cleaved by NS3 protease (e.g., polypeptide substrate DLEVVT- Refers to the NS3 protease moiety that interacts with amino acid V in STWVLV. Examples of such moieties include, but are not limited to, peptide backbone atoms or side chain atoms of amino acids His57, Arg155, Va178, Asp79, G1n80, and Asp81. See Yao et al., Structure 1999, 7, 1353.

  As used herein, a first portion “positioned by” a second portion is a spatial portion of the first portion determined by the properties of the second portion to which the first atom or portion is covalently bonded. Refers to orientation. For example, the phenyl carbon can position the oxygen atom attached to the phenyl carbon in the spatial arrangement such that the oxygen atom hydrogen bonds with the hydroxyl moiety in the NS3 active site.

  Before further describing the embodiments, it is to be understood that the invention is not limited to the specific embodiments described, but can naturally vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not limiting.

  When referring to a range of values, each value that is between the upper and lower limits of the range, as well as any other value described in or within the stated range, is not otherwise specified by the context. Unless otherwise noted, it should be understood that up to one-tenth of the lower limit unit is included within the scope of the embodiments. Upper and lower limits of a smaller range that may be independently included in the smaller range are also included in the scope of the embodiments, assuming that there are areas that are specifically excluded from the described range. In the case where the described range includes one or both of the boundary values, a range excluding either of the included boundary values is also included in the embodiment.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which an embodiment belongs. Although methods and materials similar or equivalent to those described herein can also be used in the practice or experimentation of the embodiments, the preferred methods and materials are now described. All publications mentioned in this specification are herein incorporated by reference to disclose and describe the relevant methods and / or materials from which the publications are cited.

  In this specification and the appended claims, it should be understood that references to the singular include the plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a method” includes a plurality of such methods, and reference to “a dose” is known to one or more doses and persons of ordinary skill in the art. Including references to their equivalents, and so on.

  The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Also, the release date shown may be different from the actual release date that would need to be independently verified.

  Embodiments provide pharmaceutical compositions and formulations comprising a compound of Formulas I-XIX, and any compound of Formulas I-XIX. The subject compounds are useful for the treatment of flavivirus infections such as HCV infection and other disorders, as discussed below.

Compositions Various embodiments of the compositions are described below. For ease of discussion, the description of these embodiments is divided into sections A, B, C, D, and E. It should be understood that various terms that can be defined within a particular section apply within that section and apply elsewhere in this specification when that particular section is referenced. Similarly, unless otherwise indicated, all references in a section with respect to a particular number or label are not likely in the context of a similar or identical numbered or labeled scheme used in an unrelated section, It should be understood in the context of the corresponding numbered or labeled scheme used within that section.

Section A
Embodiments of section A provide compounds having the following general formula I:

[In the above formula,
Q is a core ring selected from:

In the above formula, the core ring is unsubstituted or H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy -C _{1 to 6} alkyl, C _{1 to 6} alkyl, substituted C _{1 to 6} alkyl, C _{1 to 6} alkoxy, substituted C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl , Furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide, urea, thiourea, amide, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocycle, alkylamino, alkylcarboxy, Carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or B cyclic cyclohexyl may be substituted by,
Or Q is R ¹ -R ² and R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, 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 with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or up to 5 substituents C _{1 to 6} Al be optionally substituted with fluoro, Le or may be optionally substituted with optionally C _{1 to 6} alkoxy substituted optionally up at the 5 fluoro,; R ² 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 up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy- C _1-6 alkyl, optionally placed with up to 5 fluoro Optionally substituted by optionally substituted C _1-6 alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. May be C _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is bonded through the C ₄ position of the tetrapyranyl ring. Is a tetrapyranyl ring;
Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ and R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl , All of which may be optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl, or R ⁹ may have up to 3 halo, cyano, nitro , Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or up to 5 good C _{1 to 6} alkyl which may be optionally substituted with fluoro, optionally optionally substituted with up to 5 substituents C _{1 to 6} alkoxy which may be optionally substituted with fluoro C _{6 or} be ₁₀ aryl; or R ⁹ is the highest 5 fluoro good C _{1 to 6} alkyl which may be optionally substituted with groups, a ^{NR 6 R 7, NR 1a R} 1b , or (CO) OH,, or R ⁹ is halo, cyano, nitro, Is an aromatic heterocycle optionally substituted up to two times by hydroxyl or C _1-6 alkoxy; or Y is a carboxylic acid, or a pharmaceutically acceptable salt, solvate, or Is a prodrug;
R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C _1-6 Optionally substituted 1-3 times by alkoxy, amide, or phenyl,
Alternatively, R ^1a and R ^1b are each independently H, and up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, optionally by 5 fluoro hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy,
Alternatively, R ^1a and R ^1b are each independently H, a heterocyclic ring, which includes 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Or a 7-membered saturated or unsaturated heterocyclic molecule,
Alternatively, NR ^1a R ^1b is a 3-6 membered alicyclic secondary amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, Optionally substituted 1-3 times by C _1-6 alkoxy, amide or phenyl,
Or NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

In the above formula, R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl,
Or R ^1c is NH (CO) OR ^1e and R ^1e is C _1-6 alkyl or C _3-6 cycloalkyl;
p = 0 or 1;
V is selected from O, S, or NH;
When V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy By, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or up to 5 fluoro C _1-6 alkyl optionally substituted, C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro Is aryl; Alternatively or R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, there oxazolyl, phenoxy, or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro C _1-6 alkyl, which may be substituted, or optionally substituted 1-3 times with phenyl. ].

  In preferred embodiments, the embodiments of section A provide compounds having the general formula I, wherein the core ring is

  In preferred embodiments, the embodiments of section A provide compounds having the general formula I, wherein the core ring is

  In preferred embodiments, the embodiments of section A provide compounds having the general formula I, wherein the core ring is

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Ia:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Ib:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Ic:

  In a preferred embodiment, the embodiment of Section A provides a compound having the following general formula Id:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Ie:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula If:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Ig:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Ih:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Ii:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Ij:

  In preferred embodiments, the embodiments of Section A provide compounds having the following general formula Iz:

In a preferred embodiment, the embodiment of section A provides a compound having the general formula I, Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ , and R ⁹ is C Selected from the group consisting of _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, and NR ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl Or C _3-7 cycloalkyl.

  In preferred embodiments, the embodiments of Section A provide compounds having the general formula I, wherein the C13-C14 double bond is cis.

  In a preferred embodiment, the embodiments of section A provide compounds having general formula I, wherein the C13-C14 double bond is trans.

  In certain embodiments, compounds of general formula I do not include compounds disclosed in PCT / US04 / 33970. For example, in certain embodiments, compounds of general formula I do not include compounds of formulas II, III, and IV in Section B below.

Section B
Embodiments of Section B provide compounds having the following general formulas II, III, and IV:

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, it is optionally substituted with up to 5 fluoro good C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, ^{_{thiophenoxy, S (O) 2 NR 6}} R 7, NHC (O) NR 6 R 7 , NHC (S) NR ⁶ R ⁷ , C (O) NR ⁶ R ⁷ , NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , NHC (O) R ⁸ , NHC (O) OR ⁸ , SO _m R ⁸ , NHS (O) ₂ R ⁸ , CH _n NR ⁶ R ⁷ , OCH _n NR ⁶ R ⁷ , or OCH _n R ⁹ (R ⁹ is imidazolyl or pyrazolyl); R ¹ the provisions of and R ² It said thienyl, Pirimi Jill, furanyl, thiazolyl, and oxazolyl are up to two halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 6} alkenyl, optionally by 5 fluoro C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, in substituted may be optionally substituted with also a good C _{1 to 6} alkoxy; said C _{6 or 10} aryl of R ¹ and R ² defined, pyridyl, phenoxy and thiophenoxy is the highest three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, optionally substituted optionally by 5 fluoro optionally optionally substituted C _{1 to 6} alkyl or a maximum, by up to 5 fluoro C _{1 to 6} Optionally substituted by alkoxy;
m = 0, 1, or 2;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, any cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl or up by 5 fluoro Optionally substituted C _1-6 alkyl, optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Optionally substituted three times; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, up to 5 fluoro, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by; or R ⁸ is optionally substituted by up to 5 fluoro groups Have been Be also good C _{1 to 6} alkyl; or R ⁸ is an tetrahydrofuran ring attached via a C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is, via the C ₄ position of Tetorapiraniru ring A bound tetrapyranyl ring;
Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ and R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl , All of which may be optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl, or R ⁹ may have up to 3 halo, cyano, nitro , Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or up to 5 good C _{1 to 6} alkyl which may be optionally substituted with fluoro, optionally optionally substituted with up to 5 substituents C _{1 to 6} alkoxy which may be optionally substituted with fluoro C _{6 or} be ₁₀ aryl; or R ⁹ is the highest 5 fluoro good C _{1 to 6} alkyl which may be optionally substituted with groups is NR ⁶ R ^7, or (CO) OH, or R ⁹ is halo, cyano, nitro, hydroxyl, or C _1, An aromatic heterocycle optionally substituted up to 2 times with up to ₆ alkoxy; or Y is a carboxylic acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
R ¹⁰ and R ¹¹ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, at most C _1-6 alkyl optionally substituted by 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _{1 6} alkyl, C _{3 to 7} cycloalkyl, or C _{4 to 10} alkylcycloalkyl), all of which halo, cyano, nitro, hydroxy, optionally three times C _{1 to 6} alkoxy or by phenyl, Optionally substituted; or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 ~ 6} alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy. _{6 or 10} aryl; said C _{6 or 10} aryl as defined for R ¹⁰ and R ¹¹ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or, Optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ¹⁰ and R ¹¹ together with the carbon to which they are attached. Become cyclopropi To form cyclobutyl, cyclopentyl, or cyclohexyl; or R ¹⁰ and R ¹¹ are coalesced as O;
p = 0 or 1;
R ¹² and R ¹³ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, at most C _1-6 alkyl optionally substituted by 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _{1 ~ 6alkyl} , _{C3-7cycloalkyl} , _{C4-10alkylcycloalkyl} ), all of which are optionally 1-3 times by halo, cyano, nitro, hydroxy, _C1-6 alkoxy, or phenyl Or R ¹⁴ may be up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2-6 6} alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoros C _1-6 alkyl optionally substituted, or C ₆ optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro, _or It is ₁₀ aryl; wherein C _{6 or 10} aryl provisions of R ¹² and R ^13, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, _{C. 4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by C _1-6 alkoxy optionally substituted by 5 fluoro; or R ¹² and R ¹³ together with the carbon to which they are attached. Cyclopropyl, Si Robuchiru, cyclopentyl or cyclohexyl to form,; or R ¹² and R ¹³ are each independently, (CH ₂₎ by _n OR ⁸ be a good C _{1 to 6} alkyl substituted optionally;
R ²⁰ is optionally selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted with (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _1-6 alkyl, C _{3 7-cycloalkyl,} C _{4 to 10} alkyl cycloalkyl), all of which halo, cyano, nitro, hydroxy, C _{1 to 6} alkoxy, or substituted optionally 1-3 times by phenyl Well; or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy -C _{1 to 6} alkyl, optionally substituted by up to 5 fluoro It is which may be C _{6 or 10} aryl optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with optionally C _{1 to 6} alkyl or up, depending on the five fluoro and; R Said C _{6 or 10} aryl as defined for ¹² and R ¹³ is a maximum of 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl optionally or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, by up to 5 fluoro, Optionally substituted by optionally substituted C _1-6 alkoxy;
n = 1-4;
V is selected from O, S, or NH;
When V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, _or C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro. Is aryl; Or R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, there phenoxy or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro. C _1-6 alkyl, which may optionally be substituted, or optionally substituted 1 to 3 times by phenyl. ].

  Embodiments of section B provide compounds having the following general formula II:

[In the above formula,
R ¹ is H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluoro, or C _1-6 alkoxy optionally substituted with up to 5 fluoro Yes;
R ^{2 _{is, H, OCH n NR 6 R}} 7, OCH n R 16, halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, _{C. 2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up to optionally by 5 fluoro, Optionally substituted C _1-6 alkoxy; R ⁶ and R ⁷ as defined for R ² are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _{4-6 10} alkyl cycloalkyl; or wherein R ⁶ and R ⁷ in R ² defined, together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
n = 1-3;
R ⁴ = H;
R ⁵ is H, C (O) NR ⁶ R ⁷ , or C (O) OR ⁸ , and R ⁶ and R ⁷ as defined for R ⁵ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Optionally substituted three times; or R ⁸ is C _1-6 alkyl optionally substituted with up to 5 fluoro groups; or R ⁸ is of the tetrahydrofuran ring. A tetrahydrofuran ring bonded through the C ₃ or C ₄ position; or R ⁸ is a tetrapyranyl ring bonded through the C ₄ position of the tetrapyranyl ring;
Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ and R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl All of which may be optionally substituted 1-3 times with halo, C _1-6 alkoxy, or phenyl;
R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ are H;
p = 0 or 1;
V = O;
W is, O, is selected from NH or CH _2,. ]

  In preferred embodiments, the embodiments of Section B provide compounds having the general formulas II, III, and IV, where p may be 0. In preferred embodiments, the embodiments of Section B provide compounds having the general formulas II, III, and IV, where p may be 1.

In preferred embodiments, Section B embodiments provide compounds having the general formulas II, III, and IV, wherein either or both of R ¹ and R ² are H. In some embodiments, p is 0. In another embodiment, p is 1.

In preferred embodiments, the embodiments of Section B provide compounds having general formulas II, III, and IV, where neither R ¹ nor R ² is H. In some embodiments, p is 0. In another embodiment, p is 1.

In preferred embodiments, the Section B embodiments provide compounds having general formulas II, III, and IV, wherein R ² is OCH _n NR ⁶ R ⁷ or OCH _n R ¹⁶ .

In preferred embodiments, the embodiment of Section B is that R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy Provided are compounds having general formulas II, III, and IV, optionally substituted 1-3 times with C _1-6 alkoxy, or phenyl.

In preferred embodiments, the embodiment of section B is such that R ⁹ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, Provided are compounds having the general formulas II, III, and IV, which are C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy.

In preferred embodiments, the embodiment of Section B is an aromatic heterocycle where R ⁹ is optionally substituted up to two times by halo, cyano, nitro, hydroxyl, or C _1-6 alkoxy. Provides compounds having the general formulas II, III, and IV.

In preferred embodiments, Section B embodiments are those wherein R ⁹ is C _1-6 alkyl, NR ⁶ R ⁷ , or (CO) OH optionally substituted with up to 5 fluoro groups. Certain compounds having the general formulas II, III, and IV are provided.

  In preferred embodiments, the embodiments of Section B provide compounds having the general formulas II, III, and IV, where the dashed line in formula (II), (III), or (IV) represents a single bond.

  Embodiments of section B provide compounds having the following general formula II:

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, by up to 5 fluoro may be optionally substituted C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, ^{_{thiophenoxy, S (O) 2 NR 6}} R 7, NHC (O) NR 6 R 7, NHC (S) NR ⁶ R ⁷ , C (O) NR ⁶ R ⁷ , NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , NHC (O) R ⁸ , NHC (O) OR ⁸ , SO _m R ⁸ , NHS (O) ₂ R ⁸ , CH _n NR ⁶ R ⁷ , OCH _n NR ⁶ R ⁷ , or OCH _n R ¹⁶ (R ¹⁶ is imidazolyl or pyrazolyl), the thienyl, Pirimi , Furanyl, thiazolyl, and oxazolyl, in defining R ¹ and R ^2, up to two halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkyl cycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, up to five may be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, said C _{6 or 10} aryl, pyridyl, phenoxy and thiophenoxy is of R ¹ and R ² by convention, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, optionally substituted optionally by 5 fluoro optionally optionally substituted C _{1 to 6} alkyl or a maximum, by up to 5 fluoro C _{1 to 6} Optionally substituted by alkoxy,
m = 0, 1, or 2,
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by, or C _1-6 alkoxy, optionally substituted by up to 5 fluoro,
R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro in an optionally substituted C _{1 to 6} alkyl, it may be optionally substituted with up to 5 substituents C _{1 to 6} alkoxy which may be optionally substituted with fluoro, or R ⁶ and R ⁷ together with their binding partner nitrogen forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, any of which are optional by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 1 to 3 times, or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, 5 fluoro up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by or R ⁸ is optionally substituted by up to 5 fluoro groups Have been A good C _{1 to 6} alkyl or R ^8, is a tetrahydrofuran ring linked via the C ₃ position or C ₄ position of the tetrahydrofuran ring, or R ⁸ is, via the C ₄ position of Tetorapiraniru ring A bound tetrapyranyl ring,
Y is a sulfonimide of the formula -C (O) NHS (O) 2 R 9, R 9 is C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, these Are all optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl, or R ⁹ is up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, _or C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro. aryl, or R ⁹ is 5 fluoro at the highest Any is optional substituted with C _{1 to 6} alkyl, NR ⁶ R ^7, or (CO) OH, or R ⁹ is halo, cyano, nitro, hydroxyl or by C _{1 to 6} alkoxy by Is an aromatic heterocycle which is optionally substituted at most twice, or Y is a carboxylic acid or a pharmaceutically acceptable salt, solvate or prodrug thereof,
R ¹⁰ and R ¹¹ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to C _1-6 alkyl, optionally substituted with 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ , wherein R ¹⁴ is H , C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally once with halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Substituted 3 times or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 depending ₆ alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, in up to 5 fluoro Optionally substituted with C _{1 to 6} alkyl or up to 5 substituents C _{6 or} be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, ₁₀ aryl, said C _{6 or 10} aryl, as defined by R ¹⁰ and R ¹¹ , up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro at the highest Optionally substituted by 5-6 fluoro, optionally substituted by C _1-6 alkoxy, or R ¹⁰ and R ¹¹ together with their binding partner carbon. , Cyclopropi , Cyclobutyl, cyclopentyl, or cyclohexyl, or R ¹⁰ and R ¹¹ are combined as O;
p = 0 or 1,
R ¹² and R ¹³ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, at most C _1-6 alkyl, optionally substituted with 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ , wherein R ¹⁴ is H , C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally once with halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Substituted 3 times or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 depending ₆ alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, in up to 5 fluoro Optionally substituted with C _{1 to 6} alkyl or up to 5 substituents C _{6 or} be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, a ₁₀ aryl, said C _{6 or 10} aryl, in the provision of R ¹² and R ^13, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up, Optionally substituted by 5 fluoro and optionally substituted by C _1-6 alkoxy, or R ¹² and R ¹³ together with their binding partner carbon. Cyclo Form propyl, cyclobutyl, cyclopentyl, or cyclohexyl, or R ¹² and R ¹³ are each independently C _1-6 alkyl optionally substituted by (CH ₂ ) _n OR ⁸ ,
R ²⁰ is optionally selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted with (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ , wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted 1 to 3 times optionally by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 Alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro C _1-6 alkyl, or C _{6 or 10} aryl optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy, said C _{6 or 10} aryl, as defined for R ¹² and R ¹³ , up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro, optionally with C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkoxy, which may be substituted with
n = 1 to 4,
V is selected from O, S, or NH;
When V is O or S, W is selected from O, NR ¹⁵ , or CR ^15; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ ; R ¹⁵ is H, C _{1 to 6} alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted by up to 5 fluoro,
The dashed line represents an optional double bond,
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 Optionally substituted by fluoro of C _1-6 alkyl, or optionally substituted by phenyl 1 to 3 times, or R ²¹ is up to 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro C _1-6 alkyl optionally substituted, C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro Is aryl, Rui R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy,,
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted by halo, cyano, nitro, hydroxy, up to 5 fluoro Optionally substituted 1 to 3 times by optionally substituted C _1-6 alkyl, or phenyl. ]

  Embodiments of section B provide compounds of general formula IIa:

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy,
R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
Y is a sulfonimide of the formula -C (O) NHS (O) 2 R 9, R 9 is 2 halo up to, cyano, nitro, hydroxy, C _{1 to 3} alkyl, C _{3 to 7} cycloalkyl alkyl thereof or a C _{1 to 3} alkoxy by which may be C _{1 to 3} alkyl optionally substituted, C _{3 to 7} cycloalkyl or phenyl, or Y is acceptable acid or agent, A salt, a solvate, or a prodrug,
R ¹⁰ and R ¹¹ are each independently H, or C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with their binding carbons are cyclopropyl, cyclobutyl, cyclopentyl, Or forming cyclohexyl,
W is selected from O or NH;
The dashed line represents an optional double bond. ]

  Embodiments of section B provide compounds of general formula IIIa:

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy,
R ⁴ is H,
R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
Y is a sulfonimide of the formula -C (O) NHS (O) 2 R 9, R 9 is 2 halo up to, cyano, nitro, hydroxy, C _{1 to 3} alkyl, C _{3 to 7} cycloalkyl alkyl thereof or a C _{1 to 3} alkoxy by which may be C _{1 to 3} alkyl optionally substituted, C _{3 to 7} cycloalkyl or phenyl, or Y is acceptable acid or agent, A salt, a solvate, or a prodrug,
W is selected from O or NH, and the dashed line represents an optional double bond. ]

  Embodiments of Section B provide compounds of general formula IIb below.

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy,
R ⁵ is H, C (O) OR ⁸ or C (O) NHR ⁸ ,
R ⁸ is C _1-6 alkyl, C _5-6 cycloalkyl, or 3-tetrahydrofuryl;
R ⁹ is C _1-3 alkyl, C _3-4 cycloalkyl, optionally substituted by up to two halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy, Or phenyl,
R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with their binding carbons are cyclopropyl, cyclobutyl, cyclopentyl, or Forming cyclohexyl,
W is selected from O or NH;
The dashed line represents an optional double bond. ]

  Embodiments of section B provide compounds of general formula IIIb:

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy,
R ⁵ is H, C (O) OR ⁸ or C (O) NHR ⁸ ,
R ⁸ is C _1-6 alkyl, C _5-6 cycloalkyl, or 3-tetrahydrofuryl;
R ⁹ is, up to two halo, cyano, hydroxy, C _{1 to 3} alkyl or C _{1 to 3} alkoxy by which may be C _{1 to 3} alkyl optionally substituted, C _{3 to 5} cycloalkyl, Or phenyl,
R ¹⁰ and R ¹¹ are each independently H, C _1-3 alkyl, or C _4-5 cycloalkyl;
W is selected from O or NH, and the dashed line represents an optional double bond. ]

  Embodiments of section B provide compounds of general formula IIc:

[In the above formula,
R ¹ and R ² are each independently H, chloro, fluoro, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy,
R ⁵ is H, C (O) OR ⁸ or C (O) NHR ⁸ ,
R ⁸ is C _1-6 alkyl or C _5-6 cycloalkyl,
R ⁹ is C _1-3 alkyl, C _3-4 cycloalkyl, optionally substituted by up to two halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy, Or phenyl,
(e) R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with their binding carbons form cyclopropyl or cyclobutyl. Forming, and
(f) The dashed line represents an optional double bond. ]

  Embodiments of section B provide compounds of general formula IIIc:

[In the above formula,
R ¹ and R ² are each independently H, chloro, fluoro, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy,
R ⁵ is H, C (O) OR ⁸ or C (O) NHR ⁸ ,
R ⁸ is C _1-6 alkyl or C _5-6 cycloalkyl,
R ⁹ is C _1-3 alkyl, C _3-4 cycloalkyl, optionally substituted by up to two halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy, Or phenyl, and the dashed line represents an optional double bond. ]

  Embodiments of section B provide compounds of general formula IIId:

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy,
R ⁴ is H,
R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
Y is a sulfonimide of the formula -C (O) NHS (O) 2 R 9, R 9 is 2 halo up to, cyano, nitro, hydroxy, C _{1 to 3} alkyl, C _{3 to 7} cycloalkyl alkyl thereof or a C _{1 to 3} alkoxy by which may be C _{1 to 3} alkyl optionally substituted, C _{3 to 7} cycloalkyl or phenyl, or Y is acceptable acid or agent, A salt, a solvate, or a prodrug,
R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with their binding carbons are cyclopropyl, cyclobutyl, cyclopentyl, or Forming cyclohexyl,
R ²⁰ is optionally selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted with (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ , wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro Good C _{1 to 6} alkyl optionally, or a maximum of 5 substituents C _{6 or 10} aryl which is optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, Said C _{6 or 10} aryl, as defined for R ¹² and R ¹³ , is a maximum of 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, 5 fluoro up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by C _1-6 alkoxy, optionally substituted by, and
W is selected from O or NH;
The dashed line represents an optional double bond. ]

  Embodiments of section B provide compounds of general formula IVa:

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy,
R ⁴ is H,
R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
Y is a sulfonimide of the formula -C (O) NHS (O) 2 R 9, R 9 is 2 halo up to, cyano, nitro, hydroxy, C _{1 to 3} alkyl, C _{3 to 7} cycloalkyl alkyl thereof or a C _{1 to 3} alkoxy by which may be C _{1 to 3} alkyl optionally substituted, C _{3 to 7} cycloalkyl or phenyl, or Y is acceptable acid or agent, A salt, a solvate, or a prodrug,
R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with their binding carbons are cyclopropyl, cyclobutyl, cyclopentyl, or Forming cyclohexyl,
R ²⁰ is optionally selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl _optionally substituted with (CH ₂ ) _n NR ⁶ R ⁷ , and (CH ₂ ) _n C (O) OR ¹⁴ , wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro Good C _{1 to 6} alkyl optionally or highest in 5 substituents C _{6 or 10} aryl which is optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, Said C _{6 or 10} aryl, as defined for R ¹² and R ¹³ , is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, up to 5 fluoro, Optionally substituted by C _1-6 alkoxy, optionally substituted by
W is selected from O or NH;
The dashed line represents an optional double bond,
Z is a fused or added arylheteroaryl ring system].

Section C
Embodiments of Section C provide compounds having the following general formula XI:

[In the above formula,
R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C _1-6 May be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
Alternatively, R ^1a and R ^1b are each independently H, or up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, optionally by 5 fluoro hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy;
Alternatively, R ^1a and R ^1b are each independently H or a heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur Or a 7-membered, saturated or unsaturated heterocyclic molecule;
Alternatively, NR ^1a R ^1b is a 3-6 membered alicyclic secondary amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, Optionally substituted 1-3 times by C _1-6 alkoxy, amide, or phenyl;
Or NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

In the above formula, R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl;
Or R ^1c is NH (CO) OR ^1e and R ^1e is C _1-6 alkyl or C _3-6 cycloalkyl;
W is O or NH;
V is selected from O, S, or NH;
When V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
R ² is a bicyclic secondary amine having the structure:

In the above formula, R ²¹ and R ²² are each independently H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6. alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, optionally by up to 5 fluoro, substituted which may C _{1 to 6} alkoxy optionally, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, ^{_{thiophenoxy, S (O) 2 NR 6}} R 7, NHC (O) NR ⁶ R ⁷ , NHC (S) NR ⁶ R ⁷ , C (O) NR ⁶ R ⁷ , NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , NHC (O) R ⁸ , NHC _{^{(O) oR 8, SO m}} R 8 (m = 0,1, or 2), or NHS (O) be ₂ R ^8; wherein thienyl provisions of R ²¹ and R ^22, Pirimi Jill, furanyl, thiazolyl , And oxazolyl up to two halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy , hydroxy -C _{1 to 6} alkyl, optionally substituted optionally by 5 fluoro optionally optionally substituted C _{1 to 6} alkyl or a maximum, by up to 5 fluoro C ₁ may be optionally substituted with ₆ alkoxy; said C _{6 or 10} aryl provisions of R ²¹ and R ^22, pyridyl, phenoxy and thiophenoxy is up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Assignment Optionally substituted C _1-6 alkyl, or optionally substituted with up to 5 fluoro, optionally substituted with C _1-6 alkoxy;
Wherein R ¹⁰ and R ¹¹ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl , Or C _1-6 alkyl, (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is optionally substituted with up to 5 fluoro , H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl), all of which are 1 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Optionally substituted 3 times; or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcyclo alkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or, High at 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, it is optionally substituted with up to 5 substituents C _{1 to 6} alkoxy which may be optionally substituted with fluoro be a good C _{6 or 10} aryl optionally; said C _{6 or 10} aryl provisions of R ¹² and R ^13, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to five may be _{C. 1 to} substituted optionally by fluoro Optionally substituted by ₆ alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ¹⁰ and R ¹¹ are attached Together with carbon Te cyclopropyl, form a cyclobutyl, cyclopentyl or cyclohexyl; or R ¹⁰ and R ¹¹ are coalesced as O;
Where p = 0 or 1;
Wherein R ¹² and R ¹³ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl C _1-6 alkyl, optionally substituted with up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H _Are C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl), all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted once; or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Good C ₆ be optionally substituted with optionally C _{1 to 6} alkoxy substituted optionally which may be C _{1 to 6} alkyl substituted optionally with up by 5 fluoro I _Or C _{6 or 10} aryl as defined for R ¹² and R ¹³ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up, Optionally substituted by 5 fluoro and optionally substituted by C _1-6 alkoxy; or R ¹² and R ¹³ together with the carbon to which they are attached. Cyclopropyl, Forming Robuchiru, cyclopentyl, or cyclohexyl;
Wherein R ²⁰ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl, optionally substituted by (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _1-6 alkyl All of which are optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl), C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl) Or R ¹⁴ may be up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, substituted hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro optionally Which may be C _{1 to 6} alkyl, up to five which may be C _{6 or 10} aryl optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro; The C _{6 or 10} aryl as defined for R ¹² and R ¹³ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, Optionally substituted by optionally substituted C _1-6 alkoxy;
Where n = 0-4;
In the formula, R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, and the phenyl has a maximum of 3 Halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy, optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
Or R ² is R ^2a R ^2b when W = NH, V = O,
R ^2a is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, Pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _{1 6} alkyl, optionally substituted with C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 fluoro C _1-6 alkyl, optionally up to 5 fluoro Optionally substituted by optionally substituted C _1-6 alkoxy;
R ^2b 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 up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, up to 5 fluoro, the good C _{1 to 6} alkoxy which may be optionally substituted with It may be substituted with meaning selected;
R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halos. , Cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, optional up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted, or C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ^2c And R ^2d together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally up to 5 fluoro Optionally substituted by C _1-6 alkyl, which may be substituted, or C _1-6 alkoxy, optionally substituted by up to 5 fluoro;
R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , or S (O) ₂ R ⁸ ;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Optionally substituted three times; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, 5 fluoro up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by:
The dashed line represents an optional double bond. ]

  Embodiments of Section C provide compounds having the following general formula XII:

[In the above formula,
R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C _1-6 May be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

In the above formula, R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl;
Alternatively, NR ^1a R ^1b is a 3-6 membered alicyclic secondary amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, Optionally substituted 1-3 times by C _1-6 alkoxy, amide, or phenyl;
R ²¹ and R ²² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy;
R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
R ¹⁰ and R ¹¹ are each independently H, halo, or C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with the carbon to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl Or form cyclohexyl;
R ¹² and R ¹³ are each independently H, halo, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, Or C _1-6 alkyl optionally substituted with up to 5 fluoro;
The dashed line represents an optional double bond. ]

  Embodiments of Section C provide compounds having the following general formula XIII:

[In the above formula,
R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, which are all halo, cyano, nitro, C _1-6 alkoxy Optionally substituted 1-3 times by amide, amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

In the above formula, R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl;
Alternatively, NR ^1a R ^1b is a 3-6 membered alicyclic secondary amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, Optionally substituted 1-3 times by C _1-6 alkoxy, amide, or phenyl;
R ²¹ and R ²² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy;
R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
The dashed line represents an optional double bond. ]

  Embodiments of Section C provide compounds having the following general formula XIV:

[In the above formula,
R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, which are all halo, cyano, nitro, C _1-6 alkoxy, Optionally substituted 1 to 3 times by amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

In the above formula, R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl;
Alternatively, NR ^1a R ^1b is a 3-6 membered alicyclic secondary amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, Optionally substituted 1-3 times by C _1-6 alkoxy, amide, or phenyl;
R ^2a is up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkyl, or up to 5 fluoro Is C ₆ or C ₁₀ aryl optionally substituted by C _1-6 alkoxy;
R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halos. , Cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, optional up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted, or C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ^2c And R ^2d together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
Or R ^2a is a 5- or 6-membered unsaturated heteroaryl, or such defined heteroaryl fused to another ring, which may be a heterocycle or any other ring;
R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
The dashed line represents an optional double bond. ]

  Embodiments of Section C provide compounds having the following general formula XV:

[In the above formula,
R ¹ and R ² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy;
R ⁵ is H, C (O) OR ⁸ , or C (O) NHR ⁸ ;
R ⁸ is C _1-6 alkyl, C _5-6 cycloalkyl, or 3-tetrahydrofuryl;
R ⁹ may be optionally substituted by C _1-3 alkyl, C _3-5 cycloalkyl, or up to 2 halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy Good phenyl ;
W is selected from O or NH;
The dashed line represents an optional double bond. ]

  Embodiments of Section C provide compounds having the following general formula XVI:

[In the above formula,
R ¹ and R ² are each independently H, chloro, fluoro, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy;
R ⁵ is H, C (O) OR ⁸ , or C (O) NHR ⁸ ;
R ⁸ is C _1-6 alkyl or C _5-6 cycloalkyl;
R ⁹ may be optionally substituted with C _1-3 alkyl, C _3-4 cycloalkyl, or up to 2 halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy. Good phenyl;
R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with the carbon to which they are attached form cyclopropyl or cyclobutyl;
The dashed line represents an optional double bond. ]

  Embodiments of Section C provide compounds having the following general formula XVII:

[In the above formula,
R ¹ and R ² are each independently H, chloro, fluoro, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy;
R ⁵ is H, C (O) OR ⁸ , or C (O) NHR ⁸ ;
R ⁸ is C _1-6 alkyl or C _5-6 cycloalkyl;
R ⁹ may be optionally substituted with C _1-3 alkyl, C _3-4 cycloalkyl, or up to 2 halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy. Good phenyl;
The dashed line represents an optional double bond. ]

Section D
Embodiments of Section D provide compounds having the following general formula XVIII:

[In the above formula,
R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, 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 up to 3 NR ⁵ R ⁶ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally up to 5 fluoro Optionally substituted C _1-6 alkyl, or up to 5 fluoro Thus optionally substituted by optionally substituted C _1-6 alkoxy;
R ² 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 up to 3 NR ⁵ R ⁶ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, 5 fluoro up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Ren by good C _{1 to 6} alkoxy which may be optionally substituted with It may be substituted by selected;
R ³ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally up to 5 fluoro Optionally substituted by C _1-6 alkyl, which may be substituted, or C _1-6 alkoxy, optionally substituted by up to 5 fluoro;
R ⁴ is C _1-6 alkyl, C (O) NR ⁵ R ⁶ , C (S) NR ⁵ R ⁶ , C (O) R ⁷ , C (O) OR ⁷ , or S (O) ₂ R ⁷ Is;
R ⁵ and R ⁶ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁵ and R ⁶ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
R ⁷ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, which are all 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. Optionally substituted three times; or R ⁷ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, 5 fluoro up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by:
R ⁸ may be optionally substituted with C _1-3 alkyl, C _3-4 cycloalkyl, or up to 2 halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy. Good phenyl;
The dashed line represents an optional double bond. ]

Section E
Embodiments of Section E provide compounds having the following general formula XIX:

[In the above formula,
Z is a group arranged to hydrogen bond to the NS3 protease His57 imidazole moiety and hydrogen bond to the NS3 protease Gly137 nitrogen atom;
P1 ′ is a group arranged so as to have nonpolar interaction with at least one NS3 protease S1 ′ pocket portion selected from the group consisting of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42, and Phe43 Is;
L is a linking group consisting of 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
P2 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocycle, and substituted heterocycle; P2 is His57, Arg155, Val78, Asp79, Gln80, and Asp81 Positioned by L to have nonpolar interaction with at least one NS3 protease S2 pocket portion selected from the group consisting of:
The dashed line represents an optional double bond;
R ⁵ is selected from the group consisting of C (O) NR ⁶ R ⁷ and C (O) OR ⁸ ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkyl; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro, optionally with _1-6 alkyl, up to 5 fluoro C _{6 or 10} aryl optionally substituted with optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted with up to 5 fluoro groups. which may be _C 1~6 It is alkyl; or R ⁸ is an tetrahydrofuran ring attached via a C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is Tetorapiraniru ring linked via the C ₄ position of Tetorapiraniru ring It is. ]

  As used herein, the term “hydrogen bond” refers to a hydrogen atom that is covalently bonded to an electronegative atom (oxygen, nitrogen, sulfur, halogen, etc.) and another electronegative atom (oxygen, nitrogen, sulfur, halogen, etc.). Refers to the attractive force between See, for example, Stryer et al., “Biochemistry”, 5th edition, 2002, Freeman & Co. N.Y. Usually, a hydrogen bond exists between a hydrogen atom and two unshared electrons of another atom. A hydrogen atom is about 2.5 angstroms to about 3.8 angstroms from a non-covalent electronegative atom, and 3 atoms (non-covalent to electronegative atom, hydrogen, and electronegative atom covalently bonded to hydrogen) When the deviation from an angle of 180 degrees formed by (electronegative atom) is about 45 degrees or less, a hydrogen bond between a hydrogen atom and an electronegative atom that is not covalently bonded to the hydrogen atom is Can exist. The distance between a hydrogen atom and a non-covalent electronegative atom is sometimes referred to herein as the “hydrogen bond distance” and is 3 atoms (electronegative atom covalently bonded to hydrogen, hydrogen, And the angle formed by an electronegative atom that is non-covalently bonded to the electronegative atom) may be referred to herein as a “hydrogen bond angle”. Stronger hydrogen bonds may be formed when the hydrogen bond distance is shorter; for example, the hydrogen bond distance may be in the range of about 2.7 angstroms to about 3.6 angstroms, or about 2.9 angstroms to about 3.4 angstroms. Stronger hydrogen bonds may be formed when the hydrogen bond angle is closer to a straight line; for example, the deviation of the hydrogen bond angle from 180 degrees may be about 25 degrees or less, or about 10 degrees or less.

As used herein, non-polar interaction refers to the proximity of non-polar molecules or moieties that are sufficient for van der Waals interactions between the moieties and / or sufficient to exclude polar solvent molecules such as water molecules, or low Refers to the proximity of a polar molecule or moiety. See, for example, Stryer et al., “Biochemistry”, 5th edition, 2002, Freeman & Co. NY. In general, the distance between atoms (excluding hydrogen atoms) of nonpolar interacting moieties may range from about 2.9 angstroms to about 6 angstroms. The space separating the nonpolar interaction portions may be smaller than the space containing water molecules. As used herein, a nonpolar portion or a low polarity portion is a portion having a low dipole moment (usually less than the dipole moment of the OH bond of H ₂ O and the NH bond of NH ₃ ) and / or It refers to a moiety that does not normally exist in hydrogen bonding or electrostatic interaction. Examples of low polarity moieties include alkyl, alkenyl, and unsubstituted aryl moieties.

  As used herein, an NS3 protease S1 ′ pocket moiety refers to an NS3 protease moiety that interacts with an amino acid at a single residue from the polypeptide substrate cleavage site cleaved by NS3 protease to the C-terminus (e.g., polypeptide NS3 protease moiety that interacts with amino acid S in the substrate DLEVVT-STWVLV. Examples of such moieties include, but are not limited to, peptide backbone atoms or side chain moiety atoms of amino acids Lys136, G1y137, Ser139, His57, G1y58, G1n41, Ser42, and Phe43. See Yao et al., Structure 1999, 7, 1353.

  As used herein, an NS3 protease S2 pocket moiety refers to an NS3 protease moiety that interacts with an amino acid located at 2 residues from the polypeptide substrate cleavage site cleaved by NS3 protease to the N-terminus (e.g., a polypeptide substrate This refers to the NS3 protease moiety that interacts with amino acid V in DLEVVT-STWVLV. Examples of such moieties include, but are not limited to, peptide backbone atoms or side chain atoms of amino acids His57, Arg155, Va178, Asp79, G1n80, and Asp81. See Yao et al., Structure 1999, 7, 1353.

  As used herein, a first portion “positioned by” a second portion is a spatial portion of the first portion determined by the properties of the second portion to which the first atom or portion is covalently bonded. Refers to orientation. For example, the phenyl carbon can position the oxygen atom attached to the phenyl carbon in the spatial arrangement such that the oxygen atom hydrogen bonds with the hydroxyl moiety in the NS3 active site.

  Also provided herein are compounds that comprise a moiety arranged to interact with a particular region, a particular amino acid residue, or a particular atom of NS3 protease. Some compounds provided herein include one or more moieties arranged to hydrogen bond with NS3 protease at specific regions, amino acid residues, or atoms. Some compounds provided herein comprise one or more moieties arranged to have nonpolar interactions with NS3 protease at specific regions, amino acid residues, or atoms. For example, a compound having the general formula XIX can include one or more moieties that hydrogen bond with peptide backbone atoms or side chain moieties located within the substrate binding pocket of NS3 protease. In another example, a compound having the general formula XIX can include one or more moieties that undergo nonpolar interactions with peptide backbone or side chain atoms located within the substrate binding pocket of NS3 protease. In the compound of formula XIX, the dashed line between carbons 13 and 14 may be a single bond or a double bond.

  For compounds having the general formula XIX, Z is a peptide backbone or side chain moiety located within the substrate binding pocket of NS3 protease and hydrogen, including but not limited to the NS3 protease His57 imidazole moiety and the NS3 protease G1y137 nitrogen atom. Can be arranged to be joined. In some cases, Z can be arranged to hydrogen bond to both the NS3 protease His57 imidazole moiety and the NS3 protease G1y137 nitrogen atom.

  The P1 ′ group of the compound having the general formula XIX is not limited to peptide backbone or side chain atoms located within the NS3 protease substrate binding pocket, including but not limited to the amino acid residues that form the NS3 protease S1 ′ pocket. It can be arranged to carry out polar interactions. For example, the P1 ′ group can undergo a nonpolar interaction with at least one amino acid selected from Lys136, Glyl37, Ser139, His57, Gly58, G1n41, Ser42, and Phe43.

  The P2 group of the compound having the general formula XIX includes, but is not limited to, a peptide backbone or side chain atom located within the substrate binding pocket of NS3 protease, including amino acid residues that form the NS3 protease S2 pocket. It can be arranged to act. For example, the P2 group can have a nonpolar interaction with at least one amino acid selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81. The P2 group can also be placed to hydrogen bond with peptide backbone or side chain atoms located within the substrate binding pocket of NS3 protease, including but not limited to the amino acid residues that form the NS3 protease S2 pocket. . For example, the P2 group can hydrogen bond with at least one amino acid selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81. P2 may be capable of both nonpolar interactions and hydrogen bonding with peptide backbones or side chain moieties or atoms located within the substrate binding pocket of NS3 protease, such amino acids are His57, Arg155, Selected from Val78, Asp79, Gln80, and Asp8l. Such hydrogen bonding and nonpolar interactions can occur with the same or different amino acid residues within the S2 pocket of NS3 protease. In some embodiments, P2 can be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocycle, and substituted heterocycle.

  In some embodiments, the position of the P2 group is determined by the linking group L. For example, but not limited to linking P2 to allow nonpolar interactions with peptide backbone or side chain atoms located within the NS3 protease substrate binding pocket, including the amino acid residues that form the NS3 protease S2 pocket Can be positioned by the base L. For example, P2 can be positioned by the linking group L so as to cause a nonpolar interaction with at least one amino acid selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81. In another example, P2 is a linking group to hydrogen bond with peptide backbone or side chain atoms located within the substrate binding pocket of NS3 protease, including but not limited to the amino acid residues that form the NS3 protease S2 pocket. L can be arranged. For example, P2 can be positioned by the linking group L so as to form a hydrogen bond with at least one amino acid selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81. P2 may be arranged to allow both nonpolar interactions and hydrogen bonding with peptide backbones or side chain moieties or atoms located within the substrate binding pocket of NS3 protease, such amino acids are Selected from His57, Arg155, Val78, Asp79, Gln80, and Asp8l. Such hydrogen bonding and nonpolar interactions can occur with the same or different amino acid residues within the S2 pocket of NS3 protease.

  In compounds having general formula XIX, L may be a linking group that links P2 to the heterocyclic backbone of the compound of formula XIV. The linking group L can include any of a variety of atoms and moieties suitable for positioning P2 within the substrate binding pocket of NS3 protease. In one embodiment, L can include 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. In another embodiment, L can comprise 2-5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. For example, L can include a group having the formula -W-C (= V)-, and V and W can each be independently selected from O, S, or NH. Specific examples of L groups include, but are not limited to, esters, amides, carbamates, thioesters, and thioamides.

Compounds of formula XIX may also may also include a group R ^5, R ⁵ groups may include a carboxyl moiety. Examples of the carboxyl moiety of R ⁵ include C (O) NR ⁶ R ⁷ and C (O) OR ⁸ , wherein R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _{3 7-cycloalkyl,} C _{4 to 10} alkylcycloalkyl or phenyl, said phenyl, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 ~ 10} alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally from _1-6 alkyl, up to 5 fluoro Optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁶ and R ⁷ together with the nitrogen to which they are attached are indolinyl, pyrrolidinyl, piperidinyl, Form piperazinyl, or morpholinyl Teeth; R ⁸ is, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, all of which halo, cyano, nitro, hydroxy, C _{1 to 6} alkoxy or 1 by phenyl, Optionally substituted 3 times; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcyclo alkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, up to 5 fluoro C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by; or R ⁸ is optionally substituted by up to 5 fluoro groups an optionally C ₁ Be ₆ alkyl; or R ⁸ is an tetrahydrofuran ring attached via a C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is attached via a C ₄ position of Tetorapiraniru ring Tetorapiraniru It is a ring.

  In some embodiments, some bonds of the compound of formula XIX can have a particular chirality.

  Embodiments of Section E provide compounds wherein the C13-C14 double bond is cis. Embodiments of section E provide compounds wherein the C13-C14 double bond is trans.

  In a preferred embodiment, the embodiment of section E provides a compound having the general formula XIX, wherein L consists of 2-5 atoms.

  In a preferred embodiment, the embodiment of section E has the general formula XIX, wherein L comprises a -WC (= V)-group, and V and W are each independently selected from O, S, or NH. A compound having is provided.

  In preferred embodiments, the embodiments of section E provide compounds having the general formula XIX, wherein L is selected from the group consisting of esters, amides, carbamates, thioesters, and thioamides.

  In a preferred embodiment, the embodiment of Section E is such that P2 further has a hydrogen bonding interaction with at least one NS3 protease S2 pocket portion selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80, and Asp81. Provided is a compound having the general formula XIX, positioned by L to do.

  In preferred embodiments, the embodiments of Section E provide compounds having the following formula XIXa:

  In a preferred embodiment, the embodiment of section E provides a compound having the general formula XIXa, where L consists of 2-5 atoms.

  In a preferred embodiment, the embodiment of section E has the general formula XIXa, wherein L comprises a -WC (= V)-group, and V and W are each independently selected from O, S, or NH. A compound having is provided.

  In preferred embodiments, the embodiments of section E provide compounds having the general formula XIXa, wherein L is selected from the group consisting of esters, amides, carbamates, thioesters, and thioamides.

  In a preferred embodiment, the embodiment of Section E is such that P2 further has a hydrogen bonding interaction with at least one NS3 protease S2 pocket portion selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80, and Asp81. Provided is a compound having the general formula XIXa, which is positioned by L to do.

  In preferred embodiments, the embodiments of section E provide compounds having the general formula XIX, wherein P2 is:

  In preferred embodiments, the embodiments of Section E provide compounds having the following formula XIXb:

  In preferred embodiments, the embodiments of Section E provide compounds having the general formula XIXb, wherein L consists of 2-5 atoms.

  In a preferred embodiment, the embodiment of section E has the general formula XIXb, wherein L comprises a -WC (= V)-group, and V and W are each independently selected from O, S, or NH. A compound having is provided.

  In preferred embodiments, the embodiments of section E provide compounds having the general formula XIXb, wherein L is selected from the group consisting of esters, amides, carbamates, thioesters, and thioamides.

  In a preferred embodiment, the embodiment of Section E is such that P2 further has a hydrogen bonding interaction with at least one NS3 protease S2 pocket portion selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80, and Asp81. Provided is a compound having the general formula XIXb, positioned by L to do.

  In a preferred embodiment, the embodiment of Section E provides a compound having the general formula XIXb, wherein the C13-C14 double bond is cis.

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

  Compounds of formula XIX can be prepared in the same general manner as compounds of formulas I-XVII.

  In certain embodiments, the compound of general formula XIX does not include the compound disclosed in PCT / US04 / 33970. For example, in certain embodiments, compounds of general formula I do not include compounds of formulas II, III, and IV in Section B above.

Pharmaceutical Compositions Embodiments further provide compositions comprising pharmaceutical compositions comprising a compound of general formula I-XIX, salt, ester, or other derivative thereof. The subject pharmaceutical composition comprises the subject compound and a pharmaceutically acceptable excipient. A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients are described, for example, by A. Gennaro (2000), `` Remington: The Science and Practice of Pharmacy, '' 20th edition, Lippincott, Williams, &Wilkins; `` Pharmaceutical Dosage Forms and Drug Delivery Systems. (1999), HCAnsel et al., 7th edition, Lippincott, Williams, &Wilkins; and "Handbook of Pharmaceutical Excipients" (2000), AHKibbe et al., 3rd edition, Amer.Pharmaceutical Assoc. It is fully described in the publication.

  Pharmaceutically acceptable excipients such as media, adjuvants, carriers, diluents and the like can be easily obtained by anyone. Furthermore, pharmaceutically acceptable auxiliary substances such as pH adjusters, buffers, isotonicity adjusters, stabilizers, wetting agents and the like can be easily obtained by anyone. Examples of suitable pharmaceutical composition embodiments, as well as examples of methods of making them, are described in more detail below.

Inhibition of Flavivirus Enzyme Activity In many embodiments, the subject compounds inhibit flavivirus enzyme activity. Whether a target compound inhibits flavivirus can be easily determined using any known method. Flavivirus infections include those caused by flaviviruses, including but not limited to hepatitis C virus, West Nile virus, GB virus, Japanese encephalitis virus, dengue virus and yellow fever virus. In many embodiments, the subject compounds inhibit the enzymatic activity of hepatitis C virus (HCV) protease NS3. Whether a subject compound inhibits HCV NS3 can be easily determined using known methods. A typical method is to determine whether an HCV polyprotein, or other polypeptide containing an NS3 recognition site, is cleaved by NS3 in the presence of the agent. In many embodiments, a subject compound has 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 at least about 10% of NS3 enzyme activity without that compound. Inhibits NS3 enzyme activity by about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% or more.

In many embodiments, the subject compound inhibits the enzymatic activity of HCV NS3 protease with an IC ₅₀ of less than about 50 μM, e.g., the subject compound is less than about 40 μM, less than about 25 μM, less than about 10 μM, less than about 1 μM, about Inhibits HCV NS3 protease with an IC ₅₀ of less than 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.

  In many embodiments, the subject compounds inhibit viral replication of HCV. For example, the subject compound is 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 HCV virus replication without the compound, Inhibits HCV viral replication by about 60%, at least about 70%, at least about 80%, or at least about 90% or more. Whether a subject compound inhibits viral replication of HCV can be determined using methods known in the art including viral replication assays.

Treatment of flavivirus infections The methods and compositions described herein are generally useful for the treatment of flavivirus infections.

  Whether the subject method is effective in treating flavivirus infections is reduced viral load, reduced time to antibody seroconversion (no virus detected in patient serum), increased ratio of sustained viral response to treatment, It can be determined by a reduction in morbidity or mortality in clinical outcome, or other disease response indicators.

  In general, an effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is an amount effective to reduce viral load or achieve a sustained viral response to therapy. .

  Whether the subject method is effective in the treatment of flavivirus infection depends on flavivirus infection, including but not limited to measurement of viral load, or liver fibrosis, elevated serum transaminase levels, and necroinflammatory activity in the liver. It can be determined by measuring relevant parameters. Indicators of liver fibrosis are described in detail below.

  The method includes administration of an effective amount of a compound of Formulas I-XIX, optionally in combination with one or more effective amounts of additional antiviral agents. In some embodiments, the effective amount of the compound of Formulas I-XIX and the optional one or more additional antiviral agents is at a level at which no viral titer is detectable, such as about 1000 to about 5000, about An amount effective to reduce to 500 to about 1000, or about 100 to about 500 genomic replicas / mL of serum. In some embodiments, the effective amount of the compound of Formulas I-XIX and the optional one or more additional antiviral agents is an amount effective to reduce viral load below 100 genome replicates / mL serum. It is.

  In some embodiments, an effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents provides a log reduction in viral titer in the individual serum of 1.5, 2, 2.5, 3, Effective amount to 3.5, 4, 4.5, or 5.

  In many embodiments, an effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is an amount effective to achieve a sustained viral response, such as at least about after treatment cessation. No detectable HCV RNA in the patient's serum for 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months (e.g., serum 1 Less than about 500, less than about 400, less than about 200, or less than about 100 genome replicas per milliliter).

  As described above, whether a subject method is effective in treating flavivirus infection can be determined by measuring parameters associated with flavivirus infection, such as liver fibrosis. The method for determining the degree of liver fibrosis is detailed below. In some embodiments, the serum marker level of liver fibrosis is an indicator of the degree of liver fibrosis.

  As a non-limiting example, serum alanine aminotransferase (ALT) levels are measured using standard assays. Generally, ALT levels are considered normal if they are below about 45 international units. In some embodiments, the effective amount of the compound of Formulas I-XIX and the optional one or more additional antiviral agents is an amount effective to reduce ALT levels below 45 IU / ml of serum. .

  A therapeutically effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is a marker level of an untreated individual, or at least about 10%, at least about 20% of an individual treated with a placebo. 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%, An amount effective to reduce serum levels of liver fibrosis markers by at least about 75%, or at least up to about 80%, or less. Examples of the method for measuring a serum marker include an immunological method using an antibody specific for a given serum marker, such as an enzyme immunoassay (ELISA), a radioimmunoassay, and the like.

  In many embodiments, an effective amount of a compound of 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 Formulas I-XIX and an additional antiviral agent refers to (i) the formula when administered at the same dosage as a monotherapy. Predicted or inferred simply by additionally combining the therapeutic or prophylactic benefit of the compounds of I to XIX with (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy It is a combination administration that is more effective in the treatment or prevention of HCV infection than the gradual improvement in therapeutic outcomes that can be achieved.

  In some embodiments, a selected amount of a compound of Formulas I-XIX and a selected amount of an additional antiviral agent is effective when used in a combination therapy for a disease, but the selected amount of the formula The use of a compound of I-XIX and / or its selected amount of an additional antiviral agent is not effective in monotherapy of the disease. Thus, embodiments provide that (1) when used in combination therapy of disease, a selected amount of an additional antiviral agent enhances the therapeutic benefit of a selected amount of a compound of Formulas I-XIX and is selected Dosing regimen where no additional amount of additional antiviral agent provides therapeutic benefit when used in monotherapy of the disease, (2) when used in combination therapy of disease, selected amounts of formulas I-XIX Of the compound enhances the therapeutic benefit of the selected amount of the additional antiviral agent, and the selected amount of the compound of Formulas I-XIX does not provide a therapeutic benefit when used in monotherapy of the disease When used in a dosing regimen, and (3) combination therapy of disease, a selected amount of a compound of Formulas I-XIX and a selected amount of an additional antiviral agent provides a therapeutic benefit, each selected An amount of a compound of formulas I-XIX and an additional antiviral agent is monotherapy for the disease Containing regimen does not result in each therapeutic benefit be used. As used herein, a “synergistically effective amount” of a compound of Formulas I-XIX and an additional antiviral agent, and synonyms thereof, refer to any dosing schedule included in any of (1)-(3) above. Shall be included.

Treatment of Hepatitis Virus Infection The methods and compositions described herein are usually useful for the treatment of HCV infection.

  Whether the target method is effective in treating HCV infection is reduced viral load, reduced time to antibody seroconversion (no virus detected in patient serum), increased ratio of sustained viral response to treatment Can be determined by reduction in morbidity or mortality in clinical outcome, or other disease response indicators.

  In general, an effective amount of a compound of Formulas I-XIX and an effective amount of an optional one or more additional antiviral agents is an amount effective to reduce viral load or achieve a sustained viral response to therapy. .

  Whether the subject method is effective in the treatment of HCV infection depends on the measurement of viral load or HCV infection, including but not limited to liver fibrosis, elevated serum transaminase levels, and necroinflammatory activity in the liver. It can be determined by measuring relevant parameters. Indicators of liver fibrosis are detailed below.

  The method includes administration of an effective amount of a compound of Formulas I-XIX, optionally in combination with one or more effective amounts of additional antiviral agents. In some embodiments, the effective amount of the compound of Formulas I-XIX and the optional one or more additional antiviral agents is at a level at which no viral titer is detectable, such as about 1000 to about 5000, about An amount effective to reduce to 500 to about 1000, or about 100 to about 500 genomic replicas / mL of serum. In some embodiments, the effective amount of the compound of Formulas I-XIX and the optional one or more additional antiviral agents is an amount effective to reduce viral load below 100 genome replicates / mL serum. It is.

  In some embodiments, an effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents provides a log reduction in viral titer in the individual serum of 1.5, 2, 2.5, 3, Effective amount to 3.5, 4, 4.5, or 5.

  In many embodiments, an effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is an amount effective to achieve a sustained viral response, such as at least about after treatment cessation. No detectable HCV RNA in the patient's serum for 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months (e.g., serum 1 Less than about 500, less than about 400, less than about 200, or less than about 100 genome replicas per milliliter).

  As described above, whether a subject method is effective in treating HCV infection can be determined by measuring parameters associated with HCV infection, such as liver fibrosis. The method for determining the degree of liver fibrosis is detailed below. In some embodiments, the serum marker level of liver fibrosis is an indicator of the degree of liver fibrosis.

  As a non-limiting example, serum alanine aminotransferase (ALT) levels are measured using standard assays. Generally, ALT levels are considered normal if they are below about 45 international units. In some embodiments, the effective amount of the compound of Formulas I-XIX and the optional one or more additional antiviral agents is an amount effective to reduce ALT levels to less than about 45 IU / ml of serum. .

  A therapeutically effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is a marker level of an untreated individual, or at least about 10%, at least about 20% of an individual treated with a placebo. 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%, An amount effective to reduce serum levels of liver fibrosis markers by at least about 75%, or at least up to about 80%, or less. Examples of the method for measuring a serum marker include an immunological method using an antibody specific for a given serum marker, such as an enzyme immunoassay (ELISA), a radioimmunoassay, and the like.

  In many embodiments, an effective amount of a compound of 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 Formulas I-XIX and an additional antiviral agent refers to (i) the formula when administered at the same dosage as a monotherapy. Predicted or inferred from simply and additionally combining the therapeutic or prophylactic benefit of the compounds of I to XIX with (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy It is a combined dose that is more effective in the therapeutic or prophylactic treatment of HCV infection than the gradual improvement in possible therapeutic outcome.

  In some embodiments, a selected amount of a compound of Formulas I-XIX and a selected amount of an additional antiviral agent is effective when used in a combination therapy for a disease, but the selected amount of the formula The use of a compound of I-XIX and / or its selected amount of an additional antiviral agent is not effective in monotherapy of the disease. Thus, this embodiment provides: (1) When used in a combination therapy of disease, a selected amount of an additional antiviral agent enhances the therapeutic benefit of a selected amount of a compound of Formulas I-XIX A dosage regimen wherein a given amount of an additional antiviral agent does not provide a therapeutic benefit when used in a monotherapy of the disease, (2) when used in a combination therapy of the disease, a selected amount of Formula I- A compound of XIX enhances the therapeutic benefit of a selected amount of an additional antiviral agent, and the selected amount of a compound of Formulas I-XIX also provides a therapeutic benefit when used in monotherapy of the disease. No dosage regimen, and (3) a selected amount of a compound of formula I and a selected amount of an additional antiviral agent when used in a combination therapy of the disease provides a therapeutic benefit, each selected amount thereof A compound of formulas I-XIX and an additional antiviral agent in a monotherapy of the disease Even if use containing regimen does not result in a therapeutic benefit, respectively. As used herein, a “synergistically effective amount” of a compound of Formulas I-XIX and an additional antiviral agent, and synonyms thereof, refer to any dosing schedule included in any of (1)-(3) above. Shall be included.

Embodiments of fibrosis generally involve administering a therapeutic amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents (resulting from or associated with HCV infection). A method of treating liver fibrosis (including the forms of liver fibrosis). Effective amounts of the compounds of Formulas I-XIX in the presence and absence of one or more additional antiviral agents, and dosing schedules are as discussed below.

  Whether treatment with a compound of Formulas I-XIX and one or more optional additional antiviral agents is effective in reducing liver fibrosis is some sufficient for liver fibrosis and liver function measurements Determine by any of the established techniques. Reduction of liver fibrosis is determined by analyzing a liver biopsy sample. Liver biopsy analysis shows necrotic inflammation assessed by “stage” as a measure of severity and ongoing disease activity, and fiber assessed by “stage” as reflecting long-term disease progression. Assessment of the two major components that are remodeling of the lesion and parenchyma or blood vessels See, for example, Brunt (2000), Hepatol. 31: 241-246; and METAVIR (1994), Hepatology 20: 15-20. Based on liver biopsy analysis, assign a score. There are several standard scoring systems that provide a quantitative assessment of the stage and severity of fibrosis. These include METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring schemes.

  The METAVIR scoring system consists of fibrosis (portal fibrosis, centrilobular fibrosis, cirrhosis), necrosis (fragment and leaflet necrosis, eosinophil retraction, balloon degeneration), inflammation (portal inflammation) , Lymphocyte aggregation in the portal vein, distribution of portal vein inflammation), bile duct changes, and Knodell index (periportal necrosis, leaflet necrosis, portal vein inflammation, fibrosis, and general disease activity Based on analysis of various features of liver biopsy including each score). The definition of each stage of the METAVIR system is as follows. Score 0: no fibrosis, score 1: astral enlargement of the portal tract but no septum formation, score 2: rarely septum formation with astral enlargement of the portal tract, score 3: many There is no cirrhosis but score 4: cirrhosis.

  Knodell's scoring system, also called the hepatitis activity index, categorizes specimens into the following four histological features based on the score. I. Periportal necrosis and / or bridging necrosis, II. Intralobular degeneration and focal necrosis, III. Portal inflammation, and IV. Fibrosis. In Knodell's staging system, the scores are: Score 0: no fibrosis, score 1: mild fibrosis (fibrous portal vein enlargement), score 2: moderate fibrosis, score 3: severe fibrosis (cross-linking fibrosis), and score 4: Cirrhosis. The higher the score, the more severe liver tissue damage. Knodell (1981), Hepatol. Volume 1: 431.

  The score of the Scheuer scoring system is as follows. Score 0: no fibrosis, score 1: enlarged and fibrotic portal tract, score 2: periportal septum or portal-portal septum but intact structure, score 3: distortion of structure With fibrosis but no obvious cirrhosis, score 4: high accuracy or clear cirrhosis. Scheuer (1991), J. Hepatol. 13: 372.

  The Ishak scoring system is described in Ishak (1995), J. Hepatol. 22: 696-699. Stage 0: No fibrosis, Stage 1: Fibrous enlargement of a single vein with or without a short fibrous septum, Stage 2: Most portal vein with or without a short fibrous septum Fibrous enlargement, stage 3: Fibrous enlargement of most portal vein regions with occasional portal vein-portal (PP) bridges, stage 4: Portal vein-center (PC) bridges as well as (PP) Significant portal vein fibrosis, Stage 5: Significant cross-linking (PP and / or PC) with occasional nodules (incomplete cirrhosis), Stage 6: Probable or clear cirrhosis.

  Anti-fibrotic therapy using the Child-Pugh scoring system, including a multi-component scoring system based on serum bilirubin levels, serum albumin levels, abnormal prothrombin time, presence and severity of ascites, and presence and severity of encephalopathy Profits can also be measured and evaluated. Based on the presence and severity of these parameter abnormalities, patients can be allocated to any one of the three departments in ascending clinical disease severity, ie, A, B, or C.

  In some embodiments, the therapeutically effective amount of the compound of Formula I and the optional one or more additional antiviral agents is at least one unit of fibrotic stage based on liver biopsy before and after treatment. It is the amount that brings about change. In certain embodiments, the therapeutically effective amount of the compound of Formulas I-XIX and the optional one or more additional antiviral agents is at least 1 unit in each METAVIR, Knodell, Scheuer, Ludwig, or Ishak scoring system. An amount that reduces liver fibrosis.

  Secondary or indirect indices of liver function can also be used to assess the effectiveness of treatment with compounds of Formulas I-XIX. Quantitative liver fibrosis based on staining of collagen and / or liver fibrosis serum markers can also be measured as an indicator of the effectiveness of the targeted treatment method by morphometric computerized semi-automated evaluation. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin levels, and Child-Pugh score assessment.

  An effective amount of the compound of Formulas I-XIX and the optional one or more additional antiviral agents is at least about 10%, at least about 20%, at least about at least about the liver function index of an untreated individual or an individual treated with placebo. 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 An amount effective to increase liver function index by 75%, or at least up to about 80% or more. Those skilled in the art can readily measure these liver function indices using standard assays, many of which are commercially available and routinely used in clinical settings.

  Serum markers of liver fibrosis can also be measured as an indicator of the effectiveness of the subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronic acid, type III procollagen N-terminal peptide, type IV collagen 7S domain, type I procollagen C-terminal peptide, and laminin. Additional biochemical markers of liver fibrosis include α-2-macroglobulin, haptoglobin, γ globulin, apolipoprotein A, and γ glutamyl transpeptidase.

  A therapeutically effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is a marker level of an untreated individual, or at least about 10%, at least about 20% of an individual treated with a placebo. 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%, An amount effective to reduce serum liver fibrosis marker levels by at least about 75%, or at least up to about 80%, or less. Those of ordinary skill in the art can readily measure these liver fibrosis serum markers using standard assays, many of which are commercially available and routinely used in clinical settings. Examples of the method for measuring a serum marker include an immunological method using an antibody specific for a given serum marker, such as an enzyme immunoassay (ELISA), a radioimmunoassay, and the like.

  A quantitative test of liver reserve can also be used to assess the effectiveness of treatment with an interferon receptor agonist and pirfenidone (or a pirfenidone analog). These methods include indocyanine green clearance (ICG), galactose excretion (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidine (MEG-X) clearance, and caffeine clearance.

  As used herein, “complication of cirrhosis” refers to a disorder that is a sequelae of decompensated liver disease, ie, a disorder that occurs following and as a result of liver fibrosis. , But not limited to, ascites, varicose bleeding, portal hypertension, jaundice, progressive liver failure, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver related death.

  A therapeutically effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents will determine the incidence of the disorder associated with cirrhosis (e.g., the likelihood that the individual will be), an untreated individual or placebo 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% of individuals treated with An amount effective to reduce to at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or less.

  Whether a treatment with a compound of Formulas I-XIX and optionally one or more additional antiviral agents is effective in reducing the disorders associated with cirrhosis can be readily determined by one skilled in the art.

  Reduction of liver fibrosis enhances liver function. Thus, embodiments provide a method of enhancing liver function, generally administering a therapeutically effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents. Liver function includes, but is not limited to, serum proteins (e.g., albumin, clotting factor, alkaline phosphatase, aminotransferase (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, γ-glutaminyl transpeptidase, etc.) Synthetic functions including protein synthesis, bilirubin synthesis, cholesterol synthesis, and bile acid synthesis; liver metabolism functions including but not limited to carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; foreign Drug detoxification; including hemodynamic functions including visceral and portal hemodynamics.

  Whether liver function is enhanced can be readily ascertained by one skilled in the art using well-established liver function tests. For example, the synthesis of liver function markers such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin can be achieved by measuring the levels of these markers in serum using standard immunoassays and enzyme assays. Can be evaluated. Visceral circulation and portal hemodynamics can be measured by portal wedge pressure and / or resistance using standard methods. Metabolic function can be measured by measuring ammonia levels in serum.

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

  A therapeutically effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about at least about liver function. An amount effective to enhance 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, a therapeutically effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is at least about 10%, at least about 20%, at least about 30 at elevated levels of liver function serum markers. %, At least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or less, or to reduce its liver function serum marker level to within the normal range Effective amount. A therapeutically effective amount of a compound of Formulas I-XIX and an optional one or more additional antiviral agents is at least about 10%, at least about 20%, at least about 30%, at least about a reduced level of liver function serum marker. An amount effective to increase about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or increase the liver function serum marker level within the normal range But there is.

Type I Interferon Receptor Agonist In any of the above methods, in some embodiments, a Type I interferon receptor agonist is administered. Type I interferon receptor agonists include IFN-α, IFN-β, IFN-τ, IFN-ω; antibody agonists specific for type I interferon receptors; and any other type I, including non-polypeptide agonists Interferon receptor agonists are included.

Interferon alpha
In the embodiment, any known IFN-α may be used. The term “interferon α” as used herein refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate the immune response. The term “IFN-α” includes naturally occurring IFN-α, synthetic IFN-α, derivatized IFN-α (eg, PEGylated IFN-α, glycosylated IFN-α, etc.), and naturally occurring Essentially any IFN-α, including analogs of IFN-α or synthetic IFN-α, has antiviral properties as described for naturally occurring IFN-α.

  Suitable alpha interferons include, but are not limited to, naturally occurring IFN-alpha (including naturally occurring IFN-alpha 2a, IFN-alpha 2b); intron A interferon available from Schering Corporation (Kenilworth, NJ, USA) Recombinant interferon α-2b such as: Recombinant interferon α-2a such as roferon interferon available from Hoffmann-La Roche (Nattry, NJ, USA); Boehringer Ingelheim Pharmaceutical, Inc. (Ridgefield, Connecticut, USA) Recombinant interferon α-2C, such as Beroforα2 interferon available from: Interferon α-n1, such as Sumiferon available from Sumitomo Pharma, a natural α interferon purified blend, or available from Glaxo-Wellcome Ltd. (London, UK) Wellferon as interferon α-n1 (INS); Interfer This includes but is not limited to interferon α-n3, a natural α-interferon mixture, manufactured by on Sciences and available from Purdue Frederick Co. (Norwalk, Conn.) under the trade name Alferon.

  The term “IFN-α” also includes consensus IFN-α. Consensus IFN-α (also referred to as `` CIFN '' and `` IFN-con '' and `` consensus interferon '') includes, but is not limited to, IFN-con1, IFN-, disclosed in US Pat. Nos. 4,695,623 and 4,897,471. amino acids sequences called con2, and IFN-con3; and a consensus interferon defined by determination of the consensus sequence of naturally occurring interferon alpha (e.g., Infergen®, InterMune, Inc., Brisbane, Calif., USA) . IFN-con1 is a consensus interferon agent in the Infergen® alphacon-1 product. Infergen® consensus interferon products are referred to herein by their brand name (Infergen®) or their generic name (interferon αcon-1). The DNA sequence encoding IFN-con can be synthesized as described in the aforementioned patent or by standard methods. The use of CIFN is of particular interest.

  Also suitable for use in embodiments is a fusion polypeptide comprising IFN-α and a heterologous polypeptide. Suitable IFN-α fusion polypeptides include, but are not limited to, Albuferon-alpha® (human albumin and IFN-α fusion products, Human Genome Sciences, such as Osborn et al. (2002), J. Pharmacol. Exp. Therap. 303: see pages 540-548). A gene mixed form of IFN-α is also suitable for use in the embodiments. See, for example, Masci et al. (2003), Curr. Oncol. Rep. 5: 108-113.

PEGylated interferon alpha
The term “IFN-α” also includes IFN-α derivatives that have been derivatized (eg, chemically modified) to alter certain properties, such as serum half-life. As such, the term “IFN-α” includes glycosylated IFN-α, IFN-α derivatized with polyethylene glycol (“PEGylated IFN-α”), and the like. PEGylated IFN-α and its preparation are discussed, for example, in US Pat. Nos. 5,382,657, 5981709, and 5,951,974. PEGylated IFN-α is a combination of PEG interferon α-2a (Roferon, Hoffman La-Roche, Natory, NJ, USA), interferon α2b (Intron, Schering-Plough, Madison, NJ), interferon α-2c (Beroforα, Boehringer Ingelheim, Ingelheim, Germany); and the consensus interferon defined by determination of the consensus sequence of naturally occurring interferon alpha (Infergen®, InterMune, Inc., Brisbane, Calif.) Including, but not limited to, a conjugate of PEG and any of the IFN-α molecules described above.

  Any of the IFN-α polypeptides listed above can be modified, ie, PEGylated, with one or more polyethylene glycol moieties. The PEG molecule of a PEGylated IFN-α polypeptide is linked to one or more amino acid side chains of the IFN-α polypeptide. In some embodiments, the PEGylated IFN-α includes a PEG moiety only on one amino acid. In other embodiments, the PEGylated IFN-α comprises a PEG moiety on two or more amino acids, for example, IFN-α is 2, 3, 4, 5, 6, 7, 8, 9, Or a PEG moiety attached to 10 different amino acid residues.

  IFN-α may be linked directly to PEG (ie, without a linking group) through an amino group, sulfhydryl group, hydroxyl group, or carboxyl group.

  In some embodiments, the PEGylated IFN-α is PEGylated at or near the amino terminus (N-terminus) of the IFN-α polypeptide, eg, the PEG moiety is amino acid 1 to amino acid 4 Or at one or more amino acid residues from amino acid 5 to amino acid 10 to the IFN-α polypeptide.

  In other embodiments, the PEGylated IFN-α is PEGylated at one or more amino acid residues from about 10 to about 28.

  In other embodiments, the PEGylated IFN-α has one or more residues at or near the carboxyl terminus (C terminus) of the IFN-α polypeptide, for example, amino acids 156-166, or amino acids 150-155. It is PEGylated at the base.

  In other embodiments, PEGylated IFN-α is PEGylated at one or more residues of amino acids 100-114.

  Derivation of amino acid residues at or near the receptor binding site domain and / or active site domain of IFN-α protein with polyethylene glycol may interfere with the function of these domains. In certain embodiments, amino acids to avoid PEGylation there include amino acid residues from amino acid 30 to amino acid 40, and amino acid residues from amino acid 113 to amino acid 149.

  In some embodiments, PEG is attached to IFN-α via a linking group. The linking group is any linking group that is biocompatible, and “biocompatible” means that the compound or group is non-toxic in vitro or in vivo without causing injury, illness, disease, or death. It indicates that it can be used. PEG can be attached to the linking group by, for example, an ether bond, an ester bond, a thiol bond, or an amide bond. Suitable biocompatible linking groups include, but are not limited to, ester groups, amide groups, imide groups, carbamate groups, carboxyl groups, hydroxyl groups, carbohydrates, succinimide groups (e.g., succinimidyl succinate (SS), propionate). Succinimidyl acid (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA), or N-hydroxysuccinimide (NHS)), epoxide groups, Oxycarbonylimidazole group (for example, carbonyldiimidazole (CDI) is included), nitrophenyl group (for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC) is included), trisylate group, aldehyde group, isocyanate group , Vinyl sulfone group, tyrosine group, cysteine group, histidine group, Or a primary amine is included.

  The preparation of PEG activated by succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) esters is described in US Pat. No. 5,672,662 (Harris et al.) And WO 97/03106.

  Methods for conjugating PEG to IFN-α polypeptides are known in the art and any known method can be used. For example, Park et al., Anticancer Res., 1: 373-376 (1981); Zaplipsky and Lee, `` Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, '' JMHarris, Plenum Press, New York, USA, Chapter 21. (1992); U.S. Pat. No. 5,985,265; U.S. Pat. No. 5,672,662 (Harris et al.); And WO 97/03106.

  PEGylated IFN-α and its preparation are discussed, for example, in US Pat. Nos. 5,382,657, 5981709, 5985265, and 5951974. PEGylated IFN-α is PEG conjugated to interferon α-2a (Roferon, Hoffman La-Roche, Natley, NJ, USA) [PEGylated loferon is known as Pegasys (Hoffman LaRoche)]; interferon conjugated to α2b (Intron, Schering-Plough, Madison, NJ, USA) [PEGylated intron is known as PEG-Intron]; Interferon α-2c (Beroforα, Boehringer Ingelheim, Germany Conjugated to a consensus interferon (CIFN) (Infergen®, InterMune, Inc., Brisbane, Calif., USA) defined by determination of the consensus sequence of naturally occurring interferon alpha (PEGylated Infergen) Includes a conjugate of PEG and any of the IFN-α molecules described above, including but not limited to PEG-Infergen

  In many embodiments, PEG is a monomethoxy PEG molecule that reacts with a primary amine group on an IFN-α polypeptide. Methods for modifying polypeptides with monomethoxy PEG by reductive alkylation are known in the art. See, for example, Chamow et al. (1994) Bioconj. Chem. 5: 133-140.

  In one non-limiting example, PEG is linked to IFN-α via a SPA linking group. The SPA ester of PEG and its preparation are described in US Pat. SPA binding provides for binding to free amine groups on the IFN-α polypeptide.

  For example, the PEG molecule is covalently linked by a bond consisting of an amide bond between the propionyl group of the PEG moiety and the ε-amino group of the lysine residue exposed on the surface in the IFN-α polypeptide. Such a linkage can be made by condensation of α-methoxy PEG ester (mPEGspa) activated by ω-propionic acid.

In one non-limiting example, a preferred mono-PEGylated CIFN conjugate for use herein has an approximately 30 kD linear PEG moiety covalently attached to the CIFN polypeptide, It is an amide bond between the propionyl group of the PEG moiety and the ε-amino group of the lysine residue exposed on the surface of the CIFN polypeptide, and the resin residue exposed on the surface is lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ Lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ , the amide bond is made by condensation of α-methoxy PEG ester activated by ω-propionic acid.

Polyethylene glycol
Polyethylene glycols suitable for conjugation to IFN-α polypeptides are water soluble at room temperature and have the general formula R (O—CH ₂ —CH ₂ ) _n OR _where R is hydrogen or an alkyl or alkanol group. And n is an integer from 1 to 1000). When R is a protecting group, it generally has 1 to 8 carbons.

  In many embodiments, the PEG has at least one hydroxyl group, such as a terminal hydroxyl group, and the hydroxyl group is modified to form an amino group, such as the ε-amino group of a lysine residue, at the polypeptide N-terminus. It generates a free amino group or a functional group that is reactive with any other amino group, such as the amino group of asparagine, glutamine, arginine, histidine.

In other embodiments, PEG is derivatized to be reactive with a free carboxyl group in the IFN-α polypeptide, eg, a free carboxyl group on the carboxyl terminal side of the IFN-α polypeptide. Suitable PEG derivatives reactive with the free carboxyl group on the carboxyl terminal side of IFN-α include, but are not limited to, PEG-amine and hydrazine derivatives of PEG (eg, PEG-NH-NH ₂ ). .

  In other embodiments, PEG is derivatized to include a terminal thiocarboxylic acid group —COSH that selectively reacts with an amino group to form an amide derivative. Because of the reactive nature of thioacids, selectivity for certain amino groups over others is realized. For example, -SH exhibits sufficient leaving group ability in reaction with the N-terminal amino group at appropriate pH conditions, so that the ε-amino group in the lysine residue is protonated and remains non-nucleophilic. Become. On the other hand, when the reaction is carried out under an appropriate pH condition, a part of the accessible lysine residue can be selectively reacted.

In other embodiments, the PEG comprises a reactive ester such as N-hydroxysuccinimidate at the end of the PEG chain. PEG molecules containing such N-hydroxysuccinimidates react with selected amino groups under certain pH conditions such as neutral 6.5-7.5. For example, the N-terminal amino group is selectively modified under neutral pH conditions. However, if the reactivity of the reagent exceeds the degree, the NH ₂ group accessible to lysine can also react.

  PEG can be linked directly to the IFN-α polypeptide or through a linker. In some embodiments, a linker is attached to the IFN-α polypeptide to produce a linker-modified IFN-α polypeptide. Such a linker becomes a reactive group, such as a sulfhydryl group, an amino group, a carboxyl group, etc., for coupling the PEG reagent to the linker-modified IFN-α polypeptide.

  In some embodiments, the PEG conjugated to the IFN-α polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-α polypeptide is branched. A number of arms, such as those described in US Pat. No. 5463575, branched PEG derivatives such as those described in US Pat. No. 5463575, “star-PEG”, and catalog “Polyethylene Glycol Derivatives 1997-1998” of Shearwater Polymers, Inc. PEG with star PEG has been described in the art, including, for example, US Pat. No. 6046305.

  PEG with a molecular weight in the range of about 2 kDa to about 100 kDa is commonly used, but the term “about” means that for PEG, some polyethylene glycol preparations have molecules larger than the molecular weight described, and are small Indicates that there are also molecules. For example, a PEG suitable for conjugation to IFN-α has a molecular weight of about 2 kDa to about 5 kDa, about 5 kDa to about 10 kDa, about 10 kDa to about 15 kDa, about 15 kDa to about 20 kDa, about 20 kDa to about 25 kDa, about 25 kDa to about 30 kDa, about 30 kDa to about 40 kDa, about 40 kDa to about 50 kDa, about 50 kDa to about 60 kDa, about 60 kDa to about 70 kDa, about 70 kDa to about 80 kDa, about 80 kDa to about 90 kDa, or about 90 kDa to about 100 kDa.

Preparation of PEG-IFN-α conjugates As discussed above, the PEG moiety can be directly or via a linker at or near the N-terminus of the IFN-α polypeptide, within, or at or near the C-terminus. It can be attached to an amino acid residue. Binding can be performed in solution or in the solid phase.

N-terminal ligation
Methods for attaching a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-α polypeptide are known in the art. See, for example, US Pat. No. 5,985,265.

In some embodiments, known methods are used to selectively obtain IFN-α chemically modified at the N-terminus. For example, a protein modification method by reductive alkylation can be used that takes advantage of the different reactivity of different types of primary amino groups (lysine versus N-terminus) available for derivatization of a particular protein. Under appropriate reaction conditions, substantially selective protein derivatization at the N-terminus with carbonyl group-containing polymers is achieved. The reaction is the difference between the pK _a of _the α-amino groups of ε-amino groups and the N-terminal residue of a lysine residue of the protein is carried out at a pH become available. Such selective derivatization controls the binding of the PEG moiety to IFN-α. That is, the coupling with the polymer is mainly performed at the N-terminus of IFN-α, and the modification of other reactive groups such as lysine side chain amino groups hardly occurs.

Conjugation at the C-terminus A conjugation procedure specific for the N-terminus, such as that described in US Pat. No. 5,985,265, yields primarily mono-PEGylated products. However, purification procedures aimed at removing excess reagents and small amounts of multiple PEGylated products remove the polypeptide with the N-terminal blockade. In terms of treatment, such methods add significant manufacturing costs. For example, when examining the structure of the amino acid sequence of a well-characterized Infergen® Alfacon-1 CIFN polypeptide, clipping at the carboxyl-terminal side is about 5%, so only one major C It becomes clear that there is a terminal sequence. Thus, in some embodiments, the N-terminal PEGylated IFN-α is not used and instead the C-terminal of the IFN-α polypeptide is PEGylated.

  Therefore, an effective synthetic method and therapeutic method for obtaining a monoPEGylated Infergen product are envisioned as follows.

  The PEG reagent selective at the C-terminus may be prepared with or without a spacer. For example, polyethylene glycol modified as methyl ether at one end and having an amino functional group at the other end can be used as a starting material.

  A water-soluble carbodiimide can be prepared or obtained as a condensation reagent. Conjugation of IFN-α (e.g., Infergen® Alfacon-1 CIFN or consensus interferon) with water soluble carbodiimide as a condensation reagent generally results in an amide bond in an aqueous medium containing a suitable buffer system. At an optimum pH. When a high molecular weight PEG is covalently attached to a protein, the molecular weight can be increased.

  The reagent selected will depend on the process optimization study. Non-limiting examples of suitable reagents are EDAC or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. Since EDAC is soluble in water, it can be added directly to the reaction without the need for prior dissolution in an organic solvent. Both excess reagent and isourea produced as a by-product of the cross-linking reaction are water soluble and can be easily removed by dialysis or gel filtration. In order to make it easier to add a small molar amount to the reaction solution, a concentrated aqueous solution of EDAC is prepared. A stock solution is prepared and used immediately, taking into account that the reagent is unstable in water. Most of the synthetic protocols in the literature suggest that the optimal reaction medium is in the pH range between 4.7 and 6.0. However, this condensation reaction proceeds at a maximum pH of 7.5 without much loss of yield. Water may be used as a solvent. In view of Infergen's intended use, the medium is preferably a 2- (N-morpholino) ethanesulfonic acid buffer that has been previously titrated to a pH between 4.7 and 6.0. However, 0.1M phosphoric acid at pH 7-7.5 may be used given that the product is in that same buffer. The ratio of PEG amine to IFN-α molecules is optimized so that the C-terminal carboxyl residue is selectively PEGylated to give a monoPEGylated derivative.

Although the use of PEG amines was mentioned by name or structure, such derivatives are only examples and also condense with carboxyl groups of IFN-α proteins, such as hydrazine derivatives of PEG-NH-NH _2. Other groups may be used. In addition to the aqueous phase, the reaction can also be carried out in the solid phase. The polyethylene glycol can be selected from a list of compounds having a molecular weight in the range of 300-40000. The choice of the various polyethylene glycols will also depend on the coupling efficiency and the in vitro and in vivo biological performance of the purified derivative, ie, circulation time, antiviral activity, etc.

Furthermore, an appropriate spacer can be added to the C-terminus of the protein. The spacer has a reactive group such as SH, NH ₂ , COOH and can be coupled with a suitable PEG reagent to give a high molecular weight IFN-α derivative. To prepare C-terminal PEGylated interferon, a solid / solution phase combined method can be devised. For example, a Gly-Gly-Cys-NH ₂ spacer is used to extend the C-terminus of IFN-α in the solid phase, and then the appropriate molar amount of activated dithiopyridyl-PEG reagent is used to Perform PEG conversion. The conjugation at the C-terminus is independent of the N-terminal blockade, so the envisaged methods and products are beneficial in terms of cost (eliminating one third of the protein waste of the N-terminal PEGylation method) Contributes to saving treatment for treating viral infections.

  Carboxyl groups of more reactive amino acid residues elsewhere in the molecule react with PEG reagents, resulting in monoPEGylation at that site, or -COOH groups at the C-terminus of IFN-α May result in multiple PEGylation. These reactions are assumed to be minimal at best because the configuration is unconstrained at the C-terminus of the molecule and PEG reagents such as carbodiimide and branched chain molecules impose a constraint on the configuration. Thus, this method improves efficacy and increases in vivo biological activity for Infergen, where the N-terminus may be blocked to varying degrees, and similar proteins expressed in native or host systems. This is the preferred PEG modification scheme to keep.

  Another way to achieve C-terminal PEGylation is as follows. Selectivity for C-terminal PEGylation is achieved using a configurationally constrained reagent that excludes reactions at carboxyl residues buried in or within the helix in IFN-α. For example, one such reagent could be a branched PEG with a molecular weight of about 40 kd, and this agent could be synthesized as follows.

OH ₃ C- (CH ₂ CH ₂ O) n-CH ₂ CH ₂ NH ₂ + glutamic acid, i.e. HOCO-CH ₂ CH ₂ CH (NH2) -COOH, and a suitable agent such as dicyclohexylcarbodiimide or water-soluble EDC Branched PEG agonists OH ₃ C- (CH ₂ CH ₂ O) _n -CH ₂ CH ₂ NHCOCH (NH ₂ ) CH ₂ OCH _3- (CH ₂ CH ₂ O) _n -CH ₂ CH _{2 Get} NHCOCH ₂ .

  When this reagent is used in excess, it is possible to bond the amino group to the unconstrained and adaptable IFN-α carboxyl group to form a peptide bond.

  If desired, PEGylated IFN-α can be converted from unPEGylated IFN-α using any known method including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. To separate. For example, if the PEG-IFN-α conjugate is monoPEGylated IFN-α, the products are first separated by ion exchange chromatography to yield a material that has the charge characteristics of the monoPEGylated material (same appearance) There may be other multiple PEGylated materials with charge), then size exclusion chromatography is used to separate the monoPEGylated material.

Mono PEG (30kD, linear) IFN-α
PEGylated IFN-α that is optimal for use in this embodiment includes a monoPEGylated consensus interferon (CIFN) molecule comprising a single CIFN polypeptide and a single polyethylene glycol (PEG) molecule, where PEG The molecule is linear and has a molecular weight of approximately 30 kD and is bound, either directly or indirectly, by a stable covalent bond to either the N-terminal residue in the CIFN polypeptide or the lysine residue in the CIFN polypeptide. . In some embodiments, the mono PEG (30 kD, linear) IFN-α is a mono PEG (30 kD, linear) consensus IFN-α.

  In some embodiments, the PEG molecule is linked to either the α-amino group of the N-terminal residue in the CIFN polypeptide or the ε-amino group of the lysine residue of the CIFN polypeptide. In another embodiment, the linkage comprises an amide bond between the PEG molecule and either the α-amino group of the N-terminal residue or the ε-amino group of the lysine residue in the CIFN polypeptide. In yet another embodiment, the linkage comprises an amide bond between the propionyl group of the PEG molecule and either the α-amino group of the N-terminal residue or the ε-amino group of the lysine residue in the CIFN polypeptide. In an additional embodiment, the amide bond is between an α-methoxy PEG ester molecule activated by ω-propionic acid and the α-amino group of the N-terminal residue in the CIFN polypeptide or the ε-amino group of a lysine residue. It is formed by condensation with either, thereby forming a hydrolytically stable bond between the PEG molecule and the CIFN polypeptide.

  In some embodiments, the PEG molecule is attached to the N-terminal residue in the CIFN polypeptide. In other embodiments, the PEG molecule is attached to the α-amino group of the N-terminal residue in the CIFN polypeptide. In another embodiment, the linkage comprises an amide bond between the PEG molecule and the α-amino group of the N-terminal residue in the CIFN polypeptide. In yet another embodiment, the linkage comprises an amide bond between the propionyl group of the PEG molecule and the α-amino group of the N-terminal residue in the CIFN polypeptide. In an additional embodiment, the amide bond is formed by condensing an α-methoxy PEG ester molecule activated by ω-propionic acid with the α-amino group of the N-terminal residue in the CIFN polypeptide.

  In some embodiments, the PEG molecule is attached to a lysine residue in the CIFN polypeptide. In other embodiments, the PEG molecule is attached to the ε-amino group of a lysine residue in the CIFN polypeptide. In another embodiment, the linkage comprises an amide bond between the PEG molecule and the ε-amino group of a lysine residue in the CIFN polypeptide. In yet another embodiment, the linkage comprises an amide bond between the propionyl group of the PEG molecule and the ε-amino group of a lysine residue in the CIFN polypeptide. In an additional embodiment, the amide bond is formed by condensing an α-methoxy PEG ester molecule activated by ω propionic acid with the ε amino group of a lysine residue of a CIFN polypeptide.

  In some embodiments, the PEG molecule is attached to a lysine residue exposed on the surface of the CIFN polypeptide. In other embodiments, the PEG molecule is attached to the ε-amino group of the lysine residue exposed on the surface in the CIFN polypeptide. In another embodiment, the linkage comprises an amide bond between the PEG molecule and the ε-amino group of the lysine residue exposed on the surface in the CIFN polypeptide. In yet another embodiment, the linkage comprises an amide bond between the propionyl group of the PEG molecule and the ε-amino group of a lysine residue exposed on the surface of the CIFN polypeptide. In an additional embodiment, the amide bond is formed by condensing an α-methoxy PEG ester molecule activated by ω-propionic acid and the ε-amino group of a lysine residue exposed on the surface in a CIFN polypeptide. .

In some embodiments, the PEG molecule binds to a lysine selected from the CIFN polypeptides lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ^165. ing. In other embodiments, the PEG molecule is a ε-amino group of lysine selected from lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ of the CIFN polypeptide. Is bound to. In another embodiment, the linkage comprises an amide bond between the PEG molecule and the ε amino group of the selected lysine residue in the CIFN polypeptide. In yet another embodiment, the linkage comprises an amide bond between the propionyl group of the PEG molecule and the ε amino group of the selected lysine residue in the CIFN polypeptide. In an additional embodiment, the amide bond is formed by condensing an α-methoxy PEG ester molecule activated by ω-propionic acid with the ε-amino group of a selected lysine residue in the CIFN polypeptide.

In a me embodiment, the PEG molecule is conjugated to a lysine selected from the CIFN polypeptides lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ . In other embodiments, the PEG molecule is attached to the ε-amino group of lysine selected from lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ of the CIFN polypeptide. In another embodiment, the linkage comprises an amide bond between the PEG molecule and the ε amino group of the selected lysine residue in the CIFN polypeptide. In yet another embodiment, the linkage comprises an amide bond between the propionyl group of the PEG molecule and the ε amino group of the selected lysine residue in the CIFN polypeptide. In an additional embodiment, the amide bond is formed by condensing an α-methoxy PEG ester molecule activated by ω-propionic acid with the ε-amino group of a selected lysine residue in the CIFN polypeptide.

In relation to the above monoPEGylated CIFN molecule, the present invention provides that the CIFN polypeptide is selected from interferon α-con ₁ , interferon α-con ₂ , and interferon α-con ₃ and the amino acid sequence of the CIFN polypeptide is Embodiments of each molecule are contemplated as disclosed in US Pat. No. 4,695,623.

Population of IFN-α Further, any of the methods of this embodiment can employ a PEGylated IFN-α composition comprising a population of mono-PEGylated IFN-α molecules, where the population is described above. 1 type or multiple types of monoPEGylated IFNα. The subject compositions comprise a population of modified IFN-α polypeptides, each comprising a single PEG molecule attached to a single amino acid residue of the polypeptide.

  In some of these embodiments, the population is a first IFN-α polypeptide attached to the PEG molecule at a first amino acid residue; and at least a second IFN-α polypeptide attached to the PEG molecule at a second amino acid residue. Comprising a mixture of two IFN-α polypeptides, wherein the first and second IFN-α polypeptides are the same or different, wherein the first amino acid in the amino acid sequence of the first IFN-α polypeptide The position of the residue is not the same as the position of the second amino acid residue in the second IFN-α polypeptide. By way of a non-limiting example, a subject composition comprises a population of PEG-modified IFN-α polypeptides, the population comprising an IFN-α polypeptide conjugated to a linear PEG molecule at its amino terminus; and a lysine residue. Contains an IFN-α polypeptide having a group attached to a linear PEG molecule.

  Usually, a given modified IFN-α species refers to about 0.5% to about 99.5% of the total population of monoPEGylated IFN-α polypeptide molecules in the population, for example, a given modified IFN-α The species is about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 10% of the total population of monoPEGylated IFN-α polypeptide molecules in the population. 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75% , About 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5%. In some embodiments, a subject composition comprises a population of monoPEGylated IFN-α polypeptides that is at least about 70% conjugated to PEG at the same site, e.g., the N-terminal amino acid. At least about 80%, at least about 90%, at least about 95%, or at least about 99% IFN-α polypeptide.

  In a particular embodiment of interest, the subject composition comprises a population of monoPEGylated CIFN molecules, the population comprising one or more molecular species, wherein each molecular species is a single molecular weight of 30 kD. Characterized by a single CIFN polypeptide covalently linked directly or indirectly to a linear PEG molecule, wherein the linkage is either a lysine residue of the CIFN polypeptide or the N-terminal amino acid residue of the CIFN polypeptide. For either of the groups.

In many embodiments, the amino acid residue to which PEG is attached is the N-terminal amino acid residue. In other embodiments, the PEG molecule is attached to a surface-exposed lysine residue (directly or through a linker). In additional embodiments, the PEG molecule is selected (directly or through a linker) from CIFN polypeptides lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ^165. To the lysine residue. In another embodiment, the PEG molecule is linked (directly or through a linker) to a lysine residue selected from lys ^121, lys ¹³⁴ , lys ¹³⁵ , and lys ^{165 of the} CIFN polypeptide.

  As an example, a subject composition comprises a population of monoPEGylated CIFN molecules, which comprises a first monoPEGylated CIFN polymorphism characterized by a PEG molecule attached to the N-terminal amino acid residue of the first CIFN polypeptide. A peptide molecular species and a second monoPEGylated CIFN polypeptide species characterized by a PEG molecule attached to a first lysine residue of a second CIFN polypeptide, wherein the first and second CIFN The polypeptides are the same or different. The subject composition can further comprise at least one additional monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to a lysine residue of the CIFN polypeptide, wherein each additional monomono The location of the binding site of a PEGylated CIFN polypeptide species is not the same as the location of the binding site of any other species. For all species in this example, the PEG molecule is a linear PEG molecule with an average molecular weight of about 30 kD.

  In connection with the population of monoPEGylated CIFN molecules described above, a first monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to the N-terminal amino acid residue of the first CIFN polypeptide; A second monoPEGylated CIFN polypeptide species characterized by a PEG molecule attached to a first lysine residue exposed on the surface of a second CIFN polypeptide, wherein the first and second The CIFN polypeptides can be the same or different. The subject composition can further comprise at least one additional monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to a lysine residue exposed on the surface of the CIFN polypeptide, wherein The location of the binding site of each additional monoPEGylated CIFN polypeptide species is not the same as the location of the binding site of any other species. For all species in this example, the PEG molecule is a linear PEG molecule with an average molecular weight of about 30 kD.

In another example, a subject composition comprises a population of monoPEGylated CIFN molecules, which is a first monoPEG characterized by a PEG molecule attached to the N-terminal amino acid residue of the first CIFN polypeptide. A selected CIFN polypeptide molecular species and one of lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ in the second CIFN polypeptide It consists of a second monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to a first lysine residue, wherein the first and second CIFN polypeptides are the same or different. A second composition selected from one of lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ in the third CIFN polypeptide A third monoPEGylated CIFN polypeptide species characterized by a PEG molecule attached to a lysine residue can further comprise a third CIFN polypeptide comprising the first and second CIFN polypeptides Wherein the second lysine residue is at a position in the amino acid sequence of the third CIFN polypeptide, which is the first in the amino acid sequence of the second CIFN polypeptide. The location of lysine is not the same. The subject composition is at least one additional characterized by a PEG molecule attached to one of lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ Additional monoPEGylated CIFN polypeptide molecular species, wherein the location of the binding site of each additional monoPEGylated CIFN polypeptide species is not the same as the location of the binding site of any other species. In all species of this example, the PEG molecule is a linear PEG molecule with an average molecular weight of about 30 kD.

In another example, a first monoPEGylated CIFN characterized by a composition of interest comprising a population of monoPEGylated CIFN molecules and characterized by a PEG molecule attached to the N-terminal amino acid residue of the first CIFN polypeptide A polypeptide molecular species and a PEG molecule characterized by a PEG molecule attached to a first lysine residue selected from one of lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ^{165 in} a second CIFN polypeptide It consists of two monoPEGylated CIFN polypeptide molecular species, wherein the first and second CIFN polypeptides may be the same or different. A third composition characterized by a PEG molecule conjugated to a second lysine residue selected from one of lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ^{165 in} a third CIFN polypeptide A monoPEGylated CIFN polypeptide molecular species, wherein the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, wherein the second lysine residue The group is at a position in the amino acid sequence of the third CIFN polypeptide that is not identical to the location of the first lysine residue in the amino acid sequence in the second CIFN polypeptide. The subject composition further comprises at least one additional monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to one of lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ Where the location of the binding site within each additional monoPEGylated CIFN polypeptide species is not the same as the location of the binding site of any other species. In all species of this example, the PEG molecule is a linear PEG molecule with an average molecular weight of about 30 kD.

  In another non-limiting example, the subject composition comprises a population of monoPEGylated CIPN molecules, which features a PEG molecule attached to the first lysine residue in the first CIFN polypeptide. A first monoPEGylated CIFN polypeptide molecular species and a second monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule linked to a second lysine residue in the second CIFN polypeptide Wherein the first and second CIFN polypeptides are the same or different, wherein the first lysine is the location of the second lysine residue in the amino acid sequence in the second CIFN polypeptide Are in positions within the amino acid sequence of the first CIFN polypeptide, which are not identical. The subject compositions can further comprise at least one additional monoPEGylated CIFN molecular species characterized by a PEG molecule attached to a lysine residue in the CIFN polypeptide, wherein each additional monoPEG The location of the binding site in the modified CIFN polypeptide species is not the same as the location of the binding site of any other species. In all species of this example, the PEG molecule is a linear PEG molecule with an average molecular weight of about 30 kD.

In another non-limiting example, the subject composition comprises a population of monoPEGylated CIFN molecules, which are lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , in the first CIFN polypeptide, a first monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to a first lysine residue selected from lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ ; and a second CIFN poly Characterized by a PEG molecule attached to a second lysine residue selected from lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ^{165 in the} peptide A second monoPEGylated CIFN polypeptide molecular species, wherein the first and second CIFN polypeptides are the same or different, wherein the second lysine residue is within the first CIFN polypeptide It is in a position in the amino acid sequence of the second CIFN polypeptide that is not identical to the location of the first lysine residue. The composition comprises at least one additional monolayer characterized by a PEG molecule attached to one of lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ^165. PEGylated CIFN molecular species can further be included, wherein the location of the binding site in each additional monoPEGylated CIFN polypeptide species is not the same as the location of the binding site of any other species. In all species of this example, the PEG molecule is a linear PEG molecule with an average molecular weight of about 30 kD.

In another non-limiting example, the subject composition comprises a population of monoPEGylated CIFN molecules, which is selected from lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ^{165 in} the first CIFN polypeptide. A first monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to the first lysine residue, and lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ^{165 in} the second CIFN polypeptide A second monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to a second lysine residue selected from wherein the first and second CIFN polypeptides are identical Or differently, wherein the second lysine residue is in a position in the amino acid sequence of the second CIFN polypeptide that is not identical to the location of the first lysine residue in the first CIFN polypeptide . The composition can further comprise at least one additional monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule attached to one of lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ Where the location of the binding site of each additional monoPEGylated CIFN polypeptide species is not the same as the location of the binding site of any other species. In all species of this example, the PEG molecule is a linear PEG molecule with an average molecular weight of about 30 kD.

  In another non-limiting example, the subject composition comprises one monoPEGylated CIFN molecular population that is bound to the first exposed lysine residue in the first CIFN polypeptide. A first monoPEGylated CIFN polypeptide molecular species characterized by a PEG molecule and a PEG molecule characterized by a PEG molecule attached to a second lysine residue exposed on the surface of the second CIFN polypeptide. Consisting of two monoPEGylated CIFN polypeptide molecular species, wherein the first and second CIFN polypeptides are the same or different, wherein the first lysine exposed on the surface is the second CIFN polypeptide The location of the second lysine residue exposed on the surface in the amino acid sequence is not identical to the position in the amino acid sequence of the first CIFN polypeptide. The subject composition can further comprise at least one additional monoPEGylated CIFN molecular species characterized by a PEG molecule attached to a surface exposed lysine residue in the CIFN polypeptide, wherein the addition The location of the binding site within each typical monoPEGylated CIFN polypeptide species is not the same as the location of the binding site of any other species. In all species of this example, the PEG molecule is a linear PEG molecule with an average molecular weight of about 30 kD.

In relation to each of the above monoPEGylated CIFN molecular populations, the present invention relates to molecules of each such population from interferon alpha-con ₁ , interferon alpha-con ₂ , and interferon alpha-con _3. Embodiments comprising a selected CIFN polypeptide are contemplated.

  Certain embodiments further feature a product produced by the process of reacting a CIFN polypeptide with a succinimide ester of α-methoxy ω propionyl poly (ethylene glycol) (mPEGspa) having a linear molecular weight of about 30 kD, wherein The reactants are initially present in a CIFN: mPEGspa molar ratio of about 1: 1 to about 1: 5, where the reaction is carried out at a pH of about 7 to about 9, and then the reaction product is monoPEGylated The CIFN product is recovered. In one embodiment, the reactants are initially present in a CIFN: mPEGspa molar ratio of about 1: 3 and the reaction is conducted at a pH of about 8. In another embodiment where the product is produced by a scaled-up procedure required for toxicity studies and clinical studies, the reactant is initially present in a CIFN: mPEGspa molar ratio of 1: 2 and the reaction is Perform at about pH 8.0.

In connection with the reactants from the above process, the present invention contemplates embodiments in which the CIFN reactant is selected from interferon alpha-con ₁ , interferon alpha-con ₂ , and interferon alpha-con ₃ .

IFN-β
The term interferon β (“IFN-β”) refers to the naturally occurring IFN-β polypeptide, the non-naturally occurring IFN-β polypeptide, and the antiviral activity of the naturally occurring or non-naturally occurring parent IFN-β. Including naturally occurring or non-naturally occurring analogs of IFN-β.

  Any of a variety of beta interferons can be delivered by the sustained delivery methods of the present invention. Suitable beta interferons include, but are not limited to, naturally occurring IFN-β; IFN-β1a, such as Avonex® (Biogen, Inc.) and Rebif® (Serono, SA); IFN -β1b (Betaseron (registered trademark); Berlex) and the like.

  The IFN-β formulation may include a N-blocked species in which the N-terminal amino acid is acylated with an acyl group such as a formyl group, acetyl group, malonyl group or the like. Consensus IFN-β is also suitable for use.

  The IFN-β polypeptide can be produced by any known method. The DNA sequence encoding IFN-β can be synthesized using standard methods. In many embodiments, the IFN-β polypeptide is transformed by placing the produced DNA sequence into a bacterial host, such as E. coli, or a eukaryotic host cell (e.g., mammalian cells such as yeast, CHO cells, etc.). Or the expression product of those transfected into them. In these embodiments, the IFN-β is “recombinant IFN-β”. If the host cell is a bacterial host cell, IFN-β is modified to include an N-terminal methionine.

  It should be understood that the IFN-β described herein may include one or more modified amino acid residues, such as glycosylation, chemical modifications, and the like.

IFN-τ
The term interferon-τ is a naturally occurring IFN-τ polypeptide, a non-naturally occurring IFN-τ polypeptide, and a natural that retains the antiviral activity of a naturally occurring or non-naturally occurring parent IFN-τ. Including analogs of IFN-τ that are present in nature or non-naturally occurring.

  Suitable τ interferons include, but are not limited to, naturally occurring IFN-τ, Tauferon® (Pepgen Corp.), and the like.

  IFN-τ includes an amino acid sequence represented by any of GenBank accession numbers P15696, P56828, P56832, P56829, P56831, Q29429, Q28595, Q28594, S08072, Q08071, Q08070, Q08053, P56830, P28169, P28172, and P28171 Things can be used. The sequence of any known IFN-τ polypeptide can be altered by various means known in the art to effect the desired change in the sequence. A variant polypeptide will generally be substantially similar to the sequence shown herein, ie, at least one amino acid may be different and two or more but less than about 10 amino acids may be different. The sequence change may be a substitution, insertion, or deletion. Conservative amino acid substitutions usually include (glycine, alanine), (valine, isoleucine, leucine), (aspartic acid, glutamic acid), (asparagine, glutamine), (serine, threonine), (lysine, arginine), or Substitution within each group of (phenylalanine, tyrosine) is included.

  Significant modifications may or may not alter the primary amino acid sequence, but chemical derivatization of the polypeptide, such as acetylation or carboxylation; alteration of the amino acid sequence that introduces or removes glycosylation sites ; Changes in amino acids that make proteins susceptible to PEGylation are included. Glycosylation changes, for example, polypeptides are exposed to enzymes that affect glycosylation, such as mammalian glycosylation enzymes and deglycosylases, during their synthesis and processing, or in further processing steps Those obtained by changing the glycosylation pattern are also included. Also included are sequences having phosphorylated amino acid residues such as phosphotyrosine, phosphoserine, phosphothreonine.

  The IFN-τ preparation may include a N-blocked species in which the N-terminal amino acid is acylated with an acyl group such as a formyl group, an acetyl group, or a malonyl group. Consensus IFN-τ is also suitable for use.

  The IFN-τ polypeptide can be produced by any known method. The DNA sequence encoding IFN-τ can be synthesized using standard methods. In many embodiments, the IFN-τ polypeptide is transformed by placing the produced DNA sequence into a bacterial host, such as E. coli, or a eukaryotic host cell (e.g., a mammalian cell such as a yeast, CHO cell, etc.). Or the expression product of those transfected into them. In these embodiments, the IFN-τ is “recombinant IFN-τ”. If the host cell is a bacterial host cell, IFN-τ is modified to include an N-terminal methionine.

  It should be understood that the IFN-τ described herein may include one or more modified amino acid residues, such as glycosylation, chemical modifications, and the like.

IFN-ω
The term interferon-ω (“IFN-ω”) is a naturally occurring IFN-ω polypeptide; a non-naturally occurring IFN-ω polypeptide; and a naturally occurring or non-naturally occurring parent IFN-ω antiviral Includes naturally occurring or non-naturally occurring analogs of IFN-ω that retain activity.

  Any known omega interferon can be delivered by the sustained delivery method of the present invention. Suitable IFN-ω includes, but is not limited to, naturally occurring IFN-ω; recombinant IFN-ω, such as Biomed 510 (BioMedicines).

  IFN-ω may include an amino acid sequence represented by GenBank accession number NP_002168 or AAA70091. The sequence of any known IFN-ω polypeptide can be altered by various means known in the art to effect the desired change in the sequence. A variant polypeptide will generally be substantially similar to the sequence shown herein, ie, at least one amino acid may be different and two or more but less than about 10 amino acids may be different. The sequence change may be a substitution, insertion, or deletion. Conservative amino acid substitutions usually include (glycine, alanine), (valine, isoleucine, leucine), (aspartic acid, glutamic acid), (asparagine, glutamine), (serine, threonine), (lysine, arginine), or Substitution within each group of (phenylalanine, tyrosine) is included.

  Significant modifications may or may not alter the primary amino acid sequence, but chemical derivatization of the polypeptide, such as acetylation or carboxylation; alteration of the amino acid sequence that introduces or removes glycosylation sites ; Changes in amino acids that make proteins susceptible to PEGylation are included. Glycosylation changes, for example, polypeptides are exposed to enzymes that affect glycosylation, such as mammalian glycosylation enzymes and deglycosylases, during their synthesis and processing, or in further processing steps Those obtained by changing the glycosylation pattern are also included. Also included are sequences having phosphorylated amino acid residues such as phosphotyrosine, phosphoserine, phosphothreonine.

  The IFN-ω formulation may include a N-blocked species in which the N-terminal amino acid is acylated with an acyl group such as a formyl group, an acetyl group, or a malonyl group. Consensus IFN-ω is also suitable for use.

  IFN-ω polypeptides can be produced by any known method. The DNA sequence encoding IFN-ω can be synthesized using standard methods. In many embodiments, an IFN-ω polypeptide is transformed by placing the produced DNA sequence into a bacterial host, such as E. coli, or a eukaryotic host cell (e.g., mammalian cells such as yeast, CHO cells, etc.). Or the expression product of those transfected into them. In these embodiments, the IFN-ω is “recombinant IFN-ω”. If the host cell is a bacterial host cell, IFN-ω is modified to include an N-terminal methionine.

  It should be understood that the IFN-ω described herein may include one or more modified amino acid residues, such as glycosylation, chemical modifications, and the like.

Type III Interferon Receptor Agonist In any of the above methods, in some embodiments, the interferon receptor agonist is an agonist of a Type III interferon receptor (eg, a “Type III interferon agonist”). Type III interferon agonists include IL-28b polypeptide, IL-28a polypeptide, IL-29 polypeptide; antibodies specific for type III interferon receptor; and other type III interferon receptors including non-polypeptide agonists Any agonist of

  IL-28A, IL-28B, and IL-29 (collectively referred to herein as “type III interferon” or “type III IFN”) are Sheppard et al. (2003), Nature 4:63:63. ~ Page 68. Each polypeptide binds a heterodimeric receptor consisting of IL-10 receptor β chain and IL-28 receptor α. Sheppard et al. (2003) supra. The amino acid sequences of IL-28A, IL-28B, and IL-29 are found at GenBank accession numbers NP_742150, NP_742151, and NP_742152, respectively.

  The amino acid sequence of a type III IFN polypeptide can be altered by various means known in the art to effect the desired change in the sequence. A variant polypeptide will generally be substantially similar to the sequence shown herein, ie, at least one amino acid may be different and two or more but less than about 10 amino acids may be different. The sequence change may be a substitution, insertion, or deletion. Scanning mutations that intentionally insert alanine or other residues can be used to determine key amino acids. Detailed amino acid substitutions in question include conservative and non-conservative changes. Conservative amino acid substitutions usually include (glycine, alanine), (valine, isoleucine, leucine), (aspartic acid, glutamic acid), (asparagine, glutamine), (serine, threonine), (lysine, arginine), or Substitution within each group of (phenylalanine, tyrosine) is included.

  Significant modifications may or may not alter the primary amino acid sequence, but chemical derivatization of the polypeptide, such as acetylation or carboxylation; alteration of the amino acid sequence that introduces or removes glycosylation sites ; Changes in amino acids that make proteins susceptible to PEGylation are included. Glycosylation changes, for example, polypeptides are exposed to enzymes that affect glycosylation, such as mammalian glycosylation enzymes and deglycosylases, during their synthesis and processing, or in further processing steps Those obtained by changing the glycosylation pattern are also included. Also included are sequences having phosphorylated amino acid residues such as phosphotyrosine, phosphoserine, phosphothreonine.

  The subject invention uses a conventional chemical technique to modify its resistance to proteolytic degradation to optimize its dissolution properties, or to make it more suitable as a therapeutic agent. Peptides are included. For example, the peptide backbone can be cyclized to increase stability (see Friedler et al. (2000) J. Biol. Chem. 275: 23783-23789). Analogs containing residues other than naturally occurring L-amino acids, such as D-amino acids and non-naturally occurring synthetic amino acids may be used. Proteins can be PEGylated to increase stability. The polypeptide may be fused with albumin.

  The polypeptide may be prepared using conventional methods known in the art, i.e., by in vitro synthesis by recombinant methods, or isolated from induced cells or cells that naturally produce proteins. May be separated. The specific sequence and mode of preparation are determined by convenience, economic aspects, required purity, and the like. If desired, various groups that allow attachment to other molecules or surfaces can be introduced into the polypeptide during synthesis or expression. For example, cysteine can be used to form a thioether, histidine to bind to a metal ion complex, a carboxyl group to form an amide or ester, an amino group to form an amide, and the like.

Type II interferon receptor agonist
Type II interferon receptor agonists include any naturally occurring or non-naturally occurring human type II interferon receptor ligand that binds to and causes signaling through the receptor. Type II interferon receptor agonists include naturally occurring interferons, modified interferons, synthetic interferons, PEGylated interferons, fusion proteins containing interferon and heterologous proteins, interferons including mixed interferons; specific for interferon receptors Antibodies; non-peptide chemical agonists and the like.

  A detailed example of a type II interferon receptor agonist is IFN-γ and its variants. While the embodiments illustrate the use of IFN-γ polypeptides, it will be appreciated that any type II interferon receptor agonist can be used in the subject methods.

Interferon-γ
Nucleic acid sequences encoding IFN-γ polypeptides can be obtained from public databases such as Genbank and journal publications. Various mammalian IFN-γ polypeptides are of interest for the treatment of human diseases, but generally human proteins are used. The coding sequence for human IFN-γ can be found at Genbank accession numbers X13274, V00543, and NM_000619. Corresponding genomic sequences can be found at Genbank accession numbers J00219, M37265, and V00536. See, for example, Gray et al. (1982) Nature 295: 501 (Genbank X13274); and Rinderknecht et al. (1984) JBC 259: 6790.

  IFN-γ1b (Actimmune (registered trademark), human interferon) is a single-chain polypeptide consisting of 140 amino acids. This polypeptide is produced recombinantly in E. coli and is not glycosylated. Rinderknecht et al. (1984), J. Biol. Chem. Vol. 259: 6790-6797. Recombinant IFN-γ, discussed in US Pat. No. 6,649,871, is also suitable for use herein.

  The IFN-γ to be used in the method of the embodiment may be any of natural IFN-γ, recombinant IFN-γ, and derivatives thereof as long as it has IFN-γ activity, particularly human IFN-γ activity. . Human IFN-γ exhibits not only the antiviral and antiproliferative properties unique to interferon, but also several other immunomodulatory activities known in the art. Although IFN-γ is based on the sequence shown above, protein production and proteolytic processing may result in its processing variants. The unprocessed amino acid obtained by Gray et al., Supra consists of 166 amino acids (aa). Recombinant IFN-γ produced in E. coli was originally thought to be 146 amino acids (starting with amino acid 20), but later, native human IFN-γ was cleaved after residue 23. Thus, it has been found that the presence of the 143aa protein or the terminal methionine required for expression in bacteria results in the 144aa protein. During purification, the mature protein is further cleaved on the C-terminal side after residue 162 (for the Gray et al. Sequence) and is required for expression by, for example, bacteria if 139 amino acids, or the first methionine is present. If it becomes, the protein which consists of 140 amino acids can be obtained. N-terminal methionine is an artificial product encoded by the “start” signal AUG of translation from mRNA that is not removed by processing in the specific case of expression in E. coli. In other microbial or eukaryotic expression systems, methionine may be removed.

  For use in the subject methods, any of the natural IFN-γ peptides, modified forms and variants thereof, or combinations of one or more peptides can be used. The problematic IFN-γ peptide includes a fragment, and the carboxyl terminal side can be variously truncated from the full-length sequence. Such fragments will continue to exhibit the unique properties of human gamma interferon as long as amino acids 24 to about 149 are present (counted from the unprocessed polypeptide residues). An irrelevant sequence can replace the amino acid following amino acid 155 without loss of activity. See, for example, US Pat. No. 5,609,925. Naturally-occurring IFN-γ moieties include molecules that extend 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 having IFN-γ activity, can be used in the methods of the invention.

  The sequence of an IFN-γ polypeptide can be altered by various means known in the art to effect a desired change in the sequence. A variant polypeptide will generally be substantially similar to the sequence shown herein, ie, at least one amino acid may be different and two or more but less than about 10 amino acids may be different. The sequence change may be a substitution, insertion, or deletion. Scanning mutations that intentionally insert alanine or other residues can be used to determine key amino acids. Detailed amino acid substitutions in question include conservative and non-conservative changes. Conservative amino acid substitutions usually include (glycine, alanine), (valine, isoleucine, leucine), (aspartic acid, glutamic acid), (asparagine, glutamine), (serine, threonine), (lysine, arginine), or Substitution within each group of (phenylalanine, tyrosine) is included.

  Significant modifications may or may not alter the primary amino acid sequence, but chemical derivatization of the polypeptide, such as acetylation or carboxylation; alteration of the amino acid sequence that introduces or removes glycosylation sites ; Changes in amino acids that make proteins susceptible to PEGylation are included. In one embodiment, engineered to result in glycosyl and / or PEG derivatized polypeptides with reduced serum clearance, such as the IFN-γ polypeptide variants described in International Patent Application No. WO 01/36001. Also contemplated is the use of IFN-γ variants having one or more non-naturally occurring glycosylation sites and / or PEGylation sites. Glycosylation changes, for example, polypeptides are exposed to enzymes that affect glycosylation, such as mammalian glycosylation enzymes and deglycosylases, during their synthesis and processing, or in further processing steps Those obtained by changing the glycosylation pattern are also included. Also included are sequences having phosphorylated amino acid residues such as phosphotyrosine, phosphoserine, phosphothreonine.

  Embodiments include polymorphs that are modified using conventional chemical techniques to improve their resistance to proteolytic degradation to optimize dissolution properties or to make it more suitable as a therapeutic agent. Peptides are included. For example, the peptide backbone can be cyclized to increase stability (see Friedler et al. (2000) J. Biol. Chem. 275: 23783-23789). Analogs containing residues other than naturally occurring L-amino acids, such as D-amino acids and non-naturally occurring synthetic amino acids may be used. Proteins can be PEGylated to increase stability.

  The polypeptide may be prepared using conventional methods known in the art, i.e., by in vitro synthesis by recombinant methods, or isolated from induced cells or cells that naturally produce proteins. May be separated. The specific sequence and mode of preparation are determined by convenience, economic aspects, required purity, and the like. If desired, various groups that allow attachment to other molecules or surfaces can be introduced into the polypeptide during synthesis or expression. For example, cysteine can be used to form a thioether, histidine to bind to a metal ion complex, a carboxyl group to form an amide or ester, an amino group to form an amide, and the like.

  The polypeptide may be isolated and purified according to conventional recombinant synthetic methods. An expression host lysate can be prepared and the lysate can be purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification techniques. The composition used is usually at least 20% by weight of the desired product, more usually at least about 75% by weight, preferably at least about 30% by weight compared to the contaminants associated with the method of preparation and purification of the product. About 95% by weight, and usually for therapeutic purposes usually contains at least about 99.5% by weight. Usually, the percentage amount is relative to the total protein.

Pirfenidone and its analogs Pirfenidone (5-methyl-1-phenyl-2- (1H) -pyridone) and certain pirfenidone analogs have been disclosed for the treatment of fibrotic conditions. A “fibrotic condition” is a condition that is susceptible to treatment by administration of a compound having antifibrotic activity.

Description of substituents R ₁ , R ₂ , X
R ₁ : Carbocycle (saturated and unsaturated), heterocyclic ring (saturated or unsaturated), alkyl (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.

R ₁ has a carbocyclic or heterocyclic moiety substituted with a substituent such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl, combinations thereof and the like Such as 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2,5-dichlorocyclohexyl, guanidinyl-cyclohexenyl, and the like. .

R ₂ : alkyl, carbocycle, aryl, heterocycle. Examples include methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.

  X may be any number (1-3) of substituents on the carbocycle or heterocycle. These substituents may be the same or different. Substituents can include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl, and the like.

  Substituents may be optionally further substituted with 1 to 3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl, and halo groups. Examples include methyl, 2,3-dimethyl, phenyl, p-toluyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.

  Detailed examples include the compounds listed in Table 1.

  U.S. Pat.Nos. 3,974281, 3839346, 4042699, 4052509, 5310562, 5518729, 5716632, and 6090822 are used in the method of the present invention. Describes methods for the synthesis and formulation of pirfenidone and certain pirfenidone analogs in the form of suitable pharmaceutical compositions.

Thymosin alpha
Thymosin alpha (Zadaxin ™, SciClone Pharmaceuticals, Inc., available from San Mateo, Calif., USA) is a synthetic form of thymosin alpha1, a hormone found naturally in the circulation and produced by the thymus. Thymosin alpha increases the activity of T cells and NK cells. Zadaxin ™ formulated for subcutaneous injection is a sterile preparation of purified and lyophilized chemically synthesized thymosin α1 identical to human thymosin α1. Thymosin α1 has the following sequence: Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-lle-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys An acetylated polypeptide having -Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH and a molecular weight of 3108 daltons. The lyophilized preparation contains 1.6 mg synthetic thymosin-α, 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8.

Ribavirin Ribavirin, ie 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is a nucleoside analog available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif. Compound No. 8199, 11th edition. Its manufacture and formulation is described in US Pat. No. 4,211,771. Embodiments also contemplate the use of derivatives of ribavirin (see, eg, US Pat. No. 6,277,830). Ribavirin can be administered orally in the form of capsules or tablets. Of course, other types of ribavirin administration that are available are contemplated, such as nasal spray administration, transdermal administration, suppository administration, and sustained release dosage forms. Any dosage form will work as long as the proper dose is delivered without destroying the active ingredient.

  Ribavirin is generally administered in an amount in the range of about 400 mg to about 1200 mg, about 600 mg to about 1000 mg, or about 700 to about 900 mg per day. In some embodiments, ribavirin is administered throughout the entire course of NS3 inhibitor therapy.

Levovirin Levovirin is the L-enantiomer of ribavirin and exhibits properties that enhance the Th1 immune response over the Th2 immune response. Levovirin is manufactured by ICN Pharmaceuticals.

  Levovirin has the following structure:

Viramidine
Viramidine is a 3-carboxamidine derivative of ribavirin and acts as a prodrug for ribavirin. This is efficiently converted to ribavirin by adenosine deaminase.

  Viramidine has the following structure:

Nucleoside analogs Nucleoside analogs suitable for use in subject combination therapy include, but are not limited to, ribavirin, levovirin, viramidine, isatoribine, US Pat. No. 5,555,011, and formula I of US Pat. L-ribofuranosyl nucleosides (e.g., 1-β-ribofuranosyluracil, 1-β-L-ribofuranosyl-5-fluorouracil, 1-β-L-ribofuranosylcytosine, 9-β-L- Ribofuranosyl adenine, 9-β-L-ribofuranosyl hypoxanthine, 9-β-L-ribofuranosyl guanine, 9-β-L-ribofuranosyl-6-thioguanine, 2-amino-α-L-ribofuranyl [ 1 ′, 2 ′: 4,5] oxazoline, O ² , O ² -anhydrous-1-α-L-ribofuranosyluracil, 1-α-L-ribofuranosyluracil, 1- (2,3,5 -Tri-O-benzoyl-α-ribofuranosyl) -4-thiouracil, 1-α-L-ribofuranosylcytosine, 1-α-L- Ribofuranosyl-4-thiouracil, 1-α-L-ribofuranosyl-5-fluorouracil, 2-amino-β-L-arabinofurano [1 ', 2': 4,5] oxazoline, O ² , O ² -anhydro-β- L-arabinofuranosyluracil, 2'-deoxy-β-L-uridine, 3'5'-di-O-benzoyl-2'deoxy-4-thioβ-L-uridine, 2'-deoxy-β- L-cytidine, 2'-deoxy-β-L-4-thiouridine, 2'-deoxy-β-L-thymidine, 2'-deoxy-β-L-5-fluorouridine, 2 ', 3'-dideoxy- β-L-uridine, 2′-deoxy-β-L-5-fluorouridine, and 2′-deoxy-β-L-inosine); disclosed in U.S. Pat. A compound contained in Formula I of U.S. Patent Publication No. 2002/0058635 and contained in Formula I of U.S. Patent Publication No. 2002/0058635; a nucleoside analog as disclosed in WO 01/90121 A2 (Idenix) Body; WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.) Etc. WO 02/057287 A2 or WO 02/057425 A2 (both Merck / Isis) as disclosed in nucleoside analogues; indicated nucleoside analogues, such as those.

TNF antagonists In some embodiments, a subject method comprises administration of an effective amount of an NS3 inhibitor and an effective amount of a tumor necrosis factor α (TNF-α) antagonist. TNF-α antagonists suitable for use herein include agents that reduce the level of TNF-α synthesis, agents that block or inhibit TNF-α binding to the TNF-α receptor (TNFR), and TNFR-. Agents that block or inhibit mediated signaling are included. Unless otherwise specified, any reference to “TNF-α antagonist” or “TNF antagonist” is understood herein to mean a TNF-α antagonist other than pirfenidone or a pirfenidone analog.

  As used herein, the terms “TNF receptor polypeptide” and “TNFR polypeptide” refer to a polypeptide derived from TNFR (derived from any species) capable of binding to TNF. Two different cell surface TNFRs have been described, type II TNFR (or p75 TNFR or TNFRII) and type I TNFR (or p55 TNFR or TNFRI). Mature full-length human p75 TNFR is a glycoprotein with a molecular weight of about 75-80 kilodaltons (kD). Mature full-length human p55 TNFR is a glycoprotein with a molecular weight of about 55-60 kD. Exemplary TNFR polypeptides are those derived from TNFR type I and / or TNFR type II. Soluble TNFRs include p75 TNFR polypeptides; fusions of p75 TNFR with heterologous fusion partners, eg, the Fc portion of an immunoglobulin.

  The TNFR polypeptide may be intact TNFR or an appropriate TNFR fragment. US Pat. No. 5,605,690 provides examples of TNFR polypeptides suitable for use in embodiments, including soluble TNFR polypeptides. In many embodiments, the TNFR polypeptide comprises the extracellular domain of TNFR. In some embodiments, the TNFR polypeptide is a fusion polypeptide comprising the extracellular domain of TNFR linked to the constant domain of an immunoglobulin molecule. In other embodiments, the TNFR polypeptide is a fusion polypeptide comprising the extracellular domain of p75 TNFR linked to the constant domain of an IgG1 molecule. In some embodiments, when intended for human administration, the Ig used for the fusion protein is a human, eg, human IgG1.

  In embodiments, monovalent and multivalent forms of TNFR polypeptides can be used. Multivalent forms of TNFR polypeptides have more than one TNF binding site. In some embodiments, the TNFR is a divalent or dimeric form of TNFR. For example, as described in U.S. Pat.No. 5605690 and Mohler et al., 1993, J. Immunol. 151: 154-1561, variable of either or both immunoglobulin heavy or light chains. A chimeric antibody polypeptide in which a TNFR extracellular domain is used in place of a domain should be a TNFR polypeptide for embodiments. In general, such TNFR: antibody chimeric polypeptides form dimers through disulfide bonds between immunoglobulin domains when produced by cells. Such a TNFR: antibody chimeric polypeptide is referred to as TNFR: Fc.

  In one embodiment, the subject method involves administering an effective amount of ENBREL®, a soluble TNFR. ENBREL® is a dimeric fusion protein consisting of an extracellular ligand binding portion of human 75 kilodalton (p75) TNFR linked to the Fc portion of human IgG1. The Fc component of ENBREL® includes the CH2 domain, CH3 domain, and hinge region of IgG1, but does not include the CH1 domain. ENBREL® is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. This protein consists of 934 amino acids and has an apparent molecular weight of about 150 kilodaltons. Smith et al. (1990), Science 248: 1019-1023; Mohler et al. (1993) J. Immunol. 151: 1548-1561; US Pat. No. 5,395,760; and US Pat. No. 5605690.

Monoclonal antibodies that bind TNF-α are also suitable for use. Monoclonal antibodies include “humanized” mouse monoclonal antibodies; chimeric antibodies; monoclonal antibodies in which at least about 80%, at least about 90%, at least about 95%, or 100% of the amino acid sequence is human. See, for example, WO 90/10077, WO 90/04036, and WO 92/02190. Suitable monoclonal antibodies include antibody fragments such as Fv, F (ab ′) ₂ , Fab; synthetic antibodies; artificial antibodies; phage display antibodies.

  Examples of suitable monoclonal antibodies include infliximab (REMICADE®, Centocor) and adalimumab (HUMIRA ™, Abbott). REMICADE® is a chimeric monoclonal anti-TNF-α antibody containing about 25% mouse amino acid sequence and about 75% human amino acid sequence. REMICADE® contains the variable region of a mouse monoclonal anti-TNF-α antibody fused to the constant region of human IgG1. Elliott et al. (1993), Arthritis Rheum. 36: 1681-1690; Elliott et al. (1994), Lancet 344: 1105-1110; Baert et al. (1999), Gastroenterology 116: 22- 28 pages. HUMIRA ™ is a human full length IgG1 monoclonal antibody identified using the phage display method. Piascik (2003), J. Am. Pharm. Assoc. Volume 43: 327-328.

  Stress activated protein kinase (SAPK) inhibitors are also included in the term “TNF antagonist” and are therefore suitable for use in the subject methods. SAPK inhibitors are known in the art and include, but are not limited to, 2-alkylimidazoles disclosed in US Pat. No. 6,485,520; disclosed in US Pat. No. 6,643,925, positions 1,4,5 Substituted imidazole compounds; disclosed in U.S. Pat. No. 6,656,871, imidazole compounds substituted in positions 1,4,5; heteroaryl aminophenyl ketones disclosed in published U.S. patent application 2003/0073832 This includes the pyridylimidazole compounds disclosed in US Pat. No. 6,288,889; and the heteroarylaminobenzophenones disclosed in US Pat. No. 6,329,622. Also of interest are the compounds disclosed in US Patent Application Publication No. 2003/0149041 and US Pat. No. 6,214,854. Stress activated protein kinases are a member of a family of mitogen activated protein kinases that are activated in response to stress stimuli. SAPK includes, but is not limited to, p38 (Lee et al. (1994) Nature 372: 739) and c-jun N-terminal kinase (JNK).

  Methods for assessing TN antagonist activity are known in the art and are also exemplified herein. For example, TNF antagonist activity can be assessed by a cell competitive binding assay. In such assays, radiolabeled TNF is mixed with serially diluted TNF antagonists and cells that express cell membrane-bound TNFR. The suspension in small portions is centrifuged to separate the TNF bound to the free TNF, and the amount of radioactivity in the free fraction and the bound fraction is measured. TNF antagonist activity is evaluated by whether TNF binding to cells was inhibited in the presence of TNF antagonist.

  As another example, a bioassay that uses cells susceptible to the cytotoxic activity of TNF as target cells may analyze whether a TNF antagonist can neutralize TNF activity in vitro. In such assays, target cells cultured with TNF are treated with various amounts of TNF antagonist and then examined for cell lysis. TNF antagonist activity is assessed by whether TNF-induced cytolysis of target cells is reduced in the presence of TNF antagonist.

NS5B inhibitors In some embodiments, administration of an effective amount of a subject NS3 inhibitor and an effective amount of an HCV nonstructural protein 5 (NS5, RNA-dependent RNA polymerase) inhibitor to an HCV patient in need thereof A method comprising: Suitable NS5B inhibitors include, but are not limited to, compounds disclosed in US Pat. No. 6,479,508 (Boehringer-Ingelheim); international patent applications PCT / CA02 / 01127, PCT / CA02 / 01128, and PCT / CA02 / Compounds disclosed in any of 01129 (all filed on July 18, 2002 by Boehringer Ingelheim); compounds disclosed in US Pat. No. 6,409,985 (ViroPharma); compounds disclosed in WO 01/47883 E.g., JTK-003 (Japan Tobacco Inc.); Zhong et al. (2003), Antimicrob. Agents Chemother. 47: 2674-2681; the dinucleotide analogs disclosed in Dhanak et al. (2002), J. Biol Chem. 277 (41): benzothiadiazine compounds disclosed on pages 38322-7; NS5B inhibitors disclosed in WO 02/100846 A1 or WO 02/100851 A2 (both Shire); WO NS5B inhibitors disclosed in 01/85172 A1 or WO 02/098424 A1 (both Glaxo SmithKline); NS5B inhibitors disclosed in WO 00/06529 or WO 02/06246 A1 ( NS5B inhibitor disclosed in WO 03/000254 (Japan Tobacco); NS5B inhibitor disclosed in EP 1 256628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan Tobacco Inc.).

  Of particular importance among many embodiments is the inhibition of specific NS5 inhibitors, such as NS5 RNA-dependent RNA polymerase, and significant inhibitory effects on other RNA-dependent and DNA-dependent RNA polymerases. NS5 inhibitor without any.

Additional antiviral agents Additional antiviral therapeutics that can be administered in conjunction with the subject NS3 inhibitor compound include, but are not limited to, inosine monophosphate dehydrogenase (IMPDH) inhibitors, complementary to viral nucleotide sequences Ribozymes, antisense RNA inhibitors and the like.

IMPDH inhibitors IMPDH inhibitors suitable for use in the subject combination therapy include, but are not limited to, VX-497 ((S) -N-3- [3- (3-methoxy-4-oxazol-5-yl- Phenyl) -ureido] -benzyl-carbamic acid tetrahydrofuran-3-yl-ester, Vertex Pharmaceuticals; see, for example, Markland et al. (2000) Antimicrob. Agents Chemother. 44: 859-866). Examples include ribavirin, revovirin (Ribapharm; see, for example, Watson (2002), Curr Opin Investig Drugs 3 (5): 680-3), viramidine (Ribapharm), and the like.

Ribozymes and antisense Ribozymes and antisense antiviral agents suitable for use in subject combination therapy include, but are not limited to, ISIS 14803 (ISIS Pharmaceuticals / Elan Corporation; e.g., Witherell (2001), Curr Opin Investig Drugs. Volume (11): see pages 1523-9), Heptazyme ™ and the like.

  In some embodiments, the additional antiviral agent is administered throughout the entire course of treatment with the NS3 inhibitor compound. In other embodiments, the additional antiviral agent is administered for a period that overlaps with treatment with the NS3 inhibitor compound, e.g., treatment with the additional antiviral agent begins before the NS3 inhibitor compound treatment begins, and NS3 Treatment with the inhibitor compound can be completed before treatment with the additional antiviral agent can begin after treatment with the NS3 inhibitor compound begins and after treatment with the NS3 inhibitor compound is over; additional treatment Treatment with an antiviral agent can begin after treatment with an NS3 inhibitor compound begins, and can end before treatment with an NS3 inhibitor compound ends; or treatment with an additional antiviral agent begins before treatment with an NS3 inhibitor compound begins It can also begin after treatment with NS3 inhibitor compounds.

Dosage, Formulation, and Route of Administration In the subject methods, the active agent (e.g., a compound of formula I and optionally one or more additional antiviral agents) uses any conventional means that can provide the desired therapeutic effect. And may be administered to a host. That is, the drug may be incorporated into various formulations for therapeutic administration. More specifically, the medicament of the embodiment can be combined with a suitable pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition, and further tablets, capsules, powders, granules, ointments, solutions, suppositories. The preparation can be in the form of a solid, semi-solid, liquid, or gas, such as an agent, injection, inhalant, aerosol and the like.

Formulation The active agents discussed above can be formulated using well-known reagents and methods. The composition is provided in a formulation with pharmaceutically acceptable excipients. A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients are described, for example, in A. Gennaro (2000), `` Remington: The Science and Practice of Pharmacy '', 20th edition, Lippincott, Williams, &Wilkins; `` Pharmaceutical Dosage Forms and Drug Delivery Systems (1999), HCAnsel et al., 7th edition, Lippincott, Williams, &Wilkins; and "Handbook of Pharmaceutical Excipients" (2000), AHKibbe et al., 3rd edition, Amer.Pharmaceutical Assoc. Fully described in the publication.

  Pharmaceutically acceptable excipients such as media, adjuvants, carriers, diluents and the like can be easily obtained by anyone. Furthermore, pharmaceutically acceptable auxiliary substances such as pH adjusters, buffers, isotonicity adjusters, stabilizers, wetting agents and the like can be easily obtained by anyone.

  In some embodiments, the drug can be formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, 5 mM to 100 mM various strength acetic acid, succinic acid, citrate, and phosphate buffers. In some embodiments, the aqueous buffer includes reagents that render the solution isotonic. Such reagents include, but are not limited to, sodium chloride and sugars such as mannitol, dextrose, sucrose, and the like. In some embodiments, the aqueous buffer further comprises a nonionic surfactant, such as polysorbate 20 or 80. Optionally, the formulation may further comprise a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the formulation is stored at about 4 ° C. The formulation may be lyophilized, in which case the formulation generally includes a cryoprotectant such as sucrose, trehalose, lactose, maltose, mannitol. The lyophilized formulation can be stored for extended periods at ambient temperatures.

  Accordingly, administration of the drug can be accomplished by a variety of means including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal and the like. In many embodiments, administration is by bulk injection, such as subcutaneous bulk injection, intramuscular bulk injection, and the like.

  The pharmaceutical compositions of the embodiments can be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection is preferred.

  Subcutaneous administration of the pharmaceutical composition of the embodiment is done using standard methods and devices such as needles and syringes, subcutaneous injection port delivery systems, and the like. See, for example, U.S. Pat. Nos. 3,547,119, 4,755,173, 4531937, 4311137, and 6017328. A combination of a subcutaneous injection port and a device for administering the pharmaceutical composition of the embodiment to a patient through the port is referred to herein as a “subcutaneous injection port delivery system”. In many embodiments, subcutaneous administration is achieved by bulk delivery with a needle and syringe.

  Drugs in pharmaceutical dosage form may be administered in the form of a pharmaceutically acceptable salt thereof, or used alone or in a suitable combination with other pharmaceutically active compounds. In addition, it may be used in combination with such compounds. The following methods and excipients are merely exemplary and are in no way limiting.

  For oral formulations, the drug can be used alone or as a conventional additive such as tablets, powders, granules, or capsules, for example, lactose, mannitol, corn starch, potato starch; Binders such as microcrystalline cellulose, cellulose derivatives, acacia, corn starch, gelatin; disintegrants such as corn starch, potato starch, sodium carboxymethylcellulose; lubricants such as talc and magnesium stearate; and diluents if desired , Buffering agents, wetting agents, preservatives, and flavoring agents can be used in combination.

  The drug can be a vegetable oil or other similar oils, synthetic fatty acids with conventional additives such as solubilizers, tonicity agents, suspending agents, emulsifiers, stabilizers, preservatives, if desired. It can be formulated into an injectable preparation by dissolving, suspending or emulsifying it in an aqueous or non-aqueous solvent such as glyceride, higher fatty acid or propylene glycol ester.

  In addition, the drug can be mixed with various bases such as an emulsifying base and a water-soluble base to form a suppository. The compounds of the embodiments can be administered rectally via a suppository. Suppositories may contain a medium that melts at body temperature but solidifies at room temperature, such as cacao butter, carbowax, polyethylene glycol, and the like.

  Syrups, elixirs, suspensions in which each dosage unit, for example, a teaspoon, a tablespoon, a tablet, or a suppository, contains a predetermined amount of the composition containing one or more inhibitors Etc., unit dosage forms for oral or rectal administration may also be provided. Similarly, unit dosage forms for injection or intravenous administration may contain the inhibitor in a composition as a solution in sterile water, defined saline, or other pharmaceutically acceptable carrier.

  The term “unit dosage form” as used herein refers to physically discrete units suitable as unit dosages for human and animal subjects, each unit being an amount sufficient to produce the desired effect. A predetermined amount of the compound of the embodiment calculated in (1) above is contained together with a pharmaceutically acceptable diluent, carrier or medium. The details for the novel unit dosage forms of the embodiments will vary depending on the particular compound used, the effect sought, and the pharmacodynamics associated with each compound in the host.

  Pharmaceutically acceptable excipients such as media, adjuvants, carriers, diluents and the like can be easily obtained by anyone. Furthermore, pharmaceutically acceptable auxiliary substances such as pH adjusters, buffers, isotonicity adjusters, stabilizers, wetting agents and the like can be easily obtained by anyone.

Other Antiviral Agents As discussed above, the subject method is, in some embodiments, by administration of an NS3 inhibitor, ie, a compound of Formulas I-XIX and an optional one or more additional antiviral agents. carry out.

  In some embodiments, the method further comprises administration of one or more interferon receptor agonists. Interferon receptor agonists are described above.

  In other embodiments, the method further comprises administration of pirfenidone or a pirfenidone analog. Pirfenidone and pirfenidone analogs are described above.

  Additional antiviral agents suitable for use in combination therapy include, but are not limited to, nucleotide and nucleoside analogs. Non-limiting examples include azidothymidine (AZT) (didovudine) and analogs and derivatives thereof; 2 ', 3'-dideoxyinosine (DDI) (didanocin) and analogs and derivatives thereof; 2', 3'-dideoxy Cytidine (DDC) (dideoxycytidine) and analogs and derivatives thereof; 2'3, '-didehydro-2', 3'-dideoxythymidine (D4T) (stavudine) and analogs and derivatives thereof; combivir; abacavir; adefovir di Poxyl; cidofovir; ribavirin; ribavirin itself.

  In some embodiments, the method further comprises administration of ribavirin. Ribavirin, i.e. 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, CA, USA, Merck Index, Compound No. 8199, No. It is described in the 11th edition. Its manufacture and formulation is described in US Pat. No. 4,211,771. The present invention also contemplates the use of derivatives of ribavirin (see, eg, US Pat. No. 6,277,830). Ribavirin can be administered orally in the form of a capsule or tablet, or in the same or different route in the same or different dosage form as the interferon receptor agonist. Of course, other types of administration of both medicaments are contemplated, such as administration by nasal spray, transdermal administration, intravenous administration, administration by suppository, administration by sustained release form, as long as they are available. Any dosage form will work as long as the proper dose is delivered without destroying the active ingredient.

  In some embodiments, the additional antiviral agent is administered throughout the entire course of treatment with the NS3 inhibitor compound. In other embodiments, the additional antiviral agent is administered for a period that overlaps with treatment with the NS3 inhibitor compound, e.g., treatment with the additional antiviral agent begins before the NS3 inhibitor compound treatment begins, and NS3 Treatment with the inhibitor compound can be completed before treatment with the additional antiviral agent can begin after treatment with the NS3 inhibitor compound begins and after treatment with the NS3 inhibitor compound is over; additional treatment Treatment with an antiviral agent can begin after treatment with an NS3 inhibitor compound begins, and can end before treatment with an NS3 inhibitor compound ends; or treatment with an additional antiviral agent begins before treatment with an NS3 inhibitor compound begins It can also begin after treatment with NS3 inhibitor compounds.

  The NS3 inhibitor compounds of the embodiments are optimal for use in dosage forms that require good water solubility. For example, the compounds of the embodiments do not include sugar alcohols and polyols such as trivalent or higher polyvalent sugar alcohols, such as glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol, but propylene glycol and poly (ethylene Other alcohols such as (glycol) (PEG) can also be used in dosage forms that do not include other agents used to supplement insufficient water solubility. In one aspect, an embodiment provides a subject NS3 inhibitor compound that is a capsule, tablet, or caplet dosage form, wherein the capsule, tablet, or caplet dosage form is superior in water solubility of the compound. Thus providing sufficient bioavailability. In some embodiments, the solubility of the subject compound allows for a dose of 1 mg or more of the drug compound per kg patient body weight.

Methods of Treatment Monotherapy The NS3 inhibitor compounds of the embodiments can be used in the treatment of acute or chronic HCV disease. In many embodiments, the NS3 inhibitor compound is about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month. To about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or for at least one year However, it may be administered over a longer period. NS3 inhibitor is administered 5 times daily, 4 times daily, 3 times daily, 2 times daily, daily, every other day, twice a week, 3 times a week, weekly, every other week, 3 times a month, or once a month can do. In other embodiments, the NS3 inhibitor compound is administered as a continuous infusion.

  In many embodiments, the NS3 inhibitor compound of the embodiments is administered orally.

  Regarding the above-described method of treating HCV disease in a patient, the NS3 inhibitor compound of the embodiment is administered to the patient at a dose of about 0.01 mg to about 100 mg per kg of the patient's body weight, divided into 1 to 5 times a day. can do. In some embodiments, the NS3 inhibitor compound is administered at a dosage of about 0.5 mg to about 75 mg per day per kilogram of the patient's body weight, divided into 1 to 5 times per day.

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

  One skilled in the art will readily appreciate that dose levels can vary depending on the particular NS3 inhibitor compound, the severity of the symptoms, and the subject's susceptibility to side effects. Preferred dosages for a given NS3 inhibitor compound can be readily determined by a person skilled in the art by various means. A preferred means is to measure the physiological potency of a given interferon receptor agonist.

  In many embodiments, the NS3 inhibitor compound is administered multiple times. For example, the NS3 inhibitor compound is about 1 day to about 1 week, about 2 weeks to about 4 weeks, about 1 month to about 2 months, about 2 months to about 4 months, about 4 months to about 6 months, about 6 months About 8 months, about 8 months to about 1 year, about 1 year to about 2 years, or about 2 years to about 4 years, or more, once a month, twice a month, 3 times a month Administered every other week, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, every other day, twice a day (qid), or three times a day (tid).

Combination therapy with ribavirin In some embodiments, the method is a combination therapy comprising administration of an NS3 inhibitor compound as described above and an effective amount of ribavirin. Ribavirin can be administered at a dosage of about 400 mg, about 800 mg, about 1000 mg, or about 1200 mg daily.

  In one embodiment, a variation of any of the above methods is provided to include co-administering a therapeutically effective amount of ribavirin to the patient during the desired course of treatment with an NS3 inhibitor compound.

  In another embodiment, any of the above methods are modified to include orally co-administering about 800 mg to about 1200 mg of ribavirin daily to the patient during the desired course of treatment with an NS3 inhibitor compound. Provide what you did.

  In another embodiment, during the desired course of treatment with an NS3 inhibitor compound (a) 1000 mg ribavirin daily if the patient's weight is less than 75 kg, or (b) if the patient's weight is 75 kg or more. Provides a modified version of any of the above methods to optionally divide the daily dose of ribavirin into two doses, including orally coadministering 1200 mg of ribavirin daily to the patient .

Combination Therapy with Levovirin In some embodiments, the method is a combination therapy comprising administration of an NS3 inhibitor compound as described above and an effective amount of levovirin. Levovirin is generally about 30 mg to about 60 mg, about 60 mg to about 125 mg, about 125 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 1200 mg, about 600 mg to about 1000 mg per day, or An amount in the range of about 700 to about 900 mg, or about 10 mg per day per kg body weight is administered. In some embodiments, levovirin is administered orally at a dosage of about 400, about 800, about 1000, or about 1200 mg daily during the desired course of treatment with an NS3 inhibitor compound.

Combination Therapy with Viramidine In some embodiments, the method is a combination therapy comprising administration of an NS3 inhibitor compound as described above and an effective amount of viramidine. Viramidine is generally about 30 mg to about 60 mg, about 60 mg to about 125 mg, about 125 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 1200 mg, about 600 mg to about 1000 mg per day, or An amount in the range of about 700 to about 900 mg, or about 10 mg per kg body weight is administered. In some embodiments, viramidine is administered orally at a dosage of about 800 or about 1600 mg per day during the desired course of treatment with an NS3 inhibitor compound.

Combination therapy with thymosin alpha In some embodiments, the method is a combination therapy comprising administration of an NS3 inhibitor compound as described above and an effective amount of thymosin alpha. Thymosin alpha (Zadaxin ™) is generally administered by subcutaneous injection. Thymosin alpha is 3 times a day, 2 times a day, daily, every other day, twice a week, 3 times a week, weekly, every other week, 3 times a month, or once a month during the desired course of treatment with an NS3 inhibitor compound. It can be administered almost continuously or continuously. In many embodiments, thymosin alpha is administered twice weekly for the desired period of treatment with an NS3 inhibitor compound.

  An effective dosage of thymosin alpha is about 0.5 mg to about 5 mg, such as about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5 mg, about It ranges from 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In certain embodiments, thymosin alpha is administered at a dosage of 1.0 mg or 1.6 mg.

  Thymosin alpha is about 1 day to about 1 week, about 2 weeks to about 4 weeks, about 1 month to about 2 months, about 2 months to about 4 months, about 4 months to about 6 months, about 6 months to about 8 It can be administered over a period of about 8 months to about 1 year, about 1 year to about 2 years, or about 2 years to about 4 years, or longer. In one embodiment, thymosin alpha is administered during the desired course of treatment with an NS3 inhibitor compound.

Combination Therapy with Interferon In many embodiments, the method is a combination therapy comprising administration of an NS3 inhibitor compound and an effective amount of an interferon receptor agonist as described above. In some embodiments, a compound of Formula I and a Type I or Type III interferon receptor agonist are co-administered with the therapeutic methods of the embodiments. Type I interferon receptor agonists suitable for use in the present invention include any interferon α (IFN-α). In certain embodiments, interferon alpha is PEGylated interferon alpha. In certain other embodiments, interferon α is a consensus interferon, such as INFERGEN® interferon alfacon-1. In yet another embodiment, interferon α is a mono-PEG (30 kD, linear) consensus interferon.

  Effective dosages of IFN-α range from about 3 μg to about 27 μg, from about 3 MU to about 10 MU, from about 90 μg to about 180 μg, or from about 18 μg to about 90 μg. Effective doses of Infergen® consensus IFN-α are 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 at a time. including. Effective doses of IFN-α2a and IFN-α2b range from 3 million units (MU) to 10 MU at a time. A therapeutic dose of PEGASYS® PEGylated IFN-α2a contains about 90 μg to 270 μg or about 180 μg of drug at a time. Effective doses of PEG-INTRON® PEGylated IFN-α2b contain an amount of drug of about 0.5 μg to 3.0 μg / kg body weight per dose. Effective doses of PEGylated consensus interferon (PEG-CIFN) comprise PEG-CIFN in an amount of about 18 μg to about 90 μg, or about 27 μg to about 60 μg, or about 45 μg of CIFN amino acid weight at a time. Effective doses of mono-PEG (30 kD, linear) CIFN comprise a dose of about 45 μg to about 270 μg, or about 60 μg to about 180 μg, or about 90 μg to about 120 μg of drug at a time. IFN-α can be administered daily, every other day, once a week, three times a week, every other week, three times a month, once a month, almost continuously or continuously.

  In many embodiments, the Type I or Type III interferon receptor agonist and / or Type II interferon receptor agonist is from about 1 day to about 7 days, or from about 1 week to about 2 weeks, or from about 2 weeks to about 3 Weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 It is administered over a period of from about 12 months to about 12 months, or at least one year, but may be administered over a longer period. The dosing regimen can include three times daily, twice daily, daily, every other day, twice weekly, three times weekly, weekly, every other week, three times a month, or once a month. In some embodiments, in any of the above-described methods, the desired dose of IFN-α is delivered daily, every other day, three times a week, twice a week, every week, every other week, during a desired treatment period, by bulk delivery. A method of subcutaneously administering to a patient three times a month or monthly, or subcutaneously to a patient by near continuous or continuous delivery per day is provided. In other embodiments, in any of the methods described above, a desired dose of PEGylated IFN-α (PEG-IFN-α) is administered weekly, biweekly, monthly, by bulk delivery during the desired treatment period. Or a method for subcutaneous administration to a patient monthly.

  In other embodiments, the NS3 inhibitor compound and the type II interferon receptor agonist are co-administered in the method of treatment of the embodiment. Suitable type II interferon receptor agonists for use herein include any interferon γ (IFN-γ).

Effective dosages of IFN-gamma is about 0.5 [mu] g / m ² ~ about 500 [mu] g / m ² depending on the size of the patient, typically may range from about ^{1.5μg / m 2 ~200μg / m 2} . This activity is based on 10 ⁶ international units (U) per 50 μg protein. IFN-γ can be administered daily, every other day, three times a week, or nearly continuously or continuously.

  In important specific embodiments, IFN-γ is administered to an individual in a unit dosage form of about 25 μg to about 500 μg, about 50 μg to about 400 μg, or about 100 μg to about 300 μg. In an important detailed embodiment, the dose is about 200 μg IFN-γ. In many important embodiments, IFN-γ1b is administered.

  When the dose is 200 μg IFN-γ per dose, the amount of IFN-γ per body weight is approximately 4.4 μg IFN-γ per kg body weight (assuming a weight range of about 45 kg to about 135 kg). ~ Range of IFN-γ of about 1.48 μg / kg body weight.

The body surface area of the subject individual generally ranges from about 1.33 m ² to about 2.50 m ² . Thus, in many embodiments, the IFN-γ dosage will range from about 150 μg / m ² to about 20 μg / m ² . For example, the dosage of IFN-γ is about 20 μg / m ² to about 30 μg / m ² , about 30 μg / m ² to about 40 μg / m ² , about 40 μg / m ² to about 50 μg / m ² , about 50 μg / m ² to about 60 μg / m ² , about 60 μg / m ² to about 70 μg / m ² , about 70 μg / m ² to about 80 μg / m ² , about 80 μg / m ² to about 90 μg / m ² , about 90 μg / m ² to About 100 μg / m ² , about 100 μg / m ² to about 110 μg / m ² , about 110 μg / m ² to about 120 μg / m ² , about 120 μg / m ² to about 130 μg / m ² , about 130 μg / m ² to about 140 μg / m ² , or in the range of about 140 μg / m ² to about 150 μg / m ² . In some embodiments, dosage groups range from about 25 μg / m ² to about 100 μg / m ² . In other embodiments, the dosage groups range from about 25 [mu] g / m ² ~ about 50 [mu] g / m ^2.

  In some embodiments, the Type I or Type III interferon receptor agonist is administered on a first dosing schedule followed by a second dosing schedule. A first dosage regimen for a Type I or Type III interferon receptor agonist (also referred to as an “introduction regimen”) generally involves administering a higher dose of a Type I or Type III interferon receptor agonist. For example, in the case of Infergen® consensus IFN-α (CIFN), the first dosing regimen includes administration of CIFN at about 9 μg, about 15 μg, about 18 μg, or about 27 μg. The first dosing regimen may include a single dosing event or may include at least two or more dosing events. Administration of the first regimen of type I or type III interferon receptor agonist can be performed daily, every other day, three times a week, every other week, three times a month, once a month, substantially continuously or continuously.

  Administration of the first regimen of type I or type III interferon receptor agonist occurs during a first period of time that can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.

  A second regimen (also referred to as “maintenance administration”) of a Type I or Type III interferon receptor agonist is generally one that administers a smaller amount of a Type I or Type III interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen includes 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 18 μg. The second dosing regimen may include a single dosing event, or at least two or more dosing events.

  Administration of the second regimen of type I or type III interferon receptor agonist can occur every other day, three times a week, every other week, three times a month, once a month, substantially continuously or continuously.

  Some embodiments of implementing an “introduction” / “maintenance” regimen of a Type I or Type III interferon receptor agonist include a “preparation” dose of a Type II interferon receptor agonist (eg, IFN-γ) It is. In these embodiments, the IFN-γ is about 1 day to about 14 days, about 2 days to about 10 days, or about 3 days to about 7 days before initiating treatment with a Type I or Type III interferon receptor agonist. Over the period of time. This period is called the “preparation” period.

  In some of these embodiments, the type II interferon receptor agonist treatment continues throughout the entire period of treatment with the type I or type III interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before treatment with the Type I or Type III interferon receptor agonist ends. In these embodiments, the total time (including the “preparation” phase) of the type II interferon receptor agonist treatment is about 2 days to about 30 days, about 4 days to about 25 days, about 8 days to about 20 days, From about 10 days to about 18 days, or from about 12 days to about 16 days. In yet another embodiment, type II interferon receptor agonist treatment is discontinued once type I or type III interferon receptor agonist treatment has begun.

  In other embodiments, the Type I or Type III interferon receptor agonist is administered on a single dosing schedule. For example, in the case of CIFN, CIFN doses generally range from about 3 μg to about 15 μg, or from about 9 μg to about 15 μg. The dose of a type I or type III interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times a month, once a month, or nearly continuously. The dose of a Type I or Type III interferon receptor agonist is administered over a period that can be, for example, at least about 24 weeks to at least about 48 weeks, or longer.

  Some embodiments of implementing a single dose regimen of a Type I or Type III interferon receptor agonist include a “preparation” dose of a II interferon receptor agonist (eg, IFN-γ). In these embodiments, the IFN-γ is about 1 day to about 14 days, about 2 days to about 10 days, or about 3 days to about 7 days before initiating treatment with a Type I or Type III interferon receptor agonist. Over the period of time. This period is called the “preparation” period. In some of these embodiments, the type II interferon receptor agonist treatment continues throughout the entire period of treatment with the type I or type III interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is discontinued before treatment with the Type I or Type III interferon receptor agonist ends. In these embodiments, the total time of treatment with a Type II interferon receptor agonist (including the “preparation” phase) is about 2 days to about 30 days, about 4 days to about 25 days, about 8 days to about 20 days. About 10 days to about 18 days, or about 12 days to about 16 days. In yet another embodiment, type II interferon receptor agonist treatment is discontinued once type I or type III interferon receptor agonist treatment has begun.

  In additional embodiments, the NS3 inhibitor compound, the type I or type III interferon receptor agonist, and the type II interferon receptor agonist are co-administered during the desired treatment period of the method of the embodiment. In some embodiments, the NS3 inhibitor compound, interferon alpha, and interferon gamma are co-administered during the desired treatment period of the embodiment method.

  In some embodiments, methods of using effective amounts of a type I or type III interferon receptor agonist, a type II interferon receptor agonist, and an NS3 inhibitor compound for treating HCV infection in a patient are provided. In some embodiments, methods of using effective amounts of IFN-α, IFN-γ, and NS3 inhibitor compounds in treating HCV infection in a patient are provided. In one embodiment, methods of using effective amounts of consensus IFN-α, IFN-γ, and NS3 inhibitor compounds in treating HCV infection in a patient are provided.

  In general, an effective amount of consensus interferon (CIFN) and IFN-γ suitable for use in the methods of the invention is 1 μg CIFN: 10 μg when CIFN and IFN-γ are both non-PEGylated and non-glycosylated species. Provided at a dose ratio of IFN-γ.

  In one embodiment, any of the above methods are modified to use an effective amount of INFERGEN® consensus IFN-α and IFN-γ for treating HCV infection in a patient, comprising an NS3 inhibitor compound During the desired treatment period, daily, every other day, three times a week, twice a week, weekly, every other week, month of IFN-γ dosage containing an amount of drug of about 10 μg to about 300 μg per dose of IFN-γ INFERGEN® containing drug in an amount of about 1 μg to about 30 μg per dose of INFERGEN® in combination with three, once a month, or nearly continuous or continuous subcutaneous administration per day Provided is a method comprising subcutaneously administering a dose to a patient daily, every other day, three times a week, twice a week, weekly, every other week, three times a month, once a month, or almost continuously or continuously per day .

  In another embodiment, any of the methods described above is modified to use an effective amount of INFERGEN® consensus IFN-α and IFN-γ for treating viral infection in a patient, comprising an NS3 inhibitor compound During a desired treatment period, daily, every other day, three times a week, twice a week, every week, every other week, an IFN-γ dose containing an amount of drug of about 10 μg to about 100 μg per dose of IFN-γ INFERGEN® containing drug in an amount of about 1 μg to about 9 μg per dose of INFERGEN®, combined with subcutaneous administration, three times a month, once a month, or almost continuously or daily ) Provide a method comprising administering a dose subcutaneously to a patient daily, every other day, three times a week, twice a week, weekly, every other week, three times a month, once a month, or almost continuously or continuously per day To do.

  In another embodiment, any of the methods described above is modified to use an effective amount of INFERGEN® consensus IFN-α and IFN-γ for treating viral infection in a patient, comprising an NS3 inhibitor compound During the desired treatment period, daily, every other day, three times a week, twice a week, every week, every other week, an IFN-γ dose containing an amount of drug of about 10 μg to about 50 μg per dose of IFN-γ INFERGEN® dosage amount containing approximately 1 μg of drug per dose of INFERGEN®, combined with almost continuous or continuous subcutaneous administration three times a month, once a month, or daily Is administered subcutaneously to a patient daily, every other day, three times a week, twice a week, weekly, every other week, three times a month, once a month, or almost continuously or continuously per day.

  In another embodiment, any of the methods described above is modified to use an effective amount of INFERGEN® consensus IFN-α and IFN-γ for treating viral infection in a patient, comprising an NS3 inhibitor compound During the desired treatment period, daily, every other day, three times a week, twice a week, every week, every other week, an IFN-γ dose containing an amount of drug of about 90 μg to about 100 μg per dose of IFN-γ INFERGEN® dosage amount containing approximately 9 μg of drug per dose of INFERGEN®, combined with almost continuous or continuous subcutaneous administration three times a month, once a month, or daily Is administered subcutaneously to a patient daily, every other day, three times a week, twice a week, weekly, every other week, three times a month, once a month, or almost continuously or continuously per day.

  In another embodiment, any of the methods described above is modified to use an effective amount of INFERGEN® consensus IFN-α and IFN-γ for treating a viral infection in a patient, comprising an NS3 inhibitor compound During the desired treatment period, daily, every other day, three times a week, twice a week, weekly, every other week, month of IFN-γ dose containing about 200 μg to about 300 μg of drug per dose of IFN-γ INFERGEN® dose containing about 30 μg of drug per dose of INFERGEN®, combined with almost continuous or continuous subcutaneous administration three times, once a month, or daily Daily, every other day, three times a week, twice a week, weekly, every other week, three times a month, once a month, or substantially continuously or continuously per day per day.

  In another embodiment, any of the above methods are modified to use an effective amount of PEGylated consensus IFN-α and IFN-γ for the treatment of viral infections in a patient, wherein an NS3 inhibitor compound provides a desired During the treatment period, daily, every other day, 3 times a week, twice a week subcutaneously, divided into several total weekly doses of IFN-γ containing about 30 μg to about 1,000 μg of drug per week, Or a dose of PEGylated consensus IFN-α (PEG-CIFN) comprising CIFN amino acid weight in an amount of about 4 μg to about 60 μg per dose of PEG-CIFN in combination with near continuous or continuous administration, Methods are provided that include subcutaneous administration to a patient weekly, biweekly, three times a month, or monthly.

  In another embodiment, any of the above methods are modified to use an effective amount of PEGylated consensus IFN-α and IFN-γ in the treatment of a viral infection in a patient, wherein an NS3 inhibitor compound provides a desired During the treatment period, daily, every other day, three times a week, twice a week, or almost continuous, divided into several daily total doses of IFN-γ containing about 100 μg to about 300 μg of drug per week Alternatively, a dose of PEGylated consensus IFN-α (PEG-CIFN) containing CIFN amino acid weight in an amount of about 18 μg to about 24 μg per dose of PEG-CIFN in conjunction with continuous subcutaneous administration can be administered weekly, biweekly A method comprising subcutaneously administering to a patient three times a month or monthly.

  In general, an effective amount of IFN-α2a or 2b or 2c and IFN-γ suitable for use in the methods of the invention is that both IFN-α2a or 2b or 2c and IFN-γ are non-PEGylated and non-glycosylated species In some cases, a dose ratio of 1 million units (MU) of IFN-α2a or 2b or 2c: 30 μg of IFN-γ is provided.

  In another embodiment, any of the above methods are modified to use an effective amount of IFN-α2a or 2b or 2c and IFN-γ in the treatment of a viral infection in a patient, wherein the desired treatment with an NS3 inhibitor compound Almost continuous daily, every other day, twice a week, twice a week, or daily for IFN-γ doses containing about 30 μg to about 600 μg of drug per dose of IFN-γ Alternatively, IFN-α2a, 2b, or 2c, containing a dose of about 1 MU to about 20 MU per dose of IFN-α2a, 2b, or 2c, in combination with continuous subcutaneous administration, every day, every other day A method comprising subcutaneously administering to a patient three times a week, twice a week, or substantially continuously or continuously per day.

  In another embodiment, any of the above methods are modified to use an effective amount of IFN-α2a or 2b or 2c and IFN-γ in the treatment of a viral infection in a patient, wherein the desired treatment with an NS3 inhibitor compound Almost continuous or continuous daily, every other day, twice a week, twice a week, or daily of an IFN-γ dose containing approximately 100 μg of drug per dose of IFN-γ during the treatment period IFN-α2a, 2b, or 2c containing about 3 MU of drug per dose of IFN-α2a, 2b, or 2c, daily, every other day, 3 times a week A method is provided that includes subcutaneously administering to a patient twice, or approximately continuously or continuously per day.

  In another embodiment, any of the above methods are modified to use an effective amount of IFN-α2a or 2b or 2c and IFN-γ in the treatment of a viral infection in a patient, wherein the desired treatment with an NS3 inhibitor compound Almost continuous or continuous daily, every other day, twice a week, twice a week, or daily of an IFN-γ dose containing approximately 300 μg of drug per dose of IFN-γ during the treatment period IFN-α2a, 2b, or 2c containing about 10 MU of drug per dose of IFN-α2a, 2b, or 2c, daily, every other day, 3 times a week, A method is provided that includes subcutaneously administering to a patient twice, or approximately continuously or continuously per day.

  In another embodiment, any of the above methods is modified to use an effective amount of PEGASYS® PEGylated IFN-α2a and IFN-γ in the treatment of a viral infection in a patient comprising NS3 inhibition Daily, every other day, 3 times a week, or 2 times a week, divided into several total weekly doses of IFN-γ containing about 30 μg to about 1,000 μg of drug per week during the desired treatment period of the compound Multiple doses of PEGASYS® containing about 90 μg to about 360 μg of drug per dose of PEGASYS®, combined with multiple subcutaneous administrations, or nearly continuous or continuous administration, weekly A method comprising subcutaneously administering to a patient every other week, three times a month, or monthly.

  In another embodiment, any of the above methods is modified to use an effective amount of PEGASYS® PEGylated IFN-α2a and IFN-γ in the treatment of a viral infection in a patient comprising NS3 inhibition Daily, every other day, three times a week, or twice a week divided into several weekly doses of the total weekly dose of IFN-γ containing about 100 μg to about 300 μg of drug per week during the desired treatment period of the compound A dose of PEGASYS® containing about 180 μg of drug per dose of PEGASYS®, combined with subcutaneous or near continuous or continuous administration, weekly, biweekly, monthly Methods are provided that include subcutaneous administration to a patient three times or monthly.

  In another embodiment, any of the above methods are modified to use an effective amount of PEG-INTRON® PEGylated IFN-α2b and IFN-γ in treating a viral infection in a patient, Daily, every other day, three times a week, or divided into several doses of the total weekly dose of IFN-γ containing about 30 μg to about 1000 μg of drug per week during the desired treatment period of NS3 inhibitor compound PEG-INTRON containing drug in an amount of about 0.75 μg to about 3.0 μg per dose of PEG-INTRON® per kg body weight, combined with two subcutaneous administrations, or almost continuous or continuous administration A method is provided comprising subcutaneously administering a dose of ® to a patient every week, every other week, three times a week, or monthly.

  In another embodiment, any of the above methods are modified to use an effective amount of PEG-INTRON® PEGylated IFN-α2b and IFN-γ in treating a viral infection in a patient, Daily, every other day, three times a week, or weekly divided into several total weekly doses of IFN-γ containing an amount of drug of about 100 μg to about 300 μg per week during the desired treatment period of the NS3 inhibitor compound PEG-INTRON® containing approximately 1.5 μg of drug per kg body weight per kg body weight, combined with two subcutaneous administrations, or almost continuous or continuous administration ) A method is provided comprising administering a dose subcutaneously to a patient weekly, biweekly, three times a week, or monthly.

  In one embodiment, an effective dosage of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg subcutaneously administered daily or three times a week and ribavirin administered orally daily is administered to a person suffering from HCV infection A variation of any of the above methods is provided to include administering during a 48 week treatment period. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg subcutaneously administered daily or 3 times weekly, and Actimmune® human IFN-γ1b 50 μg subcutaneously administered 3 times weekly. Thus, a regimen of daily oral administration of ribavirin is provided that modifies any of the methods described above to include administering to a person suffering from HCV infection during a 48-week treatment period. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg is administered daily or subcutaneously three times a week, and Actimmune® human IFN-γ1b 100 μg is administered subcutaneously three times a week. Thus, a regimen of daily oral administration of ribavirin is provided that modifies any of the methods described above to include administering to a person suffering from HCV infection during a 48-week treatment period. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg subcutaneously administered daily or 3 times weekly, and Actimmune® human IFN-γ1b 50 μg subcutaneously administered 3 times weekly. A dosing regimen is provided that modifies any of the methods described above to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective amount of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg is administered daily or subcutaneously three times a week, and Actimmune® human IFN-γ1b 100 μg is administered subcutaneously three times a week. A dosing regimen is provided that modifies any of the methods described above to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective amount of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg are administered daily or subcutaneously 3 times a week, and Actimmune® human IFN-γ1b 25 μg is administered subcutaneously 3 times a week. Thus, a regimen of daily oral administration of ribavirin is provided that modifies any of the methods described above to include administering to a person suffering from HCV infection during a 48-week treatment period. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg are administered daily or subcutaneously three times a week, and Actimmune® human IFN-γ1b 200 μg is administered subcutaneously three times a week. Thus, a regimen of daily oral administration of ribavirin is provided that modifies any of the methods described above to include administering to a person suffering from HCV infection during a 48-week treatment period. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg are administered daily or subcutaneously 3 times a week, and Actimmune® human IFN-γ1b 25 μg is administered subcutaneously 3 times a week. A dosing regimen is provided that modifies any of the methods described above to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective amount of NS3 inhibitor and INFERGEN® consensus IFN-α 9 μg are administered daily or subcutaneously three times a week, and Actimmune® human IFN-γ1b 200 μg is administered subcutaneously three times a week. A dosing regimen is provided that modifies any of the methods described above to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective regimen of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 100 μg administered subcutaneously every 10 days or weekly and ribavirin daily administered orally is affected by HCV infection. Are provided with a modification of any of the methods described above to include administration during a 48-week treatment period. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 100 μg are administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 50 μg is administered weekly. A regimen of 3 subcutaneous administrations and daily oral administration of ribavirin modified to one of the above methods to include administration to a person with HCV infection during a 48-week treatment period provide. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 100 μg is administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 100 μg is administered weekly. A regimen of 3 subcutaneous administrations and daily oral administration of ribavirin modified to one of the above methods to include administration to a person with HCV infection during a 48-week treatment period provide. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 100 μg are administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 50 μg is administered weekly. A dosage regimen of 3 subcutaneous administrations is provided that modifies any of the above methods to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective amount of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 100 μg is administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 100 μg is administered weekly. A dosage regimen of 3 subcutaneous administrations is provided that modifies any of the above methods to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective regimen of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 150 μg administered subcutaneously every 10 days or weekly and ribavirin daily orally administered to HCV infection Affected persons are provided with a modification of any of the methods described above to include administration during a 48 week treatment period. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 150 μg is administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 50 μg is administered weekly. A regimen of 3 subcutaneous administrations and daily oral administration of ribavirin modified to one of the above methods to include administration to a person with HCV infection during a 48-week treatment period provide. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and mono-PEG (30 kD, linear) consensus IFN-α 150 μg is administered subcutaneously every 10 days or weekly and Actimmune® human IFN-γ1b 100 μg is administered weekly. A regimen of 3 subcutaneous administrations and daily oral administration of ribavirin modified to one of the above methods to include administration to a person with HCV infection during a 48-week treatment period provide. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 150 μg is administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 50 μg is administered weekly. A dosage regimen of 3 subcutaneous administrations is provided that modifies any of the above methods to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective amount of NS3 inhibitor and mono-PEG (30 kD, linear) consensus IFN-α 150 μg is administered subcutaneously every 10 days or weekly and Actimmune® human IFN-γ1b 100 μg is administered weekly. A dosage regimen of 3 subcutaneous administrations is provided that modifies any of the above methods to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective regimen of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 200 μg administered subcutaneously every 10 days or weekly and ribavirin daily administered orally is affected by HCV infection. Are provided with a modification of any of the methods described above to include administration during a 48-week treatment period. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 200 μg is administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 50 μg is administered weekly. A regimen of 3 subcutaneous administrations and daily oral administration of ribavirin modified to one of the above methods to include administration to a person with HCV infection during a 48-week treatment period provide. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and mono-PEG (30 kD, linear) consensus IFN-α 200 μg is administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 100 μg is administered weekly. A regimen of 3 subcutaneous administrations and daily oral administration of ribavirin modified to one of the above methods to include administration to a person with HCV infection during a 48-week treatment period provide. In this embodiment, ribavirin is administered to a person whose 1000 mg amount is less than 75 kg and to a person whose 1200 mg amount is 75 kg or more.

  In one embodiment, an effective amount of NS3 inhibitor and monoPEG (30 kD, linear) consensus IFN-α 200 μg is administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 50 μg is administered weekly. A dosage regimen of 3 subcutaneous administrations is provided that modifies any of the above methods to include administering to a person suffering from HCV infection during a 48-week treatment period.

  In one embodiment, an effective amount of NS3 inhibitor and mono-PEG (30 kD, linear) consensus IFN-α 200 μg is administered subcutaneously every 10 days or weekly, and Actimmune® human IFN-γ1b 100 μg is administered weekly. A dosage regimen of 3 subcutaneous administrations is provided that modifies any of the above methods to include administering to a person suffering from HCV infection during a 48-week treatment period.

  Any of the methods described above comprising administering an NS3 inhibitor, a type I interferon receptor agonist (e.g., IFN-α), and a type II interferon receptor agonist (e.g., IFN-γ) comprises a TNF-α antagonist (e.g., Administration of an effective amount of a TNF-α antagonist other than pirfenidone or a pirfenidone analog). Typically, it is not limited to TNF-α antagonists suitable for use in such combination therapy, but includes ENBREL®, REMICADE®, and HUMIRA ™.

  In one embodiment, for treating HCV infection in a patient, an effective amount of ENBREL®; an effective amount of IFN-α; an effective amount of INF-γ; and an effective amount of NS3 inhibitor are administered for a desired treatment period. About 0.1 μg to about 23 mg, about 0.1 μg to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 100 μg, about 100 μg to about 1 mg, about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to ENBREL® doses containing ENBREL® in an amount of about 15 mg, about 15 mg to about 20 mg, or about 20 mg to about 23 mg daily, every other day, three times a week, twice a week, weekly, every other week, week A method of use is provided that includes subcutaneously administering to a patient three times, once a month, or once every other month, or approximately continuously or continuously per day.

  In one embodiment, an effective amount of REMICADE®; an effective amount of IFN-α with or without an effective amount of INF-γ; and an effective amount of NS3 inhibitor for the treatment of HCV infection in a patient. About 0.1 mg / kg to about 4.5 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.0 mg / kg, about 1.0 mg / kg to About 1.5 mg / kg, about 1.5 mg / kg to about 2.0 mg / kg, about 2.0 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 3.0 mg / kg, about 3.0 mg / kg to about 3.5 REMICADE® dosage containing REMICADE® in an amount of mg / kg, about 3.5 mg / kg to about 4.0 mg / kg, or about 4.0 mg / kg to about 4.5 mg / kg daily, every other day, Uses comprising intravenous administration to a patient three times a week, twice a week, weekly, biweekly, three times a week, once a month, or once every other month, or almost continuously or continuously daily I will provide a.

  In one embodiment, an effective amount of HUMIRA®; an effective amount of IFN-α; an effective amount of IFN-γ; and an effective amount of NS3 inhibitor for treating HCV infection in a patient during a desired treatment period. About 0.1 μg to about 35 mg, about 0.1 μg to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 100 μg, about 100 μg to about 1 mg, about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about HUMIRATM dosages containing HUMIRATM in an amount of 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, or about 30 mg to about 35 mg daily, every other day, 3 times a week A method of use is provided comprising subcutaneously administering to a patient twice a week, weekly, biweekly, three times a week, once a month, or once every other month, or almost continuously or continuously daily.

Combination Therapy with Pirfenidone In many embodiments, the method provides a combination therapy comprising administering an NS3 inhibitor compound and an effective amount of pirfenidone or a pirfenidone analog as described above. In some embodiments, the NS3 inhibitor compound, one or more type I interferon receptor agonist (s), and pirfenidone or pirfenidone analog are co-administered in the therapeutic methods of the invention. In certain embodiments, one NS3 inhibitor compound, a type I interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are administered in combination. In other embodiments, an NS3 inhibitor compound, a type I interferon receptor agonist, a type II interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are administered in combination. Type I interferon receptor agonists suitable for use herein include any IFN-α, such as interferon α2a, interferon α2b, interferon alphacon-1, and PEGylated IFN-αs, and PEG The PEGylated IFN-αs include PEGylated interferon-α2a, PEGylated interferon-α2b, and PEGylated consensus interferons, and the PEGylated consensus interferons include monoPEG (30 kD, linear) consensus interferon. Type II interferon receptor agonists suitable for use herein contain any interferon γ.

  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, six times a week, daily, or daily. Divided into 1 to 5 times a day, about 1 day to about 1 week, about 2 weeks to about 4 weeks, about January to about February, about February to about 4 months, about 4 months to about Can be administered for periods of 6 months, about 6 months to about 8 months, about 8 months to about 1 year, about 1 year to about 2 years, or about 2 years to about 4 years or longer .

  Effective doses of pirfenidone or special pirfenidone analogs are based on body weight ranging from about 5 mg / kg / day to about 125 mg / kg / day, administered orally in divided doses from 1 to 5 times per day Doses, or fixed doses of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day. Other doses and dosage forms of pirfenidone and special pirfenidone analogs suitable for use in the treatment of fibrosis are described in U.S. Patent Nos. 5310562, 5518729, 5716632, and 6090822. The

  In one embodiment, a modification of any of the above methods to include administering to a patient a therapeutically effective amount of pirfenidone or pirfenidone analog during the desired therapeutic unit with NS3 inhibitor compound treatment. I will provide a.

Combination therapy with TNF-α antagonists In many embodiments, the methods administer an effective amount of the NS3 inhibitor compound and an effective amount of a TNF-α antagonist in combination therapy for the treatment of HCV infection. To provide a combination therapy.

  Effective doses of the TNF-α antagonist are from 0.1 μg to 40 mg per dose, for example, from about 0.1 μg to about 0.5 μg per dose, from about 0.5 μg to about 1.0 μg per dose, about per dose 1.0 μg to about 5.0 μg, about 5.0 μg to about 10 μg per dose, about 10 μg to about 20 μg per dose, about 20 μg to about 30 μg per dose, about 30 μg to about 40 μg per dose, dose 1 About 40 μg to about 50 μg per dose, about 50 μg to about 60 μg per dose, about 60 μg to about 70 μg per dose, about 70 μg to about 80 μg per dose, about 80 μg to 100 μg per dose, single dose About 100 μg to about 150 μg per dose, about 150 μg to about 200 μg per dose, about 200 μg to about 250 μg per dose, about 250 μg to about 300 μg per dose, about 300 μg to about 400 μg per dose, single dose About 400 μg to 500 μg per dose, about 500 μg to about 600 μg per dose, about 600 μg to about 700 μg per dose About 700 μg to about 800 μg per dose, about 800 μg to about 900 μg per dose, about 900 μg to about 1000 μg per dose, about 1 mg to about 10 mg per dose, about 10 mg to about 15 mg per dose, About 15 mg to about 20 mg per dose, about 20 mg to about 25 mg per dose, about 25 mg to about 30 mg per dose, about 30 mg to about 35 mg per dose, or about 35 mg to about 40 mg per dose It is.

  In some embodiments, the effective dosage of a TNF-α antagonist is expressed as mg / kg body weight. In these embodiments, an effective dosage of a TNF-α antagonist is about 0.1 mg / kg body weight to about 10 mg / kg body weight, such as about 0.1 mg / kg body weight to about 0.5 mg / kg body weight, about 0.5 mg / kg body weight. kg body weight to 1.0 mg / kg body weight, about 1.0 mg / kg body weight to about 2.5 mg / kg body weight, about 2.5 mg / kg body weight to about 5.0 mg / kg body weight, about 5.0 mg / kg body weight to about 7.5 mg / kg body weight Or about 7.5 mg / kg body weight to about 10 mg / kg body weight.

  In many embodiments, the TNF-α antagonist is about 1 to 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month. Administered for about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least 1 year However, it can be administered for a longer period. TNF-α antagonist can be administered three times a day, twice a day, daily, every other day, twice a week, three times a week, weekly, every other week, three times a week, once a month, almost continuously or continuously is there.

  In many embodiments, the TNF-α antagonist is administered in multiple doses. For example, TNF-α antagonists are once a month, twice a month, three times a week, every other week, every week, twice a week, three times a week, four times a week, five times a week, six times a week, every other day, every day, one day 2 times or 3 times a day, substantially continuously or continuously, about 1 day to about 1 week, about 2 weeks to about 4 weeks, about 1 month to about 2 months, about 2 months to about Administer for a period of about April, about April to about June, about June to about August, about August to about 1 year, about 1 year to about 2 years, or about 2 years to about 4 years or more .

  The TNF-α antagonist and NS3 inhibitor are generally administered in separate formulations. TNF-α antagonist and NS3 inhibitor are about the same, or 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 Within about 4 days, about 7 days, or about 2 weeks.

  In one embodiment, an effective amount of a TNF-α antagonist and an effective amount of NS3 inhibitor for treating HCV infection in a patient is administered at about 0.1 μg per dose of TNF-α antagonist during the desired period of treatment with an NS3 inhibitor compound. A method of use comprising subcutaneously administering to a patient a TNF-α antagonist dosage comprising an amount of about 40 mg daily, every other day, three times a week, or twice a week, or almost continuously or continuously per day I will provide a.

  In one embodiment, an effective amount of ENBREL® and an effective amount of NS3 inhibitor for treating an HCV infection in a patient is administered at a dose of about ENBREL® per dose during a desired treatment period with an NS3 inhibitor compound. 0.1 μg to about 23 mg, about 0.1 μg to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 100 μg, about 100 μg to about 1 mg, about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about ENBREL® doses containing amounts of 15 mg to about 20 mg, or about 20 mg to about 23 mg daily, every other day, three times a week, twice a week, weekly, every other week, three times a week, once a month, or every other month A method of use is provided that includes subcutaneous administration to a patient once, or substantially continuously or continuously per day.

  In one embodiment, an effective amount of REMICADE® and an effective amount of NS3 inhibitor for the treatment of HCV infection in a patient are administered at about a REMICADE® dose per desired dose during a desired treatment period with an NS3 inhibitor compound. 0.1 mg / kg to about 4.5 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1.0 mg / kg, about 1.0 mg / kg to about 1.5 mg / kg, about 1.5 mg / kg to about 2.0 mg / kg, about 2.0 mg / kg to about 2.5 mg / kg, about 2.5 mg / kg to about 3.0 mg / kg, about 3.0 mg / kg to about 3.5 mg / kg, about 3.5 mg / kg REMICADE® dosages including amounts of ~ 4.0 mg / kg, or 4.0 mg / kg to 4.5 mg / kg daily, every other day, twice a week, twice a week, weekly, every other week, three times a week A method of use comprising intravenous administration to a patient once a month, once every other month, or approximately continuously or continuously per day.

  In one embodiment, an effective amount of HUMIRATM and an effective amount of NS3 inhibitor for treating HCV infection in a patient is about 0.1 μg per dose of HUMIRATM during a desired period of treatment with an NS3 inhibitor compound. About 35 mg, about 0.1 μg to about 1 μg, about 1 μg to about 10 μg, about 10 μg to about 100 μg, about 100 μg to about 1 mg, about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 15 mg HUMIRATM dosages containing amounts of about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, or about 30 mg to about 35 mg daily, every other day, twice a week, twice a week, weekly, every other week, week 3 A method of use is provided that includes subcutaneously administering to a patient once, once a month, or once every other month, or approximately continuously or continuously per day.

Combination therapy with thymosin-α In many embodiments, the method comprises administering an effective amount of the NS3 inhibitor compound and an effective amount of thymosin α to treat HCV infection. Provide combination therapy for the disease.

  Effective amounts of thymosin alpha are about 0.5 mg to about 5 mg, such as about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about 2.0 mg, about 2.0 mg to about 2.5 mg, about 2.5 mg. To about 3.0 mg, about 3.0 mg to about 3.5 mg, about 3.5 mg to about 4.0 mg, about 4.0 mg to about 4.5 mg, or about 4.5 mg to about 5.0 mg. In particular embodiments, thymosin alpha is administered at a dose comprising an amount of 1.0 mg or 1.6 mg.

  In one embodiment, an effective amount of ZADAXIN® thymosin alpha and an effective amount of NS3 inhibitor for treating HCV infection in a patient is administered at about 1.0 mg to about about 1.0 mg per dose during the desired period of treatment with an NS3 inhibitor compound. A method of use is provided comprising subcutaneously administering to a patient a ZADAXIN ™ dose comprising an amount of 1.6 mg twice a week.

TNF-α antagonist and interferon combination therapy In some embodiments, a person with HCV infection is treated with an effective amount of an NS3 inhibitor, and an effective amount of a TNF-α antagonist, and an effective amount of one or more interferons. A method of treatment comprising administering is provided.

  In one embodiment, any of the above methods are modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist for treating HCV infection in a patient, wherein the desired by an NS3 inhibitor compound Daily, every other day, every other day, three times a week, or twice a week subcutaneously, or per day, during the treatment period of TNF-α antagonist, including an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist IFN-γ doses containing about 10 μg to about 300 μg of drug per dose of IFN-γ daily, every other day, 3 times a week, 2 times a week, combined with almost continuous or continuous administration at A method comprising subcutaneously administering to a patient weekly, biweekly, three times a week, once a month, or substantially continuously or continuously per day.

  In one embodiment, any of the above methods are modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist for treating HCV infection in a patient, wherein the desired by an NS3 inhibitor compound Daily, every other day, every other day, three times a week, or twice a week subcutaneously, or per day, during the treatment period of TNF-α antagonist, including an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist Daily, every other day, 3 times a week, 2 times a week, with a dose of 10 μg to about 100 μg of drug per dose of IFN-γ administration combined with almost continuous or continuous administration at A method comprising subcutaneously administering to a patient weekly, biweekly, three times a week, once a month, or substantially continuously or continuously per day.

  In another embodiment, any of the above methods are modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient, comprising an NS3 inhibitor compound Daily, every other day, three times weekly, or twice weekly subcutaneous administration of a TNF-α antagonist dose comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during the desired treatment period, or Daily, every other day, every week divided into several daily total doses of IFN-γ containing approximately 30 μg to about 1000 μg of drug per week, combined with almost continuous or continuous administration per day A method is provided comprising administering subcutaneously three times, three times a month, or substantially continuously or continuously to a patient per day.

  In another embodiment, any of the above methods are modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient, comprising an NS3 inhibitor compound Daily, every other day, three times weekly, or twice weekly subcutaneous administration of a TNF-α antagonist dose comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during the desired treatment period, or Daily, every other day, every week divided into several daily total doses of IFN-γ containing approximately 100 μg to about 300 μg of drug per week, combined with almost continuous or continuous administration per day A method is provided that includes subcutaneously administering three times, twice weekly, or administering to a patient approximately continuously or continuously per day.

  In one embodiment, any of the above methods is modified to use an effective amount of INFERGEN® consensus IFN-α and an effective amount of a TNF-α antagonist for the treatment of HCV infection in a patient. A daily, every other day, three times a week, or twice a week of a TNF-α antagonist dose comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during the desired treatment period with an NS3 inhibitor compound Or a dose of INFERGEN® containing about 1 μg to about 30 μg of drug per dose of INFERGEN® in combination with daily or near continuous or continuous administration per day. Daily, every other day, three times a week, twice a week, weekly, every other week, three times a month, once a month, or administered to a patient almost continuously or continuously per day To do.

  In one embodiment, any of the above methods is modified to use an effective amount of INFERGEN® consensus IFN-α and an effective amount of a TNF-α antagonist for the treatment of HCV infection in a patient. A daily, every other day, three times a week, or twice a week of a TNF-α antagonist dose comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during the desired treatment period with an NS3 inhibitor compound Infergen® doses containing about 1 μg to about 9 μg of drug per dose of INFERGEN® combined with subcutaneous administration, or almost continuous or continuous administration per day Daily, every other day, three times a week, twice a week, weekly, every other week, three times a month, once a month, or almost continuously or continuously per day To do.

  In another embodiment, any of the above methods is modified to use an effective amount of PEGylated consensus IFN-α and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient, comprising NS3 Daily, every other day, three times weekly, or twice weekly subcutaneously of a TNF-α antagonist dose comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during the desired treatment period with the inhibitor compound PEGylated consensus IFN-α (PEG-CIFN) comprising CIFN amino acids in an amount of about 4 μg to about 60 μg per dose of PEG-CIFN in combination with administration, or near continuous or continuous administration per day A method is provided that includes administering a dose subcutaneously to a patient weekly, biweekly, three times a month, or monthly.

  In another embodiment, any of the above methods is modified to use an effective amount of PEGylated consensus IFN-α and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient, comprising NS3 Daily, every other day, three times weekly, or twice weekly subcutaneous administration of a TNF-α antagonist dose comprising about 0.1 μg to about 40 mg per dose of TNF-α antagonist during the desired treatment period with the inhibitor compound PEGylated consensus IFN-α (PEG-CIFN) comprising CIFN amino acids in an amount of about 18 μg to about 24 μg per dose of PEG-CIFN, in conjunction with almost continuous or continuous administration per day Is administered subcutaneously to a patient every week, every other week, three times a month, or monthly.

  In another embodiment, any of the above methods are modified to use an effective amount of IFN-α2a or IFN-α2b or IFN-α2c and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient. A TNF-α antagonist dose comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during a desired treatment period with an NS3 inhibitor compound, daily, every other day, three times a week, or weekly Contains about 1 MU to about 20 MU of drug per dose of IFN-α2a, IFN-α2b, or IFN-α2c, combined with two subcutaneous administrations or almost continuous or continuous administration per day A method comprising administering a dose of IFN-α2a, IFN-α2b or IFN-α2c daily, every other day, three times a week, twice a week, or substantially continuously or continuously to a patient per day I will provide a.

  In another embodiment, any of the above methods modified to use an effective amount of IFN-α2a or IFN-α2b or IFN-α2c and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient A TNF-α antagonist dosage comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during a desired treatment period with an NS3 inhibitor compound, daily, every other day, three times a week, or weekly IFN-α2a containing about 3 MU of drug per dose of IFN-α2a, IFN-α2b or IFN-α2c, combined with two subcutaneous administrations, or almost continuous or continuous administration per day, Provided is a method comprising subcutaneously administering a dose of IFN-α2b or IFN-α2c daily, every other day, three times a week, twice a week, or substantially continuously or continuously per day .

  In another embodiment, any of the above methods are modified to use an effective amount of IFN-α2a or IFN-α2b or IFN-α2c and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient. Wherein a TNF-α antagonist dose comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during a desired treatment period of an NS3 inhibitor compound is administered daily, every other day, three times a week, or two weeks IFN-α2a containing about 10 MU of drug per dose of IFN-α2a, IFN-α2b or IFN-α2c, in combination with multiple subcutaneous administrations, or almost continuous or continuous administration per day, A method is provided comprising administering a dose of IFN-α2b or IFN-α2c daily, every other day, three times a week, twice a week, or to a patient substantially continuously or continuously per day.

  In another embodiment, any of the above methods have been modified to use an effective amount of PEGASYS® PEGylated IFN-α2a and an effective amount of a TNF-α antagonist for treating a viral infection in a patient. Every day, every other day, three times a week, or twice a week for a TNF-α antagonist dose comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during the desired treatment period with an NS3 inhibitor compound A dose of PEGASYS® containing about 90 μg to about 360 μg of drug per dose of PEGASYS® dose in combination with subcutaneous administration of, or almost continuous or continuous administration per day Methods are provided that include subcutaneous administration to a patient weekly, biweekly, three times a month, or monthly.

  In another embodiment, any of the above methods are modified to use an effective amount of PEGASYS® PEGylated IFN-α2a and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient. Patients who receive a PEGASYS® dose containing about 180 μg of drug per dose of PEGASYS® dose during weekly, biweekly, monthly, or monthly during the desired treatment period with an NS3 inhibitor compound Daily, every other day, three times weekly, or twice weekly subcutaneous doses of a TNF-α antagonist dose comprising about 0.1 μg to about 40 mg per dose of TNF-α antagonist, including 1 A PEGASYS® dose containing approximately 180 μg of drug per dose of PEGASYS® dose combined with near continuous or continuous administration per day, weekly, biweekly, monthly, or monthly A method is provided that includes subcutaneously administering to a patient.

  In another embodiment, a modification of any of the above methods to use an effective amount of PEG-INTRON® PEGylated IFN-α2b and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient. A TNF-α antagonist dosage comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during a desired treatment period with an NS3 inhibitor compound, daily, every other day, three times a week, or weekly In combination with two subcutaneous doses, or almost continuous or continuous administration per day, a dose of about 0.75 μg to about 3.0 μg of body weight per kg of PEG-INTRON (registered trademark) Provided is a method comprising subcutaneously administering to a patient a weekly, biweekly, three times monthly, or monthly dose of PEG-INTRON® comprising.

  In another embodiment, any of the above methods were modified to use an effective amount of PEG-INTRON® PEGylated INF-α2b and an effective amount of a TNF-α antagonist for the treatment of a viral infection in a patient. A TNF-α antagonist dosage comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-α antagonist during a desired treatment period with an NS3 inhibitor compound, daily, every other day, three times a week, Or PEG containing 1 kg body weight, approximately 1.5 μg of drug per dose of PEG-INTRON®, combined with subcutaneous administration twice a week, or almost continuous or continuous administration per day A method is provided that includes administering a dose of INTRON® subcutaneously to a patient weekly, biweekly, three times a month, or monthly.

Combination therapy with other antiviral drugs
Other agents such as NS3 helicase inhibitors of HCV are also drugs of interest in combination therapy and are contemplated for use in the combination therapy described herein. Ribozymes such as Heptazyme ™ and phosphorothioate oligonucleotides that are complementary to the HCV protein sequence and inhibit the expression of the viral core protein are also suitable for use in the combination therapy described herein. .

  In some embodiments, the additional antiviral agent (s) is administered during the entire therapeutic unit period of treatment with the NS3 inhibitor compound of the present invention to coincide the start and end times of treatment. In other embodiments, the additional antiviral agent (s) is administered in a period that overlaps with treatment with the NS3 inhibitor compound, e.g., the additional antiviral agent (s) treatment is initiated prior to initiation of treatment with the NS3 inhibitor compound. Completed before the end of treatment with an NS3 inhibitor compound; treatment with an additional antiviral agent (s) begins after the start of treatment with an NS3 inhibitor compound and ends after the end of NS3 inhibitor compound treatment; an additional antiviral agent Treatment with (s) begins after treatment with NS3 inhibitor compound and ends before treatment with NS3 inhibitor compound; or treatment with additional antiviral agent (s) begins before treatment with NS3 inhibitor compound begins And terminated after completion of NS3 inhibitor compound.

  NS3 inhibitor compound together with one or more antiviral drugs (i.e. separate formulations simultaneously; same formulations simultaneously; separate formulations within about 48 hours, within about 36 hours, within about 24 hours) Within about 16 hours, within about 12 hours, within about 8 hours, within about 4 hours, within about 2 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes Administration) It is possible to administer.

  As a non-limiting example, any of the methods described above characterized by an IFN-α dosing regimen can be used to convert a subject IFN-α dosing regimen into a single dose during the desired treatment period with an NS3 inhibitor compound. MonoPEG (30 kD, linear), administered subcutaneously once weekly, once every 8 days, or once every 10 days, with monoPEG (30 kD, linear) consensus containing 100 μg of drug per dose It can be modified to replace the consensus IFN-α dosing schedule.

  As a non-limiting example, any of the methods described above characterized by an IFN-α dosing regimen can be used to convert a subject IFN-α dosing regimen into a single dose during the desired treatment period with an NS3 inhibitor compound. MonoPEG (30 kD, linear), administered subcutaneously once weekly, once every 8 days, or once every 10 days, with a mono-PEG (30 kD, linear) consensus containing 150 μg of drug per dose It can be modified to replace the consensus IFN-α dosing schedule.

  As a non-limiting example, any of the methods described above characterized by an IFN-α dosing regimen can be used to convert a subject IFN-α dosing regimen into a single dose during the desired treatment period with an NS3 inhibitor compound. MonoPEG (30 kD, linear), administered subcutaneously once weekly, once every 8 days, or once every 10 days, with monoPEG (30 kD, linear) consensus containing 200 μg of drug per dose It can be modified to replace the consensus IFN-α dosing schedule.

  As a non-limiting example, any of the methods described above characterized by an IFN-α dosing regimen can be used to convert a subject IFN-α dosing regimen into a single dose during the desired treatment period with an NS3 inhibitor compound. INFERGEN®, which is interferon alfacon-1 containing 9 μg of drug per dose, is administered to INFERGEN®, which is interferon alfacon-1, administered subcutaneously once a day or 3 times a week It can be changed to replace.

  As a non-limiting example, any of the methods described above characterized by an IFN-α dosing regimen can be used to convert a subject IFN-α dosing regimen into a single dose during the desired treatment period with an NS3 inhibitor compound. INFERGEN®, an interferon alfacon-1 containing 15 μg of drug per dose, is administered to INFERGEN®, an interferon alfacon-1 subcutaneous administration once a day or 3 times a week It can be changed to replace.

  As a non-limiting example, any of the methods described above characterized by an IFN-γ dosing regimen can be used to administer the subject IFN-γ dosing regimen during a desired treatment period with an NS3 inhibitor compound. Modifications can be made to replace the IFN-γ dosage containing 25 μg of drug per dose with an IFN-γ dosage regimen administered subcutaneously three times a week.

  As a non-limiting example, any of the methods described above characterized by an IFN-γ dosing regimen can be used to administer the subject IFN-γ dosing regimen during the desired treatment period with an NS3 inhibitor compound. Modifications can be made to replace the IFN-γ dosage containing 50 μg of drug per dose with an IFN-γ dosage regimen administered subcutaneously three times a week.

  As a non-limiting example, any of the methods described above characterized by an IFN-γ dosing regimen can be used to administer the subject IFN-γ dosing regimen during the desired treatment period with an NS3 inhibitor compound. Modifications can be made to replace the IFN-γ dosage containing 100 μg of drug per dose with an IFN-γ dosage regimen administered subcutaneously three times a week.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired treatment period with the compound, (a) a mono-PEG (30 kD, linear) consensus IFN-α dose containing 100 μg of drug per dose is administered subcutaneously once a week, once every 8 days. IFN-α and IFN-γ, or administered once every 10 days; and (b) subcutaneous administration of a dose of IFN-γ containing 50 μg of drug per dose three times a week; Can be changed to replace the combined administration regimen.

  As a non-limiting example, any of the methods described above characterized by a TNF antagonist dosing regimen can be used to (a) etanercept the desired TNF antagonist dosing regimen during the desired treatment period with an NS3 inhibitor compound. 25 mg of drug per dose, subcutaneously twice a week, (b) 1 kg body weight, 3 mg of infliximab dose, intravenously at weeks 0, 2, and 6 and then 8 weeks A TNF antagonist comprising administering a dose of a TNF antagonist selected from a group at a time, or (c) a dose of 40 mg of adalimumab dose subcutaneously once a week or once every two weeks; It can be changed to replace the dosing schedule.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired treatment period with the compound, (a) a dose of mono-PEG (30 kD, linear) consensus IFN-α containing 100 μg of drug per dose is administered once a week, once every 8 days, Or administered subcutaneously once every 10 days; and (b) IFN-γ dose containing 100 μg of drug per dose, administered subcutaneously 3 times a week; IFN-α and IFN It can be changed to replace the -γ combination regimen.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired treatment period with the compound, (a) a mono-PEG (30 kD, linear) consensus IFN-α dose containing 150 μg of drug per dose, once a week, once every 8 days, or IFN-α and IFN-γ, administered subcutaneously once every 10 days; and (b) administered subcutaneously a dose of IFN-γ containing 50 μg of drug per dose 3 times a week Can be changed to replace the combined administration regimen.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired treatment period with the compound, (a) a mono-PEG (30 kD, linear) consensus IFN-α dose containing 150 μg of drug per dose, once a week, once every 8 days, or IFN-α and IFN-γ, administered subcutaneously once every 10 days; and (b) subcutaneously administered a dose of IFN-γ containing 100 μg of drug per dose three times a week Can be changed to replace the combined administration regimen.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired treatment period with the compound, (a) a mono-PEG (30 kD, linear) consensus IFN-α dose containing 200 μg of drug per dose, once a week, once every 8 days, or IFN-α and IFN-γ, administered subcutaneously once every 10 days; and (b) administered subcutaneously a dose of IFN-γ containing 50 μg of drug per dose 3 times a week Can be changed to replace the combined administration regimen.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired treatment period with the compound, (a) a mono-PEG (30 kD, linear) consensus IFN-α dose containing 200 μg of drug per dose, once a week, once every 8 days, or IFN-α and IFN-γ, administered subcutaneously once every 10 days; and (b) subcutaneously administered a dose of IFN-γ containing 100 μg of drug per dose three times a week Can be changed to replace the combined administration regimen.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) administering an INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose 3 times a week; and (b ) IFN-γ dose containing 25 μg of drug per dose can be administered subcutaneously three times a week; can be modified to replace the combined IFN-α and IFN-γ regimen is there.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) administering an INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose 3 times a week; and (b ) IFN-γ dose containing 50 μg of drug per dose administered subcutaneously 3 times a week; can be modified to replace IFN-α and IFN-γ combination regimen is there.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) administering an INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose 3 times a week; and (b ) IFN-γ dose containing 100 μg of drug per dose can be administered subcutaneously three times a week; can be modified to replace the combined IFN-α and IFN-γ regimen is there.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alfacon-1 containing an amount of 9 μg of drug per dose is administered subcutaneously once a day; and ( b) Subcutaneous administration of IFN-γ dose containing 25 μg of drug per dose 3 times weekly; can be modified to replace IFN-α and IFN-γ combination regimen It is.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alfacon-1 containing an amount of 9 μg of drug per dose is administered subcutaneously once a day; and ( b) Subcutaneous administration of an IFN-γ dose containing 50 μg of drug per dose 3 times a week; can be modified to replace a combined IFN-α and IFN-γ regimen It is.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alfacon-1 containing an amount of 9 μg of drug per dose is administered subcutaneously once a day; and ( b) Subcutaneous administration of IFN-γ dose containing 100 μg of drug per dose 3 times weekly; can be modified to replace IFN-α and IFN-γ combination regimen It is.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alphacon-1 containing 15 μg of drug per dose is administered subcutaneously three times a week; and (b ) IFN-γ dose containing 25 μg of drug per dose can be administered subcutaneously three times a week; can be modified to replace the combined IFN-α and IFN-γ regimen is there.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alphacon-1 containing 15 μg of drug per dose is administered subcutaneously three times a week; and (b ) IFN-γ dose containing 50 μg of drug per dose administered subcutaneously 3 times a week; can be modified to replace IFN-α and IFN-γ combination regimen is there.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alphacon-1 containing 15 μg of drug per dose is administered subcutaneously three times a week; and (b ) IFN-γ dose containing 100 μg of drug per dose can be administered subcutaneously three times a week; can be modified to replace the combined IFN-α and IFN-γ regimen is there.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alfacon-1 containing 15 μg of drug per dose is administered subcutaneously once a day; and ( b) Subcutaneous administration of IFN-γ dose containing 25 μg of drug per dose 3 times weekly; can be modified to replace IFN-α and IFN-γ combination regimen It is.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alfacon-1 containing 15 μg of drug per dose is administered subcutaneously once a day; and ( b) Subcutaneous administration of an IFN-γ dose containing 50 μg of drug per dose 3 times a week; can be modified to replace a combined IFN-α and IFN-γ regimen It is.

  As a non-limiting example, any of the methods described above characterized by a combined administration regimen of IFN-α and IFN-γ can be used to treat the subject combination administration regimen of IFN-α and IFN-γ with NS3 inhibition. During the desired period of treatment with the compound, (a) an INFERGEN® dose of interferon alfacon-1 containing 15 μg of drug per dose is administered subcutaneously once a day; and ( b) Subcutaneous administration of IFN-γ dose containing 100 μg of drug per dose 3 times weekly; can be modified to replace IFN-α and IFN-γ combination regimen It is.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined monotherapy (30 kD, linear) consensus IFN-α dose containing 100 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a week Administered subcutaneously once every 8 days or once every 10 days; (b) subcutaneously administered a dose of IFN-γ containing 100 μg of drug per dose 3 times a week; and ( c) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter Or (iii) a dose of adalimumab 40 mg subcutaneously once weekly or every other week, at a dose of TNF antagonist selected from ; IFN-alpha containing, IFN-gamma, and can be modified to replace the combination regimen of TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined monotherapy (30 kD, linear) consensus IFN-α dose containing 100 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a week Administered subcutaneously once every 8 days or once every 10 days; (b) subcutaneously administered a dose of IFN-γ containing 50 μg of drug per dose 3 times a week; and ( c) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter Or (iii) administering a dose of adalimumab 40 mg subcutaneously once a week or every other week in a TNF antagonist dose selected from Can be modified to replace the combined administration regimen of IFN-α, IFN-γ, and TNF antagonists.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined dose regimen of (a) mono-PEG (30 kD, linear) consensus IFN-α dose containing 150 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a week Administered subcutaneously once every 8 days or once every 10 days; (b) subcutaneously administered a dose of IFN-γ containing 50 μg of drug per dose 3 times a week; and ( c) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter Or (iii) administering a dose of adalimumab 40 mg subcutaneously once a week or every other week in a TNF antagonist dose selected from Can be modified to replace the combined administration regimen of IFN-α, IFN-γ, and TNF antagonists.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined dose regimen of (a) mono-PEG (30 kD, linear) consensus IFN-α dose containing 150 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a week Administered subcutaneously once every 8 days or once every 10 days; (b) subcutaneously administered a dose of IFN-γ containing 100 μg of drug per dose 3 times a week; and ( c) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter Or (iii) a dose of adalimumab 40 mg subcutaneously once weekly or every other week, at a dose of TNF antagonist selected from ; IFN-alpha containing, IFN-gamma, and can be modified to replace the combination regimen of TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined monotherapy (30 kD, linear) consensus IFN-α dose containing 200 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a week Administered subcutaneously once every 8 days or once every 10 days; (b) subcutaneously administered a dose of IFN-γ containing 50 μg of drug per dose 3 times a week; and ( c) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter Or (iii) administering a dose of adalimumab 40 mg subcutaneously once a week or every other week in a TNF antagonist dose selected from Can be modified to replace the combined administration regimen of IFN-α, IFN-γ, and TNF antagonists.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined monotherapy (30 kD, linear) consensus IFN-α dose containing 200 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a week Administered subcutaneously once every 8 days or once every 10 days; (b) subcutaneously administered a dose of IFN-γ containing 100 μg of drug per dose 3 times a week; and ( c) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter Or (iii) a dose of adalimumab 40 mg subcutaneously once weekly or every other week, at a dose of TNF antagonist selected from ; IFN-alpha containing, IFN-gamma, and can be modified to replace the combination regimen of TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist The combined dose regimen of (3) INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose during the desired treatment period with NS3 inhibitor compound 3 times a week (B) subcutaneous administration of IFN-γ dose containing 25 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter, or (iii) adalimumab 40 mg subcutaneously, weekly Administering a TNF antagonist dose selected from once or every other week; And can be modified to replace the combined IFN-α, IFN-γ, and TNF antagonist regimen.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist The combined dose regimen of (3) INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose during the desired treatment period with NS3 inhibitor compound 3 times a week Administer subcutaneously; (b) administer IFN-γ dose containing 50 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter, or (iii) adalimumab 40 mg subcutaneously, weekly Administering a TNF antagonist dose selected from once or every other week; And can be modified to replace the combined IFN-α, IFN-γ, and TNF antagonist regimen.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist The combined dose regimen of (3) INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose during the desired treatment period with NS3 inhibitor compound 3 times a week (B) subcutaneous administration of IFN-γ dose containing 100 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously. Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter, or (iii) adalimumab 40 mg subcutaneously, weekly Administering a TNF antagonist dose selected from once or every other week; No IFN-α, IFN-γ, and may be modified to replace the combination regimen of TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined dosage regimen of: INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a day (B) IFN-γ dose containing 25 μg of drug per dose is administered subcutaneously 3 times a week; and (c) (i) Etanercept 25 mg of drug is administered subcutaneously. Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or every other week, administering a TNF antagonist dose selected from Modifications can be made to replace the combined regimen of N-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined dosage regimen of: INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a day (B) subcutaneous administration of IFN-γ dose containing 50 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or every other week, administering a TNF antagonist dose selected from Modifications can be made to replace the combined regimen of N-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined dosage regimen of: INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a day (B) subcutaneous administration of IFN-γ dose containing 100 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or administering a TNF antagonist dose selected from every other week; Modifications can be made to replace the combined regimen of FN-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist The combined dosage regimen of: INFERGEN®, an interferon alfacon-1 containing 15 μg of drug per dose during the desired treatment period with NS3 inhibitor compound, 3 times a week (B) subcutaneous administration of IFN-γ dose containing 25 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously. Twice a week, (ii) Infliximab 3 mg / kg body weight of drug intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) Adalimumab 40 mg subcutaneously once a week or Every other week, administering a TNF antagonist dose selected from Modifications can be made to replace the combined regimen of N-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist The combined dosage regimen of: INFERGEN®, an interferon alfacon-1 containing 15 μg of drug per dose during the desired treatment period with NS3 inhibitor compound, 3 times a week (B) subcutaneous administration of IFN-γ dose containing 50 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously. Twice a week, (ii) Infliximab 3 mg / kg body weight of drug intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) Adalimumab 40 mg subcutaneously once a week or Every other week, administering a TNF antagonist dose selected from Modifications can be made to replace the combined regimen of N-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist The combined dosage regimen of: INFERGEN®, an interferon alfacon-1 containing 15 μg of drug per dose during the desired treatment period with NS3 inhibitor compound, 3 times a week (B) subcutaneous administration of IFN-γ dose containing 100 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously. Twice a week, (ii) Infliximab 3 mg / kg body weight of drug intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) Adalimumab 40 mg subcutaneously once a week or Administering a TNF antagonist dose selected from every other week; I Modifications can be made to replace the combined regimen of FN-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the methods described above characterized by a combined dosing regimen of INF-α, INF-γ, and TNF antagonist may include IFN-α, IFN-γ, and TNF antagonists of interest. A combined dosage regimen of: INFERGEN® dose of interferon alfacon-1 containing 15 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a day (B) IFN-γ dose containing 25 μg of drug per dose is administered subcutaneously 3 times a week; and (c) (i) Etanercept 25 mg of drug is administered subcutaneously. Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or administering a TNF antagonist dose selected from every other week; Modifications can be made to replace the combined regimen of FN-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined dosage regimen of: INFERGEN® dose of interferon alfacon-1 containing 15 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a day (B) subcutaneous administration of IFN-γ dose containing 50 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or administering a TNF antagonist dose selected from every other week; Modifications can be made to replace the combined regimen of FN-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the above-described methods characterized by a combined dosing regimen of IFN-α, IFN-γ, and TNF antagonist can be targeted IFN-α, IFN-γ, and TNF antagonist A combined dosage regimen of: INFERGEN® dose of interferon alfacon-1 containing 15 μg of drug per dose during the desired treatment period with NS3 inhibitor compound once a day (B) subcutaneous administration of IFN-γ dose containing 100 μg of drug per dose 3 times a week; and (c) (i) etanercept 25 mg of drug subcutaneously Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or administering a TNF antagonist dose selected from every other week; Modifications can be made to replace a combined regimen of IFN-α, IFN-γ, and TNF antagonist.

  As a non-limiting example, any of the methods described above characterized by a combined dosage regimen of IFN-α and a TNF antagonist may be used to convert the subject combined dosage regimen of IFN-α and a TNF antagonist with an NS3 inhibitor compound. During the desired treatment period, (a) a monoPEG (30 kD, linear) consensus IFN-α dose containing 100 μg of drug per dose, once a week, once every 8 days, or 10 days And (b) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg body weight intravenously 0, 2, and Administering a TNF antagonist dose selected from week 6 and every 8 weeks thereafter, or (iii) a dose of adalimumab 40 mg subcutaneously once a week or every other week; Can be modified to replace a TNF antagonist combination regimen A.

  As a non-limiting example, any of the methods described above characterized by a combined dosage regimen of IFN-α and a TNF antagonist may be used to convert the subject combined dosage regimen of IFN-α and a TNF antagonist with an NS3 inhibitor compound. During the desired treatment period, (a) a monoPEG (30 kD, linear) consensus IFN-α dose containing 150 μg of drug per dose is administered once a week, once every 8 days, or 10 Administered subcutaneously once daily; and (b) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg body weight intravenously 0, 2, and Administering a TNF antagonist dose selected from week 6 and every 8 weeks thereafter, or (iii) a dose of adalimumab 40 mg subcutaneously once a week or every other week; Can be modified to replace a TNF antagonist combination regimen A.

  As a non-limiting example, any of the methods described above characterized by a combined dosage regimen of IFN-α and a TNF antagonist may be used to convert the subject combined dosage regimen of IFN-α and a TNF antagonist with an NS3 inhibitor compound. During the desired treatment period, (a) a mono-PEG (30 kD, linear) consensus IFN-α dose containing 200 μg of drug per dose, once a week, once every 8 days, or 10 days And (b) (i) a dose of 25 mg of etanercept subcutaneously twice weekly, (ii) a dose of 3 mg of infliximab per kg of body weight intravenously 0, 2, and 6 Administering a TNF antagonist dose selected from a week, and every 8 weeks thereafter, or (iii) a dose of adalimumab 40 mg subcutaneously once a week or every other week; comprising IFN-α and a TNF antagonist Can be changed to replace .

  As a non-limiting example, any of the methods described above characterized by a combined dosage regimen of IFN-α and a TNF antagonist may be used to convert the subject combined dosage regimen of IFN-α and a TNF antagonist with an NS3 inhibitor compound. During the desired treatment period: (a) subcutaneous administration of INFERGEN® dose of interferon alfacon-1 containing 9 μg of drug per dose; once a day or 3 times a week; And (b) (i) Etanercept 25 mg drug subcutaneously twice weekly, (ii) Infliximab 3 mg drug / kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter Or (iii) administering 40 mg of adalimumab subcutaneously once or every other week to a TNF antagonist dose selected from: a combination regimen of IFN-α and TNF antagonist Is possible .

  As a non-limiting example, any of the methods described above characterized by a combined dosage regimen of IFN-α and a TNF antagonist may be used to convert the subject combined dosage regimen of IFN-α and a TNF antagonist with an NS3 inhibitor compound. During the desired treatment period: (a) subcutaneous administration of an INFERGEN® dose of interferon alfacon-1 containing 15 μg of drug per dose; once a day or three times a week; And (b) (i) Etanercept 25 mg drug subcutaneously twice weekly, (ii) Infliximab 3 mg drug / kg body weight intravenously at 0, 2 and 6 weeks, and every 8 weeks thereafter Or (iii) administering 40 mg of adalimumab subcutaneously once or every other week to a TNF antagonist dose selected from: a combination regimen of IFN-α and TNF antagonist Is possible .

  As a non-limiting example, any of the methods described above characterized by a combined dosage regimen of IFN-γ and a TNF antagonist can be used to convert the targeted IFN-γ and TNF antagonist dosage regimen with an NS3 inhibitor compound. During the desired treatment period, (a) a dose of IFN-γ containing 25 μg of drug per dose is administered subcutaneously three times a week; and (b) (i) a dose of etanercept 25 mg subcutaneously. Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or, every other week, a TNF antagonist dose selected from can be administered; and can be modified to replace a combined dosage regimen of IFN-γ and a TNF antagonist.

  As a non-limiting example, any of the methods described above characterized by a combined dosage regimen of IFN-γ and a TNF antagonist can be used to convert the targeted IFN-γ and TNF antagonist dosage regimen with an NS3 inhibitor compound. During the desired treatment period, (a) a dose of IFN-γ containing 50 μg of drug per dose is administered subcutaneously three times a week; and (b) (i) a dose of etanercept 25 mg is administered subcutaneously. Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or, every other week, a TNF antagonist dose selected from can be administered; and can be modified to replace a combined dosage regimen of IFN-γ and a TNF antagonist.

  As a non-limiting example, any of the methods described above characterized by a combined dosage regimen of IFN-γ and a TNF antagonist can be used to convert the targeted IFN-γ and TNF antagonist dosage regimen with an NS3 inhibitor compound. During the desired treatment period, (a) IFN-γ dose containing 100 μg of drug per dose is administered subcutaneously three times a week; and (b) (i) etanercept 25 mg of drug is administered subcutaneously. Twice weekly, (ii) intravenous dose of 3 mg of infliximab / kg body weight intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter, or (iii) 40 mg of adalimumab subcutaneously once weekly Or, every other week, a TNF antagonist dose selected from can be administered; and can be modified to replace a combined dosage regimen of IFN-γ and a TNF antagonist.

  As a non-limiting example, any of the methods described above, including a mono PEG (30 kD, linear) consensus IFN-α dosing regimen, can include a mono PEG (30 kD, linear) consensus IFN-α dosing regimen. Peginterferon alfa-2a dosage regimen comprising subcutaneous administration of peginterferon alfa-2a containing 180 μg of drug per dose during the desired treatment period with NS3 inhibitor compound It can be changed to replace.

  As a non-limiting example, any of the methods described above, including a mono PEG (30 kD, linear) consensus IFN-α dosing regimen, can include a mono PEG (30 kD, linear) consensus IFN-α dosing regimen. Peginterferon α-2b containing 1 kg body weight and 1.0 μg to 1.5 μg of drug per dose during the desired treatment period with an NS3 inhibitor compound, administered subcutaneously once or twice a week Modifications can be made to replace the pegylated interferon alpha-2b dosing regime.

  As a non-limiting example, any of the methods described above can be administered orally with ribavirin doses containing 400 mg, 800 mg, 1000 mg, or 1200 mg of drug per day during the desired period of treatment with an NS3 inhibitor compound. It may be modified to contain administration in daily doses, possibly divided into two or more.

  By way of non-limiting example, any of the methods described above can be used during the desired period of treatment with an NS3 inhibitor compound (i) a drug in an amount of 1000 mg orally per day for a patient weighing less than 75 kg, or (ii ) It can be modified to include a dose of ribavirin containing orally 1200mg of drug per day for patients weighing 75kg or more, sometimes in two or more divided daily doses It is.

  As a non-limiting example, any of the above-described methods may be used to administer a subject NS3 inhibitor dosage regimen between 0.01 mg / kg and 0.1 mg / kg body weight during the desired treatment period with the NS3 inhibitor compound. The amount can be altered to replace an NS3 inhibitor dosing regimen that involves administering the dose orally daily, sometimes in two or more divided daily doses.

  As a non-limiting example, any of the above-described methods can be used to determine a subject NS3 inhibitor dosage regimen from 0.1 mg to 1 mg drug dose per kg body weight during the desired treatment period with the NS3 inhibitor compound. Can be modified to replace an NS3 inhibitor dosing regimen that includes daily oral administration, possibly in two or more divided daily doses.

  As a non-limiting example, any of the above-described methods can be used to determine a subject NS3 inhibitor dosage regimen at a drug dosage of 1 mg to 10 mg / kg body weight during the desired treatment period with the NS3 inhibitor compound. Modifications can be made to replace the NS3 inhibitor dosing regimen, which involves administering orally daily, sometimes in two or more divided daily doses.

  As a non-limiting example, any of the above-described methods can be used to determine a subject NS3 inhibitor dosing regimen at a dose of 10 mg to 100 mg / kg body weight during the desired treatment period with the NS3 inhibitor compound. Modifications can be made to replace the NS3 inhibitor dosing regimen, which involves administering orally daily, sometimes in two or more divided daily doses.

  As a non-limiting example, any of the methods described above characterized by an NS5B inhibitor dosing regimen can be used to convert the subject NS5B inhibitor dosing regimen per kg body weight during the desired treatment period with an NS3 inhibitor compound. Modifications can be made to replace the NS5B inhibitor dosing regimen that involves administering a drug dose of 0.01 mg to 0.1 mg orally daily, sometimes in two or more divided daily doses.

  As a non-limiting example, any of the methods described above characterized by an NS5B inhibitor dosing regimen can be used to convert the subject NS5B inhibitor dosing regimen per kg body weight during the desired treatment period with an NS3 inhibitor compound. Modifications can be made to replace an NS5B inhibitor regimen that involves administering a drug dose of 0.1 mg to 1 mg orally daily, sometimes in divided doses per day or more.

  As a non-limiting example, any of the methods described above characterized by an NS5B inhibitor dosing regimen can be used to convert the subject NS5B inhibitor dosing regimen per kg body weight during the desired treatment period with an NS3 inhibitor compound. Modifications can be made to replace the NS5B inhibitor regimen, which involves administering a drug dose of 1 mg to 10 mg daily orally, sometimes in two or more divided daily doses.

  As a non-limiting example, any of the methods described above characterized by an NS5B inhibitor dosing regimen can be used to convert the subject NS5B inhibitor dosing regimen per kg body weight during the desired treatment period with an NS3 inhibitor compound. Modifications can be made to replace the NS5B inhibitor regimen, which involves administering a drug dose of 10 mg to 100 mg orally daily, sometimes in two or more divided daily doses.

Patient Identification In certain embodiments, the specific regimen of pharmacotherapy used to treat HCV patients includes initial viral load, genotype of HCV infection in the patient, liver histology, and / or patient liver. Selected according to certain disease parameters indicated by the patient, such as the stage of fibrosis.

  Next, in some embodiments, any of the above-described methods wherein the subject method for treatment of HCV infection is modified to treat treatment failure patients with a 48 week treatment unit is provided.

  In other embodiments, the subject method provides any of the above-described methods for HCV that have been modified so that the patient receives 48 weeks of treatment units to treat a patient who is unresponsive.

  In other embodiments, to treat a relapse patient, any of the above-described methods for the treatment of HCV infection, wherein the patient has been modified to receive a 48-week treatment unit of treatment, is provided.

  In another embodiment, to treat a naïve patient infected with HCV genotype 1 of the above-described method for the treatment of HCV infection, wherein the patient has been modified to receive 48 weeks of treatment units. Provide one.

  In another embodiment, to treat a naïve patient infected with HCV genotype 4 of the above method for the treatment of HCV infection, wherein the patient has been modified to receive 48 weeks of treatment units. Provide one.

In another embodiment, to treat a naïve patient infected with HCV genotype 1, the patient has a high viral load (HVL), where “HVL” is 2 × 10 ⁶ or more HCV per mL of serum. Means HCV viral load of gene copy and provides any of the methods described above for the treatment of HCV infection that has been modified to allow patients to receive treatment units of 48 weeks.

  In one embodiment, (1) identifying a patient with advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4, then (2) subject method drug therapy from about 24 weeks About 60 weeks, or about 30 weeks to about 1 year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or Any of the above methods for the treatment of HCV infection, modified to include administering to the patient for a period of at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks, is provided.

  In another embodiment, (1) identifying a patient with advanced or severe stage liver fibrosis, as measured by a Knodell score of 3 or 4, then (2) subject method pharmacotherapy for about 40 weeks Provided is any of the above-described methods for the treatment of HCV infection modified to include administering to a patient for a period of from about 50 weeks, or about 48 weeks.

  In another embodiment, (1) identifying a patient with an HCV genotype 1 infection with an initial viral load of more than 2 million viral gene copies per ml of patient serum, then (2) a subject method About 24 weeks to about 60 weeks, or about 30 weeks to about 1 year, or 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, Or a method as described above for the treatment of HCV infection modified to include administering to a patient for a period of at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks To provide either.

  In another embodiment, (1) identifying a patient with an HCV genotype 1 infection with an initial viral load of more than 2 million viral gene copies per ml of patient serum, then (2) a subject method Any of the above-described methods for the treatment of HCV infection is provided that includes the step of administering to a patient a pharmacotherapy of about 40 weeks to about 50 weeks or about 48 weeks.

  In another embodiment, (1) HCV genotype 1 infection with an initial viral load of more than 2 million viral gene copies per ml patient serum and no liver fibrosis or Knodell score of 0, Identifying an early stage patient, measured as 1, or 2, then (2) about 24 weeks to about 60 weeks, or about 30 weeks to 1 year, or about 36 weeks of drug therapy of the subject method Weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks Any of the above-described methods for the treatment of HCV infection, modified to include administering to the patient for a period of time.

  In another embodiment, (1) an HCV genotype 1 infection with an initial viral load of more than 2 million viral gene copies per ml of patient serum and no liver fibrosis or a Knodell score of 0, Identifying the patient at an early stage measured as 1 or 2, and then (2) administering the subject method of drug therapy to the patient for a period of about 40 weeks to about 50 weeks, or about 48 weeks. Provided is any of the above-described methods for the treatment of HCV infection, modified to include.

  In another embodiment, (1) identifying a patient with an HCV genotype 1 infection and an initial viral load of no more than 2 million viral gene copies per ml of patient serum, then (2) a subject method About 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or about Provided is any of the above-described methods for the treatment of HCV infection modified to include administering to a patient for a period of up to 36 weeks or up to about 48 weeks.

  In another embodiment, (1) identifying a patient with an HCV genotype 1 infection and an initial viral load of no more than 2 million viral gene copies per ml of patient serum, then (2) a subject method Any of the above-described methods for the treatment of HCV infections are provided that are modified to include administering to a patient a pharmacotherapy of about 20 weeks to about 24 weeks.

  In another embodiment, (1) identifying a patient with HCV genotype 1 infection with an initial viral load of no more than 2 million viral gene copies per ml of patient serum, then (2) in the subject Provided is any of the above-described methods for the treatment of HCV infection that has been modified to include administering a method of drug therapy to a patient for a period of about 24 weeks to about 48 weeks.

  In another embodiment, (1) identifying a patient with an HCV genotype 2 or 3 infection, then (2) subject method drug therapy from about 24 weeks to about 60 weeks, or from about 30 weeks to About 1 year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 Any of the above-described methods for the treatment of HCV infection, modified to include administering to the patient for a week, or at least about 60 weeks, is provided.

  In another embodiment, (1) identifying a patient having an infection with HCV genotype 2 or 3, then (2) subjecting the subject's drug therapy to about 20 weeks to about 50 weeks, or about 24 weeks to Administering to the patient for a period of about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks; Any of the above-described methods for the treatment of HCV infection, modified to include

  In another embodiment, (1) identifying a patient with an HCV genotype 2 or 3 infection, then (2) administering the subject method of drug therapy to the patient for a period of about 20 weeks to about 24 weeks Any of the above-described methods for the treatment of HCV infection, modified to include the step of:

  In another embodiment, (1) identifying a patient having an HCV genotype 2 or 3 infection, then (2) administering the subject method of drug therapy to the patient for a period of at least about 24 weeks. Provided is any of the above-described methods for the treatment of HCV infection, modified to include.

  In another embodiment, (1) identifying a patient with an infection of HCV genotype 1 or 4, then (2) subjecting the subject method of drug therapy from about 24 weeks to about 60 weeks, or from about 30 weeks to About 1 year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 Any of the above-described methods for the treatment of HCV infection, modified to include administering to the patient for a week, or at least about 60 weeks, is provided.

  In another embodiment, the subject method comprises (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8, and 9, then (2) in the subject Provided is any of the above-described methods for the treatment of HCV infection modified to include administering a method of drug therapy to a patient for a period of about 20 weeks to about 50 weeks.

  In another embodiment, (1) identifying a patient with an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9, then (2) drug therapy of the subject method Any of the above-described methods for the treatment of HCV infection, modified to include administering to the patient for a period of at least about 24 weeks and up to about 48.

Patients Suitable for Treatment Any of the above treatment regimens can be administered to a person diagnosed with an HCV infection. Persons infected with HCV have been confirmed to have HCV RNA in their blood and / or anti-HCV antibodies in their serum. Any of the above treatment regimens can be administered to a person who has failed to treat a previous HCV infection ("treatment failure patients" includes non-responders and relapse patients).

  In many embodiments, those who are clinically diagnosed with HCV infection are of particular interest. Persons infected with HCV have been confirmed to have HCV RNA in their blood and / or anti-HCV antibodies in their serum. Such persons include those who are positive for anti-HCV ELISA and those who are positive for recombinant immunoblot (RIBA). Such people may have elevated serum alanine aminotransferase, but not necessarily.

  People who have been clinically diagnosed with HCV infection are naïve (i.e. those who have not previously been treated for HCV, especially IFN-α-based therapy and / or ribavirin Those who have not previously received treatment) and those who have failed previous HCV treatment ("treatment failure" patients). Patients who fail treatment are non-responders (i.e., previous HCV treatment, e.g., previous IFN-α monotherapy, previous IFN-α and ribavirin combination therapy, or previous PEGylated IFN-α and ribavirin combination therapy Who did not significantly or sufficiently reduce HCV titers); and relapsed individuals (i.e., previously treated with HCV, such as previous IFN-α monotherapy, previous IFN-α and ribavirin combination therapy) , Or those who have received previous PEGylated IFN-α and ribavirin combination therapy, but whose HCV titer has decreased but gradually increased).

In certain such embodiments, the person has an HCV titer of HCV gene copies of at least about 10 ⁵ , at least about 5 × 10 ⁵ , or at least about 10 ⁶ , or at least about 2 × 10 ⁶ per mL of serum. The patient has HCV genotypes (genotype 1, genotypes 1a and 1b, 2, 3, 4, 6, etc., and subtypes (e.g. 2a, 2b, 3c etc.)), especially HCV genotype 1 and special HCV May be infected with any of the genotypes that are difficult to treat, such as subtypes and quasi-species.

  In addition, the patient may have severe fibrosis or early cirrhosis (not decompensated, Child Pew classification A or lower) or more advanced cirrhosis (decompensated, Child Pew classification) due to chronic HCV infection. B or C) HCV positive person (above), and HCV positive person who is viremia despite previous antiviral treatment with IFN-alpha basic therapy (above), or IFN-alpha basic treatment An HCV positive person (above) that cannot be tolerated, or an HCV positive person (above) for which such treatment is contraindicated. In certain such embodiments, an HCV positive person with a liver fibrosis stage of 3 or 4 according to the METAVIR scoring system is suitable for treatment with the method of the embodiment. In other embodiments, persons suitable for treatment by the methods of the embodiments include patients with decompensated cirrhosis that have developed clinical symptoms, including those with much advanced cirrhosis or patients waiting for liver transplantation . In other embodiments, persons suitable for treatment with the methods of the embodiments include fibrosis including early fibrosis (METAVIR, Ludwig, and Scheur scoring systems 1 and 2; or the Ishak scoring system Patients with stage 1, 2 or 3) are included.

Preparation of Section A Virus Inhibitors Compounds of general formula I can be synthesized by conventional methods for compounds of general formulas II-XIX that are identical to those described below. The synthesis of various specific compounds of general formula I is described in the examples below. A person skilled in the art understands the sequence variations and also shows similar reactions that are shown or known to be suitable for use in the following process to produce compounds of formula I. Will recognize changes in the appropriate reaction conditions.

  The reaction products described herein are isolated by conventional methods such as extraction, distillation, chromatography.

  Salts of the compounds of the above formula are prepared by reacting the appropriate base or acid with a stoichiometric equivalent of the compound of formula I.

Preparation of Section B Virus Inhibitors The meanings of the terms and structure names used in this section are the same as in Section B above. Unless otherwise indicated, all references in this section relating to a particular number or label are not presumably the context of similar or identical numbered or labeled schemes used elsewhere in this specification. Should be understood in the context of this section or the corresponding numbered or labeled scheme used in section B above.

  Compounds of formula II-X can be synthesized according to the methods described below.

Methodology Compound Preparation Two methods were used to prepare compounds having general structures II-X. In both methods, Intermediates 1 and 4 were prepared according to the procedure described in international patent application PCT / CA00 / 00353 (publication number WO00 / 59929). Intermediate 4 can also be purchased from RSP amino acids.

(Example)
(Example 1-1)
Synthesis of Compound No. 101 (Compound AR00220042) by Method A:

  Method A:

  Step 1: Synthesis of 2S- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4R-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3)

  Ethyl- (1R, 2S) / (1S, 2R) -1-amino-2-vinylcyclopropylcarboxylate (1, 1.0 g, 5.2 mmol), trans-N- (tert-butoxycarbonyl) -4-hydroxy- To a flask charged with L-proline (2, 1.3 g, 1.1 eq) and HATU (2.7 g, 1.1 eq), DMF (30 mL) was added to give a solution. Cool to 0 ° C. in an ice-water bath and then slowly add a solution of DIEA (4.4 mL, 4 eq) in DMF (15 mL) with stirring. The reaction was warmed to room temperature and stirred overnight.

After 16 hours, the reaction was complete as monitored by HPLC. Dilute with EtOAc (100 mL), wash with water (3 × 40 mL), saturated NaHCO ₃ (2 × 40 mL), and brine (2 × 40 mL), then dry over Na ₂ SO ₄ and concentrate to a dark copper color. An oil was obtained. The crude product was purified on silica gel (eluent: acetone / hexane 3: 7) to give pure 3 as a tan foam powder (770 mg, 32%).

  Step 2: 1,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1-tert-butoxycarbonyl-5- (1R-ethoxycarbonyl-2S-vinyl-cyclopropylcarbamoyl) -pyrrolidin-3R-yl ester (5) And 1,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-tert-butoxycarbonyl-5- (1S-ethoxycarbonyl-2R-vinyl-cyclopropylcarbamoyl) -pyrrolidin-3R-yl ester (6) Composition

  Dipeptide 3 (300 mg, 0.81 mmol) was dissolved in DCM (8 mL) followed by the addition of CDI (163 mg, 1.2 eq) in one portion. The reaction was stirred at room temperature overnight. After 15 hours, the reaction was complete as monitored by TLC (DCM / MeOH 9: 1). 1,2,3,4-Tetrahydroisoquinoline (0.32 mL, 3 eq) was added in portions to the reaction and the reaction was stirred at room temperature overnight.

After 22 hours, TLC showed that the reaction was complete. The reaction was diluted with DCM (15 mL), washed with 1N aqueous HCl (15 mL), brine (15 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified on silica gel (eluent: DCM / Et ₂ O / acetone 30: 10: 1). The isolated top spot (5) was a white foam powder (169 mg, 40%) and the bottom spot (6) was a white solid (156 mg, 38%). ^{MS m / e 550 (M +} + Na).

  Step 3: 1,4-Dihydro-1H-isoquinoline-2-carboxylic acid 1- (2S-tert-butoxycarbonylamino-nona-8-enoyl) -5- (1R-ethoxycarbonyl-2S-vinyl-cyclopropylcarbamoyl ) -Pyrrolidin-3R-yl ester (7)

  The top isomer 5 (118 mg, 0.22 mmol) was dissolved in 4N HCl (dioxane, 8 mL) and placed at room temperature for 90 minutes to remove the BOC protecting group. It was then concentrated, dissolved in acetonitrile and concentrated again twice. To this light brown residue was added 4 (66.8 mg, 1.1 eq) and HATU (93.5 mg, 1.1 eq) followed by DMF (2 mL) under nitrogen. The reaction was cooled in an ice-water bath for 15 minutes, after which time a solution of DIEA (0.13 mL, 4 eq) in DMF (0.5 mL) was added dropwise to the reaction with stirring. The ice bath was removed and slowly raised to room temperature, and the reaction was stirred overnight.

After 24 hours, the reaction had turned dark brown. Preparative TLC indicates that the reaction is complete. The reaction is diluted with EtOAc (30 mL), washed with water (3 × 15 mL), saturated NaHCO ₃ (2 × 15 mL), brine (15 mL), dried (Na ₂ SO ₄ ) and concentrated to give 7 as an orange Obtained as a colored oily residue (156 mg). Used directly in the next step without further purification. ^{MS m / e 703 (M +} + Na).

Step 4: (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3, Synthesis of 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ethyl ester (8)

  Crude product 7 (135 mg, 0.2 mmol) was dissolved in DriSolve DCE (20 mL) to give a solution followed by addition of nolan catalyst (5 mg, 0.3 eq) at room temperature under nitrogen. The solution turned a purplish color. The reaction was placed in a preheated oil bath (50 ° C.) and stirred overnight.

After 10 hours, the reaction turned dark brown. TLC (DCM / EtOAc 1: 1) showed clean conversion to a new spot with a slightly lower Rf value. The reaction was concentrated and purified on silica gel (eluent: DCM / EtOAc 5: 1 to 2: 1 gradient) to give product 8 as a tan foam powder (75 mg, 58%). . MS m / e 653.1 (M ⁺ +1).

Step 5: (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3, Synthesis of 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (Compound No. 101)

Macrocyclic ester 8 (60 mg, 0.092 mmol) was dissolved in 0.9 mL of a mixed solvent (THF / MeOH / H ₂ O 2: 1: 1), followed by addition of LiOH—H ₂ O (23 mg, 6 eq). The mixture was stirred at room temperature overnight. After 18 hours, TLC (DCM / MeOH 9: 1) showed a clean new spot with low Rf value. The reaction was nearly concentrated to dryness and partitioned between 1N aqueous HCl (15 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2 × 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%). ¹ H NMR (CD ₃ OD, 400 MHz) δ 1.20 to 1.67 (m, 21H), 1.70 to 1.83 (m, 1H), 1.88 to 2.10 (m, 1H), 2.12 to 2.58 (m, 4H), 2.82 ( m, 2H), 3.60-3.80 (m, 2H), 3.86 (m, 1H), 4.20 (m, 1H), 4.35 (m, 1H), 4.54 (s, 7H), 4.58 (m, 3H), 5.29 ~ 5.41 (m, 2H), 5.57 (m, 1H), 7.0-7.24 (m, 4H). MS m / e 625.1 (M ⁺⁺ 1).

(Example 1-1a)

According to the procedure described in Example 1-1, replacing compound 5 in step 3 with 6, (1S, 4S, 6R, 14S, 18R) -14-tert-butoxycarbonylamino-18- (3,4-dihydro- 1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00220122) was prepared similarly . MS m / e 625 (M ⁺ +1).

(Example 1-2)
Synthesis of Compound No. 101 (Compound AR00220042) by Method B:
Method B:

  Compound number 101 was also prepared following the above procedure. The synthesis of the macrocyclic intermediate 10 described herein is similar to the synthesis described in International Patent Application PCT / CA00 / 00353 (issue number WO00 / 59929).

  Step 1: Synthesis of 2S- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4R-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3)

  Ethyl- (1R, 2S) / (1S, 2R) -1-amino-2-vinylcyclopropylcarboxylate (1, 1.0 g, 5.2 mmol), trans-N- (tert-butoxycarbonyl) -4-hydroxy- To a flask charged with L-proline (2, 1.3 g, 1.1 eq) and HATU (2.7 g, 1.1 eq), DMF (30 mL) was added to give a solution. Cool to 0 ° C. in an ice-water bath and then slowly add a solution of DIEA (4.4 mL, 4 eq) in DMF (15 mL) with stirring. The reaction was warmed to room temperature and stirred overnight.

After 16 hours, the reaction was complete as monitored by HPLC. Dilute with EtOAc (100 mL), wash with water (3 × 40 mL), saturated NaHCO ₃ (2 × 40 mL), and brine (2 × 40 mL), then dry over Na ₂ SO ₄ and concentrate to a dark copper color. An oil was obtained. The crude product was purified on silica gel (eluent: acetone / hexane 3: 7) to give pure 3 as a tan foam powder (770 mg, 32%).

  Step 2: 1R-{[1- (2S-tert-butoxycarbonylamino-nona-8-enoyl) -4R-hydroxy-pyrrolidine-2S-carbonyl] -amino} -2S-vinyl-cyclopropanecarboxylic acid ethyl ester ( 9) Synthesis

  Compound 3 (2.85 g, 7.7 mmol) was dissolved in 4N HCl (dioxane, 10 mL) and placed at room temperature for 90 minutes to remove the Boc protecting group. It was then concentrated, dissolved 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 DMF (80 mL) under nitrogen. The reaction was cooled in an ice-water bath for 15 minutes, after which time a solution of DIEA (5.4 mL, 30.9 mmol) in DMF (5 mL) was added dropwise to the reaction with stirring. The ice bath was removed and slowly raised to room temperature, and the reaction was stirred overnight.

After 18 hours, TLC showed that the reaction was complete. The reaction was diluted with EtOAc (300 mL), washed with water (3 × 150 mL), saturated NaHCO ₃ (2 × 150 mL), brine (150 mL), dried (Na ₂ SO ₄ ) and the solvent removed. The crude product was purified by silica gel flash chromatography on Biotage 40M (eluent: 3% to 5% MeOH in DCM) to give 9 as a brown foamy solid (3.5 g, 87%).

Step 3: (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- Synthesis of 7-ene-4-carboxylic acid ethyl ester (10)

Compound 9 (2.6 g, 5.0 mmol) was dissolved in DriSolve DCE (500 mL) in a 1 L round bottom flask to give a solution. Degassed by blowing nitrogen over 1 hour. Then Hoveyda catalyst (0.25 eq) was added at room temperature under nitrogen. The reaction was placed in a preheated oil bath (50 ° C.) and stirred overnight. After 16 hours, the reaction had turned dark brown. TLC (DCM / EtOAc 1: 1) showed clean conversion to a new spot with a slightly lower Rf value. The reaction was concentrated and purified on silica gel (Biotage 40M, eluent = DCM / EtOAc 1: 1 to 1: 2 gradient) to give product 10 as a tan foam (0.64 g, 52%). Obtained. ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.21 (t, J = 7.0 Hz, 3H), 1.43 (s, 9H), 1.20 to 1.50 (m, 6H), 1.53 to 1.68 (m, 2H), 1.83 to 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 = 9.4Hz, 1H), 5.36 (d, J = 7.8Hz, 1H), 5.53 ( m, 1H), 7.19 (brs, 1H). MS m / e 494.0 (M ⁺⁺ 1).

Step 4: (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3, Synthesis of 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ethyl ester (11)

Macrocyclic intermediate 10 (110 mg, 0.22 mmol) was dissolved in DCM (2.2 mL) followed by the addition of CDI (45 mg, 0.27 mmol) in one portion. The reaction was stirred at room temperature overnight. After 15 hours, the reaction was complete as monitored by TLC (DCM / MeOH 9: 1). 1,2,3,4-Tetrahydroisoquinoline (0.14 mL, 1.1 mmol) was added dropwise to the reaction and the reaction was stirred at room temperature overnight. After 22 hours, TLC showed that the reaction was complete. The reaction was diluted with DCM (6 mL), washed with 1N aqueous HCl (2 × 2 mL), saturated sodium bicarbonate (2 mL), brine (2 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified on silica gel (Biotage 40S, eluent: 2 to 4% MeOH in DCM) to give 11 as a pale yellow foam (131 mg, 90%).

  Step 5: Compound 11 was obtained by hydrolyzing Compound 11 in the same manner as described in Step 5 of Example 1-1.

  The following compounds were also prepared according to Method B described above, substituting 1,2,3,4-tetrahydroisoquinoline with many other secondary amines. Most of these amines are commercially available or known literature compounds and were therefore prepared using the procedures given herein (1. Stokker, G., Tetrahedron Lett., 1996, 37 (31), 5453-5456. 2. Chan, N W., Bioorganic & Medicinal Chemistry, 2000, 8, 2085-2094. 3. Vecchietti, V. et al., J. Med. Chem., 1991, 34, 2624-2633.). For those amine inputs that were not prepared directly according to literature procedures, or for specific amine inputs that were not reported before we were able to know, these syntheses are shown in the respective examples. Yes.

(Example 1-3)

According to Method B, except that 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino -18- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -Ene-4-carboxylic acid (compound AR00226824) was synthesized. MS m / e 585.2 (M ⁺ + 1-100).

(Example 1-4)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-2 according to Method B, except that 2,3,4,9-tetrahydro-1H-b-carboline was used instead in step 4. , 15-Dioxo-18- (1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -A carboxylic acid (compound AR00226825) was synthesized. MS m / e 564.2 (M ⁺ + 1-100).

(Example 1-5)

According to Method B except that 2,3-dihydro-1H-isoindole was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (1,3 -Dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00291871) was synthesized . ¹ H NMR (CDCl ₃ , 500 MHz) δ 1.21 to 1.44 (m, 8H), 1.32 (s, 9H), 1.54 to 1.62 (m, 2H), 1.78 to 1.88 (m, 2H), 2.04 to 2.13 (m , 1H), 2.16 to 2.23 (m, 1H), 2.24 to 2.36 (m, 2H), 2.66 to 2.74 (m, 1H), 3.87 to 3.90 (m, 1H), 4.15 (d, J = 11.0Hz, 1H ), 4.37 to 4.43 (m, 1H), 4.61 to 4.77 (m, 5H), 5.18 (t, J = 10.3Hz, 1H), 5.24 to 5.31 (m, 1H), 5.40 to 5.45 (m, 1H), 5.58-5.66 (m, 1H), 7.11-7.30 (m, 4H). MS m / e 611.0 (M ⁺ +1).

(Example 1-6)

According to Method B, except that 2,3-dihydro-1H-indole was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (2,3- Dihydro-indole-1-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00291875) was synthesized. MS m / e 610.9 (M ⁺ +1).

(Example 1-7)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino according to Method B except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4. -2,15-Dioxo-18- (8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -Ene-4-carboxylic acid (compound AR00294382) was synthesized. MS m / e 693.0 (M ⁺ ).

(Example 1-8)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino according to Method B except that 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4. -2,15-Dioxo-18- (6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -Ene-4-carboxylic acid (compound AR00294383) was synthesized. ¹ H NMR (500 MHz, CDCl ₃ ): δ 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 to 5.15 (m, 2H), 4.78 to 4.60 (m, 3H), 4.40 (s, 1H), 4.16 to 4.00 (m, 1H), 3.92 to 3.81 (m, 1H), 3.80 to 3.60 (m, 2H), 3.00 to 2.85 (m, 2H), 2.72 to 2.64 (br s, 1H), 2.40 to 1.18 (m, 20H). MS: m / e 693.0 (M ⁺ ).

(Example 1-9)

According to Method B, except that 5-fluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino- 18- (5-Fluoro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene- 4-Carboxylic acid (compound AR00294384) was synthesized. ¹ H NMR (500 MHz, CDCl ₃ ): δ 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), 4.78 (s, 1H), 4.64 to 4.56 (m, 2H), 4.42 (s, 1H), 4.12 to 4.02 (m, 1H), 3.92 to 3.81 (m , 1H), 3.78 to 3.61 (m, 2H), 2.84 to 2.80 (m, 2H), 2.74 to 2.64 (m, 1H), 2.36 to 2.18 (m, 2H), 1.91 to 1.81 (m, 2H), 1.64 ~ 1.54 (m, 2H), 1.48 ~ 1.10 (m, 15H). MS: m / e 643.0 (M ⁺ )

(Example 1-10)

According to Method B except that 5-amino-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -18- (5-amino-3, 4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -Carboxylic acid (compound AR00301745) was synthesized. MS: m / e 640.1 (M ⁺ ).

(Example 1-11)

According to Method B except that 7-amino-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -18- (7-amino-3, 4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -Carboxylic acid (compound AR00301749) was synthesized. MS: m / e 640.1 (M ⁺ ), 641.1 (M ⁺ +1).

(Example 1-12)

According to Method B, except that phenyl- (4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) -amine was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-2,15-dioxo-18- (2-phenylamino-6,7-dihydro-4H-thiazolo [5,4-c] pyridine-5-carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304000) was synthesized. MS m / e 721.2 (M-1).

(Example 1-13)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18 according to Method B except that 7-chloro-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4. -(7-Chloro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -A carboxylic acid (compound AR00304062) was synthesized. MS m / e 659.0 (M ⁺ ), 661.0 (M ⁺⁺ 2).

(Example 1-14)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18 according to Method B, except that 6-fluoro-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4. -(6-Fluoro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -Carboxylic acid (compound AR00304063) was synthesized. MS m / e 643.0 (M ⁺ ), 644.0 (M ⁺ +1).

(Example 1-15)

According to Method B, except that 4,4-spirocyclobutyl-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxy Carbonylamino-18- (4,4-spirocyclobutyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (Compound AR00304065) was synthesized. ¹ H NMR (400 MHz, d ₆ -acetone) δ 7.99 (d, 1 H), 7.57 to 7.66 (m, 1 H), 7.27 (t, 1 H), 7.09 to 7.22 (m, 2 H), 5.99 (bs, 1 H ), 5.56 (dd, 1H), 5.42 (bs, 1H), 5.19 to 5.30 (m, 1H), 4.52 to 4.70 (m, 1H), 4.27 to 4.42 (m, 1H), 4.17 to 4.27 (m, 1H) ), 3.91 (dd, 1H), 3.63 to 3.82 (m, 2H), 2.22 to 2.51 (m, 6H), 1.93 to 2.20 (m, 3H), 1.79 to 1.91 (m, 1H), 1.52 to 1.66 (m , 1H), 1.16-1.50 (m, 19H). MS m / z 665.1 (M ⁺ +1)

(Example 1-15a)
Preparation of 4,4-spirocyclobutyl-1,2,3,4-tetrahydro-isoquinoline

A: To a solution of 1-phenyl-1-cyclopropanecarbonitrile (2.00 g, 12.7 mmol) in THF (100 mL), a 1.0 M solution of LiAlH (19.1 mL, 19.1 mmol) was added dropwise at room temperature. The reaction was stirred at room temperature for 15 hours, then H ₂ O (10 mL) was then slowly quenched at 0 ° C. with 1.0 N NaOH (10 mL) and stirred at room temperature for 1.5 hours. The solution was filtered and THF was removed by rotary evaporation. The aqueous solution was extracted with EtOAc and the organic extract was washed with H ₂ O and brine, dried over Na ₂ SO ₄ and concentrated to give 0.70 g (34%) of a clear oil that was not further purified. Used for next step.

B: Methyl chloroformate was added dropwise at 0 ° C. to a solution of C- (1-phenyl-cyclobutyl) -methylamine (0.70 g, 4.34 mmol) and TEA (0.67 mL, 4.78 mmol) in THF (40 mL). The reaction was stirred at room temperature for 15 hours. The next day, water and EtOAc were added and the organic layer was separated, washed with 1N HCl and brine, dried over Na ₂ SO ₄ , concentrated to an oil and used directly in the next step without further purification.

A mixture of C: (1-phenyl-cyclobutylmethyl) -carbamic acid methyl ester (0.95 g, 4.34 mmol) and PPA (20 mL) was added to a sand bath preheated to 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 extract was washed with brine, dried over Na ₂ SO ₄ , concentrated to a clear oil and used directly in the next step without further purification.

D: To a solution of 3,4-dihydro-2H-isoquinolin-1-one (0.406 g, 2.17 mmol) in THF (20 mL) was added dropwise a 1.0 M solution of LiAlH (3.26 mL, 3.26 mmol) at 0 ° C. The reaction was warmed to room temperature and stirred for 15 hours, then H ₂ O (5 mL) was then slowly quenched at 0 ° C. with 1.0 N NaOH (5 mL) and stirred at room temperature for 1.5 hours. The solution was filtered and THF was removed by rotary evaporation. The aqueous solution was extracted with EtOAc and the organic extract was washed with H ₂ O and brine, dried over Na ₂ SO ₄ and concentrated to give 0.21 g (56%) of a clear oil that was not further purified. Used for next step.

(Example 1-16)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino according to Method B except that 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4. -18- (4,4-Dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -Ene-4-carboxylic acid (compound AR00304066) was synthesized. ¹ H NMR (400 MHz, d ₆ -acetone) δ 7.98 (d, 1H), 7.39 (bs, 1H), 7.09-7.24 (m, 3H), 5.99 (bs, 1H), 5.57 (dd, 1H), 5.37 to 5.46 (bs, 1H), 5.24 (dd, 1H), 4.55 to 4.69 (m, 1H), 4.26 to 4.36 (m, 1H), 4.16 to 4.26 (m, 1H), 3.90 (dd, 1H), 3.40 to 3.49 (m, 1H), 2.28 to 2.50 (m, 4H), 1.98 to 2.09 (2H), 1.79 to 1.92 (m, 1H), 1.52 to 1.65 (m, 3H), 1.16 to 1.51 (m, 22H) ). MS m / z 653.0 (M ⁺ +1)

(Example 1-16a)

  According to the experiment of steps A to D in Example 1-15a, 2-methyl-2-phenyl-propionitrile (Caron, S .; Vazquez, E .; Wojcik, JM, J. Am. Chem. Soc., 2000 Year, 122, pp. 712-713) was converted to the title compound to prepare 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline.

(Example 1-17)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18 according to Method B except that 4-methyl-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4 -(4-Methyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -A carboxylic acid (compound AR00304067) was synthesized. ¹ H NMR (400 MHz, d ₆ -acetone) δ 7.93 to 8.03 (m, 1H), 7.04 to 7.28 (m, 4H), 6.02 (bs, 1H), 5.56 (dd, 1H), 5.40 (m, 1H ), 5.23 (dd, 1H), 4.66 to 4.85 (m, 1H), 4.54 to 4.64 (m, 1H), 4.34 to 4.54 (m, 1H), 4.17 to 4.34 (m, 1H), 3.91 (dd, 1H) ), 3.57 to 3.78 (m, 1H), 3.42 to 3.57 (m, 1H), 2.26 to 2.52 (m, 4H), 1.96 to 2.09 (m, 2.0), 1.77 to 1.92 (m, 1.0), 1.50 to 1.64 (m, 3.0), 1.13-1.50 (m, 17h). MS m / z 639.0 (M ⁺ +1)

(Example 1-17a)

  Grunewald, GL; Sall, DJ; Monn, JA, J. Med. Chem., 1988, 31, 433-444, 2-phenyl-propylamine to 4-methyl-1,2,3,4- Tetrahydroisoquinoline was prepared.

(Example 1-18)

According to Method B, except that tert-butyl- (4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) -amine was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (2-tert-butylamino-6,7-dihydro-4H-thiazolo [5,4-c] pyridine-5-carbonyloxy) -2 , 15-Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304103) was synthesized. MS m / e 731.2 (M ⁺ +1)

(Example 1-19)

According to method B, except that 4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-ylamine was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -18 -(2-Amino-6,7-dihydro-4H-thiazolo [5,4-c] pyridine-5-carbonyloxy) -14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza- Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304154) was synthesized. MS m / e 675.1 (M ⁺ +1).

(Example 1-20)

According to Method B, except that 2-methyl-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridine was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14 -tert-Butoxycarbonylamino-18- (2-methyl-6,7-dihydro-4H-thiazolo [5,4-c] pyridine-5-carbonyloxy) -2,15-dioxo-3,16-diaza- Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304158) was synthesized. MS m / e 546.2 (M ⁺ + 1-100).

(Example 1-21)

According to Method B except that 5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidine was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxy Carbonylamino-18- (7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (compound AR00304183) was synthesized. MS m / e 625.2 (M-1).

(Example 1-22)

Method B except that the ring-closing metathesis product 10 from Step 3 was further reduced with H ₂ / Rh—Al ₂ O ₃ followed by the next coupling step (WO 0059929, pages 76-77). (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16 -Diaza-tricyclo [14.3.0.0 ^4,6 ] nonadecane-4-carboxylic acid (compound AR00312023) was synthesized. MS m / e 625.3 (M-1).

(Example 1-23)

According to Method B except that 1,2,3,4-tetrahydro-isoquinolin-6-ylamine was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -18- (6-amino-3, 4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -A carboxylic acid (compound AR00314578) was synthesized. MS (POS ESI) m / z 540.2 [parent, (M ⁺ +1) -100 (Boc group)].

(Example 1-24)

According to Method B, except that N- (4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) -acetamide was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -18- (2-acetylamino-6,7-dihydro-4H-thiazolo [5,4-c] pyridine-5-carbonyloxy) -14-tert-butoxycarbonylamino-2,15-dioxo -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00314685) was synthesized. MS m / e 589.2 (M ⁺ + 1-100).

(Example 1-25)

According to Method B, except that dimethyl- (1,2,3,4-tetrahydro-isoquinolin-5-yl) -amine (Example 1-25a) was used instead in step 4, (1S, 4R, 6S, 14S , 18R) -14-tert-butoxycarbonylamino-18- (5-dimethylamino-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [ 14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (compound AR00315997) was synthesized. MS m / e 668.0 (M ⁺ ).

(Example 1-25a)

  The synthesis of dimethyl- (1,2,3,4-tetrahydro-isoquinolin-5-yl) -amine is described in the following scheme.

To a solution of 5-aminotetrahydroisoquinoline (3.68 g, 24.8 mmol) in 1,4-dioxane (100 mL) was added 3N NaOH (8.27 mL, 24.8 mmol). After cooling to 0 ° C., (Boc) ₂ O (5.42 g, 24.8 mmol) in 1,4-dioxane (10 mL) was added dropwise and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc (2 times). The combined organic layers were washed with saturated aqueous NaHCO ₃ solution, water, and brine, then dried and concentrated. The residue was purified by silica gel chromatography to give 5.44 g (88%) of the desired Boc-protected product as a white solid.

To a solution of the product from the previous step (0.2 g, 0.81 mmol) in THF (5 mL) was added NaH at 0 ° C. After 15 minutes, CH ₃ I was added and stirring was continued overnight at room temperature. After completion, the reaction mixture was quenched with ice water, extracted with EtOAc (25 mL), dried (Na ₂ SO ₄ ) and concentrated. Removal of the Boc group using 0% TFA-DCM (2 mL) at 0 ° C. gave 110 mg (77.5%) of the final product as a light green solid. MS: 177.1 (MH ^<+> ).

(Example 1-26)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- according to Method B except that 5-chloro-2,3-dihydro-1H-isoindole was used instead in step 4 (5-Chloro-1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid An acid (compound AR00315998) was synthesized. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.24 to 7.02 (m, 3H), 6.82 (s, 1H), 5.68 to 5.51 (m, 1H), 5.36 (s, 1H), 5.11 to 4.96 (m, 2H), 4.67 to 4.44 (m, 5H), 4.29 to 4.20 (m, 1H), 4.20 to 4.11 (m, 1H), 3.82 to 3.74 (m, 1H), 2.69 to 2.55 (m, 1H), 2.31 to 2.15 (m, 1H), 2.14 to 2.06 (m, 1H), 2.03 (s, 1H), 2.01 to 1.86 (m, 1H), 1.86 to 1.24 (m, 11H), 1.22 (s, 9H). MS: m / e 644.9 (M ⁺ ), 646.9 (M ⁺ +2)

(Example 1-27)

According to Method B, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino- 18- (5,6-dichloro-1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene -4-carboxylic acid (compound AR00315999) was synthesized. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.29 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 5.57-5.50 (m, 1H), 5.33 (s, 1H), 5.23 ~ 5.09 (m, 2H), 4.73 ~ 4.65 (m, 1H), 4.64 ~ 4.48 (m, 5H), 4.33 ~ 4.29 (m, 1H), 4.11 ~ 4.02 (m, 1H), 3.82 ~ 3.74 (m, 1H), 2.73 to 2.61 (m, 1H), 2.29 to 2.08 (m, 3H), 2.01 (s, 1H), 1.83 to 1.65 (m, 2H), 1.63 to 1.46 (m, 2H), 1.40 to 1.12 ( m, 15H). MS: m / e 678.9 (M ⁺ ), 681 (M ⁺ +2)

(Example 1-28)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18 according to Method B except that 4R-methyl-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4. -(4R-Methyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -A carboxylic acid (compound AR00320122) was synthesized. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.02 to 7.24 (m, 3H), 5.59 (dd, 1H), 5.30 to 5.44 (m, 2H), 4.66 to 4.81 (m, 1H), 4.14 to 4.64 ( m, 3H), 3.83 to 3.92 (m, 1H), 3.58 to 3.81 (m, 1H), 3.44 to 3.56 (m, 1H), 2.86 to 3.86 (m, 1H), 2.23 to 2.58 (m, 4H), 1.87 to 2.13 (m, 2H), 1.70 to 1.87 (m, 1H), 1.50 to 1.70 (m, 3H), 1.07 to 1.51 (m, 19H), 0.80 to 0.96 (m, 2H). MS m / z 639.0 (M ⁺ +1)

(Example 1-29)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18 according to Method B except that 4S-methyl-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4. -(4S-Methyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4 -A carboxylic acid (compound AR00320123) was synthesized. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.01 to 7.23 (m, 3H), 5.58 (dd, 1H), 5.32 to 5.45 (m, 2H), 4.66 to 4.82 (m, 1H), 4.12 to 4.64 ( m, 3H), 3.86 to 3.94 (m, 1H), 3.52 to 3.74 (m, 1H), 3.43 to 3.56 (m, 1H), 2.88 to 3.85 (m, 1H), 2.24 to 2.60 (m, 4H), 1.87-2.15 (m, 2H), 1.71-1.87 (m, 1H), 1.52-1.70 (m, 3H), 1.07-1.52 (m, 19H), 0.80-0.96 (m, 2H). MS m / z 639.0 (M ⁺ +1)

(Example 1-30)

According to Method B, except that 4- (2-methoxy-phenyl) -piperidine was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- [4- (2-Methoxy-phenyl) -piperidine-1-carbonyloxy] -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00320576 ) Was synthesized. MS m / e 583.3 (M ⁺ + 1-100).

(Example 1-31)

According to Method B, except that 6-methoxy-2,3,4,9-tetrahydro-1H-b-carboline was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxy Carbonylamino-18- (6-methoxy-1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (Compound AR00320577) was synthesized. MS m / e 594.2 (M ⁺ + 1-100).

(Example 1-32)

According to Method B, except that 1-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was used instead in step 4, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxy Carbonylamino-2,15-dioxo-18- (1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinolin-2-carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (compound AR00301383) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 7.33 to 7.24 (m, 4H), 7.20 (br s, 1H), 6.61 (br s, 1H), 5.75 to 5.52 (m, 2H), 5.50 to 5.33 ( m, 2H), 4.63 to 4.43 (m, 2H), 4.42 to 4.07 (m, 4H), 3.96 (br s, 1H), 3.67 to 3.11 (m, 5H), 3.06 to 2.88 (m, 2H), 2.86 ~ 2.74 (m, 2H), 2.56 ~ 2.35 (m, 3H), 2.23 (q, 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 ⁺ +1).

(Example 1-33)

Example 1 except that 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4. (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (6-methoxy-1-methoxymethyl-3,4-dihydro-1H-isoquinoline- 2-Carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00333842) was synthesized. MS (APCI-): m / z 697.2 (M-1).

(Example 1-34)

Example 1 except that 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4. (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (5-fluoro-1-methoxymethyl-3,4-dihydro-1H-isoquinoline- 2-Carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00365349) was synthesized. MS (APCI-): m / z 685.3 (M-1).

(Example 1-35)

Instead of 1,2,3,4-tetrahydro-isoquinoline in step 4, use dimethyl- (1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl) -amine (synthesized according to Example 1-35a). (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (1-dimethylaminomethyl-3,4-dihydro- 1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00333224) was synthesized. MS (APCI +): m / z 582.3 (MH ⁺ -Boc).

(Example 1-35a)

  Example 1 except that phenethylamine was used in place of 2- (3-methoxy-phenyl) -ethylamine in step 1 and dimethyl-amine was used in place of sodium methoxide as the nucleophile in the first part of step 3. Dimethyl- (1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl) -amine was synthesized by a method similar to that shown in 3-76a. The crude product was used directly in the next coupling step without further purification.

(Example 1-36)

1-morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to Example 1-36a) was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 According to the procedure described in Example 1-2, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (1-morpholin-4-ylmethyl-3,4-dihydro- 1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00333225) was synthesized. MS (APCI-): m / z 722.3 (M-1).

(Example 1-36a)

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

(Example 1-37)

Instead of 1,2,3,4-tetrahydro-isoquinoline in Step 4, 6-methoxy-1-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to Example 1-37a) (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (6-methoxy-1-piperidine-1- Ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ( Compound AR00333248) was synthesized. MS (APCI-): m / z 750.4 (M-1).

(Example 1-37a)

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

(Example 1-38)

Instead of 1,2,3,4-tetrahydro-isoquinoline in Step 4, 6-methoxy-1-morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (synthesized according to Example 1-38a) (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (6-methoxy-1-morpholine-4-one) according to the procedure described in Example 1-2, except that Ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ( Compound AR00333276) was synthesized. MS (APCI-): m / z 750.3 (M-1).

(Example 1-38a)

  In a manner similar to that shown in Example 3-76a except that morpholine was used in place of sodium methoxide as the nucleophile in the first part of Step 3, 6-methoxy-1-morpholin-4-ylmethyl -1,2,3,4-Tetrahydro-isoquinoline was synthesized. The crude product was used directly in the next coupling step without further purification.

(Example 1-39)

Instead of 1,2,3,4-tetrahydro-isoquinoline in step 4, (6-methoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl) -dimethyl-amine (synthesized according to Example 1-39a) In accordance with the procedure described in Example 1-2, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (1-dimethylaminomethyl-6- Methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ( Compound AR00333277) was synthesized. MS (APCI +): m / z 712.3 (MH ⁺ ).

(Example 1-39a)

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

(Example 1-40)

Example 1 with the exception that 4-fluoro-2,3-dihydro-1H-isoindole (synthesized according to Example 3-55a) was used instead of 1,2,3,4-tetrahydro-isoquinoline in Step 4. According to the procedure described in -2, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)- 2,15-Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (Compound AR00365369) was synthesized. ¹ H NMR (500 MHz, DMSO) δ 12.21 (br s, 1H), 8.66 (br s, 1H), 7.35 (q, 1H), 7.19 (d, 1H), 7.11 (q, 2H), 7.03 (br s, 1H), 5.51 (q, 1H), 5.33 to 5.21 (m, 2H), 4.66 (s, 4H), 4.22 (q, 1H), 4.24 (t, 1H), 3.99 to 3.89 (m, 1H) , 3.73 to 3.64 (m, 1H), 2.65 to 2.55 (m, 1H), 2.28 to 2.08 (m, 3H), 1.77 to 1.61 (m, 2H), 1.54 to 1.42 (m, 1H), 1.42 to 1.03 ( m, 16H); MS (APCI-): m / z 627.3 (M-1).

(Example 1-41)

5- (2-morpholin-4-yl-ethoxy) -2,3-dihydro-1H-isoindole (J. Med. Chem., 2002) instead of 1,2,3,4-tetrahydro-isoquinoline in Step 4 Year 45, 26, 5771, Preparation Method D, and procedures described in Bioorg. Med. Chem. Lett., 11 (2001) pp. 685-688 N-Boc protected amine input ¹ H NMR (500 MHz, CDCl ₃ ) δ 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 + 1)) According to the procedure described, (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- [5- (2-morpholin-4-yl-ethoxy) -1,3-dihydro-isoindole -2-carbonyloxy] -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00371946) was synthesized. MS (APCI +): m / z 640.3 [(M + 1) -Boc].

(Example 1-42)

Instead of 1,2,3,4-tetrahydro-isoquinoline in step 4, [2- (2,3-dihydro-1H-isoindol-5-yloxy) -ethyl] -dimethyl-amine (J. Med. Chem. 2002, 45, 26, 5771, Preparation Method D, and Bioorg. Med. Chem. Lett., 11 (2001), pages 685-688, N-Boc protected. As amine input, ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.14 (dd, 1H), 6.88-6.76 (m, 2H), 4.61 (t, 4H), 4.04 (t, 2H), 2.72 (t, 2H), 2.34 (s, 6H), 1.50 (s, 9H); MS (APCI +): m / z 307.1 (M + 1)) according to the procedure described in Example 1-2 ( 1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- [5- (2-dimethylamino-ethoxy) -1,3-dihydro-isoindole-2-carbonyloxy] -2, 15-Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (Compound AR00371947) was synthesized. MS (APCI +): m / z 698.2 (M + 1).

(Example 1-43)

Instead of 1,2,3,4-tetrahydro-isoquinoline in step 4, [2- (2,3-dihydro-1H-isoindol-5-yloxy) -ethyl] -isopropyl-amine (J. Med. Chem. 2002, 45, 26, 5771, Preparation Method D, and Bioorg. Med. Chem. Lett., 11 (2001), pages 685-688, N-Boc protection. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.13 (dd, 1H), 6.86-6.75 (m, 2H), 4.62 (t, 4H), 4.06 (t, 2H), 2.99 (t , 2H), 2.88 (sevent, 1H), 1.62 (br s, 1H), 1.51 (s, 9H), 1.10 (d, 6H); MS (APCI +): m / z 321.2 (M + 1)) (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- [5- (2-isopropylamino-ethoxy) according to the procedure described in Example 1-2, except that -1,3-Dihydro-isoindole-2-carbonyloxy] -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00371948 ) Was synthesized. MS (APCI-): m / z 710.3 (M-1).

  Preparation of compounds having general structure III

  A compound having the general structure II was prepared according to the general scheme shown above. Carbamates, amides, or ureas were formed from compounds having structure Ia by first removing the Boc protecting group followed by a nucleophilic attack on the electrophilic amino group.

(Example 2-1)

Step 1: (1S, 4R, 6S, 14S, 18R) -14-amino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza- Preparation of tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ethyl ester

  N-Boc protected starting material (102 mg, 0.16 mmol) was dissolved in 6 mL of 4N HCl (dioxane) and allowed to stand at room temperature for 90 minutes. HPLC showed that the Boc protecting group was completely removed. The reaction mixture was then concentrated, dissolved in acetonitrile and concentrated again twice. The resulting light brown foamy powder was used in the next step.

Step 2: (1S, 4R, 6S, 14S, 18R) -14-cyclopentyloxycarbonylamino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16 Of 2-Diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ethyl ester

To a solution of cyclopentanol (42 mg, 0.48 mmol) in THF (16 mL) was added dropwise a toluene solution of phosgene (0.42 mL, 1.9 M, 0.80 mmol). The mixture was stirred at room temperature for 2 hours to give cyclopentyl chloroformate reagent. The reaction was then concentrated to about half. It was then diluted to the original volume with DCM and reconcentrated in half to completely remove excess phosgene. This cyclopentyl chloroformate solution was further diluted with THF (16 mL), cooled to 0 ° C. and added to the solid residue from Step 1 above (0.16 mmol) at 0 ° C. TEA (0.11 mL, 0.81 mmol) was then added to the reaction mixture and the reaction was stirred at 0 ° C. for 2 hours. The reaction was complete according to HPLC. Concentrated and dissolved in EtOAc (15 mL), then washed with water, saturated sodium bicarbonate, water, and brine (10 mL each), dried over Na ₂ SO ₄ and concentrated. The crude yellow thick oil residue was purified by flash chromatography on Biotage 40S (eluent = hexane / EtOAc 1: 1) to give the desired product as a white crisp foam powder (65.2 mg, 63%). As obtained. MS (MH ⁺ 665.2).

Step 3: (1S, 4R, 6S, 14S, 18R) -14-cyclopentyloxycarbonylamino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16 Of 2-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00247310)

  A hydrolysis procedure similar to that in Step 5 of Example 1-1 was followed.

  Using either cyclopentyl chloroformate substituted with other electrophiles and / or P2-tetrahydroisoquinoline substituted with other amine inputs as described in Method B Step 4 of Example 1-2 The following compounds were also prepared according to procedures similar to those already described in Example 2-1.

(Example 2-2)

(1S, 4R, 6S, 14S, 18R) -18- (3,4-Dihydro-1H-isoquinoline-2, according to the procedure described in Example 2-1, except that methyl chloroformate was used instead in step 2. -Carbonyloxy) -14-methoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00294376) was synthesized.

(Example 2-3)

According to the procedure described in Examples 1-2 and 2-1, except that 5-fluoro-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4 of Example 1-2 (1S, 4R, 6S, 14S, 18R) -14-cyclopentyloxycarbonylamino-18- (5-fluoro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza -Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304074) was synthesized. MS m / e 583.2 (M ⁺ +1).

(Example 2-4)

According to the procedure described in Examples 1-2 and 2-1, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4 of Example 1-2. 1S, 4R, 6S, 14S, 18R) -14-cyclopentyloxycarbonylamino-2,15-dioxo-18- (8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -3 , 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304075) was synthesized. MS m / e 705.1 (M ⁺ +1).

(Example 2-5)

According to the procedure described in Examples 1-2 and 2-1, except that 2,3-dihydro-1H-isoindole was used instead in Step 4 of Example 1-2 (1S, 4R, 6S, 14S , 18R) -14-cyclopentyloxycarbonylamino-18- (1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (Compound AR00304076) was synthesized. MS m / e 623.2 (M ⁺⁺ 1).

(Example 2-6)

According to the procedure described in Example 2-1, except that 2-fluoroethanol was used instead of cyclopentanol to form the chloroformate reagent in step 2, (1S, 4R, 6S, 14S, 18R ) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14- (2-fluoro-ethoxycarbonylamino) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (compound AR00304125) was synthesized. MS m / e 615.1 (M ⁺⁺ 1).

(Example 2-7)

According to the procedure described in Example 2-1, except that tetrahydro-furan-3S-ol was used instead of cyclopentanol to form the chloroformate reagent in step 2, (1S, 4R, 6S, 14S, 18R) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-furan-3S-yloxycarbonylamino) -3,16-diaza -Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304126) was synthesized. MS m / e 639.2 (M ⁺ +1).

(Example 2-8)

According to the procedure described in Example 2-1, except that tetrahydro-furan-3R-ol was used instead of cyclopentanol to form the chloroformate reagent in step 2, (1S, 4R, 6S, 14S, 18R) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-furan-3R-yloxycarbonylamino) -3,16-diaza -Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304127) was synthesized. MS m / e 639.2 (M ⁺ +1).

(Example 2-9)

According to the procedure described in Example 2-1, except that tetrahydro-pyran-4-ol was used instead of cyclopentanol to form the chloroformate reagent in step 2, (1S, 4R, 6S, 14S, 18R) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-pyran-4-yloxycarbonylamino) -3,16-diaza -Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00320002) was synthesized. MS m / e 653.2 (M ⁺ +1).

(Example 2-10)

Instead of cyclopentanol to use 2,3-dihydro-1H-isoindole in Step 4 of Example 1-2 instead to form the chloroformate reagent in Step 2 of Example 2-1. According to the procedure described in Examples 1-2 and 2-1, except that tetrahydro-furan-3R-ol was used, (1S, 4R, 6S, 14S, 18R) -18- (1,3-dihydro-iso Indole-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-furan-3R-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene- 4-Carboxylic acid (Compound AR00320074) was synthesized. MS m / e 625.2 (M ⁺⁺ 1).

(Example 2-11)

Instead of cyclopentanol to use 2,3-dihydro-1H-isoindole in Step 4 of Example 1-2 instead to form the chloroformate reagent in Step 2 of Example 2-1. According to the procedure described in Examples 1-2 and 2-1, except that tetrahydro-furan-3S-ol was used, (1S, 4R, 6S, 14S, 18R) -18- (1,3-dihydro-iso Indole-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-furan-3S-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene- 4-Carboxylic acid (Compound AR00320075) was synthesized. MS m / e 625.2 (M ⁺⁺ 1).

(Example 2-12)

Instead of cyclopentanol to use 2,3-dihydro-1H-isoindole in Step 4 of Example 1-2 instead to form the chloroformate reagent in Step 2 of Example 2-1. According to the procedure described in Examples 1-2 and 2-1, except that 2-fluoroethanol was used, (1S, 4R, 6S, 14S, 18R) -18- (1,3-dihydro-isoindole-2 -Carbonyloxy) -2,15-dioxo-14- ( 2-fluoro-ethoxycarbonylamino ) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00320076) was synthesized. MS m / e 601.1 (M ⁺⁺ 1).

(Example 2-13)

Instead of cyclopentanol to use 2,3-dihydro-1H-isoindole in Step 4 of Example 1-2 instead to form the chloroformate reagent in Step 2 of Example 2-1. According to the procedure described in Examples 1-2 and 2-1, except that tetrahydro-pyran-4-ol was used, (1S, 4R, 6S, 14S, 18R) -18- (1,3-dihydro-iso Indole-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-pyran-4-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene- 4-Carboxylic acid (Compound AR00320077) was synthesized. MS m / e 601.1 (M ⁺⁺ 1).

(Example 2-14)

To use 5,6-dichloro-2,3-dihydro-1H-isoindole instead in Step 4 of Example 1-2 to form the chloroformate reagent in Step 2 of Example 2-1, According to the procedure described in Examples 1-2 and 2-1, except that tetrahydro-furan-3R-ol was used instead of cyclopentanol, (1S, 4R, 6S, 14S, 18R) -18- (5 , 6-Dichloro-1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-furan-3R-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3 .0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00320445) was synthesized. MS: m / e 693.0 (M ^<+> ), 695.1 (M ⁺⁺ 2).

(Example 2-15)

To substitute 5-chloro-2,3-dihydro-1H-isoindole in Step 4 of Example 1-2 and form the chloroformate reagent in Step 2 of Example 2-1, According to the procedure described in Examples 1-2 and 2-1, except that tetrahydro-furan-3R-ol was used instead of tanol, (1S, 4R, 6S, 14S, 18R) -18- (5-chloro -1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-14- (tetrahydro-furan-3R-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^{4, 6} ] Nonadeca-7-ene-4-carboxylic acid (Compound AR00320448) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 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 to 3.69 (m, 1H), 3.68 to 3.60 (m, 1H), 3.50 (t, 1H), 2.55 to 2.36 (m, 3H), 2.21 to 2.12 (m, 1H), 1.98 to 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)

(1S, 4R, 6S, 14S, 18R) -14- (Cyclopentanecarbonyl-amino) -18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16 Of 2-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR248689)

Cyclopentyl carboxylic acid was first introduced onto PS-TFP resin (purchased from Argonaut Technologies) to form the active ester. The active ester on the resin (26 mg, 1.16 mmol / g, 0.03 mmol) was first swollen in 0.5 mL chloroform, followed by MP-carbonate resin (purchased from Argonaut Technologies, 300 mg, 2.5 mmol / g, 0.75 mmol). added. To this resin mixture was then added a macrocycle (15 mg, 0.02 mmol) in 0.5 M chloroform and the reaction was shaken at room temperature overnight. After 16 hours, the reaction was complete by HPLC. Filtration and concentration then gave a clear N-acylated product. Hydrolysis according to a hydrolysis procedure similar to that in Example 1-1, step 5, gave the desired product AR248689 as a white solid (12.5 mg, 88%). MS (APCI +): m / z 621.3 (MH ^<+> ).

(Example 2-17)

A procedure similar to that described in Example 2-16 was followed except that tert-butylcarboxylic acid was first introduced into the PS-TFP resin, followed by (1S, 4R, 6S, 14S, 18R) -18- (3, 4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14- (2,2-dimethyl-propionylamino) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-4-carboxylic acid (compound AR00248687) was synthesized. MS (APCI +): m / z 609.3 (MH ^<+> ).

(Example 2-18)

A procedure similar to that described in Example 2-16 was followed except that isopropyl carboxylic acid was first introduced into the PS-TFP resin, followed by (1S, 4R, 6S, 14S, 18R) -18- (3,4- Dihydro-1H-isoquinoline-2-carbonyloxy) -14-isobutyrylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (Compound AR00248688) was synthesized. MS (APCI +): m / z 595.3 (MH ^<+> ).

(Example 2-19)

(1S, 4R, 6S, 14S, 18R) -14- (2-tert-Butoxycarbonylamino-3-methyl-butyrylamino) -18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2 Of 1,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR298989)

14-amino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene- 4-carboxylic acid ethyl ester (120 mg, 217 μmol) and N-α-t-Boc-L-valine N-hydroxysuccinic acid amide ester (96 mg, 300 μmol) were stirred together in 1.1 mL of dichloromethane for 14 hours. The solvent was removed in vacuo and 1 mL each of water and ethyl acetate was added. The phases were separated and the aqueous layer was washed twice with 500 μL of ethyl acetate. The combined organics were dried over MgSO ₄ and the solvent removed in vacuo to give the desired compound as a white solid (132 mg, 81%). MS m / z 752.2 (MH +).

(Example 2-20)

Instead of N-α-t-Boc-L-valine N-hydroxysuccinamide ester 3-methyl-2-[(pyrazine-2-carbonyl) -amino] -butyric acid 2,5-dioxo-pyrrolidine-1- A procedure similar to that described in Example 2-19, except that the yl ester was used, was followed by (1S, 4R, 6S, 14S, 18R) -18- (3,4-dihydro-1H-isoquinoline-2- Carbonyloxy) -14- {3-methyl-2-[(pyrazine-2-carbonyl) -amino] -butyrylamino} -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca -7-ene-4-carboxylic acid (compound AR00301338) was synthesized. MS m / e 730.3 (M ⁺ +1).

(Example 2-21)

2-[(6-Dimethylamino-pyridine-3-carbonyl) -amino] -3-methyl-butyric acid 2,5-dioxo instead of N-α-t-Boc-L-valine N-hydroxysuccinamide ester (1S, 4R, 6S, 14S, 18R) -18- (3,4-Dihydro-1H) was followed according to a procedure similar to that described in Example 2-19 except that -pyrrolidin-1-yl ester was used. -Isoquinoline-2-carbonyloxy) -14- {2-[(6-dimethylamino-pyridine-3-carbonyl) -amino] -3-methyl-butyrylamino} -2,15-dioxo-3,16-diaza- Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (Compound AR00304072) was synthesized. ¹ H NMR (CD ₃ OD, 500 MHz): δ 8.69 (s, 1H), 8.46 (s, 1H), 8.37-8.39 (m, 1H), 8.14-8.21 (m, 2H), 7.07-7.18 (m , 5H), 5.63 (q, 1H), 5.36 to 5.42 (m, 2H), 4.49 to 4.56 (m, 3H), 4.42 to 4.45 (m, 1H), 4.31 to 4.32 (m, 1H), 3.92 to 3.95 (m, 1H), 3.65 to 3.72 (m, 2H), 2.85 to 2.91 (m, 2H), 2.33 to 2.55 (m, 4H), 1.93 to 2.03 (m, 3H), 1.61 to 1.68 (m, 3H) 1.27 to 1.52 (m, 12H), 0.86 to 0.96 (m, 8H). MS m / e 770.4 (M-1).

(Example 2-22)

3-methyl-2-[(pyridine-3-carbonyl) -amino] -butyric acid 2,5-dioxo-pyrrolidine-1-instead of N-α-t-Boc-L-valine N-hydroxysuccinamide ester A procedure similar to that described in Example 2-19, except that the yl ester was used, was followed by (1S, 4R, 6S, 14S, 18R) -18- (3,4-dihydro-1H-isoquinoline-2- Carbonyloxy) -14- {3-methyl-2-[(pyridine-3-carbonyl) -amino] -butyrylamino} -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca -7-ene-4-carboxylic acid (compound AR00304073) was synthesized. MS m / e 729.2 (M ⁺⁺ 1).

(Example 2-23)

By following a procedure similar to step 1 of Example 2-1, (1S, 4R, 6S, 14S, 18R) -14- (2-amino-3-methyl-butyrylamino) -18- (3,4-dihydro -1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00 298990) was prepared . MS m / e 624.2 (M ⁺⁺ 1).

(Example 2-24)

(1S, 4R, 6S, 14S, 18R) -14- (3-Cyclopentyl-ureido) -18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16 Of 2-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR294378)

14-amino-2,15-dioxo-18- (8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid ethyl ester hydrochloride (49 mg, 74 μmol), diisopropylethylamine (29 mg, 222 μmol), and cyclopentyl isocyanate (25 mg, 222 μmol) were dissolved in 375 μL of dichloromethane and stirred at 19 ° C. for 1 hour. did. The reaction was introduced 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)

According to the procedure described in Examples 1-2 and 2-24, except that tert-butyl isocyanate was used instead of cyclopentyl isocyanate in the procedure of Example 2-24, (1S, 4R, 6S, 14S, 18R)- 14- (3-tert-butyl-ureido) -18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^{4, 6} ] Nonadeca-7-ene-4-carboxylic acid (compound AR00294377) was synthesized. MS m / e 624.1 (M ⁺⁺ 1).

(Example 2-26)

Example 1-2 and Example 1-2 except that 5-fluoro-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedure described in 2-24, (1S, 4R, 6S, 14S, 18R) -14- (3-cyclopentyl-ureido) -18- (5-fluoro-3,4-dihydro-1H-isoquinoline-2- Carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304077) was synthesized. MS m / e 654.2 (M ⁺ +1).

(Example 2-27)

Example 1 except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedures described in 2 and 2-24, (1S, 4R, 6S, 14S, 18R) -14- (3-cyclopentyl-ureido) -2,15-dioxo-18- (8-trifluoromethyl-3, 4-Dihydro-1H-isoquinoline-2-carbonyloxy) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304078) was synthesized. MS m / e 704.1 (M ⁺ +1).

(Example 2-28)

As described in Examples 1-2 and 2-24, except that 2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. (1S, 4R, 6S, 14S, 18R) -14- (3-cyclopentyl-ureido) -18- (1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo- 3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00304079) was synthesized. MS m / e 622.2 (M ⁺⁺ 1).

(Example 2-29)

Instead of 1,2,3,4-tetrahydro-isoquinoline in step 4 of Example 1-2, 2,3-dihydro-1H-isoindole was used and in the procedure of Example 2-24 instead of cyclopentyl isocyanate (1S, 4R, 6S, 14S, 18R) -14- (3-tert-butyl-ureido) -18 according to the procedure described in Examples 1-2 and 2-24, except that tert-butyl isocyanate was used -(1,3-Dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00320078) was synthesized. MS m / e 610.1 (M ⁺ +1).

(Example 2-30)

According to the procedure described in Examples 1-2 and 2-24, except that 3-isocyanate-tetrahydro-furan was used in place of cyclopentyl isocyanate in the procedure of Example 2-24 (1S, 4R, 6S, 14S, 18R) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-14- [3- (tetrahydro-furan-3-yl) -ureido] -3,16- Diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00320221) was synthesized. MS m / e 638.2 (M ⁺ +1).

(Example 2-31)

5-chloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 and cyclopentyl in the procedure of Example 2-24. According to the procedure described in Examples 1-2 and 2-24, except that tert-butyl isocyanate was used instead of isocyanate, (1S, 4R, 6S, 14S, 18R) -14- (3-tert-butyl- (Ureido) -18- (5-chloro-1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7- En-4-carboxylic acid (compound AR00320449) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 7.34 (s, 1H), 7.28-7.25 (m, 2H), 7.24 (s, 1H), 7.20 (s, 1H), 5.51 (m, 2H), 5.40 (s, 1H), 4.73-4.60 (m, 3H), 4.53 (t, 1H), 4.38 (d, 1H), 4.28 (d, 1H), 3.98 (dd, 1H), 2.43 (m, 2H) 2.38-2.30 (m, 1H), 2.12-2.00 (m, 2H), 1.81-1.70 (m, 1H), 1.64-1.56 (m, 3H), 1.48-1.20 (m, 8H), 1.18 (s, 9H). MS: m / e 644.0 (M +), 645.9 (M + +2)

(Example 2-32)

The procedure of Example 2-24, using 5,6-dichloro-2,3-dihydro-1H-isoindole in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 (1S, 4R, 6S, 14S, 18R) -14- (3-tert--) according to the procedure described in Examples 1-2 and 2-24, except that tert-butyl isocyanate was used instead of cyclopentyl isocyanate (Butyl-ureido) -18- (5,6-dichloro-1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (Compound AR00320450) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 7.50 (s, 1H), 7.38 (s, 1H), 5.56 (q, 1H), 5.42-5.38 (m, 2H), 4.72 to 4.61 (m, 4H) ), 4.55 (t, 1H), 4.34 (dd, 1H), 4.28 (d, 1H), 3.92 (dd, 1H), 2.45 to 2.32 (m, 2H), 2.32 to 2.18 (m, 1H), 2.08 to 2.00 (m, 1H), 1.75 to 1.68 (m, 1H), 1.63 to 1.54 (m, 3H), 1.50 to 1.22 (m, 8H), 1.18 (s, 9H). MS: m / e 678.0 (M ⁺ ), 680.0 (M ⁺⁺ 2).

(Example 2-33)

5-Fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. Except according to the procedures described in Examples 1-2 and 2-1, (1S, 4R, 6S, 14S, 18R) -14-cyclopentyloxycarbonylamino-18- (5-fluoro-1-methoxymethyl-3) , 4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00365381) Was synthesized. MS (APCI-): m / z 697.4 (M-1)

  Preparation of compounds having general structure IV

  Compounds having the 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 (Patent application PCT / US02 / 39926, International Patent No. 03/053349).

(Example 3-1)

(1S, 4R, 6S, 14S, 18R) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3, Synthesis of 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (AR00261408)

Macrocyclic acid compound number 101 (7 mg, 0.011 mmol) was dissolved in 0.1 mL of DMF, followed by addition of CDI (1.8 mg, 0.011 mmol). The mixture was stirred in a 40 ° C. oil bath 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 hours, LCMS showed that the reaction was complete. The reaction was cooled to room temperature and partitioned between EA (2 mL) and 5% HCl (aq, 2 mL). The organic layer was washed with water, bicarbonate (2 mL each) and then dried (Na ₂ SO ₄ ). The crude product was flushed on Biotage 12M (eluent = DCM: MeOH 20: 1) to give AR00261408 (4.2 mg, 52%). ¹ H NMR (CDCl ₃ , 500 MHz): δ 0.80 to 2.10 (m, 25H), 2.20 to 2.27 (m, 1H), 2.37 to 2.59 (m, 3H), 2.84 (m, 1H), 3.60 to 3.70 ( m, 1H), 3.82 to 3.90 (m, 1H), 4.20 to 4.30 (m, 2H), 4.45 to 4.70 (m, 5H), 4.95 to 5.05 (m, 2H), 5.30 to 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)

According to the procedure described in Example 3-1, except that isopropylsulfonamide was used instead of cyclopropylsulfonamide in the coupling step, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H -Isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4- (propane-2-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00261407) was synthesized. MS m / e 728.4 (M-1).

(Example 3-3)

According to the procedure described in Example 3-1, except that methylsulfonamide was used instead of cyclopropylsulfonamide in the coupling step, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H -Isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-methanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-18 -The yl ester (compound AR00254906) was synthesized. ¹ H NMR (CDCl ₃ , 500 MHz): δ 1.20 to 1.52 (m, 16H), 1.54 to 1.98 (m, 5H), 2.20 to 2.30 (m, 1H), 2.38 to 2.46 (m, 1H), 2.47 to 2.59 (m, 3H), 2.84 (m, 1H), 3.18 (s, 3H), 3.56 to 3.70 (m, 1H), 3.82 to 3.90 (m, 1H), 4.22 to 4.33 (m, 2H), 4.47 to 4.69 (m, 4H), 4.90 to 5.10 (m, 2H), 5.47 (brs, 1H), 5.74 (m, 1H), 6.74 (m, 1H), 7.03 to 7.23 (m, 4H). MS m / e 701.9 (M ⁺ ), 602.2 (parent, MH ⁺ -Boc group).

(Example 3-4)

According to the procedure described in Example 3-1, except that n-butylsulfonamide was used instead of cyclopropylsulfonamide in the coupling step, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro -1H-isoquinoline-2-carboxylic acid 4- (butane-1-sulfonylaminocarbonyl) -14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester (Compound AR00261409) was synthesized. ¹ H NMR (CDCl ₃ , 500 MHz): δ 0.80 to 1.03 (m, 7H), 1.20 to 2.10 (m, 22H), 2.20 to 2.60 (m, 4H), 2.84 (m, 1H), 3.20 (m, 1H), 3.44 (m, 1H), 3.65 (m, 1H), 3.80 to 3.95 (m, 1H), 4.20 to 4.34 (m, 2H), 4.50 to 4.65 (m, 4H), 4.95 to 5.05 (m, 1H), 5.30-5.39 (m, 1H), 5.44-5.49 (m, 1H), 5.74 (m, 1H), 6.74 (m, 1H), 7.0-7.23 (m, 4H). MS m / e 743.3 (M ⁺ , APCI-).

(Example 3-5)

Following the procedure described in Examples 2-1 and 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4- Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00282131) was synthesized. MS m / e 738.4 (M-1).

(Example 3-6)

Following the procedure described in Examples 1-5 and 3-1, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00294381) was synthesized. ¹ H NMR (CDCl ₃ , 500 MHz): δ 0.89 to 2.08 (m, 25H), 2.21 to 2.28 (m, 1H), 2.41 to 2.49 (m, 1H), 2.51 to 2.61 (m, 2H), 2.91 ( m, 1H), 3.83 (m, 1H), 4.21 (m, 1H), 4.40 (d, J = 11.7Hz, 1H), 4.53 to 4.80 (m, 5H), 4.95 to 5.04 (m, 2H), 5.47 (brs, 1H), 5.72 (m, 1H), 6.77 (m, 1H), 7.16 (m, 1H), 7.23-7.31 (m, 3H). MS m / e 712.3 (APCI-, MH).

(Example 3-7)

Example 1-2 and Example 1-2 except that 5-fluoro-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedure described in 3-1, (1S, 4R, 6S, 14S, 18R) -5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclo Propanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00298996) was synthesized. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.05 (s, 1H), 8.12 (s, 1H), 7.04 (s, 1H), 6.84 to 6.73 (m, 2H), 6.70 (s, 1H), 5.65 (q, 1H), 5.40 (s, 1H), 4.59 (m, 2H), 4.54 to 4.40 (m, 3H), 4.30 to 4.10 (m, 2H), 3.82 to 3.74 (m, 1H), 3.72 to 3.51 (m, 2H), 2.92 to 2.68 (m, 3H), 2.55 to 2.30 (m, 3H), 2.21 to 2.15 (m, 1H), 2.00 to 1.60 (m, 3H), 1.40 to 0.75 (m, 18H) . MS: m / e 746.0 (M ⁺ ).

(Example 3-8)

Example 1 except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedure described in 2 and 3-1, (1S, 4R, 6S, 14S, 18R) -8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino -4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00298997) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 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 to 3.62 (m, 2H), 3.00 to 2.82 (m, 3H), 2.58 to 2.52 (m, 3H), 2.51 to 2.32 (m, 2H), 1.86 to 1.56 (m, 3H), 1.41 (m, 2H), 1.32 to 1.21 (m, 5H), 1.04 to 0.98 ( m, 14H). MS: m / e 795.9 (M ⁺ ).

(Example 3-9)

Example 1-2 and Example 1-2 except that 7-chloro-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedure described in 3-1, (1S, 4R, 6S, 14S, 18R) -7-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclo Propanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00301746) was synthesized. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.10 (s, 1H), 7.08 (d, 1H), 7.02 to 6.96 (m, 2H), 6.60 (d, 1H), 5.64 (q, 1H), 5.40 (s, 1H), 4.92 to 4.41 (m, 2H), 4.55 to 4.40 (m, 3H), 4.28 to 4.12 (m, 2H), 3.82 to 3.75 (m, 1H), 3.65 to 3.46 (m, 3H) , 2.88-2.80 (m, 1H), 2.78-2.56 (m, 2H), 2.52-2.42 (m, 1H), 2.38-2.30 (m, 1H), 2.21-2.12 (q, 1H), 1.82-1.74 ( m, 2H), 1.45 to 1.12 (m, 16H), 1.10 to 0.98 (m, 2H), 0.90 to 0.75 (m, 2H). MS m / e 761.9 (M ⁺ )

(Example 3-10)

Example 1 except that 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedures described in 2 and 3-1, (1S, 4R, 6S, 14S, 18R) -6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino -4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00301747) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 7.44 (m, 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 to 4.50 (m, 1H), 4.48 (m, 1H), 4.15 (d, 1H), 3.88 (d, 1H), 3.75 to 3.67 ( m, 2H), 2.93 to 2.82 (m, 3H), 2.66 to 2.54 (m, 1H), 2.52 to 2.44 (m, 1H), 2.42 to 2.40 (m, 2H), 1.91 to 1.76 (m, 2H), 1.74 to 1.70 (dd, 1H), 1.64 to 1.58 (m, 1H), 1.54 to 1.36 (m, 4H), 1.34 to 1.25 (m, 12H), 1.50 to 1.20 (m, 2H), 1.00 to 0.70 (m , 1H), 0.52 to 0.34 (m, 1H). MS: m / e 795.9 (M ⁺ )

(Example 3-11)

Examples 1-2 and 4 except that 6-fluoro-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedure described in 3-1, (1S, 4R, 6S, 14S, 18R) -6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclo Propanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00301751) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 7.21 to 7.02 (m, 1H), 6.92 (m, 2H), 6.92 (m, 2H), 5.68 (q, 1H), 5.40 (m, 1H), 5.08 (t, 1H), 4.58 (m, 2H), 4.45 (m, 1H), 4.12 (d, 1H), 3.88 (d, 1H), 3.78 to 3.60 (m, 3H), 2.86 to 2.72 (m, 3H), 2.71 to 2.61 (m, 1H), 2.52 to 2.42 (m, 1H), 2.41 to 2.34 (m, 1H), 1.88 to 1.76 (m, 2H), 1.74 to 1.70 (m, 1H), 1.64 to 1.58 (m, 1H), 1.56-1.38 (m, 2H), 1.37-1.24 (m, 14H), 1.13-1.04 (m, 2H), 1.02-0.89 (m, 1H), 0.88-0.82 (m, 1H ). MS: m / e 746.0 (M ⁺ ). MS m / e 757.2 (M ⁺ +1).

(Example 3-12)

Example 1-2, except that 5-fluoro-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 According to the procedure described in 2-24 and 3-1, (1S, 4R, 6S, 14S, 18R) -5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14- (3-cyclopentyl- Ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00304080) was synthesized.

(Example 3-13)

Example 1 except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedures described in 2, 2-24 and 3-1, (1S, 4R, 6S, 14S, 18R) -8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14- ( 3-Cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00304081) Was synthesized. MS m / e 807.2 (M ⁺ +1).

(Example 3-14)

Examples 1-2, 2-24 and 3 except that 2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid 14- (3-cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl -2,15-Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00304082) was synthesized. MS m / e 725.2 (M ⁺ +1).

(Example 3-15)

As described in Examples 1-2, 2-1 and 3-1 except that 2-fluoroethanol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2-fluoro-ethoxycarbonylamino)- 2,15-Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00304161) was synthesized. MS m / e 718.1 (M ⁺⁺ 1).

(Example 3-16)

Examples 1-2, 2-1 and 3-, except that tetrahydro-furan-3S-ol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- ( Tetrahydro-furan-3-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00304162) was synthesized. MS m / e 742.1 (M ⁺ +1).

(Example 3-17)

Examples 1-2, 2-1 and 3-, except that tetrahydro-furan-3R-ol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- ( Tetrahydro-furan-3R-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00304163) was synthesized. ¹ H NMR (d ⁶ -benzene, 500 MHz): δ 10.53 (s, 1H), 6.78-6.96 (m, 4H), 5.83-5.90 (m, 1H), 5.66 (q, 1H), 5.18-5.21 ( m, 1H), 5.13 (brs, 1H), 5.04 (brs, 1H), 4.41 to 4.87 (m, 3H), 3.85 to 4.05 (m, 4H), 3.67 to 3.74 (m, 1H), 3.46 to 3.53 ( m, 3H), 3.23 to 3.34 (m, 1H), 2.80 to 2.85 (m, 1H), 2.34 to 2.59 (m, 4H), 1.84 to 1.99 (m, 4H), 0.98 to 1.60 (m, 14H), 0.42 to 0.47 (m, 1H), 0.27 to 0.32 (m, 1H). MS m / e 741.2 (M-1).

(Example 3-18)

Instead of 1,2,3,4-tetrahydro-isoquinoline in step 4 of Example 1-2, phenyl- (4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridin-2-yl) (1S, 4R, 6S, 14S, 18R) -2-phenylamino-6,7-dihydro-4H-thiazolo [ 5,4-c] pyridine-5-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca -7-en-18-yl ester (compound AR00311814) was synthesized. MS m / e 826.2 (M ⁺ +1).

(Example 3-19)

Example 1 except that 1-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 According to the procedure described in 1-2 and 3-1, (1S, 4R, 6S, 14S, 18R) -1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert -Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00311815) was synthesized did. ¹ H NMR (500 MHz, CD ₃ OD) δ 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 to 4.17 (m, 4H), 4.11 to 4.04 (m, 1H), 3.96 to 3.88 (m, 1H) ), 3.75 to 3.40 (m, 5H), 3.14 to 2.32 (m, 7H), 2.05 (dd, 1H), 1.99 to 1.68 (m, 5H), 1.65 to 0.95 (m, 24H); MS (POS ESI) m / z 825.4 (M ⁺ ).

(Example 3-20)

Example 4 except that 4,4-spirocyclobutyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedures described in 1-2 and 3-1, (1S, 4R, 6S, 14S, 18R) -4,4-spirocyclobutyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert -Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00312024) was synthesized did. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.54 to 7.60 (m, 1H), 7.26 (dd, 1H), 6.97 to 7.21 (m, 1H), 5.66 (dd, 1H), 5.37 to 5.48 (m, 1H), 5.11 (dd, 1H), 4.58 (s, 2H), 4.39 (t, 3H), 4.11 to 4.26 (m, 1H), 3.77 to 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)

Example 1 except that 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedures described in 2 and 3-1, (1S, 4R, 6S, 14S, 18R) -4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino -4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00312025) was synthesized. ¹ H NMR (400 MHz, CD ₃ OD) δ 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 to 4.61 (m, 1H), 4.33 to 4.44 (m, 3H), 4.11 to 4.24 (m, 1.0), 3.82 to 3.95 (m, 3H), 3.36 to 3.55 ( m, 2H), 2.84 to 2.94 (m, 1H), 2.25 to 2.69 (m, 4H), 1.68 to 2.24 (m, 4H), 1.15 to 1.68 (m, 23H), 0.81 to 1.15 (m, 3H). MS m / z 756.0 (M ⁺ +1)

(Example 3-22)

Examples 1-2 and 4 except that 4-methyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. According to the procedure described in 3-1, (1S, 4R, 6S, 14S, 18R) -4-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclo Propanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00312026) was synthesized. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.76 (s, 1H), 6.98 to 7.24 (m, 3H), 5.67 (dd, 1H), 5.2 to 5.51 (m, 1H), 5.04 to 5.15 (dd, 1H), 4.28 to 4.63 (m, 5H), 4.10 to 4.24 (m, 1H), 3.81 to 3.96 (m, 3H), 3.37 to 3.78 (m, 2H), 2.83 to 3.06 (m, 2H), 2.54 to 2.71 (m, 1H), 2.25 to 2.54 (m, 3H), 1.69 to 1.94 (m, 3H), 1.16 to 1.69 (m, 20H), 0.81 to 1.15 (3H). MS m / z 742.0 (M ⁺ +1)

(Example 3-23)

In Step 4 of Example 1-2, instead of 1,2,3,4-tetrahydro-isoquinoline, 4,4-spirocyclobutyl-1,2,3,4-tetrahydro-isoquinoline was used. As described in Examples 1-2, 2-1 and 3-1 except that tetrahydro-furan-3R-ol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of 1. According to the procedure, (1S, 4R, 6S, 14S, 18R) -4,4-spirocyclobutyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo -14- (Tetrahydro-furan-3-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00314635) was synthesized. ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 10.24-10.29 (s, 1H), 7.49-7.55 (m, 1H), 7.24 (dd, 1H), 7.14 (dd, 1H), 7.04 (dd, 1H ), 6.81 (d 1H), 5.71 (dd, 1H), 4.95 (dd, 1H), 4.90 (bs, 1H), 4.48 to 4.59 (m, 3H), 4.17 to 4.30 (m, 2H), 3.51 to 3.74 (m, 3H), 3.51 to 3.72 (6H), 2.80 to 2.86 (m, 1H), 2.36 to 2.54 (m, 3H), 2.10 to 2.33 (m, 4H), 1.80 to 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)

In Step 4 of Example 1-2, 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline was used instead of 1,2,3,4-tetrahydro-isoquinoline, and Example 2-1 Follow the procedure described in Examples 1-2, 2-1 and 3-1 except that tetrahydro-furan-3S-ol was used instead of cyclopentanol to form the chloroformate reagent in Step 2. (1S, 4R, 6S, 14S, 18R) -4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- ( Tetrahydro-furan-3S-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00314654) was synthesized. ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.51 to 8.64 (bs, 1H), 7.26 to 7.36 (m, 1H), 7.09 to 7.19 (m, 2H), 6.98 to 7.08 (m, 1H), 5.70 (dd, 1H), 4.95 (dd, 1H), 4.83 (d, 1H), 4.44 to 4.72 (m, 3H), 4.17 to 4.30 (m, 2H), 3.25 to 3.91 (m, 9H), 2.80 to 2.86 (m, 1H), 2.35 to 2.55 (m, 4H), 2.13 to 2.34 (m, 4H), 1.91 to 2.07 (m, 2H), 1.80 to 1.90 (m, 2H), 1.66 to 1.80 (m, 2H) 1.51 to 1.63 (m, 2H), 1.30 to 1.51 (m, 2H), 0.96 to 1.15 (m, 3H), 0.65 to 0.95 (m, 9H). MS m / z 770.1 (M ⁺ +1)

(Example 3-25)

4-methyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in step 4 of Example 1-2, and cyclopentyl isocyanate in Example 2-24 (1S, 4R, 6S, 14S, 18R) -4-methyl-3, according to the procedure described in Examples 1-2, 2-24 and 3-1, except that t-butylisocyanate was used instead of 4-Dihydro-1H-isoquinoline-2-carboxylic acid 14- (3-tert-butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^{4 , 6} ] Nonadeca-7-en-18-yl ester (compound AR00314656) was synthesized. ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 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 to 4.90 (bs, 1H), 4.30 to 4.72 (m, 4H), 3.40 to 3.77 (m, 5H), 2.97 (d, 1H), 2.83 to 2.90 (m , 1H), 2.37 to 2.58 (m, 3H), 2.17 to 2.30 (dt, 1H), 2.22 to 2.35 (dt, 1H), 1.97 to 2.07 (m, 1H), 1.82 to 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)

Following the procedures described in Examples 1-22 and 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4 -Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-18-yl ester (compound AR00314719) was synthesized. MS m / e 630.2 (M ⁺ + 1-100).

(Example 3-27)

According to the procedure described in Examples 1-2, 2-24 and 3-1 except that t-butyl isocyanate was used instead of cyclopentyl isocyanate in Example 2-24, (1S, 4R, 6S, 14S, 18R ) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14- (3-tert-butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [ 14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester (compound AR00320001) was synthesized. MS m / e 725.7 (M-1).

(Example 3-28)

2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and the chloroformate reagent in Step 2 of Example 2-1 According to the procedure described in Examples 1-2, 2-1 and 3-1 except that 2-fluoroethanol was used instead of cyclopentanol to form (1S, 4R, 6S, 14S , 18R) -1,3-Dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2-fluoro-ethoxycarbonylamino) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester (compound AR00320073) was synthesized. MS m / e 704.0 (M ⁺ +1).

(Example 3-29)

2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and the chloroformate reagent in Step 2 of Example 2-1 According to the procedure described in Examples 1-2, 2-1 and 3-1 except that tetrahydro-furan-3R-ol was used instead of cyclopentanol to form (1S, 4R, 6S , 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (tetrahydro-furan-3-yloxycarbonylamino) -3, 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320079) was synthesized. MS m / e 728.1 (M ⁺⁺ 1).

(Example 3-30)

2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and the chloroformate reagent in Step 2 of Example 2-1 According to the procedure described in Examples 1-2, 2-1 and 3-1 except that tetrahydro-furan-3S-ol was used instead of cyclopentanol to form (1S, 4R, 6S , 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (tetrahydro-furan-3S-yloxycarbonylamino) -3, 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320080) was synthesized. MS m / e 728.1 (M ⁺⁺ 1).

(Example 3-31)

2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and the chloroformate reagent in Step 2 of Example 2-1 According to the procedure described in Examples 1-2, 2-1 and 3-1 except that tetrahydro-pyran-4-ol was used instead of cyclopentanol to form (1S, 4R, 6S , 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (tetrahydro-pyran-4-yloxycarbonylamino) -3, 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320081) was synthesized. MS m / e 742.1 (M ⁺ +1).

(Example 3-32)

Examples 1-2, 2-1 and 3-, except that tetrahydro-pyran-4-ol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- ( Tetrahydro-pyran-4-yloxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320082) was synthesized. MS m / e 756.1 (M ⁺ +1).

(Example 3-33)

Examples 1-2 and 3 except that 5-chloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. (1S, 4R, 6S, 14S, 18R) -5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonyl Aminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320119) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 7.36 (s, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.12 to 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 to 4.48 (m, 1H), 4.10 (d, 1H), 3.85 (d, 1H), 2.90 (m, 1H), 2.65 (br s, 1H), 2.54 to 2.48 (m, 1H), 2.46 to 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 to 0.82 (m, 2H). MS m / e 747.9 (M ⁺ )

(Example 3-34)

Dimethyl- (1,2,3,4-tetrahydro-isoquinolin-5-yl) -amine (Example 1-25a) instead of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 (1S, 4R, 6S, 14S, 18R) -5-dimethylamino-3,4-dihydro-1H-isoquinoline-2 according to the procedure described in Examples 1-2 and 3-1. -Carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (Compound AR00320120) was synthesized. ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.08 (s, 1H), 7.13 to 7.05 (m, 1H), 6.88 to 6.81 (d, 1H), 6.77 (d, 1H), 6.68 (d, 1H) , 6.61 to 6.53 (s, 1H), 5.71 to 5.60 (q, 1H), 5.40 (s, 1H), 5.00 to 4.88 (m, 2H), 4.55 to 4.38 (m, 3H), 4.24 to 4.16 (m, 2H), 3.88 to 3.77 (d, 1H), 3.64 to 3.41 (m, 3H), 2.91 to 2.69 (m, 3H), 2.61 (s, 6H), 2.53 to 2.41 (m, 2H), 2.40 to 2.39 ( m, 1H), 2.22 to 2.11 (m, 1H), 1.89 to 1.72 (m, 1H), 1.61 to 1.22 (m, 10H), 1.18 (s, 9H), 1.09 to 0.97 (m, 2H), 0.91 to 0.76 (m, 2H). MS: 771.1 (M ⁺ ), 772.1 (M ⁺ +1), 773.1 (M ⁺ +2)

(Example 3-35)

Example 1-2, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 And (1S, 4R, 6S, 14S, 18R) -5,6-dichloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 -Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320121) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 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 to 4.62 (m, 3H), 4.63 to 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 to 2.45 (m, 1H), 2.46 to 2.31 (m, 2H), 1.91 to 1.75 (m, 3H), 1.67 to 1.60 (m, 1H), 1.58 to 1.25 (m, 8H), 1.18 (s, 9H), 1.12 to 1.05 (m, 2H), 1.04 to 0.81 (m, 2H). MS: m / e 781.9 (M ⁺ )

(Example 3-36)

In Step 4 of Example 1-2, 2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline, and in Example 2-24, t- According to the procedure described in Examples 1-2, 2-24 and 3-1, except that butyl isocyanate was used, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2- Carboxylic acid 14- (3-tert-butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-18 -The yl ester (compound AR00320220) was synthesized. MS m / e 713.1 (M ⁺ +1).

(Example 3-37)

According to the procedure described in Examples 1-2, 2-24 and 3-1 except that 3-isocyanate-tetrahydro-furan was used instead of cyclopentyl isocyanate in Example 2-24 (1S, 4R, 6S, 14S, 18R) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- [3- (tetrahydro-furan-3-yl) -ureido] -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320222) was synthesized. MS m / e 740.8 (M ⁺ +1).

(Example 3-38)

Following the procedures described in Examples 1-2, 2-24 and 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14- (3- Synthesis of cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320403) did. MS m / e 739.2 (M ⁺ +1).

(Example 3-39)

5-chloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2, and cyclopentyl isocyanate in Example 2-24. According to the procedure described in Examples 1-2, 2-24 and 3-1, except that t-butyl isocyanate was used instead, (1S, 4R, 6S, 14S, 18R) -5-chloro-1,3 -Dihydro-isoindole-2-carboxylic acid 14- (3-tert-butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester (compound AR00320446) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD): δ 7.35 (s, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 7.02 (s, 1H), 7.18 (s, 1H), 5.65 to 5.72 (q, 1H), 5.45 (s, 1H), 5.06 (t, 1H), 4.74 to 4.60 (m, 4H), 4.56 (t, 1H), 4.46 (m, 1H), 4.22 (d, 1H) , 3.87 to 3.91 (dd, 1H), 2.86 to 2.94 (m, 1H), 2.65 to 2.54 (m, 1H), 2.52 to 2.45 (m, 1H), 2.42 to 2.34 (m, 2H), 1.92 to 1.83 ( m, 1H), 1.78 to 1.70 (m, 2H), 1.62 to 1.56 (m, 1H), 1.54 to 3.92 (m, 4H), 1.39 to 1.23 (m, 7H), 1.12 (s, 9H), 1.02 to 0.98 (m, 1H), 0.94 to 0.86 (m, 1H). MS: m / e 747.1 (M ⁺ ), 749.1 (M ⁺ +2)

(Example 3-40)

Substituting 5,6-dichloro-2,3-dihydro-1H-isoindole for 1,2,3,4-tetrahydro-isoquinoline in step 4 of Example 1-2 and cyclopentyl in Example 2-24 According to the procedure described in Examples 1-2, 2-24 and 3-1, except that t-butyl isocyanate was used instead of isocyanate, (1S, 4R, 6S, 14S, 18R) -5,6-dichloro 1,3-Dihydro-isoindole-2-carboxylic acid 14- (3-tert-butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3. 0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320447) was synthesized. MS: m / e 781.1 (M ⁺ ). 783.1 (M ⁺⁺ 2).

(Example 3-41)

Example 1 except that 1-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 According to the procedure described in 1-2, 2-1 and 3-1, (1S, 4R, 6S, 14S, 18R) -1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxyl Acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320506 ) Was synthesized. MS (POS ESI) m / z 837.4 (M ⁺ ).

(Example 3-42)

According to the procedure described in Examples 1-2 and 3-1, except that benzenesulfonamide was used instead of cyclopropylsulfonamide in the coupling step of Example 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-benzenesulfonylaminocarbonyl-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^{4 , 6} ] nonadeca-7-en-18-yl ester (compound AR00320547) was synthesized. MS m / e 762.3 (M-1).

(Example 3-43)

According to the procedure described in Examples 1-2 and 3-1, except that 4-methoxy-benzenesulfonamide was used instead of cyclopropylsulfonamide in the coupling step of Example 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-methoxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320548) was synthesized. MS m / e 792.3 (M-1).

(Example 3-44)

According to the procedure described in Examples 1-2 and 3-1, except that 4-methyl-benzenesulfonamide was used instead of cyclopropylsulfonamide in the coupling step of Example 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4- (toluene-4-sulfonylaminocarbonyl) -3,16 -Diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320549) was synthesized. MS m / e 776.3 (M ⁺ +1).

(Example 3-45)

Example 1 except that 1-piperidin-1R-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 According to the procedure described in 1-2, 2-1 and 3-1, (1S, 4R, 6S, 14S, 18R) -1-piperidin-1R-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbon Acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320556 ) Was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 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 to 4.16 (m, 2H), 4.12 to 3.97 (m, 2H), 3.86 (d, 1H), 3.75 to 3.38 (m, 2H) , 3.07 (t, 2H), 2.96-2.86 (m, 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 to 1.21 (m, 18H), 1.15 to 0.95 (m, 3H); MS (POS ESI) m / z 837.4 (M ⁺ ).

(Example 3-46)

Example 1 except that 1-piperidin-1S-ylmethyl-1,2,3,4-tetrahydro-isoquinoline was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 According to the procedure described in 1-2, 2-1 and 3-1, (1S, 4R, 6S, 14S, 18R) -1-piperidin-1S-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbon Acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320557 ) Was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 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 to 3.86 (m, 8H), 3.67 to 3.40 (m, 2H), 3.08 to 2.85 (m, 1H), 2.78 (d, 1H), 2.65 to 2.24 (m , 4H), 2.10 to 1.22 (m, 27H), 1.19 (dt, 1H), 1.10 to 1.02 (m, 2H), 1.01 to 0.93 (m, 1H), 0.89 (q, 1H); MS (POS ESI) m / z 837.4 (M ⁺ ).

(Example 3-47)

Examples 1-2, 2 except that 5-chloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 (1S, 4R, 6S, 14S, 18R) -5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14- (3-cyclopentyl-ureido) according to the procedures described in -24 and 3-1. -4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320574) was synthesized. MS: m / e 759.1 (M ⁺ ), 761.1 (M ⁺⁺ 2).

(Example 3-48)

Example 1-2, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 1-24, 3-1 and (1S, 4R, 6S, 14S, 18R) -5,6-dichloro-1,3-dihydro-isoindole-2-carboxylic acid 14- (3- Synthesis of cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320575) did. MS: m / e 793.1 (M ⁺ ).

(Example 3-49)

Examples 1-2, 2-1 except that 2,2,2-trifluoro-ethanol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. And (3-1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo- 14- (2,2,2-trifluoro-ethoxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320578) was synthesized. MS: m / e 754.0 (M ⁺⁺ 1).

(Example 3-50)

Examples 1-2, 2-1 and 3-, except that 2,2-difluoro-ethanol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2,2-difluoro- Ethoxycarbonylamino) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320579) was synthesized. MS: m / e 736.0 (M ⁺⁺ 1).

(Example 3-51)

Examples 1-2, 2-, except that 1,3-difluoro-propan-2-ol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. According to the procedures described in 1 and 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2- Fluoro-1-fluoromethyl-ethoxycarbonylamino) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00320580) was synthesized . MS: m / e 750.1 (M ⁺⁺ 1).

(Example 3-52)

Example 1-2, except that 1,1,1-trifluoro-propan-2-ol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. In accordance with the procedures described in 2-1 and 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2, 15-Dioxo-14- (2,2,2-trifluoro-1-methyl-ethoxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (Compound AR00320581) was synthesized. MS m / e 768.1 (M ⁺⁺ 1).

(Example 3-53)

Performed except that 1,1,1-trifluoro-2-methyl-propan-2-ol was used instead of cyclopentanol to form the chloroformate reagent in Step 2 of Example 2-1. According to the procedure described in Examples 1-2, 2-1 and 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylamino Carbonyl-2,15-dioxo-14- (2,2,2-trifluoro-1,1-dimethyl-ethoxycarbonylamino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7- The en-18-yl ester (compound AR00320582) was synthesized. MS: m / e 782.1 (M ⁺⁺ 1).

(Example 3-54)

Following the procedures described in Examples 1-22, 2-1 and 3-1, (1S, 4R, 6S, 14S, 18R) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonyl Amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-18-yl ester (compound AR00324375) was synthesized. MS m / e 740.5 (M ⁺ +1).

(Example 3-55)

Examples 1-2 and 3 except that 4-fluoro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2. (1S, 4R, 6S, 14S, 18R) -4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonyl Aminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334191) was synthesized. ¹ H NMR (500 MHz, d ₆ -acetone) δ 10.70 (br s, 1 H), 8.34 (d, 1 H), 7.39 to 7.33 (m, 1 H), 7.20 (d, 1 H), 7.10 to 7.02 (m, 2H), 6.13 (d, 1H), 5.70 (q, 1H), 5.44 (br s, 1H), 4.99 (t, 1H), 4.78 to 4.59 (m, 5H), 4.18 to 4.08 (m, 1H), 3.88 to 3.81 (m, 1H), 2.86 to 2.78 (m, 3H), 2.71 to 2.60 (m, 1H), 2.52 to 2.35 (m, 3H), 1.92 to 1.81 (m, 2H), 1.75 (t, 1H) ), 1.61-1.14 (m, 17H), 1.04-0.95 (m, 2H);-APCI MS m / z 730.4 (M-1).

(Example 3-55a)
4-Fluoro-2,3-dihydro-1H-isoindole used in Example 3-55 was prepared in the following two steps.

  step 1:

  Best results are obtained when starting material is used at 0.5M in formamide and heated to 125 ° C for 1 to 5 hours depending on scale. The starting material does not dissolve in formamide until the temperature exceeds 60 ° C. When the reaction is complete as monitored by LC / MS (apcineg), the heat is removed and 3 volumes of water are added to the reaction. The reaction is then warmed to room temperature and stirred until a pale yellow precipitate forms. The yellow solid product is filtered off, washed with water and dried overnight to obtain 70-77% yield.

  Step 2:

To the starting material in the round bottom flask, 4 equivalents of 1M BH ₃ -THF was added dropwise using a dropping funnel to give a golden solution, which was heated and stirred to change the color to copper. The reaction was then heated to reflux for 18 hours.

The reaction is then cooled to room temperature and then to 0 ° C. in an ice bath. 4 equivalents of MeOH are added dropwise, the ice bath is removed and the reaction is quenched by warming to room temperature. During this warming process, the color of the reactants turns dark. Next, 6N HCl was added dropwise at room temperature until the pH test paper indicated that the reaction was acidic, and the reaction was refluxed (63 ° C.) for 1 hour. The reaction was then cooled to room temperature. At this point, the reaction was concentrated and washed with Et ₂ O (2 ×) and DCM (2 ×). The aqueous layer was then brought to pH = 11 using NaOH pellets. Further water was added and the aqueous layer was extracted with ether (4 times). The combined extracts were dried over Na ₂ SO ₄ and concentrated to give a light tan oil product that was used directly. The mass recovery is always slightly higher than the theoretical value, but using such a crude product gives a yield of over 80% in the next step.

(Example 3-56)

In a step similar to Example 1-2, 2,3-dihydro-1H-isoindole was used instead in Step 4 and the ring-closing metathesis product 10 from Step 3 of Example 1-2 was replaced with H ₂ / Rh. After further reduction with -Al ₂ O ₃ , according to Examples 1-2 and 3-1, except that it was used in the next coupling step according to the literature procedure (WO 0059929, pages 76-77) ( 1S, 4R, 6S, 14S, 18R) -1,3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16- Diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-18-yl ester (compound AR00333833) was synthesized. ¹ H NMR (400 MHz, CD ₃ SOCD ₃ ) δ 11.11 (s, 1H), 8.89 (s, 1H), 7.16-7.29 (m, 4H), 6.95 (d, 1H), 5.25 (bs, 1H), 4.50 to 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 to 1.68 (m, 2H), 0.92 to 1.40 (m, 19H). MS m / z 717.0 (M + 1).

(Example 3-57)

According to the procedure shown in the following scheme, (1S, 4R, 6S, 14S, 18R) -5-amino-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropane A sulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334286) was synthesized.

Step 1. (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-2,15-dioxo-18-triisopropylsilanyloxy-3,16-diaza-tricyclo [14.3.0.0 ^{4, 6} ] Synthesis of nonadeca-7-ene-4-carboxylic acid ethyl ester. To a DriSolve DCM (30 mL) solution of the free hydroxy macrocyclic intermediate (compound of Example 1-2, 5.0 g, 10.1 mmol) was added imidazole (827 mg, 1.2 eq) and TIPSCl (2.15 g, 1.1 eq). It was. The reaction mixture was stirred at room temperature for 18 hours. TLC (5% MeOH-DCM) showed that a considerable amount of SM still remained. To this reaction mixture was further added imidazole (410 mg), TIPSCl (1 g) and DMAP (121 mg). After stirring overnight, the reaction mixture showed a small amount of SM remaining. The reaction mixture was washed with water (2 × 25 mL). The combined organic layers were back washed with DCM (25 mL). The combined organic layers were dried and concentrated to give a pale yellow oil. The crude product was used in the next step without further purification.

Step 2: (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-2,15-dioxo-18-triisopropylsilanyloxy-3,16-diaza-tricyclo [14.3.0.0 ^{4, 6} ] Synthesis of nonadeca-7-ene-4-carboxylic acid. The ester SM from step 1 was first dissolved in a mixture of THF (20 mL) and MeOH (20 mL). To this mixture was then added LiOH.H ₂ O (2.1 g, 50 mmol) in water (10 mL) and stirred at room temperature for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was almost concentrated to dryness. The solid residue was then dissolved in water (50 mL), acidified with 2N HCl, and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was used in the next step without further purification.

Step 3: (1S, 4R, 6S, 14S, 18R)-(4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-triisopropylsilanyloxy-3,16-diaza-tricyclo [14.3.0.0 ^{4 , 6} ] Synthesis of nonadeca-7-en-14-yl) -carbamic acid tert-butyl ester. The acid SM from step 2 above was first dissolved in 25 mL of DriSolve's 1,2-dichloroethane. To this solution was added CDI (2.2 g, 13.8 mmol) in one portion and the reaction was stirred at 50 ° C. for 3 hours. Cyclopropylsulfonamide (3.3 g, 27.5 mmol) was then added to the reaction followed by DBU (4.2 g, 27.5 mmol) and the reaction was stirred at 50 ° C. for 4 hours. LCMS showed that the reaction was complete. For workup, the reaction mixture was washed with water (2 × 50 mL) and the organic layer was dried (anhydrous Na ₂ SO ₄ ) and concentrated. The crude product was used in the next step without further purification.

Step 4: (1S, 4R, 6S, 14S, 18R)-(4-Cyclopropanesulfonylaminocarbonyl-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca Synthesis of -7-en-14-yl) -carbamic acid tert-butyl ester. The crude product from Step 3 above was first dissolved in THF (40 mL). To this solution was then added TBAF (3.6 g, 13.7 mmol, 1.5 eq) and stirred at room temperature for 2 hours. TLC showed the reaction was complete. 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 mL) and washed with 3N NaOH solution. The aqueous layer was neutralized with 2N HCl and extracted with DCM (2 × 25 mL). The combined organic layers were dried (anhydrous Na ₂ SO ₄ ) and concentrated to give a pure white solid (2.4 g, 46%). MS m / z (APCI +) 469.1 (MH ⁺ -Boc).

Step 5: (1S, 4R, 6S, 14S, 18R) -5-amino-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, Synthesis of 15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334286). To a DCE solution of the product from Step 4 above (19 mg, 33 μmol) was added CDI (7 mg, 1.3 eq) and the reaction was stirred at room temperature overnight. LCMS showed that the reaction was complete. 2,3-Dihydro-1H-isoindol-5-ylamine (18 mg, 4 eq) was then added. After 4 hours at room temperature, LCMS showed that the reaction was complete. The reaction mixture was introduced directly onto silica gel and eluted with 1-5% methanol / DCM. The pure product was isolated as a white solid. MS m / z (APCI ⁺ ): 629.2 (MH ⁺ -Boc).

(Example 3-58)

In Step 5, 2,3-dihydro-1H-isoindol-5-ylamine was replaced with 2,3-dihydro-1H-isoindol-4-ylamine by a method similar to that described in Example 3-57. (1S, 4R, 6S, 14S, 18R) -4-amino-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15- Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334385) was synthesized. The final product was also purified on reverse phase column chromatography (eluent = 5 to 100% acetonitrile in water) to give the final product as a beige foamy solid. MS m / z (APCI-): 728.2 (M ⁺ ).

(Example 3-59)

(1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole was followed according to the procedure described in Example 3-6 except that trifluoro-methanesulfonamide was used instead of cyclopropanesulfonamide. 2-Carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4-trifluoromethanesulfonylaminocarbonyl-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-18- The yl ester (compound AR00340479) was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone): δ 7.98 (brs, 1H), 7.23-7.35 (m, 4H), 6.13 (brd, 1H), 5.70 (q, 1H), 5.44 (brs 1H), 4.98 to 5.02 (m, 1H), 4.61 to 4.72 (m, 5H), 4.49 (d, 1H), 4.16 to 4.18 (m, 1H), 3.87 to 3.90 (m, 1H), 2.57 to 2.59 (m, 2H) ), 2.38-2.51 (m, 2H), 1.82-1.92 (m, 2H), 1.72-1.79 (m, 2H), 1.21-1.59 (m, 8H), 1.21 (s, 9H). MS m / z (APCI-): 741.1 (M ⁺ ).

(Example 3-60)

(1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole was prepared according to the procedure described in Example 3-6 except that 4-sulfamoyl-benzoic acid was used instead of cyclopropanesulfonamide. 2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-carboxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -En-18-yl ester (compound AR00365387) was synthesized. MS m / z (APCI-): 792.3 (M-1).

(Example 3-61)

According to the procedure described in Example 3-6, except that 4-chloro-3-sulfamoyl-benzoic acid was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3- Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (5-carboxy-2-chloro-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3. 0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00365388) was synthesized. MS m / z (APCI-): 826.2 (M-2).

(Example 3-62)

According to the procedure described in Example 3-6, except that 2-methoxy-5-sulfamoyl-benzoic acid was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3- Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (3-carboxy-4-methoxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3. 0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00365425) was synthesized. MS m / z (APCI-): 822.3 (M-1).

(Example 3-63)

According to the procedure described in Example 3-6, except that 2-chloro-4-fluoro-5-sulfamoyl-benzoic acid was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R)- 1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (5-carboxy-4-chloro-2-fluoro-benzenesulfonylaminocarbonyl) -2,15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00365426) was synthesized. MS m / z (APCI-): 844.2 (M-2).

(Example 3-64)

According to the procedure described in Example 3-6 except that 4-dimethylamino-benzenesulfonamide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro- Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-dimethylamino-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester (compound AR00365572) was synthesized. MS m / z (APCI-): 791.3 (M-1).

(Example 3-65)

According to the procedure described in Example 3-6 except that propane-2-sulfonic acid amide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-iso Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4- (propane-2-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -En-18-yl ester (compound AR00333801) was synthesized. MS m / z (APCI-): 714.4 (M-1).

(Example 3-66)

According to the procedure described in Example 3-6, except that benzenesulfonamide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2- Carboxylic acid 4-benzenesulfonylaminocarbonyl-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00333802) was synthesized. MS m / z (APCI-): 748.3 (M-1).

(Example 3-67)

According to the procedure described in Example 3-6 except that methanesulfonamide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2- Carboxylic acid 14-tert-butoxycarbonylamino-4-methanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00333803) was synthesized. MS m / z (APCI-): 686.4 (M-1).

(Example 3-68)

According to the procedure described in Example 3-6 except that 5-chloro-thiophene-2-sulfonic acid amide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3 -Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (5-chloro-thiophene-2-sulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3. 0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334188) was synthesized. MS m / z (APCI-): 788.3 (M-2).

(Example 3-69)

According to the procedure described in Example 3-6, except that N- (5-sulfamoyl- [1,3,4] thiadiazol-2-yl) -acetamide was used instead of cyclopropanesulfonamide (1S, 4R , 6S, 14S, 18R) -1,3-Dihydro-isoindole-2-carboxylic acid 4- (5-acetylamino- [1,3,4] thiadiazole-2-sulfonylaminocarbonyl) -14-tert-butoxy Carbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334247) was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone): δ 7.24-7.31 (m, 4H), 5.96 (brd, 1H), 5.42 (brs 1H), 5.28 (m, 1H), 5.15 (m, 1H), 4.68 (m, 6H), 4.49 (m, 1H), 4.14 (m, 2H), 2.60 (m, 1H), 2.25 to 2.36 (m, 5H), 1.70 to 2.19 (m, 8H), 1.19 to 1.48 ( m, 4H), 1.30 (s, 9H). MS m / z (APCI-): 813.3 (M-1).

(Example 3-70)

According to the procedure described in Example 3-6 except that 4-cyano-benzenesulfonamide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-iso Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-cyano-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00334248) was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone): δ 11.32 (brs, 1H), 8.36 (brs, 1H), 8.04 to 8.15 (m, 4H), 7.22 to 7.35 (m, 4H), 6.12 (brd, 1H), 5.47 (brs 1H), 5.28 (q, 1H), 4.60 to 4.72 (m, 5H), 4.48 to 4.54 (m, 2H), 4.14 to 4.17 (m, 1H), 3.86 to 3.90 (m, 1H) ), 2.37 to 2.52 (m, 4H), 1.72 to 1.85 (m, 2H), 1.59 to 1.62 (m, 1H), 1.20 to 1.55 (m, 8H), 1.20 (s, 9H). MS m / z (APCI-): 773.3 (M-1).

(Example 3-71)

According to the procedure described in Example 3-6 except that 4-nitro-benzenesulfonamide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-iso Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-nitro-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00334249) was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone): δ 11.39 (brs, 1H), 8.46 (d, 2H), 8.35 (brs, 1H), 8.23 (d, 2H), 7.23 to 7.36 (m, 4H) , 6.11 (brd, 1H), 5.47 (brs 1H), 5.23 (q, 1H), 4.59 to 4.72 (m, 5H), 4.49 to 4.54 (m, 2H), 4.15 (m, 1H), 3.86 to 3.90 ( m, 1H), 2.40 to 2.53 (m, 4H), 1.72 to 1.85 (m, 2H), 1.59 to 1.62 (m, 1H), 1.20 to 1.56 (m, 8H), 1.20 (s, 9H). MS m / z (APCI-): 793.3 (M-1).

(Example 3-72)

According to the procedure described in Example 3-6 except that 4-chloro-benzenesulfonamide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-iso Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-chloro-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00334250) was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone): δ 11.16 (brs, 1H), 8.34 (brs, 1H), 7.96 (d, 2H), 7.65 (d, 2H), 7.22 to 7.36 (m, 4H) 6.13 (brd, 1H), 5.46 (brs 1H), 5.27 (q, 1H), 4.59 to 4.71 (m, 5H), 4.48 to 4.54 (m, 2H), 4.14 to 4.18 (m, 1H), 3.87 to 3.89 (m, 1H), 2.35 to 2.52 (m, 4H), 1.75 to 1.85 (m, 2H), 1.58 to 1.61 (m, 1H), 1.20 to 1.53 (m, 8H), 1.20 (s, 9H). MS m / z (APCI-): 782.3 (M-2).

(Example 3-73)

According to the procedure described in Example 3-6 except that 4-methoxy-benzenesulfonamide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-iso Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-methoxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00334341) was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone): δ 8.26 (brs, 1H), 7.84 (d, 2H), 7.19-7.32 (m, 4H), 7.05 (d, 2H), 6.08 (brd, 1H) , 5.43 (brs 1H), 5.25 (q, 1H), 4.55 to 4.67 (m, 5H), 4.48 (q, 2H), 4.10 to 4.14 (m, 1H), 3.87 (s, 3H), 3.82 to 3.87 ( m, 1H), 2.29-2.47 (m, 4H), 1.74-1.84 (m, 2H), 1.51-1.55 (m, 1H), 1.37-1.47 (m, 4H), 1.20-1.32 (m, 5H), 1.17 (s, 9H). MS m / z (APCI-): 779.1 (M-1).

(Example 3-74)

According to the procedure described in Example 3-6, except that 1-methyl-5-sulfamoyl-1H-pyrrole-2-carboxylic acid was used instead of cyclopropanesulfonamide (1S, 4R, 6S, 14S, 18R ) -1,3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (5-carboxy-1-methyl-1H-pyrrole-2-sulfonylaminocarbonyl) -2,15-dioxo -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00364266) was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone): δ 10.84 (brs, 1H), 8.27 (brs, 1H), 7.59 (d, 1H), 7.24-7.35 (m, 4H), 7.18 (d, 1H) , 6.10 (brd, 1H), 5.50 (br, 1H), 5.46 (m 1H), 5.36 (q, 1H), 4.59 to 4.71 (m, 6H), 4.48 (d, 1H), 4.13 to 4.17 (m, 1H), 4.00 (s, 3H), 3.85 to 3.89 (m, 1H), 2.35 to 2.59 (m, 4H), 1.71 to 1.90 (m, 2H), 1.62 to 1.65 (m, 1H), 1.20 to 1.51 ( m, 8H), 1.20 (s, 9H). MS m / z (APCI-): 795.4 (M-1).

(Example 3-75)

According to the procedure described in Example 3-6, except that thiophene-2-sulfonic acid amide was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-iso Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4- (thiophen-2-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -En-18-yl ester (compound AR00365427) was synthesized. MS m / z (APCI-): 754.4 (M-1).

(Example 3-76)

Except for using 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinoline (for synthesis see Example 3-76a) instead of 2,3-dihydro-1H-isoindole In accordance with the procedure described in Example 3-6, (1S, 4R, 6S, 14S, 18R) -6-methoxy-1-methoxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert -Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334339) was synthesized did. MS m / z (APCI-): 800.5 (M-1).

(Example 3-76a)

  The synthesis of 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride is shown in the following scheme.

Step 1: Synthesis of 2-chloro-N- [2- (3-methoxy-phenyl) -ethyl] -acetamide. The amine 2- (3-methoxy-phenyl) -ethylamine was dissolved in DCM to a 0.6M solution, followed by the addition of TEA (2 eq). The mixture was then cooled in an IPA / dry ice bath. When the reaction temperature reached -60 ° C, a DCM solution of chloroacetyl chloride (2.6M) was added dropwise so that the temperature was kept below -60 ° C. After complete addition, the reaction was stirred at -60 ° C. for 1 hour. The reaction was then warmed to −20 ° C. and filtered through GF filter paper to remove some TEA-HCl salt. The remaining filtrate was warmed to room temperature, transferred to a separatory funnel and washed with 1N HCl (2 ×) and brine. The organic layer was dried over MgSO ₄ and concentrated to give a dark purple solid. This crude product was used directly in the next step without further purification.

Step 2: Synthesis of 1-chloromethyl-6-methoxy-3,4-dihydro-isoquinolinium chloride. Two equivalents of P ₂ O ₅ (12.9 g) were boiled in xylene (180 ml) to give a 0.25M solution. The crude product from Step 1 above was also first boiled in xylene (45 mL) to give a 0.5 M solution and then added dropwise to the P ₂ O ₅ solution using a dropping funnel. The mixture was stirred and heated to reflux for 1 hour. The reaction was then cooled to room temperature, at which point xylene was decanted off. The flask was then placed in an ice bath and ice, water, EtOAc, and finally 4M NaOH were added carefully with stirring until pH> 12. The reaction was maintained at <25 ° C. until PH = 12. The reaction was then extracted with EtOAc (3 times). The combined organic extracts were dried over MgSO ₄ and concentrated to give a dark solution. While this was cooled in an ice bath, cold Et ₂ O (400 mL) was added followed by cold HCl / Et ₂ O (100 mL). A precipitate formed and was filtered off and washed with Et ₂ O. The solid was quickly placed under high vacuum for 2 hours to give the target product as a colored foamy solid. This crude product was used directly in the next step without further purification.

  Step 3: Synthesis of 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride. The crude product from Step 2 above was added in one portion to TEA in MeOH (5 eq) and NaI (0.1 eq) at 0 ° C. Then 2.2 equivalents of NaOMe was added and the homogeneous reaction became cloudy. The reaction was then stirred at 0 ° C. for 1 hour. LC / MS showed that the imine was completely free base.

The reaction was then cooled again to 0 ° C. in an ice bath and NaBH ₄ (1.5 eq) was carefully added. The reaction was then warmed to room temperature again and stirred for 2 hours. After the reaction was complete as monitored by LC / MS, it was concentrated, treated with 1N NaOH and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated. The resulting residue was dissolved in MeOH and cooled in an ice bath. HCl gas was bubbled here for 10 minutes. The reaction mixture was concentrated and redissolved in MeOH. After concentrating twice, the reaction was left under high vacuum overnight. The crude product was then triturated with EtOAc (3 times) and left under high vacuum overnight to yield the product as a brown foamy solid. This crude product was used directly in the next step without further purification. MS m / z (POSESI): 208.1 (MH ^<+> ).

(Example 3-77)

5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium instead of 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride (1S, 4R, 6S, 14S, 18R) -5-Fluoro-1-methoxymethyl was prepared according to the procedure described in Example 3-76, except that chloride (see Example 3-77a for synthesis) was used. -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^{4, 6} ] Nonadeca-7-en-18-yl ester (compound AR00365193) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.99 to 8.91 (m, 1H), 7.23 to 7.15 (m, 1H), 7.13 to 6.99 (m, 2H), 6.99 to 6.90 (m, 1H), 5.68 ( q, 1H), 5.41 (br s, 1H), 5.35 to 5.21 (m, 1H), 5.06 (t, 1H), 4.60 to 4.31 (m, 3H), 4.30 to 4.05 (m, 3H), 3.96 to 3.81 (m, 1H), 3.80 to 3.56 (m, 3H), 3.35 (d, 3H), 2.98 to 2.30 (m, 9H), 1.91 to 1.68 (m, 4H), 1.64 to 0.95 (m, 16H); MS (APCI-) m / z 788.3 (M-1).

(Example 3-77a)

  In a manner similar to that shown in Example 3-76a except that 2- (2-fluoro-phenyl) -ethylamine was used in place of 2- (3-methoxy-phenyl) -ethylamine in Step 1, 5 -Fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was synthesized.

(Example 3-78)

According to the procedure described in Example 3-55, except that 4-sulfamoyl-benzoic acid was used instead of cyclopropanesulfonamide, (1S, 4R, 6S, 14S, 18R) -4-fluoro-1,3- Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-carboxy-benzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester (compound AR00365438) was synthesized. ¹ H-NMR (500 MHz, CD ₃ OD) δ 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 to 6.95 (m, 2H), 5.42 (br s, 1H), 5.26 (q, 1H), 4.82 to 4.50 (m, 8H), 4.10 to 4.00 (m, 1H) , 3.85 (d, 1H), 3.75 to 3.69 (m, 1H), 2.60 to 2.39 (m, 4H), 2.26 (p, 2H), 1.89 to 1.84 (m, 1H), 1.81 to 1.05 (m, 15H) MS (APCI-): m / z 810.2 (M-1).

(Example 3-79)

(1S, 4R, 6S, 14S, 18R) -4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14- {2-cyclohexyl-2-[(pyrazine-2-carbonyl) -amino]- Synthesis of acetylamino} -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00340303).

  The starting material (AR00334191, Example 3-55, 10 mg, 13.7 μmol) was dissolved in 1 mL of 50% TFA (DCM) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness, dissolved in acetonitrile and concentrated again. The above process was repeated once more to remove excess TFA. The resulting solid residue was then dissolved in DCE (137 μL), cooled to 0 ° C. in an ice bath, followed by the amino acid cyclohexyl-[(pyrazine-2-carbonyl) -amino] -acetic acid (1.05 eq) , HATU (10 mg) and DIEA (4 drops) were added. The mixture was slowly warmed to room temperature and stirred overnight. For processing, the reaction mixture was introduced directly onto a C-18 column and purified by reverse phase column chromatography to yield the target compound as a white solid. MS (APCI-): m / z 876.1 (M-1).

(Example 3-80)

According to the procedure described in Example 3-79, but using acetylamino-cyclohexyl-acetic acid instead of cyclohexyl-[(pyrazine-2-carbonyl) -amino] -acetic acid, (1S, 4R, 6S, 14S, 18R) -4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14- (2-acetylamino-2-cyclohexyl-acetylamino) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo- 3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00340122) was synthesized. MS (APCI-): m / z 811.3 (M-1).

(Example 3-81)

(1S, 4R, 6S, 14S, 18R) -4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- [2- (4-methoxy-phenyl)- Synthesis of acetylamino] -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00340156).

The starting material (AR00334191, Example 3-55, 10 mg, 13.7 μmol) was dissolved in 1 mL of 50% TFA (DCM) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness, dissolved in acetonitrile and concentrated again. The above process was repeated once more to remove excess TFA. The resulting solid residue was then dissolved in DCE (137 μL) followed by the addition of acid chlorides (4-methoxy-phenyl) -acetyl chloride (2 drops) and DIEA (4 drops). The mixture was stirred at room temperature overnight. After completion, the reaction was introduced directly onto a C-18 column and purified by reverse phase column chromatography. The compound was purified by normal phase silica gel chromatography (eluent = 1% 40% EtOAc / hexane with 1% formic acid) to yield the target compound as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 7.33 (p, 1H), 7.15 (d, 1H), 7.05 to 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 to 2.57 (m, 1H), 2.52 to 2.30 (m, 5H), 2.06 to 0.80 (m, 15H); MS (APCI-): m / z 778.3 (M-1).

(Example 3-82)

According to the procedure described in Example 3-81 except that (3-methoxy-phenyl) -acetyl chloride was used instead of (4-methoxy-phenyl) -acetyl chloride, (1S, 4R, 6S, 14S, 18R ) -4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- [2- (3-methoxy-phenyl) -acetylamino] -2,15-dioxo- 3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00340178) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 7.32 (p, 1H), 7.14 (d, 1H), 7.05 to 6.92 (m, 3H), 6.76 to 6.58 (m, 2H), 5.68 (q, 1H) , 5.41 (br s, 1H), 5.09 (t, 1H), 4.76 to 4.46 (m, 7H), 4.43 to 4.26 (m, 2H), 3.91 to 3.82 (m, 1H), 3.69 (d, 3H), 2.94 to 2.85 (m, 1H), 2.70 to 2.57 (m, 1H), 2.52 to 2.30 (m, 5H), 2.06 to 0.80 (m, 15H); MS (APCI-) m / z 778.3 (M-1) .

(Example 3-83)

According to the procedure described in Example 3-81 except that phenyl-acetyl chloride was used instead of (4-methoxy-phenyl) -acetyl chloride, (1S, 4R, 6S, 14S, 18R) -4-fluoro- 1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-phenylacetylamino-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00340188) was synthesized. MS (APCI-) m / z 748.4 (M-1).

(Example 3-84)

Instead of 2,3-dihydro-1H-isoindole, 5-methoxy-2,3-dihydro-1H-isoindole (the method described in JOC, 53, 22, 1988, pages 5381-5383) (1S, 4R, 6S, 14S, 18R) -5-methoxy-1,3-dihydro-isoindole-2-in accordance with the procedure described in Example 3-6 except that (prepared by similar method) was used. Carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester ( Compound AR00334314) was synthesized. MS (APCI-) m / z 742.3 (M-1).

(Example 3-85)

4,7-difluoro-2,3-dihydro-1H-isoindole instead of 2,3-dihydro-1H-isoindole (described in JOC, 53, 22, 1988, pages 5381-5383 (1S, 4R, 6S, 14S, 18R) -4,7-difluoro-1,3-dihydro-iso, following the procedure described in Example 3-6, except that Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-18 -The yl ester (compound AR00334399) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.97 (s, 1H), 6.99-6.85 (m, 2H), 5.69 (q, 1H), 5.42 (br s, 1H), 5.07 (t, 1H), 4.83 to 4.57 (m, 6H), 4.51 (d, 1H), 4.13 to 4.02 (m, 1H), 3.85 (t, 1H), 2.94 to 2.86 (m, 1H), 2.73 to 2.59 (m, 1H), 2.55 to 2.28 (m, 4H), 1.89 to 1.70 (m, 3H), 1.65 to 1.22 (m, 10H), 1.18 to 0.96 (m, 10H), MS m / z (APCI-): 746.1 (M-1 ).

(Example 3-86)

According to the procedure described in Example 3-36 except that 4-fluoro-2,3-dihydro-1H-isoindole was used instead of 2,3-dihydro-1H-isoindole, (1S, 4R, 6S , 14S, 18R) -4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14- (3-tert-butyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3 , 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00338066) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 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 to 4.66 (m, 4H), 4.59 (q, 1H), 4.49 (d, 1H), 4.37 to 4.17 (m, 2H), 3.94 to 3.84 (m, 1H), 3.72 ( t, 1H), 2.95 to 2.87 (m, 1H), 2.68 to 2.29 (m, 5H), 2.09 to 1.22 (m, 11H), 1.12 to 0.95 (m, 12H); MS (APCI-): m / z 729.3 (M-1).

(Example 3-87)

According to the procedure described in Example 3-81 except that 3,3-dimethyl-butyryl chloride was used instead of (4-methoxy-phenyl) -acetyl chloride (1S, 4R, 6S, 14S, 18R) 4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (3,3-dimethyl-butyrylamino) -2,15-dioxo-3,16-diaza- Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00338070) was synthesized. MS (APCI-) m / z 728.3 (M-1).

(Example 3-88)

According to the procedure described in Example 3-81 except that 4,4,4-trifluoro-butyryl chloride was used instead of (4-methoxy-phenyl) -acetyl chloride, (1S, 4R, 6S, 14S , 18R) -4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (4,4,4-trifluoro-butyrylamino)- 3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00338071) was synthesized. MS (APCI-) m / z 754.3 (M-1).

(Example 3-89)

Instead of 2,3-dihydro-1H-isoindole (2,3-dihydro-1H-isoindol-5-yl) -isopropyl-amine (Org. Letters, 2003, 5, 6, 793-796 (1S, 4R, 6S, 14S, 18R) -5-isopropylamino-1, following the procedure described in Example 3-6, except that (prepared by the same method as described on page) was used. 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00341649) was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 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 to 4.66 (m, 3H), 4.60 (t, 1H), 4.52 (t, 1H), 4.08 (d , 1H), 3.85 (d, 1H), 3.80 to 3.68 (m, 1H), 2.94 to 2.87 (m, 1H), 2.71 to 2.59 (m, 1H), 2.55 to 2.45 (m, 1H), 2.45 to 2.30 (m, 3H), 1.88 to 1.69 (m, 3H), 1.61 (t, 1H), 1.58 to 0.94 (m, 25H); MS (APCI-): m / z 770.1 (M-1).

(Example 3-90)

Instead of 2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-isoindole-5-ol (the method described in JOC, 53, 22, 1988, pages 5381-5383 and (1S, 4R, 6S, 14S, 18R) -5-hydroxy-1,3-dihydro-isoindole-2-in accordance with the procedure described in Example 3-6 except that (prepared by similar method) was used. Carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester ( Compound AR00364936) was synthesized. MS m / z (APCI-): 728.2 (M-1).

(Example 3-91)

2,3-Dihydro-1H-isoindole-5-carboxylic acid methyl ester instead of 2,3-dihydro-1H-isoindol-5-ylamine in step 5 (prepared as shown in Example 3-91a) (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2,5-dicarboxylic acid 2- (14-tert) according to the procedure described in Example 3-57, except that -Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl) ester 5-methyl ester ( Compound AR00365083) was synthesized. MS m / z (APCI +): 672.2 (MH ⁺ -Boc).

(Example 3-91a)

  According to the following scheme, 2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester was synthesized.

5-Bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (200 mg, 0.67 mmol), Pd (OAc) ₂ (30 mg, 0.2 eq), DPPP (55 mg, 0.2 eq), TEA ( A mixture of 0.93 mL, 10 eq) and MeOH: DMSO (1: 1, 4 mL) was stirred at 80 ° C. for 16 h under CO (balloon). LC-MS and TLC (20% EtOAc-hexane) indicated that the reaction was complete. The reaction mixture was concentrated to remove MeOH, diluted with EtOAc (10 mL) and washed with water (2 × 25 mL). The organic layer was dried (Na ₂ SO ₄ ), concentrated and purified by silica gel column chromatography (eluent = 20% EtOAc-hexane) to give pure 1,3-dihydro-isoindole-2,5-dicarboxylic acid. 2-tert-butyl ester 5-methyl ester (150 mg, 81%) was obtained. MS (APCI +): m / z 178.1 (MH ⁺ -Boc).

The protecting group was removed from the product by treatment with 50% TFA-DCM at 0 ° C. to room temperature for 1 hour. The reaction mixture was concentrated to dryness, redissolved in DCM and neutralized with saturated NaHCO ₃ solution. The organic layer was separated, dried and concentrated to give the target compound as the free base, which was used directly in the next coupling step without further purification.

(Example 3-92)

According to the procedure described in Example 3-5, except that 2,3-dihydro-1H-isoindole was used instead of 1,2,3,4-tetrahydro-isoquinoline (1S, 4R, 6S, 14S, 18R) -1,3-Dihydro-isoindole-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^{4, 6} ] Nonadeca-7-en-18-yl ester (compound AR00333831) was synthesized. ¹ HNMR (400 MHz, CD ₃ OD): δ 7.36 to 7.22 (m, 3H), 7.21 to 7.16 (m, 1H), 5.74 to 5.60 (m, 1H), 5.40 (s, 1H), 5.20 to 5.03 ( m, 1H), 4.80 to 4.54 (m, 6H), 4.38 to 4.28 (m, 1H), 4.18 (m, 1H), 3.90 to 3.80 (m, 1H), 2.96 to 2.85 (m, 1H), 2.70 to 2.31 (m, 4H), 1.92 to 0.98 (m, 24H). MS m / z (APCI-): 724.4 (M-1).

(Example 3-93)

Instead of 2,3-dihydro-1H-isoindole, 5-morpholin-4-yl-2,3-dihydro-1H-isoindole (J. Org. Chem., 2000, 65, 1144-1157 (1S, 4R, 6S, 14S, 18R) -5-morpholin-4-yl-1 according to the procedure described in Example 3-6 except that (prepared by the same method as described) was used. , 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca -7-en-18-yl ester (compound AR00340494) was synthesized. ¹ HNMR (400 MHz, DMSO-d ⁶ ): δ 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 to 4.50 (m, 4H), 4.42 (m, 1H), 4.28 to 4.10 (m, 2H), 3.98 (m, 1H), 3.76 (m, 4H), 3.12 (m, 4H) 2.71 to 2.60 (m, 1H), 2.40 to 1.45 (m, 3H), 1.40 to 1.21 (m, 10H), 0.98 to 0.61 (m, 4H). MS m / z (APCI +): 699.2 (MH ⁺ -Boc).

(Example 3-94)

Instead of 2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-isoindole-5-carbonitrile (described in J. Org. Chem., 1998, 63, 8224-8228) (1S, 4R, 6S, 14S, 18R) -5-cyano-1,3-dihydro-isoindole according to the procedure described in Example 3-6 except that 2-Carboxylic acid 14-tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-18- The yl ester (compound AR00365082) was synthesized. MS m / z (APCI +): 639.1 (MH ⁺ -Boc).

(Example 3-95)

According to the procedure described in the following scheme, (1S, 4R, 6S, 14S, 18R) -5-ethylcarbamoyl-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclo Propanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00365252) was synthesized.

Compound AR00365083 (70 mg, 91 μmol), the synthesis of which has already been described herein, was dissolved in a THF: MeOH (2: 1, 3 mL) mixture followed by the addition of 1 mL of LiOH—H ₂ O aqueous solution. The reaction was stirred at room temperature for 1 hour. LC-MS showed that the hydrolysis was complete and the reaction was continued for another 30 minutes before being concentrated, neutralized with 0.1 N HCl and extracted with EtOAc (5 mL). The organic layer was dried (Na ₂ SO ₄ ), concentrated and purified by silica gel column chromatography (eluent = 5-7% MeOH-DCM) to give the hydrolysis product as a white solid. MS (APCI +): m / z 658.1 (MH ⁺ -Boc).

The product from the above step (23 mg, 30 μmol) is first dissolved in anhydrous DMF (2 mL), followed by the addition of ethylamine (3 eq), HOAT (3 eq), and HATU (3 eq) and finally DIEA (6 eq) was added dropwise. 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 × 10 mL). The organic layer was dried and concentrated and the crude product was purified by preparative TLC. MS (APCI +): 685.2 (MH ⁺ -Boc).

(Example 3-96)

According to the procedure described in Example 3-5, except that 5-chloro-2,3-dihydro-1H-isoindole was used instead of 1,2,3,4-tetrahydro-isoquinoline, (1S, 4R, 6S, 14S, 18R) -5-Chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza -Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334218) was synthesized. ¹ H NMR (400 MHz, CD ₃ CN) δ 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 to 4.72 (m, 5H), 4.48 (t, 1H), 4.34 to 4.44 (m, 1H), 4.06 to 4.15 (m, 1H), 2.77 to 2.90 (m, 2H), 2.54 (bs, 1H), 2.24 to 2.44 (m, 3H), 1.64 to 1.75 (m, 2H), 1.13 to 1.57 (m, 18H), 0.91 to 1.09 (m, 4H). MS m / z 759.9 (M + 1).

(Example 3-97)

According to the procedure described in Example 3-16, except that 5-chloro-2,3-dihydro-1H-isoindole was used instead of 1,2,3,4-tetrahydro-isoquinoline, (1S, 4R, 6S, 14S, 18R) -5-Chloro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (tetrahydro-furan-3-yloxycarbonyl) Amino) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334220) was synthesized. ¹ H NMR (400 MHz, CD ₃ CN) δ 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 to 5.29 (m, 1H), 4.98 (t, 1H), 4.44 to 4.71 (m, 5H), 4.29 to 4.39 (m, 1H), 4.07 to 4.18 (m, 1H), 3.70 to 3.87 (m, 4H), 3.61 to 3.70 (m, 1H), 3.44 to 3.55 (m, 2H), 3.30 to 3.42 (m, 1H), 2.76 to 2.89 (m, 2H), 2.54 (bs, 1H), 2.36 to 2.46 ( m, 1H), 2.24 to 2.36 (m, 2H), 1.69 to 1.76 (m, 1H), 1.59 to 1.69 (m, 1H), 1.13 to 1.56 (m, 8H), 0.90 to 1.10 (m, 4H). MS m / z 762.0 (M + 1)

(Example 3-98)

According to the procedure described in Example 3-28, except that 5-chloro-2,3-dihydro-1H-isoindole was used instead of 2,3-dihydro-1H-isoindole, (1S, 4R, 6S , 14S, 18R) -5-Chloro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2-fluoro-ethoxycarbonylamino) -2,15-dioxo-3 , 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334222) was synthesized. ¹ H NMR (400 MHz, CD ₃ CN) δ 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 + 1)

(Example 3-99)

Use 3,3-dimethyl-butyryl chloride instead of (4-methoxy-phenyl) -acetyl chloride and 5-chloro-2,3 instead of 4-fluoro-2,3-dihydro-1H-isoindole (1S, 4R, 6S, 14S, 18R) -5-Chloro-1,3-dihydro-isoindole-2 according to the procedure described in Example 3-81 except that -dihydro-1H-isoindole was used -Carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (3,3-dimethyl-butyrylamino) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene- An 18-yl ester (compound AR00334225) was synthesized. ¹ H NMR (400 MHz, CD ₃ CN) δ 7.60 (bs, 1H), 7.15 to 7.33 (m, 3H), 6.54 to 6.65 (m, 1H), 5.63 to 5.73 (m, 1H), 5.33 (bs, 1H), 4.93 to 5.02 (m, 1H), 4.53 to 4.65 (m, 3H), 4.39 to 4.48 (m, 2H), 4.28 to 4.38 (m, 1H), 3.74 to 3.83 (m, 2H), 2.77 to 2.89 (m, 1H), 2.54 (bs, 1H), 2.23 to 2.44 (m, 3H), 1.68 to 1.91 (m, 4H), 1.12 to 1.54 (m, 11H), 0.91 to 1.11 (m, 4H), 0.76 to 0.90 (m, 9H). MS m / z 746.2 (M + 1)

(Example 3-100)

Use cyclopentyl-acetyl chloride instead of (4-methoxy-phenyl) -acetyl chloride and 5-chloro-2,3-dihydro-1H- instead of 4-fluoro-2,3-dihydro-1H-isoindole According to the procedure described in Example 3-81 except that isoindole was used, (1S, 4R, 6S, 14S, 18R) -5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14- (2-Cyclopentyl-acetylamino) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00334226) was synthesized. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.85 (bs, 1H), 6.95 to 7.30 (m, 3H), 5.87 to 6.02 (m, 1H), 5.63 to 5.79 (m, 1H), 5.43 to 5.52 (m , 1H), 4.93 to 5.08 (m, 1H), 4.52 to 4.85 (m, 5H), 4.31 to 4.52 (m, 1H), 3.79 to 3.95 (m, 1H), 3.60 to 3.75 (m, 2H), 3.14 (q, 1H), 2.90 (bs, 1H), 2.37 to 2.63 (m, 3H), 2.14 to 2.29 (m, 1H), 1.73 to 2.12 (m, 6H), 1.16 to 1.74 (m, 13H), 0.96 ~ 1.16 (m, 4H), 0.68-0.96 (m, 9H). MS m / z 758.2 (M + 1).

(Example 3-101)

Use 5-chloro-thiophene-2-sulfonic acid amide instead of cyclopropanesulfonamide and 5-chloro-2,3-dihydro-1H-isoindole instead of 2,3-dihydro-1H-isoindole Except for the use of the procedure described in Example 3-6, (1S, 4R, 6S, 14S, 18R) -5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxy Carbonylamino-4- (5-chloro-thiophen-2-sulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (Compound AR00340173) was synthesized. ¹ H NMR (400 MHz, CD ₃ CN) δ 8.07 (d, 1H), 7.50 (d, 1H), 7.16-7.32 (m, 3H), 6.98 (d, 1H), 5.86 (bs, 1H), 5.27 To 5.39 (m, 2H), 4.81 to 4.92 (m, 1H), 4.58 to 4.64 (m, 2H), 4.51 to 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)

(Example 3-102)

According to the procedure described in Example 3-6, except that 5-bromo-2,3-dihydro-1H-isoindole was used instead of 2,3-dihydro-1H-isoindole, 1S, 4R, 6S, 14S, 18R) -5-Bromo-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza- Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00340526) was synthesized. ¹ H NMR (400 MHz, CDCl ₃ ) δ 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 to 5.13 (m, 1H), 4.99 (t, 1H), 4.52 to 4.78 (m, 5H), 4.32 to 4.44 (m, 1H), 4.16 to 4.27 (m, 1H), 3.78 to 3.89 (m) , 1H), 3.33 to 3.42 (m, 1H), 2.85 to 2.94 (m, 1H), 2.40 to 2.64 (m, 3H), 2.20 to 2.32 (m, 1H), 1.68 to 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).

(Example 3-103)

4R-methyl-1,2,3,4-tetrahydro-isoquinoline instead of 1,2,3,4-tetrahydro-isoquinoline (implemented except that enantiomerically pure starting material was used instead of racemic) (1S, 4R, 6S, 14S, 18R) -4R-methyl-3,3,4 according to the procedure described in Example 3-1, except that (prepared according to a procedure similar to that in Example 1-17a) was used. -Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00333462) was synthesized. MS m / z 642.2 (M + 1-Boc)

(Example 3-104)

4S-methyl-1,2,3,4-tetrahydro-isoquinoline in place of 1,2,3,4-tetrahydro-isoquinoline (implemented except that enantiomerically pure starting material was used in place of racemate) (1S, 4R, 6S, 14S, 18R) -4S-methyl-3,3,4 according to the procedure described in Example 3-1, except that (prepared according to the procedure similar to that in Example 1-17a) was used. -Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester (compound AR00333463) was synthesized. MS m / z 642.2 (M + 1-Boc)

(Example 3-105)

Morpholine-4-carboxylic acid 2- (2,3-dihydro-1H-isoindol-5-yloxy) -ethyl ester (J. Med. Chem., 2002) instead of 2,3-dihydro-1H-isoindole 45, 26, 5771, Preparation Method D, and Bioorg.Med.Chem.Lett., 11, 2001, 685-688). Following the procedure described in Example 3-6, (1S, 4R, 6S, 14S, 18R) -5- [2- (morpholine-4-carbonyloxy) -ethoxy] -1,3-dihydro-isoindole-2 -Carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (Compound AR00345032) was synthesized. MS (APCI-): m / z 885.4 (M-1).

(Example 3-106)

Instead of 2,3-dihydro-1H-isoindole, 5- (3-morpholin-4-yl-propoxy) -2,3-dihydro-1H-isoindole (J. Med. Chem., 2002, 45) 26, 5771, Preparation Method D, and Bioorg.Med.Chem.Lett., 11, 2001, 685-688). (1S, 4R, 6S, 14S, 18R) -5- (3-morpholin-4-yl-propoxy) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert -Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00345075) was synthesized did. MS (APCI-): m / z 855.6 (M-1).

(Example 3-107)

5- (2-morpholin-4-yl-ethoxy) -2,3-dihydro-1H-isoindole (J. Med. Chem., 2002, 45) instead of 2,3-dihydro-1H-isoindole 26, 5771, Preparation Method D, and Bioorg.Med.Chem.Lett., 11, 2001, 685-688). (1S, 4R, 6S, 14S, 18R) -5- (2-morpholin-4-yl-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert -Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00345090) was synthesized did. MS (APCI-): m / z 841.5 (M-1).

(Example 3-108)

Instead of 2,3-dihydro-1H-isoindole [2- (2,3-dihydro-1H-isoindole-5-yloxy) -ethyl] -isopropyl-amine (J. Med. Chem., 2002, 45, 26, 5771, Preparation Method D, and Bioorg.Med.Chem.Lett., 11, 2001, 685-688. Following the procedure described in Example 3-6, (1S, 4R, 6S, 14S, 18R) -5- (2-isopropylamino-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert- Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00345094) was synthesized . MS (APCI-): m / z 813.5 (M-1).

(Example 3-109)

Instead of 2,3-dihydro-1H-isoindole, [2- (2,3-dihydro-1H-isoindole-5-yloxy) -ethyl] -dimethyl-amine (J. Med. Chem., 2002, 45, 26, 5771, Preparation Method D, and Bioorg.Med.Chem.Lett., 11, 2001, 685-688. Following the procedure described in Example 3-6, (1S, 4R, 6S, 14S, 18R) -5- (2-dimethylamino-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert- Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00345095) was synthesized . MS (APCI-): m / z 799.5 (M-1).

(Example 3-110)

Instead of 2,3-dihydro-1H-isoindole, 5- (2-imidazol-1-yl-ethoxy) -2,3-dihydro-1H-isoindole (J. Med. Chem., 2002, 45) 26, 5771, Preparation Method D, and Bioorg.Med.Chem.Lett., 11, 2001, 685-688). (1S, 4R, 6S, 14S, 18R) -5- (2-imidazol-1-yl-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert -Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00345096) was synthesized did. MS (APCI-): m / z 822.5 (M-1).

(Example 3-111)

Instead of 2,3-dihydro-1H-isoindole, 5- (2-pyrazol-1-yl-ethoxy) -2,3-dihydro-1H-isoindole (J. Med. Chem., 2002, 45) 26, 5771, Preparation Method D, and Bioorg.Med.Chem.Lett., 11, 2001, 685-688). (1S, 4R, 6S, 14S, 18R) -5- (2-pyrazol-1-yl-ethoxy) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert -Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00364924) was synthesized did. MS (APCI-): m / z 742.1 [(M-100) +18].

(Example 3-112)

2,3-Dihydro-1H-isoindol-5-ylamine in Step 5 was converted to 5- (4-methyl-piperazin-1-yl) -2,3-dihydro-1H-isoindole (J. Org. Chem., (Prepared by the same method as that described in 2000, 65, pp. 1144 to 1157), by the same method as described in Example 3-57, (1S, 4R, 6S, 14S, 18R ) -5- (4-Methyl-piperazin-1-yl) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00340495) was synthesized. ¹ H-NMR (400 MHz, DMSO-d ⁶ ): 7.72 to 7.40 (m, 1H), 7.22 to 7.05 (m, 1H), 6.95 to 6.70 (m, 2H), 5.55 to 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 to 2.20 (m, 6H), 1.85 to 1.50 (m, 5H), 1.42 to 1.0 (m, 14H), 0.82 to 0.55 (m, 4H). MS (APCI +): 712.3 (MH ⁺ -Boc)

(Example 3-113)

The product AR00365083 from this example was further hydrolyzed with LiOH in a THF-MeOH-H ₂ O mixture to give AR00365084, following a procedure similar to that described in Example 3-91. (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2,5-dicarboxylic acid 2- (14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15 -Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl) ester (compound AR00365084) was synthesized. MS: 658 (M-Boc).

(Example 3-114)

Replacing 2,3-dihydro-1H-isoindol-5-ylamine in Step 5 with 5- (2-methyl-thiazol-4-yl) -2,3-dihydro-1H-isoindole, Example 3-57 (1S, 4R, 6S, 14S, 18R) -5- (2-methyl-thiazol-4-yl) -1,3-dihydro-isoindole-2-carboxylic acid 14 -tert-Butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (compound AR00364989) Was synthesized. ¹ H NMR (400 MHz, CD ₃ COCD ₃ ) δ 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 to 3.91 (m, 1H), 2.86 to 2.97 (m, 1H), 2.57 to 2.71 (m, 1H), 2.33 to 2.54 (m, 3H), 1.81 to 1.96 (m, 2H), 1.75 (dd, 1H) 1.17 to 1.63 (m, 20H), 1.06 to 1.17 (m, 1H), 0.94 to 1.06 (m, 2H). MS m / z 711.2 (M + 1-100).

(Example 3-114a)

  Instead of thioacetamide in Step E and following the experiment from Steps A to F of Example 3-115a, the 5- (2-methyl-thiazol-4-yl) -2,3-dihydro-1H-isoindole A synthesis was prepared.

(Example 3-115)

Replacing 2,3-dihydro-1H-isoindol-5-ylamine in step 5 with [4- (2,3-dihydro-1H-isoindol-5-yl) -thiazol-2-yl] -isopropyl-amine In a manner similar to that described in Example 3-57, (1S, 4R, 6S, 14S, 18R) -5- (2-isopropylamino-thiazol-4-yl) -1,3-dihydro-iso Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-18 -The yl ester (compound AR00365019) was synthesized. ¹ H NMR (400 MHz, CD ₃ COCD ₃ ) δ 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 to 5.05 (m, 1H), 4.68 to 4.76 (m, 4H), 4.59 to 4.64 (m, 1H) 4.45 to 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 to 1.94 (m, 2H), 1.70 to 1.79 (m, 1H) 1.05 to 1.65 (m, 19H) 0.95 to 1.05 (m, 2H). MS m / z 754.2 (M + 1-100).

(Example 3-115a)

  The synthesis of [4- (2,3-dihydro-1H-isoindol-5-yl) -thiazol-2-yl] -isopropyl-amine is shown in the following scheme.

To a solution of A.THF (4 mL) and ethyl vinyl ether 1 mL, t-BuLi (0.79 mL, 1.34 mmol) was added dropwise at −78 ° C. The solution was warmed to room temperature and stirred for 30 minutes. ZnCl ₂ in THF 0.5M (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.

BN ₂ aryl bromide dissolved in THF under (0.200 g, 0.67 mmol) to a solution of and _{Pd (PPh 3) 4 (39mg} , 0.33mmol), vinyl zinc species crude from Step A was inserted via cannulae. The reaction was heated at 50 ° C. for 36 h, then filtered through an Al ₂ O ₃ plug with EtOAc and concentrated to give an oil that was used without further purification.

C. The crude oil from Step B was dissolved in THF (2 mL) and 1.0 N HCl (2 mL) and stirred for 1 hour. The reaction was dissolved in EtOAc and separated and the organic layer was washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to give an orange oil. The oil was chromatographed with 5: 1 hexane: EtOAc to give a white solid (95 mg, 54%).

TMSCl (3.38 mL, 26.6 mmol) was added dropwise to a D.1.0 M LiHMDS (4.0 mL, 4.0 mmol) solution at −78 ° C. under N ₂ . To this solution was added the ketone from Step C in THF (3 mL). The reaction was stirred at −78 ° C. for 30 minutes and warmed to 0 ° C. PTTB (1.10 g, 2.93 mmol) was added and the reaction was stirred at 0 ° C. for 30 min, concentrated to a solid, dissolved in EtOAc and water. The organics were washed with water and brine, dried over Na ₂ SO ₄ , concentrated, and the oil was purified with 5: 1 hexanes: EtOAc to give a yellow solid (0.64 g, 71%).

An EtOH slurry of E. bromoketone (75 mg, 0.22 mmol), Na ₂ CO ₃ (37 mg, 0.44 mmol) and 1-isopropylthiourea (26 mg, 22 mmol) was heated to reflux for 30 minutes. The reaction was dissolved in EtOAc and separated and the organic layer was washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to a yellow oil. Purification of the oil with 3: 1 hexane: MTBE gave a clear oil (77 mg, 97%).

  F. The Boc-amine from Step E was stirred in 4N HCl / dioxane (2.0 mL) for 1 h and concentrated to a white solid. This solid was dissolved in 0.1N HCl and washed with DCM. The aqueous layer was basified with 1.0N NaOH, extracted with DCM, dried, concentrated and used without further purification.

Preparation of macrocyclic aminoproline intermediate
(Example 4-1)
(1S, 4R, 6S, 14S, 18R) -18-Amino-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene Synthesis of 4-carboxylic acid ethyl ester

  A. (2S, 4R) -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) were added. The reaction was stirred for 3 days, placed on silica gel and the product eluted with 40% EtOAc / hexanes to give a colorless oil. The oil was dissolved in methanol (20 mL) and stirred with 10% palladium on carbon under a balloon of hydrogen gas. After stirring for 4 hours, 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 adding sodium hydroxide and extracted again with methylene chloride (100 mL). Both organic extracts were combined, concentrated, and the resulting residue was purified by silica gel chromatography eluting with 10% methanol / methylene chloride to give a brownish solid (1.29 g, 70%). LCMS = 289 (H +).

  B.4 (R)-(2-Trimethylsilylethylcarbonylamino) -pyrrolidine-2 (S) -carboxylic acid methyl ester (1.29 g, 4.50 mmol), 2 (S) -tert-butoxycarbonylamino-nona-8- A solution of 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) was stirred overnight. The reaction was diluted with ethyl acetate (150 mL), washed with 1N aqueous HCl (2 × 100 mL), dried over magnesium sulfate, and concentrated. Silica gel chromatography gave an oil that was stirred with lithium hydroxide (0.28 g, 6.76 mmol) in methanol (5 mL) for 2 hours. The reaction was diluted with methylene chloride, washed with 1N aqueous HCl, dried over magnesium sulfate, and concentrated to give 1.2 g (49%) of product.

  C.1 (R) -tert-Butoxycarbonylamino-2 (S) -vinyl-cyclopropanecarboxylic acid ethyl ester (0.70 g, 2.75 mmol) was added 4N HCl / dioxane solution (2.87 mL, 11.46 mmol). It was. After stirring for 2 hours, the reaction was concentrated to give a solid. To this solid was added 1- (2 (S) -tert-butoxycarbonylamino-nona-8-enoyl) -4 (R)-(2-trimethylsilylethylcarbonylamino) -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) were added and the reaction was stirred at room temperature for 18 hours. The reaction was introduced onto silica gel and eluted with 50% ethyl acetate / hexane solution to give the product as a colorless oil (1.27 g, 83%). 665 (H +).

D: 1-{[1- (2 (S) -tert-butoxycarbonylamino-nona-8-enoyl) -4 (R)-(2-trimethylsilylethylcarbonylamino) -pyrrolidine-2 (S) -carbonyl] -Amino} -2 (S) -vinyl-cyclopropane-1- (R) -carboxylic acid ethyl ester (1.27 g, 1.91 mmol) in methylene chloride (195 mL) for 1 hour by bubbling N ₂ through the solution. Degassed. Dichloro (o-isopropoxyphenyl-methylene) (tricyclohexylphosphine) ruthenium (II) (0.057 g, 0.096 mmol) was added and the reaction was stirred at 40 ° C. for 16 hours. The reaction was concentrated, introduced onto silica gel and eluted with 50% ethyl acetate / hexane. The resulting oil was treated with TBAF (1.0 M in THF, 2.87 mL) and heated to 50 ° C. for 4 hours. The reaction was introduced onto silica gel and eluted with 20% methanol / methylene chloride to give a tan solid (0.65 g, 69%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.06 to 1.66 (m, 17H), 1.85 to 1.95 (m, 2H), 2.0 to 2.1 (m, 1H), 2.1 to 2.2 (m, 1H), 2.2 to 2.3 (m, 1H), 2.65 to 2.75 (M, 1H), 3.40 (m, 1H), 3.73 to 3.83 (m, 2H), 4.08 to 4.19 (m, 2H), 4.56 (m, 1H), 4.78 ( d, J = 5.5Hz, 1H), 5.20 (t, J = 8.1Hz, 1H), 5.34 (d, J = 8.1Hz, 1H), 5.47 (dt, J = 4.5,10.8Hz, 1H), 7.08 ( s, 1H) .493 (H +).

  Preparation of compounds having general structure V

(Example 5-1)

(1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18-[(3,4-dihydro-1H-isoquinoline-2-carbonyl) -amino] -2,15-dioxo-3, Synthesis of 16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00287262)

3,4-dihydro-1H-isoquinoline-2-carbonyl chloride (0.030 g, 0.152 mmol), (1S, 4R, 6S, 14S, 18R) -18-amino-14-tert-butoxycarbonylamino-2,15- Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ethyl ester (0.025 g, 0.050 mmol), DIEA (0.027 mL, 0.153 mmol) and catalytic amount of DMAP Were stirred together in methylene chloride (0.3 mL) for 18 hours. The reaction was introduced onto silica gel and the product was eluted with 40% acetone / hexane 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 hours, the reaction was diluted with methylene chloride (30 mL), washed with 1N aqueous HCl (30 mL), brine (30 mL), dried over magnesium sulfate and concentrated to give the title compound as a white solid. It was. LCMS = 624 (MH +).

  The following compounds were also prepared using the procedure described in Example 5-1, substituting 1,3-dihydro-isoindole-2-carbonyl chloride for 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride: did. LCMS = 610 (H +).

(Example 5-2)

According to the procedure described in Example 5-1, replacing 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride with 1,3-dihydro-isoindole-2-carbonyl chloride (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18-[(1,3-dihydro-isoindole-2-carbonyl) -amino] -2,15-dioxo-3,16-diaza-tricyclo [14.3. 0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid (compound AR00298980) was prepared. MS m / e 608.2 (M-1).

(Example 5-3)

Substituting 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride for 3,4-dihydro-2H-quinoline-1-carbonyl chloride, following the procedure described in Example 5-1, (1S, 4R, 6S , 14S, 18R) -14-tert-butoxycarbonylamino-18-[(3,4-dihydro-2H-quinoline-1-carbonyl) -amino] -2,15-dioxo-3,16-diaza-tricyclo [ 14.3.0.0 ^4,6 ] Nonadeca-7-ene-4-carboxylic acid (compound AR00304160) was prepared. MS m / e 524.3 (M ⁺ + 1-100).

  Preparation of compounds having general structure VI

(Example 6-1)

Using a procedure similar to that described in Step 4 of Example 1-2, except that carbonyldiimidazole was replaced with thiocarbonyldiimidazole, (1S, 4R, 6S, 14S, 18R) -14-tert- Butoxycarbonylamino-18-[(3,4-dihydro-1H-isoquinoline-2-carbothioyl) -amino] -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -Ene-4-carboxylic acid (compound AR00304010) was prepared. LCMS = 640 (H +), MS m / e 640.1 (M ⁺⁺ 1).

  Preparation of compounds having general structure VII

(Example 7-1)

(1S, 4R, 6S, 14S, 18R)-{4-cyclopropane, starting from the acid prepared from the procedure described in Example 5-1, following the same procedure as described in Example 3-1. Sulfonylaminocarbonyl-18-[(3,4-dihydro-1H-isoquinoline-2-carbonyl) -amino] -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 The synthesis of -en-14-yl} -carbamic acid tert-butyl ester (compound AR00287266) was prepared. MS m / e 727.0 (M ⁺⁺ 1).

(Example 7-2)

(1S, 4R, 6S, 14S, 18R)-{4-cyclopropane, starting from the acid prepared from the procedure described in Example 5-2 and following the same procedure as described in Example 3-1. Sulfonylaminocarbonyl-18-[(1,3-dihydro-isoindole-2-carbonyl) -amino] -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7- En-14-yl} -carbamic acid tert-butyl ester (compound AR00304008) was prepared. MS m / e 613.2 (M ⁺ + 1-100).

(Example 7-3)

Following the same procedure as described in Example 2-24, starting from the acylsulfonamide prepared from the procedure described in Example 7-4, (1S, 4R, 6S, 14S, 18R) -1,3 -Dihydro-isoindole-2-carboxylic acid [14- (3-cyclopentyl-ureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl] -amide (Compound AR00304014) was prepared. MS m / e 724.2 (M ⁺ +1).

(Example 7-4)

(1S, 4R, 6S, 14S, 18R)-{4-cyclopropane, starting from the acid prepared from the procedure described in Example 6-1 and following the same procedure as described in Example 3-1. Sulfonylaminocarbonyl-18-[(3,4-dihydro-1H-isoquinoline-2-carbothioyl) -amino] -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7 -En-14-yl} -carbamic acid tert-butyl ester (compound AR00304012) was prepared. MS m / e 743.0 (M ⁺ +1).

(Example 7-5)

AR00335293 (84 mg) was dissolved in 0.5 mL of 4M HCl / dioxane to give 1S, 4R, 6S, 14S, 18R) -5-fluoro-1-methoxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxyl Acid 14-amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester hydrochloride (Compound AR00424775) Was synthesized and stirred at room temperature for 16 hours. The reaction was then concentrated and dissolved in acetonitrile for concentration again. The hydrochloride salt was then dried overnight with a high vacuum pump to give the product as 80 mg of a white solid ester. + APCI MS m / z 690.1 (M + 1).

(Example 7-6)

  AR00334191 (98 mg) was dissolved in 0.5 mL of 4M HCl / dioxane to give 1S, 4R, 6S, 14S, 18R) -4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-amino-4 -Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.04,6] nonadeca-7-en-18-yl ester hydrochloride (compound AR00424874) was synthesized at room temperature 16 Stir for hours. The reaction was then concentrated and dissolved in acetonitrile for concentration again. The hydrochloride salt was then dried overnight with a high vacuum pump to give the product as a white solid (89 mg). + APCI MS m / z 632.1 (M + 1).

(Example 8)
NS3-NS4A proteolytic enzyme assay
NS3 complex formation with NS4A-2 Recombinant Escherichia coli or baculovirus full-length NS3 was diluted to 3.33 μM with assay buffer, the material was transferred to an Eppendorf tube, and placed in a water bath in a 4 ° C. refrigerator. . An appropriate amount of NS4A-2 brought to 8.3 mM in assay buffer was added to an equal volume of NS3 (conversion factor-3.8 mg / 272 μL assay buffer) in step 2.1.1. The substance was transferred to an Eppendorf tube and left in a water bath in a refrigerator at 4 ° C.

  After equilibration to 4 ° C., equal volumes of NS3 and NS4A-2 solutions were combined in an Eppendorf tube, gently mixed with a manual pipetter, and the mixture was incubated for 15 minutes in a 4 ° C. water bath. The final concentration in the mixture was 1.67 μM NS3, 4.15 mM NS4A-2 (NS4A-2 was 2485 fold molar excess).

  After 15 minutes at 4 ° C, the NS3 / NS4A-2 Eppendorf tube was removed and left in a room temperature water bath for 10 minutes. NS3 / NS4A-2 was aliquoted to an appropriate volume and stored at -80 ° C (E. coli NS3 was used for the assay at 2 nM, aliquoted to 25 μL, BV NS3 was used for the assay at 3 nM, equal to 30 μL )

NS3 Inhibition Assay Step 2.2.5. Sample compounds were dissolved in DMSO to 10 mM and then diluted to 2.5 mM (1: 4) in DMSO. Usually, compounds were added to the assay plate at a concentration of 2.5 mM and diluted to give a starting concentration of 50 μM in the assay inhibition curve. Compounds were serially diluted in assay buffer to obtain test solutions at low concentrations.

  Step 2.2.6. E. coli NS3 / NS4A-2 was diluted to 4 nM NS3 (1: 417.5 1.67 μM stock, 1.67 μM stock 18 μL + assay buffer 7497 μL).

  BV NS3 / NS4A-2 was diluted to 6 nM NS3 (1: 278.3 1.67 μM stock, 1.67 μM stock 24 μL + assay buffer 6655 μL).

  Step 2.2.7. 50 μL of assay buffer was added to wells A01-H01 of a black Coster 96 well polypropylene storage plate using a manual multichannel pipettor and being careful not to introduce air bubbles into the plate.

  Step 2.2.8. Dilute the diluted NS3 / NS4A-2 (50 μL) from step 2.2.6 in step 2.2.7 using a manual multichannel pipettor and taking care not to introduce air bubbles into the plate. Added to wells A02-H12 of the plate.

  Step 2.2.9. Using a manual multichannel pipettor and taking care not to introduce air bubbles into the plate, add 25 μL wells in the drug dilution plate in step 2.2.5 to the assay plate in step 2.2.8. Transferred to the corresponding well. The tip of the multichannel pipettor was exchanged with each row of compounds to be transferred.

  Step 2.2.10. Assay in Step 2.2.9 using a manual multichannel pipettor and by aspirating and dispensing 75 μl of 35 μL 5 times in each well, taking care not to introduce air bubbles into the plate The wells from the plate were mixed. The tip of the multichannel pipettor was exchanged with each row of wells to be mixed.

  Step 2.2.11. The plate was covered with a polystyrene plate lid and the plate from Step 2.2.10 containing NS3 proteolytic enzyme and sample compound was pre-incubated for 10 minutes at room temperature.

  While pre-incubating the plate from step 2.2.11, the RETS1 substrate was diluted into a 15 mL polypropylene centrifuge tube. RETS1 substrate was diluted to 8 μM (1: 80.75 646 μM stock, 646 μM stock 65 μL + assay buffer 5184 μL).

  After pre-incubating the plate in step 2.2.11, 25 μL of substrate was added to all wells on the plate using a manual multichannel. The well contents were mixed rapidly as shown in step 2.2.10 except that 65 μL of 100 μL in the well was mixed.

  Plates were read in kinetic mode using a Molecular Devices SpectraMax Gemini XS plate reader. Reader settings: Reading time: 30 minutes, Interval: 36 seconds, Reading: 51, Excitation λ: 335 nm, Emission λ: 495 nm, Cutoff: 475 nm, Automix: Off, Calibration: Once, PMT: High, Reading / Well : 6, Vmax pts: 21 or 28/51, depending on the linearity of the response.

IC ₅₀ was determined using a 4-parameter curve fitting equation and converted to Ki using the following Km.
Full length E. coli NS3-2.03μM
Full length BVNS3-1.74μM
Where Ki = IC ₅₀ / (1+ [S] / Km))

Quantification by ELISA of neomycin phosphotransferase II (NPTII), a selectable marker protein in the HCV subgenomic replicon GS4.3
HCV subgenomic replicon (I377 / NS3-3 ', Accession No.AJ242652) that is stably maintained in HuH-7 liver cancer cells was created by Lohmann et al., Science, 285, 110-113, 1999. It was done. A replicon-containing cell culture designated GS4.3 was obtained from Dr. Christoph Seeger, the Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

GS4.3 cells, L-glutamine 200 mM (100X) (Gibco25030-081), non-essential amino acids (NEAA) (Biowhittaker 13-114E), heat inactivated (HI) fetal calf at 37 ° C., 5% CO ₂ Maintained in DMEM (Gibco11965-092) supplemented with serum (FBS) (Hyclone SH3007.03) and 750 μg / ml geneticin (G418) (Gibco10131-035). Cells were subdivided 1: 3 or 4 every 2-3 days.

  Twenty-four hours prior to assay, GS4.3 cells were collected, counted, plated in 96-well plates (Costar 3585) at 7500 cells / well in 100 μL standard maintenance medium (above) and incubated under the conditions described above. To start the assay, the medium was removed, the cells were washed once with PBS (Gibco10010-023) and 90 μL of assay medium (DMEM, L-glutamine, NEAA, 10% HI FBS, non-G418) was added. Make inhibitors as 10x stock in assay medium (3x dilution from 10 μM to final concentration of 56 pM, final DMSO concentration 1%), add 10 μL to replicate wells, shake plate, Incubated as above for 72 hours.

  NPTII ELISA kit was obtained from AGDIA (compound direct ELISA test system for neomycin phosphotransferase II, PSP73000 / 4800). Some modifications were made and the manufacturer's instructions were followed. Ten times PEB-1 lysis buffer was made to contain 500 μM PMSF (Sigma P7626, 50 mM stock in isopropanol). After 72 hours of incubation, the cells were washed once with PBS and 150 μL of PEB-1 containing PMSF was added per well. Plates were stirred vigorously for 15 minutes at room temperature and then frozen at -70 ° C. The plate was thawed, the solution was mixed thoroughly, and 100 μL was applied to the NPTII Elisa plate. A standard curve was created. Solutions from control cells treated with DMSO were stored, serially diluted with PEB-1 containing PMSF, and applied in an initial solution volume range of 150 μL to 2.5 μL to replicate wells of an ELISA plate. In addition, only 100 μL of buffer was applied to replicate as a blank. The plate was sealed and gently agitated for 2 hours at room temperature. Following capture incubation, the plates were washed 5 times with 300 μL of PBS-T (0.5% Tween-20, PBS-T provided in the ELISA kit). For detection, dilute enzyme conjugate diluent MRS-2 (5x) once in PBS-T, and add 1: 100 dilution of enzyme conjugates A and B as per instructions for use. It was. Plates were resealed and incubated with agitation while covering for 2 hours at room temperature. The washing was then repeated and 100 μL of TMB substrate was added at room temperature. After approximately 30 minutes of incubation (room temperature, stirring, coating), the reaction was stopped with 50 μL of 3M sulfuric acid. Plates were read at 450 nm on a Molecular Devices Versamax plate reader.

The inhibitor effect was expressed as a percentage of the control signal treated with DMSO, and the inhibition curve was calculated using a 4-variable equation: y = A + ((BA) / (1 + ((C / x) ^ D))) Where C is half-maximal activity or EC ₅₀ .

Examples of activity where
A indicates an IC50 or EC50 that is less than 50 μM;
B indicates an IC50 or EC50 that is less than 10 μM;
C indicates an IC50 or EC50 that is less than 1 μM,
D indicates an IC50 or EC50 that is less than 0.1 μM.

Specific Assays When compounds are evaluated in specific assays, compounds of Formula I may be selective in that they do not show effective inhibition against cathepsin B, chymotrypsin, thrombin, or leukocyte elastase. It was found.

(Example 9)
Compound Pharmacokinetic Analysis Methods Compounds were first synthesized and tested for efficacy (IC ₅₀ ) in a fluorogenic NS3 / 4 proteolytic enzyme assay and cell-based HCV replicon system as described in Example 8 above. . Plasma pharmacokinetic analysis after IV administration in mice is then directed to design metabolically stable compounds from compounds with efficacy <20 nM in order to direct human liver microsomes (HLM) and liver in vitro. Used with cell stability test. These lead compounds were then further optimized for drug-like physical properties and administered orally to mice to assess liver, heart and plasma concentrations.

The compounds were tested for liver clearance over time after a single oral dose of 3 mg / kg to rats. For compounds that showed that the concentration in the liver at 8 hours after administration was at least 100-fold greater than the concentration of compound effective to inhibit 50% of maximal inhibition in the replicon assay (replicon EC ₅₀ ). Additional toxicity studies were conducted in rats using daily oral doses of up to 30 mg / kg and BID.

Results Compounds AR294381, AR261408, AR333833, and AR334191 gave a replicon EC ₅₀ value of approximately 2 nM, indicating stability in vitro in rat, dog and human hepatocyte incubation assays, and this data shows low clearance from the liver. Expected to be moderate. In addition, these compounds show a high selectivity for other serine proteolytic enzyme panels, with significant inhibition on cytochrome P450 isoforms or hERG channel activity even at the highest concentration tested (10 μM) Did not show.

For compounds AR294381, AR261408, AR333833 and AR334191, a single oral dose of 30 mg / kg to mice resulted in a concentration at least 200 times greater than the respective replicon EC ₅₀ value in the liver 24 hours after administration.

Compound AR334191 resulted in heart and plasma concentrations that were two orders of magnitude lower kinetically related to these than liver concentrations in the same animal. At a clinically more relevant oral dose (3 mg / kg), compound AR334191 had a concentration in the liver 8 hours after administration that was more than 100 times the replicon EC ₅₀ value of the compound. After 7 days of exposure to Compound AR334191 at 30 mg / kg, oral, BID, no deaths, body weight changes, or clinical chemistry abnormalities were observed in the treated animals.

Conclusion
We have developed an effective, metabolically stable, orally available small molecule inhibitor of HCV NS3 protease. At moderate oral dose concentrations (3 mg / kg), these compounds show high liver concentrations (100 times higher than their respective replicon EC ₅₀ values) 8 hours after dosing. Plasma and heart exposure is to the order of two orders of magnitude lower than that observed in the liver, and such low concentrations minimize potential systemic toxicity problems.

Compound AR334191 does not show toxicity in mice when given at 30 mg / kg BID for 7 days and provides a safety margin that is at least 10 times higher than the putative effective dose (3 mg / kg). A 100-fold excess of the compound's replicon EC ₅₀ value.

Preparation of Section C Antiviral Agents The meanings of the terms and structure names used in this section are the same as in Section C above. Unless otherwise indicated, all references in this section relating to a particular number or label are not presumably the context of similar or identical numbered or labeled schemes used elsewhere in this specification. Should be understood in the context of the corresponding numbered or labeled scheme used in this section or section C above.

  Compounds of formula XI-XVII can be synthesized according to the methods described below.

Methodology The NS3 inhibitors shown in Examples 1-35 were prepared according to the chemistry illustrated in Scheme 1. Intermediate 1 (R) -tert-butoxycarbonylamino-2 (S) -vinyl-cyclopropanecarboxylic acid ethyl ester, 2 (S) -tert-butoxycarbonylamino-non-8-enoic acid, and hydroxy macrocyclic intermediate The body (Step C) was prepared in a manner similar to that described in International Patent Application PCT / CA00 / 00353 (Publication No. WO00 / 59929). 2 (S) -tert-butoxycarbonylamino-non-8-enoic acid was also purchased from RSP Amino Acids.

(Example 1)
Synthesis of Compound No. 101

Step A: Synthesis of 2S- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4R-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester ethyl- (1R, 2S) / (1S, 2R)- 1-amino-2-vinylcyclopropylcarboxylate (1.0 g, 5.2 mmol), trans-N- (tert-butoxycarbonyl) -4-hydroxy-L-proline (1.3 g, 1.1 eq), and HATU (2.7 g , 1.1 eq) was added to a solution by adding 30 mL of DMF. Cool to 0 ° C. in an ice-water bath and then slowly add a solution of DIEA (4.4 mL, 4 eq) in DMF (15 mL) with stirring. The reaction was warmed to room temperature and stirred overnight.

After 16 hours, the reaction was complete as monitored by HPLC. Dilute with EtOAc (100 mL), wash with water (3 × 40 mL), saturated NaHCO ₃ (2 × 40 mL), and brine (2 × 40 mL), then dry over Na ₂ SO ₄ and concentrate to a dark copper color. An oil was obtained. The crude product was purified on silica gel (eluent: acetone / hexane 3: 7) to give the desired pure product as a tan foam (770 mg, 32%).

Step B: 1R-{[1- (2S-tert-butoxycarbonylamino-non-8-enoyl) -4R-hydroxy-pyrrolidine-2S-carbonyl] -amino} -2S-vinyl-cyclopropanecarboxylic acid ethyl ester Synthesis The dipeptide product from Step A (2.85 g, 7.7 mmol) was dissolved in 10 mL of 4 N HCl (dioxane) and placed at room temperature for 90 minutes to remove the Boc protecting group. It was then concentrated, dissolved in acetonitrile and concentrated again twice. To this light brown residue was added 2 (S) -tert-butoxycarbonylamino-non-8-enoic acid (2.2 g, 8.1 mmol) and HATU (3.2 g, 8.5 mmol), followed by 80 mL DMF under nitrogen. It was. After the reaction was cooled in an ice-water bath for 15 minutes, 5 mL of a DMF solution of DIEA (5.4 mL, 30.9 mmol) was added dropwise to the reaction with stirring. The ice bath was allowed to slowly reach room temperature and the reaction was stirred overnight.

After 18 hours, TLC showed that the reaction was complete. The reaction was diluted with EtOAc (300 mL), washed with water (3 × 150 mL), saturated NaHCO ₃ (2 × 150 mL), brine (150 mL), dried (Na ₂ SO ₄ ) and the solvent removed. The crude product was purified by silica gel flash chromatography on Biotage 40M (eluent = MeOH 3% -5% DCM) to give the desired product as a brown foamy solid (3.5 g, 87%). .

Step C: (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- Synthesis of 7-ene-4-carboxylic acid ethyl ester The product from Step B (2.6 g, 5.0 mmol) was dissolved in 500 mL of DriSolve DCE in a 1 L round bottom flask to make a solution. Nitrogen was degassed by bubbling for 1 hour. Then Hoveyda catalyst (0.25 eq) was added at room temperature under nitrogen. The reaction was placed on a preheated oil bath (50 C) and stirred overnight. After 16 hours, the reaction turned dark brown. TLC (DCM / EtOAc 1: 1) showed clear conversion to a new spot with a slightly lower Rf value. The reaction was concentrated and purified on silica gel (Biotage 40M, eluent = DCM / EtOAc, 1: 1 to 1: 2 gradient) to give the desired product as a tan foam (0.64 g, 52 %). ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.21 (t, J = 7.0 Hz, 3H), 1.43 (s, 9H), 1.20 to 1.50 (m, 6H), 1.53 to 1.68 (m, 2H), 1.83 to 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 = 9.4Hz, 1H), 5.36 (d, J = 7.8Hz, 1H), 5.53 ( m, 1H), 7.19 (brs, 1H). MS m / z 494.0 (M ⁺⁺ 1).

Step D: (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16 Synthesis of -diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid ethyl ester The macrocyclic product from Step C (110 mg, 0.22 mmol) was dissolved in DCM (2.2 mL), Subsequently CDI (45 mg, 0.27 mmol) was added without splitting. The reaction was stirred overnight at room temperature. After 15 hours, the reaction was complete as monitored by TLC (DCM / MeOH 9: 1). To the reaction was added isoindoline (0.12 mL, 1.1 mmol) dropwise and the reaction was stirred at 40 ° C. overnight. After 22 hours, TLC showed that the reaction was complete. The reaction was cooled to room temperature, diluted with DCM (6 mL), washed with 1N aqueous HCl (2 × 2 mL), saturated sodium bicarbonate (2 mL), brine (2 mL), dried (Na ₂ SO ₄ ), Concentrated. The crude was purified on silica gel (Biotage 40 S, eluent: 2% to 4% DCM in MeOH) to give the desired product as a white powder (131 mg, 90%).

Step E: (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18- (1,3-dihydro-isoindole-2-carbonyloxy) -2,15-dioxo-3,16 Synthesis of -diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene-4-carboxylic acid The macrocyclic ester product from Step D (60 mg, 0.092 mmol) was mixed with a mixed solvent (THF / MeOH / H2O 2: 1: 1) Dissolved in 0.9 mL, followed by addition of LiOH-H ₂ O (23 mg, 6 eq). The mixture was stirred overnight at room temperature. After 16 hours, TLC (DCM / MeOH 9: 1) showed clearly new spots with lower Rf values. The reaction was concentrated to near dryness and partitioned between 1N aqueous HCl (15 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2 × 20 mL). The organic layers were combined, dried over Na ₂ SO ₄ and concentrated to give the desired product as a white foam (50 mg, 87%). ¹ H NMR (CDCl ₃ , 500 MHz) δ 1.21 to 1.44 (m, 8H), 1.32 (s, 9H), 1.54 to 1.62 (m, 2H), 1.78 to 1.88 (m, 2H), 2.04 to 2.13 (m , 1H), 2.16 to 2.23 (m, 1H), 2.24 to 2.36 (m, 2H), 2.66 to 2.74 (m, 1H), 3.87 to 3.90 (m, 1H), 4.15 (d, J = 11.0Hz, 1H ), 4.37 to 4.43 (m, 1H), 4.61 to 4.77 (m, 5H), 5.18 (t, J = 10.3Hz, 1H), 5.24 to 5.31 (m, 1H), 5.40 to 5.45 (m, 1H), 5.58-5.66 (m, 1H), 7.11-7.30 (m, 4H). MS m / z 611.0 (M ⁺⁺ 1).

Step F: (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (N, N-dimethylsulfonyl-aminocarbonyl)- Synthesis of 2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester (Compound No. 101) Macrocyclic acid product from Step E (40 mg, 0.066 mmol) was dissolved in 0.7 mL DCE, followed by addition of CDI (13 mg, 0.079 mmol) without splitting. The mixture was stirred in a 50 ° C. oil bath for 2 hours. TLC (10% methanol in dichloromethane) showed that the acid starting material had disappeared and a new spot with a much higher Rf value appeared. N, N-dimethylsulfamide (12 mg, 0.098 mmol; purchased from TCI) was then added to the reaction followed by DBU (15 mg, 0.098 mmol). Heating was resumed and heated at 50 ° C. for 2 hours. Both TLC and LCMS indicated that the reaction was complete and product was formed. The reaction was concentrated and loaded directly onto a Biotage 40S silica gel column. Purification by flash chromatography (eluent = 1% ethyl acetate in 40% hexane with formic acid) gave the desired product as a white solid (30 mg, 64%). MS m / z 715.5 (APCI-) M-1).

  The following compounds in Examples 2-35 replace N, N-dimethylsulfamide in Step F with other suitable sulfamides and / or replace isoindoline with alternative other amines as described in Example 1 above. Prepared according to a procedure similar to that described in 1. The sulfamide used was purchased commercially or prepared by Route A or B described in Scheme 2 below. Methods similar to Route A are described in the literature (eg, Heteroatom Chemistry, 12 (1), 1-5, 2001). The sulfamoylating reagent a in route B was prepared according to the procedure of literature (Winum, JY et al., Organic Letters, Vol. 3, pages 2241 to 2243, 2001).

Scheme 2
Synthesis of N-cyclopropylsulfamide

  To a stirred solution of chlorosulfonyl isocyanate (1 mL, 11.5 mmol) in 20 mL DriSolve DCM was added anhydrous t-butanol (1.1 mL, 1 eq) at 0 ° C. After stirring for 90 minutes, a solution of the obtained carbamate sulfamoyl chloride solution and 5 mL of TEA dissolved in 20 mL of DCM was added dropwise to a solution of cyclopropylamine (0.66 g, 1 equivalent) 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 room temperature for 3 hours.

TLC (Hex / EA 1: 1) showed one major spot with a higher Rf value. LCMS showed product formed. The reaction mixture was then diluted with 100 mL DCM and washed with 0.1 N HCl (2 × 200 mL) and brine (150 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to obtain Boc group-protected sulfamide as 1.2 g of a pale yellow solid. ¹ H-NMR showed the desired product and a small amount of impurities. The crude product was recrystallized from EA / Hex (room temperature to 0 ° C.) to obtain 0.64 g of an off-white pure crystalline product. ¹ H NMR (CDCl ₃ , 400 MHz) δ 0.71 to 0.77 (m, 4H), 1.51 (s, 9H), 2.44 (m, 1H), 5.58 (br s, 1H), 7.42 (br s, 1H). MS m / z 234.7 (APCI-, M-1).

To remove the Boc protecting group, the above product was dissolved in 10 mL of a 1: 1 (v / v) mixture of DCM: TFA and placed at room temperature for 1 hour. It was then concentrated on a vacuum rotator and then concentrated on a high vacuum. The thick oil solidified under high vacuum to give the title product as an off-white solid. ¹ H NMR (CDCl ₃ , 400 MHz) δ 0.66 to 0.74 (m, 4H), 2.57 to 2.58 (m, 1H), 5.29 (br s, 2H), 5.42 (br s, 1H).

  Synthesis of pyrrolidinosulfamide

The title compound was prepared following the same procedure described in the synthesis of N-cyclopropylsulfamide above, replacing cyclopropylamine with pyrrolidine. For Boc protected title compounds: ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.49 (s, 9H), 1.92 to 1.95 (m, 4H), 3.48 to 3.52 (m, 4H), 7.02 (br s, 1H ). MS m / z 249 (APCI-, M-1).

  Synthesis of morpholinosulfamide

The title compound was prepared following the same procedure described in the synthesis of N-cyclopropylsulfamide above, replacing cyclopropylamine with morpholine. For the Boc protected title compound: ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.50 (s, 9H), 3.39 (t, 4H), 3.76 (t, 4H), 7.18 (br s, 1H). MS m / z 265 (APCI-, M-1)

  Synthesis of thiazol-2-ylaminosulfamide

The title compound was prepared following the same procedure described in the synthesis of N-cyclopropylsulfamide above, substituting 2-aminothiosol for cyclopropylamine. However, the Boc protected intermediate was not isolated due to the disappearance of the protecting group during the reaction procedure and the following recrystallization step. The title product was isolated after silica gel column chromatography. (Biotage 40M, eluent = MeOH in 5-10% DCM). ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 6.52 (br s, 2H), 6.75 (d, 1H), 7.19 (d, 1H), 12.1 (br s, 1H). MS m / z 180 (ESI +, MH ⁺ ).

  Synthesis of 4-methyl-piperidinosulfamide

The title compound was prepared according to Scheme 2, Route B. 4-Methyl-piperidine (0.15 g, 1.50 mmol) was dissolved in a solution of 3 mL DriSolve DCM in 10 mL RBF, followed by the addition of sulfamoylating reagent (0.45 g, 1.50 mmol). After stirring for about 5 minutes, the latter reagent gradually dissolved and a clear, almost colorless solution was obtained. Stir overnight at room temperature. After 17 hours, TLC showed the reaction was complete (DCM: MeOH 9: 1; containing 1% TEA). The reaction is concentrated and the resulting pink crude solid is flushed onto a Biotage 40S silica gel column (eluent = DCM: MeOH 10: 1; containing 1% TEA) to give essentially the Boc protected title compound. Obtained as a white powder in quantitative yield. ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.48 (s, 9H), 2.33 (s, 3H), 2.52 (t, 4H), 3.43 (t, 4H). MS m / z 278 (APCI-, M-1).

  The Boc protecting group is then removed by the same method described in the synthesis of N-cyclopropylsulfamide and the resulting title product is used directly for the next coupling step without further purification. did.

(Example 2)

Replacing N, N-dimethylsulfamide in Step F with N-cyclopropylsulfamide, following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1,3-dihydro -Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (N-cyclopropylsulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. MS m / z 728 (APCI-, M-1).

(Example 3)

Replacing N, N-dimethylsulfamide in Step F with pyrrolidinosulfamide, following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-iso Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (pyrrolidinosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7- En-18-yl ester was synthesized. MS m / z742 (APCI-, M-1).

(Example 4)

Replacing N, N-dimethylsulfamide in Step F with morpholinosulfamide, following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole 2-carboxylic acid 14-tert-butoxycarbonylamino-4- (morpholinosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene- 18-yl ester was synthesized. MS m / z758 (APCI-, M-1).

(Example 5)

Replacing N, N-dimethylsulfamide in Step F with thiozoyl-2-ylaminosulfamide, following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1,3 -Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (thiozol-2-ylaminosulfonylaminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^{4 , 6} ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.15 (s, 9H), 1.22-1.54 (m, 11H), 1.60 (m, 1H), 1.68-1.88 (m, 2H), 2.35-2.45 (m , 3H), 2.57 (m, 1H), 3.85 (m, 1H), 4.15 (br d, 1H), 4.48 (m, 1H), 4.65 (m, 4H), 4.74 (t, 1H), 4.92 (t , 1H), 5.43-5.52 (m, 2H), 6.92 (d, 1H), 7.20-7.33 (m, 5H), 8.18 (s, 1H). MS m / z 770 (ESI-, M-1).

(Example 6)

Instead, the isoindoline in Step D is replaced with 5-fluoroisoindoline, and the same procedure as described in Example 1 is followed, followed by 1S, 4R, 6S, 14S, 18R) -5-fluoro-1,3-dihydro- Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (N, N-dimethylsulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, CD ₃ OD) δ 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 to 4.51 (m, 7H), 4.10 to 4.02 (m, 1H), 3.83 (d, 1H), 2.84 (s, 6H), 2.73 to 2.64 (m, 1H), 2.55 to 2.47 (m, 1H), 2.43 to 2.29 (m, 3H), 1.84 to 1.67 (m, 4H), 1.64 to 1.57 (m, 2H), 1.13 (d, 9H), 0.94 ~ 0.82 (m, 4H). MS m / z 733.4 (APCI-, M-1).

(Example 7)

Instead, the isoindoline in Step D was replaced with 1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline, following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R )-1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4- (N, N-dimethyl-sulfonylaminocarbonyl) ) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, CD ₃ OD) δ 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 to 4.17 (m, 3H), 4.12 to 4.02 (m, 1H), 3.99 to 3.88 (m, 1H), 3.70 to 3.38 (m, 6H), 3.14 to 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, 1H). MS m / z 826.6 (APCI-, M-1).

(Example 8)

Instead, isoindoline in Step D is replaced with 1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline, and N, N-dimethylsulfamide in Step F is replaced with N-cyclopropylsulfamide. According to the same procedure described in Example 1, 1S, 4R, 6S, 14S, 18R) -1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert- Synthesis of butoxycarbonylamino-2,15-dioxo-4- (N-cyclopropyl-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester did. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.31-7.15 (m, 4H), 5.75-5.58 (m, 2H), 5.47 (br s, 1H), 5.11 (t, 1H), 4.62-4.57 (m , 1H), 4.52 to 4.45 (m, 1H), 4.41 to 4.17 (m, 3H), 4.15 to 3.84 (m, 3H), 3.73 to 3.34 (m, 5H), 3.16 to 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)

Instead, the isoindoline in Step D was replaced with 1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline, and the N, N-dimethylsulfamide in Step F was replaced with pyrrolidinosulfamide. Following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonyl Amino-2,15-dioxo-4- (pyrrolidino-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, CD ₃ OD) δ 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 to 3.84 (m, 7H), 3.72 to 3.39 (m, 7H), 3.28 to 3.20 (m, 2H), 3.17 to 2.25 (m, 10H), 2.12 to 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)

Instead, the isoindoline in Step D was replaced with 1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline, and the N, N-dimethylsulfamide in Step F was replaced with morpholinosulfamide. 1S, 4R, 6S, 14S, 18R)-1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino -2,15-Dioxo-4- (morpholino-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, CD ₃ OD) δ 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 to 3.36 (m, 9H), 3.29 to 3.19 (m, 3H), 3.16 to 2.14 (m, 11H), 2.13 to 1.23 (m, 24H), 0.94 to 0.81 (m, 1H); MS m / z 868.6 (APCI-, M-1).

(Example 11)

Instead, the isoindoline in Step D was replaced with 1-morpholin-1-ylmethyl-3,4-dihydro-1H-isoquinoline, and the N, N-dimethylsulfamide in Step F was replaced with pyrrolidinosulfamide. Following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1-morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonyl Amino-2,15-dioxo-4- (pyrrolidine-1-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. MS m / z 874.3 (APCI-, M + 18).

(Example 12)

Instead, the isoindoline in step D was replaced with 2-morpholin-4-yl-1-phenyl-ethylamine, and the N, N-dimethylsulfamide in step F was replaced with pyrrolidinosulfamide, as described in Example 1. 1S, 4R, 6S, 14S, 18R)-(2-morpholin-4-yl-1-phenyl-ethyl) -carbamic acid 14-tert-butoxycarbonylamino-2,15-dioxo- 4- (Pyrrolidine-1-sulfonylaminocarbonyl) -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. MS m / z 828.3 (APCI-, M-18).

(Example 13)

Instead, the isoindoline in Step D is replaced with 5-chloroisoindoline, and the same procedure as described in Example 1 is followed, followed by 1S, 4R, 6S, 14S, 18R) -5-chloro-1,3-dihydro- Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (N, N-dimethylsulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. MS m / z651 (APCI +, M-Boc).

(Example 14)

Instead, replace the isoindoline in step D with 5-chloroisoindoline, replace N, N-dimethylsulfamide in step F with N-cyclopropylsulfamide, and follow the same procedure as described in Example 1. , 1S, 4R, 6S, 14S, 18R) -5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (N-cyclopropyl-sulfonyl-aminocarbonyl) -2,15-Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. MS m / z663 (APCI +, M-Boc).

(Example 15)

Instead, the isoindoline in step D was replaced with 5-chloroisoindoline, the N, N-dimethylsulfamide in step F was replaced with pyrrolidinosulfamide, and the same procedure as described in Example 1 was followed. , 4R, 6S, 14S, 18R) -5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (pyrrolidino-sulfonyl-aminocarbonyl) -2,15- Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. MS m / z 677 (APCI +, M-Boc).

(Example 16)

Instead, the isoindoline in step D was replaced with 5-chloroisoindoline, the N, N-dimethylsulfamide in step F was replaced with morpholinosulfamide, and the same procedure as described in Example 1 was followed, 1S, 4R, 6S, 14S, 18R) -5-Chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (morpholino-sulfonyl-aminocarbonyl) -2,15-dioxo -3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. MS m / z693 (APCI +, M-Boc).

(Example 17)

Instead, replace N, N-dimethylsulfamide in Step F with azetidine-1-sulfonamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1,3 -Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (azetidino-sulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.21 (s, 9H), 1.28 to 1.54 (m, 8H), 1.59 to 1.63 (m, 1H), 1.77 to 1.89 (m, 3H), 2.38 to 2.42 (m, 1H), 2.46 to 2.52 (m, 2H), 3.77 (t, 2H), 3.84 to 3.94 (m, 3H), 4.14 to 4.22 (m, 3H), 4.50 (br d, 1H), 4.61 to 4.72 (m, 5H), 5.12 (t, 1H), 5.44 (br s, 1H), 5.78 (q, 1H), 6.17 (br d, 1H), 7.23-7.36 (m, 4H), 8.38 (s, 1H). MS m / z 727.4 (APCI-, M-1).

Example 17a

The title compound, azetidine-1-sulfonamide, was prepared according to Route B in Scheme 2. Azetidine (0.16 g, 2.8 mmol) was dissolved in a solution of 5.6 mL of DriSolve DCM in 10 mL of RBF, followed by the addition of sulfamoylating reagent a (0.85 g, 2.8 mmol). After stirring for about 5 minutes, the latter reagent gradually dissolved and a clear, almost colorless solution was obtained. Stir overnight at room temperature. After 17 hours, TLC showed the reaction was complete (DCM: MeOH 9: 1). The reaction is concentrated and the resulting white crude solid is flushed onto a Biotage 40S silica gel column (eluent = 5-10% MeOH / DCM) to give the Boc protected title compound in essentially quantitative yield. Obtained. The product was initially a thick oil but gradually solidified overnight in a high vacuum. ¹ H NMR (CDCl ₃ , 400 MHz) Δ1.52 (s, 9H), 2.27 (m, 2H), 4.15 (t, 4H), 7.18 (br s, 1H).

The product from the above step (0.4 g, 2 mmol) was dissolved in 10 mL of a TFA / DCM (1: 1 v / v) mixture and placed at room temperature for 2 hours. The volatiles were then removed. The oily residue obtained was treated with diethyl ether and filtered. The white powder product from filtration was used for the coupling step without further purification. ¹ H NMR (d ⁶ -acetone, 400 MHz) δ 2.12 to 2.19 (m, 2H), 3.77 (t, 4H), 6.05 (br s, 2H).

(Example 18)

Instead, replace N, N-dimethylsulfamide in Step F with 4-methylpiperazine-1-sulfonamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R)- 1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-methylpiperazine-1-sulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.21 (s, 9H), 1.19 to 1.58 (m, 9H), 1.70 to 1.73 (m, 1H), 1.85 to 1.88 (m, 2H), 2.24 (s , 3H), 2.36 to 2.48 (m, 7H), 2.53 (m, 1H), 3.24 to 3.29 (m, 4H), 3.84 to 3.88 (m, 1H), 4.14 to 4.18 (m, 1H), 4.49 (br d, 1H), 4.60 to 4.72 (m, 5H), 5.04 (t, 1H), 5.44 (br s, 1H), 5.71 (q, 1H), 6.16 (br d, 1H), 7.23 to 7.36 (m, 4H), 8.31 (s, 1H). MS m / z 770.5 (APCI-, M-1).

(Example 19)

Instead, N, N-dimethylsulfamide in Step F was replaced with 4- (2-trimethylsilylethoxycarbonyl) piperazine-1-sulfonamide, following the same procedure as described in Example 1, 1S, 4R, 6S , 14S, 18R) -1,3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4- (2-trimethylsilylethoxycarbonyl) piperazine-1-sulfonyl-aminocarbonyl) -2 , 15-Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 0.06 (s, 9H), 0.94 to 0.98 (m, 2H), 1.15 (s, 9H), 1.17 to 1.50 (m, 8H), 1.50 to 1.54 (m , 1H), 1.65 to 1.68 (m, 1H), 1.75 to 1.82 (m, 2H), 2.30 to 2.44 (m, 3H), 2.56 to 2.68 (m, 1H), 3.17 to 3.26 (m, 4H), 3.44 ~ 3.47 (m, 4H), 3.78 ~ 3.81 (m, 1H), 4.08 ~ 4.14 (m, 3H), 4.44 (br d, 1H), 4.54 ~ 4.66 (m, 5H), 4.98 (t, 1H), 5.38 (br s, 1H), 5.56 to 5.63 (m, 1H), 6.12 (br d, 1H), 7.16 to 7.30 (m, 4H), 8.26 (s, 1H). MS m / z 901.3 (APCI-, M-1)

Example 19a

  The title compound, 4- (2-trimethylsilylethoxycarbonyl) piperazine-1-sulfonamide, was prepared according to Scheme 3 below.

  Scheme 3

Step 1: Dissolve tert-butyl piperazine-1-carboxylate (1.0 g, 5.4 mmol) in a solution of 10 mL DriSolve DCM in 50 mL RBF, followed by sulfamoylating reagent a (1.6 g, 5.4 mmol). added. After stirring for about 5 minutes, the latter reagent gradually dissolved and a clear, almost colorless solution was obtained. Stir overnight at room temperature. After 17 hours, TLC showed the reaction was complete (DCM: MeOH 20: 1). The reaction was concentrated and the resulting white crude solid was flushed onto a Biotage 40M silica gel column (eluent = 2% MeOH / DCM) to give the Boc protected product as a white foamy solid. ¹ H NMR (d ⁶ -acetone, 400 MHz) δ 1.45 (s, 9H), 1.46 (s, 9H), 3.30-3.32 (m, 4H), 3.48-3.50 (m, 4H). LCMS m / z 364.1 (APCI-, M-1).

  Step 2: The product from Step 1 above (0.90 g, 2.5 mmol) was dissolved in about 20 mL of TFA-DCM 1: 1 (v / v) mixture and left at room temperature for 2 hours. It was then concentrated. The solid residue was dissolved in MeCN and reconcentrated to give the deprotected group product as a white fine powder.

To this deprotected product was added 20 mL of DriSolve DCM followed by 1 mL of TEA. Teoc-succimate (0.70 g, 2.7 mmol) was added to the resulting white suspension without partitioning with stirring. The white suspension quickly disappeared and the colorless clear solution was stirred at room temperature overnight. The reaction was then concentrated and purified by silica chromatography (Biotage 40S, eluent = Hex: EA 2: 1) to give the pure product as a white solid 0.65 g (85%). ¹ H NMR (d ⁶ -acetone, 400 MHz) δ 0.06 (s, 9H), 0.94 to 0.98 (m, 2H), 3.01 (t, 4H), 3.48 (t, 4H), 4.10 to 4.14 (m, 2H ), 6.03 (br s, 2H). LCMS m / z 308.2 (APCI-, M-1).

(Example 20)

By removing the protecting group of Compound No. 119, 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (piperazine-1 -Sulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. First, Compound No. 119 (54.8 mg, 60.7 μmol) was dissolved in 0.5 mL of DriSolve THF, and then 1.0 M TBAF THF solution (0.2 mL, 200 μmol) was added. The reaction was heated in a 60 ° C. oil bath for 2 hours and TLC indicated that the reaction was complete. The reaction was purified by silica chromatography (Biotage 12M; eluent = MeOH 0-20% DCM solution) to give compound no. 120 as a white solid 42.4 mg (92%). MS m / z 756.4 (APCI-, M-1).

(Example 21)

Instead, replace N, N-dimethylsulfamide in Step F with N-cyclopropylsulfamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -4- Fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (N-cyclopropylsulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [ 14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.91 (d, 1H), 7.32 (q, 1H), 7.14 (d, 1H), 7.01 (t, 1H), 5.63 (q, 1H), 5.40 (br s, 1H), 5.13 (t, 1H), 4.80 to 4.68 (m, 4H), 4.61 (q, 1H), 4.56 to 4.49 (m, 1H), 4.06 (t, 1H), 3.83 (br s, 1H ), 3.72 (p, 1H), 3.22 (p, 1H), 2.72 to 2.60 (m, 1H), 2.57 to 2.48 (m, 1H), 2.46 to 2.31 (m, 4H), 1.83 to 1.69 (m, 4H) ), 1.66 to 1.58 (m, 1H), 1.56 to 1.19 (m, 5H), 1.13 (d, 9H), 0.71 to 0.51 (m, 4H). MS m / z 745.3 (APCI-, M-1).

(Example 22)

Instead, replace N, N-dimethylsulfamide in Step F with sulfamide and follow the same procedure as described in Example 1 and follow 1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole 2-carboxylic acid 14-tert-butoxycarbonylamino-4- (aminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene- 18-yl ester was synthesized. MS m / z688.2 (APCI-, M-1).

(Example 23)

Instead, replace N, N-dimethylsulfamide in Step F with 1-cyanocyclopropylsulfamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1 , 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (N- (1-cyanocyclopropyl) aminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza -Tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.22 (s, 9H), 1.20 to 1.55 (m, 11H), 1.58 to 1.61 (m, 1H), 1.66 to 1.69 (m, 1H), 1.71 to 1.75 (m, 1H), 1.81-1.90 (m, 2H), 2.42-2.48 (m, 3H), 2.60-2.70 (m, 1H), 3.84-3.88 (m, 1H), 4.16-4.20 (m, 1H) , 4.48 (br d, 1H), 4.58-4.71 (m, 5H), 5.07 (t, 1H), 5.44 (br s, 1H), 5.62 (q, 1H), 6.14 (br d, 1H), 7.22- 7.36 (m, 4H), 7.88 (br s, 1H), 8.20 (s, 1H). MS m / z 752.3 (APCI-, M-1)

Example 23a

Substituting cyclopropylamine for 1-aminocyclopropanecarbonitrile hydrochloride, following the same procedure described for the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), the title compound, 1-cyanocyclopropylsulfamid Prepared. ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.41-1.44 (m, 2H), 1.52-1.55 (m, 2H), 5.86 (br s, 2H), 7.19 (br s, 1H).

(Example 24)

Instead, replace N, N-dimethylsulfamide in Step F with cyclopropyl (1-methylpiperidin-4-yl) sulfamide and follow the same procedure as described in Example 1 for 1S, 4R, 6S, 14S. , 18R) -1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (cyclopropyl (1-methylpiperidin-4-yl) aminosulfonyl-aminocarbonyl) -2,15 -Dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 0.75 to 0.77 (m, 2H), 0.96 to 1.01 (m, 2H), 1.21 (s, 9H), 1.20 to 1.57 (m, 7H), 1.60 to 1.66 (m, 1H), 1.71-1.74 (m, 1H), 1.80-1.92 (m, 3H), 1.97-2.06 (m, 1H), 2.38-2.60 (m, 5H), 2.68 (s, 3H), 2.88 ~ 3.02 (m, 2H), 3.32 ~ 3.41 (m, 2H), 3.90 ~ 3.96 (m, 2H), 4.17 ~ 4.23 (m, 2H), 4.41 ~ 4.47 (m, 2H), 4.59 ~ 4.72 (m, 5H), 5.10 (t, 1H), 5.45 (br s, 1H), 5.63-5.70 (m, 1H), 6.11 (br d, 1H), 6.95 (s, 1H), 7.19-7.35 (m, 4H) , 8.42 (s, 1H). MS m / z 824.4 (APCI-, M-1).

Example 24a

The title compound, cyclopropyl (1-methylpiperidin-4-yl) sulfamide, was prepared by the same method described in Example 17a, replacing azetidine with N-cyclopropyl-1-methylpiperidin-4-amine. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 0.67 to 0.76 (m, 4H), 1.93 to 1.97 (m, 2H), 2.07 to 2.18 (m, 2H), 2.22 to 2.26 (m, 1H), 2.75 (s, 3H), 2.96 to 3.05 (m, 2H), 3.45 to 3.48 (m, 2H), 3.77 to 3.83 (m, 1H), 6.93 (br s, 2H), 9.78 (br s, 1H).

(Example 25)

Instead, replace N, N-dimethylsulfamide in Step F with 2-cyanoethyl (cyclopropyl) sulfamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1 , 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (2-cyanoethyl (cyclopropyl) aminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 0.74 to 0.78 (m, 2H), 0.98 to 1.01 (m, 2H), 1.21 (s, 9H), 1.20 to 1.54 (m, 7H), 1.59 to 1.63 (m, 1H), 1.74 to 1.77 (m, 1H), 1.82 to 1.87 (m, 2H), 2.41 to 2.65 (m, 6H), 2.79 to 2.83 (m, 2H), 3.49 to 3.56 (m, 1H) , 3.84 to 3.88 (m, 1H), 3.97 to 4.04 (m, 1H), 4.14 to 4.18 (m, 1H), 4.50 (br d, 1H), 4.60 to 4.72 (m, 5H), 5.05 (t, 1H) ), 5.45 (br s, 1H), 5.68 (q, 1H), 6.15 (br d, 1H), 7.22 to 7.36 (m, 4H), 8.33 (s, 1H). MS m / z 781.3 (APCI-, M).

Example 25a

The title compound, 2-cyanoethyl (cyclopropyl) sulfamide, was prepared by the same method described in Example 17a, replacing azetidine with 3- (cyclopropylamino) propanenitrile. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 0.68 to 0.76 (m, 4H), 2.36 to 2.37 (m, 1H), 2.78 (t, 2H), 3.35 (t, 2H), 7.05 (br s, 2H).

(Example 26)

Instead, replace N, N-dimethylsulfamide in Step F with N, N-diisopropylsulfamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1 , 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (N, N-diisopropylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3 .0.0 ^4,6 ] nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.21 (s, 9H), 1.25 to 1.53 (m, 20H), 1.68 to 1.71 (m, 1H), 1.81 to 1.87 (m, 2H), 2.38 to 2.45 (m, 3H), 2.56 to 2.68 (m, 1H), 3.84 to 3.87 (m, 1H), 3.94 to 4.01 (m, 2H), 4.14 to 4.18 (m, 1H), 4.47 (br d, 1H), 4.58 to 4.68 (m, 5H), 5.03 (t, 1H), 5.44 (br s, 1H), 5.62 (q, 1H), 6.11 (br d, 1H), 7.23 to 7.36 (m, 4H), 8.24 ( s, 1H), 10.29 (br s, 1H). MS m / z 772.3 (APCI-, M).

Example 26a

The title compound, N, N-diisopropylsulfamide, was prepared by the same method described in Example 17a, replacing azetidine with diisopropylamine. ¹ H NMR (d ⁶ -acetone, 400 MHz) δ 1.23 (d, 12H), 3.70-3.77 (m, 2H), 5.67 (br s, 2H).

(Example 27)

Instead, replace N, N-dimethylsulfamide in Step F with phenylsulfamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1,3-dihydro -Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (phenylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.20 (s, 9H), 1.20 to 1.50 (m, 8H), 1.60 to 1.70 (m, 2H), 1.78 to 1.86 (m, 1H), 2.30 to 2.44 (m, 4H), 3.81 to 3.85 (m, 1H), 4.12 to 4.17 (m, 1H), 4.45 (br d, 1H), 4.54 to 4.75 (m, 6H), 5.28 (q, 1H), 5.43 ( br s, 1H), 6.11 (br d, 1H), 7.14-7.35 (m, 9H), 8.22 (s, 1H), 8.97 (br s, 1H), 10.80 (br s, 1H). MS m / z 764.3 (APCI-, M).

Example 27a

The title compound, phenylsulfamide, was prepared following the same procedure described in the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2) substituting aniline for cyclopropylamine. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 6.95-6.98 (m, 1H), 7.06 (br s, 2H), 7.14-7.16 (m, 2H), 7.24-7.28 (m, 2H), 9.46 ( br s, 1H).

(Example 28)

Instead, replace N, N-dimethylsulfamide in Step F with 4-chlorophenylsulfamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1,3 -Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-chlorophenylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^{4, 6} ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.19 (s, 9H), 1.18 to 1.51 (m, 8H), 1.61 to 1.72 (m, 2H), 1.76 to 1.87 (m, 1H), 2.32 to 2.44 (m, 4H), 3.82 to 3.86 (m, 1H), 4.12 to 4.16 (m, 1H), 4.45 (br d, 1H), 4.54 to 4.72 (m, 6H), 5.28 (q, 1H), 5.43 ( br s, 1H), 6.10 (br d, 1H), 7.22 to 7.38 (m, 8H), 8.24 (s, 1H). MS m / z 798.2 (APCI-, M).

Example 28a

The title compound, 4-chlorophenylsulfamide, was prepared according to the same procedure described in the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), replacing cyclopropylamine with 4-chlorobenzeneamine. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 7.09 to 7.12 (m, 4H), 7.27 (d, 2H), 9.59 (br s, 1H).

(Example 29)

Instead, replacing N, N-dimethylsulfamide in Step F with 4-methoxyphenylsulfamide, following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1, 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-methoxyphenylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.20 (s, 9H), 1.18 to 1.54 (m, 8H), 1.64 to 1.87 (m, 3H), 2.22 to 2.46 (m, 4H), 3.80 (s , 3H), 3.77 to 3.82 (m, 1H), 4.14 (m, 1H), 4.43 (br d, 1H), 4.52 to 4.70 (m, 5H), 4.88 (t, 1H), 5.40 to 5.50 (m, 2H), 6.10 (br d, 1H), 6.88-6.90 (d, 2H), 7.18-7.35 (m, 6H), 8.18 (s, 1H). MS m / z 794.3 (APCI-, M).

Example 29a

The title compound, 4-methoxyphenylsulfamide, was prepared following the same procedure described in the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), replacing cyclopropylamine with 4-methoxybenzenamine. . ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 3.71 (s, 3H), 6.85 to 6.87 (m, 4H), 7.11 (d, 2H), 9.01 (br s, 1H).

(Example 30)

Instead, replacing N, N-dimethylsulfamide in Step F with 4-methylphenylsulfamide, following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1, 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-methylphenylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.20 (s, 9H), 1.20 to 1.52 (m, 8H), 1.60 to 1.74 (m, 2H), 1.76 to 1.87 (m, 1H), 2.26 to 2.42 (m, 4H), 2.31 (s, 3H), 3.81 to 3.84 (m, 1H), 4.14 to 4.17 (m, 1H), 4.44 (br d, 1H), 4.52 to 4.79 (m, 6H), 5.32 ( q, 1H), 5.42 (br s, 1H), 6.11 (br d, 1H), 7.14-7.35 (m, 8H), 8.20 (s, 1H), 8.79 (br s, 1H), 10.69 (br s, 1H). MS m / z 778.2 (APCI-, M).

Example 30a

The title compound, 4-methylphenylsulfamide, was prepared following the same procedure described in the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), replacing cyclopropylamine with 4-methylbenzenamine. . ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 2.18 (s, 3H), 6.91 (s, 2H), 7.01 (s, 4H), 9.20 (s, 1H).

(Example 31)

Instead, replacing N, N-dimethylsulfamide in Step F with 4-cyanophenylsulfamide, following the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1, 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-cyanophenylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.20 (s, 9H), 1.18 to 1.53 (m, 8H), 1.60 to 1.70 (m, 2H), 1.76 to 1.87 (m, 1H), 2.32 to 2.48 (m, 4H), 3.85 to 3.88 (m, 1H), 4.15 to 4.17 (m, 1H), 4.46 (br d, 1H), 4.57 to 4.71 (m, 6H), 5.16 (q, 1H), 5.46 ( br s, 1H), 6.10 (br d, 1H), 7.24-7.35 (m, 4H), 7.42 (d, 2H), 7.76 (d, 2H), 8.28 (s, 1H). MS m / z 788.3 (APCI-, M-1).

Example 31a

The title compound, 4-cyanophenylsulfamide, was prepared following the same procedure described in the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), replacing cyclopropylamine with 4-aminobenzonitrile. . ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 7.22 (d, 2H), 7.40 (br s, 2H), 7.70 (d, 2H), 10.24 (br s, 1H).

(Example 32)

Instead, replace N, N-dimethylsulfamide in Step F with 4-trifluoromethylphenylsulfamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R)- 1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-trifluoromethylphenylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.19 (s, 9H), 1.18 to 1.64 (m, 10H), 1.82 (q, 1H), 2.30 to 2.46 (m, 4H), 3.84 to 3.87 (m , 1H), 4.12 to 4.16 (m, 1H), 4.47 (br d, 1H), 4.57 to 4.71 (m, 6H), 5.11 (q, 1H), 5.45 (s, 1H), 6.12 (br d, 1H ), 7.23-7.35 (m, 4H), 7.45 (d, 2H), 7.69 (d, 2H), 8.30 (s, 1H), 9.53 (br s, 1H), 11.06 (br s, 1H). MS m / z 832.2 (APCI-, M).

Example 32a

Substituting 4- (trifluoromethyl) benzeneamine for cyclopropylamine, following the same procedure described in the synthesis of N-cyclopropylsulfamide (Route A, Scheme 2), the title compound, 4-trifluoromethylphenyl Sulfamide was prepared. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 7.26-7.30 (m, 4H), 7.59 (d, 2H), 10.05 (br s, 1H).

(Example 33)

Instead, replace N, N-dimethylsulfamide in Step F with cyclobutylsulfamide and follow the same procedure as described in Example 1, 1S, 4R, 6S, 14S, 18R) -1,3- Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (cyclobutylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] Nonadeca-7-en-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.21 (s, 9H), 1.20 to 1.70 (m, 11H), 1.80 to 1.90 (m, 2H), 2.02 to 2.09 (m, 2H), 2.21 to 2.30 (m, 2H), 2.41 to 2.47 (m, 3H), 2.58 to 2.68 (m, 1H), 3.75 to 3.87 (m, 2H), 4.15 to 4.18 (m, 1H), 4.47 (br d, 1H), 4.57 to 4.72 (m, 5H), 5.11 (t, 1H), 5.44 (s, 1H), 5.63 (q, 1H), 6.14 (br d, 1H), 6.34 (br d, 1H), 7.23 to 7.36 ( m, 4H), 8.18 (s, 1H). MS m / z 741.4 (APCI-, M-1).

Example 33a

The title compound, cyclobutylsulfamide, was prepared by the same method described in Example 17a, replacing azetidine with cyclobutanamine. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 1.20 to 1.60 (m, 2H), 1.89 to 1.94 (m, 2H), 2.14 to 2.21 (m, 2H), 3.67 (m, 1H), 6.42 (br s, 2H), 6.82 (br s, 1H).

(Example 34)

Instead, replace N, N-dimethylsulfamide in Step F with cyclopentylsulfamide and follow the same procedure as described in Example 1 to obtain 1S, 4R, 6S, 14S, 18R) -1,3-dihydro -Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (cyclopentylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.21 (s, 9H), 1.20 to 1.73 (m, 15H), 1.87 to 1.96 (m, 4H), 2.41 to 2.49 (m, 3H), 2.56 to 2.68 (m, 1H), 3.55 to 3.60 (m, 1H), 3.84 to 3.87 (m, 1H), 4.15 to 4.18 (m, 1H), 4.48 (br d, 1H), 4.57 to 4.72 (m, 5H), 5.08 (t, 1H), 5.44 (s, 1H), 5.63 (q, 1H), 6.15 (br d, 1H), 6.24 (br d, 1H), 7.23-7.35 (m, 4H), 8.25 (s, 1H), 10.25 (br s, 1H). MS m / z 755.4 (APCI-, M-1).

Example 34a

The title compound, cyclopentylsulfamide, was prepared by the same method described in Example 17a, replacing azetidine with cyclopentanamine. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 1.43-1.61 (m, 6H), 1.80-1.83 (m, 2H), 3.54 (m, 1H), 6.42 (br s, 3H).

(Example 35)

Instead, replace N, N-dimethylsulfamide in Step F with cyclohexylsulfamide and follow the same procedure as described in Example 1 to obtain 1S, 4R, 6S, 14S, 18R) -1,3-dihydro -Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (cyclohexylaminosulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca- 7-ene-18-yl ester was synthesized. ¹ H NMR (400 MHz, d ⁶ -acetone) δ 1.21 (s, 9H), 1.14 to 2.0 (m, 21H), 2.41 to 2.48 (m, 3H), 2.57 to 2.67 (m, 1H), 3.07 to 3.16 (m, 1H), 3.84 to 3.87 (m, 1H), 4.15 to 4.19 (m, 1H), 4.47 (br d, 1H), 4.57 to 4.72 (m, 5H), 5.08 (t, 1H), 5.44 ( s, 1H), 5.64 (q, 1H), 6.13-6.17 (m, 2H), 7.23-7.36 (m, 4H), 8.23 (s, 1H), 10.30 (br s, 1H). MS m / z 769.4 (APCI-, M-1).

Example 35a

Compound No. 101 (79 mg) was dissolved in 0.5 mL 4M HCl / dioxane to give (1S, 4R, 6S, 14S, 18R) -1,3-dihydro-isoindole-2-carboxylic acid 14-amino-4- (N, N-dimethylsulfonyl-aminocarbonyl) -2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-en-18-yl ester hydrochloride (Compound No. 136) Was synthesized and stirred at room temperature for 16 hours. The reaction was then concentrated and dissolved in acetonitrile for concentration again. The hydrochloride salt was then dried with a high vacuum pump overnight to give the product as a white solid (76 mg). + APCI MS m / z 617.1 (M + 1).

Example 35b

The title compound, cyclohexylsulfamide, was prepared by the same method described in Example 17a, replacing azetidine with cyclohexanamine. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 1.08 to 1.23 (m, 5H), 1.50 to 1.54 (m, 1H), 1.65 to 1.68 (m, 2H), 1.86 to 1.89 (m, 2H), 3.02 (m, 1H), 6.40 (br s, 3H).

Example 36
NS3-NS4 protease assay
NS3 complex formation with NS4A-2 Recombinant Escherichia coli or baculovirus full-length NS3 was diluted to 3.33 μM with assay buffer, the material was transferred to an Eppendorf tube, and placed in a water bath in a 4 ° C. refrigerator. . An appropriate amount of NS4A-2 brought to 8.3 mM in assay buffer was added to equal the volume of NS3 in step 2.1.1 (Conversion factor-3.8 mg / 272 μL assay buffer). The substance was transferred to an Eppendorf tube and left in a water bath in a refrigerator at 4 ° C.

  After equilibration to 4 ° C., equal volumes of NS3 and NS4A-2 solutions were combined in an Eppendorf tube, gently mixed with a manual pipetter, and the mixture was incubated for 15 minutes in a 4 ° C. water bath. The final concentration in the mixture is 1.67 μM NS3, 4.15 mM NS4A-2 (NS4A-2 is 2485-fold molar excess).

  After 15 minutes at 4 ° C, the NS3 / NS4A-2 Eppendorf tube was removed and left in a room temperature water bath for 10 minutes. NS3 / NS4A-2 was aliquoted to an appropriate volume and stored at -80 ° C (E. coli NS3 was used for the assay at 2 nM, aliquoted to 25 μL, BV NS3 was used for the assay at 3 nM, equal to 30 μL )

(Example 37)
NS3 Inhibition Assay Step 2.2.5. Sample compounds were dissolved in DMSO to 10 mM and then diluted to 2.5 mM (1: 4) in DMSO. Usually, compounds were added to the assay plate at a concentration of 2.5 mM and diluted to give a starting concentration of 50 μM in the assay inhibition curve. Compounds were serially diluted with assay buffer to obtain test solutions at low concentrations.

  Step 2.2.6. E. coli NS3 / NS4A-2 was diluted to 4 nM NS3 (1: 417.5 1.67 μM stock, 1.67 μM stock 18 μL + assay buffer 7497 μL). BV NS3 / NS4A-2 was diluted to 6 nM NS3 (1: 278.3 1.67 μM stock, 1.67 μM stock 24 μL + assay buffer 6655 μL).

  Step 2.2.7. 50 μL of assay buffer was added to wells A01-H01 of a black Coster 96 well polypropylene storage plate using a manual multi-channel pipettor and being careful not to introduce air bubbles into the plate.

  Step 2.2.8. Dilute the diluted NS3 / NS4A-2 (50 μL) from step 2.2.6 in step 2.2.7 using a manual multichannel pipettor and being careful not to introduce air bubbles into the plate. Added to wells A02-H12 of the plate.

  Step 2.2.9. Using a manual multichannel pipettor and taking care not to introduce air bubbles into the plate, add 25 μL wells in the drug dilution plate in step 2.2.5 to the assay plate in step 2.2.8. Transferred to the corresponding well. The tip of the multichannel pipettor was exchanged with each row of compounds to be transferred.

  Step 2.2.10.Assay in step 2.2.9 using a manual multichannel pipettor and aspirate 35 μL of 75 μL 5 times in each well and dispense, taking care not to introduce air bubbles into the plate The contents of the wells from the plate were mixed. The tip of the multichannel pipettor was exchanged with each row of wells to be mixed.

  Step 2.2.11. The plate was covered with a polystyrene plate lid and the plate from Step 2.2.10 containing NS3 protease and sample compound was preincubated for 10 minutes at room temperature.

  While pre-incubating the plate from step 2.2.11, the RETS1 substrate was diluted in a 15 mL polypropylene centrifuge tube. RETS1 substrate was diluted to 8 μM (1: 80.75 646 μM stock, 646 μM stock 65 μL + assay buffer 5184 μL).

  After pre-incubating the plate in step 2.2.11, 25 μL of substrate was added to all wells on the plate using a manual multichannel. The well contents of the plate were mixed rapidly as in step 2.2.10, except that 65 μL of 100 μL in the well was mixed.

  Plates were read in kinetic mode using a Molecular Devices SpectraMax Gemini XS plate reader. Reader settings: Reading time: 30 minutes, Interval: 36 seconds, Reading: 51, Excitation λ: 335 nm, Emission λ: 495 nm, Cutoff: 475 nm, Automix: Off, Calibration: Once, PMT: High, Reading / Well : 6, Vmax pts: 21 or 28/51, depending on the linearity of the response.

IC ₅₀ was determined using a 4-parameter curve fitting equation and converted to Ki using the following Km.
Full length E. coli NS3-2.03μM
Full length BVNS3-1.74μM
Where Ki = IC ₅₀ / (1+ [S] / Km))

Quantification by ELISA of neomycin phosphotransferase II (NPTII), a selectable marker protein in the HCV subgenomic replicon GS4.3
HCV subgenomic replicon (I377 / NS3-3 ', Accession No.AJ242652) that is stably maintained in HuH-7 liver cancer cells was generated by Lohmann et al., Science, 285, 110-113, 1999. did. A replicon-containing cell culture designated GS4.3 was obtained from Dr. Christoph Seeger, the Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

GS4.3 cells, L-glutamine 200 mM (100X) (Gibco25030-081), non-essential amino acids (NEAA) (Biowhittaker 13-114E), heat inactivated (HI) fetal calf at 37 ° C., 5% CO ₂ Serum (FBS) (Hyclone SH3007.03) and maintained in DMEM (Gibco11965-092) supplemented with 750 μg / ml geneticin (G418) (Gibco10131-035). Cells were subdivided 1: 3 or 4 every 2-3 days.

  Twenty-four hours prior to assay, GS4.3 cells were collected, counted, plated in 96-well plates (Costar 3585) at 7500 cells / well in 100 μL standard maintenance medium (above) and incubated under the conditions described above. To start the assay, the medium was removed, the cells were washed once with PBS (Gibco10010-023) and 90 μL of assay medium (DMEM, L-glutamine, NEAA, 10% HI FBS, non-G418) was added. Make inhibitors as 10X stock in assay medium (3X dilution from 10 μM to final concentration of 56 pM, final DMSO concentration 1%), add 10 μL to replicate wells, shake plate, Incubated as above for 72 hours.

  NPTII Elisa kit was obtained from AGDIA (compound direct ELISA test system for neomycin phosphotransferase II, PSP73000 / 4800). Some changes were made and the manufacturer's instructions were followed. Ten times PEB-1 lysis buffer was made to contain 500 μM PMSF (Sigma P7626, 50 mM stock in isopropanol). After 72 hours of incubation, the cells were washed once with PBS and 150 μL of PEB-1 containing PMSF was added per well. Plates were stirred vigorously for 15 minutes at room temperature and then frozen at -70 ° C. The plate was thawed, the solution was mixed thoroughly, and 100 μL was applied to the NPTII Elisa plate. A standard curve was created. Solutions from control cells treated with DMSO were stored, serially diluted with PEB-1 containing PMSF, and applied in an initial solution volume range of 150 μL to 2.5 μL to replicate wells of an ELISA plate. In addition, only 100 μL of buffer was applied to replicate as a blank. The plate was sealed and gently agitated for 2 hours at room temperature. Following capture incubation, the plates were washed 5 times with 300 μL of PBS-T (0.5% Tween-20, PBS-T provided in the ELISA kit). For detection, dilute enzyme conjugate diluent MRS-2 (5x) once in PBS-T, and add 1: 100 dilution of enzyme conjugates A and B as per instructions for use. It was. Plates were resealed and incubated with agitation while covering for 2 hours at room temperature. The washing was then repeated and 100 μL of TMB substrate was added at room temperature. After approximately 30 minutes of incubation (room temperature, stirring, coating), the reaction was stopped with 50 μL of 3M sulfuric acid. Plates were read at 450 nm on a Molecular Devices Versamax plate reader.

The inhibitor effect was expressed as a percentage of the control signal treated with DMSO, and the inhibition curve was calculated using a 4-variable equation: y = A + ((BA) / (1 + ((C / x) ^ D))) Where C is half-maximal activity or EC ₅₀ .

Examples of activity where
A indicates an IC ₅₀ or EC ₅₀ of less than 1 μM,
B represents an IC ₅₀ or EC ₅₀ of less than 0.1 μM.

(Example 38)
Specificity Assays When compounds were evaluated in specificity assays, compounds of formula I were found to be selective in that they did not show effective inhibition against cathepsin B, chymotrypsin, thrombin, or leukocyte elastase. .

(Example 39)
Compound Pharmacokinetic Analysis Compounds were first synthesized and tested for efficacy (IC ₅₀ ) in a fluorogenic NS3 / 4 protease assay and cell-based HCV replicon system as described above. Plasma pharmacokinetic analysis after IV administration in mice is then directed to design metabolically stable compounds from compounds with efficacy <20 nM in order to direct human liver microsomes (HLM) and liver in vitro. Used with cell stability test. These lead compounds were then further optimized for drug-like physical properties and administered orally to mice to assess liver, heart and plasma concentrations.

Methods Compounds were first synthesized and tested for efficacy (IC ₅₀ ) in a fluorogenic NS3 / 4 protease assay and a cell-based HCV replicon system as described in Example 8 above. Plasma pharmacokinetic analysis after IV administration in mice is then directed to design metabolically stable compounds from compounds with efficacy <20 nM in order to direct human liver microsomes (HLM) and liver in vitro. Used with cell stability test. These lead compounds were then further optimized for drug-like physical properties and administered orally to mice to assess liver, heart and plasma concentrations.

The compounds were tested for liver clearance over time after a single oral dose of 3 mg / kg to rats. For compounds that showed that the concentration in the liver at 8 hours after administration was at least 100-fold greater than the concentration of compound effective to inhibit 50% of maximal inhibition in the replicon assay (replicon EC ₅₀ ). Additional toxicity studies were conducted in rats using daily oral doses of up to 30 mg / kg and BID.

Results Compound AR334187 gave a replicon EC ₅₀ value of approximately 2 nM, indicating stability in vitro in rat, dog and human hepatocyte incubation assays, and this data predicts low to moderate clearance from the liver Is done. In addition, this compound is highly selective for other serine prolease panels, and shows significant inhibition of cytochrome P450 isoforms or hERG channel activity even at the highest concentration tested (10 μM). There wasn't.

With compound AR334187, a single oral dose of 30 mg / kg to mice resulted in a concentration at least 200 times greater than the replicon EC ₅₀ value of this compound in the liver 24 hours after administration.

Compound AR334187 resulted in heart and plasma concentrations that were two orders of magnitude kinetically related to those in the same animal than in liver concentrations. At a clinically more relevant oral dose (3 mg / kg), compound AR334187 had a concentration in the liver 8 hours after administration that was more than 100 times the replicon EC ₅₀ value of the compound. After 7 days of exposure to compound AR334187 at 30 mg / kg, oral, BID, no deaths, body weight changes, or clinical chemistry abnormalities were observed in the treated animals.

Conclusion
We have developed an effective, metabolically stable, orally available small molecule inhibitor of HCV NS3 protease. At moderate oral dose concentrations (3 mg / kg), these compounds show high liver concentrations (100 times higher than their respective replicon EC ₅₀ values) 8 hours after dosing. Plasma and heart exposure is to the order of two orders of magnitude lower than that observed in the liver, and such low concentrations minimize potential systemic toxicity problems.

Compound AR334187 does not show toxicity in mice when given at 30 mg / kg BID for 7 days and provides a safety margin that is at least 10 times higher than the putative effective dose (3 mg / kg). A 100-fold excess of the compound's replicon EC ₅₀ value.

Preparation of Section D Antiviral Agents The meanings of the terms and structure names used in this section are the same as in Section D above. Unless otherwise indicated, all references in this section relating to a particular number or label are not presumably the context of similar or identical numbered or labeled schemes used elsewhere in this specification. Should be understood in the context of this section or the corresponding numbered or labeled scheme used in section D above.

  The compound of formula XVIII can be synthesized according to the method described below.

  (2S, 4R) -4-Amino-1- [benzyloxycarbonyl] pyrrolidine-2-methylcarboxylate hydrochloride is available from Array Biopharma, 2 (S) -tert-butoxycarbonylamino-non-8-enone Acid and 1 (R) -tert-butoxycarbonylamino-2 (S) -vinyl-cyclopropanecarboxylic acid ethyl ester were prepared according to the procedure disclosed in International Patent Application PCT / CA00 / 00353 (Publication No. WO 00/59929) did. 2 (S) -tert-butoxycarbonylamino-non-8-enoic acid was also purchased from RSP Amino Acids.

  Two important aminoproline macrocyclic intermediates A and B were used in preparing the NS3 inhibitors shown in Examples 1-69.

1. Preparation of aminoproline macrocyclic acylsulfonamide intermediate A
(1S, 4R, 6S, 14S, 18R)-(18-Amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.04,6] nonadeca-7-ene Of 14-yl) -carbamic acid tert-butyl ester

Scheme 1
Step A. To a solution of (2S, 4R) -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) were added. The reaction was stirred for 3 days, placed on silica gel and the product eluted with 40% EtOAc / hexanes to give a colorless oil. The oil was dissolved in methanol (20 ml) and stirred with carbon carrying 10% palladium under a balloon of hydrogen gas. After stirring for 4 hours, 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 made basic by adding sodium hydroxide and extracted again with methylene chloride (100 ml). Both organic extracts were combined and concentrated, and the resulting residue was purified by silica gel chromatography, eluting with 10% methanol / methylene chloride to give a brown solid (1.29 g, 70%). LCMS = 289 (H +).

  Step B.4 (R)-(2-Trimethylsilylethylcarbonylamino) -pyrrolidine-2 (S) -carboxylic acid methyl ester (1.29 g, 4.50 mmol), 2 (S) -tert-butoxycarbonylamino-non-8 A solution of enonic 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) was stirred overnight. The reaction was diluted with ethyl acetate (150 ml), washed with 1N aqueous HCl (2 × 100 ml), dried over magnesium sulfate and concentrated. Silica gel chromatography gave an oil that was stirred in a solution of lithium hydroxide (0.28 g, 6.76 mmol) in methanol (5 ml) for 2 hours. The reaction was diluted with methylene chloride, washed with 1N aqueous HCl, dried over magnesium sulfate and concentrated to give 1.2 g (49%) of product.

  Step C.1 To (R) -tert-butoxycarbonylamino-2 (S) -vinyl-cyclopropanecarboxylic acid ethyl ester (0.70 g, 2.75 mmol) was added 4N HCl / dioxane solution (2.87 ml, 11.46 mmol). . After stirring for 2 hours, the reaction was concentrated to give a solid. To this solid was added 1- (2 (S) -tert-butoxycarbonylamino-non-8-enoyl) -4 (R)-(2-trimethylsilylethylcarbonylamino) -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) were added and the reaction was stirred at room temperature for 18 hours. The reaction was placed on silica gel and the product eluted with 50% ethyl acetate / hexane solution to give the product as a colorless oil (1.27 g, 83%). 665 (H +).

Step D. 1-{[1-2 (S) -tert-butoxycarbonylamino-non-8-enoyl) -4 (R)-(2-trimethylsilylethylcarbonylamino) -pyrrolidine-2 (S) -carbonyl] - amino} -2 (S) - vinyl - cyclopropane-1-(R) - carboxylic acid ethyl ester (2.57 g, 3.87 mmol) solution in methylene chloride (500 ml) and the the solution by N ₂ 1 Degassed by bubbling for hours. Dichloro (o-isopropoxyphenyl-methylene) (tricyclohexylphosphine) ruthenium (II) (0.116 g, 0.193 mmol) was added and the reaction was stirred at 40 ° C. for 16 hours. The reaction was concentrated and placed on silica gel and the product eluted with 50% ethyl acetate / hexane to give the product (2.01 g, 3.16 mmol, 82%). 637.0 (H +).

  Step E. (1S, 4R, 6S, 14S, 18R)-(14-tert-butoxycarbonylamino-2,15-dioxo-18- (2-trimethylsilanyl-ethoxycarbonylamino-3,16-diaza-tricyclo) [14.3.0.04,6] Nonadeca-7-ene-4-carboxylic acid ethyl ester (1.94 g, 3.04 mmol) dissolved in 10: 1 methanol / water (10 ml) was dissolved in lithium hydroxide (1.02 g, 24.37 mmol). The reaction was stirred overnight at room temperature, quenched with 1N HCl (50 ml) and extracted into methylene chloride (2 × 50 ml) The combined organic layers were washed with brine (50 ml). , Dried over magnesium sulfate and concentrated to give a solid (1.78 g, 2.92 mmol) A solution of this acid and carbonyldiimidazole (0.711 g, 4.39 mmol) in dichloroethane was heated at 50 ° C. After time, HPLC analysis indicated the presence of starting material, so additional carbonyldiimidazole (0.1 g) was added and stirred at 50 ° C. for an additional hour. , HPLC analysis showed that the starting material was completely consumed.To this reaction was added a solution of cyclopropanesulfonyl chloride (0.46 g, 3.80 mmol) and DBU (0.57 g, 3.80 mmol) and the reaction was Heated at 50 ° C. After 1 hour, the reaction was not complete as judged by HPLC monitoring, so an additional 0.07 g of cyclopropylsulfonamide and 0.1 g of DBU were added. The reaction was cooled, placed on silica gel and the product eluted with a gradient from 3% methanol / DCM to 7.5% methanol / DCM to give the product as a white solid. LCMS 710.5 (H-).

  A solution of Step F.1 (0.80 g, 1.124 mmol) and tetrabutylammonium fluoride (1.0 M THF solution, 1.4 ml) were stirred together at 50 ° C. for 1 hour. The reaction was cooled and placed on silica gel and the product (0.51 g) eluted as a white solid with a gradient 5% methanol / DCM to 25% methanol / DCM. LCMS = 568.0 (H +).

2. Preparation of aminoproline macrocyclic ester intermediate B
(1S, 4R, 6S, 14S, 18R) -18-Amino-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.0 ^4,6 ] nonadeca-7-ene Synthesis of 4-carboxylic acid ethyl ester

Scheme 2
Compound 1 from Scheme 1 above was treated with TBAF (1.0 M THF solution, 1.5 eq) and heated at 50 ° C. for 4 h. The reaction was placed on silica gel and eluted with 20% methanol / methylene chloride to give B as a tan solid (69% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.06 to 1.66 (m, 17H), 1.85 to 1.95 (m, 2H), 2.0 to 2.1 (m, 1H), 2.1 to 2.2 (m, 1H), 2.2 to 2.3 (m, 1H), 2.65 to 2.75 (M, 1H), 3.40 (m, 1H), 3.73 to 3.83 (m, 2H), 4.08 to 4.19 (m, 2H), 4.56 (m, 1H), 4.78 ( d, J = 5.5Hz, 1H), 5.20 (t, J = 8.1Hz, 1H), 5.34 (d, J = 8.1Hz, 1H), 5.47 (dt, J = 4.5,10.8Hz, 1H), 7.08 ( s, 1H). 493 (H +).

  The acylsulfonamide NS3 inhibitors shown in Examples 1-69 above were then prepared via one of the following two routes utilizing the above two intermediates A and B. All carboxylic acid NS3 inhibitors in the examples were prepared via Route 2 in Scheme 3.

Scheme 3
(Example 1)
(1S, 4R, 6S, 14S, 18R)-{18-[(3-Chloro-benzo [b] thiophen-2-carbonyl) -amino] -4-cyclopropanesulfonylcarbonyl-2,15-dioxo-3, Synthesis of 16-diaza-tricyclo [14.3.0.04,6] nonadeca-7-en-14-yl} -carbamic acid tert-butyl ester

(1S, 4R, 6S, 14S, 18R)-(18-Amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo [14.3.0.04,6] nonadeca-7-ene -14-yl) -carbamic acid tert-butyl ester (0.254 g, 0.44 mmol), 3-chloro-benzo [b] thiophene-2-carbonyl chloride (0.124 g, 0.54 mmol), and DIEA (0.087 g, 0.67 mmol) was stirred together in DCM at room temperature. After 1 hour, the reaction was placed on silica gel and the product eluted as a white solid using a gradient 1% methanol / DCM to 5% methanol / DCM. ¹ H NMR (C ₆ D ₆ , 400 MHz) δ 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 to 4.50 (b, 1H), 4.26 (t, 1H), 3.8 to 4.0 (m, 1H), 3.65 to 3.74 (m, 1H), 3.20 to 3.35 (M, 1H), 2.78 to 2.85 (M, 1H), 2.55 to 2.65 (m, 1H), 2.3 to 2.4 (m, 1H), 1.95 to 2.15 (m , 2H), 1.75 to 1.85 (m, 1H), 1.20 to 1.40 (m, 16H), 0.95 to 1.15 (m, 5H) 0.4 to 0.5 (M, 1H), 0.25 to 0.35 (M, 1H); LCMS = 662 (H ⁺ -Boc)

(Examples 2 to 69)
By following or following the general procedure described for the synthesis of Example 1 by substituting 3-chloro-benzo [b] thiophene-2-carbonyl chloride with the appropriate acid chloride or carboxylic acid / HATU The following examples were made by following similar amide and acylsulfonamide coupling procedures as described in the synthesis of Examples 1 and A, but employing Route 2 of Scheme 3 instead.

NS3-NS4 protease assay
NS3 complex formation with NS4A-2 Recombinant Escherichia coli or baculovirus full-length NS3 was diluted to 3.33 μM with assay buffer, the material was transferred to an Eppendorf tube, and placed in a water bath in a 4 ° C. refrigerator. . An appropriate amount of NS4A-2 brought to 8.3 mM in assay buffer was added to equal the volume of NS3 in step 2.1.1 (Conversion factor-3.8 mg / 272 μL assay buffer). The substance was transferred to an Eppendorf tube and left in a water bath in a refrigerator at 4 ° C.

  After equilibration to 4 ° C., equal volumes of NS3 and NS4A-2 solutions were combined in an Eppendorf tube, gently mixed with a manual pipetter, and the mixture was incubated for 15 minutes in a 4 ° C. water bath. The final concentration in the mixture is 1.67 μM NS3, 4.15 mM NS4A-2 (NS4A-2 is 2485-fold molar excess).

  After 15 minutes at 4 ° C, the NS3 / NS4A-2 Eppendorf tube was removed and left in a room temperature water bath for 10 minutes. NS3 / NS4A-2 was aliquoted to an appropriate volume and stored at -80 ° C (E. coli NS3 was used for the assay at 2 nM, aliquoted to 25 μL, BV NS3 was used for the assay at 3 nM, equal to 30 μL )

NS3 Inhibition Assay Sample compounds were dissolved in DMSO to 10 mM and then diluted to 2.5 mM (1: 4) in DMSO. Usually, compounds were added to the assay plate at a concentration of 2.5 mM and diluted to give a starting concentration of 50 μM in the assay inhibition curve. Compounds were serially diluted with assay buffer to obtain test solutions at low concentrations.

  E. coli NS3 / NS4A-2 was diluted to 4 nM NS3 (1: 417.5 1.67 μM stock, 1.67 μM stock 18 μL + assay buffer 7497 μL).

  BV NS3 / NS4A-2 was diluted to 6 nM NS3 (1: 278.3 1.67 μM stock, 1.67 μM stock 24 μL + assay buffer 6655 μL).

  50 μL of assay buffer was added to wells A01-H01 of a black Coster 96 well polypropylene storage plate using a manual multichannel pipettor and being careful not to introduce air bubbles into the plate.

  Using a manual multichannel pipettor and taking care not to introduce air bubbles into the plate, dilute the diluted NS3 / NS4A-2 (50 μL) from step 2.2.6 in the plate well A02- Added to H12.

  Using a manual multichannel pipettor and taking care not to introduce air bubbles into the plate, transfer 25 μL wells in the drug dilution plate in step 2.2.5 to the corresponding wells in the assay plate in step 2.2.8. Liquid. The tip of the multichannel pipettor was exchanged with each row of compounds to be transferred.

  Using a step manual multichannel pipettor and taking care not to introduce air bubbles into the plate, aspirate 35 μL of 75 μL in each well 5 times to dispense wells from the assay plate in step 2.2.9. Were mixed. The tip of the multichannel pipettor was exchanged with each row of wells to be mixed.

  Cover the plate with a polystyrene plate lid and preincubate the plate from step 2.2.10 containing NS3 protease and sample compound for 10 minutes at room temperature.

  While pre-incubating the plate from step 2.2.11, dilute the RETS1 substrate in a 15 mL polypropylene centrifuge tube.

  Dilute the RETS1 substrate to 8 μM (1: 80.75 646 μM stock, 646 μM stock 65 μL + assay buffer 5184 μL).

  After pre-incubating the plate in step 2.2.11, add 25 μL of substrate to all wells on the plate using manual multichannel. The plate is mixed quickly as in step 2.2.10 except that 65 μL of 100 μL in the well is mixed.

  Read the plate in kinetic mode using a Molecular Devices SpectraMax Gemini XS plate reader. Reader settings: Reading time: 30 minutes, Interval: 36 seconds, Reading: 51, Excitation λ: 335 nm, Emission λ: 495 nm, Cutoff: 475 nm, Automix: Off, Calibration: Once, PMT: High, Reading / Well : 6, Vmax pts: 21 or 28/51, depending on the linearity of the response.

IC ₅₀ is determined using a 4-parameter curve fitting equation and converted to Ki using the following Km.
Full length E. coli NS3-2.03μM
Full length BVNS3-1.74μM
Where Ki = IC ₅₀ / (1+ [S] / Km))

Examples of activity where
A indicates an IC50 of less than 10 μM,
B shows an IC50 of less than 1 μM,
C indicates an IC50 of less than 0.1 μM.

Synthetic Intermediates Several intermediates from the synthetic scheme are included in the embodiments. Examples of useful intermediates are shown below.

  A compound having the formula:

[In the above formula,
Q is a core ring selected from:

In the above formula, the core ring is unsubstituted or H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy -C _{1 to 6} alkyl, C _{1 to 6} alkyl, substituted C _{1 to 6} alkyl, C _{1 to 6} alkoxy, substituted C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, Pirimi Jill, thienyl , Furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide, urea, thiourea, amide, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocycle, alkylamino, alkylcarboxy, Carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or B cyclic cyclohexyl may be substituted by,
Or Q is R ¹ -R ² and R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan , Thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl , up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or, May be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with 5 fluoro at high; R ² 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 with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 Alkyl, optionally substituted with up to 5 fluoro Optionally substituted by C _1-6 alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ , Or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl. may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. Even if Good C _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring attached through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is attached through the C ₄ position of the tetrapyranyl ring A tetrapyranyl ring;
Y is COOR ⁹ and R ⁹ is C _1-6 alkyl;
p = 0 or 1;
V is selected from O, S, or NH;
When V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, _or C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro. In aryl Ri; or alternatively R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, there phenoxy or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro C _1-6 alkyl, which may be substituted, or optionally substituted 1-3 times with phenyl. ].

  A compound having the formula:

[In the above formula:
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. C _{1 ~ 6} alkyl; or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is bonded through the C ₄ position of the tetrapyranyl ring A tetrapyranyl ring;
Y is COOR ⁹ and R ⁹ is C _1-6 alkyl;
p = 0 or 1;
V is selected from OH, SH, or NH ₂ ;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro And yes Is or R ²¹ is pyridyl, Pirimi Jill, pyrazinyl, thienyl, furanyl, thiazolyl, there oxazolyl, phenoxy, or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro. C _1-6 alkyl, which may optionally be substituted, or optionally substituted 1 to 3 times by phenyl. ].

Metabolites Some embodiments are metabolites of compounds of Formulas I-XIX. In some cases, the metabolite is a compound of Formulas I-XIX itself. Examples of useful metabolites are shown below.

  Metabolites of compounds of Formulas I-XIX can be identified by the following procedure.

1. Suspend in live KHB (Krebs-Henseleit Buffer @ pH 7.3) at a live liver cell density of about 2 × 10 ⁶ per ml.

  2. Prepare a stock solution (20 μM) of ITMN-187 and ITMN-191 in KHB.

  3. Add 50 μl of ITMN-187 or ITMN-191 to 50 μM hepatocyte suspension in a 96-well polypropylene plate. The final concentration of substrate is 10 μM (˜7 μg / mL).

4. Incubate the plate at 5% CO ₂ at 37 ° C for 0 or 2 hours at saturated humidity.

  5. Terminate the reaction with 100 μl of acetonitrile and shake the plate for 30 seconds at 700 rpm.

  6. Immediately spin the plate with a centrifuge (1,500 xg) for 10 minutes to pellet denatured hepatocytes.

  7. Transfer 180 μl of supernatant to another plate.

8. Pool wells, evaporate solvent with N _{2 at} 37 ° C., reconstitute the residue in 75/25 water / acetonitrile (v / v) and analyze by LC-MS / MS.

  While the invention has been described with reference to specific embodiments thereof, those skilled in the art will recognize that various changes and equivalents can be made without departing from the true spirit and scope of the invention. Will be understood. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, method, method steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (202)

A compound having formula I or a pharmaceutically acceptable salt thereof.

[In the above formula,
Q is a core ring selected from:

In the above formula, the core ring is unsubstituted or H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, substituted C _1-6 alkyl, C _1-6 alkoxy, substituted C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidyl, thienyl, furanyl , Thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide, urea, thiourea, amide, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocycle, alkylamino, alkylcarboxy, carbonyl, Spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or B cyclic cyclohexyl by may be substituted;
Alternatively, Q is R ¹ -R ² and R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, 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 with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _{1- 6} alkyl or up to 5 substituents C _{1 to 6} a be optionally substituted with fluoro, Kill, may be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with up to 5 fluoro; R ² 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 up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. May be C _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is bonded through the C ₄ position of the tetrahydropyran ring. Is a tetrahydropyran ring;
Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ and R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl , All of which may be optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl, or R ⁹ may have up to 3 halo, cyano, nitro , Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or up to 5 good C _{1 to 6} alkyl which may be optionally substituted with fluoro, optionally optionally substituted with up to 5 substituents C _{1 to 6} alkoxy which may be optionally substituted with fluoro C _{6 or} be ₁₀ aryl; or R ⁹ is the highest 5 fluoro groups, NR ⁶ R ^7, an NR ^1a R ^1b, or (CO) optionally C _{1 to 6} alkyl which may be optionally substituted with OH,, or R ⁹ is halo, cyano, nitro, Is an aromatic heterocycle optionally substituted up to two times by hydroxyl or C _1-6 alkoxy; or Y is a carboxylic acid, or a pharmaceutically acceptable salt, solvate, or Is a prodrug;
R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C _1-6 Optionally substituted 1-3 times by alkoxy, amide, or phenyl,
Alternatively, R ^1a and R ^1b are each independently H, and up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, optionally by 5 fluoro hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy,
Alternatively, R ^1a and R ^1b are each independently H, a heterocyclic ring, which includes 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Or a 7-membered saturated or unsaturated heterocyclic group,
Alternatively, NR ^1a R ^1b is a 3-6 membered cycloaliphatic amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl,
Or NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

Wherein R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl,
Or R ^1c is NH (CO) OR ^1e and R ^1e is C _1-6 alkyl or C _3-6 cycloalkyl;
p = 0 or 1;
V is selected from O, S, or NH;
When V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy By, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or up to 5 fluoro C _1-6 alkyl optionally substituted, C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro Is aryl; Or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro Optionally substituted C _1-6 alkyl, or optionally substituted 1-3 times by phenyl;
However, the compound of the formula I does not include a compound having the following formula II, III, or IV.

[In the above formulas II, III, and IV,
(aa) R ¹ and R ² are each independently H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkyl, up to 5 fluoro C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (O) ₂ NR ⁶ R ⁷ , NHC (O) NR ⁶ R ⁷ , NHC (S) NR ⁶ R ⁷ , C (O) NR ⁶ R ⁷ , NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , NHC (O) R ⁸ , NHC (O) OR ⁸ , SO _m R ⁸ , NHS (O) ₂ R ⁸ , (CH ₂ ) _n NR ⁶ R ⁷ , O (CH ₂ ) _n NR ⁶ R ⁷ , or O (CH ₂ ) _n R ⁹ (R ⁹ is , there is imidazolyl or pyrazolyl a is); R ¹ Contact Fine R ² defined in the thienyl, pyrimidyl, furanyl, thiazolyl, and oxazolyl are up to two halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkyl cycloalkyl, C _{2 to 6} alkenyl, 5 C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by fluoro, optionally substituted by C _1-6 alkoxy; as defined above for R ¹ and R ² C _{6 or 10} aryl, pyridyl, phenoxy, and thiophenoxy It is up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy Shi, hydroxy -C _{1 to 6} alkyl, optionally substituted optionally by 5 fluoro optionally optionally substituted C _{1 to 6} alkyl or a maximum, by up to 5 fluoro C Optionally substituted by _1-6 alkoxy;
(bb) m = 0, 1, or 2;
(cc) R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, wherein phenyl or benzyl is a maximum of 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, with up to 5 Optionally substituted by C _1-6 alkyl optionally substituted by ₁ fluoro, or C _1-6 alkoxy optionally substituted by up to 5 fluoro Often;
(dd) R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O ) ₂ R ⁸ , or (CO) CHR ²¹ NH (CO) R ²² ;
(ee) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, and the phenyl is a maximum of 3 Halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, or up to 5 Optionally substituted by C _1-6 alkyl, optionally substituted by fluoro, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(ff) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 1-3 times by; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, at the highest 5 C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by ₁ fluoro; or R ⁸ is optionally substituted by up to 5 fluoro groups Replaced by selection Be a good C _{1 to 6} alkyl optionally; or R ⁸ is an tetrahydrofuran ring attached via a C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a C ₄ position of the tetrahydropyran ring A tetrahydropyran ring bonded through
(gg) Y is a formula -C (O) NHS (O) sulfonimide is ₂ R ^9, R ⁹ is C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl or C _{4 to 10} alkyl cycloalkyl, Alkyl, all of which may be optionally substituted 1 to 3 times with halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl, or R ⁹ is up to 3 halo, Cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or at most C _1-6 alkyl optionally substituted with 5 fluoro, optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro It is a good C _{6 or 10} aryl; or R ⁹ is most In 5 fluoro groups by which may be C _{1 to 6} alkyl optionally substituted, an NR ⁶ R ⁷ or, (CO) OH or R ^9, is selected from halo, cyano, nitro, hydroxyl or C, An aromatic heterocycle optionally substituted up to 2 times by _1-6 alkoxy; or Y is a carboxylic acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
(hh) R ¹⁰ and R ¹¹ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl C _1-6 alkyl, optionally substituted with up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H , C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl), which are all 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. May be optionally substituted three times; or R ¹⁴ may be up to three halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, with up to five fluoro Accordingly optionally optionally substituted C _{1 to 6} alkyl or up to 5 substituents be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro C _{6, Or} C _{10 or 10} aryl as defined for R ¹⁰ and R ¹¹ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up, Optionally substituted by 5 fluoro and optionally substituted by C _1-6 alkoxy; or R ¹⁰ and R ¹¹ together with the carbon to which they are attached. Cyclopro Le, cyclobutyl, cyclopentyl or cyclohexyl to form,; or R ¹⁰ and R ¹¹ are coalesced as O;
(ii) p = 0 or 1;
(jj) R ¹² and R ¹³ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl C _1-6 alkyl, optionally substituted with up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H _Are C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl), all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted once; or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} depending alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, in up to 5 fluoro Optionally substituted with C _{1 to 6} alkyl or up to 5 substituents C _{6 or} be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, It is ₁₀ aryl; wherein C _{6 or 10} aryl provisions of R ¹² and R ^13, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, _{C. 4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by C _1-6 alkoxy optionally substituted by 5 fluoro; or R ¹² and R ¹³ together with the carbon to which they are attached. Cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl to form,; or R ¹² and R ¹³ are each independently, (CH ₂₎ by _n OR ⁸ be a good C _{1 to 6} alkyl substituted optionally;
(kk) R ²⁰ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted by, or (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _1-6 alkyl All of which are optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl), C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl) Or R ¹⁴ may be up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro Good C _{1 to 6} alkyl optionally or at the highest, the 5 fluoro be which may be C _{6 or 10} aryl optionally substituted with optionally C _{1 to 6} alkoxy substituted optionally; The C _{6 or 10} aryl as defined for R ¹² and R ¹³ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, by up to 5 fluoro Optionally substituted by optionally substituted C _1-6 alkoxy;
(ll) n = 1-4;
(mm) V is selected from O, S, or NH;
(nn) when V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
(oo) dashed line represents an optional double bond;
(pp) R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 C _1-6 alkyl optionally substituted by ₁ fluoro, or optionally substituted 1-3 times by phenyl; or R ²¹ is a maximum of 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to five C _1-6 alkyl optionally substituted with fluoro, or C _1-6 alkoxy optionally substituted with up to 5 fluoro, optionally substituted with C _1-6 alkoxy _{6 or 10} aryl Or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
(qq) R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally selected by halo, cyano, nitro, hydroxy, up to 5 fluoro Optionally substituted with 1 to 3 times C _1-6 alkyl, optionally substituted with phenyl;
(rr) Z is a fused or added aryl or heteroaryl ring system. ]] The compound of claim 1, wherein the core ring is of the formula:

The compound of claim 1, wherein the core ring is of the formula:

The compound of claim 1, wherein the core ring is of the formula:

2. A compound according to claim 1 which is formula Ia.

2. A compound according to claim 1 of formula Ib.

2. A compound according to claim 1 of formula Ic.

2. A compound according to claim 1 of formula Id.

2. A compound according to claim 1 of formula Ie.

The compound of claim 1, which is of formula If.

2. A compound according to claim 1 which is of formula Ig.

2. A compound according to claim 1 of formula Ih.

2. A compound according to claim 1 of formula Ii.

2. A compound according to claim 1 of formula Ij.

2. A compound according to claim 1 of formula Iz.

Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, and NR ^2. The compound of claim 1, selected from the group consisting of ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl, or C _3-7 cycloalkyl. Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, and NR 3. The compound of claim 2, selected from the group consisting of ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl, or C _3-7 cycloalkyl. Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, and NR ^4. The compound of claim 3, selected from the group consisting of ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl, or C _3-7 cycloalkyl. Y is a sulfonimide having the formula —C (O) NHS (O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, and NR ^5. The compound of claim 4, selected from the group consisting of ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl, or C _3-7 cycloalkyl.   2. The compound of claim 1, wherein the C13-C14 double bond is cis.   The compound according to claim 1, wherein the C13-C14 double bond is trans. a) the compound of claim 1;
b) to treat hepatitis C virus infection in an individual, to treat hepatic fibrosis in an individual, or to enhance liver function in an individual having hepatitis C virus infection, comprising a pharmaceutically acceptable carrier. Pharmaceutical composition.   23. A pharmaceutical composition according to claim 22 in a formulation free of any alcohol and any poly-ol.   24. A pharmaceutical composition according to claim 23, wherein the formulation does not comprise any sugar alcohol and any poly (ethylene glycol) (PEG).   23. A pharmaceutical composition according to claim 22 in an aqueous formulation that does not include any excipients that reduce polarity in the aqueous formulation.   23. A pharmaceutical composition according to claim 22 in a tablet formulation.   23. A pharmaceutical composition according to claim 22 in a caplet formulation.   23. A pharmaceutical composition according to claim 22 in a capsule formulation. a) the compound of claim 1;
b) A pharmaceutical composition for treating hepatitis C virus infection in an individual, comprising a pharmaceutically acceptable carrier.   30. A pharmaceutical composition according to claim 29 for realizing a sustained viral response.   30. A pharmaceutical composition according to claim 29 for treating hepatitis C virus infection in an individual in combination with an effective amount of a nucleoside analog.   32. The pharmaceutical composition according to claim 31, wherein the nucleoside analogue is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatribin.   30. The pharmaceutical composition of claim 29 for treating hepatitis C virus infection in an individual in combination with an effective amount of an NS5B RNA dependent RNA polymerase inhibitor.   30. A pharmaceutical composition according to claim 29 for treating hepatitis C virus infection in an individual in combination with an effective amount of thymosin- [alpha].   35. The pharmaceutical composition according to claim 34, wherein thymosin- [alpha] in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   30. The pharmaceutical composition of claim 29 for treating hepatitis C virus infection in an individual in combination with an effective amount of interferon-γ (IFN-γ).   37. The pharmaceutical composition according to claim 36, wherein IFN- [gamma] is administered subcutaneously in an amount of 10 [mu] g to 300 [mu] g.   30. The pharmaceutical composition according to claim 29 for treating hepatitis C virus infection in an individual in combination with an effective amount of interferon-α (IFN-α).   39. The pharmaceutical composition according to claim 38, wherein the IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of every 8 to 14 days.   39. The pharmaceutical composition according to claim 38, wherein IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of once every 7 days. 39. The pharmaceutical composition according to claim 38, wherein IFN- [alpha] is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir, 30. A pharmaceutical composition according to claim 29 for treating hepatitis C virus infection in an individual in combination with an effective amount of a drug selected from and an inosine monophosphate dehydrogenase inhibitor. a) the compound of claim 1;
b) A pharmaceutical composition for treating liver fibrosis in an individual, comprising a pharmaceutically acceptable carrier.   44. A pharmaceutical composition according to claim 43 for treating liver fibrosis in an individual in combination with an effective amount of a nucleoside analog.   45. The pharmaceutical composition of claim 44, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatoribine.   44. A pharmaceutical composition according to claim 43 for treating liver fibrosis in an individual in combination with an effective amount of an NS5B RNA dependent RNA polymerase inhibitor.   44. A pharmaceutical composition according to claim 43 for treating liver fibrosis in an individual in combination with an effective amount of thymosin-α.   48. The pharmaceutical composition according to claim 47, wherein thymosin- [alpha] in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   44. The pharmaceutical composition of claim 43, for treating liver fibrosis in an individual in combination with an effective amount of interferon-γ (IFN-γ).   50. The pharmaceutical composition according to claim 49, wherein an amount of 10 [mu] g to 300 [mu] g of IFN- [gamma] is administered subcutaneously.   44. The pharmaceutical composition of claim 43, for treating liver fibrosis in an individual in combination with an effective amount of interferon-α (IFN-α).   52. The pharmaceutical composition of claim 51, wherein IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of every 8-14 days.   52. The pharmaceutical composition of claim 51, wherein IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of once every 7 days. 52. The pharmaceutical composition according to claim 51, wherein IFN-α is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir, 44. A pharmaceutical composition according to claim 43 for treating liver fibrosis in an individual in combination with an effective amount of a drug selected from and an inosine monophosphate dehydrogenase inhibitor. a) the compound of claim 1;
b) A pharmaceutical composition for enhancing liver function in an individual having hepatitis C virus infection, comprising a pharmaceutically acceptable carrier.   57. The pharmaceutical composition of claim 56 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of a nucleoside analog.   58. The pharmaceutical composition of claim 57, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatoribine.   57. The pharmaceutical composition of claim 56 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of an NS5B RNA dependent RNA polymerase inhibitor.   57. A pharmaceutical composition according to claim 56 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of thymosin- [alpha].   61. The pharmaceutical composition according to claim 60, wherein thymosin- [alpha] in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   57. The pharmaceutical composition of claim 56 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of interferon-γ (IFN-γ).   64. The pharmaceutical composition according to claim 62, wherein IFN- [gamma] is administered subcutaneously in an amount of 10 [mu] g to 300 [mu] g.   57. The pharmaceutical composition according to claim 56 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of interferon-α (IFN-α).   65. The pharmaceutical composition of claim 64, wherein IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of every 8-14 days.   65. The pharmaceutical composition of claim 64, wherein IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of once every 7 days. The pharmaceutical composition according to claim 64, wherein IFN-α is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir and 57. A pharmaceutical composition according to claim 56 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of a drug selected from an inosine monophosphate dehydrogenase inhibitor. A compound having the formula XI or a pharmaceutically acceptable salt thereof.

[In the above formula,
(a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C Optionally substituted 1 to 3 times by 1 to ₆ alkoxy, amide, or phenyl;
Alternatively, R ^1a and R ^1b are each independently H, and up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, optionally by 5 fluoro hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy;
Alternatively, R ^1a and R ^1b are each independently H or a heterocycle, the heterocycle containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur Or a 7-membered, saturated or unsaturated heterocyclic group;
Alternatively, NR ^1a R ^1b is a 3-6 membered cycloaliphatic amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
Or NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

Wherein R ^1c is H, halo, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, NO ₂ , N (R ^1d ) ₂ , NH ( CO) R ^1d , or NH (CO) NHR ^1d , each R ^1d is independently H, C _1-6 alkyl, or C _3-6 cycloalkyl;
Or R ^1c is NH (CO) OR ^1e and R ^1e is C _1-6 alkyl or C _3-6 cycloalkyl;
(b) V is selected from O, S, or NH;
(c) when V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
(d) R ² is a bicyclic amine having the structure:

In the above formula, R ²¹ and R ²² are each independently H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6. Alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkyl, up to 5 fluoro C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (O) ₂ NR ⁶ R ⁷ , NHC (O) NR ⁶ R ⁷ , NHC (S) NR ⁶ R ⁷ , C (O) NR ⁶ R ⁷ , NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , NHC (O) R ⁸ , NHC (O) OR ⁸ , SO _m R ⁸ (m = 0, 1, or 2), or NHS (O) ₂ R ⁸ ; the thienyl, pyrimidyl, furanyl, thiazolyl, and R ²¹ and R ²² as defined above Fine oxazolyl is up to two halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up to five which may _{C. 1 to} substituted optionally by fluoro, Optionally substituted by ₆ alkoxy; said C _{6 or 10} aryl, pyridyl, phenoxy and thiophenoxy as defined for R ²¹ and R ²² is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally up to 5 fluoro Optionally substituted by C _1-6 alkyl, which may be substituted, or C _1-6 alkoxy, optionally substituted by up to 5 fluoro;
Wherein R ¹⁰ and R ¹¹ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl , C _1-6 alkyl, (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is optionally substituted with up to 5 fluoro H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl), which are all 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. May be optionally substituted three times; or R ¹⁴ may be up to three halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 C _1-6 alkyl optionally substituted by Luoro, C ₆ optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro C _{6 Or} C _{10 or 10} aryl as defined for R ¹⁰ and R ¹¹ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up, Optionally substituted by 5 fluoro and optionally substituted by C _1-6 alkoxy; or R ¹⁰ and R ¹¹ together with the carbon to which they are attached. Cyclop Pills, cyclobutyl, cyclopentyl or cyclohexyl to form,; or R ¹⁰ and R ¹¹ are coalesced as O;
Where p = 0 or 1;
Wherein R ¹² and R ¹³ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl C _1-6 alkyl, optionally substituted with up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H , C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl), which are all 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. May be optionally substituted three times; or R ¹⁴ may be up to three halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluors C _1-6 alkyl optionally substituted by b, optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro C _{6 Or} C _{6 or 10} aryl as defined for R ¹² and R ¹³ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up, Optionally substituted by 5 fluoro and optionally substituted by C _1-6 alkoxy; or R ¹² and R ¹³ together with the carbon to which they are attached. Cyclopropi To form cyclobutyl, cyclopentyl, or cyclohexyl;
Wherein R ²⁰ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl, optionally substituted by (CH ₂ ) _n NR ⁶ R ⁷ , or (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _1-6 alkyl All of which are optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl), C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl) Or R ¹⁴ may be up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl. , optionally by 5 fluoro C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, with the highest Optionally substituted C _{1 to 6} alkyl or up to 5 amino which may be C _{6 or 10} aryl optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, Yes; said C _{6 or 10} aryl as defined for R ²⁰ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, optionally by 5 fluoro hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by optionally substituted C _1-6 alkoxy;
Where n = 0-4;
In the formula, R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, and the phenyl has a maximum of 3 Halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by, or C _1-6 alkoxy, optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
Or R ² is R ^2a R ^2b when W = NH, V = O,
R ^2a is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, 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 up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally up to 5 fluoro Optionally substituted C _1-6 alkyl, or up to 5 fluoro Optionally substituted by C _1-6 alkoxy optionally substituted by;
R ^2b 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 up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, 5 fluoro up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, the good C _{1 to 6} alkoxy which may be optionally substituted with It may be substituted with meaning selected;
R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halos. , Cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, optional up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted, or C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ^2c And R ^2d together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(e) R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being up to 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted C _1-6 alkyl, or optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy;
(f) R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , or S ( O) ₂ R ⁸ ;
(g) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 1-3 times by; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, 5 C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by ₁ fluoro;
(h) The dashed line represents an optional double bond. ] 2. A compound according to claim 1 having the formula XII or a pharmaceutically acceptable salt thereof.

[In the above formula,
(a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C Optionally substituted 1 to 3 times by 1 to ₆ alkoxy, amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

In which R ^1c is H;
Alternatively, NR ^1a R ^1b is a 3-6 membered alicyclic secondary amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, Optionally substituted 1-3 times by C _1-6 alkoxy, amide, or phenyl;
(b) R ²¹ and R ²² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy;
(c) R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
(d) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
(e) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
(f) R ¹⁰ and R ¹¹ are each independently H, halo, C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with the carbon to which they are attached are cyclopropyl, cyclobutyl , Cyclopentyl, or cyclohexyl;
(g) R ¹² and R ¹³ are each independently H, halo, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _{1- 6} alkyl, or C _1-6 alkyl optionally substituted with up to 5 halogen atoms;
(h) The dashed line represents an optional double bond. ] 2. A compound according to claim 1 having the formula XIII or a pharmaceutically acceptable salt thereof.

[In the above formula,
(a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C Optionally substituted 1 to 3 times by 1 to ₆ alkoxy, amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

In which R ^1c is H;
Alternatively, NR ^1a R ^1b is a 3-6 membered cycloaliphatic amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
(b) R ²¹ and R ²² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy;
(c) R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
(d) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
(e) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
(f) The dashed line represents an optional double bond. ] 2. A compound according to claim 1 having the formula XIV or a pharmaceutically acceptable salt thereof.

[In the above formula,
(a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C ₁ Optionally substituted 1-3 times by alkoxy- ₆ , amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

In which R ^1c is H;
Alternatively, NR ^1a R ^1b is a 3-6 membered cycloaliphatic amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
(b) R ^2a is up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, optionally by up to 5 fluoro, substituted C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy;
R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halos. , Cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, optional up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy; or R ^2c and R ^2d together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(c) R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
(d) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
(e) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
(f) The dashed line represents an optional double bond. ] a) a compound according to claim 69;
b) to treat hepatitis C virus infection in an individual, to treat hepatic fibrosis in an individual, or to enhance liver function in an individual having hepatitis C virus infection, comprising a pharmaceutically acceptable carrier. Pharmaceutical composition.   74. A pharmaceutical composition according to claim 73 in a formulation that does not comprise any alcohol and any poly-ol.   75. The pharmaceutical composition of claim 74, wherein the formulation does not comprise any sugar alcohol and any poly (ethylene glycol) (PEG).   74. The pharmaceutical composition of claim 73 in an aqueous formulation that does not include any excipients that reduce polarity in the aqueous formulation.   74. A pharmaceutical composition according to claim 73 in a tablet formulation.   74. A pharmaceutical composition according to claim 73 in caplet formulation.   74. A pharmaceutical composition according to claim 73 in a capsule formulation. a) a compound according to claim 69;
b) A pharmaceutical composition for treating hepatitis C virus infection in an individual, comprising a pharmaceutically acceptable carrier.   81. A pharmaceutical composition according to claim 80 for realizing a sustained viral response.   81. A pharmaceutical composition according to claim 80 for treating hepatitis C virus infection in an individual in combination with an effective amount of a nucleoside analog.   83. The pharmaceutical composition of claim 82, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatoribine.   81. A pharmaceutical composition according to claim 80 for treating hepatitis C virus infection in an individual in combination with an effective amount of an NS5B RNA dependent RNA polymerase inhibitor.   81. A pharmaceutical composition according to claim 80 for treating hepatitis C virus infection in an individual in combination with an effective amount of thymosin- [alpha].   86. The pharmaceutical composition according to claim 85, wherein thymosin- [alpha] in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   81. A pharmaceutical composition according to claim 80 for treating hepatitis C virus infection in an individual in combination with an effective amount of interferon-y (IFN-y).   88. The pharmaceutical composition of claim 87, wherein IFN- [gamma] is administered subcutaneously in an amount of 10 [mu] g to 300 [mu] g.   81. The pharmaceutical composition of claim 80, for treating hepatitis C virus infection in an individual in combination with an effective amount of interferon-α (IFN-α).   90. The pharmaceutical composition of claim 89, wherein IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of every 8-14 days.   90. The pharmaceutical composition of claim 89, wherein the IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of once every 7 days. 90. The pharmaceutical composition according to claim 89, wherein IFN- [alpha] is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir, 81. A pharmaceutical composition according to claim 80 for treating hepatitis C virus infection in an individual in combination with an effective amount of a drug selected from and an inosine monophosphate dehydrogenase inhibitor. a) a compound according to claim 69;
b) A pharmaceutical composition for treating liver fibrosis in an individual, comprising a pharmaceutically acceptable carrier.   95. The pharmaceutical composition of claim 94 for treating liver fibrosis in an individual in combination with an effective amount of a nucleoside analog.   96. The pharmaceutical composition of claim 95, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatoribine.   95. The pharmaceutical composition of claim 94 for treating liver fibrosis in an individual in combination with an effective amount of an NS5B RNA dependent RNA polymerase inhibitor.   95. The pharmaceutical composition of claim 94 for treating liver fibrosis in an individual in combination with an effective amount of thymosin- [alpha].   99. The pharmaceutical composition according to claim 98, wherein thymosin- [alpha] in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   95. The pharmaceutical composition of claim 94 for treating liver fibrosis in an individual in combination with an effective amount of interferon-γ (IFN-γ).   101. The pharmaceutical composition of claim 100, wherein IFN- [gamma] is administered subcutaneously in an amount of 10 [mu] g to 300 [mu] g.   95. The pharmaceutical composition of claim 94 for treating liver fibrosis in an individual in combination with an effective amount of interferon- [alpha] (IFN- [alpha]).   103. The pharmaceutical composition of claim 102, wherein IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of every 8-14 days.   103. The pharmaceutical composition of claim 102, wherein IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of once every 7 days. 103. The pharmaceutical composition according to claim 102, wherein IFN- [alpha] is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir, 95. A pharmaceutical composition according to claim 94 for treating liver fibrosis in an individual in combination with an effective amount of a drug selected from and an inosine monophosphate dehydrogenase inhibitor. a) a compound according to claim 69;
b) A pharmaceutical composition for enhancing liver function in an individual having hepatitis C virus infection, comprising a pharmaceutically acceptable carrier.   108. The pharmaceutical composition of claim 107 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of a nucleoside analog.   109. The pharmaceutical composition of claim 108, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatoribine.   108. The pharmaceutical composition of claim 107 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.   108. The pharmaceutical composition according to claim 107 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of thymosin- [alpha].   112. The pharmaceutical composition according to claim 111, wherein thymosin- [alpha] in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   108. The pharmaceutical composition of claim 107, for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of interferon-γ (IFN-γ).   114. The pharmaceutical composition according to claim 113, wherein IFN- [gamma] is administered subcutaneously in an amount of 10 [mu] g to 300 [mu] g.   108. The pharmaceutical composition of claim 107, for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of interferon-α (IFN-α).   116. The pharmaceutical composition of claim 115, wherein the IFN- [alpha] is monoPEG (30 kD, linear) consensus IFN- [alpha] and is administered at an administration interval of every 8-14 days.   116. The pharmaceutical composition of claim 115, wherein the IFN-α is monoPEG (30 kD, linear) consensus IFN-α and is administered at an administration interval of once every 7 days. 116. The pharmaceutical composition according to claim 115, wherein IFN- [alpha] is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir and 108. The pharmaceutical composition of claim 107 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of a drug selected from an inosine monophosphate dehydrogenase inhibitor. Compound having formula XVIII

[In the above formula,
(a) R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, 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 up to 3 NR ⁵ R ⁶ , halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted C _1-6 alkyl, or up to 5 fluoro Optionally substituted by C _1-6 alkoxy optionally substituted by;
(b) R ² 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 up to 3 NR ⁵ R ⁶ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, 5 the good C _{1 to 6} alkoxy which may be optionally substituted with number of fluoro It may be substituted with meaning selected;
(c) R ³ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being up to 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted C _1-6 alkyl, or optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy;
(d) R ⁴ is C _1-6 alkyl, C (O) NR ⁵ R ⁶ , C (S) NR ⁵ R ⁶ , C (O) R ⁷ , C (O) OR ⁷ , or S (O) ₂ R ⁷ ;
(e) R ⁵ and R ⁶ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, and the phenyl is at most 3 Halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, or up to 5 Optionally substituted by C _1-6 alkyl, optionally substituted by fluoro, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
(f) R ⁷ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 1-3 times; or R ⁷ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, 5 C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by fluoro;
(g) R ⁸ is optionally substituted with C _1-3 alkyl, C _3-4 cycloalkyl, or up to two halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy. Optionally phenyl;
(h) the dashed line represents an optional double bond],
Or a pharmaceutically acceptable salt thereof. R ¹ is phenyl, benzothiazole, benzothiophene, benzofuran, or benzimidazole, each up to 1-2 NR ⁵ R ⁶ , halo, cyano, nitro, hydroxy, C _1-2 alkyl, C _{3 7-cycloalkyl,} C _{4 to 10} alkylcycloalkyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or, Optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ² is H, phenyl, pyridine, pyrimidine, thiazole, oxazole, isoxazole, or pyrazole, each of up to 1 to 2 NR ⁵ R ⁶ , halo, cyano, nitro, hydroxy, C _1-6 Alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro Optionally substituted by C _1-6 alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ³ is H;
R ⁴ is C _1-6 alkyl, C (O) NR ⁵ R ⁶ , C (S) NR ⁵ R ⁶ , C (O) R ⁷ , C (O) OR ⁷ , or S (O) ₂ R ⁷ Is;
R ⁵ and R ⁶ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being at most 2 halo, Optionally by cyano, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, or up to 5 fluoro Optionally substituted by optionally substituted C _1-6 alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁷ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 3 times; or R ⁷ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, 5 fluoro up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by:
R ⁸ may be optionally substituted with C _1-3 alkyl, C _3-4 cycloalkyl, or up to 2 halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy 121. The compound of claim 120, wherein the compound is good phenyl; the dashed line represents an optional double bond. R ¹ is phenyl, benzothiazole, or benzothiophene, each optionally substituted by up to _1-2 halo, hydroxy, C _1-2 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ² is either a H, or up to 1-2 halo, hydroxy, C _{1 to 3} alkyl, alkyl or up which may be optionally substituted with five fluoro C _{1 to 3,} Alkyl, or phenyl optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ³ is H;
R ⁴ is C _1-6 alkyl, C (O) NR ⁵ R ⁶ , C (O) R ⁷ , or C (O) OR ⁷ ;
R ⁵ is H and R ⁶ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, said phenyl being at most 2 halo, Optionally by cyano, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, or up to 5 fluoro Optionally substituted C _1-6 alkyl, optionally substituted with up to 5 fluoro, optionally substituted with C _1-6 alkoxy;
R ⁷ is C _1-6 alkyl or C _3-7 cycloalkyl, which may all be optionally substituted 1-3 times with halo or phenyl; or R ⁷ is at most 1 Halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or Optionally substituted by C _1-6 alkyl optionally substituted by up to 5 fluoro, or C _1-6 alkoxy optionally substituted by up to 5 fluoro. Optionally C _{6 or 10} aryl;
R ⁸ may be optionally substituted with C _1-3 alkyl, C _3-4 cycloalkyl, or up to 2 halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy 121. The compound of claim 120, wherein the compound is good phenyl; the dashed line represents an optional double bond. a) the compound of claim 120;
b) to treat hepatitis C virus infection in an individual, to treat hepatic fibrosis in an individual, or to enhance liver function in an individual having hepatitis C virus infection, comprising a pharmaceutically acceptable carrier. Pharmaceutical composition.   124. The pharmaceutical composition of claim 123 in a formulation that does not include any alcohol and any poly-ol.   125. The pharmaceutical composition of claim 124, wherein the formulation does not comprise any sugar alcohol and any poly (ethylene glycol) (PEG).   124. The pharmaceutical composition of claim 123, in an aqueous formulation that does not include any excipients that reduce polarity in the aqueous formulation.   124. The pharmaceutical composition of claim 123, in a tablet formulation.   124. The pharmaceutical composition of claim 123, in a caplet formulation.   124. The pharmaceutical composition according to claim 123, in a capsule formulation. a) the compound of claim 120;
b) A pharmaceutical composition for treating hepatitis C virus infection in an individual, comprising a pharmaceutically acceptable carrier.   135. The pharmaceutical composition of claim 130, for realizing a sustained virus response.   134. The pharmaceutical composition of claim 130 for treating hepatitis C virus infection in an individual in combination with an effective amount of a nucleoside analog.   135. The pharmaceutical composition of claim 132, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatoribine.   131. The pharmaceutical composition of claim 130, for treating hepatitis C virus infection in an individual in combination with an effective amount of an NS5B RNA dependent RNA polymerase inhibitor.   134. The pharmaceutical composition of claim 130, for treating hepatitis C virus infection in an individual in combination with an effective amount of thymosin-α.   138. The pharmaceutical composition of claim 135, wherein thymosin-α in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   132. The pharmaceutical composition of claim 130, for treating hepatitis C virus infection in an individual in combination with an effective amount of interferon-γ (IFN-γ).   138. The pharmaceutical composition of claim 137, wherein IFN-γ in an amount of 10 μg to 300 μg is administered subcutaneously.   134. The pharmaceutical composition of claim 130, for treating hepatitis C virus infection in an individual in combination with an effective amount of interferon-α (IFN-α).   140. The pharmaceutical composition of claim 139, wherein IFN- [alpha] is monoPEG (30kD, linear) consensus IFN- [alpha] and is administered at an administration interval of every 8-14 days.   140. The pharmaceutical composition of claim 139, wherein IFN-α is monoPEG (30 kD, linear) consensus IFN-α and is administered at an administration interval of once every 7 days. 140. The pharmaceutical composition according to claim 139, wherein IFN- [alpha] is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir, 132. The pharmaceutical composition of claim 130, for treating hepatitis C virus infection in an individual in combination with an effective amount of a drug selected from and an inosine monophosphate dehydrogenase inhibitor. a) the compound of claim 120;
b) A pharmaceutical composition for treating liver fibrosis in an individual, comprising a pharmaceutically acceptable carrier.   145. The pharmaceutical composition of claim 144 for treating liver fibrosis in an individual in combination with an effective amount of a nucleoside analog.   146. The pharmaceutical composition of claim 145, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatoribine.   145. The pharmaceutical composition of claim 144, for treating liver fibrosis in an individual in combination with an effective amount of an NS5B RNA dependent RNA polymerase inhibitor.   145. The pharmaceutical composition of claim 144, for treating liver fibrosis in an individual in combination with an effective amount of thymosin-α.   149. The pharmaceutical composition of claim 148, wherein thymosin- [alpha] in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   145. The pharmaceutical composition of claim 144 for treating liver fibrosis in an individual in combination with an effective amount of interferon-γ (IFN-γ).   150. The pharmaceutical composition according to claim 150, wherein IFN- [gamma] is administered subcutaneously in an amount of 10 [mu] g to 300 [mu] g.   145. The pharmaceutical composition of claim 144, for treating liver fibrosis in an individual in combination with an effective amount of interferon-α (IFN-α).   153. The pharmaceutical composition of claim 152, wherein the IFN-α is monoPEG (30 kD, linear) consensus IFN-α and is administered at an administration interval of every 8-14 days.   153. The pharmaceutical composition of claim 152, wherein the IFN-α is monoPEG (30 kD, linear) consensus IFN-α and is administered at an administration interval of once every 7 days. 153. The pharmaceutical composition according to claim 152, wherein IFN-α is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir, 145. The pharmaceutical composition of claim 144, for treating liver fibrosis in an individual in combination with an effective amount of a drug selected from an inosine monophosphate dehydrogenase inhibitor. a) the compound of claim 120;
b) A pharmaceutical composition for enhancing liver function in an individual having hepatitis C virus infection, comprising a pharmaceutically acceptable carrier.   158. The pharmaceutical composition of claim 157 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of a nucleoside analog.   159. The pharmaceutical composition of claim 158, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, L-nucleoside, and isatoribine.   158. The pharmaceutical composition of claim 157 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of an NS5B RNA dependent RNA polymerase inhibitor.   158. The pharmaceutical composition of claim 157 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of thymosin-α.   164. The pharmaceutical composition according to claim 161, wherein thymosin-α in an amount of 1.0 mg to 1.6 mg is administered subcutaneously twice a week.   158. The pharmaceutical composition of claim 157 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of interferon-γ (IFN-γ).   164. The pharmaceutical composition of claim 163, wherein an amount of 10 [mu] g to 300 [mu] g of IFN- [gamma] is administered subcutaneously.   158. The pharmaceutical composition of claim 157 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of interferon-α (IFN-α).   166. The pharmaceutical composition of claim 165, wherein the IFN-α is monoPEG (30 kD, linear) consensus IFN-α and is administered at an administration interval of every 8-14 days.   166. The pharmaceutical composition of claim 165, wherein the IFN-α is monoPEG (30 kD, linear) consensus IFN-α and is administered at an administration interval of once every 7 days. 166. The pharmaceutical composition of claim 165, wherein IFN-α is interferon alfacon-1 .   3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2-, 3-didehydro-2 ', 3'-dideoxythymidine, combivir, abacavir, adefovir dipoxyl, cidofovir and 158. The pharmaceutical composition of claim 157 for enhancing liver function in an individual having hepatitis C virus infection in combination with an effective amount of a drug selected from an inosine monophosphate dehydrogenase inhibitor. Or a pharmaceutically acceptable salt thereof.

[In the above formula,
(a) Z is a group arranged to hydrogen bond to the NS3 protease His57 imidazole moiety and hydrogen bond to the NS3 protease Gly137 nitrogen atom;
(b) P ₁ ′ undergoes a nonpolar interaction with at least one NS3 protease S1 ′ pocket portion selected from the group consisting of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42, and Phe43 A group placed on
Wherein Z and P ₁ ′ together are selected from the group consisting of substituted N-sulfonamidyl, or hydroxyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof;
(c) L is a -WC (= V)-group, and V and W are each independently selected from O, S, or NH ;
(d) P2 is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocycle, and substituted heterocycle; P2 is His57, Arg155, Val78, Asp79, Gln80 , And at least one NS3 protease S2 pocket portion selected from the group consisting of Asp81 and positioned by L to perform a nonpolar interaction;
(e) the dashed line represents an optional double bond;
(f) R ⁵ is selected from the group consisting of H, C (O) NR ⁶ R ⁷ , and C (O) OR ⁸ ;
(g) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, and the phenyl is at most 3 Halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy, optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(h) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 1-3 times; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, up to five C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by fluoro; or R ⁸ is optionally substituted by up to 5 fluoro groups C _1-optionally substituted Be ₆ alkyl; or R ⁸ is an tetrahydrofuran ring attached via a C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is attached via a C ₄ position of the tetrahydropyran ring A tetrahydropyran ring;
However, this compound does not include compounds having the formula II, III or IV.

In Formulas II, III, and IV,
(aa) R ¹ and R ² are each independently H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkyl, up to 5 fluoro C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S (O) ₂ NR ⁶ R ⁷ , NHC (O) NR ⁶ R ⁷ , NHC (S) NR ⁶ R ⁷ , C (O) NR ⁶ R ⁷ , NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , NHC (O) R ⁸ , NHC (O) OR ⁸ , SO _m R ⁸ , NHS (O) ₂ R ⁸ , (CH ₂ ) _n NR ⁶ R ⁷ , O (CH ₂ ) _n NR ⁶ R ⁷ , or O (CH ₂ ) _n R ⁹ (R ⁹ is , there is imidazolyl or pyrazolyl a is); R ¹ Contact Fine R ² defined in the thienyl, pyrimidyl, furanyl, thiazolyl, and oxazolyl are up to two halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkyl cycloalkyl, C _{2 to 6} alkenyl, 5 C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by fluoro, optionally substituted by C _1-6 alkoxy; as defined above for R ¹ and R ² C _{6 or 10} aryl, pyridyl, phenoxy, and thiophenoxy It is up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy Shi, hydroxy -C _{1 to 6} alkyl, optionally substituted optionally by 5 fluoro optionally optionally substituted C _{1 to 6} alkyl or a maximum, by up to 5 fluoro C Optionally substituted by _1-6 alkoxy;
(bb) m = 0, 1, or 2;
(cc) R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, wherein phenyl or benzyl is a maximum of 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, with up to 5 Optionally substituted by C _1-6 alkyl optionally substituted by ₁ fluoro, or C _1-6 alkoxy optionally substituted by up to 5 fluoro Often;
(dd) R ⁵ is H, C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O ) ₂ R ⁸ , or (CO) CHR ²¹ NH (CO) R ²² ;
(ee) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, and the phenyl is a maximum of 3 Halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, or up to 5 Optionally substituted by C _1-6 alkyl, optionally substituted by fluoro, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkoxy; or R ⁶ and R ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(ff) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted 1-3 times by; or R ⁸ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, at the highest 5 C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by ₁ fluoro; or R ⁸ is optionally substituted by up to 5 fluoro groups Replaced by selection Be a good C _{1 to 6} alkyl optionally; or R ⁸ is an tetrahydrofuran ring attached via a C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a C ₄ position of the tetrahydropyran ring A tetrahydropyran ring bonded through
(gg) Y is a formula -C (O) NHS (O) sulfonimide is ₂ R ^9, R ⁹ is C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl or C _{4 to 10} alkyl cycloalkyl, Alkyl, all of which may be optionally substituted 1 to 3 times with halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl, or R ⁹ is up to 3 halo, Cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or at most C _1-6 alkyl optionally substituted with 5 fluoro, optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro It is a good C _{6 or 10} aryl; or R ⁹ is most In 5 fluoro groups by which may be C _{1 to 6} alkyl optionally substituted, an NR ⁶ R ⁷ or, (CO) OH or R ^9, is selected from halo, cyano, nitro, hydroxyl or C, An aromatic heterocycle optionally substituted up to 2 times by _1-6 alkoxy; or Y is a carboxylic acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
(hh) R ¹⁰ and R ¹¹ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl C _1-6 alkyl, optionally substituted with up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H , C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl), which are all 1- to halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl. May be optionally substituted three times; or R ¹⁴ may be up to three halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl , C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, with up to five fluoro Accordingly optionally optionally substituted C _{1 to 6} alkyl or up to 5 substituents be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro C _{6, Or} C _{10 or 10} aryl as defined for R ¹⁰ and R ¹¹ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or up, Optionally substituted by 5 fluoro and optionally substituted by C _1-6 alkoxy; or R ¹⁰ and R ¹¹ together with the carbon to which they are attached. Cyclopro Le, cyclobutyl, cyclopentyl or cyclohexyl to form,; or R ¹⁰ and R ¹¹ are coalesced as O;
(ii) p = 0 or 1;
(jj) R ¹² and R ¹³ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl C _1-6 alkyl, optionally substituted with up to 5 fluoro, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H _Are C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl), all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl Optionally substituted once; or R ¹⁴ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} depending alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, in up to 5 fluoro Optionally substituted with C _{1 to 6} alkyl or up to 5 substituents C _{6 or} be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with fluoro, It is ₁₀ aryl; wherein C _{6 or 10} aryl provisions of R ¹² and R ^13, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, _{C. 4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or at the highest, Optionally substituted by C _1-6 alkoxy optionally substituted by 5 fluoro; or R ¹² and R ¹³ together with the carbon to which they are attached. Cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl to form,; or R ¹² and R ¹³ are each independently, (CH ₂₎ by _n OR ⁸ be a good C _{1 to 6} alkyl substituted optionally;
(kk) R ²⁰ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted by, or (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C (O) OR ¹⁴ (R ¹⁴ is H, C _1-6 alkyl All of which are optionally substituted 1 to 3 times by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl), C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl) Or R ¹⁴ may be up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted with up to 5 fluoro Good C _{1 to 6} alkyl optionally or at the highest, the 5 fluoro be which may be C _{6 or 10} aryl optionally substituted with optionally C _{1 to 6} alkoxy substituted optionally; The C _{6 or 10} aryl as defined for R ¹² and R ¹³ is up to 3 halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl or up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, by up to 5 fluoro Optionally substituted by optionally substituted C _1-6 alkoxy;
(ll) n = 1-4;
(mm) V is selected from O, S, or NH;
(nn) when V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
(oo) dashed line represents an optional double bond;
(pp) R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 C _1-6 alkyl optionally substituted by ₁ fluoro, or optionally substituted 1-3 times by phenyl; or R ²¹ is a maximum of 3 halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to five C _1-6 alkyl optionally substituted with fluoro, or C _1-6 alkoxy optionally substituted with up to 5 fluoro, optionally substituted with C _1-6 alkoxy _{6 or 10} aryl Or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
(qq) R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally selected by halo, cyano, nitro, hydroxy, up to 5 fluoro Optionally substituted with 1 to 3 times C _1-6 alkyl, optionally substituted with phenyl;
(rr) Z is a fused or added aryl or heteroaryl ring system;
However, the following formula

The compound of the formula

Does not include compounds having ]   171. The compound of claim 170, wherein L is selected from the group consisting of esters, amides, carbamates, thioesters, and thioamides.   The P2 is further positioned by L to effect hydrogen bonding interaction with at least one NS3 protease S2 pocket portion selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80, and Asp81. 170. The compound according to 170.   171. The compound of claim 170, wherein the C13-C14 double bond is cis.   171. The compound of claim 170, wherein the C13-C14 double bond is trans. 171. The compound of claim 170, wherein P2 is of the formula

171. A compound of claim 170, or a pharmaceutically acceptable salt thereof, of the formula:

177. The compound of claim 176 , wherein L is selected from the group consisting of esters, amides, carbamates, thioesters, and thioamides. The P2 is further positioned by L to effect hydrogen bonding interaction with at least one NS3 protease S2 pocket portion selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80, and Asp81. 176. The compound according to 176 . 177. The compound of claim 176 , wherein the C13-C14 double bond is cis. 177. The compound of claim 176 , wherein the C13-C14 double bond is trans. 171. A compound of claim 170, or a pharmaceutically acceptable salt thereof, of the formula:

184. The compound of claim 181 , wherein L is selected from the group consisting of esters, amides, carbamates, thioesters, and thioamides. The P2 is further positioned by L to effect hydrogen bonding interaction with at least one NS3 protease S2 pocket portion selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80, and Asp81. 181. The compound according to 181 . 184. The compound of claim 181 , wherein the C13-C14 double bond is cis. 184. The compound of claim 181 , wherein the C13-C14 double bond is trans. A compound having the formula: or a pharmaceutically acceptable salt thereof.

[In the above formula,
Q is a core ring selected from:

Wherein the core ring is unsubstituted or H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1 6} alkoxy, hydroxy -C _{1 to 6} alkyl, C _{1 to 6} alkyl, substituted C _{1 to 6} alkyl, C _{1 to 6} alkoxy, substituted C _{1 to 6} alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidyl, thienyl, Furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide, urea, thiourea, amide, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocycle, alkylamino, alkylcarboxy, carbonyl , Spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or It may be substituted by pyro cyclic cyclohexyl;
Or Q is R ¹ -R ² and R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, 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 with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro, Other may be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with up to 5 fluoro; R ² 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 up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _{1 ~ 6} alkyl, optionally substituted with up to 5 fluoro Optionally substituted by C _1-6 alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ , Or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. May be C _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is bonded through the C ₄ position of the tetrahydropyran ring. Is a tetrahydropyran ring;
Y is COOR ^{9 wherein} R ⁹ is C _1-6 alkyl;
V is selected from O, S, or NH;
When V is O or S, W is selected from O, NR ¹⁵ , or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ and R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or C _1-6 alkyl optionally substituted with up to 5 fluoro;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, _or C _{6 or 10} optionally substituted with C _1-6 alkoxy optionally substituted with up to 5 fluoro. Is aryl; Or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro rather it may also be substituted with optionally 1 to 3 times by which may C _{1 to 6} alkyl optionally or phenyl;
However, this compound has the formula

Does not include compounds having ] 186. The compound of claim 186 , or a pharmaceutically acceptable salt thereof, of the formula:

A compound or pharmaceutically acceptable salt having the formula:

[In the above formula,
Q is a core ring selected from:

Wherein the core ring is unsubstituted or H, halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, substituted C _1-6 alkyl, C _1-6 alkoxy, substituted C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidyl, Thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide, urea, thiourea, amide, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocycle, alkylamino, alkylcarboxy , Carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, Others may be substituted by spirocyclic cyclohexyl;
Or Q is R ¹ -R ² and R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan , Thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl , up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or, May be optionally substituted with optionally C _{1 to 6} alkoxy which may be optionally substituted with 5 fluoro at high; R ² 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 with up to 3 NR ⁶ R ⁷ , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 Alkyl, optionally substituted with up to 5 fluoro Optionally substituted by C _1-6 alkyl, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, or benzyl, where phenyl or benzyl is a maximum of 3 halo, cyano, nitro Hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted by, or C _1-6 alkoxy optionally substituted by up to 5 fluoro;
R ⁵ is C _1-6 alkyl, C (O) NR ⁶ R ⁷ , C (S) NR ⁶ R ⁷ , C (O) R ⁸ , C (O) OR ⁸ , S (O) ₂ R ⁸ , Or (CO) CHR ²¹ NH (CO) R ²² ;
R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halo, cyano, optionally nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, hydroxy -C _{1 to 6} alkyl, by up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by up to 5 fluoro, or optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ⁶ and R ⁷ together with the nitrogen to which they are attached forms indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are 1-3 by halo, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl may be substituted with round optionally; or R ⁸ is, up to three halo, cyano, nitro, hydroxy, C _{1 to 6} alkyl, C _{3 to 7} cycloalkyl, C _{4 to 10} alkylcycloalkyl, C _{2 to 6} alkenyl, C _{1 to 6} alkoxy, hydroxy -C _{1 to 6} alkyl, up to 5 substituents C _{1 to 6} alkyl which may be optionally substituted with fluoro or by up to 5 fluoro, C _{6 or 10} aryl optionally substituted by optionally substituted C _1-6 alkoxy; or R ⁸ is optionally substituted by up to 5 fluoro groups. May be C _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring bonded through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is bonded through the C ₄ position of the tetrahydropyran ring. Is a tetrahydropyran ring;
Y is, R ⁹ is C _{1 to 6} alkyl, COOR ^9; or Y is the formula -C (O) NHS (O) sulfonimide is ₂ R ^9, R ⁹ is _{C. 1 to} Optionally substituted by ₃ alkyl, C _3-7 cycloalkyl, or up to 2 halo, cyano, nitro, hydroxy, C _1-3 alkyl, C _3-7 cycloalkyl, or C _1-3 alkoxy Optionally phenyl, or Y is a carboxylic acid;
V and W are each independently selected from O, S, or NH;
The dashed line represents an optional double bond;
R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, hydroxy, C _1-6 alkoxy, up to 5 fluoro Optionally substituted by C _1-6 alkyl, optionally substituted by phenyl, or optionally substituted 1-3 times by phenyl; or R ²¹ is up to 3 halo, cyano, nitro, hydroxy Optional, by C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, up to 5 fluoro C _1-6 alkyl optionally substituted, C _{6 or 10} aryl optionally substituted by C _1-6 alkoxy optionally substituted by up to 5 fluoro And yes R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted with halo, cyano, nitro, hydroxy, up to 5 fluoro. Optionally substituted C _1-6 alkyl, or optionally substituted 1-3 times by phenyl;
However, this compound has the formula

Does not include compounds having ] L is selected from the group consisting of -WC (= V) -NH- and -WC (= V) -O-, and V and W are each independently selected from O, S, or NH. Item 170. The compound according to item 170 . L is selected from the group consisting of -WC (= V) -NH- and -WC (= V) -O-, and V and W are each independently selected from O, S, or NH. Item 176. The compound according to Item 176 . L is selected from the group consisting of -WC (= V) -NH- and -WC (= V) -O-, and V and W are each independently selected from O, S, or NH. Item 181. The compound according to Item 181 .   171. The compound of claim 170, wherein P2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 175. The compound of claim 172 , wherein P2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 177. The compound of claim 176 , wherein P2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 179. The compound of claim 178 , wherein P2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 184. The compound of claim 181 , wherein P2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 184. The compound of claim 183 , wherein P2 is selected from the group consisting of unsubstituted heterocycle and substituted heterocycle. 2. A compound according to claim 1 having the following formula XII or a pharmaceutically acceptable salt thereof.

[In the above formula,
(a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

(Wherein R ^1c is H);
Alternatively, NR ^1a R ^1b is a 3-6 membered cycloaliphatic amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
(b) R ²¹ and R ²² are each independently H, halo, cyano, nitro, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;
(c) R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
(d) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
(e) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
(f) R ¹⁰ and R ¹¹ are each independently H, halo, C _1-3 alkyl, or R ¹⁰ and R ¹¹ together with the carbon to which they are attached are cyclopropyl, Form cyclobutyl, cyclopentyl, or cyclohexyl;
(g) R ¹² and R ¹³ are each independently H, halo, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxy-C _{1- 6} alkyl, or C _1-6 alkyl optionally substituted with up to 5 halogen atoms;
(h) The dashed line represents an optional double bond. ] 2. A compound according to claim 1 having the following formula XIII or a pharmaceutically acceptable salt thereof.

[In the above formula,
(a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C Optionally substituted 1 to 3 times by 1 to ₆ alkoxy, amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

(Wherein R ^1c is H);
Alternatively, NR ^1a R ^1b is a 3-6 membered cycloaliphatic amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
(b) R ²¹ and R ²² are each independently H, halo, cyano, hydroxy, C _1-3 alkyl, or C _1-3 alkoxy;
(c) R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
(d) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
(e) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
(f) The dashed line represents an optional double bond. ] 2. A compound according to claim 1 having the following formula XIV or a pharmaceutically acceptable salt thereof.

[In the above formula,
(a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
Or R ^1a and R ^1b are each independently H or heteroaryl selected from the group consisting of:

(Wherein R ^1c is H);
Alternatively, NR ^1a R ^1b is a 3-6 membered cycloaliphatic amine, which optionally has 1 to 3 heteroatoms incorporated into the ring, and is halo, cyano, nitro, C _{1- 6} may be optionally substituted 1-3 times with alkoxy, amide, or phenyl;
(b) R ^2a is up to 3 NR ^2c R ^2d , halo, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 Alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted by up to 5 fluoro, optionally substituted by C _1-6 alkyl, or up to 5 fluoro C ₆ or C ₁₀ aryl optionally substituted by optionally substituted C _1-6 alkoxy;
R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, wherein the phenyl is a maximum of 3 halos. , Cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, optional up to 5 fluoro Optionally substituted by C _1-6 alkyl optionally substituted, or C _1-6 alkoxy optionally substituted by up to 5 fluoro; or R ^2c And R ^2d together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(c) R ⁵ is H, C (O) NR ⁶ R ⁷ , C (O) R ⁸ , or C (O) OR ⁸ ;
(d) R ⁶ and R ⁷ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl;
(e) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or 3-tetrahydrofuryl;
(f) The dashed line represents an optional double bond. ] -C (= O) -Z-P ₁ 171. The compound of claim 170, wherein 'is Y as defined in claim 1. Z comprises a group selected from the group consisting of O, N, S or halogen; P ₁ 171. The compound of claim 170, wherein 'comprises a group selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, and unsubstituted aryl.