CN1938311A - Macrocyclic compounds as inhibitors of viral replication - Google Patents

Abstract

This invention provides macrocyclic compounds and compositions comprising target compounds, including pharmaceutical compositions. This invention also provides treatment methods, including methods for treating flavivirus infections (including hepatitis C virus infection) and methods for treating liver fibrosis, said methods generally comprising administering an effective amount of the target compound or composition to an individual in need.

Description

Macrocycles as Inhibitors of Viral Replication

cross-related applications

This application is a continuation-in-part of U.S. Patent Application Serial No. 11/064,445, filed February 23, 2005, which is a continuation-in-part of PCT/US04/33970, filed October 13, 2004 PCT/US04/33970, claiming priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 60/511,541, filed October 14, 2003; U.S. Provisional Application No. 60/612,381 filed on April 22, U.S. Provisional Application No. 60/562,418 filed on April 14, 2004, and U.S. Provisional Application No. 60/558,161 filed on March 30, 2004 ; these applications are hereby incorporated by reference in their entirety.

technical field

The present invention relates to compounds, methods for their synthesis, pharmaceutical compositions and methods of treating flavivirus infections such as hepatitis C virus (HCV) infection. In detail, the present invention provides novel peptide analogs, pharmaceutical compositions containing these analogs and methods of using these analogs to treat yellow fever virus infection.

Background technique

Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States. Although the number of new infections has decreased, the burden of chronic infection is considerable, with the Centers for Disease Control estimating that 3.9 million (1.8%) of the US population has been infected. Chronic liver disease is the tenth leading cause of death among adults in the United States, and as such, accounts for approximately 25,000 deaths each year, or 1 percent of all deaths. Studies have shown that 40% of chronic liver disease is associated with HCV, resulting in an estimated 8,000-10,000 deaths per year. HCV-associated end-stage liver disease is the most common indication for liver transplantation in adults.

Antiviral therapies for chronic hepatitis C have developed rapidly over the past decade, with significant improvements seen in therapeutic efficacy. Nevertheless, even with combination therapy of pegylated IFN-[alpha] and ribavirin, 40% to 50% of patients fail treatment, ie are non-responders or relapsers. These patients currently have no effective treatment options. In detail, patients who already have advanced fibrosis or cirrhosis at the time of liver biopsy are at substantial risk of developing complications of advanced liver disease, including ascites, jaundice, venous Variceal bleeding, encephalopathy, and progressive liver failure.

The high incidence of chronic HCV infection poses a major public health concern regarding the future burden of chronic liver disease in the United States. Data from the National Health and Nutrition Examination Survey (NHANES III) indicate that a large increase in the rate of new HCV infections occurred from the late 1960s to the early 1980s, especially among those aged Among those between the ages of 20 and 40. It is estimated that the number of people aged 20 or over with long-standing HCV infection may have more than quadrupled by 2015 from 1990, ie, from 750,000 to over 3 million. The proportion of infected people between the ages of 30 and 40 will increase faster. Since the risk of HCV-associated chronic liver disease is related to the duration of infection, with an increasing risk of cirrhosis for those infected for more than 20 years, the increase in the number of people with long-standing HCV infection may have contributed to the Substantial increases in cirrhosis-related morbidity and mortality.

HCV is an enveloped, positive-sense RNA virus in the Flaviviridae family. The single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has an open reading frame (ORF) encoding a large polyprotein of approximately 3000 amino acids. In infected cells, the polyprotein is cleaved at multiple sites by cellular and viral proteases, yielding the structural and nonstructural (NS) proteins of the virus. In the case of HCV, the production of mature nonstructural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B) is accomplished by two viral proteases. The first viral protease cleaves the NS2-NS3 junction of the polyprotein. The second viral protease is a serine protease contained within the N-terminal region of NS3 (referred to herein as "NS3 protease"). The NS3 protease mediates all subsequent cleavage events at sites in the polyprotein that are downstream relative to the position of NS3 (ie, sites located between the C-terminus of NS3 and the C-terminus of the polyprotein). The NS3 protease exhibits activity 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 have multiple functions, serving as a cofactor for the NS3 protease and possibly assisting the membrane localization of NS3 and other viral replicase components. Clearly, complex formation between NS3 and NS4A is required for NS3-mediated processing events and increases 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.

literature:

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Contents of the invention

The examples provide compounds having the formula I:

in:

Q is a core ring selected from the following:

Wherein, the core ring can be unsubstituted or substituted by the following groups: H, halogen, cyano, nitro, hydroxyl, 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 Base, substituted C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl (pyridal), pyrimidyl (pyrimidal), thienyl, furyl, thiazolyl, oxazolyl, phenoxy, thiobenzene Oxygen, sulfonamide, urea, thiourea, amido, keto, carboxyl, carbamoyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkoxyheterocyclyl, alkylamino, Alkylcarboxy, carbonyl, spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl,

Alternatively, Q is R ¹ -R ² , wherein R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridyl Oxazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran , indole or benzimidazole, each of which is optionally substituted by up to three of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C ₁ optionally substituted by up to 5 fluorine _-6 alkyl, _C1-6 alkoxy optionally substituted with up to 5 fluorines; and ^R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxa oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, these groups Each is optionally substituted with up to three of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl ring Alkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or optionally substituted by up to 5 fluorines Substituted C _1-6 alkoxy;

R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three of the following Group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or ^R and ^R together with the nitrogen to which they are attached Formation of indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances C _1-6 alkyl substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 alkyl optionally substituted with up to 5 fluorines ; or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, All of these groups are optionally substituted one to three times by: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁹ is C _{6 or 10} aryl, which group is optionally Cases are substituted by up to three of the following groups: halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkene radical, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines or R ⁹ is C _1-6 alkyl, NR ⁶ R ⁷ , NR ^1a R ^1b or (CO)OH optionally substituted by up to 5 fluoro groups; or R ⁹ is optionally substituted by at most Two heteroaromatic rings: halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

Wherein, 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 these groups are optionally substituted by the following groups from one to Three times: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl,

Alternatively, R ^1a and R ^1b are each independently H and C _{6 or 10} aryl optionally substituted with up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances through up to 5 fluorine Substituted C _1-6 alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines,

Alternatively, R ^1a and R ^1b are each independently H, a heterocycle, which is a 5-, 6-, or 7-membered saturated or unsaturated heterocyclic molecule, and contains one to four groups selected from the group consisting of nitrogen, oxygen, and sulfur group of heteroatoms,

Alternatively, NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally containing one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro Base, C _1-6 alkoxy, amido or phenyl,

Alternatively, NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

和

and

Wherein, R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl,

Or R ^1c is NH(CO)OR ^1e , wherein 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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines ^, _or phenyl; The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{1- 6} alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines; or R ²¹ is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; with the proviso that the compounds of formula I do not include compounds of formula II, III or IV as defined below.

The examples provide compounds having formula II, III or IV:

in:

a) R ¹ and R ² are each independently H, halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 substituted by up to 5 fluorines ₆ alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, 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 (wherein R ⁹ is imidazolyl or pyr Azolyl); said thienyl, pyrimidinyl, furyl, thiazolyl and oxazolyl in the definition of R ^{and R} are optionally substituted by up to two of the following groups: halogen, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; said C _{6 or 10} in the definition of R ¹ and R ² Aryl, pyridyl, phenoxy and thiophenoxy are optionally substituted with up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl or benzyl is optionally modified Up to three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl- C _1-6 alkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines; or R ⁶ and R ⁷ are attached to The nitrogens together 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 groups are optionally substituted one to three times by the following groups: halogen, cyano, nitrate radical, hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, optionally substituted by up to three of the following groups: halogen, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines; or R ⁸ is C _1-6 optionally substituted by up to 5 fluoro Alkyl; or R ⁸ is a tetrahydrofuran ring connected via C ₃ or C ₄ of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via C ₄ of the tetrapyranyl ring;

g) Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkane groups, all of which are optionally substituted one to three times by: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁹ is C _{6 or 10} aryl, the aryl The group is optionally substituted with up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2- 6} alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 substituted by up to 5 fluorines Alkoxy; or R ⁹ is C _1-6 alkyl, NR ⁶ R ⁷ or (CO)OH optionally substituted by up to 5 fluoro groups; or R ⁹ is optionally substituted up to twice by the following groups Heteroaromatic ring: halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

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, hydroxyl-C _{1- 6} alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _{1 -6} alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl), all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _{1 -6} alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances through up to 5 fluorine A substituted C _1-6 alkyl group or a C _1-6 alkoxy group substituted by at most 5 fluorines; the C _{6 or 10} aryl group in the definition of R ¹⁰ and R ¹¹ is optionally replaced by at most three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ¹⁰ and R ¹¹ together with the carbon to which it is attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R ¹⁰ and R ¹¹ are combined to be 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, hydroxyl-C _{1- 6} alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _{1 -6} alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl), wherein all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ₁₄ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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 substituted by fluorine or C _1-6 alkoxy substituted by up to 5 fluorine as the case may be; the C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally up to 5 aryl Three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ¹² and R ¹³ together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R ¹² and R ¹³ are each independently optionally substituted with (CH ₂ ) _n OR ⁸ C _1-6 alkyl;

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, as appropriate C _1-6 alkyl substituted by up to 5 fluorines or (CH ₂ ) _n NR ⁶ R ⁷ , (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), wherein all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C ₁ optionally substituted by up to 5 fluorine _-6 alkyl or, optionally, C _1-6 alkoxy substituted by at most 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by at most three of the following groups Group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkane Oxygen, hydroxy-C _1-6 alkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines;

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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines;

o) dashed lines indicate optional double bonds;

p) R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitrate radical, hydroxy, C _1-6 alkoxy, optionally C _1-6 alkyl or phenyl substituted by up to 5 fluorines; or R ²¹ is C _{6 or 10} aryl, which is optionally substituted by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{or _ _ _} ^R is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

q) R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro radical, hydroxyl, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

The examples provide compounds of formula XI:

in:

a) R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkylcycloalkyl, all of which are optionally substituted by one to Three times: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Or R ^1a and R ^1b are each independently H and C _{6 or 10} aryl, optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances through up to 5 fluorine Substituted C _1-6 alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

Alternatively, each of R ^1a and R ^1b is independently H or a heterocyclic ring, which is a 5-, 6-, or 7-membered saturated or unsaturated heterocyclic molecule containing one to four groups selected from the group consisting of nitrogen, oxygen, and sulfur group of heteroatoms;

Or NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally having one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Alternatively, NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

and

Wherein R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl;

Or R ^1c is NH(CO)OR ^1e , wherein 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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines;

e) Q is a bicyclic secondary amine having the following structure:

Wherein, R ²¹ and R ²² are each independently H, halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines, C _1-6 optionally substituted by up to 5 fluorines ₆ alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, 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)2R ⁸ ; thienyl, pyrimidinyl, furan in the definition of R ²¹ and R ²² Base, thiazolyl and oxazolyl are optionally substituted by up to two of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkane Cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or optionally up to 5 C _1-6 alkoxy substituted by fluorine; said C _{6 or 10} aryl, pyridyl, phenoxy and thiophenoxy in the definition of R ²¹ and R ²² are optionally modified by up to three of the following Group substitution: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (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), wherein all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _{1 -6} alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkane 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 substituted by fluorine, C _1-6 alkoxy substituted by up to 5 fluorine as the case may be; the C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{or _ _ _} R ¹⁰ and R ¹¹ together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon to which they are attached; or R ¹⁰ and R ¹¹ are combined as O; wherein 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, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (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 these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _{1- 6} alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances through up to 5 fluorine Substituted C _1-6 alkyl, optionally C _1-6 alkoxy substituted by up to 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ optionally via up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ¹² and R ¹³ together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon to which they are attached;

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, as the case may be C _1-6 alkyl substituted by up to 5 fluorines or (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _{3 -7} cycloalkyl, C _4-10 alkylcycloalkyl), wherein all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or Phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 Cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1- optionally substituted by up to 5 fluorine ₆ alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by up to three of the following groups : Halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

where n=0-4;

Wherein 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 optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which ^R and ^R are attached together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

Or R ² is R ^2a R ^2b when W=NH and V=O, wherein

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, oxa oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, these groups Each is optionally substituted with up to three of the following groups: NR ^2c R ^2d , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl ring Alkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or optionally substituted by up to 5 fluorines 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 of which is optionally substituted by up to three of the following groups: NR ^2c R ^2d , halogen, cyano, Nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

The R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl or phenyl, and the phenyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl- C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ^2c and R ^2d are attached to The nitrogens together 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, the phenyl is optionally substituted by up to three of the following groups : Halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, C _4-10 alkyl cycloalkyl, all of these groups are substituted one to three times by the following groups as appropriate: halogen, cyano, nitrate radical, hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl , C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, _C1-6 alkoxy, hydroxy-C _1-6 alkyl, depending _C1-6 alkyl optionally substituted with up to 5 fluorines or _C1-6 alkoxy optionally substituted with up to 5 fluorines; and

i) Dashed lines indicate optional double bonds.

The examples provide compounds of formula XVIII:

in:

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, which The groups are each optionally substituted with up to three of the following groups: NR ⁵ R ⁶ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkane Cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy- _C1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or optionally up to 5 Fluorine-substituted C _1-6 alkoxy;

^b ) R is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, iso Quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of these groups optionally substituted by up to three of each of the following groups: NR ⁵ R ⁶ , halogen, cyano Base, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

c) R ³ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl or phenyl, the phenyl is optionally substituted by up to three of the following groups : Halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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 optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl- C _1-6 alkyl or C ^1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines; or R ⁵ and R ⁶ are attached to them The nitrogens together 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 these groups are substituted one to three times by the following groups as appropriate: halogen, cyano, nitrate radical, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁷ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl , 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines;

g) R ⁸ is C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkane or C _1-3 alkoxy; and

h) dashed lines indicate optional double bonds;

or a pharmaceutically acceptable salt thereof.

The examples provide compounds having the formula:

in:

a) Z is a group set to hydrogen bond with the imidazole part of NS3 protease His57 and hydrogen bond with the nitrogen atom of NS3 protease Gly137;

b) P ₁ ' is a group configured to form a non-polar interaction with at least one NS3 protease S1 ' pocket portion selected from the group consisting of Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and the group consisting of Phe43;

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 heterocyclyl and substituted heterocyclyl; P2 is positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81;

e) dashed lines indicate optional double bonds;

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 optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl- C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁶ and R ⁷ are attached to The nitrogens together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

h) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are substituted one to three times by the following groups as appropriate: halogen, cyano, nitrate radical, hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl , 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 fluorines, C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 optionally substituted with up to 5 fluorines ₆ alkyl; or R ⁸ is a tetrahydrofuran ring connected through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected through the C ₄ position of the tetrapyranyl ring; the restriction is that Said compounds do not include compounds of formula II, III or IV described above.

The examples provide compounds having the formula:

or

in:

R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three of the following Group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or ^R and ^R together with the nitrogen to which they are attached Formation of indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate C _1-6 alkyl substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁸ is C _1-6 alkane optionally substituted by up to 5 fluorines or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, and the phenyl is optionally at most Two of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl or C _1-3 alkoxy; or Y is carboxylic acid;

p = 0 or 1;

V is selected from OH, SH or NH ₂ ;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines ^, _or phenyl; The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

The examples provide compounds having the formula:

in:

Q is a core ring selected from the following:

Wherein, the core ring can be unsubstituted or substituted by the following groups: H, halogen, cyano, nitro, hydroxyl, 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 Base, substituted C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide , urea, thiourea, amido, keto, carboxyl, carbamoyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkoxyheterocyclic, alkylamino, alkylcarboxy, carbonyl, Spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl,

Alternatively, Q is R ¹ -R ² , wherein R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridyl Oxazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran , indole or benzimidazole, each of these groups is optionally substituted by up to three of each of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 Cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1- optionally substituted by up to 5 fluorine ₆ alkyl or _C1-6 alkoxy optionally substituted with up to 5 fluorines; and ^R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole , imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of these groups Optionally substituted with up to three of each of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkane C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or optionally substituted with up to 5 fluorines C _1-6 alkoxy;

R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which ^R and ^R are attached together 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 these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, depending on the _{circumstances} C _1-6 alkyl substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 alkyl optionally substituted with up to 5 fluorines ; or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

Y is COOR ⁹ , wherein R ⁹ is C _1-6 alkyl; or Y is a sulfonimide of formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, which phenyl is optionally substituted by up to two of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl or C _1-3 alkoxy; or Y is carboxylic acid;

p = 0 or 1;

V and W are each independently selected from O, S or NH;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines ^, _or phenyl; The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

The examples provide pharmaceutical compositions comprising a preferred compound and a pharmaceutically acceptable carrier.

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

The embodiments provide methods of treating liver fibrosis in an individual comprising administering to the individual an effective amount of a preferred compound.

The examples provide methods of enhancing liver function in an individual having a hepatitis C virus infection comprising administering to the individual an effective amount of a preferred compound.

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

Description of drawings

none

Detailed ways

definition

As used herein, the term "hepatic fibrosis" is used interchangeably with "liver fibrosis" and refers to the growth of scar tissue in the liver, which may occur in the context of chronic hepatitis infection.

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

As used herein, the term "liver function" refers to the normal function of the liver, including, but not limited to, synthetic function, including, but not limited to, such as serum proteins (eg, albumin, coagulation factors, alkaline phosphatase, amino Synthesis of transferases (e.g., alanine aminotransferase, aspartate aminotransferase, 5'-nucleosidase, γ-glutamyl transpeptidase, etc.), bilirubin synthesis, cholesterol Synthesis and synthesis of bile acids; liver metabolic functions, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exotic drugs; hemodynamic functions, including splanchnic and portal hemodynamics ; and similar functions.

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 stated, the term "NS3 inhibitor" is used interchangeably with the terms "HCV NS3 protease inhibitor" and "NS3 protease inhibitor".

As used herein, the term "polyol" means a hydrocarbon comprising at least two hydroxyl groups bonded to carbon atoms, including sugars (reducing and non-reducing sugars), sugar alcohols and sugar acids. Polyols may include other functional groups. Examples of polyols include sugar alcohols such as mannitol and trehalose, and polyethers. "Reducing sugars" contain hemiacetal groups that can reduce metal ions or covalently react with lysine and other amino groups in proteins, while "non-reducing sugars" do not have these properties of reducing sugars. Examples of reducing sugars are: fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose and glucose. Non-reducing sugars include sucrose, trehalose, sorbose, melezitose, and raffinose. Mannitol, xylitol, erythritol, threitol, sorbitol, and glycerin are examples of sugar alcohols. As for sugar acids, L gluconate and its metal salts are included.

The term "polyether" as used herein means a hydrocarbon containing at least three ether linkages. The polyethers may include other functional groups. Polyethers include polyethylene glycol (PEG).

As used herein, the term "sustained viral response" (sustained viral response, SVR, also known as "sustained response" and "durable response") refers to the individual's response to serum HCV titers Response to treatment regimens for HCV infection. Generally, a "sustained viral response" refers to at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months after cessation of treatment. HCV RNA is undetectable (e.g., less than about 500, less than about 200, or less than about 100 genomic copies per milliliter of serum) in the patient's serum.

As used herein, "treatment failure patient" refers to an HCV-infected patient who has not responded to previous HCV therapy (termed a "non-responder") or an HCV-infected patient who initially responded to a previous therapy but was unable to maintain a therapeutic response (termed a "non-responder"). Relapser"). Prior therapy may typically include treatment with IFN-a monotherapy or IFN-a combination therapy, where combination therapy includes administration of IFN-a and an antiviral agent such as ribavirin.

As used herein, the term "treating" refers to achieving a desired pharmacological and/or physiological effect. Said effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms, and/or therapeutic in terms of partial or complete cure of the disease and/or adverse effects resulting from the disease. "Treatment" as used herein encompasses any therapeutic effect on a disease in a mammal, such as a human, including: (a) preventing the development of a disease in a subject who may be susceptible to it but has not yet been diagnosed with the disease; (b) inhibiting the disease, ie arresting the progression of the disease; and (c) relieving the disease, ie causing the disease to regress.

The terms "individual," "subject," "subject," and "patient" are used interchangeably herein to refer to mammals, including, but not limited to, murines, apes, humans, mammalian farm animals, mammalian sport animals and mammals.

As used herein, the term "pirfenidone" refers to 5-methyl-1-phenyl-2-(1H)-pyridone. As used herein, the term "pirfenidone analogs" refers to any of the compounds of formula I, HA or IIB in the section below entitled "Pirfenidone and its analogs". "Specific pirfenidone analogs" and all grammatical variations thereof mean, but are not limited to, any of the A pirfenidone analogue.

As used herein, the term "type I interferon receptor agonist" refers to any naturally occurring or non-naturally occurring ligand of the human type I interferon receptor that binds to said receptor and causes a signal via the receptor divert. Type I interferon receptor agonists include interferons, including naturally occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising interferon and heterologous proteins, shuffled interferons Shuffled interferons; antibodies specific for interferon receptors; 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 ligand of the human Type II interferon receptor that binds to said receptor and causes a signal via the receptor divert. Type II interferon receptor agonists include natural human interferon gamma, recombinant IFN-gamma, glycosylated IFN-gamma, pegylated IFN-gamma, modified or variant IFN-gamma, IFN- Gamma fusion proteins, antibody agonists specific for said receptors, non-peptide agonists, and the like.

As used herein, the term "Type III interferon receptor agonist" refers to any naturally-occurring or non-human IL-28 receptor ("IL-28R", the amino acid sequence of which is described by Sheppard et al. (see below)) of the human IL-28 receptor. A naturally occurring ligand that binds to the receptor and causes signal transduction via the receptor.

As used herein, the term "interferon receptor agonist" refers to any Type I interferon receptor agonist, Type II interferon receptor agonist, or Type III interferon receptor agonist.

The term "administration event" as used herein refers to the administration of an antiviral agent to a patient in need thereof, the event comprising one or more releases of the antiviral agent from the drug dispensing device. Thus, as used herein, the term "dose event" includes, but is not limited to, placement of a continuous delivery device (eg, pump or other controlled release injection system); and placement of a continuous delivery system followed by a single subcutaneous injection.

"Continuous administration" as used herein (e.g. in the context of "continuous administration of a substance to a tissue") means moving the drug to the site of administration, e.g. A desired amount of substance wherein the patient receives approximately the same amount of drug per minute during the selected time period.

As used herein, "controlled release" (e.g., in the context of "controlled drug release") means releasing a substance (e.g., a Type I or Type III drug) at a selected or otherwise controllable rate, interval, and/or amount. For interferon receptor agonists, such as IFN-a), the rate, interval and/or amount are substantially unaffected by the environment of use. "Controlled release" thus includes, but is not necessarily limited to, substantially continuous administration and patterned delivery (eg, intermittent administration for periods of time interrupted by timed or irregular intervals).

"Patterned" or "temporal" as used in the context of administration includes a certain pattern ( Usually in a generally regular pattern) dosing. "Modelized" or "temporary" administration includes administration at an increasing, decreasing, substantially constant, or pulsatile rate or range of rates (e.g., the amount of drug per unit of time or the volume of drug formulation per unit of time) , also further includes continuous or substantially continuous or slow administration.

The term "controlled drug delivery device" includes devices in which the release (e.g. rate of release, timing of release) of a drug or other desired substance contained in the device is controlled or determined by the device itself and is substantially independent of the environment of use or A device that releases at a rate that is reproducible within the environment of use.

"Substantially continuous" as used in the context of "substantially continuous infusion" or "substantially continuous administration" means that the administration is continued in a substantially uninterrupted manner for a predetermined period of time, wherein the The amount of drug received by the patient never dropped to zero during any 8-hour interval. In addition, "substantially continuous" administration may also include administration at a substantially constant predetermined rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation per unit time) that is substantially uninterrupted for a predetermined period of time to give medicine.

"Substantially steady state" as used in the context of a biological parameter that may vary as a function of time means that the biological parameter exhibits a substantially constant value over the course of time such that the value defined by the value of the biological parameter as a function of time The area under the curve is no more than about 20% or more or about 20% or less, preferably no more than about 15% or less, more preferably no more than about 10% or less, over any 8-hour period (AUC8hr) over the time course About 10% less, the mean area under the curve (AUC8hr mean) of the biological parameter over an 8-hour period in the time course. The AUC8hr mean value is defined as the quotient (q) of the area under the curve (AUCtotal) of the biological parameter in the entire time course divided by the number of 8-hour intervals (total/3days) in the time course, that is, q=(AUCtotal)( total/3days). For example, in the context of drug serum concentrations, when the area under the curve (AUC8hr) of the drug serum concentration over any 8-hour period over the time course is no greater than about 20% above or about 20% below the drug serum concentration over the time course The average area under the curve (AUC8hr average) in the 8-hour period, that is, with respect to the drug serum concentration in the time course, when AUC8hr is not greater than about 20% above or about 20% below the AUC8hr average, the drug serum concentration is Remains roughly constant during the time course.

As used herein, "hydrogen bond" refers to the bond between an electronegative atom (such as oxygen, nitrogen, sulfur, or halogen) and a hydrogen atom that is covalently bonded to another electronegative atom (such as oxygen, nitrogen, sulfur, or halogen). attraction between. See, eg, Stryer et al. "Biochemistry", 2002, Fifth Edition, Freeman & Co. NY. Hydrogen bonds are usually formed between a hydrogen atom and two unshared electrons of another atom. When the hydrogen atom is separated from the noncovalently bound electronegative atom by about 2.5 angstroms to about 3.8 angstroms and consists of three atoms (the covalently bound electronegative atom, hydrogen and the noncovalently bound electronegative atom Atoms) deviate from 180 degrees by about 45 degrees or less, hydrogen bonds may exist between hydrogen and an electronegative atom non-covalently bound to hydrogen. The distance between a hydrogen atom and a non-covalently bonded electronegative atom may be referred to herein as the "hydrogen bond length", whereas the distance between the three atoms (electronegative atom covalently bonded to hydrogen, hydrogen and non-covalently bonded The angle formed by the electronegativity atom of hydrogen) may be referred to herein as a "hydrogen bond angle". In some cases, the shorter the hydrogen bond length, the stronger the hydrogen bond formed; thus, in some cases, the hydrogen bond length may be between about 2.7 Angstroms to about 3.6 Angstroms, or about 2.9 Angstroms to about 3.4 Angstroms. In some cases, the closer the hydrogen bond angle is to a straight line, the stronger the hydrogen bond is formed, so in some cases the hydrogen bond angle may deviate from 180 degrees by 25 degrees or less, or by 10 degrees or less.

As used herein, "non-polar interaction" refers to a non-polar molecule or moiety or an interaction of a molecule or moiety with low polarity sufficiently close to van der Waals interactions between said moieties and/or sufficiently to exclude polarity such as water molecules Interactions of solvent molecules. See, eg, Stryer et al. "Biochemistry", 2002, Fifth Edition, Freeman & Co. NY. The distance between atoms (excluding hydrogen atoms) of the non-polar interacting moiety can generally be between about 2.9 Angstroms and about 6 Angstroms. In some cases, the distance between the non-polar interacting moieties is less than the distance to accommodate one water molecule. As used herein, a non-polar moiety or a moiety with low polarity refers to a moiety with a low dipole moment (typically smaller than the dipole moment of the OH bond of _H2O and the NH bond of _NH3 ) and/or in the hydrogen bond Moieties not normally present in binding or electrostatic interactions. Examples of moieties with low polarity are alkyl, alkenyl and unsubstituted aryl moieties.

As used herein, the NS3 protease S1' pocket portion refers to the part of the NS3 protease that interacts with an amino acid that positions one residue C-terminal to the cleavage site of a substrate polypeptide cleaved by NS3 protease (e.g., with the polypeptide substrate DLEVVT - the NS3 protease portion of the amino acid S interaction in STWVLV). Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and Phe43, see Yao. et al., Structure 1999, 7, 1353.

As used herein, the NS3 protease S2 pocket portion refers to the part of the NS3 protease that interacts with the amino acid that positions the two residues N-terminal to the cleavage site of a substrate polypeptide cleaved by the NS3 protease (e.g., with the polypeptide substrate DLEVVT - the NS3 protease portion of the amino acid V interaction in STWVLV). Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids His57, Arg155, Val78, Asp79, Gln80 and Asp81, see Yao. et al., Structure 1999, 7, 1353.

As used herein, a second moiety "positioning" a first moiety means that the spatial orientation of the first moiety is determined by the properties of the second moiety covalently bonded to the first atom or moiety. For example, a phenyl carbon can position its bound oxygen atom in a steric position such that the oxygen atom forms a hydrogen bond with the hydroxyl moiety in the NS3 active site.

Before the embodiments are further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not for limitation.

When a range of values is given, it is understood that, unless expressly stated otherwise, each intervening value between the upper and lower limits of said range (to the nearest tenth of the unit of the lower limit) and every intervening value within said range Any other stated or intervening values are included in the examples. The upper and lower limits of these smaller ranges may individually be included in the smaller ranges also included in the Examples, any limit within said range may be excluded. Where the stated range includes one or both of the limits, ranges excluding either of the limits are also included in the embodiments.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments belong. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the Examples, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It should be noted that as used herein and in the appended claims, the singular form "a" and "an" includes plural referents unless expressly stated otherwise. Thus, for example, reference to "a method" includes a plurality of methods, while reference to "a dose" includes one or more doses and equivalents known to those skilled in the art, and so on.

The publications described herein present only their disclosure prior to the filing date of the present application. It is not to be understood that the present invention is not entitled to antedate this disclosure by virtue of prior invention. In addition, the dates of publication provided may be different from the actual dates of publication which may need to be independently confirmed.

The Examples provide compounds of Formulas I-XIX, as well as pharmaceutical compositions and formulations comprising any compound of Formulas I-XIX. The compounds of the invention are useful in the treatment of flavivirus infections, such as HCV infection and other conditions, as described below.

combination

Various composition examples are described below. For ease of discussion, these example descriptions are divided into Sections A, B, C, D, and E. It should be understood that various terms that may be defined in a particular section apply to that section, as well as elsewhere in the text where that particular section is referred to. Likewise, any reference within a section to a specific number or designation should be read in context of the corresponding numbering or labeling scheme used within that section, and not in context of a potentially similar or equivalent numbering or labeling scheme used in an unrelated section ,Unless otherwise indicated.

Part A

Part A Examples provide compounds having the general formula I:

in:

Q is a core ring selected from:

and

Wherein, the core ring can be unsubstituted or substituted by the following groups: H, halogen, cyano, nitro, hydroxyl, 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 Base, substituted C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide , urea, thiourea, amido, keto, carboxyl, carbamoyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkoxyheterocyclic, alkylamino, alkylcarboxy, carbonyl, Spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl,

Alternatively, Q is R ¹ -R ² , wherein R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridyl Oxazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran , indole or benzimidazole, each of these groups is optionally substituted by up to three of each of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 Cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1- optionally substituted by up to 5 fluorine ₆ alkyl or _C1-6 alkoxy optionally substituted with up to 5 fluorines; and ^R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole , imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of these groups Optionally substituted with up to three of each of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkane C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or optionally substituted with up to 5 fluorines C _1-6 alkoxy;

R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three of the following Group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or ^R and ^R together with the nitrogen to which they are attached Formation of indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate C _1-6 alkyl substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁸ is C _1-6 alkane optionally substituted by up to 5 fluorines or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, All of these groups are optionally substituted one to three times by: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁹ is C _{6 or 10} aryl, which aryl is optionally Cases are substituted by up to three of the following groups: halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkene C _1-6 alkoxy group, C 1-6 alkoxy group, hydroxy-C _1-6 alkyl group or C _1-6 alkyl group optionally substituted by up to 5 fluorines, C _1-6 alkoxy group optionally substituted by up to 5 fluorines or R ⁹ is C _1-6 alkyl, NR ⁶ R ⁷ , NR ^1a R ^1b or (CO)OH optionally substituted by up to 5 fluoro groups; or R ⁹ is optionally substituted by at most Two heteroaromatic rings: halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

wherein R _1a and R _1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkylcycloalkyl, all of which are optionally substituted one to three times by : Halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Or R ^1a and R ^1b are each independently H and C _{6 or 10} aryl, optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances through up to 5 fluorine Substituted C _1-6 alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

Alternatively, each of R ^1a and R ^1b is independently H or a heterocyclic ring, which is a 5-, 6-, or 7-membered saturated or unsaturated heterocyclic molecule containing one to four groups selected from the group consisting of nitrogen, oxygen, and sulfur group of heteroatoms;

Or NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally having one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Alternatively, NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

和

and

Wherein R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl;

Or R ^1c is NH(CO)OR ^1e , wherein 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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines ^, _or phenyl; The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted with up to 5 fluorines, C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

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

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

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

In preferred embodiments, the Part A examples provide compounds having the general formula Ia:

In preferred embodiments, the Part A examples provide compounds having the general formula Ib:

In preferred embodiments, the Part A examples provide compounds having the general formula Ic:

In preferred embodiments, the Part A examples provide compounds having the general formula Id:

In preferred embodiments, the Part A examples provide compounds having the general formula Ie:

In preferred embodiments, the Part A examples provide compounds having the general formula If:

In preferred embodiments, the Part A examples provide compounds having the general formula Ig:

In preferred embodiments, the Part A examples provide compounds having the general formula Ih:

In preferred embodiments, the Part A examples provide compounds having the general formula Ii:

In preferred embodiments, the Part A examples provide compounds having the general formula Ij:

In preferred embodiments, the Part A examples provide compounds having the general formula Iz:

In preferred embodiments, the Part A embodiment provides compounds having the general formula I, wherein Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is selected from the group consisting of C _1-6 alkane group consisting of radical, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl 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 Part A examples provide compounds having the general formula I, wherein the C13-C14 double bond is cis.

In preferred embodiments, the Part A examples provide compounds having the 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 exclude compounds of formula II, III, and IV in Section B below.

Part B

Part B Examples provide compounds having the general formulas II, III and IV:

in:

R ¹ and R ² are each independently H, halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines, C _1-6 alkane optionally substituted by up to 5 fluorines Oxygen, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, 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)2R ⁸ , CH _n NR ⁶ R ⁷ , OCH _n NR ⁶ R ⁷ or OCH _n R ⁹ (wherein R ⁹ is imidazolyl or pyrazolyl) ; said thienyl, pyrimidinyl, furyl, thiazolyl and oxazolyl in the definitions of R ^{and R} are optionally substituted by up to two of the following groups: halogen, cyano, nitro, hydroxyl, 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 A C _1-6 alkyl group optionally substituted by at most 5 fluorines or a C _1-6 alkoxy group optionally substituted by at most 5 fluorines; the C _{6 or 10} aryl group in the definition of R ¹ and R ² , pyridyl, phenoxy and thiophenoxy are optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or optionally C _1-6 alkoxy substituted by at most 5 fluorines;

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, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C ^2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which R ^{and R} are attached together 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 these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate C _1-6 alkyl substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁸ is C _1-6 alkane optionally substituted by up to 5 fluorines or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-5 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, All of these groups are optionally substituted one to three times by: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁹ is C _{6 or 10} aryl, which aryl is optionally Cases are substituted by up to three of the following groups: halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkene C _1-6 alkoxy group, C 1-6 alkoxy group, hydroxy-C _1-6 alkyl group or C _1-6 alkyl group optionally substituted by up to 5 fluorines, C _1-6 alkoxy group optionally substituted by up to 5 fluorines or R ⁹ is C _1-6 alkyl optionally substituted with up to 5 fluoro groups, NR ⁶ R ⁷ or (CO)OH; or R ⁹ is heteroaromatic optionally substituted up to twice by Ring: halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

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 alkane radical, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl), all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 Alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted by up to 5 fluorine C _1-6 alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹⁰ and R ¹¹ is optionally substituted by at most three of the following Group substitution: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ^and R ¹¹ together with the carbon to which it is attached forms cyclopropyl, 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 alkane radical, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 Alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl), wherein all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _{1- 6} alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances through up to 5 fluorine A substituted C _1-6 alkyl group or a C _1-6 alkoxy group substituted by at most 5 fluorines; the C _{6 or 10} aryl group in the definition of R ¹² and R ¹³ is optionally replaced by at most three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ¹² and R ¹³ together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R ¹² and R ¹³ are each independently C ₁ optionally substituted with (CH ₂ ) _n OR ⁸ _-6 alkyl;

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, as the case may be C _1-6 alkyl substituted by 5 fluorines, or (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _{3 -7} cycloalkyl, C _4-10 alkylcycloalkyl), wherein all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or Phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 Cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1- optionally substituted by up to 5 fluorine ₆ alkyl or, optionally, C _1-6 alkoxy substituted by up to 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by up to three of the following groups Substitution: halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines;

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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy, C _1-6 alkyl or phenyl optionally substituted by up to 5 fluorines; or R ²¹ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ²¹ is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

Part B Examples provide compounds having the general formula II:

in:

R ¹ is H, halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

R ² is H, OCH _n NR ⁶ R ⁷ , OCH _n R ¹⁶ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkane C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or optionally substituted with up to 5 fluorines C _1-6 alkoxy; said R ⁶ and R ⁷ in the definition of R ² are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl ring Alkyl group; or R ⁶ and R ⁷ in the definition of R ² form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl together with the nitrogen to which they are attached;

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 in the definition of 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 optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _1-6 alkyl optionally substituted by up to 5 fluoro groups; or R ⁸ is connected via C ₃ or C ₄ of the tetrahydrofuran ring Tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected through the C ₄ position of the tetrapyranyl ring;

Y is formula-C(O)NHS(O) ₂ R ⁹ sulfonimide, wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, these The groups are all optionally substituted one to three times by: halogen, C _1-6 alkoxy or phenyl;

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are all H;

p = 0 or 1;

V = O; and

W is selected from O, NH or _CH2 .

In preferred embodiments, the Part B examples provide compounds having general formulas II, III and IV, wherein p can be zero. In preferred embodiments, the Part B examples provide compounds having general formulas II, III, and IV, wherein p can be one.

In preferred embodiments, Part B provides compounds having general formulas II, III and IV, wherein either or both of R ^{and R} are H. In some embodiments, p is 0. In other embodiments, p is 1.

In preferred embodiments, the Part B embodiments provide compounds having general formulas II, III, and IV, wherein neither ^R nor ^R is H. In some embodiments, p is 0. In other embodiments, p is 1.

In preferred embodiments, the Part 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 Part B embodiments provide compounds having general formulas II, III, and IV, wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or C _4-10 alkylcycloalkyl , all of these groups are optionally substituted one to three times with halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl.

In preferred embodiments, Part B provides compounds having general formulas II, III and IV, wherein R ^is C _{or C} aryl optionally substituted with up to three of each of the following groups: halogen, cyano , nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

In preferred embodiments, the Part B embodiments provide compounds having general formulas II, III, and IV, wherein R is a heteroaromatic ring optionally substituted up to ^twice with: halogen, cyano, nitro, hydroxyl Or C _1-6 alkoxy.

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

In preferred embodiments, Part B provides compounds having the general formulas II, III and IV, wherein the dashed lines in formula (II), (III) or (IV) represent single bonds.

Part B Examples provide compounds having the general formula II:

in:

R ¹ and R ² are each independently H, halogen, cyano, nitro, hydroxyl, 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 fluorines, C _1-6 alkane optionally substituted with up to 5 fluorines Oxygen, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, 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 , OCH _n NR ⁶ R ⁷ or OCH _n R ¹⁶ (where R ¹⁶ is imidazolyl or pyrazolyl); the R ¹ Thienyl, pyrimidinyl, furyl, thiazolyl and oxazolyl in the definition of ^R are optionally substituted by up to two of each of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances through up to 5 fluorine Substituted C _1-6 alkyl or C _1-6 alkoxy substituted by at most 5 fluorines; said C _{6 or 10} aryl, pyridyl, phenoxy in the definition of R ¹ and R ² and thiophenoxy are optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl ring Alkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or optionally substituted by up to 5 fluorines Substituted C _1-6 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, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which R ^{and R} are attached together 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 these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate C _1-6 alkyl substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁸ is C _1-6 alkane optionally substituted by up to 5 fluorines or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, All of these groups are optionally substituted one to three times by: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁹ is C _{6 or 10} aryl, which aryl is optionally The case is substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 Alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines, C _1-6 alkane optionally substituted by up to 5 fluorines Oxygen; or R ⁹ is C _1-6 alkyl, NR ⁶ R ⁷ or (CO)OH optionally substituted by up to 5 fluoro groups; or R ⁹ is hetero which is optionally substituted up to twice by Aromatic ring: halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug;

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 alkane radical, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl), all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 Alkoxy or phenyl; or R ₁₄ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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 fluorine The C _1-6 alkyl group or the C _1-6 alkoxy group substituted by up to 5 fluorines; the C _{6 or 10} aryl group in the definition of R ¹⁰ and R ¹¹ is optionally up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ¹⁰ and R ¹¹ together with the carbon to which it is attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R ¹⁰ and R ¹¹ are combined to be 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 alkane radical, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ^{14 is} H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl), all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 Alkoxy or phenyl; or R ₁₄ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted by up to 5 fluorine C _1-6 alkyl or C _1-6 alkoxy optionally substituted by at most 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by at most three of the following Group substitution: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ¹² and R ¹³ together with the carbon to which it is attached forms cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R ¹² and R ¹³ are each independently C _1-6 optionally substituted with (CH ₂ ) _n OR ⁸ alkyl;

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, as the case may be C _1-6 alkyl substituted by 5 fluorines, or (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _{3 -7} cycloalkyl, C _4-10 alkylcycloalkyl), wherein all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or Phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 Cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1- optionally substituted by up to 5 fluorine ₆ alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines; said C _{6 or 10} aryl in the definition of R ₁₂ and R ₁₃ is optionally substituted by up to three of the following groups : Halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines;

n=0-4;

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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy, C _1-6 alkyl or phenyl optionally substituted by up to 5 fluorines; or R ²¹ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, _C2-6 alkenyl, C _1-6 Alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ²¹ is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

Part B Examples provide compounds having the general formula IIa:

in:

R ¹ and R ² are each independently H, halogen, cyano, hydroxyl, 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 , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, and the phenyl is optionally at most Two of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl or C _1-3 alkoxy; or Y is carboxylic acid or its pharmaceutical acceptable salts, solvates or prodrugs;

R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon to which they are attached;

W is selected from O, NH; and

Dashed lines indicate optional double bonds;

Part B Examples provide compounds having the general formula IIIa:

in:

R ¹ and R ² are each independently H, halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

^R4 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 , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, and the phenyl is optionally at most Two of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl or C _1-3 alkoxy; or Y is carboxylic acid or its pharmaceutical acceptable salts, solvates or prodrugs;

W is selected from O, NH; and

Dashed lines indicate optional double bonds;

Part B Examples provide compounds having the general formula IIb:

in:

R ¹ and R ² are each independently H, halogen, cyano, hydroxyl, 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 or phenyl, and this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon to which they are attached;

W is selected from O, NH; and

Dashed lines indicate optional double bonds;

Part B Examples provide compounds having the general formula IIIb:

in:

R ¹ and R ² are each independently H, halogen, cyano, hydroxyl, 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 _3-5 cycloalkyl or phenyl, and this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

R ¹⁰ and R ¹¹ are each independently H, C _1-3 alkyl or C _4-5 cycloalkyl;

W is selected from O, NH; and

Dashed lines indicate optional double bonds;

Part B Examples provide compounds having the general formula IIc:

in:

R ^and R are ^each independently H, chlorine, fluorine, cyano, hydroxyl, 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 or phenyl, and this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

(e) R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ together form cyclopropyl or cyclobutyl with the carbon to which they are attached; and

(f) dashed lines indicate optional double bonds;

Part B Examples provide compounds having the general formula IIIc:

in:

R ^and R are ^each independently H, chlorine, fluorine, cyano, hydroxyl, 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 or phenyl, and this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; and

Dashed lines indicate optional double bonds;

Part B Examples provide compounds having the general formula IIId:

in:

R ¹ and R ² are each independently H, halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

^R4 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 , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, and the phenyl is optionally at most Two of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl or C _1-3 alkoxy; or Y is carboxylic acid or its pharmaceutical acceptable salts, solvates or prodrugs;

R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon to which they are attached;

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, as the case may be C _1-6 alkyl substituted by 5 fluorines, (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), wherein all of these groups are optionally substituted one to three times by: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or benzene or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 ring Alkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 optionally substituted by up to 5 fluorine Alkyl or, optionally, C _1-6 alkoxy substituted by up to 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by up to three of the following groups : Halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines;

W is selected from O or NH; and

Dashed lines indicate optional double bonds;

Part B Examples provide compounds having the general formula IVa:

in:

R ¹ and R ² are each independently H, halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

^R4 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 , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, and the phenyl is optionally at most Two of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl or C _1-3 alkoxy; or Y is carboxylic acid or its pharmaceutical acceptable salts, solvates or prodrugs;

R ¹⁰ and R ¹¹ are each independently H or C _1-3 alkyl, or R ¹⁰ and R ¹¹ form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon to which they are attached;

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, as the case may be C _1-6 alkyl substituted by 5 fluorines, (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), wherein all of these groups are optionally substituted one to three times by: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or benzene or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 ring Alkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 optionally substituted by up to 5 fluorine Alkyl or C _1-6 alkoxy substituted by at most 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by at most three of the following groups: Halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines;

W is selected from O or NH;

Dashed lines indicate optional double bonds;

wherein Z is a fused or appended arylheteroaryl ring system.

Part C

Part C Examples provide compounds having the general formula XI:

in:

R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, all of which are optionally substituted one to three times by the following groups: Halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Or R ^1a and R ^1b are each independently H and C6 or 10 aryl, optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, _C1-6 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 fluorine C _1-6 alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

Alternatively, each of R ^1a and R ^1b is independently H or a heterocyclic ring, which is a 5-, 6-, or 7-membered saturated or unsaturated heterocyclic molecule containing one to four groups selected from the group consisting of nitrogen, oxygen, and sulfur group of heteroatoms;

Or NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally having one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Alternatively, NR ^1a R ^1b is a heteroaryl selected from the group consisting of:

and

Wherein R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl;

Or R ^1c is NH(CO)OR ^1e , wherein 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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines;

^R is a bicyclic secondary amine having the following structure:

Wherein, R ²¹ and R ²² are each independently H, halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines, C _1-6 optionally substituted by up to 5 fluorines ₆ alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, 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 is 0, 1 or 2) or NHS(O) ₂ R ⁸ ; the ^thienyl , ^pyrimidinyl , Furyl, thiazolyl and oxazolyl are optionally substituted by up to two of each of the following groups: halogen, cyano, nitro, hydroxyl, _C1-6 alkyl, _C3-7 cycloalkyl, _C4-10 Alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or optionally up to C _1-6 alkoxy substituted by 5 fluorines; the C _{6 or 10} aryl, pyridyl, phenoxy and thiophenoxy in the definition of R ₂₁ and R ²² are optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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 alkane radical, C _1-6 alkyl optionally substituted by up to 5 fluorines, (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 these groups are optionally replaced by

The following groups are substituted one to three times: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally modified by up to three of the following Group substitution: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; C _{6 or 10} aryl in the definitions of ¹⁰ and R ¹¹ are optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ¹⁰ and R ¹¹ together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon to which they are attached; or R ¹⁰ and R ¹¹ combines to 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, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (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 these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _{1- 6} alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances through up to 5 fluorine Substituted C _1-6 alkyl, optionally C _1-6 alkoxy substituted by up to 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ optionally via up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ¹² and R ¹³ together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon to which they are attached;

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, as the case may be C _1-6 alkyl, (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 alkylcycloalkyl), wherein all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or Phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 Cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1- optionally substituted by up to 5 fluorine ₆ alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by up to three of the following groups : Halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines, optionally C _1-6 alkoxy substituted by up to 5 fluorines;

where n=0-4:

Wherein 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 optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl- C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁶ and R ⁷ are attached to The nitrogens together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

Or R ² is R ^2a R ^2b when W=NH and V=O, wherein

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, oxa oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, these groups Each is optionally substituted with up to three of the following groups: NR ^2c R ^2d , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl ring Alkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or optionally substituted by up to 5 fluorines 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 of which is optionally substituted by up to three of the following groups: NR ^2c R ^2d , halogen, cyano, Nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

The R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl or phenyl, and the phenyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl- C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ^2c and R ^2d are attached to The nitrogens together 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 optionally substituted by up to three of the following groups: halogen , cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl -C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate C _1-6 alkyl substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; and

Dashed lines indicate optional double bonds;

Part C Examples provide compounds having the general formula XII:

in:

R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, all of which are optionally substituted one to three times by the following groups: Halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Or R ^1a and R ^1b are each independently H or a heteroaryl selected from the group consisting of:

和

and

Wherein R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl;

Or NR _1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally having one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

R ²¹ and R ²² are each independently H, halogen, cyano, hydroxyl, 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, halogen or C _1-3 alkyl, or R ¹⁰ and R ¹¹ form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon to which they are attached;

R ¹² and R ¹³ are each independently H, halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxyl-C _{1- 6} alkyl or C _1-6 alkyl optionally substituted with up to 5 halogen atoms; and

Dashed lines indicate optional double bonds.

Part C Examples provide compounds having the general formula XIII:

in:

R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, all of which are optionally substituted one to three times by the following groups: Halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Or R ^1a and R ^1b are each independently H or a heteroaryl selected from the group consisting of:

and

Wherein R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl;

Or NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally having one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

R ²¹ and R ²² are each independently H, halogen, cyano, hydroxyl, 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; and

Dashed lines indicate optional double bonds.

Part C Examples provide compounds having the general formula XIV:

in:

R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, all of which are optionally substituted one to three times by the following groups: Halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

Or R ^1a and R ^1b are each independently H or a heteroaryl selected from the group consisting of:

和

and

Wherein R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C ^1-6 alkyl or C ^3-6 cycloalkyl;

Or NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally having one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl;

R ^2a is C _{6 or 10} aryl optionally substituted by up to three of the following groups: NR ^2c R ^2d , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkane Base, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl-C _1-6

Alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines;

The R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl or phenyl, and the phenyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl -C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ^2c and R ^2d are attached to The nitrogens together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

Or R ^is an unsaturated five- or six-membered heteroaryl, or a heteroaryl as defined herein is fused with another ring to form 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; and

Dashed lines indicate optional double bonds.

Part C Examples provide compounds having the general formula XV:

in:

R ¹ and R ² are each independently H, halogen, cyano, hydroxyl, 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 _3-5 cycloalkyl or phenyl, and this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

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

Dashed lines indicate optional double bonds.

Part C Examples provide compounds having the general formula XVI:

in:

R ^and R are ^each independently H, chlorine, fluorine, cyano, hydroxyl, 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 or phenyl, and this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy;

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; and

Dashed lines indicate optional double bonds.

Part C Examples provide compounds having the general formula XVII:

in:

R ^and R are ^each independently H, chlorine, fluorine, cyano, hydroxyl, 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 or phenyl, and this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; and

Dashed lines indicate optional double bonds.

Part D

Part D Examples provide compounds having the general formula XVIII:

in:

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, oxa oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, these groups Each is optionally substituted with up to three of the following groups: NR ⁵ R ⁶ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl ring Alkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or optionally substituted by up to 5 fluorines Substituted C _1-6 alkoxy;

^R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline , quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which is optionally substituted by up to three of the following groups: NR ⁵ R ⁶ , halogen, cyano, Nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

R ³ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, or phenyl, which is optionally substituted by up to three of the following groups: halogen , cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl -C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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 ;

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 optionally modified by at most three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to ⁵ fluorines; or the nitrogen to which R and ^R are attached together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

R ⁷ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁷ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate _C1-6 alkyl substituted by up to 5 fluorines or _C1-6 alkoxy optionally substituted by up to 5 fluorines;

R ⁸ is C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, and this phenyl is optionally substituted by up to two of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; and

Dashed lines indicate optional double bonds.

Part E

Part E Examples provide compounds having the general formula XIX:

in:

Z is a group set to be hydrogen bonded to the imidazole part of NS3 protease His57 and hydrogen bonded to the nitrogen atom of NS3 protease Gly137;

_P1 ' is a group configured to form a non-polar interaction with at least one NS3 protease S1' pocket moiety selected from Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and Phe43 formed groups;

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 heterocyclyl and substituted P2 is positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81;

Dashed lines indicate optional double bonds;

R ^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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which ^R and ^R are attached together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate C _1-6 alkyl substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁸ is C _1-6 alkane optionally substituted by up to 5 fluorines or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ⁴ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

As used herein, "hydrogen bond" refers to the bond between an electronegative atom (such as oxygen, nitrogen, sulfur, or halogen) and a hydrogen atom that is covalently bonded to another electronegative atom (such as oxygen, nitrogen, sulfur, or halogen). attraction between. See, eg, Stryer et al. "Biochemistry", 2002, Fifth Edition, Freeman & Co. NY. Hydrogen bonds are usually formed between a hydrogen atom and two unshared electrons of another atom. When the hydrogen atom is separated from the noncovalently bound electronegative atom by about 2.5 angstroms to about 3.8 angstroms and consists of three atoms (the covalently bound electronegative atom, hydrogen and the noncovalently bound electronegative atom Atoms) deviate from 180 degrees by about 45 degrees or less, hydrogen bonds may exist between hydrogen and an electronegative atom non-covalently bound to hydrogen. The distance between a hydrogen atom and a non-covalently bonded electronegative atom may be referred to herein as the "hydrogen bond length", whereas the distance between the three atoms (electronegative atom covalently bonded to hydrogen, hydrogen and non-covalently bonded The angle formed by the electronegativity atom of hydrogen) may be referred to herein as a "hydrogen bond angle". In some cases, the shorter the hydrogen bond length, the stronger the hydrogen bond formed; thus, in some cases, the hydrogen bond length may be between about 7 Angstroms to about 3.6 Angstroms or about 2.9 Angstroms to about 3.4 Angstroms. In some cases, the closer the hydrogen bond angle is to a straight line, the stronger the hydrogen bond is formed, so in some cases the hydrogen bond angle may deviate from 180 degrees by 25 degrees or less, or by 10 degrees or less.

As used herein, "non-polar interaction" refers to a non-polar molecule or moiety or an interaction of a molecule or moiety with low polarity sufficiently close to van der Waals interactions between said moieties and/or sufficiently to exclude polarity such as water molecules Interactions of solvent molecules. See, eg, Stryer et al. "Biochemistry", 2002, Fifth Edition, Freeman & Co. NY. The distance between atoms (excluding hydrogen atoms) of the non-polar interacting moiety can generally be between about 2.9 Angstroms and about 6 Angstroms. In some cases, the distance between the non-polar interacting moieties is less than the distance to accommodate one water molecule. As used herein, a non-polar moiety or a moiety with low polarity refers to a moiety with a low dipole moment (typically smaller than the dipole moment of the OH bond of _H2O and the NH bond of _NH3 ) and/or in the hydrogen bond Moieties not normally present in binding or electrostatic interactions. Examples of moieties with low polarity are alkyl, alkenyl and unsubstituted aryl moieties.

As used herein, the NS3 protease S1' pocket portion refers to the part of the NS3 protease that interacts with an amino acid that positions one residue C-terminal to the cleavage site of a substrate polypeptide cleaved by NS3 protease (e.g., with the polypeptide substrate DLEVVT - the NS3 protease portion of the amino acid S interaction in STWVLV). Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42 and Phe43, see Yao. et al., Structure 1999, 7, 1353.

As used herein, the NS3 protease S2 pocket portion refers to the part of the NS3 protease that interacts with the amino acid that positions the two residues N-terminal to the cleavage site of a substrate polypeptide cleaved by the NS3 protease (e.g., with the polypeptide substrate DLEVVT - the NS3 protease portion of the amino acid V interaction in STWVLV). Exemplary moieties include, but are not limited to, atoms of the peptide backbone or side chains of amino acids His57, Arg155, Val78, Asp79, Gln80 and Asp81, see Yao. et al., Structure 1999, 7, 1353.

As used herein, a second moiety "positioning" a first moiety means that the spatial orientation of the first moiety is determined by the properties of the second moiety covalently bonded to the first atom or moiety. For example, a phenyl carbon can position its bound oxygen atom in a steric position such that the oxygen atom forms a hydrogen bond with the hydroxyl moiety in the NS3 active site.

Also provided herein are compounds containing moieties programmed to interact with specific regions, specific amino acid residues, or specific atoms of NS3 protease. Some of the compounds provided herein contain one or more moieties configured to form hydrogen bonds with specific regions, specific amino acid residues, or specific atoms of NS3 protease. Some of the compounds provided herein contain one or more moieties configured to form non-polar interactions with specific regions, specific amino acid residues, or specific atoms of NS3 protease. For example, a compound of general formula XIX may contain one or more moieties that form hydrogen bonds with peptide backbone atoms or side chain moieties located in the substrate binding pocket of NS3 protease. In another example, a compound of formula XIX may contain one or more moieties that form non-polar interactions with peptide backbone or side chain atoms located in the substrate binding pocket of NS3 protease. In compounds of formula XIX, the dashed line between carbon 13 and carbon 14 may be a single or double bond.

As provided in compounds of general formula XIX, Z can be set to interact with peptide backbone atoms or side chain moieties located in the substrate binding pocket of NS3 protease (including, but not limited to, NS3 protease His57 imidazole moiety and NS3 protease Gly137 nitrogen atoms) to form hydrogen bonds. In some cases, Z can be programmed to form hydrogen bonds with both the NS3 protease His57 imidazole moiety and the NS3 protease Gly137 nitrogen atom.

The P1' group of the compound having the general formula XIX can be configured to bind to peptide backbone or side chain atoms located in the substrate binding pocket of NS3 protease (including, but not limited to, amino acid residues forming the S1' pocket of NS3 protease) form non-polar interactions. For example, the P1' group can form a non-polar interaction with at least one amino acid selected from Lys136, Gly137, Ser139, His57, Gly58, Gln41, Ser42, and Phe43.

The P2 group of the compound having the general formula XIX can be configured to form non-binding peptide backbone or side chain atoms (including, but not limited to, amino acid residues forming the S2 pocket of NS3 protease) located in the substrate binding pocket of NS3 protease. polar interaction. For example, the P2 group can form a non-polar interaction with at least one amino acid selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81. The P2 group can also be configured to form hydrogen bonds with peptide backbone or side chain atoms located in the substrate-binding pocket of NS3 protease (including, but not limited to, amino acid residues that form the S2 pocket of NS3 protease). For example, the P2 group can form a hydrogen bond with at least one amino acid selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81. In some cases, P2 can form nonpolar interactions with peptide backbone or side chain moieties or atoms (such as amino acids selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81) located in the substrate-binding pocket of NS3 protease. interaction and hydrogen bonding. The hydrogen bonding and non-polar interactions can occur at the same amino acid residues or at different amino acid residues in the S2 pocket of the NS3 protease. In some embodiments, P2 can be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocycles and substituted heterocycles.

In some embodiments, the position of the P2 group is determined by the linking group L. For example, P2 can be positioned by linker L to form nonpolar interactions with peptide backbone or side chain atoms located in the substrate-binding pocket of NS3 protease (including, but not limited to, amino acid residues that form the S2 pocket of NS3 protease). effect. For example, the P2 group can be positioned by L to form a non-polar interaction with at least one amino acid selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81. In another example, P2 can be positioned by linker L to form with peptide backbone or side chain atoms located in the substrate binding pocket of NS3 protease (including, but not limited to, amino acid residues that form the S2 pocket of NS3 protease) hydrogen bond. For example, the P2 group can be positioned from L to form a hydrogen bond with at least one amino acid selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81. In some cases, P2 can be positioned to form non-polar peptide backbone or side chain atoms (such as amino acids selected from His57, Arg155, Val78, Asp79, Gln80, and Asp81) located in the substrate-binding pocket of NS3 protease interactions and hydrogen bonding. The hydrogen bonding and non-polar interactions can occur at the same amino acid residues or at different amino acid residues in the S2 pocket of the NS3 protease.

As provided in compounds of general formula XIX, L may be a linking group linking P2 to the heterocyclic backbone of the compound of formula XIX. The linking group L may contain any kind of atom and moiety suitable for positioning P2 in the substrate binding pocket of the NS3 protease. In one embodiment, L may contain 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. In another embodiment, L may contain 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur. For example, L may contain a group of formula -W-C(=V)-, where V and W are each 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 contain an ^R group, where the ^R group may contain a carboxyl moiety. Examples of R ⁵ carboxyl moieties 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 _4-10 alkylcycloalkyl or phenyl optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 Cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, C ^1-6 alkyl optionally substituted by up to 5 fluorine, optionally up to 5 fluorine-substituted C _1-6 alkoxy groups; or R ⁶ and R ⁷ form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl together with the nitrogen to which they are attached; and wherein R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of these groups are substituted one to three times by the following groups as appropriate: halogen, cyano, nitro, hydroxyl , C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances C _1-6 alkyl substituted with up to 5 fluorines, C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 alkyl optionally substituted with up to 5 fluorines or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring.

In some embodiments, several bonds of the compound of Formula XIX may have a particular chirality.

The Part E examples provide compounds wherein the C13-C14 double bond is in cis. The Part E examples provide compounds wherein the C13-C14 double bond is trans.

In preferred embodiments, the Part E embodiments provide compounds having the general formula XIX, wherein L consists of 2 to 5 atoms.

In preferred embodiments, Moiety E provides compounds of general formula XIX, wherein L comprises a -W-C(=V)- group, wherein V and W are each independently selected from O, S or NH.

In preferred embodiments, the Part E embodiments 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 Part E embodiment provides a compound having the general formula XIX, wherein P2 is additionally positioned by L to interact with at least one NS3 protease S2 pocket selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81 Partially forms hydrogen bonding.

In preferred embodiments, the Part E examples provide compounds having the general formula XIXa:

In preferred embodiments, the Part E embodiments provide compounds having the general formula XIXa, wherein L consists of 2 to 5 atoms.

In preferred embodiments, part E provides a compound of general formula XIXa, wherein L comprises a -W-C(=V)- group, wherein V and W are each independently selected from O, S or NH.

In preferred embodiments, the Part E embodiments 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 Part E embodiment provides a compound having the general formula XIXa, wherein P2 is additionally positioned by L to interact with at least one NS3 protease S2 pocket selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81 Partially forms hydrogen bonding.

In preferred embodiments, the Part E embodiments provide compounds having the general formula XIX, wherein P2 is

In preferred embodiments, the Part E Examples provide compounds having formula XIXb:

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

In preferred embodiments, Moiety E provides compounds of general formula XIXb, wherein L comprises a -W-C(=V)- group, wherein V and W are each independently selected from O, S or NH.

In preferred embodiments, the Part E embodiments 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 Part E embodiment provides a compound having the general formula XIXb, wherein P2 is additionally positioned by L to interact with at least one NS3 protease S2 pocket selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81 Partially forms hydrogen bonding.

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

In preferred embodiments, the Part E embodiments 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, compounds of general formula XIX exclude compounds disclosed in PCT/US04/33970. For example, in certain embodiments, compounds of general formula I exclude compounds of formula II, III and IV in section B above.

pharmaceutical composition

The examples further provide compositions, including pharmaceutical compositions, comprising compounds of general formula I-XIX and salts, esters or other derivatives thereof. The pharmaceutical composition comprises the compound and a pharmaceutically acceptable excipient. A variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been described in detail in various publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th Edition, Lippincott, Williams, &Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al. eds. 7th ed. Lippincott, Williams, &Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al. eds. 3rd ed. Amer. Pharmaceutical Assoc.

Such pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Furthermore, pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents, and the like are readily available to the public. Examples of suitable pharmaceutical composition embodiments and methods for their production are described in more detail below.

Inhibits the enzymatic activity of flaviviruses

In some embodiments, the compound inhibits the enzymatic activity of a Flavivirus. Whether the compound inhibits flaviviruses can be readily determined using known methods. Flavivirus infections include, but are not limited to, hepatitis C virus, West Nile Virus, GB virus, Japanese Encephalitis, Dengue virus, and yellow fever virus ( Infection caused by the flavivirus genus of Yellow Fever virus). In many embodiments, the compounds inhibit the enzymatic activity of the hepatitis C virus (HCV) protease NS3. Whether the compound inhibits HCV NS3 can be readily determined using known methods. Typical methods include determining whether an HCV polyprotein or other polypeptide comprising an NS3 recognition site is cleaved by NS3 in the presence of the agent. In many embodiments, the compound inhibits NS3 enzymatic activity by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% compared to NS3 enzymatic activity in the absence of the compound. %, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more.

In many embodiments, the compound inhibits the enzymatic activity of HCV NS3 with an IC value of less than about ₅₀ μM, for example, the compound inhibits the enzymatic activity of HCV NS3 at about less than about 40 μM, less than about 25 μM, less than about 10 μM, less than about 1 μM, less than about 100 nM, An IC50 value of 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 inhibits HCV _NS3 protease.

In many embodiments, the compounds inhibit HCV viral replication. For example, the compound inhibits HCV viral replication by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more. Whether the compound inhibits HCV viral replication can be determined using methods known in the art, including in vitro viral replication assays.

Treating Flavivirus Infections

The methods and compositions described herein are generally useful for treating flavivirus infections.

Whether the compounds are effective in treating flavivirus infections can be measured by a reduction in viral load, a reduction in the time to seroconversion (undetectable virus in the patient's serum), an increase in the rate of sustained viral response to treatment, morbidity or mortality in clinical outcomes Decreased or other disease response indicators to determine.

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

Whether the compound is effective in treating flavivirus infection can be determined by measuring viral load or by measuring parameters associated with flavivirus infection, including but not limited to, liver fibrosis, serum aminotransferase low level High and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.

The methods comprise administering an effective amount of a compound of Formulas I-XIX, optionally in combination with an effective amount of one or more other antiviral agents. In some embodiments, the effective amount of the compound of formulas I-XIX and, optionally, one or more other antiviral agents is in an amount effective to reduce viral titers to undetectable levels, for example, to about 1000 per milliliter of serum to about 5000, about 500 to about 1000, or about 100 to about 500 genome copies. In some embodiments, the effective amount of a compound of Formulas I-XIX and, optionally, one or more other antiviral agents is in an amount effective to reduce the viral load to less than 100 genomic copies per milliliter of serum.

In some embodiments, the effective amount of the compound of Formulas I-XIX and, optionally, one or more other antiviral agents is effective to reduce the viral titer of the individual's serum by 1.5-log, 2-log, 2.5-log log, 3-log, 3.5-log, 4-log, 4.5-log, or 5-log.

In some embodiments, the effective amount of the compound of Formulas I-XIX and, optionally, one or more other antiviral agents is in an amount effective to achieve a sustained viral response, for example, for at least about one month, at least about No HCV RNA (e.g., less than about 500, less than about 400, less than about 200 or less than about 100 genome copies)

Whether the compounds are effective in treating flavivirus infection can be determined by measuring parameters associated with flavivirus infection, such as liver fibrosis, as described above. Methods for determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the levels of serum markers of liver fibrosis are indicative of the degree of liver fibrosis.

As a non-limiting example, serum alanine aminotransferase (ALT) levels are measured using standard assays. In general, ALT levels of less than about 45 international units are considered normal. In some embodiments, the effective amount of a compound of Formulas I-XIX and, optionally, one or more other antiviral agents is an amount effective to reduce ALT levels to less than about 45 IU per milliliter of serum.

A therapeutically effective amount of a compound of formula I-XIX and optionally one or more other antiviral agents is effective in an amount compared to the level of markers of liver fibrosis in an untreated individual or compared to a placebo-treated individual Reduce serum levels of markers of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% %, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more. Methods for measuring serum markers include immunological methods, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and the like, using antibodies specific for a given serum marker.

In many embodiments, the effective amount of the compound of Formula I-XIX and the other antiviral agent is a synergistic amount. As used herein, a "synergistic combination" or "synergistic amount" of a compound of formula I-XIX with another antiviral agent refers to a combined dose of both, when the same dose of compound of formula I-XIX can be used as a monotherapy according to (i) The therapeutic or prophylactic benefit of (ii) the incremental improvement in therapeutic outcome predicted or expected by a mere additive combination of therapeutic or prophylactic benefit at the same dose of other antiviral agents as monotherapy, said Combination doses are more effective for therapeutic or prophylactic treatment of HCV infection.

In some embodiments, a selected amount of a compound of Formulas I-XIX and a selected amount of another antiviral agent are effective against a disease as combination therapy, but the former and/or the latter are not effective against the disease as monotherapy. Accordingly, the embodiments encompass the following: (1) wherein a selected amount of another antiviral agent enhances the therapeutic benefit of a selected amount of a compound of formulas I-XIX when used as a combination therapy for a disease and wherein said selected amount of other antiviral agent A regimen in which a viral agent does not produce a therapeutic benefit to a disease as a monotherapy; (2) wherein a selected amount of a compound of formula I-XIX enhances the therapeutic benefit of a selected amount of another antiviral agent when used as a combination therapy for a disease. A regimen wherein the selected amount of a compound of formula I-XIX does not produce a therapeutic benefit when used as a monotherapy for a disease; and (3) wherein when used as a combination therapy for a disease, a selected amount of a compound of formula I-XIX and a selected amount of other A regimen in which the antiviral agents provide a therapeutic benefit while each does not produce a therapeutic benefit when used as a monotherapy for a disease. As used herein, a "synergistically effective amount" of a compound of Formulas I-XIX and other antiviral agent and its grammatical equivalents are understood to include any regimen encompassed by any of (1)-(3) above.

Treat hepatitis virus infection

The methods and compositions described herein are generally useful for treating HCV infection.

Whether the method is effective in treating HCV infection can be measured by a reduction in viral load, a reduction in the time to seroconversion (undetectable virus in the patient's serum), an increase in the rate of sustained viral response to treatment, a reduction in morbidity or mortality in clinical outcomes, or Other disease response indicators to determine. In general, an effective amount of a compound of Formulas I-XIX and, optionally, one or more other antiviral agents is that amount effective to reduce viral load or achieve a sustained viral response to treatment.

Whether the method is effective in treating HCV infection can be determined by measuring viral load or by measuring parameters associated with HCV infection, including but not limited to, liver fibrosis, elevated serum aminotransferase levels, and liver Necroinflammatory activity. Indicators of liver fibrosis are discussed in detail below.

The methods include administering an effective amount of a compound of Formulas I-XIX, optionally in combination with an effective amount of one or more other antiviral agents. In some embodiments, the effective amount of the compound of formulas I-XIX and, optionally, one or more other antiviral agents is in an amount effective to reduce viral titers to undetectable levels, for example, to about 1000 per milliliter of serum to about 5000, about 500 to about 1000, or about 100 to about 500 genome copies. In some embodiments, the effective amount of a compound of Formulas I-XIX and, optionally, one or more other antiviral agents is in an amount effective to reduce the viral load to less than 100 genome copies per milliliter of serum.

In some embodiments, the effective amount of the compound of Formulas I-XIX and, optionally, one or more other antiviral agents is effective to reduce the viral titer of the individual's serum by 1.5-log, 2-log, 2.5-log log, 3-log, 3.5-log, 4-log, 4.5-log, or 5-log.

In some embodiments, the effective amount of the compound of Formulas I-XIX and, optionally, one or more other antiviral agents is in an amount effective to achieve a sustained viral response, for example, for at least about one month, at least about No HCV RNA (e.g., less than about 500, less than about 400, less than about 200 or less than about 100 genome copies)

As noted above, whether the methods are effective in treating HCV infection can be determined by measuring parameters associated with HCV infection, such as liver fibrosis. Methods for determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the levels of serum markers of liver fibrosis are indicative of the degree of liver fibrosis.

As a non-limiting example, serum alanine aminotransferase (ALT) levels are measured using standard assays. In general, ALT levels of less than about 45 standard units are considered normal. In some embodiments, the effective amount of a compound of Formulas I-XIX and, optionally, one or more other antiviral agents is an amount effective to reduce ALT levels to less than about 45 IU per milliliter of serum.

A therapeutically effective amount of a compound of formula I-XIX and optionally one or more other antiviral agents is effective in an amount compared to the level of markers of liver fibrosis in an untreated individual or compared to a placebo-treated individual Reduce serum levels of markers of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% %, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more. Methods of measuring serum markers include immunological methods, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and the like, using antibodies specific for a given serum marker.

In many embodiments, the effective amount of the compound of Formula I-XIX and the other antiviral agent is a synergistic amount. As used herein, a "synergistic combination" or "synergistic amount" of a compound of formula I-XIX with another antiviral agent refers to a combined dose of both, when the same dose of compound of formula I-XIX can be used as a monotherapy according to (i) The therapeutic or prophylactic benefit of (ii) the incremental improvement in therapeutic outcome predicted or expected by a mere additive combination of therapeutic or prophylactic benefit at the same dose of other antiviral agents as monotherapy, said Combination doses are more effective for therapeutic or prophylactic treatment of HCV infection.

In some embodiments, a selected amount of a compound of Formulas I-XIX and a selected amount of another antiviral agent are effective against a disease as combination therapy, but the former and/or the latter are not effective against the disease as monotherapy. Accordingly, the embodiments encompass the following: (1) wherein a selected amount of another antiviral agent enhances the therapeutic benefit of a selected amount of a compound of formulas I-XIX when used as a combination therapy for a disease and wherein said selected amount of other antiviral agent A regimen in which a viral agent does not produce a therapeutic benefit to a disease as a monotherapy; (2) wherein a selected amount of a compound of formula I-XIX enhances the therapeutic benefit of a selected amount of another antiviral agent when used as a combination therapy for a disease. A regimen wherein the selected amount of a compound of formula I-XIX does not produce a therapeutic benefit when used as a monotherapy for a disease; and (3) wherein when used as a combination therapy for a disease, a selected amount of a compound of formula I-XIX and a selected amount of other A regimen in which the antiviral agents provide a therapeutic benefit while each does not produce a therapeutic benefit when used as a monotherapy for a disease. As used herein, a "synergistically effective amount" of a compound of Formulas I-XIX and other antiviral agent and its grammatical equivalents are understood to include any regimen encompassed by any of (1)-(3) above.

treatment of fibrosis

The embodiments provide methods for treating liver fibrosis (including forms of liver fibrosis caused by or associated with HCV infection), generally comprising administering a therapeutic amount of a compound of formulas I-XIX and optionally one or more other antiviral agent. Effective amounts of compounds of Formulas I-XIX, with or without one or more other antiviral agents, and dosing regimens are discussed below.

Whether a compound of formulas I-XIX and, optionally, one or more other antiviral agents are effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Reduction of liver fibrosis was determined by analysis of liver biopsy samples. Liver biopsy analysis includes assessment of two major components: necroinflammation, rated as a "grade" that measures severity and ongoing disease activity; and fibrosis and parenchymal or revascularized damage, rated to reflect long-term disease A "stage" of progression. See, eg, Brunt (2000) Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based on liver biopsy analysis, a score is assigned. A number of standardized scoring systems provide quantitative assessments of the degree and severity of fibrosis. These systems include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

The METAVIR scoring system is based on the analysis of various features of liver biopsy, including fibrosis (portal fibrosis, centrilobular vein fibrosis, and sclerosis); necrosis (fragmented and lobular necrosis, eosinophilic contraction, and ballooning); inflammation ( Portal duct inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (score of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and total disease activity). The stages in the METAVIR system are defined as follows: Score: 0, indicating no fibrosis; Score: 1, indicating star-shaped enlargement of the portal tract without septal wall formation; Score: 2, indicating enlargement of the portal tract with minimal septal wall formed; score: 3, indicating many septal walls without induration; and score: 4, indicating induration.

The Knodell scoring system, also known as the Hepatitis Activity Index, classifies samples based on the scores of four histological features: I. Periportal necrosis and/or bridging necrosis; II. Intralobular change and local necrosis; III. Portal vein inflammation; and IV. Fibrosis. In the Knodell grading system, scoring is performed as follows: score: 0, indicating no fibrosis; score: 1, indicating mild fibrosis (fibrous portal vein dilatation); score: 2, indicating moderate fibrosis; score: 3, indicating severe fibrosis (bridging fibrosis); and a score of 4, indicating sclerosis. The higher the score, the more serious the liver tissue damage. Knodell (1981) Hepatol. 1:431.

In the Scheuer scoring system, the score is as follows: score: 0, indicating no fibrosis; score: 1, indicating enlarged, fibrous portal tract; score: 2, indicating periportal and interportal septal wall, but the structure is intact; score: 3, indicating fibrosis with structural deformation, but no obvious hardening; score: 4, indicating possible or definite hardening. Scheuer (1991) J. Hepatol. 13:372.

The Ishak scoring system is described in Ishak (1995) J. Hepatol. 22:696-699. Stage 1, fibrous dilation of some portal areas, with or without a short fibrous septal wall; stage 2, fibrous dilation of most of the portal area, with or without a short fibrous septal wall; stage 3, fibrous expansion of most of the portal area stage 4, fibrous dilatation of the portal region with prominent portal-to-centrilobular bridging (P-P) and portal-centrilobular bridging (P-C); stage 5, marked bridging (P-P and/or P-C), occasional nodules (incomplete sclerosis); stage 6, possible or definite sclerosis.

The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system, which includes abnormalities based on abnormal serum bilirubin levels, abnormal serum albumin levels, abnormal prothrombin time, presence of ascites, and severe A multicomponent point system for gender and the presence and severity of encephalopathy. Based on the presence and severity of abnormalities in these parameters, patients can be in any of three clinical illnesses of increasing severity: A, B, or C.

In some embodiments, the therapeutically effective amount of a compound of Formulas I-XIX and, optionally, one or more other antiviral agents is an amount effective to alter the stage of fibrosis by one or more of the following pre- and post-treatment liver biopsies. units. In specific embodiments, a therapeutically effective amount of a compound of Formulas I-XIX and optionally one or more other antiviral agents reduces liver fibrosis by at least one unit in the METAVIR, Knodell, Scheuer, Ludwig, or Ishak scoring system.

Secondary or indirect indices of liver function can also be used to assess the therapeutic efficacy of compounds of formulas I-XIX.

Morphological computerized semi-automated assessment of the quantitative extent of liver fibrosis based on collagen-specific staining and/or staining for serum markers of liver fibrosis can also be measured as an indication of the efficacy of the treatment method. Secondary indices of liver function include, but are not limited to, serum aminotransferase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and Child-Pugh score assessment results.

An effective amount of the compound of formula I-XIX and optionally one or more other antiviral agents in an amount effective to reduce the index of liver function compared to the index of liver function in an untreated individual or compared to a placebo-treated individual at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, At least about 65%, at least about 70%, at least about 75%, or at least about 80% or more. These indices of liver function can be readily measured by those skilled in the art using standard assays, some of which are commercially available and routinely used in clinical settings.

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

A therapeutically effective amount of a compound of formula I-XIX and, optionally, one or more other antiviral agents is effective in an amount compared to serum levels of markers of liver fibrosis in an untreated individual or compared to a placebo-treated individual. reducing serum levels of liver fibrosis markers by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least About 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more. These serum markers of liver fibrosis can be readily measured by those skilled in the art using standard assays, some of which are commercially available and routinely used in clinical settings. Methods of measuring serum markers include immunological methods, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and the like, using antibodies specific for a given serum marker.

Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with interferon receptor agonists and pirfenidone (or pirfenidone analogs). The tests include: Indocyanine Green Clearance (ICG), Galactose Clearance Capacity (GEC), Aminopyrine Breath Test (ABT), Antipyrine Clearance, Monoethylglycylxylidine ( MEG-X) clearance and caffeine clearance.

As used herein, "complications associated with cirrhosis" refers to the subsequent onset of decompensated liver disease, i.e., a condition that occurs after and as a consequence of the development of liver fibrosis, including but not limited to , ascites, variceal bleeding, portal hypertension, jaundice, progressive hepatic insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

A therapeutically effective amount of a compound of formula I-XIX and, optionally, one or more other antiviral agents is an amount effective to reduce the severity of a condition associated with cirrhosis, compared to an untreated individual or compared to a placebo-treated individual. Incidence (e.g., the likelihood that an individual will develop) is reduced by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least About 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more.

Whether a compound of formulas I-XIX and, optionally, one or more other antiviral agents are effective in reducing the incidence of conditions associated with cirrhosis can be readily determined by one of ordinary skill in the art.

Reduced liver fibrosis enhanced liver function. Accordingly, the embodiments provide methods for enhancing liver function, generally comprising administering a therapeutically effective amount of a compound of Formulas I-XIX and, optionally, one or more other antiviral agents. Liver functions include, but are not limited to, protein synthesis, such as serum proteins (eg, albumin, coagulation factors, alkaline phosphatase, aminotransferases (eg, alanine aminotransferase, aspartate aminotransferase) , 5'-nucleosidase, γ-glutamyl transpeptidase, etc.), bilirubin synthesis, cholesterol synthesis, and bile acid synthesis; liver metabolic functions, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; hemodynamic functions, including visceral and portal hemodynamics; and similar functions.

Whether liver function is enhanced can be readily determined by one skilled in the art using recognized liver function tests. Accordingly, the synthesis of markers of liver function can be assessed by measuring the levels of markers in serum, for example, albumin, alkaline phosphatase, alanine aminotransferase, day Partate aminotransferase, bilirubin and similar substances. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic function can be determined by measuring serum ammonia levels.

Typically, serum proteins secreted by the liver are within the normal range and can be determined by measuring the levels of the proteins using standard immunological and enzymatic assays. Normal ranges for these serum proteins are known to those skilled in the art. The following are non-limiting examples. Normal levels of alanine aminotransferase are about 45 IU per milliliter of serum. The normal range for aspartate aminotransferase is about 5 to about 40 units per milliliter of serum. Bilirubin is measured using standard analytical methods. Normal bilirubin levels are usually less than about 1.2 mg/dL. Normal levels of serum albumin range from about 35 g/L to about 55 g/L. Serum albumin levels were measured using standard assays. Prolongation of prothrombin time is measured using standard assays. The normal prothrombin time is about 4 seconds longer than the control time.

A therapeutically effective amount of a compound of formulas I-XIX and optionally one or more other antiviral agents is effective to enhance liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, At least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, a therapeutically effective amount of a compound of Formulas I-XIX and, optionally, one or more other antiviral agents is effective to reduce high levels of serum markers of liver function by at least about 10%, at least about 20%, at least About 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or more, or reduce the level of serum markers of liver function to within the normal range. A therapeutically effective amount of a compound of formulas I-XIX and optionally one or more other antiviral agents is also effective in increasing low-level serum markers of liver function by at least about 10%, at least about 20%, at least about 30% , at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or more, or increase the level of serum markers of liver function to within the normal range.

Type I interferon receptor agonists

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 other type I interferon receptor agonists , including non-peptide agonists. alpha-interferon

Any known IFN-α can be used in the examples. The term "alpha-interferon" as used herein refers to a family of related polypeptides that inhibit viral replication and cell proliferation and regulate immune responses. The term "IFN-α" includes naturally occurring IFN-α; synthetic IFN-α; derived IFN-α (e.g., pegylated IFN-α, glycosylated IFN-α, and the like); and naturally occurring or synthetic IFN -analogues of alpha; essentially any IFN-alpha having antiviral properties, as described for naturally occurring IFN-alpha.

Suitable α-interferons include, but are not limited to: naturally occurring IFN-α (including but not limited to naturally occurring IFN-α2a, IFN-α2b); recombinant interferon α-2b, such as Intron-A interferon (Schering Corporation, Kenilworth, N.J.); Recombinant interferon α-2a, such as Roferon interferon (Hoffinann-La Roche, Nutley, N.J.); Recombinant interferon α-2c, such as Berofor α-2 interferon (Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.); interferon alpha-n1, a purified blend of native alpha-interferon, such as Sumiferon (Sumitomo, Japan) or Wellferon interferon alpha-n1 (INS) (available from the Glaxo-Wellcome Ltd. , London, Great Britain); and interferon alpha-n3, a mixture of natural alpha-interferon (manufactured by Interferon Sciences and available from Purdue Frederick Co. (Norwalk, Conn.) under the trade name Alferon).

The term "IFN-alpha" also includes complex IFN-alpha. Conjugate IFN-alpha (also known as "CIFN", "IFN-con" and "composite interferon") includes, but is not limited to, those named IFN-con1, IFN-con2 disclosed in U.S. Patent Nos. 4,695,623 and 4,897,471 and the amino acid sequence of IFN-con3; and a consensus interferon defined by determining the consensus sequence of naturally occurring alpha-interferon (eg, Infergen®, InterMine, Inc., Brisbane, Calif.). IFN-con1 is the complex interferon reagent in the Infergen_alfacon-1 product. The Infergen® consensus interferon product is referred to in the text by its trade name (Infergen®) or its generic name (Interferon alfacon-1). The DNA sequence encoding IFN-con can be synthesized as described in the aforementioned patents or by other standard methods. The use of CIFN is of particular interest.

Also suitable for use in embodiments are fusion polypeptides comprising IFN-[alpha] and a heterologous polypeptide. Suitable IFN-alpha fusion polypeptides include, but are not limited to, Albuferon-alpha ^™ (a fusion product of human albumin and IFN-alpha; Human GenomeSciences; see, e.g., Osborn et al. (2002) J. Pharmacol. Exp. Therap. 303:540-548). Also suitable for use in the examples is the shuffled gene form of IFN-[alpha]. See, eg, Masci et al. (2003) Curr. Oncol. Rep. 5:108-113.

pegylated interferon-alpha

The term "IFN-alpha" also includes derivatives of IFN-alpha that have been derivatized (eg, chemically modified) to alter certain properties, such as serum half-life. Thus, the term "IFN-alpha" includes glycosylated IFN-alpha, IFN-alpha derivatized with polyethylene glycol ("pegylated IFN-alpha") and the like. Pegylated IFN-[alpha] and methods for their preparation are discussed, for example, in US Patent Nos. 5,382,657, 5,981,709 and 5,951,974. Pegylated IFN-α includes conjugates of polyethylene glycol (PEG) with any of the above-mentioned IFN-α molecules, including, but not limited to, PEG conjugated to interferon α-2a (Roferon, Hoffman La- Roche, Nutley, N.J.), interferon alpha-2b (Intron, Schering-Plough, Madison, N.J.), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany) and by determining the Consensus interferons defined by consensus sequences (Infergen®, InterMune, Inc., Brisbane, Calif.).

Any of the above-mentioned IFN-alpha polypeptides may be modified, ie pegylated, with one or more polyethylene glycol moieties. The PEG molecule of the 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 contains a PEG moiety at only one amino acid. In other embodiments, PEGylated IFN-α contains a PEG moiety at two or more amino acids, for example, IFN-α contains two, three, four, five, six, seven PEG moieties at four, eight, nine or ten different amino acid residues.

IFN-[alpha] can be directly coupled to PEG (ie, without a linking group) via amino, sulfhydryl, hydroxyl, or carboxyl groups.

In some embodiments, the PEGylated IFN-α is pegylated at or near the amino terminus (N-terminus) of the IFN-α polypeptide, e.g., the PEG moiety is linked to amino acids 1 to 4 of the IFN-α polypeptide or One or more amino acid residues from amino acid 5 to about amino acid 10.

In other embodiments, the pegylated IFN-α is pegylated at one or more amino acid residues between about 10 and about 28.

In other embodiments, the PEGylated IFN-α is PEGylated at or near the carboxy-terminus (C-terminus) of the IFN-α polypeptide, i.e., at one or multiple amino acid residues.

In other embodiments, the pegylated IFN-α is pegylated at one or more amino acid residues between amino acids 100-114.

The polyethylene glycol derivatization of amino acid residues at the receptor binding domain and/or the active site domain of the IFN-α protein may interfere with the functioning of these domains. In certain embodiments, amino acids to be avoided from pegylation include amino acid residues between amino acid 30 to amino acid 40 and amino acid 113 to amino acid 149.

In some embodiments, PEG is linked to IFN-α via a linker. The linking group is any biocompatible linking group, where "biocompatible" means that the compound or group is non-toxic and can be used in vitro or in vivo without causing injury, nausea, disease or die. PEG can be attached to the linking group via, for example, an ether bond, ester bond, thiol bond, or amide bond. Suitable biocompatible linking groups include, but are not limited to: ester, amide, imide, carbamate, carboxyl, hydroxyl, carbohydrate, succinimide (including, for example, succinimide Succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (succinimidyl carboxymethylate, SCM), succinimidylsuccinamide (succinimidylsuccinamide, SSA) or N-hydroxysuccinimide (N-hydroxy succinimide, NHS)), epoxy group, oxycarbonylimidazole group (including, for example, carbonylimidazole ( carbonyldimidazole (CDI)), nitrophenyl (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC)), trysylate , aldehyde group, isocyanate group, vinyl sulfone group, tyrosine group, cysteine group, histidine group or primary amine.

Methods for preparing PEG activated with succinimidyl propionate (SPA) and succinimidyl butyrate (SBA) are described in U.S. Patent No. 5,672,662 (Harris et al.) and WO 97/03106 .

Methods for linking PEG to IFN-α polypeptides are known in the art, and any known method can be used. See, e.g., Park et al., Antimaycer Res., 1:373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry, Biotechnical and Biomedical Applications, J.M. Harris eds., Plenum Press, NY, Chapter 21 (1992); U.S. Patent No. 5,985,265; U.S. Patent No. 5,672,662 (Harris et al.); and WO 97/03106.

Pegylated IFN-[alpha] and methods for their preparation are discussed, for example, in US Patent Nos. 5,382,657, 5,981,709, 5,985,265, and 5,951,974. Pegylated IFN-α includes conjugates of polyethylene glycol (PEG) with any of the above-mentioned IFN-α molecules, including, but not limited to, PEG conjugated to interferon α-2a (Roferon, Hoffman La- Roche, Nutley, N.J.), where PEGylated Roferon is called Pegasys (Hoffman La-Roche); Interferon alpha-2b (Intron, Schering-Plough, Madison, N.J.), where PEGylated Intron is called PEG- Intron (Schering-Plough); interferon alpha-2c (Berofor Alpha, BoehringerIngelheim, Ingelheim, Germany); and composite interferon defined by determining the consensus sequence of naturally occurring alpha-interferon (Infergen_, InterMune, Inc., Brisbane , Calif.), wherein PEGylated Infergen is called PEG-Infergen.

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

In one non-limiting example, PEG is attached to IFN-α via a SPA linker. SPA esters of PEG and methods for their preparation are described in US Patent No. 5,672,662. A SPA linkage is provided for bonding to a free amine group on the IFN-α polypeptide.

For example, the PEG molecule is covalently linked via a linkage comprising an amide bond between the propionyl group of the PEG moiety and the ε-amino group of a surface exposed lysine residue in the IFN-α polypeptide. The linkage may, for example, be formed by condensation of the alpha-methoxy, omega-propionic acid activated ester of PEG (mPEGspa).

As a non-limiting example, a preferred monoPEGylated CIFN conjugate for use herein is a linear PEG moiety of about 30 kD linked to a CIFN polypeptide via a covalent bond, wherein the covalent bond is of the PEG moiety. An amide bond between a propionyl group and the ε-amino group of a surface-exposed lysine residue in a CIFN polypeptide, wherein the surface-exposed lysine residue is selected from the group consisting of lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ^{135 and} lys ¹⁶⁵ , and the amide bond is formed by the condensation of α-methoxy and ω-propionic acid activated esters of PEG.

polyethylene glycol

Polyethylene glycol suitable for conjugation with IFN-α polypeptide is soluble in water at room temperature and has the general formula R(O-CH ₂ -CH ₂ ) _n OR, wherein R is hydrogen or such as an alkyl or alkanol group, etc. a protecting group, and wherein n is an integer between 1 and 1000. When R is a protecting group, it typically has 1 to 8 carbons.

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

In other embodiments, PEG is derivatized such that it is reactive with free carboxyl groups in the IFN-α polypeptide, eg, the free carboxyl group at the carboxy terminus of the IFN-α polypeptide. Suitable PEG derivatives that can react with the free carboxyl group at the carboxyl terminus of IFN-[alpha] include, but are not limited to, PEG-amine and hydrazine derivatives of PEG (eg, PEG-NH- _NH2 ).

In other embodiments, PEG is derivatized such that it contains a terminal thiocarboxylic acid group -COSH, which selectively reacts with amino groups to produce amide derivatives. Selectivity of certain amino groups over others is achieved due to the reactivity of the thioacids. For example, -SH exhibits sufficient leaving group capacity in a reaction with an N-terminal amino group under appropriate pH conditions such that the ε-amino group in a lysine residue is protonated and remains non-nucleophilic. On the other hand, reaction at appropriate pH conditions enables selective reaction of some accessible lysine residues.

In other embodiments, the PEG comprises a reactive ester such as N-hydroxysuccinimide ester at the end of the PEG chain. This N-hydroxysuccinimide ester-containing PEG molecule selectively reacts with amino groups under specific pH conditions (eg, neutral 6.5-7.5). For example, the N-terminal amino group can be selectively modified under neutral pH conditions. However, if the reagent is extremely reactive, the accessible _NH2 group of lysine may also react.

PEG can be linked to the IFN-α polypeptide directly or via a linking group. In some embodiments, a linker group is added to an IFN-alpha polypeptide to form a linker-modified IFN-alpha polypeptide. The linking group provides various functional groups, such as reactive groups such as sulfhydryl, amino, or carboxyl, so as to couple the PEG reagent to the IFN-α polypeptide modified by the linking group.

In some embodiments, the PEG linked to the IFN-α polypeptide is linear. In other embodiments, the PEG linked to the IFN-α polypeptide is branched. Branched PEG derivatives are described in US Patent No. 5,643,575, "Star PEG Derivatives" and highly branched PEG derivatives are described in Shearwater Polymers, Inc. catalog "Polyethylene Glycol Derivatives 1997-1998." Star PEGs are described in the art, including, for example, in US Patent No. 6,046,305.

Typically used are PEGs with molecular weights between about 2 kDa and about 100 kDa, where the term "about" in reference to PEG indicates that in preparations of polyethylene glycol some molecules will be heavier than the stated molecular weight and some Could be lighter. For example, PEG suitable for binding to IFN-alpha 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 In the range of 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 described above, the PEG moiety is linked directly or via a linking group to an amino acid residue at or near the N-terminus, internally or at or near the C-terminus of the IFN-α polypeptide. Conjugation can be performed in solution or in solid phase.

N-terminal bonding

Methods for linking 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, eg, US Patent No. 5,985,265.

In some embodiments, known methods for selectively obtaining N-terminal chemically modified IFN-α are used. For example, a method of protein modification by reductive alkylation can be used that takes advantage of the differences in the different types of primary amine groups (lysine versus N-terminal) that can be derivatized in a given protein. reactivity. Under appropriate reaction conditions, substantially selective derivatization of the N-terminus of proteins is achieved with carboxyl-containing polymers. The reaction is carried out at a pH to take advantage of _the difference in pK a between the ε-amino group of a lysine residue and the α-amino group of the N-terminal residue of the protein. The attachment of the PEG moiety to IFN-α is controlled by this selective derivatization: the attachment to the polymer mainly occurs at the N-terminus of IFN-α, and no other reactive groups such as lysine side chain amino groups occur. Significantly retouched.

C-terminal bonding

The N-terminal specific coupling step as described in US Patent No. 5,985,265 provides primarily mono-PEGylated products. However, purification steps aimed at removing excess reagents and small amounts of polyPEGylated products will remove N-terminal blocking polypeptides. As far as the treatment is concerned, the procedure can lead to a huge increase in production costs. For example, examination of the structure of the well-characterized Infergen_Alfacon-1 CIFN polypeptide amino acid sequence revealed that approximately 5% was truncated at the carboxy terminus, so that there was only one major C-terminal sequence. Thus, in some embodiments, instead of using N-terminally pegylated IFN-α, the IFN-α polypeptide is C-terminally pegylated.

Efficient synthetic and therapeutic routes to obtain monoPEGylated Infergen products are thus envisaged as follows.

PEG reagents can be prepared that are selective for the C-terminus with or without a spacer group. For example, polyethylene glycol modified at one end with a methyl ester and with an amino function at the other end can be used as a starting material.

Water-soluble carbodiimides can be prepared or obtained as condensation agents. Coupling of IFN-α (e.g., Infergen_Alfacon-1 CIFN or consensus interferon) with a water-soluble carbodiimide as a condensing agent is usually performed in an aqueous medium containing a suitable buffer system at an optimal pH to complete Amide bonding. High molecular weight PEGs can be covalently added to proteins to increase molecular weight.

The choice of reagents depends on the process optimization study. A non-limiting example of a suitable reagent is EDAC or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The water solubility of EDAC enables direct addition to the reaction without prior dissolution with an organic solvent. Excess reagents and isourea, a by-product of the crosslinking reaction, are both water soluble and can be easily removed by dialysis or gel filtration. A concentrated aqueous solution of EDAC was prepared in order to add a small molar amount to the reaction. Stock solutions were prepared and used immediately due to the water instability of the reagents. Most synthetic schemes in the literature indicate that the optimal reaction medium is in the pH range between 4.7 and 6.0. However, the condensation reaction was only up to pH 7.5 without significant loss of yield. Water can be used as a solvent. In view of the intended use of Infergen, the medium is preferably a 2-(N-morpholino)ethanesulfonic acid buffer pre-titrated to a pH value between 4.7 and 6.0. However, 0.1 M phosphate at pH 7-7.5 can also be used since the product is buffered with the same. The ratio of PEG amine to IFN-[alpha] molecule is optimized such that the C-terminal carboxyl residue is selectively pegylated to yield monopegylated derivatives.

Although the PEG amines used have been mentioned by name or structure, the derivatives are exemplary only. Other groups that can also undergo condensation reaction with the carboxyl group of IFN-α protein can also be used, such as hydrazine derivative PEG-NH-NH ₂ . In addition to the aqueous phase, the reaction can also be carried out on a solid phase. Polyethylene glycol can be selected from the list of compounds with a molecular weight between 300-40000. The choice of various polyethylene glycols will also be governed by the conjugation efficiency and biological properties (ie, circulation time, antiviral activity, etc.) of the pure derivatives in vitro and in vivo.

Additionally, a suitable spacer group can be added to the C-terminus of the protein. The spacer group can have a reactive group such as SH, _NH2 or COOH to allow coupling with a suitable PEG reagent to provide high molecular weight IFN-α derivatives. A combined solid-phase/liquid-phase methodology can be designed for the preparation of C-terminal pegylated interferons. For example, the C-terminus of IFN-α was extended on solid phase using a Gly-GIy-Cys- _NH2 spacer, and then monoclonal in solution using an activated dithiopyridyl-PEG reagent of appropriate molecular weight. Pegylation. Since the coupling at the C-terminus is independent of the blocking at the N-terminus, the envisaged method and product are cost-effective (one-third of the protein is not wasted like in the N-terminal PEGylation method) And contribute to the economics of therapy for the treatment of viral infections.

There may be more reactive carboxyl groups of amino acid residues elsewhere in the IFN-α molecule to react with PEG reagents resulting in mono-PEGylation at this site or resulting in removal of the C-terminus of IFN-α- Polyglycolation outside the COOH group. These reactions are expected to be only minimal due to the steric freedom of the C-terminus of the IFN-α molecule and the steric hindrance imposed by the carbodiimide and PEG reagents (eg in branched chain molecules). Therefore, this is the preferred mode of PEGylation of Infergen and similar proteins native or expressed in host systems, which may have varying degrees of blocked N-termini to increase efficiency and maintain higher in vivo biological activity.

Another method of achieving C-terminal PEGylation is described below. Selectivity of C-terminal PEGylation was achieved with a steric hindering agent that precludes reactions at carboxyl residues embedded within the helix or internal to IFN-[alpha]. For example, one such reagent can be branched chain PEG with a molecular weight of about 40 kd, and this reagent can be synthesized as follows:

Condensation of _OH3C- ( _CH2CH2O )n _{- CH2CH2NH2} and _glutamic acid ₍ ie, HOCO- _CH2 CH ₂ CH(NH ₂ )-COOH), thus providing the branched chain PEG reagent 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 NHCOCH ₂ .

This reagent can be used in excess to couple the amino group to the free and flexible carboxyl group of IFN-[alpha] to form a peptide bond.

If desired, PEGylated IFN-α is separated from non-PEGylated IFN-α using any known method including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. For example, when the PEG-IFN-α conjugate is mono-PEGylated IFN-α, the product is first isolated by ion-exchange chromatography to obtain a species with the charging characteristics of the mono-PEGylated species (possibly present with the same apparent Charged other polyPEGylated species), followed by isolation of monoPEGylated species by size exclusion chromatography.

Mono-PEGylated (30kD, linear) IFN-α

PEGylated IFN-α suitable for use in the embodiments include monopegylated consensus interferon (CIFN) molecules comprising a single CIFN polypeptide and a single polyethylene glycol (PEG) moiety, wherein the PEG moiety is linear, The molecular weight is about 30kD, and it is directly or indirectly connected to the N-terminal residue of the CIFN polypeptide or the lysine residue of the CIFN polypeptide through a stable covalent bond. In some embodiments, the monoPEGylated (30kD, linear) IFN-α is monoPEGylated (30kD, linear) complex IFN-α.

In some embodiments, the PEG moiety is linked to the α-amino group of the N-terminal residue of the CIFN polypeptide or the ε-amino group of a lysine residue of the CIFN polypeptide. In other embodiments, the linkage comprises an amide bond between the PEG molecule and the α-amino group of the N-terminal residue or the ε-amino group of a lysine residue in the CIFN molecule. While in other embodiments, the linkage comprises an amide bond between the propionyl group of the PEG moiety and the [alpha]-amino group of the N-terminal residue or the [epsilon]-amino group of a lysine residue in the CIFN molecule. In other embodiments, the amide bond is through the α-methoxy, ω-propionic acid activated ester of the PEG moiety and the α-amino group of the N-terminal residue in the CIFN polypeptide or the ε-amino group of the lysine residue. It is formed by condensation, thereby forming a hydrolytically stable linkage between the PEG moiety and the CIFN polypeptide.

In some embodiments, the PEG moiety is linked to the N-terminal residue of the CIFN polypeptide. In other embodiments, the PEG moiety is attached to the α-amino group of the N-terminal residue in the CIFN polypeptide. In other embodiments, the linkage comprises an amide bond between the PEG moiety and the α-amino group of the N-terminal residue in the CIFN polypeptide. While in other embodiments, the linkage comprises an amide bond between the propionyl group of the PEG moiety and the α-amino group of the N-terminal residue in the CIFN polypeptide. In other embodiments, the amide bond is formed by condensation of the α-methoxy, ω-propionate activated ester of the PEG moiety with the α-amino group of the N-terminal residue of the CIFN polypeptide.

In some embodiments, the PEG moiety is linked to a lysine residue of the CIFN polypeptide. In other embodiments, the PEG moiety is attached to the epsilon-amino group of a lysine residue in the CIFN polypeptide. In other embodiments, the linkage comprises an amide bond between the PEG moiety and the ε-amino group of a lysine residue in the CIFN polypeptide. While in other embodiments, the linkage comprises an amide bond between the propionyl group of the PEG moiety and the epsilon-amino group of a lysine residue in the CIFN polypeptide. In other embodiments, the amide bond is formed by condensation of the α-methoxy, ω-propionate activated ester of the PEG moiety with the ε-amino group of a lysine residue in the CIFN polypeptide.

In some embodiments, the PEG moiety is attached to a surface exposed lysine residue of the CIFN polypeptide. In other embodiments, the PEG moiety is attached to the ε-amino group of a surface exposed lysine residue in the CIFN polypeptide. In other embodiments, the linkage comprises an amide bond between the PEG moiety and the ε-amino group of a surface exposed lysine residue in the CIFN polypeptide. While in other embodiments, the linkage comprises an amide bond between the propionyl group of the PEG moiety and the ε-amino group of a surface exposed lysine residue in the CIFN polypeptide. In other embodiments, the amide bond is formed by condensation of the α-methoxy, ω-propionic acid activated ester of the PEG moiety with the ε-amino group of a surface exposed lysine residue in the CIFN polypeptide.

In some embodiments, the PEG moiety is linked to a lysine selected from lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ of a CIFN polypeptide. In other embodiments, the PEG moiety is linked to the ε-amino group of a lysine selected from ^lys31 , ^lys50 , ^lys71 , ^lys84 , ^lys121 , ^lys122 , ^lys134 , ^lys135 , and ^lys165 of a CIFN polypeptide. In other embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of a selected lysine residue in the CIFN polypeptide. In yet other embodiments, the linkage comprises an amide bond between the propionyl group of the PEG moiety and the ε-amino group of a selected lysine residue in the CIFN polypeptide. In other embodiments, the amide bond is formed by condensation of the α-methoxy, ω-propionate activated ester of the PEG moiety with the ε-amino group of selected lysine residues in the CIFN polypeptide.

In some embodiments, the PEG moiety is linked to a lysine selected from lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ of a CIFN polypeptide. In other embodiments, the PEG moiety is linked to the ε-amino group of a lysine selected from lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ of the CIFN polypeptide. In other embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of a selected lysine residue in the CIFN polypeptide. In yet other embodiments, the linkage comprises an amide bond between the propionyl group of the PEG moiety and the ε-amino group of a selected lysine residue in the CIFN polypeptide. In other embodiments, the amide bond is formed by condensation of the α-methoxy, ω-propionate activated ester of the PEG moiety with the ε-amino group of selected lysine residues in the CIFN polypeptide.

In connection with the mono-PEGylated CIFN molecules described above, the present invention contemplates various embodiments of such molecules wherein the CIFN polypeptide is selected from interferon alpha-con1, interferon alpha-con2 and interferon alpha-con3, the CIFN The amino acid sequence of the polypeptide is disclosed in US Patent No. 4,695,623.

IFN-α groups

In addition, any of the methods of the embodiments may employ a pegylated IFN-α composition comprising a population of mono-PEGylated IFNα molecules, wherein the population is composed of one or more monomeric molecules as described above. Molecular composition of glycolated IFNα. The subject compositions comprise a population of modified IFN-alpha polypeptides, wherein each polypeptide has a single PEG molecule attached to a single amino acid residue of the polypeptide.

In some of such embodiments, the population comprises a mixture of a first IFN-alpha polypeptide and at least one second IFN-alpha polypeptide, the first polypeptide being linked to a PEG molecule at a first amino acid residue , and the at least one second polypeptide is linked to the PEG molecule at a second amino acid residue, wherein the first and second IFN-α polypeptides are the same or different, and wherein the first amino acid residue is at the first IFN-α polypeptide The position in the amino acid sequence of is different from the position of the second amino acid residue in the second IFN-alpha polypeptide. As a non-limiting example, a subject composition comprises a population of PEG-modified IFN-α polypeptides comprising an IFN-α polypeptide linked at the amino terminus to a linear PEG molecule and a linear PEG molecule linked at a lysine residue. IFN-α polypeptide of PEG molecule.

Typically, a given modified IFN-α species comprises from about 0.5% to about 99.5% of the total population of mono-PEGylated IFN-α polypeptide molecules, e.g., a given modified IFN-α species comprises mono-PEGylated IFN-α species about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, of the total population of alcoholated IFN-alpha polypeptide molecules About 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% %, about 95%, about 99%, or about 99.5%. In some embodiments, a subject composition comprises a population of monoPEGylated IFN-α polypeptides comprising at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% % IFN-α polypeptide linked at the same position (eg at the N-terminal amino acid).

In embodiments of particular interest, the composition comprises a population of mono-PEGylated CIFN molecules, said population consisting of one or more molecules, wherein each molecule is characterized by: a single CIFN polypeptide directly or with The covalent linkage is indirectly to a single linear PEG moiety having a molecular weight of about 30 kD, and wherein the linkage is to a lysine residue of a CIFN polypeptide or an N-terminal amino acid residue of a CIFN polypeptide.

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 (either directly or via a linker) to a surface exposed lysine residue. In other embodiments, the PEG moiety is linked (directly or via a linking group) to a CIFN polypeptide selected from lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ , and lys ¹⁶⁵ Lysine residues. In other embodiments, the PEG moiety is linked (directly or via a linking group) to a lysine residue selected from lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ of a CIFN polypeptide.

As an example, the composition comprises a population of mono-PEGylated CIFN molecules consisting of a first mono-PEGylated CIFN polypeptide species molecule and a second mono-PEGylated CIFN polypeptide species molecule, No. One class of molecules is characterized by a PEG moiety attached to the N-terminal amino acid residue of a first CIFN polypeptide, and a second class of molecules is characterized by a PEG moiety attached to a first lysine residue of a second CIFN polypeptide, wherein the first and The second CIFN polypeptide is the same or different. The composition may additionally comprise at least one other monoPEGylated CIFN polypeptide species molecule characterized in that a PEG moiety is attached to a lysine residue within the CIFN polypeptide, wherein in each additional monomeric The position of the binding site in the pegylated CIFN polypeptide species is different from the position of the binding site in any one of the other species. In all species of this example, the PEG moiety was a linear PEG moiety with an average molecular weight of about 30 kD.

With respect to any of the aforementioned populations of mono-PEGylated CIFN molecules, consisting of a first mono-PEGylated CIFN polypeptide species molecule and a second mono-PEGylated CIFN polypeptide species molecule, the first molecule being characterized by PEG The moiety is linked to the N-terminal amino acid residue of the first CIFN polypeptide, while the second type of molecule is characterized in that the PEG moiety is linked to a first surface-exposed lysine residue of the second CIFN polypeptide, wherein the first and second CIFN polypeptides are identical or different. The composition may additionally comprise at least one other monoPEGylated CIFN polypeptide species molecule characterized in that a PEG moiety is attached to a surface-exposed lysine residue within the CIFN polypeptide, wherein in each additional The position of the binding site in the single PEGylated CIFN polypeptide species is different from the position of the binding site in any one of the other species. In all species of this example, the PEG moiety was a linear PEG moiety with an average molecular weight of about 30 kD.

As another example, the composition comprises a population of mono-PEGylated CIFN molecules consisting of a first mono-PEGylated CIFN polypeptide species molecule and a second mono-PEGylated CIFN polypeptide species molecule, The first class of molecules is characterized by a PEG moiety linked to the N-terminal amino acid residue of the first CIFN polypeptide, and the second class of molecules is characterized by a PEG moiety linked to a lys ³¹ , lys ⁵⁰ , lys ⁷¹ selected from the second CIFN polypeptide. , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ , wherein the first and second CIFN polypeptides are the same or different. The composition may additionally comprise a third monoPEGylated CIFN polypeptide species molecule characterized in that the PEG moiety is linked to ^lys31 , ^lys50 , ^lys71 , ^lys84 , lys selected from the third CIFN polypeptide ¹²¹ , the second lysine residue of lys ¹²² , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ , wherein the third CIFN polypeptide is identical or different from any one of the first and second CIFN polypeptides, wherein the second lysine The position of the residue in the amino acid sequence of the third CIFN polypeptide is different from the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. The composition may additionally comprise at least one other monoPEGylated CIFN polypeptide species molecule characterized in that the PEG moiety is linked to lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , One of ^lys134 , ^lys135 and ^lys165 , wherein the position of the binding site in each additional monoPEGylated CIFN polypeptide species is different from the position of the binding site in any one of the other species. In all species of this example, the PEG moiety was a linear PEG moiety with an average molecular weight of about 30 kD.

As another example, the composition comprises a population of mono-PEGylated CIFN molecules consisting of a first mono-PEGylated CIFN polypeptide species molecule and a second mono-PEGylated CIFN polypeptide species molecule, The first class of molecules is characterized by a PEG moiety attached to the N-terminal amino acid residue of the first CIFN polypeptide, while the second class of molecules is characterized by a PEG moiety attached to a group selected from the group consisting of lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ and The first lysine residue of any of lys ¹⁶⁵ , wherein the first and second CIFN polypeptides are the same or different. The composition may additionally comprise a third monoPEGylated CIFN polypeptide species molecule characterized in that a PEG moiety is linked to a third CIFN polypeptide selected from lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ . Two lysine residues, wherein the third CIFN polypeptide is the same or different from any one of the first and second CIFN polypeptides, wherein the second lysine residue is at the same position in the amino acid sequence of the third CIFN polypeptide as the first The position of a lysine residue in the amino acid sequence of the second CIFN polypeptide differs. The composition may additionally comprise at least one other monoPEGylated CIFN polypeptide species molecule characterized by a PEG moiety attached to one of lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ , wherein in The position of the binding site in each additional monoPEGylated CIFN polypeptide species is different from the position of the binding site in any one of the other species. In all species of this example, the PEG moiety was a linear PEG moiety with an average molecular weight of about 30 kD.

As another non-limiting example, the composition comprises a population of mono-PEGylated CIFN molecules composed of a first mono-PEGylated CIFN polypeptide species molecule and a second mono-PEGylated CIFN polypeptide species Molecular composition, a first class of molecules is characterized by a PEG moiety attached to a first lysine residue of a first CIFN polypeptide, and a second class of molecules is characterized by a PEG moiety attached to a second lysine residue of a second CIFN polypeptide wherein the first and second CIFN polypeptides are identical or different, and wherein the position of the first lysine residue in the amino acid sequence of the first CIFN polypeptide is the same as that of the second lysine residue in the amino acid sequence of the second CIFN polypeptide The location is different. The composition may additionally comprise at least one other monoPEGylated CIFN polypeptide species molecule characterized in that a PEG moiety is attached to a lysine residue within the CIFN polypeptide, wherein in each additional monomeric The position of the binding site in the pegylated CIFN polypeptide species is different from the position of the binding site in any one of the other species. In all species of this example, the PEG moiety was a linear PEG moiety with an average molecular weight of about 30 kD.

As another non-limiting example, the composition comprises a population of mono-PEGylated CIFN molecules composed of a first mono-PEGylated CIFN polypeptide species molecule and a second mono-PEGylated CIFN polypeptide species Molecular composition, the first kind of molecule is characterized in that the PEG moiety is connected to the first member selected from lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ of the first CIFN polypeptide. lysine residues, while the second class of molecules is characterized in that the PEG moiety is linked to lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ second lysine residues, wherein the first and second CIFN polypeptides are identical or different, and wherein the second lysine residues are in the same position as the first lysine residues in the amino acid sequence of the second CIFN polypeptide The position in the first CIFN polypeptide varies. The composition may additionally comprise at least one other monoPEGylated CIFN polypeptide species molecule characterized in that the PEG moiety is linked to lys ³¹ , lys ⁵⁰ , lys ⁷¹ , lys ⁸⁴ , lys ¹²¹ , lys ¹²² , One of ^lys134 , ^lys135 and ^lys165 , wherein the position of the binding site in each additional monoPEGylated CIFN polypeptide species is different from the position of the binding site in any one of the other species. In all species of this example, the PEG moiety was a linear PEG moiety with an average molecular weight of about 30 kD.

As another non-limiting example, the composition comprises a population of mono-PEGylated CIFN molecules composed of a first mono-PEGylated CIFN polypeptide species molecule and a second mono-PEGylated CIFN polypeptide species Molecular composition, a first class of molecules is characterized by a PEG moiety attached to a first lysine residue selected from lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ of the first CIFN polypeptide, and a second class of molecules is characterized by a PEG Partially linked to a second lysine residue selected from lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ of a second CIFN polypeptide, wherein the first and second CIFN polypeptides are the same or different, and wherein the second lysine residue The position of the residue in the amino acid sequence of the second CIFN polypeptide is different from the position of the first lysine residue in the first CIFN polypeptide. The composition may additionally comprise at least one other monoPEGylated CIFN polypeptide species molecule characterized by a PEG moiety attached to one of lys ¹²¹ , lys ¹³⁴ , lys ¹³⁵ and lys ¹⁶⁵ , wherein in The position of the binding site in each additional monoPEGylated CIFN polypeptide species is different from the position of the binding site in any one of the other species. In all species of this example, the PEG moiety was a linear PEG moiety with an average molecular weight of about 30 kD.

As another non-limiting example, the composition comprises a population of mono-PEGylated CIFN molecules that is composed of a first mono-PEGylated CIFN polypeptide species molecule and a second mono-PEGylated CIFN polypeptide species molecule Composition, a first class of molecules is characterized by a PEG moiety attached to a first surface-exposed lysine residue within a first CIFN polypeptide, and a second class of molecules is characterized by a PEG moiety attached to a second surface-exposed lysine residue within a second CIFN polypeptide. The lysine residues, wherein the first and second CIFN polypeptides are the same or different, and wherein the first surface-exposed lysine is at the same position in the amino acid sequence of the first CIFN polypeptide as the second surface-exposed lysine is in the second CIFN The position in the amino acid sequence of the polypeptide varies. The composition may additionally comprise at least one other monoPEGylated CIFN polypeptide species molecule characterized in that a PEG moiety is attached to a surface-exposed lysine residue within the CIFN polypeptide, wherein in each additional monopolypeptide The position of the binding site in the pegylated CIFN polypeptide species is different from the position of the binding site in any one of the other species. In all species of this example, the PEG moiety was a linear PEG moiety with an average molecular weight of about 30 kD.

With respect to any of the aforementioned populations of mono-PEGylated CIFN molecules, the invention contemplates wherein the molecules in each such population comprise a CIFN selected from the group consisting of interferon alpha-con1, interferon alpha-con2 and interferon alpha-con3 Examples of polypeptides.

Certain embodiments additionally describe a product produced by a method of reacting a CIFN polypeptide with α-methoxy, γ-propionyl polyethylene glycol (mPEGspa) (linear, molecular weight about 30 kD), wherein the reactant is first A molar ratio of about 1:1 to about 1:5 CIFN:mPEGspa is provided, and wherein the reaction is carried out at a pH between about 7 to about 9, and the reacted monoPEGylated CIFN is then recovered product. In one embodiment, the reactants are first provided at a molar ratio of about 1:3 CIFN:mPEGspa, and the reaction is performed at a pH of about 8. In another embodiment, the product is produced by a scale-up step required for toxicology studies and clinical studies, the reactants are first provided at a molar ratio of 1:2 CIFN:mPEGspa and the reaction is at a pH of about 8.0 next.

With respect to the above process products, the present invention contemplates embodiments wherein the CIFN reactant is selected from interferon alpha-con1, interferon alpha-con2 and interferon alpha-con3.

IFN-β

The term interferon beta ("IFN-beta") includes naturally occurring, non-naturally occurring IFN-beta polypeptides, and naturally occurring or non-naturally occurring IFN-beta polypeptides that retain the antiviral activity of the parent naturally occurring or non-naturally occurring IFN-beta. β analogs.

Any one of various kinds of interferon-beta can be administered by the continuous administration method of the examples. Suitable beta interferons include, but are not limited to, naturally occurring IFN-β; IFN-β1a, such as Avonex® (Biogen, Inc.) and Rebif® (Serono, SA); and IFN-β1b (Betaseron®; Berlex); and the like.

IFN-[beta] formulations may comprise N-blocked species in which the N-terminal amino acid is acylated with an acyl group such as formyl, acetyl, malonyl, and the like. Also suitable is complex IFN-beta.

IFN-beta polypeptides can be produced by any known method. The DNA sequence encoding IFN-[beta] can be synthesized using standard methods. In many embodiments, the IFN-β polypeptide is produced by transforming or transfecting a DNA sequence into a bacterial host (such as Escherichia coli (E.coli)) or in a eukaryotic host cell (such as yeast; mammalian cells such as CHO cells; and the like). In these embodiments, the IFN-beta is "recombinant IFN-beta". Where the host cell is a bacterial host cell, IFN-[beta] is modified to include an N-terminal methionine.

It is understood that the IFN-[beta] described herein comprises one or more modified amino acid residues, such as glycosylation, chemical modification, and the like.

IFN-τ

The term interferon-tau ("IFN-tau") includes naturally occurring, non-naturally occurring IFN-tau polypeptides, and naturally occurring or non-naturally occurring IFN-tau polypeptides that retain the antiviral activity of the parent naturally occurring or non-naturally occurring IFN-tau. Analogs of τ.

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

IFN-τ may comprise any of the amino acids mentioned in GenBank accession numbers P15696, P56828, P56832, P56829, P56831, Q29429, Q28595, Q28594, S08072, Q08071, Q08070, Q08053, P56830, P28169, P28172 and P28171 sequence. The sequence of any known IFN-tau polypeptide can be altered in various ways known in the art to obtain the desired sequence variation. Variant polypeptides are generally substantially similar to the sequences provided herein, ie differ by at least one amino acid, and may differ by at least two but not more than about 10 amino acids. Sequence alterations may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine), (valine, isoleucine, leucine), (aspartic acid, glutamic acid), (asparagine , glutamine), (serine, threonine), (lysine, arginine) or (phenylalanine, tyrosine).

Relevant modifications that may or may not alter the primary amino acid sequence include: chemical derivatization of polypeptides, such as acetylation or carboxylation; amino acid sequence changes that introduce or remove glycosylation sites; amino acids that predispose proteins to pegylation Sequence changes; and similar modifications. Also included are glycosylation modifications, such as those achieved by modifying the glycosylation pattern of a polypeptide during synthesis and processing or in other processing steps, such as by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian sugars glycosylase or deglycosylase. Sequences having phosphorylated amino acid residues such as phosphotyrosine, phosphoserine or phosphothreonine are also included.

IFN-r formulations may comprise N-blocked species in which the N-terminal amino acid is acylated with an acyl group such as formyl, acetyl, malonyl, and the like. Also suitable is the complex IFN-τ.

IFN-r polypeptides can be produced by any known method. The DNA sequence encoding IFN-r can be synthesized using standard methods. In many embodiments, the IFN-τ polypeptide is produced by transforming or transfecting a DNA sequence into a bacterial host (such as Escherichia coli (E.coli)) or in a eukaryotic host cell (such as yeast; mammalian cells such as CHO cells; and the like). In some embodiments, the IFN-τ is "recombinant IFN-τ." When the host cell is a bacterial host cell, IFN-r is modified to include an N-terminal methionine.

It is understood that the IFN-r described herein comprises one or more modified amino acid residues, such as glycosylation, chemical modification, and the like.

IFN-ω

The term interferon omega ("IFN-omega") includes naturally occurring, non-naturally occurring IFN-omega polypeptides, and naturally occurring or non-naturally occurring IFN-omega polypeptides that retain the antiviral activity of the parent naturally occurring or non-naturally occurring IFN-omega. Omega analogs.

Any known omega interferon can be administered by the continuous administration method in the examples. Suitable IFN-omega include, but are not limited to, naturally occurring IFN-omega; recombinant IFN-omega, such as Biomed 510 (BioMedicines); and the like.

IFN-omega may comprise the amino acid sequence mentioned in GenBank Accession No. NP_002168 or AAA70091. The sequence of any known IFN-omega polypeptide can be altered in various ways known in the art to obtain the desired sequence variation. Variant polypeptides are generally substantially similar to the sequences provided herein, ie differ by at least one amino acid, and may differ by at least two but not more than about 10 amino acids. Sequence alterations may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine), (valine, isoleucine, leucine), (aspartic acid, glutamic acid), (asparagine , glutamine), (serine, threonine), (lysine, arginine) or (phenylalanine, tyrosine).

Relevant modifications that may or may not alter the primary amino acid sequence include: chemical derivatization of polypeptides, such as acetylation or carboxylation; amino acid sequence changes that introduce or remove glycosylation sites; amino acids that predispose proteins to pegylation Sequence changes; and similar modifications. Also included are glycosylation modifications, such as those achieved by modifying the glycosylation pattern of a polypeptide during synthesis and processing or in other processing steps, such as by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian sugars glycosylase or deglycosylase. Also included are sequences with phosphorylated amino acid residues such as phosphotyrosine, phosphoserine, or phosphothreonine.

IFN-omega preparations may comprise N-blocked species in which the N-terminal amino acid is acylated with an acyl group such as formyl, acetyl, malonyl, and the like. Also applicable is the complex IFN-omega.

IFN-omega polypeptides can be produced by any known method. The DNA sequence encoding IFN-omega can be synthesized using standard methods. In many embodiments, the IFN-omega polypeptide is produced by transforming or transfecting a DNA sequence into a bacterial host (such as Escherichia coli (E.coli)) or in a eukaryotic host cell (such as yeast; mammalian cells such as CHO cells; and the like). In these embodiments, the IFN-omega is "recombinant IFN-omega". When the host cell is a bacterial host cell, IFN-omega is modified to include an N-terminal methionine.

It is understood that the IFN-omega described herein comprise one or more modified amino acid residues, such as glycosylation, chemical modification, and the like.

Type III interferon receptor agonists

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 polypeptides; IL-28a polypeptides; IL-29 polypeptides; antibodies specific for Type III interferon receptors; and any other Type III interferon receptor agonists, including non-polypeptide agonist.

IL-28A, IL-28B and IL-29 (collectively referred to herein as "type III interferon" or "type III IFN") are described in Sheppard et al. (2003) Nature 4:63-68. Each polypeptide binds a heterodimeric receptor consisting of IL-10 receptor beta chain and IL-28 receptor alpha. Sheppard et al. (2003), supra. The amino acid sequences of IL-28A, IL-28B and IL-29 can be found under GenBank accession numbers NP_742150, NP_742151 and NP_742152, respectively.

The amino acid sequence of any known Type III IFN polypeptide can be altered in various ways known in the art to obtain the desired sequence variation. Variant polypeptides are generally substantially similar to the sequences provided herein, ie differ by at least one amino acid, and may differ by at least two but not more than about 10 amino acids. Sequence alterations may be substitutions, insertions or deletions. Scanning mutagenesis that systematically introduces alanine or other residues can be used to identify key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine), (valine, isoleucine, leucine), (aspartic acid, glutamic acid), (asparagine , glutamine), (serine, threonine), (lysine, arginine) or (phenylalanine, tyrosine).

Relevant modifications that may or may not alter the primary amino acid sequence include: chemical derivatization of polypeptides, such as acetylation or carboxylation; amino acid sequence changes that introduce or remove glycosylation sites; amino acids that predispose proteins to pegylation Sequence changes; and similar modifications. Also included are glycosylation modifications, such as those achieved by modifying the glycosylation pattern of a polypeptide during its synthesis and processing, or in other processing steps, such as by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylation enzymes or deglycosylases. Also included are sequences with phosphorylated amino acid residues such as phosphotyrosine, phosphoserine, or phosphothreonine.

Examples include polypeptides that have been modified using common chemical techniques in order to increase their resistance to proteolytic degradation, optimize solubility properties, or make them more suitable therapeutic agents. For example, the backbone of the peptide can be cyclized to enhance stability (see, Friedler et al. (2000) J. Biol. Chem. 275:23783-23789). Analogs that include residues other than naturally occurring L amino acids (eg, D amino acids) or non-naturally occurring synthetic amino acids can be used. Proteins can be pegylated to enhance stability. The polypeptide can be fused to albumin.

Polypeptides can be produced by recombinant methods via in vitro synthesis using routine methods known in the art, or can be isolated from cells that induce or naturally produce the protein. The particular preparation procedure and manner depend on factors such as convenience, economy, desired purity, and the like. If desired, different groups can be introduced into the polypeptide during synthesis or expression, enabling attachment to other molecules or attachment to a surface. Thus, cysteine can be used to make thioethers, histidine can be used to link metal ion complexes, carboxyl groups can be used to form amides or esters, amino groups can be used to form amides, and so on.

Type II interferon receptor agonists

A Type II interferon receptor agonist includes any naturally occurring or non-naturally occurring ligand of the human Type II interferon receptor that binds to the receptor or initiates signal transduction through the receptor. Type II interferon receptor agonists include interferons including: naturally occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, Shuffled interferons, antibodies specific for interferon receptors, non-peptide chemical agonists and the like.

A specific example of a Type II interferon receptor agonist is IFN-γ and variants thereof. While the present examples illustrate the use of IFN-gamma polypeptides, it should be understood that any Type II interferon receptor agonist may be used in the methods described.

interferon gamma

Nucleic acid sequences encoding IFN-γ polypeptides can be obtained from public databases such as GenBank, journal publications, and the like. While various mammalian IFN-γ polypeptides are of interest, for the treatment of human disease, human proteins will generally be used. Sequences encoding human IFN-γ can be found in Genbank accession numbers XI3274, V00543 and NM_000619. The corresponding genomic sequences can be found in Genbank accession numbers J00219, M37265 and V00536. See, eg, Gray et al. (1982) Nature 295:501 (Genbank X13274); and Rinderknecht et al. (1984) J.B.C. 259:6790.

IFN-γ1b (Actimmune®, human interferon) is a single-chain polypeptide with 140 amino acids. It is produced recombinantly in E. coli and is non-glycosylated. Rinderknecht et al. (1984) J. Biol. Chem. 259:6790-6797. Recombinant IFN-gamma as described in US Patent No. 6,497,871 is also suitable for use herein.

The IFN-γ to be used in the method of the embodiment of the present invention can be any of natural IFN-γ, recombinant IFN-γ and its derivatives, as long as they have IFN-γ activity, especially human IFN-γ activity. Human IFN-γ exhibits antiviral and antiproliferative properties characteristic of interferons and many other immunomodulatory activities known in the art. Although IFN-γ is based on the sequence described above, production and proteolytic processing of the protein can lead to variants in its processing. The unprocessed sequence provided by Gray et al. (supra) consists of 166 amino acids (aa). Although recombinant IFN-γ produced in E. coli was originally thought to have 146 amino acids, it was subsequently found that native human IFN-γ is cleaved after residue 23 (starting at amino acid 20), resulting in a 143 protein, or if expressed in bacteria The presence of a terminal methionine is required, which is 144aa. During purification, the mature protein can additionally be cleaved at the C-terminus after residue 162 (cf. Gray et al. sequence), resulting in a protein of 139 amino acids, or, for example, when the initial methionine is present for bacterial expression. 140 amino acids. The N-terminal methionine is an artifact encoded by the mRNA translation "start" signal AUG, which is not processed under the special circumstances of E. coli expression. In other microbial systems or eukaryotic expression systems, methionine can be removed.

For use in the methods, any of the native IFN-γ peptides, modifications and variants thereof, or combinations of one or more peptides may be used. IFN-[gamma] peptides of interest include fragments and may be variously truncated at the carboxy terminus relative to the complete sequence. These fragments still exhibit the properties of human gamma interferon as long as amino acids 24 to about 149 (numbering from the residues of the unprocessed polypeptide) are present. The amino acid sequence after amino acid 155 can be replaced with a foreign sequence without loss of activity. See, eg, US Patent No. 5,690,925. Native IFN-γ portions include various molecules extending from amino acid residues 24-150, 24-151, 24-152, 24-153, 24-155, and 24-157. Any of these variants, as well as 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 in various ways known in the art to obtain the desired sequence variation. Variant polypeptides are generally substantially similar to the sequences provided herein, ie differ by at least one amino acid, and may differ by at least two but not more than about 10 amino acids. Sequence alterations may be substitutions, insertions or deletions. Scanning mutagenesis that systematically introduces alanine or other residues can be used to identify key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine), (valine, isoleucine, leucine), (aspartic acid, glutamic acid), (asparagine , glutamine), (serine, threonine), (lysine, arginine) or (phenylalanine, tyrosine).

Relevant modifications that may or may not alter the primary amino acid sequence include: chemical derivatization of polypeptides, such as acetylation or carboxylation; amino acid sequence changes that introduce or remove glycosylation sites; amino acids that predispose proteins to pegylation Sequence changes; and similar modifications. One embodiment contemplates the use of IFN-γ variants with one or more naturally occurring glycosylation and/or pegylation sites designed to provide glycosyl and/or pegylation sites with low serum clearance Or polyethylene glycol derivatized polypeptides, such as IFN-γ polypeptide variants described in International Patent Publication WO 01/36001. Also included are glycosylation modifications, such as those achieved by modifying the glycosylation pattern during polypeptide synthesis and processing, or during other processing steps, for example, by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian sugars glycosylase or deglycosylase. Also included are sequences with phosphorylated amino acid residues such as phosphotyrosine, phosphoserine, or phosphothreonine.

Examples include polypeptides that have been modified using common chemical techniques in order to increase their resistance to proteolytic degradation, optimize solubility properties, or make them more suitable therapeutic agents. For example, the backbone of the peptide can be cyclized to enhance stability (see, Friedler et al. (2000) J. Biol. Chem. 275:23783-23789). Analogs comprising residues other than naturally occurring L amino acids (eg, D amino acids) or non-naturally occurring synthetic amino acids may also be used. Proteins can be pegylated to enhance stability.

Polypeptides can be produced by recombinant methods via in vitro synthesis using routine methods known in the art, or can be isolated from cells that induce or naturally produce the protein. The particular preparation procedure and manner depend on factors such as convenience, economy, desired purity, and the like. If desired, different groups can be introduced into the polypeptide during synthesis or expression, enabling attachment to other molecules or attachment to a surface. Thus, cysteine can be used to make thioethers, histidine can be used to link metal ion complexes, carboxyl groups can be used to form amides or esters, amino groups can be used to form amides, and so on.

Polypeptides can also be isolated and purified according to conventional methods of recombinant synthesis. Lysates can be prepared from expression hosts and purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification techniques. In most cases the composition used will comprise at least 20 weight percent of the desired product, more usually at least about 75 weight percent, preferably at least about 95 weight percent, and for Therapeutic purposes are generally at least about 99.5 weight percent. The percentages are generally based on total protein.

Perfenidone and its analogs

Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) and certain pirfenidone analogs are disclosed for use in the treatment of fibrotic disorders. A "fibrotic disorder" can be treated by administering a compound having anti-fibrotic activity.

pirfenidone

pirfenidone analogs

Description of substituents R ₁ , R ₂ , X

R ₁ : carbocycle (saturated or unsaturated), heterocycle (saturated or unsaturated), alkyl (saturated or unsaturated). Examples include phenyl, benzyl, pyrimidinyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidinyl, pyrrolidinyl, morpholinyl, cyclohexenyl , butadienyl and similar groups.

_R may be further substituted on the carbocyclic or heterocyclic moiety with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxy, cyano, thio, alkyl, aryl, heteroalkyl , heteroaryl and combinations thereof, such as 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2, 5-dichlorocyclohexyl, guanidino-cyclohexenyl and similar groups.

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

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

The substituent may be further substituted with 1 to 3 substituents selected from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halogen groups as appropriate. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl, and similar group.

Specific examples include the compounds listed in Table 1:

Table 1

IIA IIB 5-Methyl-1-(2′-pyridyl)-2-(1H)pyridine 6-Methyl-1-phenyl-3-(1H)pyridone 6-Methyl-1-phenyl-2-(1H)pyridone 5-Methyl-1-p-tolyl-3-(1H)pyridone 5-Methyl-3-phenyl-1-(2′-thienyl)-2-(1H)pyridone 5-Methyl-1-(2′-naphthyl)-3-(1H)pyridone 5-Methyl-1-(2′-naphthyl)-2-(1H)pyridone 5-Methyl-1-phenyl-3-(1H)pyridone 5-Methyl-1-p-tolyl-2-(1H)pyridone 5-Methyl-1-(5′-quinolinyl)-3-(1H)pyridone 5-Methyl-1-(1′-naphthyl)-2-(1H)pyridone 5-Ethyl-1-phenyl-3-(1H)pyridone 5-Ethyl-1-phenyl-2-(1H)pyridone 5-Methyl-1-(4′-methoxyphenyl)-3-(1H)pyridone 5-Methyl-1-(5′-quinolinyl)-2-(1H)pyridone 4-Methyl-1-phenyl-3-(1H)pyridone 5-Methyl-1-(4′-quinolinyl)-2-(1H)pyridone 5-Methyl-1-(3′-pyridyl)-3-(1H)pyridone 5-Methyl-1-(4′-pyridyl)-2-(1H)pyridone 5-Methyl-1-(2′-thienyl)-3-(1H)pyridone 3-Methyl-1-phenyl-2-(1H)pyridone 5-Methyl-1-(2′-pyridyl)-3-(1H)pyridone 5-Methyl-1-(4′-methoxyphenyl)-2-(1H)pyridone 5-Methyl-1-(2′-quinolinyl)-3-(1H)pyridone 1-Phenyl-2-(1H)pyridone 1-Phenyl-3-(1H)pyridine 1,3-Diphenyl-2-(1H)pyridone 1-(2′-furyl)-5-methyl-3-(1H)pyridone 1,3-Diphenyl-5-methyl-2-(1H)pyridone 1-(4′-Chlorophenyl)-5-methyl-3-(1H)pyridine 5-Methyl-1-(3′-trifluoromethylphenyl)-2-(1H)pyridone 3-Ethyl-1-phenyl-2-(1H)pyridone 5-Methyl-1-(3′-pyridyl)-2-(1H)pyridone 5-Methyl-1-(3-nitrophenyl)-2-(1H)pyridone 3-(4′-Chlorophenyl)-5-methyl-1-phenyl-2-(1H)pyridone 5-Methyl-1-(2′-thienyl)-2-(1H)pyridone 5-Methyl-1-(2′-thiazolyl)-2-(1H)pyridone 3,6-Dimethyl-1-phenyl-2-(1H)pyridone 1-(4′-Chlorophenyl)-5-methyl-2-(1H)pyridone 1-(2′-imidazolyl)-5-methyl-2-(1H)pyridone 1-(4′-nitrophenyl)-2-(1H)pyridone 1-(2′-furyl)-5-methyl-2-(1H)pyridone 1-Phenyl-3-(4′-chlorophenyl)-2-(1H)pyridine

U.S. Patent Nos. 3,974,281, 3,839,346, 4,042,699, 4,052,509, 5,310,562, 5,518,729, 5,716,632, and 6,090,822 describe methods for the synthesis of pirfenidone and certain pirfenidone analogs and methods of formulating it in pharmaceutical compositions suitable for use in the methods of the embodiments of the present invention.

thymosin alpha

Thymosin alpha (Zadaxin ^™ ; available from SciClone Pharmaceuticals, Inc., San Mateo, CA) is a synthetic form of thymosin alpha 1 , a hormone found naturally in circulation and produced by the thymus. Thymosin alpha increases the activity of T cells and NK cells. Formulated for subcutaneous injection, ZadaxinTM is a purified, sterile, lyophilized preparation of chemically synthesized thymosin α1 equivalent to human thymosin α1. Thymosin alpha 1 is an acetylated polypeptide with the following sequence and a molecular weight of 3,108 Daltons: Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-lle-Thr-Thr-Lys-Asp -Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH. The lyophilized formulation contained 1.6 mg synthetic thymosin alpha, 50 mg mannitol and sodium phosphate buffer to adjust the pH to 6.8.

Ribavirin

Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is a nucleoside analog commercially available from ICN Pharmaceuticals, Inc. of Calif, Costa Mesa , and is described in The Merck Index Compound No. 8199, Eleventh Edition. Its preparation and formulation methods are described in US Patent No. 4,211,771. Embodiments also include the use of derivatives of ribavirin (see, eg, US Patent No. 6,277,830). Ribavirin is available orally in capsule or tablet form. Of course, other useful types of ribavirin administration are also contemplated, such as nasal sprays, transdermal, suppositories, sustained release formulations, and the like. Any form of administration will work so long as the proper dosage is administered without destroying the active ingredient.

Typical dosages of ribavirin are 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 course of NS3 inhibitor therapy.

Levovirin

Levovirin is the levoisomer of ribavirin and exhibits the property of enhancing Th1 immune responses over Th2 immune responses. Levovirin is manufactured by ICN Pharmaceuticals.

The structure of Levovirin is as follows:

Vilamidine (viramidine)

Veramidine is a 3-formamidine derivative of ribavirin and acts as a prodrug of ribavirin. Veramidine is efficiently converted to ribavirin by adenosine deaminase.

The structure of Veramidine is as follows:

Nucleoside analogs

Nucleoside analogs suitable for use in such combination therapy include, but are not limited to, ribavirin, levovirin, veramidine, isatoribine, as disclosed in U.S. Patent No. 5,559,101 and L-ribofuranosyl nucleosides covered by formula I of U.S. Patent No. 5,559,101 (for example, 1-β-L-ribofuranosyluracil, 1-β-L-ribofuranosyl-5-fluorouracil, 1- β-L-ribofuranosylcytosine, 9-β-L-ribofuranosyl adenine, 9-β-L-ribofuranosyl hypoxanthine, 9-β-L-ribofuranosylguanine, 9-β -L-ribofuranosyl-6-thioguanine, 2-amino-α-L-ribofuranose[1′,2′:4,5]oxazoline, O ² , O ² -anhydro-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-arabino Furanosyl [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-thio-β-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), as in U.S. Patent No. 6,423,695 Compounds as disclosed and covered by Formula I of U.S. Patent No. 6,423,695, Compounds of Formula I as disclosed in U.S. Patent No. 2002/0058635 and covered by Formula I of U.S. Patent No. 2002/0058635, as disclosed in WO 01/90121 A2 Nucleoside analogs as disclosed in (Idenix), as disclosed in WO 02/069903 A2 (Biocrystal Pharmaceuticals Inc.), as in WO 02/057287 A2 or WO 02/057425 A2 (both Merck/Isis) Nucleoside analogs disclosed in; and analogs.

TNF antagonist

In some embodiments, the method comprises administering an effective amount of an NS3 inhibitor and an effective amount of a tumor necrosis factor-alpha (TNF-alpha) antagonist. TNF-alpha antagonists suitable for use herein include agents that reduce the level of TNF-alpha synthesis, agents that block or inhibit the binding of TNF-alpha to the TNF-alpha receptor (TNFR), and agents that block or inhibit TNFR-mediated Reagents for signal transduction. Unless otherwise stated, any "TNF-alpha antagonist" or "TNF antagonist" herein is to be understood as a TNF-alpha 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 a TNFR (from any species) capable of binding TNF. Two distinct 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 p75TNFR is a glycoprotein with a molecular weight of approximately 75-80 kilodaltons (kD). Mature full-length human p55 TNFR is a glycoprotein with a molecular weight of approximately 55-60 kD. Exemplary TNFR polypeptides are derived from TNFR type I and/or TNFR type II. Soluble TNFRs include p75 TNFR polypeptides; fusions of p75 TNFR to heterologous fusion partners, eg, the Fc portion of an immunoglobulin.

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

Monovalent and multivalent forms of TNFR polypeptides can be used in embodiments of the invention. Multivalent forms of TNFR polypeptides have more than one TNF binding site. In some embodiments, the TNFR is a bivalent or dimeric form of TNFR. For example, as described in U.S. Pat. No. 5,605,690 and Mohler et al., 1993, J. Immunol., 151:1548-1561, replacement of either heavy or light immunoglobulin chains with TNFR ectodomains or Chimeric antibody polypeptides of the variable domains of both will provide TNFR polypeptides for use in the embodiments of the invention. Generally, when such chimeric TNFR:antibody polypeptides are produced by cells, bivalent molecules are formed through thioether bonding between the immunoglobulin functional domains. Such chimeric TNFR:antibody polypeptides are referred to as TNFR:Fc.

In one embodiment, the method comprises administering an effective amount of soluble TNFR ENBREL_. ENBREL® is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNFR linked to the Fc portion of IgGl. The Fc component of ENBREL_ contains CH2 functional domain, CH3 functional domain and hinge region, but does not contain the CH1 functional domain of IgG1. ENBREL_ is produced in the Chinese hamster ovary (CHO) mammalian cell expression system. ENBREL® is composed of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al. (1990) Science 248:1019-1023; Mohler et al. (1993) J. Immunol. 151:1548-1561; US Patent No. 5,395,760; and US Patent No. 5,605,690.

Also suitable for use are monoclonal antibodies that bind TNF-[alpha]. Monoclonal antibodies include "humanized" murine monoclonal antibodies; chimeric antibodies; monoclonal antibodies whose amino acid sequences are at least about 80%, at least about 90%, at least about 95%, or 100% human; and the like. 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, and Fab; synthetic antibodies; artificial antibodies; phage-displayed antibodies; and the like.

Examples of suitable monoclonal antibodies include Infliximab (REMICADE®, Centocor) and Adalimumab (HUMIRA ^™ , Abbott). REMICADE® is a chimeric monoclonal anti-TNF-alpha antibody comprising about 25% murine amino acid sequence and about 75% human amino acid sequence. REMICADE_comprises the variable region of a murine monoclonal anti-TNF-α antibody fused to a human IgG1 constant region. 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. HUMIRA ^TM is a human full-length IgG1 monoclonal antibody recognized using phage display technology. Piascik (2003) J. Am. Pharm. Assoc. 43:327-328.

Also included within the term "TNF antagonist" and thus suitable for use in the method are stress-activated protein kinase (SAPK) inhibitors. SAPK inhibitors are known in the art, including, but not limited to: 2-alkylimidazoles disclosed in U.S. Patent No. 6,548,520; 1,4,5-substituted imidazoles disclosed in U.S. Patent No. 6,489,325 ; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,569,871; heteroarylaminophenyl ketone compounds disclosed in U.S. Patent Application No. 2003/0073832; disclosed in U.S. Patent No. 6,288,089 pyridyl imidazole compounds; and heteroarylaminobenzophenones disclosed in US Patent No. 6,432,962. Also of interest are the compounds disclosed in US Patent Publication No. 2003/0149041 and US Patent No. 6,214,854. Stress-activated protein kinases are members of the mitogen-activated protein kinase family that are activated in response to stress stimuli. SAPKs include, but are not limited to, p38 (Lee et al. (1994) Nature 372:739) and c-jun N-terminal kinase (JNK).

Methods for assessing TNF antagonist activity are known in the art and are exemplified here. For example, TNF antagonist activity can be assessed using a cell-based competitive binding assay. In this assay, radiolabeled TNF is mixed with serial dilutions of TNF antagonist and cells expressing membrane-bound TNFR. The suspensions were centrifuged to separate free and bound TNF, and the amount of radioactivity in the free and bound fractions was determined. TNF antagonist activity is assessed by inhibition of TNF binding to cells in the presence of TNF antagonist.

As another example, the ability of a TNF antagonist to counteract TNF activity in vitro can be assayed in a bioassay using cells susceptible to TNF cytotoxic activity as target cells. In this assay, target cells that have been incubated with TNF are treated with varying amounts of TNF antagonists, and cell lysis is subsequently detected. TNF antagonist activity is assessed by the reduction of TNF-induced cytolysis of target cells in the presence of TNF antagonist.

NS5B inhibitors

Some embodiments provide methods comprising administering to an HCV patient in need thereof an effective amount of the NS3 inhibitor and an effective amount of an HCV nonstructural protein-5 (NS5; RNA-dependent RNA polymerase) inhibitor. Suitable NS5B inhibitors include, but are not limited to: compounds disclosed in U.S. Patent No. 6,479,508 (Boehringer-Ingelheim); International Patent Application No. PCT/CA02/01127, filed July 18, 2002 by Boehringer Ingelheim Compounds disclosed in any one of No. PCT/CA02/01128 and No. PCT/CA02/01129; compounds disclosed in U.S. Patent No. 6,440,985 (ViroPharma); compounds disclosed in WO 01/47883, e.g. JTK-003 (Japan Tobacco); dinucleotide analogs described in Zhong et al. (2003) Antimicrob, Agents Chemother. 47:2674-2681; in Dhanak et al. (2002) J. Biol Chem. 277(41): Benzothiadiazine compounds disclosed in 38322-7; NS5B inhibitors disclosed in WO 02/100846 A1 or WO 02/100851 A2 (both Shire); NS5B inhibitors disclosed in 02/098424A1 (both Glaxo SmithKline); NS5B inhibitors disclosed in WO 00/06529 or WO 02/06246 A1 (both Merck); disclosed in WO 03/000254 (Japan Tobacco) NS5B inhibitors disclosed in EP 1 256,628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan Tobacco); and the like.

Of particular interest in many embodiments are NS5 inhibitors of specific NS5 inhibitors, e.g., ones that inhibit NS5 RNA-dependent RNA polymerase and do not have a significant inhibitory effect on other RNA-dependent RNA polymerases and DNA-dependent RNA polymerases NS5 inhibitors.

other antiviral agents

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

IMPDH inhibitor

IMPDH inhibitors suitable for use in the combination therapy include, but are not limited to: VX-497((S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)- Ureado]-benzyl-carbamate tetrahydrofuran-3-yl-ester, Vertex Pharmaceuticals, see, e.g., Markland et al. (2000) Antimicrob.Agents Chemother.44:859-866); Ribavirin; Levorotatory Veramidine (Ribapharm; see, eg, Watson (2002) Curr Opin Investig Drugs 3(5):680-3); Veramidine (Ribapharm); and the like.

Ribozymes and antisense

Suitable ribozymes and antisense antiviral agents for use in such combination therapy include, but are not limited to: ISIS 14803 (ISIS Pharmaceuticals/Elan Corporation; see, e.g., Witherell (2001) Curr Opin Investig Drugs. 2(11):1523-9) ; Heptazyme ^™ ; and the like.

In some embodiments, the additional antiviral agent is administered throughout the course of NS3 inhibitor compound treatment. In other embodiments, the administration of the other antiviral agent overlaps the NS3 inhibitor compound treatment for a period of time, e.g., the other antiviral agent treatment can begin before the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; Treatment with other antiviral agents can begin after initiation of NS3 inhibitor compound treatment and end after end of NS3 inhibitor compound treatment; other antiviral agent treatment can begin after initiation of NS3 inhibitor compound treatment and before end of NS3 inhibitor compound treatment end; or other antiviral agent treatment can start before NS3 inhibitor compound treatment begins and end after NS3 inhibitor compound treatment ends.

Dosage, formulation and route of administration

In such methods, the active agent (eg, a compound of Formula I and, optionally, one or more other antiviral agents) can be administered to the host using any convenient means that produces the desired therapeutic effect. Accordingly, the agents can be incorporated into various formulations for therapeutic administration. More specifically, the reagents in the embodiments of the present invention can be formulated into pharmaceutical compositions by combining with suitable, pharmaceutically acceptable carriers or excipients, and can be formulated into solid, semi-solid, Preparations in liquid or gaseous form, for example, tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

preparation

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

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

In some embodiments, reagents are formulated in aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate and phosphate buffers at concentrations ranging from 5 mM to 100 mM. In some embodiments, aqueous buffers include agents that provide an isotonic solution. Such agents include, but are not limited to, sodium chloride; and sugars such as mannitol, dextrose, sucrose, and the like. In some embodiments, the aqueous buffer additionally includes a nonionic surfactant, such as polysorbate 20 or 80. The formulations may additionally include preservatives, if desired. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, formulations were stored at about 4°C. The formulations may also be lyophilized, in which case the formulations typically include antifreeze agents such as sucrose, trehalose, lactose, maltose, mannitol, and the like. Lyophilized formulations can be stored for extended periods of time, even at ambient temperature.

Thus, administration of an agent can be accomplished in a variety of ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, and the like. In many embodiments, administration is by bolus injection, such as a subcutaneous bolus, intramuscular bolus, and the like.

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

Subcutaneous administration of the pharmaceutical compositions of the present embodiments is accomplished using standard methods and devices, eg, needles and syringes, hypodermic port delivery systems, and the like. See, eg, US Patent Nos. 3,547,119, 4,755,173, 4,531,937, 4,311,137, and 6,017,328. The combination of a hypodermic port and a device for administering an example pharmaceutical composition to a patient via the port is referred to herein as a "hypodermic port delivery system". In many embodiments, subcutaneous administration is accomplished by bolus administration via a needle and syringe.

In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may be used alone or in appropriate combination and combination with other pharmaceutically active compounds. The following methods and excipients are exemplary only and not limiting in any way.

For oral formulations, the formulations can be used alone or in combination with suitable additives to prepare tablets, powders, granules or capsules, for example, in combination with conventional additives such as lactose, mannitol, corn starch or potato starch; and Binders (in combination with crystalline cellulose, cellulose derivatives, acacia, cornstarch, or gelatin); in combination with disintegrants (such as talc or magnesium stearate); and, if necessary, diluents, buffers agents, wetting agents, preservatives and flavoring agents.

The agent can be formulated into injection preparations by dissolving, suspending or emulsifying in aqueous or non-aqueous solvents such as vegetable oil or other similar oils, synthetic aliphatic acid glycerides, higher aliphatic acids or esters of propylene glycol; and use when necessary Usual additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

In addition, the agent can be formulated into suppositories by mixing with various bases such as emulsifying bases or water-soluble bases. The compounds of the embodiments of the present invention can be administered rectally using suppositories. Suppositories may include vehicles such as cocoa butter, carbowax, and polyethylene glycols, which vehicles melt at body temperature and solidify at room temperature.

Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be presented wherein each dosage unit, such as a teaspoon, tablespoon, tablet or suppository, contains a predetermined amount of the composition comprising one or more inhibitors. Likewise, unit dosage forms for injection or intravenous administration may contain the inhibitor in the composition as a solution in sterile aqueous solution, normal saline solution or another pharmaceutically acceptable carrier.

As used herein, the term "unit dosage form" refers to physically discrete units suitable as unitary dosages for any animal subject, each unit containing a predetermined quantity of a compound of the Examples sufficient to give a pharmaceutically acceptable The diluent, carrier or vehicle in combination produces the desired effect. The specifications for the novel unit dosage forms of the embodiments of the invention depend on the particular compound used and the effect to be achieved and the pharmacodynamics associated with each compound in the host.

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

other antiviral agents

As noted above, in some embodiments, the methods will be practiced by administering a compound of Formulas I-XIX that is an NS3 inhibitor and, optionally, one or more other antiviral agents.

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

In other embodiments, the method further comprises administering pirfenidone or a pirfenidone analog. The pirfenidone or pirfenidone analogs are as described above.

Other antiviral agents suitable for combination therapy include, but are not limited to, nucleotide and nucleoside analogs. Non-limiting examples include: azidothymidine (AZT) (zidovudine) and its analogs and derivatives; 2',3'-dideoxyinosine (2' , 3'-dideoxyinosine, DDI) (didanosine (didanosine)) and its analogues and derivatives; 2', 3'-dideoxycytidine (2', 3'-dideoxycytidine, DDC) (double Deoxycytidine (dideoxycytidine)) and its analogues and derivatives; 2',3'-didehydro-2',3'-dideoxythymidine (2',3'-didehydro-2',3 '-dideoxythymidine, D4T) (stavudine) and its analogues and derivatives; combivir; abacavir; adefovir dipoxil; Ribavirin; ribavirin analogs; and analogs.

In some embodiments, the method further comprises administering ribavirin. Ribavirin, 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc. of Calif, Costa Mesa, and is listed in version 11 Described in Compound No. 8199 of the Merck Index. Its preparation and formulation methods are described in US Patent No. 4,211,771. Embodiments also include the use of derivatives of ribavirin (see, eg, US Patent No. 6,277,830). Ribavirin can be administered orally in capsule or tablet form, or in the same or different form and by the same or different route as the interferon receptor agonist. Of course, other useful types of administration of the two drugs are also contemplated, such as nasal sprays, transdermal, intravenous, suppositories, sustained release dosage forms, and the like. Any form of administration will work so long as the proper dosage is administered without destroying the active ingredient.

In some embodiments, the additional antiviral agent is administered throughout the course of NS3 inhibitor compound treatment. In other embodiments, the administration of the other antiviral agent overlaps the NS3 inhibitor compound treatment for a period of time, e.g., the other antiviral agent treatment can begin before the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; Treatment with other antiviral agents can begin after initiation of NS3 inhibitor compound treatment and end after end of NS3 inhibitor compound treatment; other antiviral agent treatment can begin after initiation of NS3 inhibitor compound treatment and before end of NS3 inhibitor compound treatment end; or other antiviral agent treatment can start before NS3 inhibitor compound treatment begins and end after NS3 inhibitor compound treatment ends.

The NS3 inhibitor compounds of the examples are suitable for formulations requiring good water solubility. For example, the compounds of the examples can be used without sugar alcohols and polyalcohols (such as trihydric or higher sugar alcohols, such as glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol alcohol and mannitol) and are free of other alcohols such as propylene glycol and polyethylene glycol (PEG) or other agents used to compensate for insufficient water solubility. In one aspect, the embodiments provide said NS3 inhibitor compound in a capsule, tablet or caplet formulation, wherein said capsule, tablet or caplet formulation provides Adequate bioavailability. In some embodiments, the solubility of the compound permits administration of a dose equal to or greater than 1 mg of the pharmaceutical compound per kilogram of patient body weight.

treatment method

Monotherapy

Example NS3 inhibitor compounds can be used in the acute or chronic therapy of HCV disease. In many embodiments, the NS3 inhibitor compound is administered for 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 week. months to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months , or at least one year, and can be administered for a longer period. Administration of the NS3 inhibitor compound can be five times a day, four times a day, three times a day (tid), twice a day (bid), once a day (qd), every other day (qod), twice a week ( biw), three times a week (tiw), once a week (qw), every other week (qow), three times a month, or once a month. In other embodiments, the NS3 inhibitor compound is administered as a continuous infusion.

In many embodiments, the NS3 inhibitor compounds of the embodiments are administered orally.

With regard to the above method of treating HCV disease in a patient, the NS3 inhibitor compound of the embodiments may be administered to the patient in 1 to 5 doses per day at a dose of about 0.01 mg to about 100 mg per kilogram of patient body weight per day. In some embodiments, the NS3 inhibitor compound is administered in 1 to 5 divided doses per day at a dose of about 0.5 mg to about 75 mg per kilogram of patient body weight per day.

The amount of active ingredient which can be combined with the carrier materials to produce a dosage form will depend upon the host to be treated and the particular mode of administration. A typical pharmaceutical formulation may contain from about 5% to about 95% active ingredient (weight/weight). In other embodiments, pharmaceutical formulations may contain from about 20% to about 80% active ingredient.

Those skilled in the art will readily appreciate that dosage levels may vary as a function of the particular NS3 inhibitor compound, severity of symptoms, and susceptibility of the subject to side effects. Preferred dosages for a given NS3 inhibitor compound can be readily determined by one of ordinary skill in the art according to a variety of methods. A preferred method is to measure the physiological potency of a given interferon receptor agonist.

In many embodiments, multiple doses of an NS3 inhibitor compound are administered. For example, administration of the NS3 inhibitor compound is once a month, twice a month, three times a month, every other week (qow), once a week (qw), twice a week (biw), three times a week ( tiw), four times a week, five times a week, six times a week, every other day (qod), once a day (qd), twice a day (qid), or three times a day for a duration ranging from about one day to about one week, about two weeks to about four weeks, about one month to about two months, about two months to about four months, about four months to about six months, about six months to about eight months, about Eight months to about one year, about one year to about two years, about two years to about four years or more.

Combination therapy with ribavirin

In some embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as described above and an effective amount of ribavirin. Ribavirin may be administered at a dosage of about 400 mg, about 800 mg, about 1000 mg or about 1200 mg per day.

One embodiment provides a modification of any of the above methods comprising co-administering to a patient a therapeutically effective amount of ribavirin for a desired duration of NS3 inhibitor compound treatment.

Another embodiment provides a modification of any of the above methods comprising co-administering to a patient about 800 mg to about 1200 mg of ribavirin orally per day for the desired course of NS3 inhibitor compound treatment.

Another embodiment provides a modification of any of the above methods, comprising co-administering ribavirin to a patient daily by oral administration: 1000 mg per day for patients weighing less than 75 kg, and 1000 mg per day for patients weighing greater than or equal to 75 kg. The daily dose is 1200 mg; wherein the daily dose of ribavirin is divided into two dosages according to the situation, and the desired course of treatment of the NS3 inhibitor compound is continued.

Combination therapy with levovirin

In some embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as described above and an effective amount of levovirin. The usual dosage of levovirin ranges from 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, about 700 mg to about 900 mg, or about 10 mg per kilogram of body weight per day. In some embodiments, levovirin is administered orally at a dose of about 400 mg, about 800 mg, about 1000 mg, or about 1200 mg per day for the desired course of NS3 inhibitor compound treatment.

Combination therapy with viramiditie

In some embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as described above and an effective amount of vilamidine. The usual dosage range of veramidine is about 30mg to about 60mg, about 60mg to about 125mg, about 125mg to about 200mg, about 200mg to about 300mg, about 300mg to about 400mg, about 400mg to about 1200mg, about 600mg to About 1000 mg, about 700 mg to about 900 mg, or about 10 mg per kilogram of body weight per day. In some embodiments, veramidine is administered orally at a dose of about 800 mg or about 1,600 mg per day for the desired course of NS3 inhibitor compound therapy.

Combination therapy with thymosin-alpha

In some embodiments, the methods provide a combination therapy comprising administering 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 can be administered thrice daily, twice daily, once daily, every other day, twice weekly, thrice weekly, weekly, every other week, thrice monthly, monthly, and The desired course of NS3 inhibitor compound treatment is continued substantially continuously or continuously. In many embodiments, thymosin-alpha is administered twice weekly for the desired course of NS3 inhibitor compound treatment.

An effective dosage range of thymosin-alpha is from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, 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, about 4.5 mg to about 5.0 mg. In specific embodiments, the administered dose of thymosin-alpha comprises an amount of 1.0 mg or 1.6 mg.

The administration of thymosin-alpha can be continued for a period of time ranging from about one day to about one week, about two weeks to about four weeks, about one month to about two months, about two months to about four months, about four months to about six months months, from about six months to about eight months, from about eight months to about one year, from about one year to about two years, or from about two years to about four years, or longer. In one embodiment, thymosin-alpha is administered for the desired course of NS3 inhibitor compound therapy.

Combination therapy with interferon

In many embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as described above and an effective amount of an interferon receptor agonist. In some embodiments, a compound of Formula I and a Type I or Type III interferon receptor agonist are co-administered in the methods of treatment of the embodiments. Type I interferon receptor agonists suitable for use herein include any interferon-alpha (IFN-alpha). In certain embodiments, the interferon-alpha is pegylated interferon-alpha. In other certain embodiments, the interferon-alpha is a consensus interferon, such as INFERGEN_interferon alfacon-1. While in other embodiments, the interferon-alpha is monopegylated (30 kD, linear) consensus interferon.

Effective dosage ranges for IFN-α are about 3 μg to about 27 μg, about 3 MU to about 10 MU, about 90 μg to about 180 μg, or about 18 μg to about 90 μg. Effective dosage ranges for Infergen® complexed IFN-alpha include about 3 μg, about 6 μg, about 9 μg, about 12 μg, about 15 μg, about 18 μg, about 21 μg, about 24 μg, about 27 μg, or about 30 μg of drug per dose. Effective doses of IFN-α2a and IFN-α2b range from approximately 3 million units (MU) to 10 MU per dose. Effective dosages of PEGASYS_PEGylated IFN-α2a comprise an amount of about 90 μg to 270 μg or about 180 μg of drug per dose. Effective dosages of PEG-INTRON_PEGylated IFN-α2b comprise an amount of about 0.5 μg to 3.0 μg of drug per kilogram body weight per dose. An effective dose of pegylated consensus interferon (PEG-CIFN) contains an amount of about 18 μg to about 90 μg or about 27 μg to about 60 μg or about 45 μg of the CIFN amino acid weight per dose of PEG-CIFN. Effective amounts of monoPEGylated (30 kD, linear) CIFN comprise amounts 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 per dose. IFN-[alpha] can be administered substantially continuously or continuously once daily, every other day, weekly, thrice weekly, every other week, thrice monthly, monthly.

In many embodiments, the Type I or Type III interferon receptor agonist and/or the Type II interferon receptor agonist are administered for 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 months to about 8 months, or about 8 months to about 12 months, or at least one year, and longer periods of time can be administered. Dosage regimens may include thrice daily, twice daily, once daily, every other day, twice weekly, thrice weekly, weekly, every other week, thrice monthly, or monthly administration. Some embodiments provide any of the above methods, wherein the dose is administered by bolus once daily, every other day, three times a week, twice a week, once a week, every other week, three times a month, or once a month The desired dose of IFN-[alpha] is administered subcutaneously to the patient, or is administered subcutaneously to the patient daily by substantially continuous or continuous administration, for the desired duration of treatment. Other embodiments provide any of the above methods, wherein the desired dose of pegylated IFN-α (PEG-IFN-α ) subcutaneously administered to the patient for the desired duration of treatment.

In other embodiments, an NS3 inhibitor compound and a Type II interferon receptor agonist are co-administered in the methods of treatment of the embodiments. Type II interferon receptor agonists suitable for use herein include any interferon-gamma (IFN-gamma).

The effective dosage range of IFN-γ is about 0.5 μg/m ² to about 500 μg/m ² , usually about 1.5 μg/m ² to 200 μg/m ² , depending on the size of the patient. This activity is based on 10 International Units (U) per 50 μg of protein. Administration of IFN-γ can be daily, every other day, three times a week, or substantially continuously or continuously.

In particular embodiments contemplated, IFN-γ is administered to the 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 embodiment of particular interest, the dose is about 200 μg IFN-γ. In many of the embodiments of interest, IFN-γ1b is administered.

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

The body surface area of an individual subject is generally between about 1.33 ^m2 and about 2.50 ^m2 . Thus, in many embodiments, the IFN-γ dose is between about 150 μg/m ² and about 20 μg/m ² . For example, the IFN-γ dosage range 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 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 about 140 μg/m ² to about 150 μg/m ² . In other embodiments, the dosage range is between about 25 μg/m ² to about 100 μg/m ² . In other embodiments, the dose ranges from about 25 μg/m ² to about 50 μg/m ² .

In some embodiments, the Type I or Type III interferon receptor agonist is administered with a first dosing regimen followed by a second dosing regimen. The first dosing regimen for a Type I or Type III interferon receptor agonist (also referred to as an "induction regimen") typically involves administering a higher dose of the Type I or Type III interferon receptor agonist. For example, in the case of Infergen® complex IFN-alpha (CIFN), the first dosing regimen comprises administering about 9 μg, about 15 μg, about 18 μg, or about 27 μg of CIFN. The first dosing regimen may comprise a single dosing event or at least two or more dosing events. The first dosing regimen of a Type I or Type III interferon receptor agonist may be administered daily, every other day, three times a week, every other week, three times a month, once a month in substantially continuous or continuous administration.

The first dosing regimen of a Type I or Type III interferon receptor agonist is administered for a first period of time, which may be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.

A second dosing regimen (also referred to as a "maintenance dose") of a Type I or Type III interferon receptor agonist typically involves administering a lower dose of the Type I or Type III interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CIFN at a dose of at least about 3 μg, at least about 9 μg, at least about 15 μg, or at least about 18 μg. The second dosing regimen includes a single dosing event or at least two or more dosing events.

The second dosing regimen of the Type I or Type III interferon receptor agonist may be once daily, every other day, three times per week, every other week, three times per month, once per month in substantially continuous or continuous administration.

In some embodiments, an "induction/maintenance" dosing regimen of a Type I or Type III interferon receptor agonist includes a "prime ( priming)” dose. In these embodiments, IFN-γ is administered for about 1 day to about 14 days, about 2 days to about 10 days, or about 3 days to about 7 days prior to initiation of treatment with the Type I or Type III interferon receptor agonist. time period of the day. This period of time is called the "startup" period.

In some of these embodiments, the Type II interferon receptor agonist treatment is continued throughout the period of treatment with the Type I or Type III interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is interrupted prior to the end of treatment with the Type I or Type III interferon receptor agonist. In these embodiments, the total duration of treatment with the Type II interferon receptor agonist (including the "priming" period) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days , from about 10 days to about 18 days, or from about 12 days to about 16 days. In yet other embodiments, the Type II interferon receptor agonist treatment is discontinued once the Type I or Type III interferon receptor agonist treatment is initiated.

In other embodiments, the Type I or Type III interferon receptor agonist is administered with the first dosing regimen. For example, in the case of CIFN, the dose of CIFN typically ranges from about 3 μg to about 15 μg or from about 9 μg to about 15 μg. Doses of a Type I or Type III interferon receptor agonist may generally be administered daily, every other day, three times a week, every other week, three times a month, once a month in substantially continuous or continuous administration. The dose of a Type I or Type III interferon receptor agonist can be administered for a period of time which can be, for example, at least about 24 weeks to at least about 48 weeks or longer.

In some embodiments, a "prime" dose of a Type II interferon receptor agonist (eg, IFN-γ) is included when administering the first dosing regimen of a Type I or Type III interferon receptor agonist. In these embodiments, IFN-γ is administered for about 1 day to about 14 days, about 2 days to about 10 days, or about 3 days to about 7 days prior to initiation of treatment with the Type I or Type III interferon receptor agonist. time period of the day. This period of time is called the "startup" period. In some of these embodiments, the Type II interferon receptor agonist treatment is continued throughout the period of treatment with the Type I or Type III interferon receptor agonist. In other embodiments, the Type II interferon receptor agonist treatment is interrupted prior to the end of treatment with the Type I or Type III interferon receptor agonist. In these embodiments, the total duration of treatment with the Type II interferon receptor agonist (including the "priming" period) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days , from about 10 days to about 18 days, or from about 12 days to about 16 days. In yet other embodiments, the Type II interferon receptor agonist treatment is discontinued once the Type I or Type III interferon receptor agonist treatment is started.

In additional embodiments, an NS3 inhibitor compound, a Type I or Type III interferon receptor agonist, and a Type II interferon receptor agonist are co-administered in the methods of the embodiments for the desired duration of treatment. In some embodiments, an NS3 inhibitor compound, interferon-alpha, and interferon-gamma are co-administered in the methods of the embodiments for the desired duration of treatment.

Some embodiments provide methods of using a Type I or Type III interferon receptor agonist, Type II interferon receptor agonist, and NS3 inhibitor compound in an amount effective to treat an HCV infection in a patient. In some embodiments, the embodiments provide methods of using effective amounts of IFN-α, IFN-γ, and NS3 inhibitor compounds in the treatment of HCV infection in a patient. One embodiment provides methods of using an effective amount of a combination of IFN-[alpha], IFN-[gamma] and NS3 inhibitor compounds in the treatment of HCV infection in a patient.

Generally, effective amounts of consensus interferon (CIFN) and IFN-γ suitable for use in the methods of the examples are provided by a dose ratio of 1 μg CIFN: 10 μg IFN-γ, wherein both CIFN and IFN-γ are unpegylated and Unglycosylated species.

One embodiment provides any of the above methods modified to use an effective amount of INFERGEN-complexed IFN-alpha and IFN-gamma in the treatment of HCV infection in a patient, said method comprising: subcutaneous once daily, every other day INFERGEN® is administered to a patient once, three times a week, twice a week, once a week, once every other week, three times a month, or once a month, or substantially continuously or continuously each day, comprising about 1 μg to An amount of drug of about 30 μg; and administering a certain amount to the patient subcutaneously once daily, every other day, three times a week, twice a week, once a week, every other week, three times a month, or once a month, or substantially continuously or continuously every day A dose of IFN-γ comprising a drug amount of about 10 μg to about 300 μg of IFN-γ per dose; said administration continues for the duration of the NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of INFERGEN-complexed IFN-alpha and IFN-gamma in the treatment of a viral infection in a patient, said method comprising: subcutaneous once daily, Administering to the patient once every other day, three times a week, twice a week, once a week, once every other week, three times a month, or once a month, or substantially continuously or continuously, a dose of INFERGEN® comprising about 1 μg of INFERGEN® per dose up to about 9 μg of drug in an amount; and administering a certain amount to the patient subcutaneously once daily, every other day, three times a week, twice a week, once a week, every other week, three times a month, or once a month, or substantially continuously or continuously every day A dose of IFN-γ comprising a drug amount of about 10 μg to about 100 μg of IFN-γ per dose; said administration continues for the duration of NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of INFERGEN-complexed IFN-alpha and IFN-gamma in the treatment of a viral infection in a patient, said method comprising: subcutaneous once daily, Administering to the patient once every other day, three times a week, twice a week, once a week, once every other week, three times a month, or once a month, or substantially continuously or continuously, a dose of INFERGEN® comprising about 1 μg of INFERGEN® per dose amount of drug; and administering a dose of IFN to the patient subcutaneously once daily, every other day, three times a week, twice a week, once a week, every other week, three times a month, or once a month, or substantially continuously or continuously every day - gamma comprising a drug amount of about 10 μg to about 50 μg of IFN-gamma per dose; said administration continues for the duration of NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of INFERGEN-complexed IFN-alpha and IFN-gamma in the treatment of a viral infection in a patient, said method comprising: subcutaneous once daily, Administering to the patient once every other day, three times a week, twice a week, once a week, once every other week, three times a month, or once a month, or substantially continuously or continuously daily, a dose of INFERGEN® comprising about 9 μg of INFERGEN® per dose amount of drug; and administering a dose of IFN to the patient subcutaneously once daily, every other day, three times a week, twice a week, once a week, every other week, three times a month, or once a month, or substantially continuously or continuously every day - gamma comprising a drug amount of about 90 μg to about 100 μg of IFN-gamma per dose; said administration continues for the duration of NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of INFERGEN-complexed IFN-alpha and IFN-gamma in the treatment of a viral infection in a patient, said method comprising: subcutaneous once daily, Administering to the patient once every other day, three times a week, twice a week, once a week, once every other week, three times a month, or once a month, or substantially continuously or daily, a dose of INFERGEN® comprising about 30 μg of INFERGEN® per dose amount of drug; and administering a dose of IFN to the patient subcutaneously once daily, every other day, three times a week, twice a week, once a week, every other week, three times a month, or once a month, or substantially continuously or continuously every day - gamma comprising a drug amount of about 200 μg to about 300 μg of IFN-gamma per dose; said administration continues for the duration of NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of pegylated conjugated IFN-α and IFN-γ in the treatment of a viral infection in a patient, the method comprising: subcutaneous weekly Administering to the patient once, every other week, three times a month, or once a month a dose of pegylated conjugated IFN-alpha (PEG-CIFN) comprising about 4 μg to about 60 μg of CIFN amino acid weight per dose of PEG-CIFN and subcutaneous administration of a total weekly dose of IFN-γ containing about 30 μg to about 1000 [mu]g drug amount; the administration lasts for the duration of NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of pegylated conjugated IFN-α and IFN-γ in the treatment of a viral infection in a patient, the method comprising: subcutaneous weekly Administering to the patient once, every other week, three times a month, or once a month a dose of pegylated conjugated IFN-alpha (PEG-CIFN) comprising about 18 μg to about 24 μg of CIFN amino acid weight per dose of PEG-CIFN and a total weekly dose of IFN-γ by subcutaneous administration once a day, every other day, three times a week, twice a week, or in substantially continuous or continuous weekly divided doses containing about 100 μg to about 300 [mu]g drug amount; the administration lasts for the duration of NS3 inhibitor compound treatment.

Generally, effective amounts of IFN-α 2a or 2b or 2c and IFN-γ suitable for use in the methods of the examples are provided by a dose ratio of 1 million units (MU) of IFN-α 2a or 2b or 2c:30 μg IFN-γ, wherein Both IFN-α 2a or 2b or 2c and IFN-γ are non-pegylated and non-glycosylated species.

Another embodiment provides any of the above methods modified to use an effective amount of IFN-α 2a or 2b or 2c and IFN-γ in the treatment of a viral infection in a patient, the method comprising: subcutaneous once daily , once every other day, three times a week, twice a week, or substantially continuously or continuously administering to a patient a dose of IFN-α 2a or 2b or 2c each day, comprising about 1 MU to about 20 MU of IFN-α 2a or 2b or 2c per dose Amount of drug; and subcutaneous administration of a dose of IFN-γ by subcutaneous once daily, once every other day, three times a week, twice a week, or substantially continuously or continuously per day, containing a drug amount of about 30 μg to about 600 μg of IFN-γ per dose ; the administration lasts for the duration of NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of IFN-α 2a or 2b or 2c and IFN-γ in the treatment of a viral infection in a patient, the method comprising: subcutaneous once daily , administering a certain dose of IFN-α2a or 2b or 2c to the patient once every other day, three times a week, twice a week or every day substantially continuously or continuously, which comprises a drug amount of about 3 MU per dose of IFN-α2a or 2b or 2c; And subcutaneously once a day, once every other day, three times a week, twice a week or substantially continuously or continuously administering a certain dose of IFN-γ every day, which contains a drug amount of about 100 μg of IFN-γ per dose; the administration lasts for NS3 Inhibitor Compound Treatment Time.

Another embodiment provides any of the above methods modified to use an effective amount of IFN-α 2a or 2b or 2c and IFN-γ in the treatment of a viral infection in a patient, the method comprising: subcutaneous once daily , administering a dose of IFN-α 2a or 2b or 2c to the patient once every other day, three times a week, twice a week or daily, substantially continuously or continuously, comprising a drug amount of about 10 MU per dose of IFN-α 2a or 2b or 2c; And subcutaneously once a day, once every other day, three times a week, twice a week, or substantially continuously or continuously administering a certain dose of IFN-γ every day, which contains a drug amount of about 300 μg of IFN-γ per dose; the administration lasts for NS3 Inhibitor Compound Treatment Time.

Another embodiment provides any of the above methods modified to use an effective amount of PEGASYS_PEGylated IFN-α2a and IFN-γ in the treatment of a viral infection in a patient, the method comprising: subcutaneously each Administer PEGASYS® to the patient once weekly, every other week, three times monthly, or once monthly, comprising an amount of PEGASYS® of about 90 μg to about 360 μg per dose; and subcutaneously once daily, every other day, every Wednesday Administering a total weekly dose of IFN-γ containing about 30 μg to about 1,000 μg of drug per week in divided, substantially continuous or continuous weekly doses; the administration continues for the duration of the NS3 inhibitor compound treatment .

Another embodiment provides any of the above methods modified to use an effective amount of PEGASYS_PEGylated IFN-α2a and IFN-γ in the treatment of a viral infection in a patient, the method comprising: subcutaneously each Once a week, every other week, three times a month, or once a month, the patient is administered a dose of PEGASYS_ comprising approximately 180 μg per dose of PEGASYS_; and subcutaneously once a day, every other day, three times a week, every A total weekly dose of IFN-[gamma] containing about 100 [mu]g to about 300 [mu]g of drug per week is administered twice weekly or in substantially continuous or continuous weekly fractions; said administration continues for the duration of the NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of PEG-INTRON-PEGylated complex IFN-α2b and IFN-γ in the treatment of a viral infection in a patient, the method comprising: Administering PEG-INTRON to the patient subcutaneously once a week, every other week, three times a month, or once a month, comprising an amount of drug of about 0.75 μg to about 3.0 μg of PEG-INTRON per kilogram of body weight per dose; and administering a total weekly dose of IFN-γ subcutaneously once a day, every other day, three times a week, twice a week, or substantially continuously or in successive weekly divisions, the total dose containing a drug amount of about 30 μg to about 1000 μg per week ; the administration lasts for the duration of NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of PEG-INTRON_PEGylated IFN-α2b and IFN-γ in the treatment of a viral infection in a patient, the method comprising: by A dose of PEG-INTRON_ comprising about 1.5 μg per kilogram of body weight per dose of PEG-INTRON_ is administered subcutaneously to the patient once a week, every other week, three times a month, or once a month; Once, every other day, three times a week, twice a week, or substantially continuously or continuously divided into weekly doses of IFN-γ, a total weekly dose of IFN-γ containing about 100 μg to about 300 μg of drug per week; NS3 Inhibitor Compound Treatment Timing.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; subcutaneously administering 9 μg of INFERGEN-complexed IFN-α with A regimen of oral once-daily ribavirin with a duration of therapy of 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to include administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and subcutaneously administering 9 μg of INFERGEN-complexed IFN- α, Subcutaneous administration of 50 μg Actimmune_human IFN-γ1b three times a week and oral administration of ribavirin once a day, wherein the duration of treatment was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to include administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and subcutaneously administering 9 μg of INFERGEN-complexed IFN- α. Subcutaneous administration of 100 μg Actimmune_human IFN-γ1b three times a week and oral administration of ribavirin once a day, wherein the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to include administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and subcutaneously administering 9 μg of INFERGEN-complexed IFN- α and a regimen of 50 μg Actimmune_Human IFN-γ1b administered subcutaneously three times per week for a duration of 48 weeks.

One embodiment provides any of the above methods modified to include administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and subcutaneously administering 9 μg of INFERGEN-complexed IFN- α and a regimen of 100 μg Actimmune_Human IFN-γ1b administered subcutaneously three times per week for a duration of 48 weeks.

One embodiment provides any of the above methods modified to include administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and subcutaneously administering 9 μg of INFERGEN-complexed IFN- α. Subcutaneous administration of 25 μg Actimmune_human IFN-γ1b three times a week and oral administration of ribavirin once a day, wherein the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to include administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and subcutaneously administering 9 μg of INFERGEN-complexed IFN- α. Subcutaneous administration of 200 μg Actimmune_human IFN-γ1b three times a week and oral administration of ribavirin once a day, wherein the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to include administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and subcutaneously administering 9 μg of INFERGEN-complexed IFN- α and a regimen of 25 μg Actimmune_Human IFN-γ1b administered subcutaneously three times per week for a duration of 48 weeks.

One embodiment provides any of the above methods modified to include administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and subcutaneously administering 9 μg of INFERGEN-complexed IFN- α and a regimen of 200 μg Actimmune_Human IFN-γ1b administered subcutaneously three times per week for a duration of 48 weeks.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; 100 μg of monopegylated by subcutaneous administration once every ten days or once a week (30kD, linear) compound IFN-α and oral once-daily administration of ribavirin, wherein the duration of therapy is 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; 100 μg of monopegylated by subcutaneous administration once every ten days or once a week (30 kD, linear) complex IFN-α, 50 μg Actimmune-human IFN-γ1b administered subcutaneously three times per week and ribavirin orally once daily, with a duration of therapy of 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and administering 100 μg monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30kD, linear) compounded IFN-α, 100 μg Actimmune_human IFN-γ1b administered subcutaneously three times a week and ribavirin administered orally once a day, wherein the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more. One embodiment provides any of the above methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and administering 100 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30 kD, linear) complexed IFN-α and 50 μg Actimmune_human IFN-γ1b administered subcutaneously three times per week with a duration of therapy of 48 weeks.

One embodiment provides any of the above methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and administering 100 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30 kD, linear) complexed IFN-α and 100 μg Actimmune_human IFN-γ1b administered subcutaneously three times per week with a duration of therapy of 48 weeks.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and administering 150 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30kD, linear) combined with IFN-α and oral once-daily ribavirin regimen, where the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and administering 150 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30 kD, linear) complex IFN-α, 50 μg Actimmune_human IFN-γ1b administered subcutaneously three times a week and ribavirin administered orally once daily, where the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and administering 150 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30kD, linear) compounded IFN-α, 100 μg Actimmune_human IFN-γ1b administered subcutaneously three times a week and ribavirin administered orally once a day, wherein the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and administering 150 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30 kD, linear) complexed IFN-α and 50 μg Actimmune_human IFN-γ1b administered subcutaneously three times per week with a duration of therapy of 48 weeks.

One embodiment provides any of the above methods modified to comprise administering to an individual with HCV infection an effective amount of an NS3 inhibitor; and administering 150 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30 kD, linear) complexed IFN-α and 100 μg Actimmune_human IFN-γ1b administered subcutaneously three times per week with a duration of therapy of 48 weeks.

One embodiment provides any of the above methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and administering 200 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30kD, linear) combined with IFN-α and oral once-daily ribavirin regimen, where the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and administering 200 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30 kD, linear) complex IFN-α, 50 μg Actimmune_human IFN-γ1b administered subcutaneously three times a week and ribavirin administered orally once daily, where the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and administering 200 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30kD, linear) compounded IFN-α, 100 μg Actimmune_human IFN-γ1b administered subcutaneously three times a week and ribavirin administered orally once a day, wherein the duration of therapy was 48 weeks. In this example, ribavirin was administered in an amount of 1000 mg for individuals weighing less than 75 kg and 1200 mg for individuals weighing 75 kg or more.

One embodiment provides any of the above methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and administering 200 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30 kD, linear) complexed IFN-α and 50 μg Actimmune_human IFN-γ1b administered subcutaneously three times per week with a duration of therapy of 48 weeks.

One embodiment provides any of the above methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and administering 200 μg of monopolyethylene glycol subcutaneously once every ten days or once a week Alcoholated (30 kD, linear) complexed IFN-α and 100 μg Actimmune_human IFN-γ1b administered subcutaneously three times per week with a duration of therapy of 48 weeks.

Any of the above methods involving administration of an INS3 inhibitor, a type I interferon receptor agonist (e.g., IFN-α), and a type II interferon receptor agonist (e.g., IFN-γ) increases the effective amount of TNF - Administration of an alpha antagonist (eg, a TNF-alpha antagonist other than pirfenidone or a pirfenidone analog). Illustrative, non-limiting TNF-α antagonists suitable for use in such combination therapy include ENBREL®, REMICADE®, and HUMIRA ^™ .

One embodiment provides a method for using an effective amount of ENBREL-, an effective amount of IFN-α, an effective amount of IFN-γ, and an effective amount of an NS3 inhibitor in the treatment of HCV infection in a patient, the method comprising subcutaneously once a day, every other day, every other day, Three times a week, once a week, once every other week, three times a month, once a month or once every other month, or substantially continuously or daily, the patient is administered a dose of ENBREL® comprising 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 about 15 mg, about 15 mg to about 20 mg or about 20 mg to about 23 mg of ENBREL®, administered for the desired duration of treatment.

One embodiment provides a method of using an effective amount of REMICADE®, an effective amount of IFN-α, with or without an effective amount of IFN-γ, and an effective amount of an NS3 inhibitor in the treatment of HCV infection in a patient, said method comprising intravenously once daily, Administer REMICADE® to a patient once every other day, three times a week, twice a week, once a week, once every other week, three times a month, once a month or every other month, or substantially continuously or daily, comprising each dose of REMICADE - 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 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, the administration continues for the desired treatment time.

One embodiment provides a method of using an effective amount of HUMIRA ^™ , an effective amount of IFN-α, an effective amount of IFN-γ and an effective amount of an NS3 inhibitor in the treatment of HCV infection in a patient, said method comprising subcutaneously once daily, every other day, Three times a week, twice a week, once a week, once every other week, three times a month, once a month or ^{once every other month, or substantially continuously or daily, the patient is administered a dose of HUMIRA™ comprising} 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 15 mg, about From 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg, administered for the desired duration of treatment.

Combination therapy with pirfenidone

In many embodiments, the methods provide a combination therapy comprising administering an NS3 inhibitor compound as described above and an effective amount of pirfenidone or a pirfenidone analog. In some embodiments, an NS3 inhibitor compound, one or more interferon receptor agonists, and pirfenidone or a pirfenidone analog are co-administered in the methods of treatment of the embodiments. In certain embodiments, an NS3 inhibitor compound, a Type I interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered. In other embodiments, an NS3 inhibitor compound, a Type I interferon receptor agonist, a Type II interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered. Type I interferon receptor agonists suitable for use herein include any IFN-α, such as interferon-α2a, interferon-α2b, interferon alfacon-1; and pegylated IFN-α, such as pegylated interferon pegylated interferon-alpha 2a, pegylated interferon-alpha 2b; and pegylated consensus interferon, such as monopegylated (30 kD, linear) consensus interferon. Type II interferon receptor agonists suitable for use herein include any interferon-gamma (IFN-gamma).

Administration of pirfenidone or pirfenidone analogs can be 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, once a day, or divide the daily dose into once to five times a day, and the administration period is about one day to about one week, about two weeks to about four weeks, about one month to about two months, about two months months to about four months, about four months to about six months, about six months to about eight months, about eight months to about one year, about one year to about two years, or about two years to about four years, or longer.

Effective amounts of pirfenidone or specific pirfenidone analogs include doses based on body weight of between about 5 mg/kg to about 125 mg/kg per day, or about 400 mg to about 3600 mg or about 800 mg to about 2400 mg or about A fixed dose of 1000 mg to about 1800 mg or about 1200 mg to about 1600 mg is administered in one to five divided doses per day. Other dosages and formulations of pirfenidone and certain pirfenidone analogs useful in the treatment of fibrotic diseases are described in US Patent Nos. 5,310,562, 5,518,729, 5,716,632 and 6,090,822.

One embodiment provides a modification of any of the above methods comprising co-administering to a patient a therapeutically effective amount of pirfenidone or a pirfenidone analog for a desired duration of NS3 inhibitor compound treatment.

Combination therapy with TNF-α antagonists

In many embodiments, the methods provide a combination therapy comprising administering an effective amount of an NS3 inhibitor compound described above and an effective amount of a TNF-α antagonist in a combination therapy for the treatment of HCV infection.

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

In some embodiments, effective doses of TNF-alpha antagonists are expressed in mg/kg body weight. In these embodiments, the effective dose of TNF-alpha antagonist is about 0.1 mg/kg body weight to about 10 mg/kg body weight, for example, about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, about 0.5 mg/kg body weight to about 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 administered for 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 months 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 months, or at least a year, and can be administered for longer periods of time. The administration of TNF-α antagonist can be three times a day, twice a day, once a day, once every other day, twice a week, three times a week, once a week, once every other week, three times a month, once a month, Generally continuous or continuous.

In many embodiments, multiple doses of the TNF-alpha antagonist are administered. For example, the administration of TNF-alpha antagonist is once a month, twice a month, three times a month, every other week (qow), once a week (qw), twice a week (biw), three times a week (tiw), four times a week, five times a week, six times a week, every other day (qod), once a day (qd), twice a day (bid), or three times a day, generally continuous or continuous, continuous The time range is from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about About eight months, about eight months to about one year, about one year to about two years, about two years to about four years or more.

TNF-α antagonists and NS3 inhibitors are usually administered in separate formulations. The TNF-alpha antagonist and the NS3 inhibitor can be substantially continuously or continuously for about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours Hours, about 72 hours, about 4 days, about 7 days, or about 2 weeks.

One embodiment provides a method of using an effective amount of a TNF-alpha antagonist and an effective amount of an NS3 inhibitor in the treatment of HCV infection in a patient, said method comprising subcutaneously once daily, every other day, three times a week or twice a week or every day Doses of the TNF-alpha antagonist comprising from about 0.1 μg to about 40 mg per dose of the TNF-alpha antagonist are administered to the patient substantially continuously or continuously for the desired time of NS3 inhibitor compound treatment.

One embodiment provides a method of using an effective amount of ENBREL® and an effective amount of an NS3 inhibitor in the treatment of HCV infection in a patient, said method comprising subcutaneously once daily, every other day, three times a week, twice a week, once a week , once every other week, three times a month, once a month or once every other month, or daily substantially continuously or continuously to a patient, administer a dose of ENBREL_ comprising about 0.1 μg to about 23 mg, about 0.1 μg to about 1 μg, about 1 μg per dose 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 20 mg, or about 20 mg to about 23 mg of ENBREL®, this administration The NS3 inhibitor compound treatment is continued for as long as desired.

One embodiment provides a method of using an effective amount of REMICADE® and an effective amount of an NS3 inhibitor in the treatment of HCV infection in a patient, said method comprising intravenously once daily, every other day, three times a week, twice a week, once a week , once every other week, three times a month, once a month or once every other month, or substantially continuously or continuously administer a dose of REMICADE_ to the patient every day, which includes each dose of REMICADE_ from 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 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 to about 4.0 mg/kg, or about 4.0 mg/kg to An amount of about 4.5 mg/kg is administered for the time required for NS3 inhibitor compound treatment.

One embodiment provides a method of using an effective amount of HUMIRA ^™ and an effective amount of an NS3 inhibitor in the treatment of HCV infection in a patient, said method comprising subcutaneously once daily, every other day, three times a week, twice a week, once a week , once every other week, three times a month, once a month or once every other month, or substantially continuously or daily, to a patient a dose of HUMIRA ^™ comprising about 0.1 μg to about 35 mg, about 0.1 μg to about 1 μg of HUMIRA™ ^per dose , 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 20 mg, about 20 mg to about 25 mg , in an amount of from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg, administered for the time desired for NS3 inhibitor compound treatment.

Combination therapy with thymosin-alpha

In many embodiments, the methods provide a combination therapy comprising administering an effective amount of an NS3 inhibitor compound described above and an effective amount of thymosin-alpha in combination therapy for the treatment of HCV infection.

An effective dosage range of thymosin-alpha is from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, 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, about 4.5 mg to about 5.0 mg. In specific embodiments, the administered dose of thymosin-alpha comprises an amount of 1.0 mg or 1.6 mg.

One embodiment provides a method of using an effective amount of ZADAXIN ^™ thymosin-alpha and an effective amount of an NS3 inhibitor in the treatment of HCV infection in a patient, the method comprising subcutaneously administering to the patient twice weekly a dose of ZADAXIN ^™ containing The administration is in the amount of about 1.0 mg to about 1.6 mg per dose for the desired time of NS3 inhibitor compound treatment.

Combination therapy with TNF-α antagonists and interferon

Some embodiments provide methods of treating HCV infection in an individual having HCV infection comprising administering an effective amount of an NS3 inhibitor and an effective amount of a TNF-alpha antagonist and an effective amount of one or more interferons.

One embodiment provides any of the above methods modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist in the treatment of HCV infection in a patient, said method comprising subcutaneous once daily, every other day, Three times a week, twice a week, once a week, once every other week, three times a month, once a month or daily, a dose of IFN-γ containing about 10 μg of IFN-γ per dose is administered to the patient substantially continuously or continuously up to about 300 μg of drug in an amount; and subcutaneous administration of a dose of the TNF-α antagonist once a day, every other day, three times a week, or twice a week, or substantially continuously or continuously each day, containing each dose of the TNF-α antagonist The dose is in an amount from about 0.1 μg to about 40 mg; the administration is continued for the time required for NS3 inhibitor compound treatment.

One embodiment provides any of the above methods modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist in the treatment of HCV infection in a patient, said method comprising subcutaneous once daily, every other day, Three times a week, twice a week, once a week, once every other week, three times a month, once a month or daily, a dose of IFN-γ containing about 10 μg of IFN-γ per dose is administered to the patient substantially continuously or continuously up to about 100 μg of the drug in an amount; and administering a dose of the TNF-α antagonist subcutaneously once a day, every other day, three times a week, or twice a week, or substantially continuously or continuously each day, containing each dose of the TNF-α antagonist The dose is in an amount from about 0.1 μg to about 40 mg; the administration is continued for the time required for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist in the treatment of HCV infection in a patient, said method comprising subcutaneous once-daily, every-other-day , administering to a patient a total weekly dose of IFN-γ containing from about 30 μg to about 1,000 μg of drug in weekly divided doses substantially continuously or continuously three times a week, twice a week, or daily; Once a day, once every other day, three times a week or twice a week, or substantially continuously or continuously administering a certain dose of TNF-α antagonists every day, it contains an amount of about 0.1 μg to about 40 mg of TNF-α antagonists per dose; Such administration is continued for the time required for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of IFN-γ and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient comprising subcutaneous once-daily, every-other-day Administering to the patient a total weekly dose of IFN-γ containing a drug amount of from about 100 μg to about 300 μg once, three times a week, twice a week, or substantially continuously or continuously daily in divided doses every week; Once a day, once every other day, three times a week or twice a week, or substantially continuously or continuously administering a certain dose of TNF-α antagonists every day, it contains an amount of about 0.1 μg to about 40 mg of TNF-α antagonists per dose; Such administration is continued for the time required for NS3 inhibitor compound treatment.

One embodiment provides any of the above methods modified to use an effective amount of INFERGEN® complex IFN-α and TNF-α antagonist in the treatment of HCV infection in a patient, said method comprising subcutaneous once-daily, every-other-day , three times a week, twice a week, once a week, once every other week, three times a month, once a month, or daily, substantially continuously or continuously, to a patient a dose of INFERGEN® containing about 1 μg to about 30 μg of the drug amount; and subcutaneous once a day, every other day, three times a week or twice a week or a dose of TNF-α antagonists administered substantially continuously or continuously, each dose of TNF-α antagonists containing about Amounts ranging from 0.1 μg to about 40 mg; the administration is continued for the time desired for NS3 inhibitor compound treatment.

One embodiment provides any of the above methods modified to use an effective amount of INFERGEN® complex IFN-α and TNF-α antagonist in the treatment of HCV infection in a patient, said method comprising subcutaneous once-daily, every-other-day , three times a week, twice a week, once a week, once every other week, three times a month, once a month, or daily, substantially continuously or continuously, to a patient a dose of INFERGEN® containing about 1 μg to about A drug amount of 9 μg; and subcutaneous administration of a dose of TNF-α antagonist once a day, once every other day, three times a week or twice a week or substantially continuously or continuously every day, which contains about Amounts ranging from 0.1 μg to about 40 mg; the administration is continued for the time desired for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of pegylated conjugated IFN-α and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, the method comprising: Administer to the patient subcutaneously weekly, every other week, three times a month, or once a month a dose of pegylated conjugated IFN-alpha (PEG-CIFN) comprising about 4 μg to about 60 μg of PEG-CIFN per dose The amount of CIFN amino acid weight; And once a day, once every other day, three times a week, twice a week or substantially continuous or continuous administration of a certain dose of TNF-α antagonist, which contains each dose of TNF-α antagonist about Amounts ranging from 0.1 μg to about 40 mg; the administration is continued for the time desired for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of pegylated conjugated IFN-α and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, the method comprising: Administer to the patient subcutaneously weekly, every other week, three times a month, or once a month a dose of pegylated conjugated IFN-alpha (PEG-CIFN) comprising about 18 μg to about 24 μg of PEG-CIFN per dose The amount of CIFN amino acid weight; And once a day, once every other day, three times a week, twice a week or substantially continuous or continuous administration of a certain dose of TNF-α antagonist, which contains each dose of TNF-α antagonist about Amounts ranging from 0.1 μg to about 40 mg; the administration is continued for the time desired for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of IFN-α 2a or 2b or 2c and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, the method comprising: Subcutaneously once daily, every other day, three times a week, twice a week, or daily substantially continuously or continuously, the patient is administered a dose of IFN-α 2a or 2b or 2c comprising about 1 MU to about 20 MU of the drug; and a dose of the TNF-α antagonist administered subcutaneously once daily, every other day, three times a week, twice a week, or substantially continuously or continuously each day, containing each dose of the TNF-α antagonist The dose is in an amount from about 0.1 μg to about 40 mg; the administration is for the time desired for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of IFN-α 2a or 2b or 2c and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, the method comprising: Subcutaneously once daily, every other day, three times a week, twice a week, or daily substantially continuously or continuously, the patient is administered a dose of IFN-α 2a or 2b or 2c comprising about 3MU of the drug; and by subcutaneous once a day, once every other day, three times a week, twice a week or substantially continuous or continuous administration of a certain dose of TNF-α antagonists every day, it contains each dose of TNF-α antagonists is about Amounts ranging from 0.1 μg to about 40 mg; the administration is continued for the time desired for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of IFN-α 2a or 2b or 2c and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, the method comprising: Subcutaneously once daily, every other day, three times a week, twice a week, or daily substantially continuously or continuously, the patient is administered a dose of IFN-α 2a or 2b or 2c comprising about A drug amount of 10 MU; and a dose of TNF-α antagonist administered subcutaneously once a day, once every other day, three times a week, twice a week, or substantially continuously or continuously every day, containing about Amounts ranging from 0.1 μg to about 40 mg; the administration is continued for the time desired for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of PEGASYS_PEGylated IFN-α2a and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, the method comprising : Administer PEGASYS_ subcutaneously once a week, every other week, three times a month or once a month to a patient, comprising an amount of PEGASYS_ of about 90 μg to about 360 μg per dose; and subcutaneously once a day, every other day , three times a week, twice a week, or substantially continuously or continuously administering a dose of a TNF-α antagonist comprising an amount of about 0.1 μg to about 40 mg per dose of the TNF-α antagonist; the administration continues for the NS3 inhibitor The time required for compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of PEGASYS_PEGylated IFN-α2a and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, the method comprising : Administer a dose of PEGASYS_ containing approximately 180 μg per dose of PEGASYS_ subcutaneously once a week, every other week, three times a month or once a month to the patient; and subcutaneously once a day, every other day, every Wednesday Administering a dose of TNF-alpha antagonist once, twice a week or substantially continuously or continuously, comprising an amount of about 0.1 μg to about 40 mg per dose of TNF-alpha antagonist; time.

Another embodiment provides any of the above methods modified to use an effective amount of PEG-INTRON-PEGylated IFN-α2b and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, said The method comprises: subcutaneously administering to a patient once a week, every other week, three times a month, or once a month a dose of PEG-INTRON® comprising an amount of drug of about 0.75 μg to about 3.0 μg of PEG-INTRON® per dose; and Administered subcutaneously once daily, every other day, three times a week, twice a week, or substantially continuously or continuously, a dose of the TNF-alpha antagonist comprising about 0.1 μg to about 40 mg of the TNF-alpha antagonist per dose ; the administration is continued for the time required for NS3 inhibitor compound treatment.

Another embodiment provides any of the above methods modified to use an effective amount of PEG-INTRON-PEGylated IFN-α2b and an effective amount of a TNF-α antagonist in the treatment of a viral infection in a patient, said The method comprises: subcutaneously administering to a patient once a week, every other week, three times a month, or once a month a dose of PEG-INTRON® comprising about 1.5 μg of drug per kilogram of body weight per dose of PEG-INTRON®; Subcutaneously once daily, every other day, three times a week, twice a week, or substantially continuously or continuously administering a dose of the TNF-α antagonist, which contains an amount of about 0.1 μg to about 40 mg of the TNF-α antagonist per dose; The administration is continued for as long as required for NS3 inhibitor compound treatment.

Combination therapy with other antiviral agents

Other agents such as HCV NS3 helicase inhibitors are also attractive agents for combination therapy and are contemplated for use in the combination therapy described herein. Ribozymes (eg, Heptazyme ^(TM )) and phosphorothioate oligonucleotides that are complementary to HCV protein sequences and inhibit expression of the viral core protein are also suitable for use in the combination therapies described herein.

In some embodiments, the additional antiviral agent is administered throughout the course of treatment with the NS3 inhibitor compound of the embodiments, and the beginning and end of the treatment period occur concurrently. In other embodiments, the administration of the other antiviral agent overlaps the NS3 inhibitor compound treatment for a period of time, e.g., the other antiviral agent treatment can begin before the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; Treatment with other antiviral agents can begin after initiation of NS3 inhibitor compound treatment and end after end of NS3 inhibitor compound treatment; other antiviral agent treatment can begin after initiation of NS3 inhibitor compound treatment and before end of NS3 inhibitor compound treatment end; or other antiviral agent treatment can start before NS3 inhibitor compound treatment begins and end after NS3 inhibitor compound treatment ends.

The NS3 inhibitor compound can be co-administered with one or more other antiviral agents (i.e., simultaneously in separate formulations; simultaneously in the same formulation; in separate formulations and within about 48 hours, about 36 hours, about 24 hours hours, about 16 hours, about 12 hours, about 8 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, or about 15 minutes or less).

As a non-limiting example, any of the above methods featuring an IFN-α protocol may be modified by replacing the IFN-α protocol with a mono-pegylated (30 kD, linear) complex IFN-α protocol, Including subcutaneous administration of a dose of monopegylated (30 kD, linear) complex IFN-α, containing 100 μg per dose, sustained NS3 inhibition The time required for compound treatment.

As a non-limiting example, any of the above methods featuring an IFN-α protocol may be modified by replacing the IFN-α protocol with a mono-pegylated (30 kD, linear) complex IFN-α protocol, Including subcutaneous administration of a dose of monopegylated (30 kD, linear) complexed IFN-α, containing 150 μg per dose, sustained NS3 inhibition The time required for compound treatment.

As a non-limiting example, any of the above methods featuring an IFN-α protocol may be modified by replacing the IFN-α protocol with a mono-pegylated (30 kD, linear) complex IFN-α protocol, Including subcutaneous administration of a dose of monopegylated (30 kD, linear) complexed IFN-α, containing 200 μg per dose, sustained NS3 inhibition The time required for compound treatment.

As a non-limiting example, any of the above methods featuring an IFN-α regimen may be modified by replacing the IFN-α regimen with a regimen of INFERGEN_interferon alfacon-1, including subcutaneous once-daily or A dose of INFERGEN® interferon alfacon-1 containing a drug amount of 9 μg per dose was administered three times a week for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring an IFN-α regimen may be modified by replacing the IFN-α regimen with a regimen of INFERGEN_interferon alfacon-1, including subcutaneous once-daily or A dose of INFERGEN® interferon alfacon-1 containing a drug amount of 15 μg per dose was administered three times a week for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring an IFN-γ regimen may be modified by replacing the IFN-γ regimen with the following IFN-γ regimen, comprising administering a dose three times a week by subcutaneous IFN-γ, which contains a drug amount of 25 μg per dose, is administered for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring an IFN-γ regimen may be modified by replacing the IFN-γ regimen with the following IFN-γ regimen, comprising administering a dose three times a week by subcutaneous IFN-γ, which contains a drug amount of 50 μg per dose, is administered for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring an IFN-γ regimen may be modified by replacing the IFN-γ regimen with the following IFN-γ regimen, comprising administering a dose three times a week by subcutaneous IFN-γ, which contains a drug amount of 100 μg per dose, is administered for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ γ-combination regimen, including: (a) subcutaneous administration of a dose of monopegylated (30kD, linear) complex IFN-α containing 100 μg per dose once weekly, once every eight days or once every ten days Drug amount; and (b) three times weekly subcutaneous administration of a dose of IFN-γ containing a drug amount of 50 μg per dose; this administration is continued for the desired time of NS3 inhibitor compound treatment. As a non-limiting example, any of the above methods featuring a TNF antagonist regimen may be modified by replacing the TNF antagonist regimen with the following TNF antagonist regimen, comprising administering a group selected from the group consisting of Doses of TNF antagonists in the group: (a) etanercept in doses of 25 mg per dose subcutaneously twice a week, (b) intravenously at weeks 0, 2, and 6 and Thereafter, infliximab at a dose of 3 mg/kg body weight every 8 weeks, or (c) adalimumab at a dose of 40 mg per dose subcutaneously once a week or every two weeks ); the administration is continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ γ-combination regimen, including: (a) administering a dose of monopegylated (30 kD, linear) complex IFN-α subcutaneously once a week, once every eight days, or once every ten days, containing 100 μg of the drug per dose and (b) three times weekly subcutaneous administration of a dose of IFN-γ containing a drug amount of 100 μg per dose; said administration for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ Gamma-combination regimen, including: (a) administering a dose of monopegylated (30kD, linear) complex IFN-α subcutaneously once a week, once every eight days, or once every ten days, containing 150 μg of the drug per dose and (b) three times weekly subcutaneous administration of a dose of IFN-γ containing a drug amount of 50 μg per dose; said administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ Gamma-combination regimen, including: (a) administering a dose of monopegylated (30kD, linear) complex IFN-α subcutaneously once a week, once every eight days, or once every ten days, containing 150 μg of the drug per dose and (b) three times weekly subcutaneous administration of a dose of IFN-γ containing a drug amount of 100 μg per dose; said administration for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ Gamma-combination regimen, including: (a) administering a dose of monopegylated (30 kD, linear) complex IFN-α subcutaneously once a week, once every eight days, or once every ten days, containing 200 μg of the drug per dose and (b) three times weekly subcutaneous administration of a dose of IFN-γ containing a drug amount of 50 μg per dose; said administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ Gamma-combination regimen, including: (a) administering a dose of monopegylated (30 kD, linear) complex IFN-α subcutaneously once a week, once every eight days, or once every ten days, containing 200 μg of the drug per dose and (b) three times weekly subcutaneous administration of a dose of IFN-γ containing a drug amount of 100 μg per dose; said administration for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 9 μg per dose; and (b) subcutaneous administration of a certain dose of IFN- γ, which contained a drug amount of 25 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 9 μg per dose; and (b) subcutaneous administration of a certain dose of IFN- γ, which contained a drug amount of 50 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 9 μg per dose; and (b) subcutaneous administration of a certain dose of IFN- γ, which contained a drug amount of 100 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 9 μg per dose; and (b) subcutaneous administration of a certain dose of IFN-alfacon-1 three times a week γ, which contained a drug amount of 25 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 9 μg per dose; and (b) subcutaneous administration of a certain dose of IFN-alfacon-1 three times a week γ, which contained a drug amount of 50 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 9 μg per dose; and (b) subcutaneous administration of a certain dose of IFN-alfacon-1 three times a week γ, which contained a drug amount of 100 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneously administering a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 15 μg per dose; and (b) subcutaneously administering a certain dose of IFN- γ, which contained a drug amount of 25 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneously administering a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 15 μg per dose; and (b) subcutaneously administering a certain dose of IFN- γ, which contained a drug amount of 50 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneously administering a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 15 μg per dose; and (b) subcutaneously administering a certain dose of IFN- γ, which contained a drug amount of 100 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 15 μg per dose; and (b) subcutaneous administration of a certain dose of IFN-alfacon-1 three times a week γ, which contained a drug amount of 25 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 15 μg per dose; and (b) subcutaneous administration of a certain dose of IFN-alfacon-1 three times a week γ, which contained a drug amount of 50 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and IFN-γ can be modified by replacing the combination of IFN-α and IFN-γ with the following combination regimen of IFN-α and IFN-γ The γ-combination regimen, including: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 15 μg per dose; and (b) subcutaneous administration of a certain dose of IFN-alfacon-1 three times a week γ, which contained a drug amount of 100 μg per dose; the administration continued for the duration of the NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) administering a certain dose of monopegylated (30kD, linear) subcutaneously once a week, once every eight days or once every ten days Composite IFN-α containing a drug amount of 100 μg per dose; (b) subcutaneously administering a dose of IFN-γ containing a drug amount of 100 μg per dose three times a week; and (c) administering a drug selected from the following Doses of TNF antagonists consisting of cohorts: (i) etanercept in the amount of 25 mg twice a week by subcutaneous, (ii) by intravenous at weeks 0, 2 and 6 and every 8 weeks thereafter Infliximab in a drug amount of 3 mg per kg body weight once, or (iii) adalimumab in an amount of 40 mg once a week or every two weeks subcutaneously; said administration continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) administering a certain dose of monopegylated (30kD, linear) subcutaneously once a week, once every eight days or once every ten days Composite IFN-α containing a drug amount of 100 μg per dose; (b) subcutaneously administering a dose of IFN-γ containing a drug amount of 50 μg per dose three times a week; and (c) administering a drug selected from the following Doses of TNF antagonists consisting of cohorts: (i) etanercept in the amount of 25 mg twice a week subcutaneously, (ii) intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter Infliximab in a drug amount of 3 mg per kg body weight once, or (iii) adalimumab in an amount of 40 mg once a week or every two weeks subcutaneously; said administration continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) administering a certain dose of monopegylated (30kD, linear) subcutaneously once a week, once every eight days or once every ten days Composite IFN-α containing a drug amount of 150 μg per dose; (b) subcutaneously administering a dose of IFN-γ containing a drug amount of 50 μg per dose three times a week; and (c) administering a drug selected from the following Doses of TNF antagonists consisting of cohorts: (i) etanercept in the amount of 25 mg twice a week subcutaneously, (ii) intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter Infliximab in a drug amount of 3 mg per kg body weight once, or (iii) adalimumab in an amount of 40 mg once a week or every two weeks subcutaneously; said administration continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) administering a certain dose of monopegylated (30kD, linear) subcutaneously once a week, once every eight days or once every ten days Composite IFN-α containing a drug amount of 150 μg per dose; (b) subcutaneously administering a dose of IFN-γ containing a drug amount of 100 μg per dose three times a week; and (c) administering a drug selected from the following Doses of TNF antagonists consisting of cohorts: (i) etanercept in the amount of 25 mg twice a week subcutaneously, (ii) intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter Infliximab in a drug amount of 3 mg per kg body weight once, or (iii) adalimumab in an amount of 40 mg once a week or every two weeks subcutaneously; said administration continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) administering a certain dose of monopegylated (30kD, linear) subcutaneously once a week, once every eight days or once every ten days Composite IFN-α containing a drug amount of 200 μg per dose; (b) subcutaneously administering a dose of IFN-γ containing a drug amount of 50 μg per dose three times a week; and (c) administering a drug selected from the following Doses of TNF antagonists consisting of cohorts: (i) etanercept in the amount of 25 mg twice a week subcutaneously, (ii) intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter Infliximab in a drug amount of 3 mg per kg body weight once, or (iii) adalimumab in an amount of 40 mg once a week or every two weeks subcutaneously; said administration continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) administering a certain dose of monopegylated (30kD, linear) subcutaneously once a week, once every eight days or once every ten days Composite IFN-α containing a drug amount of 200 μg per dose; (b) subcutaneously administering a dose of IFN-γ containing a drug amount of 100 μg per dose three times a week; and (c) administering a drug selected from the following Doses of TNF antagonists consisting of cohorts: (i) etanercept in the amount of 25 mg twice a week subcutaneously, (ii) intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter Infliximab in a drug amount of 3 mg per kilogram of body weight once, or (iii) adalimumab in an amount of 40 mg via subcutaneous once-weekly or bi-weekly; said administration continues for the time required for NS3 inhibitor compound treatment .

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 9 μg per dose; (b) Administer a dose of IFN-γ subcutaneously three times per week, containing a drug amount of 25 μg per dose; and (c) administer a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously per dose Etanercept in the amount of 25 mg twice weekly, (ii) infliximab in the amount of 3 mg/kg body weight intravenously at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab in an amount of 40 mg by subcutaneous once-weekly or bi-weekly; said administration continues for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 9 μg per dose; (b) Administer a dose of IFN-γ subcutaneously three times per week, containing a drug amount of 50 μg per dose; and (c) administer a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously per dose Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 9 μg per dose; (b) Administering a dose of IFN-γ subcutaneously three times a week containing a drug amount of 100 μg per dose; and (c) administering a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously each Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 9 μg per dose; (b) Administer a dose of IFN-γ subcutaneously three times per week, containing a drug amount of 25 μg per dose; and (c) administer a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously per dose Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 9 μg per dose; (b) Administer a dose of IFN-γ subcutaneously three times per week, containing a drug amount of 50 μg per dose; and (c) administer a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously per dose Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 9 μg per dose; (b) Administering a dose of IFN-γ subcutaneously three times a week containing a drug amount of 100 μg per dose; and (c) administering a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously each Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 15 μg per dose; (b) Administer a dose of IFN-γ subcutaneously three times per week, containing a drug amount of 25 μg per dose; and (c) administer a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously per dose Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 15 μg per dose; (b) Administer a dose of IFN-γ subcutaneously three times per week, containing a drug amount of 50 μg per dose; and (c) administer a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously per dose Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The combined regimen of IFN-α, IFN-γ and TNF antagonists includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 three times a week, which contains a drug amount of 15 μg per dose; (b) Administering a dose of IFN-γ subcutaneously three times a week containing a drug amount of 100 μg per dose; and (c) administering a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously each Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 15 μg per dose; (b) Administer a dose of IFN-γ subcutaneously three times per week, containing a drug amount of 25 μg per dose; and (c) administer a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously per dose Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 15 μg per dose; (b) Administer a dose of IFN-γ subcutaneously three times per week, containing a drug amount of 50 μg per dose; and (c) administer a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously per dose Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α, IFN-γ and a TNF antagonist may be modified and replaced by the following combination regimen of IFN-α, IFN-γ and a TNF antagonist The IFN-α, IFN-γ and TNF antagonist combination regimen includes: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day, which contains a drug amount of 15 μg per dose; (b) Administering a dose of IFN-γ subcutaneously three times a week containing a drug amount of 100 μg per dose; and (c) administering a dose of a TNF antagonist selected from the group consisting of: (i) subcutaneously each Etanercept in an amount of 25 mg twice weekly, (ii) infliximab in an amount of 3 mg/kg body weight by IV at weeks 0, 2, and 6 and every 8 weeks thereafter, or (iii) Adalimumab is administered subcutaneously once weekly or biweekly in amounts of 40 mg; such administration is continued for as long as required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and a TNF antagonist may be modified by replacing the IFN-α and TNF antagonist with the following combination regimen of an IFN-α and TNF antagonist Combination regimen of doses, including: (a) subcutaneous administration of a certain dose of monopegylated (30kD, linear) complex IFN-α, which contains 100 μg of drug per dose, once a week, once every eight days, or once every ten days and (b) administering a dose of a TNF antagonist selected from the group consisting of (i) subcutaneous etanercept twice weekly in an amount of 25 mg, (ii) intravenous week 0 , the 2nd week and the 6th week and every 8 weeks thereafter, once every 8 weeks, infliximab in the amount of 3 mg per kilogram of body weight, or (iii) adalimumab in the amount of 40 mg once a week or once every two weeks by subcutaneous; Administration is continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and a TNF antagonist may be modified by replacing the IFN-α and TNF antagonist with the following combination regimen of an IFN-α and TNF antagonist Combination regimen of doses, including: (a) subcutaneous administration of a certain dose of monopegylated (30kD, linear) complex IFN-α, which contains 150 μg of the drug per dose, once a week, once every eight days, or once every ten days and (b) administering a dose of a TNF antagonist selected from the group consisting of (i) subcutaneous etanercept twice weekly in an amount of 25 mg, (ii) intravenous week 0 , the 2nd week and the 6th week and every 8 weeks thereafter, once every 8 weeks, infliximab in the amount of 3 mg per kilogram of body weight, or (iii) adalimumab in the amount of 40 mg once a week or once every two weeks by subcutaneous; Administration is continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and a TNF antagonist may be modified by replacing the IFN-α and TNF antagonist with the following combination regimen of an IFN-α and TNF antagonist Combination regimen of doses, including: (a) subcutaneous administration of a certain dose of monopegylated (30 kD, linear) complex IFN-α, which contains 200 μg of the drug per dose, once a week, once every eight days, or once every ten days and (b) administering a dose of a TNF antagonist selected from the group consisting of (i) subcutaneous etanercept twice weekly in an amount of 25 mg, (ii) intravenous week 0 , at weeks 2 and 6 and every 8 weeks thereafter, infliximab at a drug dose of 3 mg/kg body weight, or (iii) adalimumab at a dose of 40 mg subcutaneously once a week or every two weeks ; the administration is continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and a TNF antagonist may be modified by replacing the IFN-α and TNF with the following combination regimen of an IFN-α and TNF antagonist Antagonist combination regimen, comprising: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day or three times a week, which contains a drug amount of 9 μg per dose; and (b) administration selected from the following A dose of TNF antagonists in groups consisting of: (i) etanercept in the amount of 25 mg subcutaneously twice a week, (ii) intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter. Infliximab in a drug amount of 3 mg per kg body weight once weekly, or (iii) adalimumab in an amount of 40 mg by subcutaneous weekly or biweekly; said administration continues for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-α and a TNF antagonist may be modified by replacing the IFN-α and TNF with the following combination regimen of an IFN-α and TNF antagonist Antagonist combination regimen, comprising: (a) subcutaneous administration of a certain dose of INFERGEN_interferon alfacon-1 once a day or three times a week, which contains a drug amount of 15 μg per dose; and (b) administration selected from the following A dose of TNF antagonists in groups consisting of: (i) etanercept in the amount of 25 mg subcutaneously twice a week, (ii) intravenously at weeks 0, 2 and 6 and every 8 weeks thereafter. Infliximab in a drug amount of 3 mg per kg body weight once weekly, or (iii) adalimumab in an amount of 40 mg by subcutaneous weekly or biweekly; said administration continues for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-γ and a TNF antagonist may be modified by replacing the IFN-γ and TNF with the following combination regimen of an IFN-γ and TNF antagonist An antagonist combination regimen comprising: (a) subcutaneous administration of a dose of IFN-γ three times per week containing a drug amount of 25 μg per dose; and (b) administration of a dose selected from the group consisting of TNF antagonists: (i) etanercept in an amount of 25 mg twice a week subcutaneously, (ii) in an amount of 3 mg/kg body weight intravenously at weeks 0, 2, and 6 and every 8 weeks thereafter Infliximab, or (iii) Adalimumab in an amount of 40 mg subcutaneously once a week or once every two weeks; said administration continues for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-γ and a TNF antagonist may be modified by replacing the IFN-γ and TNF with the following combination regimen of an IFN-γ and TNF antagonist An antagonist combination regimen comprising: (a) subcutaneously administering a dose of IFN-γ three times per week containing a drug amount of 50 μg per dose; and (b) administering a dose selected from the group consisting of TNF antagonists: (i) etanercept in an amount of 25 mg twice a week subcutaneously, (ii) in an amount of 3 mg/kg body weight intravenously at weeks 0, 2, and 6 and every 8 weeks thereafter Infliximab, or (iii) Adalimumab in an amount of 40 mg subcutaneously once a week or once every two weeks; said administration continues for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring a combination regimen of IFN-γ and a TNF antagonist may be modified by replacing the IFN-γ and TNF with the following combination regimen of an IFN-γ and TNF antagonist An antagonist combination regimen comprising: (a) subcutaneously administering a dose of IFN-γ three times per week containing a drug amount of 100 μg per dose; and (b) administering a dose selected from the group consisting of TNF antagonists: (i) etanercept in an amount of 25 mg twice a week subcutaneously, (ii) in an amount of 3 mg/kg body weight intravenously at weeks 0, 2, and 6 and every 8 weeks thereafter Infliximab, or (iii) Adalimumab in an amount of 40 mg subcutaneously once a week or once every two weeks; said administration continues for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods including the protocol for monopegylated (30 kD, linear) complexed IFN-α can be modified by replacing the protocol with pegylated interferon α-2a. A regimen of monopegylated (30kD, linear) complex IFN-α, comprising administering a dose of pegylated interferon α-2a subcutaneously once a week, containing a drug amount of 180 μg per dose, and the administration lasts Time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods including the protocol for monopegylated (30kD, linear) complexed IFN-α can be modified by replacing the protocol with pegylated interferon α-2b. A regimen of monopegylated (30kD, linear) complexed IFN-α, consisting of once or twice weekly subcutaneous administration of a dose of pegylated interferon alfa-2b containing 1.0 per kg body weight per dose [mu]g to 1.5 [mu]g of drug, the administration is continued for the time desired for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods may be modified to include administering a dose of ribavirin containing 400 mg, 800 mg, 1000 mg orally per day and optionally in two or more doses per day or 1200 mg of drug for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods may be modified to include administering a dose of ribavirin comprising (i) an oral dose of 1000 mg per day for a patient weighing less than 75 kg, or (ii ) for patients with a body weight greater than or equal to 75 kg orally in an amount of 1200 mg per day; the administration is continued for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods may be modified to replace the NS3 inhibitor regimen with the following NS3 inhibitor regimen, comprising daily oral administration of each Drug doses of 0.01 mg to 0.1 mg per kilogram of body weight for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods may be modified to replace the NS3 inhibitor regimen with the following NS3 inhibitor regimen, comprising daily oral administration of each Drug doses of 0.1 mg to 1 mg per kilogram of body weight for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods may be modified to replace the NS3 inhibitor regimen with the following NS3 inhibitor regimen, comprising daily oral administration of each Drug doses of 1 mg to 10 mg per kilogram of body weight for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods may be modified to replace the NS3 inhibitor regimen with the following NS3 inhibitor regimen, comprising daily oral administration of each A drug dose of 10 mg to 100 mg per kilogram of body weight for the time required for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring an NS5B inhibitor regimen may be modified to replace the NS5B inhibitor regimen with the following NS5B inhibitor regimen comprising daily oral administration and optionally twice daily A dose of 0.01 mg to 0.1 mg drug per kilogram of body weight is administered in one or more doses for as long as desired for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring an NS5B inhibitor regimen may be modified to replace the NS5B inhibitor regimen with the following NS5B inhibitor regimen comprising daily oral administration and optionally twice daily A dose of 0.1 mg to 1 mg drug per kilogram of body weight is administered in one or more doses for as long as desired for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring an NS5B inhibitor regimen may be modified to replace the NS5B inhibitor regimen with the following NS5B inhibitor regimen comprising daily oral administration and optionally twice daily A dose of 1 mg to 10 mg drug per kilogram body weight is administered in one or more doses for the time desired for NS3 inhibitor compound treatment.

As a non-limiting example, any of the above methods featuring an NS5B inhibitor regimen may be modified to replace the NS5B inhibitor regimen with the following NS5B inhibitor regimen comprising daily oral administration and optionally twice daily A dose of 10 mg to 100 mg drug per kilogram body weight is administered in one or more doses for the time desired for NS3 inhibitor compound treatment.

patient identification

In certain embodiments, the specific regimen of drug therapy used to treat HCV patients is selected based on certain disease parameters exhibited by the patient, such as the patient's initial viral load, the patient's HCV infection genotype, the patient's liver disease history and/or stage of liver fibrosis in patients.

Accordingly, some embodiments provide any of the above methods for treating HCV infection, wherein the method is modified to treat treatment failure patients for 48 weeks.

Other embodiments provide any of the above methods for HCV, wherein the method is modified to treat non-responding patients, wherein the patients receive a 48-week course of therapy.

Other embodiments provide any of the above methods for treating HCV infection, wherein the method is modified to treat a relapsed patient, wherein the patient receives a 48 week course of treatment.

ve)患者，其中患者接受48周疗程。Other embodiments provide any of the above-described methods for treating HCV infection, wherein the method is modified to treat treatment-naïve patients infected with HCV genotype 1 (na

ve) patients, wherein the patients received a 48-week course of treatment.

Further embodiments provide any of the above methods for treating HCV infection, wherein the method is adapted to treat a treatment naive patient infected with HCV genotype 4, wherein the patient receives a 48 week course of treatment.

Other embodiments provide any of the above methods for treating HCV infection, wherein the method is modified to treat a treatment naive patient infected with HCV genotype 1, wherein the patient has a high viral load (HVL) , where "HVL" refers to the HCV viral load greater than 2×10 ⁶ HCV genome copies per milliliter of serum, where the patient received a 48-week course of treatment.

One embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying patients with advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the method for about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks , or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or a period of at least about 60 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying liver fibrosis with an advanced or severe stage as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the method for a period of about 40 weeks to about 50 weeks, or about 48 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying patients with HCV genotype 1 infection and greater than 2 million per milliliter of serum a patient with an initial viral load of viral genome copies; and then (2) administering the drug therapy of the method to the patient for about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or a period of at least about 60 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying patients with HCV genotype 1 infection and greater than 2 million per milliliter of serum a patient with an initial viral load of viral genome copies; and then (2) administering to the patient the drug therapy of the method for a period of about 40 weeks to about 50 weeks, or about 48 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying patients with HCV genotype 1 infection and greater than 2 million per milliliter of serum initial viral load of viral genome copies and patients without or early stage liver fibrosis as measured by a Knodell score of 0, 1 or 2; and then (2) administering the drug therapy of the method to the patient for about 24 weeks to About 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks weeks, or a period of at least about 48 weeks, or at least about 60 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying patients with HCV genotype 1 infection and greater than 2 million per milliliter of serum initial viral load of viral genome copies and patients without or early stage liver fibrosis as measured by Knodell score 0, 1 or 2; and then (2) administering the drug therapy of the method to the patient for about 40 weeks to About 50 weeks, or about a 48-week period.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying patients with HCV genotype 1 infection and less than or equal to 200 per milliliter of serum an initial viral load of 10,000 viral genome copies; and then (2) administering the drug therapy of the method to the patient for about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to A period of 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.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying patients with HCV genotype 1 infection and less than or equal to 200 per milliliter of serum an initial viral load of 10,000 viral genome copies; and then (2) administering the drug therapy of the method to the patient for a period of about 20 weeks to about 24 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying patients with HCV genotype 1 infection and less than or equal to 200 per milliliter of serum an initial viral load of 10,000 viral genome copies; and then (2) administering the drug therapy of the method to the patient for a period of about 24 weeks to about 48 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying a patient with HCV genotype 2 or 3 infection; and then (2) administering the drug therapy of the method to the patient for about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or A period of 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.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying a patient with HCV genotype 2 or 3 infection; and then (2) administering the drug therapy of the method to the patient for 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 A period of up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying a patient with HCV genotype 2 or 3 infection; and then (2) The drug therapy of the method is administered to the patient for a period of about 20 weeks to about 24 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying a patient with HCV genotype 2 or 3 infection; and then (2) The drug therapy of the method is administered to the patient for a period of at least about 24 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying a patient with HCV genotype 1 or 4 infection; and then (2) administering the drug therapy of the method to the patient for about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or A period of 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.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying the an HCV-infected patient of either; and then (2) administering to the patient the drug therapy of the method for a period of about 20 weeks to about 50 weeks.

Another embodiment provides any of the above methods for treating HCV infection, wherein the method is modified to include the steps of: (1) identifying the an HCV-infected patient of either; and then (2) administering to the patient the drug therapy of the method for a period of at least about 24 weeks and up to about 48 weeks.

Eligible subjects for treatment

Any of the above treatment regimens can be administered to individuals who have been diagnosed with HCV infection. Individuals who have been infected with HCV are identified as having HCV RNA in the blood and/or anti-HCV antibodies in the serum. Any of the above treatment regimens can be administered to individuals who have failed treatment for previous HCV infection ("treatment failure patients", including non-responders and relapsers).

Of particular interest in many embodiments are individuals clinically diagnosed with HCV infection. Individuals who have been infected with HCV are identified as having HCV RNA in the blood and/or anti-HCV antibodies in the serum. The individuals include anti-HCVELISA positive individuals, and individuals with positive recombinant immunoblot assay (RIBA). The individual may also, but need not, have high serum ALT levels.

Individuals clinically diagnosed with HCV infection include treatment-naive individuals (e.g., individuals who have not previously been treated for HCV, particularly individuals who have not previously received IFN-α-based and/or ribavirin-based therapy) and Individuals who have failed prior HCV treatment ("treatment failure" patients). Treatment failure patients include: non-responders (i.e., individuals whose HCV titers have not been significantly or sufficiently reduced by prior HCV therapy, e.g., prior IFN monotherapy, prior IFN-alpha and ribavirin combination therapy, or prior aggregated pegylated IFN-α and ribavirin combination therapy); and relapsers (i.e., individuals who have previously received HCV treatment, e.g., previously received IFN-α monotherapy, IFN-α and ribavirin combination therapy or pegylated IFN-α and ribavirin combination therapy in individuals whose HCV decreased but then increased).

In embodiments of particular interest, the individual has an HCV titer 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 HCV genomic copies per milliliter of serum. The patient can be infected with any HCV genotype (genotype 1, including 1a and 1b, 2, 3, 4, 6, etc., and subtypes (eg, 2a, 2b, 3a, etc.)), especially refractory genotypes , such as HCV genotype 1 and special HCV subtypes and quasispecies.

Also of concern are those exhibiting severe fibrosis or early cirrhosis (decompensated, Child's-Pugh grade A or lower) due to chronic HCV infection and despite prior antiviral therapy with IFN-α-based therapy HCV-positive individuals who are viremic or cannot tolerate or have contraindications to IFN-[alpha]-based therapy (as described above). In embodiments of particular interest, HCV positive individuals with stage 3 or 4 liver fibrosis according to the METAVIR scoring system are suitable for treatment using the methods of embodiments of the invention. In other embodiments, individuals suitable for treatment by the methods of the embodiments are patients with clinically manifested decompensated cirrhosis, including patients with very advanced cirrhosis, including patients undergoing liver transplantation. In yet other embodiments, individuals suitable for treatment by the methods of the described embodiments include patients with mild degrees of fibrosis, including patients with early-stage fibrosis (stages 1 and 2 in the METAVIR, Ludwig, and Scheuer scoring system; or in stage 1, 2 or 3 in the Ishak scoring system).

Preparation of Part A Virus Inhibitors

Compounds of general formula I can be synthesized in the same general manner as described below for compounds of general formula II-XIX. The synthesis of various specific compounds of general formula I is described in the examples below. Variations in sequence will be appreciated by those skilled in the art and will further appreciate the importance of appropriate reaction conditions for similar reactions shown or otherwise known that may be suitably used in the processes described hereinafter for the preparation of compounds of formula I. Variety.

The products of the reactions described herein are isolated by conventional means such as extraction, distillation, chromatography and the like.

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

Preparation of Part B Virus Inhibitors

The terms and structural names used in this section have the same meanings as in Section B above. Any reference in this section to a specific number or designation should be read in context with the corresponding numbering or labeling scheme used in this section or in Section B above, and not a potentially similar or equivalent numbering or labeling scheme used elsewhere herein The content is to be understood unless otherwise stated.

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

Methodology

Compound preparation

Compounds of formula II-X are prepared using two methods. In both methods, Intermediates 1 and 4 were prepared according to the procedure disclosed in International Application PCT/CA00/00353 (Publication No. WO 00/59929). Intermediate 4 was also purchased from RSP Ammo Acids.

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

Compound #101 (Compound AR00220042)

Method A:

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

Add ethyl-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropylcarboxylate (1, 1.0g, 5.2mmol), trans-N-(tert-butyl Oxycarbonyl)-4-hydroxy-L-proline (2, 1.3 g, 1.1 equiv) and HATU (2.7 g, 1.1 equiv) were added to a flask with 30 mL of DMF to make a solution. The solution was cooled to 0°C in an ice-water bath, then a solution of DIEA (4.4ml, 4eq) in DMF (15ml) was added slowly with stirring. The reaction was allowed to warm to room temperature and stirred overnight.

After 16 h, the reaction was monitored for completion by HPLC. Diluted with EtOAc (100 mL), washed with water (3 x 40 mL), saturated sodium bicarbonate (NaHCO ₃ (2 x 40 mL)) and brine (2 x 40 mL), then dried over Na ₂ SO ₄ and concentrated to give a dark copper color Oil. The crude product was purified on silica gel (eluent: acetone/hexane 3:7) to give pure product 3 (770 mg, 32%) as a tan foamy powder.

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

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

After 22h, TLC showed that the reaction was complete. The reaction was diluted with DCM (15 mL), washed with 1 N aqueous hydrochloric acid (15 mL), brine (15 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude product was purified on silica gel (eluent: DCM/ _Et2O /acetone 30:10:1). The top spot isolate (5) was a white foamy powder (169 mg, 40%), while the bottom spot (6) was a white solid (156 mg, 38%). MS m/e 550 (M ⁺⁺ Na).

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

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

After 24 h, the reaction turned dark brown. A sample TLC showed the reaction to be complete. The reaction was diluted with EtOAc (30 mL) and washed with water (3 x 15 mL), saturated sodium bicarbonate (2 x 15 mL), brine (15 mL), dried (Na ₂ SO ₄ ) and concentrated to give 7 as an orange oily residue. (156 mg). This product was 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 Synthesis of -dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-ene-4-carboxylic acid ethyl ester (8)

The crude product 7 (135 mg, 0.2 mmol) was dissolved in 20 mL of DriSolve DCE to give a solution, followed by the addition of Nolan's catalyst (5 mg, 0.3 equiv) at room temperature under nitrogen.

The solution turned purple. The reaction was placed on a preheated oil bath (50 °C) and stirred overnight.

After 10 h, the reaction turned dark brown. TLC (DCM/EtOAc 1:1) showed clean conversion to a new spot with slightly lower _Rf value. The crude product was concentrated and purified on silica gel (eluent: DCM/EtOAc gradient from 5:1 to 2:1) to give product 8 (75 mg, 58%) as a tan foamy powder. 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 - Synthesis of dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadeca-7-ene-4-carboxylic acid (Compound #101)

Macrocyclic ester 8 (60 mg, 0.092 mmol) was dissolved in 0.9 mL (THF/MeOH/H ₂ O 2:1:1) mixed solvent, followed by addition of LiOH-H ₂ O (23 mg, 6 equiv). The mixture was stirred overnight at room temperature. After 18 h, TLC (DCM/MeOH 9:1 ) showed a clean new spot with a lower _Rf value. The reaction was concentrated to almost dryness and partitioned between 1N aqueous hydrochloric acid (15 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The organic layers were combined, dried over _Na2SO4 and concentrated to give compound #101 ₍ 50 mg, 87%) as a beige foamy powder.

¹ H NMR (CD ₃ OD, 400 MHz) δ1.20-1.67 (m, 21H), 1.70-1.83 (m, 1H), 1.88-2.10 (m, 1H), 2.12-2.58 (m, 4H), 2.82 (m, 2H), 3.60-3.80(m, 2H), 3.86(m, 1H), 4.20(m, 1H), 4.35(m, 1H), 4.54(s, 7H), 4.58(m, 3H), 5.29-5.41 (m, 2H), 5.57 (m, 1H), 7.0-7.24 (m, 4H). MS m/e 625.1 (M ⁺ +1).

Example 1-1a:

Similarly, (1S, 4S, 6R, 14S, 18R)-14-tert-butoxycarbonylamino-18-( 3,4-Dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nineteen-7 -ene-4-carboxylic acid (compound AR00220122). MS m/e 625.1 (M ⁺ +1).

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

Method B:

Compound #101 was also prepared according to the above procedure. The synthesis of macrocyclic intermediate 10 described herein is analogous to that described in International Application PCT/CA00/00353 (publication No. WO 00/59929).

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

Add ethyl-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropylcarboxylate (1, 1.0g, 5.2mmol), trans-N-(tert-butyl Oxycarbonyl)-4-hydroxy-L-proline (2, 1.3 g, 1.1 equiv) and HATU (2.7 g, 1.1 equiv) were added to a flask with 30 mL of DMF to make a solution. The solution was cooled to 0°C in an ice-water bath, then a solution of DIEA (4.4ml, 4eq) in DMF (15ml) was added slowly with stirring. The reaction was allowed to warm to room temperature and stirred overnight.

After 16 h, the reaction was monitored for completion by HPLC. Diluted with EtOAc (100 mL), washed with water (3 x 40 mL), saturated sodium bicarbonate (2 x 40 mL) and brine (2 x 40 mL), then dried over _Na2SO4 and concentrated to give a dark copper colored oil _. The crude product was purified on silica gel (eluent: acetone/hexane 3:7) to give pure product 3 (770 mg, 32%) as a tan foamy powder.

Step 2: 1R-{[1-(2S-tert-butoxycarbonylamino-non-8-enoyl)-4R-hydroxy-pyrrolidine-2S-carbonyl]-amino}-2S-vinyl-cyclopropanecarboxy Synthesis of Ethyl Acid (9)

Compound 3 (2.85 g, 7.7 mmol) was dissolved in 10 mL of 4N HCl (dioxane) and kept at room temperature for 90 min to remove the Boc protecting group. It was then concentrated, taken up in acetonitrile and concentrated twice more. To this beige residue was added 4 (2.2 g, 8.1 mmol) and HATU (3.2 g, 8.5 mmol), followed by 80 mL of DMF under nitrogen. The reaction was cooled on an ice-water bath for 15 min, after which a solution of DIEA (5.4 mL, 30.9 mmol) in 5 mL DMF was added dropwise with stirring. The ice bath was removed and allowed to warm slowly to room temperature, and the reaction was stirred overnight.

After 18h, TLC showed that the reaction was complete. The reaction was diluted with EtOAc (300 mL) and washed with water (3 x 150 mL), saturated sodium bicarbonate (2 x 150 mL), brine (150 mL), _dried ( _Na2SO4 ) and the solvent was removed. The crude product was purified by flash chromatography on silica gel on Biotage 40M (eluent = 3% to 5% MeOH in DCM) to afford 9 (3.5 g, 87%) as a brown foamy solid.

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 ] Synthesis of ethyl nonadecan-7-ene-4-carboxylate (10)

Compound 9 (2.6 g, 5.0 mmol) was dissolved in 500 mL of DriSolve DCE in a 1 L round bottom flask to give a solution. Degassing was performed by bubbling nitrogen through for 1 hour. Hoveyda's catalyst (0.25 equiv) was then added at room temperature under nitrogen. The reaction was placed on a preheated oil bath (50 °C) and stirred overnight. After 16 h, the reaction turned dark brown. TLC (DCM/EtOAc 1:1) showed clean conversion to a new spot with slightly lower _Rf value. The reaction was concentrated and purified on silica gel (Biotage 40M, eluent = DCM/EtOAc gradient from 1:1 to 1:2) to afford product 10 (0.64 g, 52%) as a tan foamy powder. ¹ H NMR (CDCl ₃ , 400MHz) δ1.21(t, J=7.0Hz, 3H), 1.43(s, 9H), 1.20-1.50(m, 6H), 1.53-1.68(m, 2H), 1.83- 1.96(m, 2H), 1.98-2.28(m, 4H), 2.60(m, 1H), 3.13(brs, 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 Synthesis of -dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-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 overnight at room temperature. After 15 h, the reaction was complete as monitored by TLC (DCM/MeOH 9:1). 1,2,3,4-Tetrahydroisoquinoline (0.14 mL, 1.1 mmol) was added dropwise to the reaction, and the reaction was stirred at room temperature overnight. After 22h, TLC showed that the reaction was complete. The reaction was diluted with DCM (6 mL), washed with 1 N aqueous hydrochloric acid (2 x 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 (131 mg, 90%) as a pale yellow foamy powder.

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

The following compounds were also prepared according to Method B above, substituting various other secondary amines for 1,2,3,4-tetrahydroisoquinoline. Most of these amines are available from commercial sources, or are known literature compounds and can therefore be prepared using the procedures described here (1. Stokker, G E. Tetrahedron Lett. 1996, 37(31), 5453- 5456; 2. Chan, N W. Bioorganic & Medicinal Chemistry 2000, 8, 2085-2094; 3. Vecchietti, V. et al, J. Med. Chem. 1991, 34, 2624-2633.). The synthesis of amine starting materials that cannot be prepared directly from literature procedures, or specific starting materials that have not been reported in the literature just before our full knowledge, are given in each example.

Examples 1-3:

According to method B, but using 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline in step 4, to synthesize (1S,4R,6S,14S,18R)-14- tert-butoxycarbonylamino-18-(6,7-dimethoxy-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3, 16-Diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00226824). MS m/e 585.2 (M ⁺ +1-100).

Examples 1-4:

Compound AR00226825

According to Method B, but using 2,3,4,9-tetrahydro-1H-b-carboline in step 4, to synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino -2,15-dioxo-18-(1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy)-3,16-diaza-tricyclo[14.3.0.0 ^{4 ,6} ] Nonadece-7-ene-4-carboxylic acid (compound AR00226825). MS m/e 564.2 (M ⁺ +1-100).

Examples 1-5:

(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 ]nonadecan-7-ene- 4-Carboxylic acid (compound AR00291871). ¹ H NMR (CDCl ₃ , 500MHz) δ1.21-1.44(m, 8H), 1.32(s, 9H), 1.54-1.62(m, 2H), 1.78-1.88(m, 2H), 2.04-2.13(m , 1H), 2.16-2.23(m, 1H), 2.24-2.36(m, 2H), 2.66-2.74(m, 1H), 3.87-3.90(m, 1H), 4.15(d, J=11.0Hz, 1H ), 4.37-4.43(m, 1H), 4.61-4.77(m, 5H), 5.18(t, J=10.3Hz, 1H), 5.24-5.31(m, 1H), 5.40-5.45(m, 1H), 5.58-5.66 (m, 1H), 7.11-7.30 (m, 4H). MS m/e 611.0 (M ⁺ +1).

Examples 1-6:

(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 ]nonadecan-7-ene-4- Carboxylic acid (compound AR00291875). MS m/e 610.9 (M ⁺ +1).

Examples 1-7:

Synthesis of (1S, 4R, 6S, 14S, 18R)-14-tert-butyl according to method B, but using 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline in step 4 Oxycarbonylamino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-3,16-diazepine - Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00294382). MS m/e 693.0 (M ⁺ ).

Examples 1-8:

(1S, 4R, 6S, 14S, 18R)-14-tert-butyl was synthesized according to method B, but using 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline in step 4 Oxycarbonylamino-2,15-dioxo-18-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-3,16-diazepine - Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00294383). ¹ H NMR (500MHz, CDCl ₃ ): δ7.46-7.38(m, 2H), 7.26-7.18(m, 1H), 6.98(s, 1H), 5.62(q, 1H), 5.42(s, 1H) , 5.21-5.15(m, 2H), 4.78-4.60(m, 3H), 4.40(s, 1H), 4.16-4.00(m, 1H), 3.92-3.81(m, 1H), 3.80-3.60(m, 2H), 3.00-2.85 (m, 2H), 2.72-2.64 (br s, 1H), 2.40-1.18 (m, 20H). MS: m/e 693.0 (M ⁺ ).

Examples 1-9:

According to Method B, but using 5-fluoromethyl-1,2,3,4-tetrahydro-isoquinoline in step 4, (1S,4R,6S,14S,18R)-14-tert-butoxy Cylcarbonylamino-18-(5-fluoro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3.0.0 ^4,6 ] Nonadece-7-ene-4-carboxylic acid (compound AR00294384). ¹ H NMR (500MHz, CDCl ₃ ): δ7.19-7.11(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), 4.64-4.56(m, 2H), 4.42(s, 1H), 4.12-4.02(m, 1H), 3.92-3.81(m , 1H), 3.78-3.61(m, 2H), 2.84-2.80(m, 2H), 2.74-2.64(m, 1H), 2.36-2.18(m, 2H), 1.91-1.81(m, 2H), 1.64 -1.54 (m, 2H), 1.48-1.10 (m, 15H). MS: m/e 643.0 (M ⁺ ).

Examples 1-10:

(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 ] nonadece-7-ene-4-carboxylic acid (compound AR00301745). MS: m/e 640.1 (M ⁺ ).

Examples 1-11:

(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 ] nonadece-7-ene-4-carboxylic acid (compound AR00301749). MS: m/e 640.1 (M ⁺ ), 641.1 (M ⁺ +1).

Examples 1-12:

(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[ ^14.3.0.04,6 ]nonadeca-7-ene-4-carboxylic acid (compound AR00304000). MS m/e 721.2 (M-1).

Examples 1-13:

According to Method B, but using 7-chloro-1,2,3,4-tetrahydro-isoquinoline in step 4, to synthesize (1S,4R,6S,14S,18R)-14-tert-butoxycarbonyl Amino-18-(7-chloro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3. 0.0 ^4,6 ] nonadece-7-ene-4-carboxylic acid (compound AR00304062). MS m/e 659.0 (M ⁺ ), 661.0 (M ⁺ +2).

Examples 1-14:

Synthesis of (1S,4R,6S,14S,18R)-14-tert-butoxycarbonyl according to method B, but using 6-fluoro-1,2,3,4-tetrahydro-isoquinoline in step 4 Amino-18-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3. 0.0 ^4,6 ] nonadece-7-ene-4-carboxylic acid (compound AR00304063). MS m/e 643.0 (M ⁺ ), 644.0 (M ⁺ +1).

Examples 1-15:

According to Method B, but using 4,4-spiro-cyclobutyl-1,2,3,4-tetrahydro-isoquinoline in step 4, (1S,4R,6S,14S,18R)-14 -tert-butoxycarbonylamino-18-(4,4-spiro-cyclobutyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3 , 16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00304065). ¹ H NMR (400MHz, d ₆ -acetone) δ7.99(d, 1H), 7.57-7.66(m, 1H); 7.27(t, 1H), 7.09-7.22(m, 2H), 5.99(bs, 1H ), 5.56(dd, 1H), 5.42(bs, 1H), 5.19-5.30(m, 1H), 4.52-4.70(m, 1H), 4.27-4.42(m, 1H), 4.17-4.27(m, 1H ), 3.91(dd, 1H), 3.63-3.82(m, 2H), 2.22-2.51(m, 6H), 1.93-2.20(m, 3H), 1.79-1.91(m, 1H), 1.52-1.66(m , 1H), 1.16-1.50 (m, 19H). MS m/z 665.1 (M ⁺⁺ 1).

Example 1-15a:

Preparation of 4,4-spiro-cyclobutyl-1,2,3,4-tetrahydro-isoquinoline

A: To a solution of 1-phenyl-1-cyclopropylnitrile (2.00 g, 12.7 mmol) in 100 ml THF was added dropwise a 1.0 M solution of LiAlH (19.1 ml, 19.1 mmol) at room temperature. The reaction was stirred at room temperature for 15 hours before being slowly quenched at 0 °C with 10 ml _H2O followed by 10 ml 10N NaOH and stirred at room temperature for 1.5 hours. The solution was filtered and THF was removed by rotary evaporation. The aqueous _mixture was extracted with EtOAc, and the organic extract was washed with _H2O and brine, dried over _Na2SO4 , and concentrated to give 0.70 g (34%) of a clear oil, which was used in the next step without further purification.

B: To a solution of C-(1-phenyl-cyclobutyl)-methylamine (0.70 g, 4.34 mmol) and TEA (0.67 ml, 4.78 mmol) in 40 ml THF was added dropwise chlorine at 0 °C Methyl formate. The reaction was stirred at room temperature for 15 hours. Water and _EtOAc were added the next day, the organic layer was separated and washed with 1N HCl and brine, dried over _Na2SO4 , concentrated to an oil which was used directly in the next step without further purification.

C: A mixture of (1-phenyl-cyclobutylmethyl)-carbamate 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 (rt). After cooling, water was added dropwise and the solution was extracted twice with DCM. The organic extracts were washed with brine, dried _{over Na2SO4} and concentrated to give a clear oil which was 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 20 ml THF was added dropwise a solution of LiAlH (3.26 ml, 3.26 mmol) at 0 °C 1.0M solution. The reaction was allowed to warm to room temperature and stirred for 15 hours before being slowly quenched at 0°C with 5ml _H2O followed by 5ml 1.0N NaOH and stirred at room temperature for 1.5 hours. The solution was filtered and THF was removed by rotary evaporation. The aqueous _mixture was extracted with EtOAc, and the organic extract was washed with _H2O and brine, dried over _Na2SO4 , and concentrated to give 0.21 g (56%) of a clear oil, which was used in the next step without further purification.

Examples 1-16:

(1S, 4R, 6S, 14S, 18R)-14-tert Butoxycarbonylamino-18-(4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-di Aza-tricyclo[14.3.0.0 ^4,6 ]nonade-7-ene-4-carboxylic acid (compound AR00304066). ¹ H NMR (400MHz, d ₆ -acetone) δ7.98(d, 1H), 7.39(bs, 1H), 7.09-7.24(m, 3H), 5.99(bs, 1H), 5.57(dd, 1H), 5.37-5.46(bs, 1H), 5.24(dd, 1H), 4.55-4.69(m, 1H), 4.26-4.36(m, 1H), 4.16-4.26(m, 1H), 3.90(dd, 1H), 3.40-3.49(m, 1H), 2.28-2.50(m, 4H), 1.98-2.09(2H), 1.79-1.92(m, 1H), 1.52-1.65(m, 3H), 1.16-1.51(m, 22H ). MS m/z 653.0 (M ⁺⁺ 1).

Example 1-16a:

Prepare 4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline according to the experimental procedure of steps A to D in the example 1-15a, 2-methyl-2-phenyl-propionitrile ( Prepared according to Caron, S.; Vazquez, E.; Wojcik, J.M.J. Am. Chem. Soc. 2000, 122, 712-713) into the title compound.

Examples 1-17:

According to method B, but using 4-methyl-1,2,3,4-tetrahydro-isoquinoline in step 4, to synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxy Carbonylamino-18-(4-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3.0.0 ^4,6 ] Nonadece-7-ene-4-carboxylic acid (compound AR00304067). ¹ H NMR (400MHz, d ₆ -acetone) δ7.93-8.03(m, 1H), 7.04-7.28(m, 4H), 6.02(bs, 1H), 5.56(dd, 1H), 5.40(m, 1H ), 5.23(dd, 1H), 4.66-4.85(m, 1H), 4.54-4.64(m, 1H), 4.34-4.54(m, 1H), 4.17-4.34(m, 1H), 3.91(dd, 1H ), 3.57-3.78(m, 1H), 3.42-3.57(m, 1H), 2.26-2.52(m, 4H), 1.96-2.09(m, 2.0), 1.77-1.92(m, 1.0), 1.50-1.64 (m, 3.0), 1.13-1.50 (m, 17h). MS m/z 639.0 (M ⁺⁺ 1).

Example 1-17a:

Preparation of 4-methyl-1,2,3,4-tetrahydroisoquinone from 2-phenyl-propylamine according to Grunewald, G.L.; Sall, D.J.; Monn, J.A.J.Med.Chem. 1988, 31, 433-444 phylloline.

Example 1-18:

(1S,4R , 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-(2-tert-butylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyl Oxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonade-7-ene-4-carboxylic acid (compound AR00304103). MS m/e 731.2 (M ⁺ +1).

Examples 1-19:

According to method B, but using 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine in step 4, to synthesize (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 Geno-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00304154). MS m/e 675.1 (M ⁺ +1).

Examples 1-20:

According to method B, but using 2-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine in step 4, to synthesize (1S, 4R, 6S, 14S, 18R) -14-tert-butoxycarbonylamino-18-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-2,15-di Oxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00304158). MS m/e 546.2 (M ⁺ +1-100).

Example 1-21:

Synthesis of (1S,4R,6S,14S,18R)-14-tert-butyl according to method B, but using 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine in step 4 Oxycarbonylamino-18-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbonyloxy)-2,15-dioxo-3,16-diazepine - Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00304183). MS m/e 625.2 (M-1).

Example 1-22:

Compound AR00312023

_{( 1S _} , 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-(3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo- 3,16-Diaza-tricyclo[ ^14.3.0.04,6 ]nonadecane-4-carboxylic acid (compound AR00312023). MS m/e 625.3 (M-1).

Example 1-23:

(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] Nonadece-7-ene-4-carboxylic acid (compound AR00314578). MS (POS ESI) m/z 540.2 [parent, (M ⁺ +1)-100 (Boc group)].

Examples 1-24:

(1S,4R, 6S, 14S, 18R)-18-(2-acetylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carbonyloxy)-14-tert-butoxycarbonyl Amino-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonade-7-ene-4-carboxylic acid (compound AR00314685). MS m/e 589.2 (M ⁺ +1-100).

Examples 1-25:

Synthesis of (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 ]nonadec-7-ene-4-carboxylic acid (compound AR00315997). 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 3 N 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 (2x). The combined organic layers were washed with saturated aqueous sodium bicarbonate, water and brine, then dried and concentrated. The residue was purified by silica gel column chromatography to afford 5.44 g (88%) of the Boc protected product as a white solid.

To a solution of the product from the previous step above (0.2 g, 0.81 mmol) in THF (5 mL) was added NaH at 0 °C. After 15 minutes, _CH3I was added and stirring was continued at room temperature overnight. Upon completion, the reaction mixture _was quenched with ice water, extracted with EtOAc (25 mL), dried ( _Na2SO4 ) and concentrated. The Boc group was removed using 60% TFA-DCM (2 mL) at 0°C to afford 110 mg (77.5%) of the final product as a pale green solid. MS: 177.1 (MH ⁺ ).

Examples 1-26:

(1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino- 18-(5-Chloro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] nonadecan-7-ene-4-carboxylic acid (compound AR00315998). ¹ H NMR (400MHz, CDCl ₃ ): δ7.24-7.02(m, 3H), 6.82(s, 1H), 5.68-5.51(m, 1H), 5.36(s, 1H), 5.11-4.96(m, 2H), 4.67-4.44(m, 5H), 4.29-4.20(m, 1H), 4.20-4.11(m, 1H), 3.82-3.74(m, 1H), 2.69-2.55(m, 1H), 2.31- 2.15 (m, 1H), 2.14-2.06 (m, 1H), 2.03 (s, 1H), 2.01-1.86 (m, 1H), 1.86-1.24 (m, 11H), 1.22 (s, 9H). MS: m/e 644.9 (M ⁺ ), 646.9 (M ⁺ +2).

Example 1-27:

According to method B, but using 5,6-dichloro-2,3-dihydro-1H-isoindole in step 4, to synthesize (1S,4R,6S,14S,18R)-14-tert-butoxy Carbonylamino-18-(5,6-dichloro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3.0.0 ^4,6 ] Nonadece-7-ene-4-carboxylic acid (compound AR00315999). ¹ H NMR (400MHz, CDCl ₃ ): δ7.29(s, 1H), 7.02(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, 1H), 4.33-4.29-4.11(m, 1H), 3.82-3.74(m, 1H), 2.69-2.55(m , 1H), 2.73-2.61(m, 1H), 2.29-2.08(m, 3H), 2.01(s, 1H), 1.83-1.65(m, 1H), 1.63-1.46(m, 11H), 1.40-1.12 (s, 9H). MS: m/e 678.9 (M ⁺ ), 681 (M ⁺⁺ 2).

Example 1-28:

According to method B, but using 4R-methyl-1,2,3,4-tetrahydro-isoquinoline in step 4, to synthesize (1S,4R,6S,14S,18R)-14-tert-butoxy Carbonylamino-18-(4R-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04.6 ] nonadece-7-ene-4-carboxylic acid (compound AR00320122). ¹ H NMR (400MHz, CD ₃ OD) δ7.02-7.24 (m, 3H), 5.59 (dd, 1H), 5.30-5.44 (m, 2H), 4.66-4.81 (m, 1H), 4.14-4.64 ( m, 3H), 3.83-3.92(m, 1H), 3.58-3.81(m, 1H), 3.44-3.56(m, 1H), 2.86-3.86(m, 1H), 2.23-2.58(m, 4H), 1.87-2.13 (m, 2H), 1.70-1.87 (m, 1H), 1.50-1.70 (m, 3H), 1.07-1.51 (m, 19H), 0.80-0.96 (m, 2H). MS m/z 639.0 (M ⁺⁺ 1).

Example 1-29:

According to method B, but using 4S-methyl-1,2,3,4-tetrahydro-isoquinoline in step 4, to synthesize (1S,4R,6S,14S,18R)-14-tert-butoxy Carbonylamino-18-(4S-methyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3.0.0 ^4,6 ] Nonadece-7-ene-4-carboxylic acid (compound AR00320123). ¹ H NMR (400MHz, CD ₃ OD) δ7.01-7.23 (m, 3H), 5.58 (dd, 1H), 5.32-5.45 (m, 2H), 4.66-4.82 (m, 1H), 4.12-4.64 ( m, 3H), 3.86-3.94(m, 1H), 3.52-3.74(m, 1H), 3.43-3.56(m, 1H), 2.88-3.85(m, 1H), 2.24-2.60(m, 4H), 1.87-2.15 (m, 2H), 1.71-1.87 (m, 1H), 1.52-1.70 (m, 3H), 1.07-1.52 (m, 19H), 0.80-0.96 (m, 2H). MS m/z 639.0 (M ⁺⁺ 1).

Examples 1-30:

Synthesis of (1S,4R,6S,14S,18R)-14-tert-butoxycarbonylamino-18 according to Method B, but using 4-(2-methoxy-phenyl)-piperidine in step 4 -[4-(2-Methoxy-phenyl)-piperidine-1-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] nonadece-7-ene-4-carboxylic acid (compound AR00320576). MS m/e 583.3 (M ⁺ +1-100).

Example 1-31:

(1S, 4R, 6S, 14S, 18R)-14- tert-butoxycarbonylamino-18-(6-methoxy-1,3,4,9-tetrahydro-b-carboline-2-carbonyloxy)-2,15-dioxo-3,16 - Diaza-tricyclo[14.3.0.0 ^4,6 ]nonade-7-ene-4-carboxylic acid (compound AR00320577). MS m/e 594.2 (M ⁺ +1-100).

Instance 1-32:

(1S, 4R, 6S, 14S, 18R)- 14-tert-butoxycarbonylamino-2,15-dioxo-18-(1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) - 3,16-Diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00301383). ¹ HNMR (500MHz, CD ₃ OD) δ7.33-7.24 (m, 4H), 7.20 (br s, 1H), 6.61 (br s, 1H), 5.75-5.52 (m, 2H), 5.50-5.33 (m , 2H), 4.63-4.43(m, 2H), 4.42-4.07(m, 4H), 3.96(br s, 1H), 3.67-3.11(m, 5H), 3.06-2.88(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:

According to the procedure described in Example 1-2, but using 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride in step 4 instead of 1 , 2,3,4-tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-(6-methoxy-1-methoxy Methyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] Nonadecan-7-ene-4-carboxylic acid (compound AR00333842). MS (APCI-): m/z 697.2 (M-1).

Instance 1-34:

Following the procedure described in Example 1-2, but using 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride in place of 1,2 in step 4 , 3,4-tetrahydro-isoquinoline, to synthesize (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[ ^14.3.0.04,6 ]nineteen-7 -ene-4-carboxylic acid (compound AR00365349). MS (APCI-): m/z 685.3 (M-1).

Examples 1-35:

According to the procedure described in Example 1-2, but in step 4 using dimethyl-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-amine (according to example 1- 35a synthesis) instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-(1-dimethyl Aminomethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] Nonadecan-7-ene-4-carboxylic acid (compound AR00333224). MS (APCI+): m/z 582.3 (MH ⁺ -Boc).

Example 1-35a:

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

Instance 1-36:

Compound AR00333225

According to the procedure described in Example 1-2, but using 1-morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline in step 4 (synthesized according to Example 1-36a) Instead of 1,2,3,4-tetrahydro-isoquinoline, to synthesize (1S,4R,6S,14S,18R)-14-tert-butoxycarbonylamino-18-(1-morpholin-4-yl Methyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]dec Nona-7-ene-4-carboxylic acid (compound AR00333225). MS (APCI-): m/z 722.3 (M-1).

Example 1-36a:

By a similar manner as shown in Example 3-76a, except that phenethylamine was used instead of 2-(3-methoxy-phenyl)-ethylamine in step 1 and morpholine was used instead of methanol in the first part of step 3 Sodium was used as a nucleophile to synthesize 1-morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline. This crude product was used directly in the next coupling step without further purification.

Instance 1-37:

According to the procedure described in Example 1-2, but in step 4 using 6-methoxy-1-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (according to Example 1-37a synthesis) replaces 1,2,3,4-tetrahydro-isoquinoline to synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-(6- Methoxy-1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diazepine - Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00333248).

MS (APCI-): m/z 750.4 (M-1).

Example 1-37a

6-Methoxy-1-piperidin-1-ylmethyl- 1,2,3,4-Tetrahydro-isoquinoline. This crude product was used directly in the next coupling step without further purification.

Example 1-38:

According to the procedure described in Example 1-2, but in step 4 using 6-methoxy-1-morpholin-4-ylmethyl-1,2,3,4-tetrahydro-isoquinoline (according to Example 1-38a synthesis) replaces 1,2,3,4-tetrahydro-isoquinoline to synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-(6- Methoxy-1-morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diazepine - Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00333276). MS (APCI-): m/z 750.3 (M-1).

Example 1-38a

6-Methoxy-1-morpholin-4-ylmethyl- 1,2,3,4-Tetrahydro-isoquinoline. This crude product was used directly in the next coupling step without further purification.

Example 1-39:

According to the procedure described in Example 1-2, but in step 4 using (6-methoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-dimethyl- Amine (synthesized according to Example 1-39a) instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (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-diazepine Hetero-tricyclo[14.3.0.0 ^4,6 ]nonade-7-ene-4-carboxylic acid (compound AR00333277). MS (APCI+): m/z 712.3 (MH ⁺ ).

Example 1-39a:

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

Instances 1-40:

Compound AR00365369

According to the procedure described in Example 1-2, but using 4-fluoro-2,3-dihydro-1H-isoindole (synthesized according to Example 3-55a) in step 4 instead of 1,2,3,4- Tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2- Carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadeca-7-ene-4-carboxylic acid (compound AR00365369). ¹ H NMR (500MHz, DMSO) δ12.21(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), 5.33-5.21(m, 2H), 4.66(s, 4H), 4.22(q, 1H), 4.24(t, 1H), 3.99-3.89(m, 1H) , 3.73-3.64(m, 1H), 2.65-2.55(m, 1H), 2.28-2.08(m, 3H), 1.77-1.61(m, 2H), 1.54-1.42(m, 1H), 1.42-1.03( m, 16H); MS (APCI-): m/z 627.3 (M-1).

Example 1-41:

Compound AR00371946

According to the procedure described in Example 1-2, but in step 4 using 5-(2-morpholin-4-yl-ethoxy)-2,3-dihydro-1H-isoindole (according to J. Med.Chem.2002, volume 45, number 26, 5771, preparation method D; : ¹ H NMR (500 MHz, CDCl ₃ ) δ7.13 (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)) instead of 1,2,3,4-tetrahydro- Isoquinoline, to synthesize (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 ]nonadecan-7-ene-4- Carboxylic acid (compound AR00371946). MS (APCI+): m/z 640.3 [(M+1)-Boc].

Instance 1-42:

Compound AR00371947

According to the procedure described in Example 1-2, but using [2-(2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-dimethyl-amine in step 4 (according to J.Med.Chem.2002, the 45th volume, the 26th phase, 5771, preparation method D; And the step preparation described in Bioorg.Med.Chem.Lett.11 (2001) 685-688. For N- Boc protected amine material: ¹ H NMR (500MHz, CDCl ₃ ) δ7.14(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)) instead of 1,2,3,4-tetrahydro-isoquinoline, to synthesize (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[ ^14.3.0.04,6 ]nonade-7-ene-4-carboxylic acid (compound AR00371947). MS (APCI+): m/z 698.2 (M+1).

Instance 1-43:

Compound AR00371948

According to the procedure described in Example 1-2, but using [2-(2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-isopropyl-amine in step 4 (according to J.Med.Chem.2002, the 45th volume, the 26th phase, 5771, preparation method D; And the step preparation described in Bioorg.Med.Chem.Lett.11 (2001) 685-688. For N- Boc protected amine material: ¹ H NMR (500MHz, CDCl ₃ ) δ7.13(dd, 1H), 6.86-6.75(m, 2H), 4.62(t, 4H), 4.06(t, 2H), 2.99(t, 2H), 2.88 (septet, 1H), 1.62 (br s, 1H), 1.51 (s, 9H), 1.10 (d, 6H); MS (APCI+): m/z 321.2 (M+1)) instead of 1 , 2,3,4-tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-[5-(2-isopropylamino- Ethoxy)-1,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]deca Nona-7-ene-4-carboxylic acid (compound AR00371948). MS (APCI-): m/z 710.3 (M-1).

Preparation of compounds with general structure III

Compounds of general structure II are prepared according to the general scheme shown above. Removal of the Boc protecting group of the compound having structure Ia is followed by nucleophilic attack of the amino group on the electrophile to form a carbamate, amide or urea.

Example 2-1:

Compound AR00247310

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

The N-Boc protected starting material (102 mg, 0.16 mmol) was dissolved in 6 mL 4N HCl (dioxane) and kept at room temperature for 90 minutes. HPLC showed complete removal of the Boc protecting group. The reaction mixture was then concentrated, taken up in acetonitrile, and concentrated twice more. The resulting beige 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, Preparation of ethyl 15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadeca-7-ene-4-carboxylate

To a solution of cyclopentanol (42 mg, 0.48 mmol) in THF (16 mL) was added dropwise a solution of phosgene (0.42 mL, 1.9 M, 0.80 mmol) in toluene. The mixture was stirred at room temperature for 2 hours to form the cyclopentyl chloroformate reagent. The reaction was concentrated to about half volume. It was then diluted to original volume with DCM and concentrated again to half volume in order 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 (0.16 mmol) above 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 monitored for completion by HPLC. It was concentrated, taken up in EtOAc (15 _mL ), then washed with water, saturated sodium bicarbonate, water and brine (10 mL each), dried over _Na2SO4 , and concentrated. The crude yellow thick oily residue was purified by flash chromatography on a Biotage 40S (eluent = Hexane/EtOAc 1 :1 ) to give the desired product (65.2 mg, 63%) as a white friable foamy powder. MS (MH ⁺ 665.2).

Step 3: (1S, 4R, 6S, 14S, 18R)-14-cyclopentyloxycarbonylamino-18-(3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2, Preparation of 15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadeca-7-ene-4-carboxylic acid (compound AR00247310)

The same hydrolysis procedure as in Step 5 of Example 1-1 was followed.

The following compounds were also prepared following the same procedure in the preceding Example 2-1, wherein cyclopentyl chloroformate was replaced with other electrophiles as described in step 4 of Method B in Example 1-2, and/or P2 was replaced with other amine starting materials - Tetrahydroisoquinoline.

Example 2-2:

Compound AR00294376

(1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline was synthesized according to the procedure described in Example 2-1, but using methyl chloroformate in step 2 -2-carbonyloxy)-14-methoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-ene-4 - Carboxylic acids (compound AR00294376).

Example 2-3:

Compound AR00304074

(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 ]nonadec-7-ene-4-carboxylic acid (compound AR00304074). MS m/e 583.2 (M ⁺⁺ 1).

Example 2-4:

Compound AR00304075

Synthesized according to the procedures described in Examples 1-2 and 2-1, but using 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline in Step 4 of Example 1-2 (1S, 4R, 6S, 14S, 18R)-14-cyclopentyloxycarbonylamino-2,15-dioxo-18-(8-trifluoromethyl-3,4-dihydro-1H-iso Quinoline-2-carbonyloxy)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonade-7-ene-4-carboxylic acid (compound AR00304075). MS m/e 705.1 (M ⁺ +1).

Example 2-5:

Compound AR00304076

(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 ]nonadec-7-ene-4-carboxylic acid (compound AR00304076). MS m/e 623.2 (M ⁺ +1).

Example 2-6:

Compound AR00304125

(1S, 4R, 6S, 14S, 18R)-18-(3 , 4-dihydro-1H-isoquinoline-2-carbonyloxy)-14-(2-fluoro-ethoxycarbonylamino)-2,15-dioxo-3,16-diaza-tri Cyclo[14.3.0.0 ^4,6 ]nonade-7-ene-4-carboxylic acid (compound AR00304125). MS m/e 615.1 (M ⁺ +1).

Example 2-7:

Compound AR00304126

(1S, 4R, 6S, 14S, 18R)-18-( 3,4-Dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-14-(tetrahydrofuran-3S-yloxycarbonylamino)-3,16-diaza- Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00304126). MS m/e 639.2 (M ⁺ +1).

Example 2-8:

Compound AR00304127

(1S,4R,6S,14S,18R)-18-( 3,4-Dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-14-(tetrahydrofuran-3R-yloxycarbonylamino)-3,16-diaza- Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00304127). MS m/e 639.2 (M ⁺ +1).

Example 2-9:

Compound AR00320002

(1S, 4R, 6S, 14S, 18R)- 18-(3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-14-(tetrahydropyran-4-yloxycarbonylamino)-3, 16-Diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00320002). MS m/e 653.2 (M ⁺⁺ 1).

Example 2-10:

Compound AR00320074

According to the procedures described in Examples 1-2 and 2-1, but using 2,3-dihydro-1H-isoindole in step 4 of Example 1-2 and tetrahydrofuran in step 2 of Example 2-1- 3R-alcohols instead of cyclopentanols to form chloroformate reagents to synthesize (1S,4R,6S,14S,18R)-18-(1,3-dihydro-isoindole-2-carbonyloxy)- 2,15-dioxo-14-(tetrahydrofuran-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-ene-4-carboxy acid (compound AR00320074). MS m/e 625.2 (M ⁺⁺ 1).

Example 2-11:

Compound AR00320075

According to the procedures described in Examples 1-2 and 2-1, but using 2,3-dihydro-1H-isoindole in step 4 of Example 1-2 and tetrahydrofuran in step 2 of Example 2-1- 3S-alcohols instead of cyclopentanols to form chloroformate reagents to synthesize (1S,4R,6S,14S,18R)-18-(1,3-dihydro-isoindole-2-carbonyloxy)- 2,15-Dioxo-14-(tetrahydrofuran-3S-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-ene 4-carboxylic acid (compound AR00320075). MS m/e 625.2 (M ⁺⁺ 1).

Example 2-12:

Compound AR00320076

According to the procedures described in Examples 1-2 and 2-1, but using 2,3-dihydro-1H-isoindole in step 4 of Example 1-2 and 2- Fluoroethanol instead of cyclopentanol to form a chloroformate reagent for the synthesis of (1S,4R,6S,14S,18R)-18-(1,3-dihydro-isoindole-2-carbonyloxy)-2 , 15-dioxo-14-(tetrahydrofuran-3S-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-ene-4-carboxylic acid (compound AR00320076). MS m/e 601.1 (M ⁺ +1).

Example 2-13:

Compound AR00320077

According to the procedures described in Examples 1-2 and 2-1, but using 2,3-dihydro-1H-isoindole in step 4 of Example 1-2 and tetrahydro in step 2 of Example 2-1 Pyran-4-ol instead of cyclopentanol to form the chloroformate reagent for the synthesis of (1S,4R,6S,14S,18R)-18-(1,3-dihydro-isoindole-2-carbonyloxy Base)-2,15-dioxo-14-(tetrahydropyran-4-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nineteen-7 -ene-4-carboxylic acid (compound AR00320077). MS m/e 601.1 (M ⁺ +1).

Example 2-14:

Compound AR00320445

According to the procedures described in Examples 1-2 and 2-1, but using 5,6-dichloro-2,3-dihydro-1H-isoindole in step 4 of Example 1-2 and in Example 2-1 Using tetrahydrofuran-3R-alcohol in step 2 instead of cyclopentanol to form the chloroformate reagent, to synthesize (1S, 4R, 6S, 14S, 18R)-18-(5,6-dichloro-1,3- Dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-14-(tetrahydrofuran-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] Nonadece-7-ene-4-carboxylic acid (compound AR00320445). MS: m/e 693.0 (M ⁺ ), 695.1 (M ⁺ +2).

Example 2-15:

Compound AR00320448

According to the procedures described in Examples 1-2 and 2-1, while using 5-dichloro-2,3-dihydro-1H-isoindole in Step 4 of Example 1-2 and the procedure in Example 2-1 The synthesis of (1S, 4R, 6S, 14S, 18R)-18-(5-chloro-1,3-dihydro-isoindinyl) using tetrahydrofuran-3R-alcohol instead of cyclopentanol to form chloroformate reagent in 2 Indole-2-carbonyloxy)-2,15-dioxo-14-(tetrahydrofuran-3R-yloxycarbonylamino)-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]deca Nona-7-ene-4-carboxylic acid (compound AR00320448). ¹ H NMR (500MHz, CD ₃ OD): δ7.38(s, 1H), 7.32-7.28(m, 2H), 7.22(d, 1H), 7.10(br s, 1H), 5.56-5.50(q, 1H), 5.42-5.38(t, 1H), 5.35(br s, 1H), 4.80-4.48(m, 6H), 4.44(m, 1H), 4.16(d, 1H), 3.84(dd, 1H), 3.78-3.69(m, 1H), 3.68-3.60(m, 1H), 3.50(t, 1H), 2.55-2.36(m, 3H), 2.21-2.12(m, 1H), 1.98-1.85(m, 1H ), 1.72-1.62 (m, 2H), 1.61-1.51 (m, 2H), 1.50-1.20 (m, 9H). MS: m/e 659.1 (M ⁺ ), 661.1 (M ⁺ +2).

Example 2-16:

AR00248689

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

Cyclopentyl carboxylic acid was first loaded on PS-TFP resin (purchased from Argonaut Technologies) to form an active ester. The active ester on resin (26mg, 1.16mmol/g, 0.03mmol) was first expanded in 0.5mL chloroform, followed by the addition of MP-carbonate resin (purchased from Argonaut Technologies, 300mg, 2.5mmol/g, 0.75mmol). Then, a 0.5 M chloroform solution of the macrocyclic substance (15 mg, 0.02 mmol) was added to this resin mixture, and the reaction was shaken at room temperature overnight. After 16 hours, the reaction was monitored for completion by HPLC. It was then filtered and concentrated to give the clean N-acylated product. It was hydrolyzed following the same hydrolysis procedure in step 5 of Example 1-1 to give the desired product AR248689 (12.5 mg, 88%) as a white solid. MS (APCI+): m/z 621.3 (MH ⁺ ).

Example 2-17:

Compound AR00248687

Following the same procedures described in Examples 2-16, but first loading tert-butyl carboxylic acid on PS-TFP resin, to synthesize (1S, 4R, 6S, 14S, 18R)-18-(3,4-bis Hydrogen-1H-isoquinoline-2-carbonyloxy)-14-(2,2-dimethyl-propionylamino)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3.0.0 ^4,6 ] Nonadece-7-ene-4-carboxylic acid (compound AR00248687). MS (APCI+): m/z 609.3 (MH ⁺ ).

Example 2-18:

Compound AR00248688

(1S, 4R, 6S, 14S, 18R)-18-(3,4-di Hydrogen-1H-isoquinoline-2-carbonyloxy)-14-isobutyrylamino-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nadecane -7-ene-4-carboxylic acid (compound AR00248688). MS (APCI+): m/z 595.3 (MH ⁺ ).

Example 2-19:

Compound AR298989

(1S, 4R, 6S, 14S, 18R)-14-(2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-18-(3,4-dihydro-1H-isoquinoline- Synthesis of 2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-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 ] Nonadecan-7-ene-4-carboxylic acid ethyl ester (120mg, 217μmol) and N-α-t-Boc-L-valine N-hydroxysuccinamide ester (96mg, 300μmol) together in 1.1 mL of dichloromethane was stirred for 14 hours. The solvent was removed in vacuo, and 1 mL each of water and ethyl acetate was added. The resulting phases were separated and the aqueous layer was washed twice with 500uL ethyl acetate. The combined organic phases were dried over MgSO ₄ and the solvent was removed in vacuo to give the desired compound (132 mg, 81%) as a white solid. MS m/z 752.2 (MH ⁺ ).

Example 2-20:

Compound AR00301338

Following the same procedure as described in Examples 2-19, except using 3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butanoic acid 2,5-dioxo-pyrrolidin-1-yl Ester instead of N-α-t-Boc-L-valine N-hydroxysuccinamide ester, to synthesize (1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquine Phenyl-2-carbonyloxy)-14-{3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino)-2,15-dioxo-3,16-di Aza-tricyclo[14.3.0.0 ^4,6 ]nonade-7-ene-4-carboxylic acid (compound AR00301338). MS m/e 730.3 (M ⁺ +1).

Example 2-21:

Compound AR00304072

Following the same procedure as described in Examples 2-19, except using 2-[(6-Dimethylamino-pyridine-3-carbonyl)-amino]-3-methyl-butanoic acid 2,5-dioxo- Pyrrolidin-1-yl ester instead of N-α-t-Boc-L-valine N-hydroxysuccinamide ester to synthesize (1S, 4R, 6S, 14S, 18R)-18-(3,4-di Hydrogen-1H-isoquinoline-2-carbonyloxy)-14-{2-[(6-dimethylamino-pyridine-3-carbonyl)-amino]-3-methyl-butyrylamino}-2 , 15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadeca-7-ene-4-carboxylic acid (compound AR00304072). ¹ H NMR (CD ₃ OD, 500MHz): δ8.69(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), 5.36-5.42(m, 2H), 4.49-4.56(m, 3H), 4.42-4.45(m, 1H), 4.31-4.32(m, 1H), 3.92-3.95 (m, 1H), 3.65-3.72(m, 2H); 2.85-2.91{m, 2H}, 2.33-2.55(m, 4H), 1.93-2.03(m, 3H), 1.61-1.68(m, 3H) , 1.27-1.52 (m, 12H), 0.86-0.96 (m, 8H). MS m/e 770.4 (M-1).

Example 2-22:

Compound AR00304073

Following the same procedure as described in Examples 2-19 except using 3-methyl-2-[(pyridine-3-carbonyl)-amino]-butanoic acid 2,5-dioxo-pyrrolidin-1-yl ester Synthesis of (1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline instead of N-α-t-Boc-L-valine N-hydroxysuccinamide ester -2-carbonyloxy)-14-{3-methyl-3-[(pyridine-3-carbonyl)-amino]-butyrylamino}-2,15-dioxo-3,16-diazepine - Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00304073). MS m/e 729.2 (M ⁺ +1).

Example 2-23:

Compound AR00298990

According to the same procedure as in step 1 of Example 2-1, (1S, 4R, 6S, 14S, 18R)-14-(2-amino-3-methyl-butyrylamino)-18-(3,4-di Hydrogen-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-ene-4- Carboxylic acid (compound 298990). MS m/e 624.2 (M ⁺⁺ 1).

Example 2-24:

Compound AR00294378

(1S, 4R, 6S, 14S, 18R)-14-(3-cyclopentyl-ureido)-18-(3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2, Synthesis of 15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]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-diazepine -tricyclo[ ^14.3.0.04,6 ]nonadeca-7-ene-4-carboxylate ethyl ester hydrochloride (49 mg, 74 μmol), diisopropylethylamine (29 mg, 222 μmol) and cyclopentyl isocyanate The ester (25 mg, 222 μmol) was treated in 375 uL of dichloromethane and stirred at 19° C. for 1 hour. The reaction was directly loaded on a C18 flash column and eluted with water/acetonitrile (10% to 100%) containing 0.1% TFA to afford the title product (42 mg, 77%) as a white solid. MS m/z 732.2 (MH ⁺ ).

Example 2-25:

Compound AR00294377

(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 ]nonade-7-ene-4-carboxylic acid (compound AR00294377). MS m/e 624.1 (M ⁺ +1).

Example 2-26:

Compound AR00304077

According to the procedures described in Examples 1-2 and 2-24, except that 5-fluoro-1,2,3,4-tetrahydro-isoquinoline was used instead of 1,2,3 in step 4 of Example 1-2 , 4-tetrahydro-isoquinoline, to synthesize (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 ]nonadecan-7-ene-4-carboxy acid (compound AR00304077). MS m/e 654.2 (M ⁺⁺ 1).

Example 2-27:

Compound AR00304078

Following the procedures described in Examples 1-2 and 2-24, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead of 1 in Step 4 of Example 1-2, 2,3,4-Tetrahydro-isoquinoline, to synthesize (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 ]nineteen-7 -ene-4-carboxylic acid (compound AR00304078). MS m/e 704.1 (M ⁺ +1).

Example 2-28:

Compound AR00304079

Following the procedures 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, to synthesize (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 ]nonade-7-ene-4-carboxylic acid (compound AR00304079). MS m/e 622.2 (M ⁺⁺ 1).

Example 2-29:

Compound AR00320078

Following the procedures 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- Synthesis of isoquinoline and (1S, 4R, 6S, 14S, 18R)-14-(3-tert-butyl-urea using tert-butyl isocyanate instead of cyclopentyl isocyanate in the procedures of Examples 2-24 Base)-18-(1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] Nonadecet-7-ene-4-carboxylic acid (compound AR00320078). MS m/e 610.1 (M ⁺ +1).

Example 2-30:

Compound AR00320221

(1S, 4R, 6S, 14S, 18R)-18-(3,4-dihydro-1H-isoquinoline-2-carbonyloxy)-2,15-dioxo-14-[3-(tetrahydrofuran-3-yl)-ureido] - 3,16-Diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00320221). MS m/e 638.2 (M ⁺ +1).

Example 2-31:

Compound AR00320449

Following the procedures described in Examples 1-2 and 2-24, except that 5-chloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4 in Step 4 of Example 1-2 - Tetrahydro-isoquinoline and the use of tert-butyl isocyanate instead of cyclopentyl isocyanate in the procedures of Example 2-24 to synthesize (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-tricyclic [14.3.0.0 ^4,6 ] nonadece-7-ene-4-carboxylic acid (compound AR00320449). ¹ H NMR (500MHz, CD ₃ OD): δ7.34(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:

Compound AR00320450

Following the procedures described in Examples 1-2 and 2-24, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used instead of 1,2 in Step 4 of Example 1-2, 3,4-Tetrahydro-isoquinoline and the use of tert-butyl isocyanate instead of cyclopentyl isocyanate in the procedure of Example 2-24 to synthesize (1S, 4R, 6S, 14S, 18R)-14-( 3-tert-butyl-ureido)-18-(5,6-dichloro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16- Diaza-tricyclo[14.3.0.0 ^4,6 ]nonade-7-ene-4-carboxylic acid (compound AR00320450). ¹ H NMR (500MHz, CD ₃ OD): δ7.50(s, 1H), 7.38(s, 1H), 5.56(q, 1H), 5.42-5.38(m, 2H), 4.72-4.61(m, 4H ), 4.55(t, 1H), 4.34(dd, 1H), 4.28(d, 1H), 3.92(dd, 1H), 2.45-2.32(m, 2H), 2.32-2.18(m, 1H), 2.08- 2.00 (m, 1H), 1.75-1.68 (m, 1H), 1.63-1.54 (m, 3H), 1.50-1.22 (m, 8H), 1.18 (s, 9H). MS: m/e 678.0 (M ⁺ ), 680.0 (M ⁺ +2).

Example 2-33:

Compound AR00365381

According to the procedures described in Examples 1-2 and 2-1, except that 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-chloro was used in step 4 of Example 1-2 Synthesis of (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 ] Nonadece-7-ene-4-carboxylic acid (compound AR00365381). MS (APCI-): m/z 697.4 (M-1).

Preparation of Compounds with General Structure IV

Compounds with general structure IV were prepared according to the scheme shown above (1. Khan et al., Bioorg. & Med. Chem. Lett., 1997, 7(23), 3017-3022; 2. International Application PCT/US02/39926, WO 03/053349).

Example 3-1:

Compound AR00261408

(1S, 4R, 6S, 14S, 18R)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15 Synthesis of -dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (AR00261408)

Macrocyclic acid compound #101 (7 mg, 0.011 mmol) was dissolved in 0.1 mL of DMF, followed by the addition of CDI (1.8 mg, 0.011 mmol). The mixture was heated 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 overnight at 40°C for 4 nights. After 14h, LCMS showed the reaction was complete. The reaction was cooled to room temperature and partitioned between 2 mL EA and 2 mL 5% HCL(aq). The organic layer was washed with water, sodium bicarbonate (2 mL each) and _dried ( _Na2SO4 ). The crude product was flash-passed on Biotage 12M (eluent = DCM:MeOH 20:1) to afford AR00261408 (4.2 mg, 52%). ¹ H NMR (CDCl ₃ , 500MHz): δ0.80-2.10 (m, 25H), 2.20-2.27 (m, 1H), 2.37-2.59 (m, 3H), 2.84 (m, 1H), 3.60-3.70 ( m, 1H), 3.82-3.90(m, 1H), 4.20-4.30(m, 2H), 4.45-4.70(m, 5H), 4.95-5.05(m, 2H), 5.74(m, 1H), 6.74( m, 1H), 7.0-7.23 (m, 4H). MS m/e 728.0 (M ⁺ +H).

Example 3-2:

Compound AR00261407

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

Example 3-3:

Compound AR00254906

(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 ] nonadecan-7-en-18-yl ester (compound AR00254906). ¹ H NMR (CDCl ₃ , 500MHz): δ1.20-1.52(m, 16H), 1.54-1.98(m, 5H), 2.20-2.30(m, 1H), 2.38-2.46(m, 1H), 2.47- 2.59(m, 3H), 2.84(m, 1H), 3.18(s, 3H), 3.56-3.70(m, 1H), 3.82-3.90(m, 1H), 4.22-4.33(m, 2H), 4.47- 4.69 (m, 4H), 4.90-5.10 (m, 2H), 5.47 (brs, 1H), 5.74 (m, 1H), 6.74 (m, 1H), 7.03-7.23 (m, 4H). MS m/e 701.9 (M ⁺ ), 602.2 (parent, MH ⁺ -Boc group).

Example 3-4:

Compound AR00261409

(1S, 4R, 6S, 14S, 18R)-3,4-dihydro-1H was synthesized according to the procedure described in Example 3-1 except that n-butylsulfonamide was used instead of cyclopropylsulfonamide in the coupling step -Isoquinoline-2-carboxylic acid 4-(butane-1-sulfonylaminocarbonyl)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (compound AR00261409). ¹ H NMR (CDCl ₃ , 500MHz): δ0.80-1.03(m, 7H), 1.20-2.10(m, 22H), 2.20-2.60(m, 4H), 2.84(m, 1H), 3.20(m, 1H), 3.44(m, 1H), 3.65(m, 1H), 3.80-3.95(m, 1H), 4.20-4.34(m, 2H), 4.50-4.65(m, 4H), 4.95-5.05(m, 1H), 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:

Compound AR00282131

(1S, 4R, 6S, 14S, 18R)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentadiene was synthesized according to the procedures described in Examples 2-1 and 3-1 Oxyoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-ene-18- base ester (compound AR00282131). MS m/e 738.4 (M-1).

Example 3-6:

Compound AR00294381

(1S,4R,6S,14S,18R)-3,4-dihydro-isoindole-2-carboxylic acid 14-tert-butoxyl was synthesized according to the procedures described in Examples 1-5 and 3-1 Carbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester ( Compound AR00294381). ¹ H NMR (CDCl ₃ , 500MHz): δ0.89-2.08(m, 25H), 2.21-2.28(m, 1H), 2.41-2.49(m, 1H), 2.51-2.61(m, 2H), 2.91( m, 1H), 3.83(m, 1H), 4.21(m, 1H), 4.40(d, /=11.7Hz, 1H), 4.53-4.80(m, 5H), 4.95-5.04(m, 2H), 5.47 (brs, 1H), 5.72 (m, 1H), 6.77 (m, 1H), 7.16 (m, 1H), 7.23-7.31 (m, 3H). MS m/e 712.3 (APCI-, MH).

Example 3-7:

Compound AR00298996

According to the procedures described in Examples 1-2 and 3-1, except that 5-fluoro-1,2,3,4-tetrahydro-isoquinoline was used instead of 1,2,3 in step 4 of Example 1-2, 4-tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxy Carbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester ( Compound AR00298996). ¹ H NMR (400MHz, CDCl ₃ ): δ10.05(s, 1H), 8.12(s, 1H), 7.04(s, 1H), 6.84-6.73(m, 2H), 6.70(s, 1H), 5.65 (q, 1H), 5.40(s, 1H), 4.59(m, 2H), 4.54-4.40(m, 2H), 3.82-3.74(m, 1H), 3.72-3.51(m, 2H), 2.92-2.68 (m, 3H), 2.55-2.30 (m, 3H), 2.21-2.15 (m, 1H), 2.00-1.60 (m, 3H), 1.40-0.75 (m, 18H). MS: m/e 746.0 (M ⁺ ).

Example 3-8:

Compound AR00298997

According to the procedures described in Examples 1-2 and 3-1, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead of 1,2 in step 4 of Example 1-2 , 3,4-tetrahydro-isoquinoline, to synthesize (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 ]nonadecan-7-ene -18-yl ester (compound AR00298997). ¹ H NMR (500MHz, CD3OD): δ7.55(dd, 1H), 7.42(dd, 1H), 7.35(t, 1H), 5.71-5.61(m, 1H), 5.40(m, 1H), 4.60( s, 1H), 4.52(m, 1H), 4.42(m, 1H), 4.15(m, 1H), 3.91(m, 1H), 3.78-3.62(m, 2H), 3.00-2.82(m, 3H) , 2.58-2.52(m, 3H), 2.51-2.32(m, 2H), 1.86-1.56(m, 3H), 1.41(m, 2H), 1.32-1.21(m, 5H), 1.04-0.98(m, 14H). MS: m/e 795.9 (M ⁺ ).

Example 3-9:

Compound AR00301746

According to the procedures described in Examples 1-2 and 3-1, except that 7-chloro-1,2,3,4-tetrahydro-isoquinoline was used instead of 1,2,3 in step 4 of Example 1-2, 4-tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-7-chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxy Carbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester ( Compound AR00301746). ¹ H NMR (400MHz, CDCl ₃ ): δ10.10(s, 1H), 7.08(d, 1H), 7.02-6.96(m, 2H), 6.60(d, 1H), 5.64(q, 1H), 5.40 (s, 1H), 4.92-4.41(m, 2H), 4.55-4.40(m, 3H), 4.28-4.12(m, 2H), 3.82-3.75(m, 1H), 3.65-3.46(m, 3H) , 2.88-2.80(m, 1H), 2.78-2.56(m, 2H), 2.52-2.42(m, 1H), 2.38-2.30(m, 1H), 2.21-2.12(q, 1H), 1.82-1.74( m, 2H), 1.45-1.12 (m, 16H), 1.10-0.98 (m, 2H), 0.90-0.75 (m, 2H). MS m/e 761.9 (M ⁺ ).

Example 3-10:

Compound AR00301747

According to the procedures described in Examples 1-2 and 3-1, except that 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline was used instead of 1,2 in step 4 of Example 1-2 , 3,4-tetrahydro-isoquinoline, to synthesize (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 ]nonadecan-7-ene -18-yl ester (compound AR00301747). ¹ H NMR (500MHz, CD3OD): δ7.44(m ₅ 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(br s, 2H), 4.60-4.50(m, 1H), 4.48(m, 1H), 4.15(d, 1H), 3.88(d, 1H), 3.75-3.67(m , 2H), 2.93-2.82(m, 3H), 2.66-2.54(m, 1H), 2.52-2.44(m, 1H), 2.42-2.40(m, 2H), 1.91-1.76(m, 2H), 1.74 -1.70(dd, 1H), 1.64-1.58(m, 1H), 1.54-1.36(m, 4H), 1.34-1.25(m, 12H), 1.50-1.20(m, 2H), 1.00-0.70(m, 1H), 0.52-0.34 (m, 1H). MS: m/e 795.9 (M ⁺ ).

Example 3-11:

Compound AR00301751

According to the procedures described in Examples 1-2 and 3-1, except that 6-fluoro-1,2,3,4-tetrahydro-isoquinoline was used instead of 1,2,3 in step 4 of Example 1-2, 4-tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxy Carbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester ( Compound AR00301751). ¹ H NMR (500MHz, CD ₃ OD): δ7.21-7.02(m, 1H), 6.92(m, 2H), 6.92(m, 2H), 5.68(q, 1H), 5.40(m, 1H), 5.08(t, 1H), 4.58(m, 2H), 4.45(m, 1H), 4.12(d, 1H), 3.88(d, 1H), 3.78-3.60(m, 3H), 2.86-2.72(m, 3H), 2.71-2.61(m, 1H), 2.52-2.42(m, 1H), 2.41-2.34(m, 1H), 1.88-1.76(m, 2H), 1.74-1.70(m, 1H), 1.64- 1.58(m, 1H), 1.56-1.38(m, 2H), 1.37-1.24(m, 14H), 1.13-1.04(m, 2H), 1.02-0.89(m, 1H), 0.88-0.82(m, 1H ). MS: m/e 746.0 (M ⁺ ). MS m/e 757.2 (M ⁺⁺ 1).

Example 3-12:

Compound AR00304080

Following the procedures described in Examples 1-2, 2-24, and 3-1, except that 5-fluoro-1,2,3,4,-tetrahydro-isoquinoline was used instead in Step 4 of Example 1-2 1,2,3,4-tetrahydro-isoquinoline instead, to synthesize (1S,4R,6S,14S,18R)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxy Acid 14-(3-cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]deca Nona-7-en-18-yl ester (compound AR00304080).

Example 3-13:

Compound AR00304081

Following the procedures described in Examples 1-2, 2-24, and 3-1, except that 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquine was used in step 4 of Example 1-2 morphine instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (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} ] Nonadec-7-en-18-yl ester (compound AR00304081). MS m/e 807.2 (M ⁺ +1).

Example 3-14:

Compound AR00304082

Following the procedures described in Examples 1-2, 2-24, and 3-1, except that 2,3-dihydro-1H-isoindole was used in place of 1,2,3,4 in Step 4 of Example 1-2 -Tetrahydro-isoquinoline, to synthesize (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 ]nonadecan-7-en-18-yl ester (compound AR00304082) . MS m/e 725.2 (M ⁺⁺ 1).

Example 3-15:

Compound AR00304161

(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 ]nonadec-7-en-18-yl ester (compound AR00304161). MS m/e 718.1 (M ⁺ +1).

Example 3-16:

Compound AR00304162

Synthesized according to the procedures described in Examples 1-2, 2-1 and 3-1 except that tetrahydrofuran-3S-alcohol 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-(tetrahydrofuran -3-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00304162). MS m/e 742.1 (M ⁺ +1).

Example 3-17:

Compound AR00304163

Synthesized according to the procedures described in Examples 1-2, 2-1 and 3-1 except that tetrahydrofuran-3R-alcohol 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-(tetrahydrofuran -3R-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00304163). ¹ H NMR (d ⁶ -benzene, 500MHz): δ10.53(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), 4.41-4.87(m, 3H), 3.85-4.05(m, 4H), 3.67-3.74(m, 1H), 3.46-3.53( m, 3H), 3.23-3.34(m, 1H), 2.80-2.85(m, 1H), 2.34-2.59(m, 4H), 1.84-1.99(m, 4H), 0.98-1.60(m, 14H), 0.42-0.47 (m, 1H), 0.27-0.32 (m, 1H). MS m/e 741.2 (M-1).

Example 3-18:

Compound AR00311814

According to the procedures described in Examples 1-2 and 3-1, except that phenyl-(4,5,6,7-tetrahydro-thiazolo[5,4-c] was used in step 4 of Example 1-2 Pyridin-2-yl)-amine instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (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-diazepine Hetero-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00311814). MS m/e 826.2 (M ⁺ +1).

Example 3-19:

Compound AR00311815

Following the procedure described in Examples 1-2 and 3-1, except that 1-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-isoquine was used in step 4 of Example 1-2 morphine instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (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} ] Nonadec-7-en-18-yl ester (compound AR00311815). ¹ HNMR (500MHz, CD ₃ OD) δ8.94(d, 1H), 7.59(s, 1H), 7.31-7.23(m, 3H), 7.22-7.15(m, 2H), 5.74-5.64(m, 2H ), 5.47(br s, 1H), 5.06(t, 1H), 4.54(dt, 1H), 4.40-4.17(m, 4H), 4.11-4.04(m, 1H), 3.96-3.88(m, 1H) , 3.75-3.40(m, 5H), 3.14-2.32(m, 7H), 2.05(dd, 1H), 1.99-1.68(m, 5H), 1.65-0.95(m, 24H); MS(POS ESI)m /z 825.4(M ⁺ ).

Example 3-20:

Compound AR00312024

Following the procedure described in Examples 1-2 and 3-1, except that 4,4-spiro-cyclobutyl-1,2,3,4-tetrahydro-isoquinoline was used in step 4 of Example 1-2 Instead of 1,2,3,4-tetrahydro-isoquinoline, to synthesize (1S,4R,6S,14S,18R)-4,4-spiro-cyclobutyl-3,4-dihydro-1H-iso Quinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] nonadecan-7-en-18-yl ester (compound AR00312024). ¹ H NMR (400MHz, CD ₃ OD) δ7.54-7.60(m, 1H), 7.26(dd, 1H), 6.97-7.21(m, 1H), 5.66(dd, 1H), 5.37-5.48(m, 1H), 5.11(dd, 1H), 4.58(s, 2H), 4.39(t, 3H), 4.11-4.26(m, 1H), 3.77-3.96(m, 1H), 3.87(t, 3H), 3.60 -3.70(m, 1H), 2.83-2.93(m, 1H), 2.23-2.68(m, 6H), 1.70-2.23(m, 7H), 1.18-1.69(m, 18H), 0.81-1.12(m, 3H). MS m/e 767.9 (M ⁺ +1).

Example 3-21:

Compound AR00312025

According to the procedures described in Examples 1-2 and 3-1, except that 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline was used instead of 1 in step 4 of Example 1-2 , 2,3,4-tetrahydro-isoquinoline, to synthesize (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[ ^14.3.0.04,6 ]nonadeca- 7-en-18-yl ester (compound AR00312025). ¹ H NMR (400MHz, CD ₃ OD) δ7.31-7.40 (m, 1H), 6.97-7.23 (m, 3H), 5.67 (dd, 1H), 5.34-5.49 (m, 1H), 5.09 (dd, 1H), 4.64(s, 1H), 4.50-4.61(m, 1H), 4.33-4.44(m, 3H), 4.11-4.24(m, 1.0), 3.82-3.95(m, 3H), 3.36-3.55( m, 2H), 2.84-2.94 (m, 1H), 2.25-2.69 (m, 4H), 1.68-2.24 (m, 4H), 1.15-1.68 (m, 23H), 0.81-1.15 (m, 3H). MS m/z 756.0 (M ⁺⁺ 1).

Example 3-22:

Compound AR00312026

According to the procedures described in Examples 1-2 and 3-1, except that 4-methyl-1,2,3,4-tetrahydro-isoquinoline was used instead of 1,2 in step 4 of Example 1-2, 3,4-tetrahydro-isoquinoline, to synthesize (1S,4R,6S,14S,18R)-4-methyl-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 ]nonadecan-7-ene-18- base ester (compound AR00312026). ¹ H NMR (400MHz, CD ₃ OD) δ7.76(s, 1H), 6.98-7.24(m, 3H), 5.67(dd, 1H), 5.2-5.51(m, 1H), 5.04-5.15(dd, 1H), 4.28-4.63(m, 5H), 4.10-4.24(m, 1H), 3.81-3.96(m, 3H), 3.37-3.78(m, 2H), 2.83-3.06(m, 2H), 2.54- 2.71 (m, 1H), 2.25-2.54 (m, 3H), 1.69-1.94 (m, 3H), 1.16-1.69 (m, 20H), 0.81-1.15 (3H). MS m/z 742.0 (M ⁺⁺ 1).

Example 3-23:

Compound AR00314635

Following the procedure described in Examples 1-2, 2-1 and 3-1, except that 4,4-spiro-cyclobutyl-1,2,3,4-tetrahydro was used in step 4 of Example 1-2 -isoquinoline instead of 1,2,3,4-tetrahydro-isoquinoline and using tetrahydrofuran-3R-alcohol instead of cyclopentanol in step 2 of Example 2-1 to form the chloroformate reagent, to synthesize ( 1S, 4R, 6S, 14S, 18R)-4,4-spiro-cyclobutyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15 -Dioxo-14-(tetrahydrofuran-3-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonade-7-en-18-yl ester (compound AR00314635). ¹ HNMR (500MHz, CD ₂ Cl ₂ ) δ10.24-10.29(s, 1H), 7.49-7.55(m, 1H), 7.24(dd, 1H), 7.14(dd, 1H), 7.04(dd, 1H) , 6.81(d 1H), 5.71(dd, 1H), 4.95(dd, 1H), 4.90(bs, 1H), 4.48-4.59(m, 3H), 4.17-4.30(m, 2H), 3.51-3.74( m, 3H), 3.51-3.72(6H), 2.80-2.86(m, 1H), 2.36-2.54(m, 3H), 2.10-2.33(m, 4H), 1.80-2.10(m, 6H), 1.24- 1.80(m, 7H), 0.65-1.24(m, 10H). MS m/z 741.2 (M ⁺ +1).

Example 3-24:

Compound AR00314654

According to the procedures described in Examples 1-2, 2-1, and 3-1, except that 4,4-dimethyl-1,2,3,4-tetrahydro-iso Quinoline was substituted for 1,2,3,4-tetrahydro-isoquinoline and tetrahydrofuran-3S-alcohol was used instead of cyclopentanol to form the chloroformate reagent in step 2 of Example 2-1 to synthesize (1S, 4R, 6S, 14S, 18R)-4,4-Dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo - 14-(Tetrahydrofuran-3S-yloxycarbonylamino)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonade-7-en-18-yl ester (compound AR00314654). ¹ H NMR (500MHz, CD ₂ Cl ₂ ) δ8.51-8.64 (bs, 1H), 7.26-7.36 (m, 1H), 7.09-7.19 (m, 2H), 6.98-7.08 (m, 1H), 5.70 (dd, 1H), 4.95(dd, 1H), 4.83(d, 1H), 4.44-4.72(m, 3H), 4.17-4.30(m, 2H), 3.25-3.91(m, 9H), 2.80-2.86 (m, 1H), 2.35-2.55(m, 4H), 2.13-2.34(m, 4H), 1.91-2.07(m, 2H), 1.80-1.90(m, 2H), 1.66-1.80(m, 2H) , 1.51-1.63 (m, 2H), 1.30-1.51 (m, 2H), 0.96-1.15 (m, 3H), 0.65-0.95 (m, 9H). MS m/z 770.1 (M ⁺⁺ 1).

Example 3-25:

Compound AR00314656

Following the procedures described in Examples 1-2, 2-24, and 3-1, except that 4-methyl-1,2,3,4-tetrahydro-isoquinoline was used instead in Step 4 of Example 1-2 1,2,3,4-Tetrahydro-isoquinoline and the use of tert-butyl isocyanate instead of cyclopentyl isocyanate in Example 2-24 to synthesize (1S, 4R, 6S, 14S, 18R)- 4-Methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-(3-tert-butyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo Dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00314656). ¹ H NMR (500MHz, CD ₂ Cl ₂ ) δ7.60-7.72(m, 1H), 7.06-7.48(m, 4H), 5.73(dd, 1H), 5.39-5.48(m 1H), 5.18-5.27( bs 1H), 4.98(dd, 1H), 4.79-4.90(bs, 1H), 4.30-4.72(m, 4H), 3.40-3.77(m, 5H), 2.97(d, 1H), 2.83-2.90(m , 1H), 2.37-2.58(m, 3H), 2.17-2.30(dt, 1H), 2.22-2.35(dt, 1H), 1.97-2.07(m, 1H), 1.82-1.95(m, 2H), 1.68 -1.79 (m, 1H), 1.55-1.66 (m, 2H), 1.05-1.55 (m, 15H), 0.83-0.98 (m, 3H). MS m/z 741.2 (M ⁺ +1).

Example 3-26:

Compound AR00314719

(1S,4R,6S,14S,18R)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butyl was synthesized according to the procedures described in Examples 1-22 and 3-1 Oxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-18-yl ester (compound AR00314719). MS m/e 630.2 (M ⁺ +1-100).

Example 3-27:

Compound AR00320001

(1S, 4R, 6S, 14S, 18R)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-(3-tert-butyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo Subo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00320001). MS m/e 725.7 (M-1).

Example 3-28:

Compound AR00320073

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

Example 3-29:

Compound AR00320079

Following the procedure described in Examples 1-2, 2-1, and 3-1, except that 2,3-dihydro-1H-isoindole was used in place of 1,2,3,4 in step 4 of Example 1-2 - Tetrahydro-isoquinoline and (1S, 4R, 6S, 14S, 18R)-1 , 3-Dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydrofuran-3-yloxycarbonylamino)-3,16-di Aza-tricyclo[14.3.0.0 ^4,6 ]-nona-7-en-18-yl ester (compound AR00320079). MS m/e 728.1 (M ⁺ +1).

Example 3-30:

Compound AR00320080

Following the procedure described in Examples 1-2, 2-1, and 3-1, except that 2,3-dihydro-1H-isoindole was used in place of 1,2,3,4 in step 4 of Example 1-2 - Tetrahydro-isoquinoline and (1S, 4R, 6S, 14S, 18R)-1 , 3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydrofuran-3S-yloxycarbonylamino)-3,16-di Aza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00320080). MS m/e 728.1 (M ⁺ +1).

Example 3-31:

Compound AR00320081

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

Example 3-32:

Compound AR00320082

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

Example 3-33:

Compound AR00320119

Following the procedure described in Examples 1-2 and 3-1, except that 5-chloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4 in step 4 of Example 1-2 -Tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-5-chloro-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 ]nonadecan-7-en-18-yl ester (compound AR00320119) . ¹ H NMR (500MHz, CD ₃ OD): δ7.36(s, 1H), 7.30(s, 1H), 7.28(s, 1H), 7.22(s, 1H), 7.12-7.20(m, 1H), 6.64(br s, 1H), 5.72-5.64(m, 1H), 5.41(s, 1H), 5.14-5.04(m, 1H), 4.80-4.62(m, 2H), 4.61-4.56(t, 1H) , 4.54-4.48(m, 1H), 4.10(d, 1H), 3.85(d, 1H), 2.90(m, 1H), 2.65(br s, 1H), 2.54-2.48(m, 1H), 2.46- 2.32(m,2H), 1.91-1.72(m,2H), 1.64-1.56(m,2H), 1.56-1.21(m,8H), 1.18(s,9H), 1.12-1.05(m,1H)1.00 (m, 1H), 0.94-0.82 (m, 2H). MS m/e 747.9 (M ⁺ ).

Example 3-34:

Compound AR00320120

According to the procedures described in Examples 1-2 and 3-1, except that dimethyl-(1,2,3,4-tetrahydro-isoquinolin-5-yl)- Amine (Example 1-25a) instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (1S,4R,6S,14S,18R)-5-dimethylamino-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 ] Nonadec-7-en-18-yl ester (compound AR00320120). ¹ H NMR (400MHz, CDCl ₃ ): δ10.08(s, 1H), 7.13-7.05(m, 1H), 6.88-6.81(d, 1H), 6.77(d, 1H), 6.68(d, 1H) , 6.61-6.53(s, 1H), 5.71-5.60(q, 1H), 5.40(s, 1H), 5.00-4.88(m, 2H), 4.55-4.38(m, 3H), 4.24-4.16(m, 2H), 3.88-3.77(d, 1H), 3.64-3.41(m, 3H), 2.91-2.69(m, 3H), 2.61(s, 6H), 2.53-2.41(m, 2H), 2.40-2.39( m, 1H), 2.22-2.11(m, 1H), 1.89-1.72(m, 1H), 1.61-1.22(m, 10H), 1.18(s, 9H), 1.09-0.97(m, 2H), 0.91- 0.76 (m, 2H). MS: 771.1 (M ⁺ ), 772.1 (M ⁺ +1), 773.1 (M ⁺ +2).

Example 3-35:

Compound AR00320121

Following the procedure described in Examples 1-2 and 3-1, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used in place of 1,2,3 in step 4 of Example 1-2 , 4-tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-5,6-dichloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butyl Oxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-en-18-yl Esters (Compound AR00320121). ¹ H NMR (500MHz, CD ₃ OD): δ7.52(s, 1H), 7.38(s, 1H), 6.61(br s, 1H), 5.72-5.65(q, 1H), 5.40(s, 1H) , 5.08(t, 1H), 4.78-4.62(m, 3H), 4.63-4.57(t, 1H), 4.50(d, 1H), 4.20(d, 1H), 3.65(d, 1H), 2.90(m , 1H), 2.55(m, 1H), 2.52-2.45(m, 1H), 2.46-2.31(m, 2H), 1.91-1.75(m, 3H), 1.67-1.60(m, 1H), 1.58-1.25 (m, 8H), 1.18 (s, 9H), 1.12-1.05 (m, 2H), 1.04-0.81 (m, 2H). MS: m/e 781.9 (M ⁺ ).

Example 3-36:

Compound AR00320220

Following the procedures described in Examples 1-2, 2-24, and 3-1, except that 2,3-dihydro-1H-isoindole was used in place of 1,2,3,4 in Step 4 of Example 1-2 -Tetrahydro-isoquinoline and the use of tert-butyl isocyanate instead of cyclopentyl isocyanate in Example 2-24 to synthesize (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 ] Nonadec-7-en-18-yl ester (compound AR00320220). MS m/e 713.1 (M ⁺ +1).

Example 3-37:

Compound AR00320222

(1S, 4R, 6S , 14S, 18R)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-[3-(tetrahydrofuran-3- yl)-ureido]-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00320222). MS m/e 740.8 (M ⁺⁺ 1).

Example 3-38:

Compound AR00320403

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

Example 3-39:

Compound AR00320446

According to the procedures described in Examples 1-2, 2-24, and 3-1, except that 5-chloro-2,3-dihydro-1H-isoindole was used in place of 1,2 in Step 4 of Example 1-2 , 3,4-tetrahydro-isoquinoline and using tert-butyl isocyanate instead of cyclopentyl isocyanate in Example 2-24 to synthesize (1S, 4R, 6S, 14S, -5R)-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 ]nonadec-7-en-18-yl ester (compound AR00320446). ¹ H NMR (500MHz, CD ₃ OD): δ7.35(s, 1H), 7.28(s, 1H), 7.26(s, 1H), 7.02(s, 1H), 7.18(s, 1H), 5.65- 5.72(q, 1H), 5.45(s, 1H), 5.06(t, 1H), 4.74-4.60(m, 4H), 4.56(t, 1H), 4.46(m, 1H), 4.22(d, 1H) , 3.87-3.91(dd, 1H), 2.86-2.94(m, 1H), 2.65-2.54(m, 1H), 2.52-2.45(m, 1H), 2.42-2.34(m, 2H), 1.92-1.83( m, 1H), 1.78-1.70(m, 2H), 1.62-1.56(m, 1H), 1.54-3.92(m, 4H), 1.39-1.23(m, 7H), 1.12(s, 9H), 1.02- 0.98 (m, 1H), 0.94-0.86 (m, 1H). MS: m/e 747.1 (M ⁺ ), 749.1 (M ⁺ +2).

Example 3-40:

Compound AR00320447

Following the procedures described in Examples 1-2, 2-24, and 3-1, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used in Step 4 of Example 1-2 instead of 1,2,3,4-Tetrahydro-isoquinoline and the use of tert-butyl isocyanate instead of cyclopentyl isocyanate in Example 2-24 to synthesize (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 Subo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00320447). MS: m/e 781.1 (M ⁺ ). 783.1 (M ⁺⁺ 2).

Example 3-41:

Compound AR00320506

According to the procedures described in Examples 1-2, 2-1, and 3-1, except that 1-piperidin-1-ylmethyl-1,2,3,4-tetra Hydrogen-isoquinoline instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (1S,4R,6S,14S,18R)-1-piperidin-1-ylmethyl-3,4- Dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (compound AR00320506). MS (POS ESI) m/z 837.4 (M ⁺ ).

Example 3-42:

Compound AR00320547

(1S, 4R, 6S, 14S, 18R)- 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-benzenesulfonylaminocarbonyl-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diazepine- Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00320547). MS m/e 762.3 (M-1).

Example 3-43:

Compound AR00320548

(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 ]nonadec-7-en-18-yl ester (compound AR00320548). MS m/e 792.3 (M-1).

Example 3-44:

Compound AR00320549

(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 ]nonadec-7-en-18-yl ester (compound AR00320549). MS m/e 776.3 (M ⁺⁺ 1).

Example 3-45:

Compound AR00320556

According to the procedures described in Examples 1-2, 2-1, and 3-1, except that 1-piperidin-1R-ylmethyl-1,2,3,4-tetra Hydrogen-isoquinoline instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (1S,4R,6S,14S,18R)-1-piperidin-1R-ylmethyl-3,4- Dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (compound AR00320556). ¹ H NMR (500MHz, CD ₃ OD) δ8.99(br s, 1H), 7.34-7.13(m, 6H), 5.75-5.65(m, 2H), 5.44(br s, 1H), 5.06(t, 1H), 4.60(t, 1H), 4.51(d, 1H), 4.44-4.16(m, 2H), 4.12-3.97(m, 2H), 3.86(d, 1H), 3.75-3.38(m, 2H) , 3.07(t, 2H), 2.96-2.86(m, 1H), 2.78(d, 1H), 2.66(brs, 1H), 2.56-2.26(m, 3H), 2.06(d, 1H), 1.99-1.66 (m, 10H), 1.65-1.21 (m, 18H), 1.15-0.95 (m, 3H); MS (POS ESI) m/z 837.4 (M ⁺ ).

Example 3-46:

Compound AR00320557

According to the procedures described in Examples 1-2, 2-1, and 3-1, except that 1-piperidin-1s-ylmethyl-1,2,3,4-tetra Hydrogen-isoquinoline instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (1S,4R,6S,14S,18R)-1-piperidin-1S-ylmethyl-3,4- Dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.0.4,6 ]nonadec-7-en-18-yl ester (compound AR00320557). ¹ H NMR (500MHz, CD ₃ OD) δ7.32-7.14 (m, 6H), 6.87 (br s, 1H), 5.72-5.60 (m, 2H), 5.47-5.39 (m, 1H), 5.11 (br s, 1H), 4.58(t, 1H), 4.53-3.86(m, 8H), 3.67-3.40(m, 2H), 3.08-2.85(m, 1H), 2.78(d, 1H), 2.65-2.24(m , 4H), 2.10-1.22(m, 27H), 1.19(dt, 1H), 1.10-1.02(m, 2H), 1.01-0.93(m, 1H), 0.89(q, 1H); MS(POS ESI) m/z 837.4 (M ⁺ ).

Example 3-47:

Compound AR00320574

According to the procedures described in Examples 1-2, 2-24, and 3-1, except that 5-chloro-2,3-dihydro-1H-isoindole was used in place of 1,2 in Step 4 of Example 1-2 , 3,4-tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-5-chloro-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 ]nonadecan-7-ene- 18-yl ester (compound AR00320574). MS: m/e 759.1 (M ⁺ ), 761.1 (M ⁺ +2).

Example 3-48:

Compound AR00320575

Following the procedures described in Examples 1-2, 2-24, and 3-1, except that 5,6-dichloro-2,3-dihydro-1H-isoindole was used in Step 4 of Example 1-2 instead of 1,2,3,4-tetrahydro-isoquinoline, to synthesize (1S,4R,6S,14S,18R)-5,6-dichloro-1,3-dihydro-isoindole-2-carboxy Acid 14-(3-cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]deca Nona-7-en-18-yl ester (compound AR00320575). MS: m/e 793.1 (M ⁺ ).

Example 3-49:

Compound AR00320578

Chloroformate was formed according to the procedure described in Examples 1-2, 2-1 and 3-1, except that 2,2,2-trifluoro-ethanol was used instead of cyclopentanol in Step 2 of Example 2-1 Reagents for the synthesis of (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 ]nonadecan-7-en-18-yl ester (compound AR00320578). MS m/e 754.0 (M ⁺ +1).

Example 3-50:

Compound AR00320579

According to the procedures described in Examples 1-2, 2-1, and 3-1, except that 2,2-difluoro-ethanol was used instead of cyclopentanol in Step 2 of Example 2-1 to form the chloroformate reagent, To synthesize (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 ]nonadec-7-en-18-yl ester (compound AR00320579). MS m/e 736.0 (M ⁺ +1).

Example 3-51:

Compound AR00320580

Chloroform was formed according to the procedure described in Examples 1-2, 2-1 and 3-1, except that 1,3-difluoro-propan-2-ol was used instead of cyclopentanol in Step 2 of Example 2-1 Ester reagent, to synthesize (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 ]nonadecan-7-en-18-yl Esters (compound AR00320580). MS m/e 750.1 (M ⁺ +1).

Example 3-52:

Compound AR00320581

According to the procedures described in Examples 1-2, 2-1, and 3-1, except that 1,1,1-trifluoro-propan-2-ol was used instead of cyclopentanol in step 2 of Example 2-1 to form Chloroformate reagent, to synthesize (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 ]nineteen-7 -en-18-yl ester (compound AR00320581). MS m/e 768.1 (M ⁺ +1).

Example 3-53:

Compound AR00320582

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

Example 3-54:

Compound AR00324375

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

Example 3-55:

Compound AR00334191

Following the procedure described in Examples 1-2 and 3-1, except that 4-fluoro-2,3-dihydro-1H-isoindole was used in place of 1,2,3,4 in step 4 of Example 1-2 -Tetrahydro-isoquinoline, to synthesize (1S, 4R, 6S, 14S, 18R)-4-fluoro-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 ]nonadecan-7-en-18-yl ester (compound AR00334191) . ¹ H NMR (500MHz, d ₆ -acetone) δ10.70(br s, 1H), 8.34(d, 1H), 7.39-7.33(m, 1H), 7.20(d, 1H), 7.10-7.02(m, 2H), 6.13(d, 1H), 5.70(q, 1H), 5.44(br s, 1H), 4.99(t, 1H), 4.78-4.59(m, 5H), 4.18-4.08(m, 1H), 3.88-3.81(m, 1H), 2.86-2.78(m, 3H), 2.71-2.60(m, 1H), 2.52-2.35(m, 3H), 1.92-1.81(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:

The 4-fluoro-2,3-dihydro-1H-isoindole used in Examples 3-55 was prepared using the following two steps:

step 1:

Best results were obtained when the starting material was a 0.5M solution in formamide and heated at 125°C for 1 h to 5 h depending on the scale. The starting material was not soluble in formamide until the temperature was above 60°C. Once the reaction was complete as monitored by LC/MS (apcineg), heating was stopped and three reaction volumes of water were added. Next, the reaction was allowed to warm to room temperature and stirred until a pale yellow precipitate formed. The yellow solid product was filtered off, washed with water and then dried overnight with yields ranging from 70% to 77%.

Step 2:

Using an addition funnel, 4 equivalents of 1M _BH3 -THF were added dropwise to the starting material in the round bottom flask, forming a golden yellow solution which changed color to copper upon heating and stirring. The reaction was then heated at reflux for 18 hours.

The reaction was then cooled to room temperature (rt) and then to 0 °C in an ice bath. The quenched reaction was allowed to warm to room temperature by adding 4 equivalents of MeOH dropwise and removing the ice bath. The reaction darkened during this warming. Next, 6N HCl was added dropwise at room temperature until pH 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, washed with _Et2O (2x) and DCM (2x). The pH of the aqueous layer was then adjusted to 11 with NaOH pellets. More water was added and the aqueous layer was extracted with ether (4x). The combined extracts were dried over _Na2SO4 and concentrated to give the product as a light brown oil which was used _directly . The mass experimental values were always slightly higher than theoretical, but the use of crude material like this gave greater than 80% yields in the next step.

Example 3-56:

Compound AR00333833

According to Examples 1-2 and 3-1, except that 2,3-dihydro-1H-isoindole was used in Step 4 in a procedure similar to Example 1-2 and the ring-closing metathesis product from Step 3 of Example 1-2 10 was further reduced with H ₂ /Ph-Al ₂ O ₃ (according to literature procedure (WO 0059929, pages 76-77)) before the subsequent coupling step to synthesize (1S, 4R, 6S, 14S, 18R)-1 , 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclic [14.3.0.0 ^4,6 ]nonadecan-18-yl ester (compound AR00333833). ¹ H NMR (400MHz, CD ₃ SOCD ₃ ) δ11.11(s, 1H), 8.89(s, 1H), 7.16-7.29(m, 4H), 6.95(d, 1H), 5.25(bs, 1H), 4.50-4.60(bs, 4H), 4.40(dd, 1H), 4.23(d, 1H), 3.93(m, 1H), 3.68(d, 1H), 2.92(m, 1H), 2.32(dd, 1H) , 2.11 (m.1H), 1.40-1.68 (m, 2H), 0.92-1.40 (m, 19H). MS m/e 717.0 (M ⁺ +1).

Example 3-57:

Compound AR00334286

(1S,4R,6S,14S,18R)-5-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 ]nonadecan-7-en-18-yl ester (compound AR00334286) .

Step 1. (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-2,15-dioxo-18-triisopropylsilyloxy-3,16-diaza- Synthesis of ethyl tricyclo[ ^14.3.0.04,6 ]nonadeca-7-ene-4-carboxylate. To a solution of the free hydroxy macrocyclic intermediate (compound 10 from Example 1-2, 5.0 g, 10.1 mmol) in DriSolve DCM (30 ml) was added imidazole (827 mg, 1.2 equiv) and TIPSCl (2.15 g, 1.1 equiv). The reaction mixture was stirred at room temperature for 18 hours. TLC (5% MeOH-DCM) showed that a lot of SM still remained. To this reaction mixture was added more 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 x 25ml). The combined aqueous layers were backwashed with DCM (25ml). The combined organic layers were dried and concentrated to give a light yellow oil. This crude material was used in the next step without further purification.

Step 2. (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-2,15-dioxo-18-triisopropylsilyloxy-3,16-diaza- Synthesis of tricyclo[ ^14.3.0.04,6 ]nonade-7-ene-4-carboxylic acid. The ester SM from step 1 was first dissolved in a mixture of THF (20ml) and MeOH (20ml). To this mixture was then added LiOH- _H2O (2.1 g, 50 mmol) in water (10 ml) and stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated to almost dryness. The solid residue was then dissolved in 50 mL of water, acidified with 2N HCl, and extracted with EtOAc (2 x 50 ml). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated. This crude material was used in the next step without further purification.

Step 3: (1S,4R,6S,14S,18R)-(4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-triisopropylsilyloxy-3,16-diazepine -Synthesis of tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-14-yl)-tert-butyl carbamate

First dissolve the acid SM from step 2 above in 25 mL of DriSolve 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 the reaction was complete. For work-up, the reaction mixture was washed with water (2 x 50 mL), the organic layer was dried (anhydrous sodium sulfate) and concentrated. This crude material 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 Synthesis of ^4,6 ]nonadec-7-en-14-yl)-tert-butyl carbamate. The crude product from step 3 above was first dissolved in THF (40 mL). Then TBAF (3.6 g, 13.7 mmol, 1.5 equiv) was added to this solution 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 sodium sulfate) 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 x 25 mL). The combined organic layers were dried (sodium sulfate) 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-cyclopropanesulfonylamino Synthesis of carbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonade-7-en-18-yl ester (compound AR00334286). To a solution of the product from step 4 above (19 mg, 33 μmol) in DCE was added CDI (7 mg, 1.3 equiv) and the reaction was stirred at room temperature overnight. LCMS showed the reaction was complete. 2,3-Dihydro-1H-isoindol-5-ylamine (18 mg, 4 equiv) was then added. After 4 hours at room temperature, LCMS showed the reaction was complete. The reaction mixture was directly loaded onto silica gel and eluted with 1% to 5% methanol/DCM. The pure product was isolated as a white solid. MS m/z (APCI+): 629.2 (MH ⁺ -Boc).

Example 3-58:

Compound AR00334385

In a similar manner as described in Example 3-57, substituting 2,3-dihydro-1H-isoindol-4-ylamine for 2,3-dihydro-1H-isoindol-4-ylamine in step 5 5-ylamine, to synthesize (1S, 4R, 6S, 14S, 18R)-4-amino-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 ]nonade-7-en-18-yl ester (compound AR00334385). Again, purification of the final product on reverse phase column chromatography (eluent = 5% to 100% acetonitrile in water) afforded the final product as a beige foamy solid. MS m/z (APCI-): 728.2 (M ⁺ ).

Example 3-59:

Compound AR00340479

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2 was synthesized according to the procedures described in Examples 3-6 except that trifluoromethanesulfonamide was used in place of cyclopropanesulfonamide -Carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4-trifluoromethanesulfonylaminocarbonyl-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nadecane -7-en-18-yl ester (compound AR00340479). ¹ H NMR (400MHz, d ⁶ -acetone): δ7.98(br s, 1H), 7.23-7.35(m, 4H), 6.13(br d, 1H), 5.70(q, 1H), 5.44(br s 1H), 4.98-5.02(m, 1H), 4.61-4.72(m, 5H), 4.49(d, 1H), 4.16-4.18(m, 1H), 3.87-3.90(m, 1H), 2.57-2.59( 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 ⁺ ). MS m/z (APCI-): 741.1 (M ⁺ ).

Example 3-60:

Compound AR00365387

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindol was synthesized according to the procedure described in Examples 3-6, except that 4-sulfamoyl-benzoic acid was used instead of cyclopropanesulfonamide Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(4-carboxy-benzenesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3. 0.0 ^4,6 ] Nonadec-7-en-18-yl ester (compound AR00365387). MS m/z (APCI-): 792.3 (M-1).

Example 3-61:

Compound AR00365388

(1S, 4R, 6S, 14S, 18R)-1 ,3-di Hydrogen-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(5-carboxy-2-chloro-benzenesulfonylaminocarbonyl)-2,15-dioxo-3,16-di Aza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00365388). MS m/z (APCI-): 826.2 (M-2).

Example 3-62:

Compound AR00365425

(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 ]nonade-7-en-18-yl ester (compound AR00365425). MS m/z (APCI-): 822.3 (M-1).

Example 3-63:

Compound AR00365426

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

Example 3-64:

Compound AR00365572

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro- Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(4-dimethylamino-benzenesulfonylaminocarbonyl)-2,15-dioxo-3,16-diazepine- Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00365572). MS m/z (APCI-): 791.3 (M-1).

Example 3-65:

Compound AR00333801

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole was synthesized according to the procedure described in Examples 3-6, except that propane-2-sulfonic acid amide was used instead of cyclopropanesulfonamide -2-Carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4-(propane-2-sulfonylaminocarbonyl)-3,16-diaza-tricyclo[14.3.0.0 ^{4 ,6} ] Nonadec-7-en-18-yl ester (compound AR00333801). MS m/z (APCI-): 714.4 (M-1).

Example 3-66:

Compound AR00333802

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxyl was synthesized according to the procedures described in Examples 3-6, except that benzenesulfonamide was used instead of cyclopropanesulfonamide Acid 4-Benzenesulfonylaminocarbonyl-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-ene -18-yl ester (compound AR00333802). MS m/z (APCI-): 748.3 (M-1).

Example 3-67:

Compound AR00333803

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxyl was synthesized according to the procedures described in Examples 3-6, except that methanesulfonamide was used instead of cyclopropanesulfonamide Acid 14-tert-butoxycarbonylamino-4-methanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-ene -18-yl ester (compound AR00333803). MS m/z (APCI-): 686.4 (M-1).

Example 3-68:

Compound AR00334188

(1S,4R,6S,14S,18R)-1,3-dihydro was synthesized according to the procedure described in Examples 3-6 except that 5-chloro-thiophene-2-sulfonic acid amide was used instead of cyclopropanesulfonamide -Isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(5-chloro-thiophene-2-sulfonylaminocarbonyl)-2,15-dioxo-3,16-diazepine - Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00334188). MS m/z (APCI-): 788.3 (M-2).

Example 3-69:

Compound AR00334247

(1S , 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 4-(5-acetylamino-[1,3,4]thiadiazole-2-sulfonylamino Carbonyl)-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-en-18-yl ester ( Compound AR00334247). ¹ H NMR (400MHz, d ⁶ -acetone): δ7.24-7.31(m, 4H), 5.96(br d, 1H), 5.42(br s 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), 2.25-2.36(m, 5H), 1.70-2.19(m, 8H), 1.19- 1.48 (m, 4H), 1.30 (s, 9H). MS m/z (APCI-): 813.3 (M-1).

Example 3-70:

Compound AR00334248

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindol was synthesized according to the procedures described in Examples 3-6, except that 4-cyano-benzenesulfonamide was used instead of cyclopropanesulfonamide Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(4-cyano-benzenesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3 .0.0 ^4,6 ] Nonadec-7-en-18-yl ester (compound AR00334248). ¹ H NMR (400MHz, d ⁶ -acetone): δ11.32(brs, 1H), 8.36(br s, 1H), 8.04-8.15(m, 4H), 7.22-7.35(m, 4H), 6.12(br d, 1H), 5.47 (br s 1H), 5.28 (q, 1H), 4.60-4.72 (m, 5H), 4.48-4.54 (m, 2H), 4.14-4.17 (m, 1H), 3.86-3.90 ( m, 1H), 2.37-2.52 (m, 4H), 1.72-1.85 (m, 2H), 1.59-1.62 (m, 1H), 1.20-1.55 (m, 8H), 1.20 (s, 9H). MS m/z (APCI-): 773.3 (M-1).

Example 3-71:

Compound AR00334249

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindol was synthesized according to the procedure described in Examples 3-6, except that 4-nitro-benzenesulfonamide was used instead of cyclopropanesulfonamide Indole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(4-nitro-benzenesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3 .0.0 ^4,6 ] Nonadec-7-en-18-yl ester (compound AR00334249). ¹ H NMR (400MHz, d ⁶ -acetone): δ11.39(br s, 1H), 8.46(d, 2H), 8.35(br s, 1H), 8.23(d, 2H), 7.23-7.36(m, 4H), 6.11(br d, 1H), 5.47(br s 1H), 5.23(q, 1H), 4.59-4.72(m, 5H), 4.49-4.54(m, 2H), 4.15(m, 1H), 3.86-3.90(m, 4H), 2.40-2.53(m, 4H), 1.72-1.85(m, 2H), 1.59-1.62(m, 1H), 1.20-1.56(m, 8H), 1.20(s, 9H) ). MS m/z (APCI-): 793.3 (M-1).

Example 3-72:

Compound AR00334250

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole was synthesized according to the procedure described in Examples 3-6, except that 4-chloro-benzenesulfonamide was used instead of cyclopropanesulfonamide -2-Carboxylic acid 14-tert-butoxycarbonylamino-4-(4-chloro-benzenesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] Nonadec-7-en-18-yl ester (compound AR00334250). ¹ H NMR (400MHz, d ⁶ -acetone): δ11.16(br s, 1H), 8.34(d, 2H), 7.96(d, 2H), 7.65(d, 2H), 7.22-7.36(m, 4H ), 6.13(br d, 1H), 5.46(br s 1H), 5.27(q, 1H), 4.59-4.71(m, 5H), 4.48-4.54(m, 2H), 4.14(m, 1H), 3.87 -3.89(m, 1H), 232-2.52(m, 4H), 1.72-1.85(m, 2H), 1.59-1.61(m, 1H), 1.20-1.53(m, 8H), 1.20(s, 9H) . MS m/z (APCI-): 782.3 (M-2).

Example 3-73:

Compound AR00334341

(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-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (compound AR00334341). ¹ H NMR (400MHz, d ⁶ -acetone): δ8.26(br s, 1H), 7.84(d, 2H), 7.19-7.32(m, 4H), 7.05(d, 2H), 6.08(br d, 1H), 5.43(br s 1H), 5.25(q, 1H), 4.55-4.67(m, 5H), 4.48(q, 2H), 4.10-4.14(m, 1H), 3.87(s, 3H), 3.82 -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:

Compound AR00364266

(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 ]nonadec-7-en-18-yl ester (compound AR00364266). ¹ H NMR (400MHz, d ⁶ -acetone): δ10.84(br s, 1H), 8.27(br s, 1H), 7.59(d, 1H), 7.24-7.35(m, 4H), 7.18(d, 1H), 6.10(br d, 1H), 5.50(br, 1H), 5.46(m 1H), 5.36(q, 1H), 4.59-4.71(m, 6H), 4.48(d, 1H), 4.13-4.17 (m, 1H), 4.00(s, 3H), 3.85-3.89(m, 1H), 2.35-2.59(m, 4H), 1.71-1.90(m, 2H), 1.62-1.65(m, 1H), 1.20 -1.51 (m, 8H), 1.20 (s, 9H). MS m/z (APCI-): 795.4 (M-1).

Example 3-75:

Compound AR00365427

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole was synthesized according to the procedure described in Examples 3-6 except that thiophene-2-sulfonic acid amide was used instead of cyclopropanesulfonamide -2-Carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4-(thiophene-2-sulfonylaminocarbonyl)-3,16-diaza-tricyclo[14.3.0.0 ^{4 ,6} ] Nonadec-7-en-18-yl ester (compound AR00365427). MS m/z (APCI-): 754.4 (M-1).

Example 3-76:

According to the procedure described in Example 3-6, except that 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinoline was used (see Example 3-76a for the synthesis ) instead of 2,3-dihydro-1H-isoindole to synthesize (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 ] Nonadec-7-en-18-yl ester (compound AR00334339). 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 described 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 worked up as a 0.6M solution in DCM followed by the addition of TEA (2 equiv). The mixture was then cooled in an IPA/dry ice bath. When the reaction temperature reached -60°C, a solution of chloroacetyl chloride in DCM (2.6M) was added dropwise in order to keep the temperature below -60°C. After the addition was complete, the reaction was stirred at -60°C for 1 hour. The reaction was then allowed to warm to -20°C and filtered through GF filter paper to remove some TEA hydrochloride. The filtrate was then allowed to warm to room temperature and transferred to a separatory funnel, washed with 1N HCl (2x) and brine. The organic layer was dried over MgSO ₄ and concentrated to give a dark purple solid. This crude product was directly used 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 a 0.25M solution. The crude product from Step 1 above was also first boiled in xylene (45 mL) to make a 0.5 M solution which was then added dropwise to the _P2O5 solution via an _addition funnel. The mixture was stirred and heated at reflux for 1 hour. The reaction was then allowed to cool to room temperature, at which point the xylenes were decanted off. The flask was then placed in an ice bath and stirred with careful addition of ice, water, EtOAc and finally 4M NaOH until the pH was >12. Keep the reaction temperature below 25°C until pH=12. The reaction mixture was then extracted with EtOAc (3x). The combined organic extracts were dried over magnesium sulfate and concentrated to give a dark solution. It was cooled in an ice bath while 400 mL of cold _Et2O was added followed by 100 mL of cold HCl/ _Et2O . A precipitate formed and was filtered off, washing with _Et2O . The solid was immediately placed under high vacuum for 2 hours to give the desired product as a colored foamy solid. This crude product was directly used 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 to TEA (5 equiv) and Nal (0.1 equiv) in MeOH in one portion at 0 °C. Next, 2.2 equivalents of NaOMe were added and the homogeneous reaction became cloudy. The reaction was then stirred at 0 °C for 1 hour. LC/MS showed complete free base of the imine.

The reaction was then cooled to 0 °C again in an ice bath and _NaBH4 (1.5 equiv) was added carefully. The reaction was then allowed to warm to room temperature again and stirred for 2 hours. When the reaction was complete as monitored by LC/MS, it was concentrated, treated with 1N NaOH, and extracted with EtOAc. The combined organic layers were dried over _MgSO4 and concentrated. The resulting residue was taken up in MeOH and cooled in an ice bath. HCl gas was bubbled thereinto for 10 minutes. The reaction mixture was concentrated and redissolved in MeOH. After reconcentration the reaction was placed under high vacuum overnight. The crude material was then triturated with EtOAc (3x) to give the product as a tan foamy solid after standing on high vacuum overnight. This crude product was directly used in the next step without further purification. MS m/z (POSESI): 208.1 (MH ⁺ ).

Example 3-77:

Compound AR00365193

According to the procedure described in Example 3-76, except that 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride was used (for synthesis see Example 3- 77a) Instead of 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydro-isoquinolinium chloride, to synthesize (1S, 4R, 6S, 14S, 18R)-5 -Fluoro-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 ]nonadec-7-en-18-yl ester (compound AR00365193). ¹ H NMR (500 MHz, CD ₃ OD) δ8.99-8.91 (m, 1H), 7.23-7.15 (m, 1H), 7.13-6.99 (m, 2H), 6.99-6.90 (m, 1H), 5.68 ( q, 1H), 5.41(br s, 1H), 5.35-5.21(m, 1H), 5.06(t, 1H), 4.60-4.31(m, 3H), 4.30-4.05(m, 3H), 3.96-3.81 MS (APCI-) m/z 788.3 (M-1).

Example 3-77a:

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

Example 3-78:

Compound AR00365438

(1S,4R,6S,14S,18R)-4-fluoro-1,3-bis(1S,4R,6S,14S,18R)-4-fluoro-1,3-di Hydrogen-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(4-carboxy-benzenesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tri Cyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00365438). ¹ H-NMR (500MHz, CD ₃ OD) δ8.92(d, 1H), 8.25-8.19(m, 1H), 8.15(d, 2H), 8.04(d, 2H), 7.36-7.27(m, 1H ), 7.14(d, 1H), 7.05-6.95(m, 2H), 5.42(br s, 1H), 5.26(q, 1H), 4.82-4.50(m, 8H), 4.10-4.00(m, 1H) , 3.85(d, 1H), 3.75-3.69(m, 1H), 2.60-2.39(m, 4H), 2.26(p, 2H), 1.89-1.84(m, 1H), 1.81-1.05(m, 15H) ; MS (APCI-): m/z 810.2 (M-1).

Example 3-79:

Compound AR00340303

(1S, 4R, 6S, 14S, 18R)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-{2-cyclohexyl-2-[(pyrazine-2-carbonyl) -amino]-acetylamino}-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-ene Synthesis of -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, taken up in acetonitrile, and concentrated again. Repeat the above process once more to remove any excess TFA. The resulting solid residue was then dissolved in DCE (137 μL), cooled to 0° C. in an ice bath, followed by the addition of the amino acid, cyclohexyl-[(pyrazine-2-carbonyl)-amino]-acetic acid (1.05 eq.) , HATU (10mg) and DIEA (4 drops). The mixture was allowed to warm slowly to room temperature and stirred overnight. For work-up, the reaction mixture was directly loaded onto a C-18 column and purified by reverse phase column chromatography to afford the title compound as a white solid. MS (APCI-): m/z 876.1 (M-1).

Example 3-80:

Compound AR00340122

(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 ]nonadec-7-en-18-yl ester (compound AR00340122). MS (APCI-): m/z 811.3 (M-1).

Example 3-81:

Compound AR00340156

(1S, 4R, 6S, 14S, 18R)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14-[2-(4-methoxy Base-phenyl)-acetylamino]-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester (compound Synthesis of 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, taken up in acetonitrile, and concentrated again. Repeat the above process once more to remove any excess TFA. The resulting solid residue was then dissolved in DCE (137 μL) before addition of the acid chloride, (4-methoxy-phenyl)-acetyl chloride (2 drops), and DIEA (4 drops). The mixture was stirred overnight at room temperature. Upon completion, the reaction was loaded directly onto a C-18 column and purified by reverse phase column chromatography. The compound was further purified on normal phase silica gel chromatography (eluent = 40% EtOAc/hexanes with 1% formic acid) to afford the title compound as a white solid. ¹ H NMR (500MHz, CD ₃ OD) δ7.33(p, 1H), 7.15(d, 1H), 7.05-6.92(m, 3H), 6.65(dd, 2H), 5.68(q, 1H), 5.40 (br s, 1H), 5.09(t, 1H), 4.78-4.46(m, 7H), 4.43-4.24(m, 2H), 3.89-3.80(m, 1H), 3.68(d, 3H), 3.21( d, 1H), 2.69-2.57 (m, 1H), 2.52-2.30 (m, 5H), 2.06-0.80 (m, 15H); MS (APCI-): m/z 778.3 (M-1).

Example 3-82:

Compound AR00340178

(1S,4R,6S, 14S, 18R)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14-[2-(3-methoxy-phenyl)-acetyl Amino]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00340178). ¹ H NMR (500MHz, CD ₃ OD) δ7.32(p, 1H), 7.14(d, 1H), 7.05-6.92(m, 3H), 6.76-6.58(m, 2H), 5.68(q, 1H) , 5.41(br s, 1H), 5.09(t, 1H), 4.76-4.46(m, 7H), 4.43-4.26(m, 2H), 3.91-3.82(m, 1H), 3.69(d, 3H), 2.94-2.85(m, 1H), 2.70-2.57(m, 1H), 2.52-2.30(m, 5H), 2.06-0.80(m, 15H); MS(APCI-)m/z778.3(M-1 ).

Example 3-83:

Compound AR00340188

(1S, 4R, 6S, 14S, 18R)-4-fluoro -1,3-Dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-phenylacetylamino-3,16-diaza-tri Cyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00340188). MS (APCI-) m/z 748.4 (M-1).

Example 3-84:

Compound AR00334314

According to the procedures described in Examples 3-6, except that 5-methoxy-2,3-dihydro-1H-isoindole (approved in JOC, Vol. 53, No. 22, 1988, pp. 5381-5383 (1S, 4R, 6S, 14S, 18R)-5-methoxy-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} ] Nonadec-7-en-18-yl ester (compound AR00334314). MS m/z (APCI-): 742.3 (M-1).

Example 3-85:

Compound AR00334399

According to the procedures described in Examples 3-6, except that 4,7-difluoro-2,3-dihydro-1H-isoindole (approved in JOC, Vol. 53, No. 22, 1988, No. 5381- (1S, 4R, 6S, 14S, 18R)-4,7-difluoro-1,3-di Hydrogen-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] Nonadec-7-en-18-yl ester (compound AR00334399). ¹ H NMR (500MHz, CD ₃ OD) δ8.97(s, 1H), 6.99-6.85(m, 2H), 5.69(q, 1H), 5.42(br s, 1H), 5.07(t, 1H), 4.83-4.57(m, 6H), 4.51(d, 1H), 4.13-4.02(m, 1H), 3.85(t, 1H), 2.94-2.86(m, 1H), 2.73-2.59(m, 1H), 2.55-2.28(m, 4H), 1.89-1.70(m, 3H), 1.65-1.22(m, 10H), 1.18-0.96(m, 10H); MS m/z(APCI-): 746.1(M-1 ).

Example 3-86

Compound AR00338066

(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[ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (compound AR00338066). ¹ H NMR (500MHz, CD ₃ OD) δ7.38-7.28 (m, 1H), 7.13 (d, 1H), 7.01 (p, 1H), 5.69 (q, 1H), 5.45 (br s, 1H), 5.07(t, 1H), 4.83-4.66(m, 4H), 4.59(q, 1H), 4.49(d, 1H), 4.37-4.17(m, 2H), 3.94-3.84(m, 1H), 3.72( t, 1H), 2.95-2.87(m, 1H), 2.68-2.29(m, 5H), 2.09-1.22(m, 11H), 1.12-0.95(m, 12H); MS(APCI-): m/z 729.3(M-1).

Example 3-87:

Compound AR00338070

(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 ]nonadec-7-en-18-yl ester (compound AR00338070). MS (APCI-) m/z 728.3 (M-1).

Example 3-88:

Compound AR00338071

(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 ]nonadec-7-en-18-yl ester (compound AR00338071). MS (APCI-) m/z 754.3 (M-1).

Example 3-89:

Compound AR00341649

According to the procedures described in Examples 3-6, except that (2,3-dihydro-1H-isoindol-5-yl)-isopropyl-amine (by e.g. Org. Letters, 2003, Vol. 5, No. 6, 793-796 prepared in a similar manner) instead of 2,3-dihydro-1H-isoindole, to synthesize (1S, 4R, 6S, 14S, 18R)-5-isopropylamino- 1,3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tri Cyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00341649). ¹ H NMR (500MHz, CD ₃ OD) δ8.94(br d, 1H), 7.52(s, 1H), 7.48(d, 1H), 7.41-7.32(m, 2H), 7.23-7.24(m, 2H ), 5.69(q, 1H), 5.41(br s, 1H), 5.07(t, 1H), 4.82-4.66(m, 3H), (t, 1H), 4.52(t, 1H), 4.08(d, 1H), 3.85(d, 1H), 3.80-3.68(m, 1H), 2.94-2.87(m, 1H), 2.71-2.59(m, 1H), 2.55-2.45(m, 1H), 2.45-2.30( m, 3H), 1.88-1.69 (m, 3H), 1.61 (t, 1H), 1.58-0.94 (m, 25H); MS (APCI-): m/z 770.1 (M-1).

Example 3-90:

Compound AR00364936

According to the procedure described in Examples 3-6, except that 2,3-dihydro-1H-isoindol-5-ol was used (by e.g. JOC, Vol. 53, No. 22, 1988, pp. 5381-5383 Prepared in a similar manner as described) instead of 2,3-dihydro-1H-isoindole to synthesize (1S, 4R, 6S, 14S, 18R)-5-hydroxyl-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 ]nadecane -7-en-18-yl ester (compound AR00364936). MS m/z (APCI-): 728.2 (M-1).

Example 3-91:

Compound AR00365083

According to the procedure described in Example 3-57, except that 2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (prepared as shown in Example 3-91a) was used in Step 5 instead of 2,3 -Dihydro-1H-isoindol-5-ylamine, to synthesize (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 ]nonadecan-7-ene -18-yl) ester 5-methyl ester (compound AR00365083). MS m/z (APCI+): 672.2 (MH ⁺ -Boc).

Example 3-91a

Synthesis of 2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester according to the following scheme

5-Bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (200 mg, 0.67 mmol), Pd(OAc) ₂ (30 mg, 0.2 Equiv), DPPP (55 mg, 0.2 equiv), TEA (0.93 mL, 10 equiv) and MeOH:DMSO (1:1, 4 mL) for 16 h. LC-MS and TLC (20% EtOAc-hexanes) showed the reaction was complete. The reaction mixture was concentrated to remove MeOH and diluted with EtOAc (10 mL), washed with water (2 x 25 mL). The organic layer was dried ( _Na2SO4 ), concentrated, and purified by silica gel chromatography (eluent ₌ 20% EtOAc-hexanes) to give pure 1,3-dihydro-isoindole-2,5- 2-tert-butyl 5-methyl dicarboxylate (150 mg, 81%). MS (APCI+): m/z 178.1 (MH ⁺ -Boc).

The protecting group in the above product was removed by treatment with 50% TFA-DCM at 0°C-RT for 1 hour. The reaction mixture was concentrated to dryness, redissolved in DCM, and neutralized with saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated to give the title compound as the free base, which was used in the next coupling step without further purification.

Example 3-92:

Compound AR00333831

(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 ]nonade-7-en-18-yl ester (compound AR00333831). ¹ H NMR (400MHz, CD3OD): δ7.36-7.22(m, 3H), 7.21-7.16(m, 1H), 5.74-5.60(m, 1H), 5.40(s, 1H), 5.20-5.03(m , 1H), 4.80-4.54(m, 6H), 4.38-4.28(m, 1H), 4.18(m, 1H), 3.90-3.80(m, 1H), 2.96-2.85(m, 1H), 2.70-2.31 (m, 4H), 1.92-0.98 (m, 24H). MS m/z (APCI-): 724.4 (M-1).

Example 3-93:

Compound AR00340494

According to the procedures described in Examples 3-6, except that 5-morpholin-4-yl-2,3-dihydro-1H-isoindole (by e.g. J.Org.Chem.2000, 65, 1144-1157 (1S, 4R, 6S, 14S, 18R)-5-morpholin-4-yl-1,3-di Hydrogen-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] Nonadec-7-en-18-yl ester (compound AR00340494). ¹ H NMR (400MHz, DMSO-d ⁶ ): δ7.80-7.22(m, 1H), 7.22-7.15(m, 1H), 7.00-6.81(m, 2H), 5.45-(m, 1H), 5.26 (m, 1H)4.62-4.50(m, 4H), 4.42(m, 1H), 4.28-4.10(m, 2H), 3.98(m, 1H), 3.76(m, 4H), 3.12(m, 4H) , 2.71-2.60 (m, 1H), 2.40-1.45 (m, 3H), 1.40-1.21 (m, 10H), 0.98-0.61 (m, 4H). MS m/z (APCI+): 699.2 (MH ⁺ -Boc).

Example 3-94:

Compound AR00365082

According to the procedures described in Examples 3-6, except that 2,3-dihydro-1H-isoindole-5-carbonitrile was used (by analogy as described in J.Org.Chem.1998, 63, 8224-8228) method) instead of 2,3-dihydro-1H-isoindole to synthesize (1S, 4R, 6S, 14S, 18R)-5-cyano-1,3-dihydro-isoindole-2-carboxy Acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nadeca-7- En-18-yl ester (compound AR00365082). MS m/z (APCI+): 639.1 (MH ⁺ -Boc).

Example 3-95:

Compound AR00365252

(1S,4R,6S,14S,18R)-5-Ethylcarbamoyl-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxyl was synthesized according to the procedure described in the scheme below Carbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester ( Compound AR00365252):

Compound AR00365083 (70 mg, 91 μmol) (synthesis of which was described earlier in this document) was dissolved in a THF:MeOH (2:1, 3 mL) mixture, followed by the addition of 1 mL of LiOH- _H2O in water. The reaction was stirred at room temperature for 1 hour. LC-MS indicated complete hydrolysis, and the reaction was continued for another 30 minutes, after which it was concentrated, neutralized with 0.1 N HCl, and extracted with 5 mL of EtOAc. The organic layer was dried ( _Na2SO4 ), concentrated and purified by silica gel chromatography (5%-7% MeOH-DCM) to give the hydrolyzate as a white solid _. MS (APCI+): m/z 658.1 (MH ⁺ -Boc).

The product from the above step (23 mg, 30 μmol) was first dissolved in anhydrous DMF (2 mL), followed by the addition of ethylamine (3 equiv), HOAT (3 equiv) and HATU (3 equiv), and finally DIEA (6 equiv) dropwise. equivalent). The reaction mixture was stirred overnight at room temperature. LC-MS showed the reaction was complete. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (2 x 10 mL). The organic layer was dried, concentrated, and the crude product was purified by prep-TLC. MS (APCI+): 685.2 (MH ⁺ -Boc).

Example 3-96:

Compound AR00334218

(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 ]nonadec-7-en-18-yl ester (compound AR00334218). ¹ H NMR (400MHz, CD ₃ CN) δ7.55(bs, 1H), 7.19-7.33(m, 3H), 5.63-5.73(m, 2H), 5.27-5.34(m, 1H), 4.98(t, 1H), 4.52-4.72(m, 5H), 4.48(t, 1H), 4.34-4.44(m, 1H), 4.06-4.15(m, 1H), 2.77-2.90(m, 2H), 2.54(bs, 1H), 2.24-2.44 (m, 3H), 1.64-1.75 (m, 2H), 1.13-1.57 (m, 18H), 0.91-1.09 (m, 4H). MS m/z 759.9 (M+1).

Example 3-97:

Compound AR00334220

(1S, 4R, 6S, 14S, 18R)-5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14-(tetrahydrofuran- 3-yloxycarbonylamino)-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (compound AR00334220). ¹ H NMR (400MHz, CD ₃ CN) δ7.57(bs, 1H), 7.20-7.34(m, 3H), 5.87-5.93(m, 1H), 5.65(q, 1H), 5.31(bs, 1H) , 5.23-5.29(m, 1H), 4.98(t, 1H), 4.44-4.71(m, 5H), 4.29-4.39(m, 1H), 4.07-4.18(m, 1H), 3.70-3.87(m, 4H), 3.61-3.70(m, 1H), 3.44-3.55(m, 2H), 3.30-3.42(m, 1H), 2.76-2.89(m, 2H), 2.54(bs, 1H), 2.36-2.46( m, 1H), 2.24-2.36 (m, 2H), 1.69-1.76 (m, 1H), 1.59-1.69 (m, 1H), 1.13-1.56 (m, 8H), 0.90-1.10 (m, 4H). MS m/z 762.0 (M+1).

Example 3-98:

Compound AR00334222

(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 ]nonadec-7-en-18-yl ester (compound AR00334222). ¹ H NMR (400MHz, CD ₃ CN) δ7.53(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:

Compound AR00334225

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 and 5-chloro-2,3-dihydro- 1H-isoindole instead of 4-fluoro-2,3-dihydro-1H-isoindole to synthesize (1S,4R,6S,14S,18R)-5-chloro-1,3-dihydro-isoindole Indole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14-(3,3-dimethyl-butyrylamino)-2,15-dioxo-3,16-diaza-tricyclo[ 14.3.0.0 ^4,6 ] Nonadec-7-en-18-yl ester (compound AR00334225). ¹ H NMR (400MHz, CD ₃ CN) δ7.60(bs, 1H), 7.15-7.33(m, 3H), 6.54-6.65(m, 1H), 5.63-5.73(m, 1H), 5.33(bs, 1H), 4.93-5.02(m, 1H), 4.53-4.65(m, 3H), 4.39-4.48(m, 2H), 4.28-4.38(m, 1H), 3.74-3.83(m, 2H), 2.77- 2.89(m, 1H), 2.54(bs, 1H), 2.23-2.44(m, 3H), 1.68-1.91(m, 4H), 1.12-1.54(m, 11H), 0.91-1.11(m, 4H), 0.76-0.90 (m, 9H). MS m/z 746.2 (M+1).

Example 3-100:

Compound AR00334226

Following the procedure described in Example 3-81, except that cyclopentyl-acetyl chloride was used in place of (4-methoxy-phenyl)-acetyl chloride and 5-chloro-2,3-dihydro-1H-isoindo Indole replaces 4-fluoro-2,3-dihydro-1H-isoindole to synthesize (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 ] nonadecan-7-en-18-yl ester (compound AR00334226). ¹ HNMR (400MHz, CDCl ₃ ) δ10.85(bs, 1H), 6.95-7.30(m, 3H), 5.87-6.02(m, 1H), 5.63-5.79(m, 1H), 5.43-5.52(m, 1H), 4.93-5.08(m, 1H), 4.52-4.85(m, 5H), 4.31-4.52(m, 1H), 3.79-3.95(m, 1H), 3.60-3.75(m, 2H), 3.14( q, 1H), 2.90(bs, 1H), 2.37-2.63(m, 3H), 2.14-2.29(m, 1H), 1.73-2.12(m, 6H), 1.16-1.74(m, 13H), 0.96- 1.16(m, 4H), 0.68-0.96(m, 9H). MS m/z 758.2 (M+1).

Example 3-101:

Compound AR00340173

Following the procedure described in Examples 3-6, except that 5-chloro-thiophene-2-sulfonic acid amide was used instead of cyclopropanesulfonamide and 5-chloro-2,3-dihydro-1H-isoindole was used instead of 2, 3-Dihydro-1H-isoindole, to synthesize (1S, 4R, 6S, 14S, 18R)-5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxy Carbonylamino-4-(5-chloro-thiophene-2-sulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nadeca-7 -en-18-yl ester (compound AR00340173). ¹ H NMR (400MHz, CD ₃ CN) δ8.07(d, 1H), 7.50(d, 1H), 7.16-7.32(m, 3H), 6.98(d, 1H), 5.86(bs, 1H), 5.27 -5.39(m, 2H), 4.81-4.92(m, 1H), 4.58-4.64(m, 2H), 4.51-4.58(m, 2H), 4.44(t, 1H), 4.33(d, 1H), 4.10 -4.20(m, 1H), 3.73-3.81(m, 1H), 2.47(bs, 1H), 2.16-2.41(m, 3H), 1.63-1.77(m, 2H), 1.47-1.57(m, 2H) , 1.07-1.47 (m, 17H). MS m/z 724.1 (M+1-Boc).

Example 3-102:

Compound AR00340526

(1S, 4R, 6S, 14S, 18R)-5-bromo-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo Dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00340526). ¹ H NMR (400MHz, CDCl ₃ ) δ10.31(bs, 1H), 7.36-7.44(m, 1H), 6.99-7.32(m, 3H), 5.70(q, 1H), 5.42-5.49(m, 1H ), 5.06-5.13(m, 1H), 4.99(t, 1H), 4.52-4.78(m, 5H), 4.32-4.44(m, 1H), 4.16-4.27(m, 1H), 3.78-3.89(m , 1H), 3.33-3.42(m, 1H), 2.85-2.94(m, 1H), 2.40-2.64(m, 3H), 2.20-2.32(m, 1H), 1.68-1.97(m, 4H), 1.17 -1.67 (m, 16H), 1.01-1.17 (m, 3H), 0.80-0.98 (m, 2H). MS m/z 694.0 (M+1-Boc).

Instance 3-103:

Compound AR00333462

Follow the procedure described in Example 3-1, except that 4R-methyl-1,2,3,4-tetrahydro-isoquinoline (prepared according to a similar procedure in Example 1-17a, except that enantiomeric Pure starting material instead of racemic starting material) instead of 1,2,3,4-tetrahydro-isoquinoline to synthesize (1S,4R,6S,14S,18R)-4R-methyl-3,4 -Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (compound AR00333462). MS m/z 642.2 (M+1-Boc).

Instance 3-104:

Compound AR00333463

Following the procedure described in Example 3-1, except using 4S-methyl-1,2,3,4-tetrahydro-isoquinoline (prepared according to a similar procedure in Example 1-17a, except using enantiomer (1S,4R,6S,14S,18R)-4S-methyl-3,4 -Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester (compound AR00333463). MS m/z 642.2 (M+1-Boc).

Instance 3-105:

Compound AR00345032

According to the procedures described in Examples 3-6, except that morpholine-4-carboxylic acid 2-(2,3-dihydro-1H-isoindol-5-yloxy)-ethyl ester (according to J.Med .Chem.2002, Vol. 45, No. 26, Method D in 5771 and prepared by the procedure described in Bioorg. Med. Chem. Lett. 11 (2001) 685-688) instead of 2,3-dihydro-1H -isoindole, to synthesize (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 ]deca Nona-7-en-18-yl ester (compound AR00345032). MS (APCI-): m/z 885.4 (M-1).

Instance 3-106:

Compound AR00345075

According to the procedures described in Examples 3-6, except that 5-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-isoindole (according to J.Med.Chem. 2002, Vol. 45, No. 26, Method D in 5771 and the procedure described in Bioorg. Med. Chem. Lett. 11 (2001) 685-688) instead of 2,3-dihydro-1H-isoindo Indole, to synthesize (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[ ^14.3.0.04,6 ]nonadecan-7-ene-18 -yl ester (compound AR00345075). MS (APCI-): m/z 855.6 (M-1).

Instance 3-107:

Compound AR00345090

According to the procedures described in Examples 3-6, except that 5-(2-morpholin-4-yl-ethoxy)-2,3-dihydro-1H-isoindole (according to J.Med.Chem. 2002, Vol. 45, No. 26, Method D in 5771 and the procedure described in Bioorg. Med. Chem. Lett. 11 (2001) 685-688) instead of 2,3-dihydro-1H-isoindo Indole, to synthesize (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[ ^14.3.0.04,6 ]nonadecan-7-ene-18 -yl ester (compound AR00345090). MS (APCI-): m/z 841.5 (M-1).

Example 3-108:

Compound AR00345094

Following the procedure described in Examples 3-6, except using [2-(2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-isopropyl-amine (according to J. Med.Chem.2002, Vol. 45, No. 26, Method D in 5771 and prepared by the procedure described in Bioorg.Med.Chem.Lett.11 (2001) 685-688) instead of 2,3-dihydro- 1H-isoindole, to synthesize (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 ]nonadecan-7-ene -18-yl ester (compound AR00345094). MS (APCI-): m/z 813.5 (M-1).

Example 3-109:

Compound AR00345095

Following the procedure described in Examples 3-6, except that [2-(2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-dimethyl-amine (according to J. Med.Chem.2002, Vol. 45, No. 26, Method D in 5771 and prepared by the procedure described in Bioorg.Med.Chem.Lett.11 (2001) 685-688) instead of 2,3-dihydro- 1H-isoindole, to synthesize (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 ]nonadecan-7-ene -18-yl ester (compound AR00345095). MS (APCI-): m/z 799.5 (M-1).

Example 3-110:

Compound AR00345096

According to the procedures described in Examples 3-6, except that 5-(2-imidazol-1-yl-ethoxy)-2,3-dihydro-1H-isoindole (according to J.Med.Chem.2002 , Vol. 45, No. 26, Method D in 5771 and the procedure described in Bioorg. Med. Chem. Lett. 11 (2001) 685-688) instead of 2,3-dihydro-1H-isoindole , to synthesize (1S, 4R, 6S, 14S, 18R)-5-(2-imidazol-1-yl-ethoxy)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butyl Oxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-en-18-yl Esters (compound AR00345096). MS (APCI-): m/z 822.5 (M-1).

Example 3-111:

Compound AR00364924

According to the procedures described in Examples 3-6, except that 5-(2-pyrazol-1-yl-ethoxy)-2,3-dihydro-1H-isoindole (according to J.Med.Chem. 2002, Vol. 45, No. 26, Method D in 5771 and the procedure described in Bioorg. Med. Chem. Lett. 11 (2001) 685-688) instead of 2,3-dihydro-1H-isoindo Indole, to synthesize (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[ ^14.3.0.04,6 ]nonadecan-7-ene-18 -yl ester (compound AR00364924). MS (APCI-): m/z 742.1 [(M-100)+18].

Example 3-112:

Compound AR00340495

In a similar manner as described in Examples 3-57, with 5-(4-methyl-piperazin-1-yl)-2,3-dihydro-1H-isoindole (by J.Org.Chem. 2000, 65, 1144-1157 in a similar manner) instead of 2,3-dihydro-1H-isoindol-5-ylamine in step 5, to synthesize (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 ]nonadec-7-en-18-yl ester (compound AR00340495). ¹ H NMR (400MHz, DMSO-d ⁶ ): δ7.72-7.40(m, 1H), 7.22-7.05(m, 1H), 6.95-6.70(m, 2H), 5.55-5.45(m, 1H), 5.35-5.22(m, 2H), 4.62-4.50(m, 4H), 4.40(m, 1H), 4.30-4.08(m, 2H), 4.0-3.89(m, 1H), 3.10(m, 3H), 2.65 (m, 1H), 2.42 (m, 3H), 2.33-2.20 (m, 6H), 1.85-1.50 (m, 5H), 1.42-1.0 (m, 14H), 0.82-0.55 (m, 4H). MS (APCI+): 712.3 (MH ⁺ -Boc).

Instance 3-113:

Compound AR00365084

(1S, 4R, 6S, 14S, 18R) was synthesized according to a similar procedure as described in Example 3-91 except that the product AR00365083 from this example was further hydrolyzed with LiOH in THF-MeOH- _H2O mixture to give AR00365084 -1,3-dihydro-isoindole-2,5-dicarboxylic acid 2-(14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3, 16-Diaza-tricyclo[ ^14.3.0.04,6 ]nonadec-7-en-18-yl)ester (compound AR00365084). MS: 658 (M-Boc).

Instance 3-114:

Compound AR00364989

By a similar manner as described in Example 3-57, substituting 2,3 in step 5 with 5-(2-methyl-thiazol-4-yl)-2,3-dihydro-1H-isoindole -Dihydro-1H-isoindol-5-ylamine, to synthesize (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} ] Nonadec-7-en-18-yl ester (compound AR00364989). ¹ H NMR (400MHz, CD ₃ COCD ₃ ) δ10.69 (bs, 1H) 8.32 (bs, 1H), 7.94 (d, 1H) 7.88 (d, 1H) 7.70 (d, 1H) 7.34 (dd, 1H) 6.08-6.16(m, 1H), 5.69(q, 1H) 5.45(bs, 1H) 5.00(t, 1H) 4.58-4.81(m, 5H), 4.44-4.53(m, 1H), 4.12-4.21(m , 1H), 3.83-3.91(m, 1H), 2.86-2.97(m, 1H), 2.57-2.71(m, 1H), 2.33-2.54(m, 3H), 1.81-1.96(m, 2H), 1.75 (dd, 1H) 1.17-1.63 (m, 20H), 1.06-1.17 (m, 1H), 0.94-1.06 (m, 2H). MS m/z 711.2 (M+1-100).

Example 3-114a:

According to the experiment of steps A to F of example 3-115a, but utilize thioacetamide in step E, to synthesize 5-(2-methyl-thiazol-4-yl)-2,3-dihydro-1H- Isoindole.

Instance 3-115:

Compound AR00365019

In a similar manner to that described in Examples 3-57, using the [4-(2,3-dihydro-1H-isoindol-5-yl)-thiazol-2-yl]-isopropyl-amine substitution step 2,3-Dihydro-1H-isoindol-5-ylamine in 5 to synthesize (1S, 4R, 6S, 14S, 18R)-5-(2-isopropylamino-thiazol-4-yl )-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazepine - Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester (compound AR00365019). ¹ H NMR (400MHz, CD ₃ COCD ₃ ) δ10.69 (bs, 1H), 8.27-8.36 (m, 1H), 7.28-7.50 (m, 2H), 7.01-7.20 (m, 1H), 6.08-6.15 ( m, 1H), 5.70(q, 1H) 4.45(bs, 1H) 4.94-5.05(m, 1H), 4.68-4.76(m, 4H), 4.59-4.64(m, 1H) 4.45-4.53(m, 1H ), 4.10-4.20(m, 1H), 3.81-3.90(m, 1H), 3.65-3.76(m, 1H), 2.86-2.98(m, 1H), 2.63(bs, 1H), 2.32-2.54(m, 3H), 1.80-1.94 (m, 2H), 1.70-1.79 (m, 1H), 1.05-1.65 (m, 19H), 0.95-1.05 (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 described in the following scheme.

A. To a solution of 4 ml THF and 1 ml ethyl vinyl ether at -78°C, t-BuLi (0.79 ml, 1.34 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 30 minutes. A 0.5M solution of _ZnCl2 in THF (3.02ml, 1.51mmol) was added dropwise and the reaction was stirred at room temperature for 30 minutes. This mixture was used without further purification.

B. To a solution of aryl bromide (0.200 g, 0.67 mmol) and Pd(PPh ₃ ) ₄ (39 mg, 0.33 mmol) dissolved in THF under _N was added the crude vinyl novel material from step A via cannula . The reaction was heated at 50 °C for 36 hours, then filtered through a plug of _Al2O3 with _EtOAc , and concentrated to an oil which was used without further purification.

C. The crude oil from Step B was dissolved in THF (2ml) and 1.0N HCl (2ml) and stirred for one hour. The reaction was taken up in EtOAc and separated, the organic layer was washed with saturated sodium bicarbonate and brine, dried over _Na2SO4 and concentrated to give an orange oil _. The oil was purified by chromatography using 5:1 hexanes:EtOAc to afford a white solid (95 mg, 54%).

D. To a solution of 1.0M LiHMDS (4.0ml, 4.0mmol) was added dropwise TMSCl (3.38ml, 26.6mmol) at -78°C under _N2 . To this solution was added the ketone from step C in 3 ml THF. 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 minutes, concentrated to a solid and worked up in EtOAc and water. The organics were washed with water and brine, dried over _Na2SO4 and concentrated, and the oil was purified using 5:1 _hexanes :EtOAc to give a yellow solid (0.64 g, 71%).

E. A slurry of bromoketone (75 mg, 0.22 mmol), _Na2CO3 (37 mg, 0.44 mmol) and 1-isopropylthiourea (26 mg _, 22 mmol) in EtOH was heated at reflux for 30 minutes. The reaction was taken up in EtOAc and separated, the organic layer was washed with saturated sodium bicarbonate and brine, dried over _Na2SO4 and concentrated to give a yellow oil _. This oil was purified using 3:1 hexanes:MTBE to give a clear oil (77 mg, 97%).

F. The Boc-amine from step E was stirred in 4N HCl/dioxane (2.0ml) for one hour and concentrated to a white solid. This solid was taken up in 0.1N HCl and washed with DCM. The aqueous layer was basified with 1.0N NaOH and extracted with DCM, dried, 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[ ^14.3.0.04,6 ]Synthesis of ethyl nonadecan-7-ene-4-carboxylate

A. To (2S, 4R)-4-amino-1-[benzyloxycarbonyl]pyrrolidine-2-methylcarboxylate hydrochloride (2.00g, 2.34mmol) in dichloromethane (25ml) To the solution in 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 was eluted with 40% EtOAc/hexanes to give a colorless oil. The oil was dissolved in methanol (20ml) and stirred with 10% palladium on carbon under a balloon of hydrogen. After stirring for 4 hours, the reaction was filtered and concentrated. The resulting solid was dissolved in 1N aqueous hydrochloric acid (75 ml), and extracted with dichloromethane (75 ml). The aqueous layer was basified by adding sodium hydroxide and extracted again with dichloromethane (100ml). The two organic extracts were combined, concentrated, and the resulting residue was purified by silica gel chromatography eluting with 10% methanol/dichloromethane to afford a tan solid (1.29 g, 70%). LCMS = 289 (H+).

B. Stir overnight 4(R)-(2-trimethylsilylethylcarbonylamino)-pyrrolidine-2(S)-carboxylic acid methyl ester (1.29g, 4.50mmol), 2(S)-tert-butyl Oxycarbonylamino-non-8-enoic acid (1.22g, 4.51mmol), HATU (2.06g, 5.41mmol) and diisopropylethylamine (1.18ml, 6.76mmol) in dimethylformamide (10ml) solution in. The reaction was diluted with ethyl acetate (150ml), washed with 1N aqueous hydrochloric acid (2 x 100ml), dried over magnesium sulfate and concentrated. Chromatography on silica gel gave an oil which was stirred with lithium hydroxide (0.28 g, 6.76 mmol) in methanol (5 mL) for 2 hours. The reaction was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid, dried over magnesium sulfate and concentrated to give 1.2 g (49%) of product.

C. Add 4N HCl/dioxane solution (2.87ml, 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 (1.21g, 2.29mmol), HATU (1.05g, 2.75mmol) and diisopropylethylamine (1.60ml, 9.17mmol) and dichloromethane (10ml) and stirred the mixture at room temperature React for 18 hours. The reaction was placed on silica gel and eluted with 50% ethyl acetate/hexanes solution to give the product (1.27 g, 83%) as a colorless oil. 665 (H+).

D. Adding 1-{[1-(2(S)-tert-butoxycarbonylamino-non-8-enoyl)-4(R)-(2-trimethylsilyl) by bubbling _N2 thereinto Ethylcarbonylamino)-pyrrolidine-2(S)-carbonyl]-amino}-2(S)-vinyl-cyclopropane-1-(R)-carboxylic acid ethyl ester (1.27g, 1.91mmol) in di The solution in methyl chloride (195ml) was 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, placed on silica gel and eluted with 50% ethyl acetate/hexanes. The resulting oil was treated with TBAF (1.0M in THF, 2.87ml) and heated to 50°C for 4 hours. The reaction was placed on silica gel and eluted with 20% methanol/dichloromethane to afford a tan solid (0.65 g, 69%). ¹ H NMR (CDCl ₃ , 400MHz): δ1.06-1.66 (m, 17H), 1.85-1.95 (m, 2H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.2- 2.3(m, 1H), 2.65-2.75(M, 1H), 3.40(m, 1H), 3.73-3.83(m, 2H), 4.08-4.19(m, 2H), 4.56(m, 1H), 4.78( d, J=5.5Hz, 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 with General Structure V

Example 5-1:

Compound AR00287262

(1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-[(3,4-dihydro-1H-isoquinoline-2-carbonyl)-amino]-2,15- Synthesis of dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonade-7-ene-4-carboxylic acid (compound AR00287262)

3,4-Dihydro-1H-isoquinoline-2-carbonyl chloride (0.030g, 0.152mmol), (1S, 4R, 6S, 14S, 18R)-18-amino-14-tert-butoxycarbonylamino -2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-ene-4-carboxylic acid ethyl ester (0.025g, 0.050mmol), DIEA ( 0.027ml, 0.153mmol) and a solution of a catalytic amount of DMAP were stirred in dichloromethane (0.3ml) for 18 hours. The reaction was placed on silica gel, eluted with 40% acetone/hexanes and the product was 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 dichloromethane (30ml), washed with 1N aqueous hydrochloric acid (30ml), brine, dried over magnesium sulfate and concentrated to give the title compound as a white solid. LCMS = 624 (MH+).

The general formula was 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 The following compounds. LCMS = 610 (H+).

Example 5-2:

Compound AR00298980

According to the procedure described in Example 5-1, but using 1,3-dihydro-isoindole-2-carbonyl chloride in place of 3,4-dihydro-1H-isoquinoline-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 ]nonadec-7-ene-4-carboxylic acid (compound AR00298980). MS m/e 608.2 (M-1).

Example 5-3:

Compound AR00304160

Prepared according to the procedure described in Example 5-1, substituting 3,4-dihydro-2H-quinoline-1-carbonyl chloride for 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-[(3,4-dihydro-2H-quinoline-1-carbonyl)-amino]-2,15-di Oxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00304160). MS m/e 524.3 (M ⁺ +1-100).

Preparation of Compounds with General Structure VI

Example 6-1:

Compound AR00304010

Using the same procedure as described in step 4 of Example 1-2, except substituting thiocarbonyldiimidazole for carbonyldiimidazole, to prepare (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino- 18-[(3,4-Dihydro-1H-isoquinoline-2-carbonsulfonyl)-amino]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^{4 ,6} ] Nonadece-7-ene-4-carboxylic acid (compound AR00304010). LCMS = 640 (H+). MS m/e 640.1 (M ⁺ +1).

Preparation of Compounds with General Structure VII

Example 7-1:

Compound AR00287266

According to the same procedure described in Example 3-1, starting from the acid prepared according to the procedure described in Example 5-1, (1S, 4R, 6S, 14S, 18R-{4-cyclopropanesulfonylamino Carbonyl-18-[(3,4-dihydro-1H-isoquinoline-2-carbonyl)-amino]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^{4 ,6} ] Nonadeca-7-en-14-yl}-tert-butyl carbamate (compound AR00287266). MS m/e 727.0 (M ⁺ +1).

Example 7-2:

Compound AR00304008

According to the same procedure described in Example 3-1, starting from the acid prepared according to the procedure described in Example 5-2, (1S, 4R, 6S, 14S, 18R-{4-cyclopropanesulfonylamino Carbonyl-18-[(1,3-dihydro-isoindole-2-carbonyl)-amino]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] nonadecan-7-en-14-yl}-tert-butyl carbamate (compound AR00304008). MS m/e 613.2 (M ⁺ +1-100).

Example 7-3:

Compound AR00304014

(1S,4R,6S,14S,18R)-1,3-dihydro was prepared according to the procedure described in Examples 2-24 starting from the acylsulfonamide prepared according to the procedure described in Example 7-4 -Isoindole-2-carboxylic acid [14-(3-cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl]-amide (compound AR00304014). MS m/e 724.2 (M ⁺⁺ 1).

Example 7-4:

Compound AR00304012

According to the same procedure described in Example 3-1, starting from the acid prepared according to the procedure described in Example 6-1, (1S, 4R, 6S, 14S, 18R)-{4-cyclopropanesulfonyl Aminocarbonyl-18-[(3,4-dihydro-1H-isoquinoline-2-carbonyl)-amino]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ] Nonadeca-7-en-14-yl}-tert-butylcarbamate (compound AR00304012). MS m/e 743.0 (M ⁺ +1).

Example 7-5:

AR00424775

(1S,4R,6S,14S,18R)-5-fluoro-1-methoxymethyl-3,4-dihydro-1H- Isoquinoline-2-carboxylic 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) and stirred at room temperature for 16 hours. The reaction was then concentrated and taken up in acetonitrile to concentrate again. The hydrochloride was then dried overnight using a high vacuum pump to afford 80 mg of the product as a white solid ester. +APCI MS m/z 690.1 (M+1).

Example 7-6:

AR004248`74

Synthesis of (1S,4R,6S,14S,18R)-4-fluoro-1,3-dihydro-isoindole-2-carboxylate by treating AR00334191 (98 mg) in 0.5 mL of 4M HCl/dioxane Acid 14-amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester hydrochloride (compound AR00424874) and stirred at room temperature for 16 hours. The reaction was then concentrated and taken up in acetonitrile to concentrate again. The hydrochloride salt was then dried overnight using a high vacuum pump to give the product (89 mg) as a white solid. + APCI MS m/z 632.1 (M+1).

Example 8

NS3-NS4A Protease Analysis

Forms the NS3 complex with NS4A-2

Recombinant E. coli or Baculovirus (Baculovirus) full-length NS3 was diluted to 3.33 μM with assay buffer, and this material was transferred into an eppendorf tube and placed in a water bath in a 4° C. refrigerator. Add an appropriate amount of NS4A-2 to reach 8.3 mM in assay buffer to equal the volume of NS3 in step 2.1.1 (conversion factor - 3.8 mg/272 µL assay buffer). This material was transferred into an eppendorf tube and placed in a water bath in a 4°C refrigerator.

After equilibrating to 4°C, equal volumes of NS3 and NS4A-2 solutions were combined in eppendorf tubes, mixed carefully using a manual pipette, and the mixture was incubated in a 4°C water bath for 15 minutes. The final concentrations in the mixture were 1.67 μM NS3, 4.15 mM NS4A-2 (2485-fold molar excess of NS4A-2).

After 15 min at 4°C, remove the NS3/NS4A-2 eppendorf tube and place in a room temperature water bath for 10 min. Aliquot NS3/NS4A-2 into appropriate volumes and store at -80 °C. (When working with 2 nM E. coli NS3 in the assay solution, divide into 25 μL aliquots; when working with 3 nM BV NS3 in the assay solution, divide into 30 μL aliquots).

NS3 Inhibition Analysis

Step 2.2.5. Dissolve sample compounds in DMSO to 10 mM, then dilute to 2.5 mM in DMSO (1:4). Typically, compounds are added to the assay plate at a concentration of 2.5 mM and diluted to give a starting concentration of 50 mM in the assay inhibition curve. Compounds were serially diluted in assay buffer to provide lower concentrations of test solutions.

Step 2.2.6. Dilute E. coli NS3/NS4A-2 to 4nM NS3 (1:417.5 of 1.67 μM stock - 18 μL of 1.67 μM stock + 7497 μL assay buffer).

Dilute BV NS3/NS4A-2 to 6 nM NS3 (1:278.3 of 1.67 μM stock - 24 μL of 1.67 μM stock + 6655 μL assay buffer).

Step 2.2.7. Using a manual multichannel pipette and being careful not to introduce air bubbles into the plate, add 50 μL of Assay Buffer to wells A01-H01 of a black Costar 96-well polypropylene storage plate.

Step 2.2.8. Using a manual multichannel pipette and being careful not to introduce air bubbles into the plate, add 50 μL of the diluted NS3/NS4A-2 from step 2.2.6 to wells A02-H12 of the plate in step 2.2.7 middle.

Step 2.2.9. Using a manual multichannel pipette and being careful not to introduce air bubbles into the plate, transfer 25 μL from the wells of the drug dilution plate in step 2.2.5 to the corresponding wells of the assay plate in step 2.2.8. Change the nozzles of the multichannel pipette as each row of compounds is transferred.

Step 2.2.10. Using a manual multichannel pipette and being careful not to introduce air bubbles into the plate, mix the wells from the assay plate in step 2.2.9 by pipetting five times and dispensing 35 μL of the 75 μL in each well. Change the nozzle of the multichannel pipette when mixing each row of wells.

Step 2.2.11. Cover the plate with a polystyrene cover and pre-incubate 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 RETS1 substrate to 8 μM (1:80.75 of 646 μM stock - 65 μL of 646 μM stock + 5184 μL of assay buffer).

After preincubating the plate from step 2.2.11, using a manual multichannel pipette, add 25 μL of substrate to all wells on the plate. Mix the well contents quickly as in step 2.2.10, but mix 65 µL of the 100 µL in the well.

Plates were read in dynamic mode on a Molecular Devices SpectraMax Gemini XS plate reader. Reader settings: Reading time: 30 minutes; Interval: 36 seconds; Number of readings: 51; Excitation wavelength λ: 335nm; Emission wavelength λ: 495nm; Threshold: 475nm; Automix: off; Calibration: once; PMT : high; reads/well: 6; Vmax pts: 21 or 28/51, depending on the linear length of the reaction.

_IC50s were determined using a four parameter curve fitting equation and converted to Ki values using the following Km values:

Full E. coli NS3-2.03μM

Full-length BV NS3 - 1.74 μM

where Ki=IC ₅₀ /(1+[S]/Km)

Quantification by ELISA of the selectable marker protein, Neomvcin phosphotransferase II (NPTII), in the HCV subgenomic replicon, GS4.3

The HCV subgenomic replicon (1377/NS3-3', accession number AJ242652), which is stably maintained in HuH-7 hepatoma cells, was established by Lohmann et al. (Science 285: 110-113 (1999)). Cell cultures containing the replicon, designated GS4.3, were obtained from Dr. Christoph Seeger, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

GS4.3 cells were maintained at 37°C, 5% CO ₂ in DMEM (Gibco 11965-092) supplemented with L-glutamine 200 mM (100 times) (Gibco2503 0-081), optional Amino acids (NEAA) (Biowhittaker 13-114E), heat inactivated (HI) fetal bovine serum (FBS) (Hyclone SH3007.03) and 750 μg/ml geneticin (G418) (Gibco 10131-035). Cells were split again 1:3 or 4 every 2-3 days.

24 hours before analysis, GS4.3 cells were harvested, counted, and plated at 7500 cells/well in 96-well plates (Costar 3585) with 100 μl of standard maintenance medium (as above) and cultured under the above conditions. To start the analysis, the medium was removed, the cells were washed once with PBS (Gibco 10010-023), and 90 μl of assay medium (DMEM, L-glutamine, NEAA, 10% HI FBS, without G418) was added. Inhibitors were made into 10x stocks in assay medium, (3-fold dilution from 10 μM to 56 pM final concentration, 1% final DMSO concentration), added 10 ul to duplicate wells, rocked plate to mix, and incubated as above for 72 Hour.

Obtain NPRII ELISA kit (compound direct ELISA test system for neomycin phosphotransferase II, PSP 73000/4800) from AGDIA company. The manufacturer's instructions were followed with some modifications. A 10×PEB-1 lysis buffer was prepared to include 500 μM PMSF (Sigma P7626, 50 mM stock solution in isopropanol). After 72 hours of culture, cells were washed once with PBS, and 150 μl of PEB-1 containing PMSF was added to each well. Plates were agitated vigorously for 15 minutes at room temperature and then frozen at -70°C. Thaw the plate, mix the lysate thoroughly, and add 100 μl to the NPTII Elisa plate. to obtain a standard curve. Lysates from DMSO-treated control wells were combined, serially diluted in PEB-1 containing PMSF, and applied to duplicate wells of an ELISA plate with initial lysate amounts ranging from 150 μl to 2.5 μl. In addition, 100 µl of buffer was applied in duplicate separately, as a blank group. The plate was sealed and agitated gently for 2 hours at room temperature. After capture incubation, the plates were washed (5 x 300 μl) with PBS-T (0.5% Tween-20, PBS-T is provided in the ELISA kit). For detection, a 1-fold dilution of enzyme conjugate dilution MRS-2 (5×) was prepared in PBS-T, to which 1:100 dilutions of enzyme conjugates A and B were added according to the instructions. Reseal the plate and incubate with agitation: cap, room temperature, 2 hours. The wash step was then repeated and 100 [mu]l of room temperature TMB substrate was added. After approximately 30 minutes of incubation (room temperature, agitation, capping), the reaction was stopped with 50 μl of 3M sulfuric acid. Plates were read on a Molecular Devices Versamax plate reader at 450nm.

Inhibitor effects were expressed as a percentage of the DMSO-treated control signal, and inhibition curves were calculated using the following 4-parameter equation: y=A+((BA)/(1+((C/x)^D))), where C is Half-maximal activity or _EC50 .

active instance

in:

A represents an _IC50 or _EC50 of less than 50 μM as indicated;

B represents an _IC50 or _EC50 less than 10 μM as indicated;

C represents an _IC50 or _EC50 of less than 1 μM as indicated;

and D represents an _IC50 or _EC50 of less than 0.1 [mu]M as indicated.

Table 2

compound NS3-NS4AIC ₅₀ replicon EC ₅₀ compound NS3-NS4AIC ₅₀ replicon EC ₅₀ AR00220042 C B AR00301383 B N/A AR00220122 A N/A AR00301745 C B AR00226824 B N/A AR00301746 D. D. AR00226825 B N/A AR00301747 D. D. AR00247310 C N/A AR00301749 C B AR00248687 C N/A AR00301751 D. D. AR00248688 B N/A AR00304000 C B AR00248689 C N/A AR00304008 D. D. AR00254906 D. C AR00304010 C B AR00261407 D. C AR00304012 D. C AR00261408 D. D. AR00304014 D. D. AR00261409 D. B AR00304062 B N/A AR00282131 D. D. AR00304063 C B AR00287262 B N/A AR00304065 C B AR00287266 D. C AR00304066 C B AR00291871 D. C AR00304067 C B AR00291875 C B AR00304072 C B AR00294376 AR00304073 C B

AR00294377 C B AR00304074 C B AR00294378 C B AR00304075 C B AR00294381 D. D. AR00304076 D. C

compound NS3-NS4AIC ₅₀ replicon EC ₅₀ compound NS3-NS4AIC ₅₀ replicon EC ₅₀ AR00294382 C N/A AR00304077 D. B AR00294383 B N/A AR00304078 D. C AR00294384 C B AR00304079 D. C AR00294980 B N/A AR00304080 D. D. AR00298989 B N/A AR00304081 D. C AR00298990 B N/A AR00304082 D. D. AR00298996 D. D. AR00304103 B B AR00298997 D. D. AR00304125 C B AR00301338 D. B AR00304126 C B AR00304183 A N/A AR00304127 C B AR00311814 D. B AR00304154 B N/A AR00311815 D. C AR00304158 A N/A AR00312023 C N/A AR00304160 A N/A AR00312024 D. D. AR00304161 D. D. AR00312025 D. D. AR00304162 D. D. AR00312026 D. D. AR00304163 D. D. AR00314578 C N/A AR00320123 C B AR00314635 D. D. AR00320220 D. D. AR00314654 D. D. AR00320221 C N/A AR00314656 D. D. AR00320222 D. B AR00314685 A N/A AR00320403 D. C AR00314719 D. D. AR00320445 B N/A AR00315997 C B AR00320446 D. D. AR00315998 C B AR00320447 D. C AR00315999 C B AR00320448 C B AR00320001 D. D. AR00320449 D. B AR00320002 C B AR00320450 C B AR00320073 D. D. AR00320506 D. D. AR00320074 D. B AR00320547 D. D. AR00320075 C B AR00320548 D. D. AR00320076 C B AR00320549 D. D. AR00320077 C B AR00320556 D. D. AR00320078 D. B AR00320557 D. D. AR00320079 D. D. AR00320574 D. D. AR00320080 D. C AR00320575 D. C AR00320081 D. D. AR00320576 B N/A AR00320082 D. D. AR00320577 C B AR00320119 D. D. AR00320578 D. D. AR00320120 D. D. AR00320579 D. D. AR00320121 D. D. AR00320580 D. D.

compound NS3-NS4A Replicon compound NS3-NS4A Replicon

_{IC50 EC50 IC50 EC50} AR00320122 c B AR00320581 D. D. AR00324375 c C AR00320582 D. D. AR00334286 D. D. AR00320774 D. C AR00334385 D. D. AR00333833 D. D. AR00365387 D. D. AR00334191 D. D. AR00365425 D. N/A AR00340479 D. D. AR00365572 D. D. AR00365388 D. N/A AR00333802 D. D. AR00365426 D. B AR00334188 D. C AR00333801 D. D. AR00334248 D. C AR00333803 D. C AR00334250 D. D. AR00334247 D. C AR00364266 D. C AR00334249 D. C AR00334339 D. D. AR00334341 D. D. AR00365438 D. D. AR00365427 D. D. AR00365349 C C AR00365193 D. D. AR00340303 D. C AR00333842 C B AR00340156 D. C AR00365381 C C AR00340188 D. C AR00340122 D. C AR00334399 D. D. AR00340178 D. D. AR00338070 D. D. AR00334314 D. D. AR00341649 D. D. AR00338066 D. D. AR00333224 B N/A AR00338071 D. D. AR00333248 B N/A AR00364936 D. C AR00333277 B N/A AR00333225 B N/A AR00365083 D. D. AR00333276 B N/A AR00340494 D. D. AR00365369 D. C AR00365252 D. C AR00333831 D. D. AR00334220 D. C AR00365082 D. C AR00334225 D. C AR00334218 D. D. AR00340173 D. B AR00334222 D. D. AR00333462 D. D. AR00334226 D. D. AR00333463 D. D. AR00340526 D. D. AR00345032 D. D. AR00345075 D. C AR00345090 D. D. AR00345094 D. D. AR00345095 D. D. AR00345096 D. D. AR00364924 D. D. AR00371946 D. N/A AR00371947 C N/A AR00371948 D. N/A AR00340495 D. D. AR00365084 D. B AR00364989 D. D. AR00365019 D. D. AR00424775 D. N/A AR00424874 D. N/A

specificity analysis

Compounds of formula I were found to be selective when compounds were evaluated in specificity assays, as they reacted against Cathepsin B, Chymotrypsin, Thrombin or Leukocyte Elastase showed no significant inhibitory effect.

Example 9: Pharmacokinetic analysis of compounds

method

Compounds were first synthesized and tested for potency ( _IC50 ) in the fluorescent NS3/4 protease assay and cell-based HCV replicon system as described in Example 8 above. Then combined with in vitro human liver microsomes (human liver microsome, HLM) and hepatocyte stability studies, using the plasma pharmacokinetic analysis in rats (Rattus sp.) after IV administration, from the potency of less than 20 nM Design metabolically stable compounds in compounds. The drug-like physical properties of these leads were further optimized and administered orally to rats (Rattus sp.) for assessment of liver, heart and plasma concentrations.

Hepatic clearance of compound over time was tested following a single 3 mg/kg oral dose in rats. Doses up to 30 mg/kg orally BID for seven days are used for any compound that exhibits a concentration in the liver that is at least 100-fold greater than the concentration of the compound effective to inhibit 50% of the maximal inhibition in the replicon assay (replicon _EC50 ) 8 hours after dosing Additional toxicology assessments were performed in rats.

result

Compounds AR294381, AR261408, AR333833, and AR334191 produced replicon EC ₅₀ values of approximately 2 nM and demonstrated in vitro stability in rat, dog, and human hepatocyte culture assays, data that would predict how to slow clearance from the liver rate. In addition, these compounds exhibited high selectivity over a panel of other serine proteases and showed no significant inhibitory effect on cytochrome P450 isoforms or hERG channel activity even at the highest concentration tested (10 μM) .

For compounds AR294381, AR261408, AR333833 and AR334191, a single 30 mg/kg oral dose in rats (Rattus sp.) produced concentrations in the liver at 24 hours post-dose that were at least 200-fold higher than their respective replicon _EC50 values.

Compound AR334191 produced cardiac and plasma levels up to two orders of magnitude lower than liver concentrations in the same animals and was kinetically correlated with liver concentrations. The clinically more reasonable oral dose (3 mg/kg) of the compound AR334191 has a concentration in the liver 8 hours after administration that is more than 100 times greater than the EC ₅₀ value of the compound's replicon. Following exposure to compound AR334191 at a dose of 30 mg/kg po BID, no mortality, body weight changes, or clinical chemistry abnormalities were observed in the treated animals.

in conclusion

Potent, metabolically stable, orally available small molecule HCV NS3 protease inhibitors have been developed. At the most modest oral administration concentration (3 mg/kg), these compounds exhibited high liver levels (100-fold higher than the respective replicon _EC50 values) 8 hours post-dose. Exposure to plasma and heart was up to two orders of magnitude lower than that observed in liver, such low concentrations that any possible systemic toxicological concerns were minimized.

When the compound AR334191 was administered at 30 mg/kg BID for 7 days, it showed no toxicity in rats (Rattus sp.), providing at least a 10-fold safety margin above the presumed effective dose (3 mg/kg), while producing more than this Liver concentrations at 100-fold replicon _EC50 values for compounds.

Preparation of Part C Virus Inhibitors

The terms and structural names used in this section have the same meanings as in Section C above. Any reference in this section to a specific number or designation should be read in context with the corresponding numbering or labeling scheme used in this section or in Section C above, and not a potentially similar or equivalent numbering or labeling scheme used elsewhere herein The content is to be understood unless otherwise stated.

Compounds of formula XI-XVII can be synthesized according to the methods described below.

Methodology

NS3 inhibitors as shown in Examples 1-35 were prepared according to the chemical reactions illustrated in Scheme 1. Intermediate 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropane was prepared in a similar manner as described in International Application PCT/CA00/00353 (publication No. WO 00/59929) Ethyl carboxylate, 2(S)-tert-butoxycarbonylamino-non-8-enoic acid and hydroxymacrocyclic intermediate (step C). 2(S)-tert-butoxycarbonylamino-non-8-enoic acid is also commercially available from RSP Amino Acids.

Example 1: Synthesis of Compound 101

Process 1

Step A: Synthesis of tert-butyl 2S-(1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-hydroxy-pyrrolidine-1-carboxylate

Add ethyl-(1R, 2S)/(1S, 2R)-1-amino-2-vinylcyclopropylcarboxylate (1.0g, 5.2mmol), trans-N-(tert-butoxy Carbonyl)-4-hydroxy-L-proline (1.3 g, 1.1 equiv) and HATU (2.7 g, 1.1 equiv) were added to a flask with 30 mL of DMF to make a solution. The solution was cooled to 0°C in an ice-water bath, then a solution of DIEA (4.4ml, 4eq) in DMF (15ml) was added slowly with stirring. The reaction was allowed to warm to room temperature and stirred overnight.

After 16 h, the reaction was monitored by HPLC for completeness. Diluted with EtOAc (100 mL), washed with water (3 x 40 mL), saturated sodium bicarbonate (2 x 40 mL) and brine (2 x 40 mL), then dried over _Na2SO4 and concentrated to give a dark copper colored oil _. The crude product was purified on silica gel (eluent: acetone/hexane 3:7) to give pure desired product (770 mg, 32%) as a tan foamy powder.

Step B: 1R-{[1-(2S-tert-butoxycarbonylamino-non-8-enoyl)-4R-hydroxy-pyrrolidine-2S-carbonyl]-amino}-2S-vinyl-cyclopropanecarboxy Synthesis of ethyl acetate

The dipeptide product from step A (2.85 g, 7.7 mmol) was dissolved in 10 mL 4N HCl (dioxane) and kept at room temperature for 90 min to remove the BOC protecting group. It was then concentrated, dissolved in acetonitrile, and concentrated twice more. To this beige 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 of DMF under nitrogen. The reaction was cooled on an ice-water bath for 15 minutes, after which a solution of DIEA (5.4 mL, 30.9 mmol) in 5 mL of DMF was added dropwise with stirring. The ice bath was removed and allowed to warm slowly to room temperature, and the reaction was stirred overnight.

After 18h, TLC showed that the reaction was complete. The reaction was diluted with EtOAc (300 mL) and washed with water (3 x 150 mL), saturated sodium bicarbonate (2 x 150 mL), brine (150 mL), _dried ( _Na2SO4 ) and the solvent was removed. The crude product was purified by flash chromatography on silica gel on Biotage 40M (eluent = 3% to 5% MeOH in DCM) to give the desired product (3.5 g, 87%) as a tan foamy solid.

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 ] Synthesis of nonadecan-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 give a solution. Stripping was performed by bubbling nitrogen gas thereinto for 1 hour. Hoveyda's catalyst (0.25 equiv) was then added at room temperature under nitrogen. The reaction was placed on a preheated oil bath (50 °C) and stirred overnight. After 16 h, the reaction turned dark brown. TLC (DCM/EtOAc 1:1) showed clean conversion to a new spot with slightly lower _Rf value. The reaction was concentrated and purified on silica gel (Biotage 40M, eluent = DCM/EtOAc gradient from 1:1 to 1:2) to give the desired product (0.64 g, 52%) as a tan foamy powder. ¹ H NRM (CDCL ₃ , 400MHz) δ1.21 (t, J=7.0Hz, 3H), 1.43 (s, 9H), 1.20-1.50 (m, 6H), 1.53-1.68 (m, 2H), 1.83- 1.96(m, 2H), 1.98-2.28(m, 4H), 2.60(m, 1H), 3.13(br s, 1H), 3.68(m, 1H), 3.94(m, 1H), 4.01-4.19(m , 2H), 4.48(m, 1H), 4.56(br s, 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 (br s, 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-di Synthesis of ethyl oxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadeca-7-ene-4-carboxylate

The macrocyclic product from Step C (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 overnight at room temperature. After 15 h, the reaction was complete as monitored by TLC (DCM/MeOH 9:1). Isoindoline (0.12 mL, 1.1 mmol) was added dropwise to the reaction and the reaction was stirred at 40 °C overnight. After 22h, TLC showed that the reaction was complete. The reaction was cooled to room temperature, diluted with DCM (6 mL), washed with 1 N aqueous hydrochloric acid (2 x 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 the desired product (131 mg, 90%) as a white powder.

Step E: (1S, 4R, 6S, 14S, 18R)-14-tert-butoxycarbonylamino-18-(1,3-dihydro-isoindole-2-carbonyloxy)-2,15-di Synthesis of Oxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-ene-4-carboxylic acid

The macrocyclic ester product from step D (60 mg, 0.092 mmol) was dissolved in 0.9 mL (THF/MeOH/ _H2O2: 1:1) mixed solvent, followed by the addition of LiOH- _H2O (23 mg, 6 equiv). The mixture was stirred overnight at room temperature. After 18 h, TLC (DCM/MeOH 9:1 ) showed a clean new spot with a lower _Rf value. The reaction was concentrated to almost dryness and partitioned between 1N aqueous hydrochloric acid (15 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The organic layers were combined, dried _{over Na2SO4} and concentrated to give the desired product (50 mg, 87%) as a white foamy powder. ¹ H NMR (CDCl ₃ , 500MHz) δ1.21-1.44(m, 8H), 1.32(s, 9H), 1.54-1.62(m, 2H), 1.78-1.88(m, 2H), 2.04-2.13(m , 1H), 2.16-2.23(m, 1H), 2.24-2.36(m, 2H), 2.66-2.74(m, 1H), 3.87-3.90(m, 1H), 4.15(d, J=11.0Hz, 1H ), 4.37-4.43(m, 1H), 4.61-4.77(m, 5H), 5.18(t, J=10.3Hz, 1H), 5.24-5.31(m, 1H), 5.40-5.45(m, 1H), 5.58-5.66 (m, 1H), 7.11-7.30 (m, 4H). MS m/z 611.0 (M ⁺ +1).

Step F: (1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(N,N-dimethylsulfonyl Synthesis of acyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester (compound 101)

The macrocyclic acid product from Step E (40 mg, 0.066 mmol) was dissolved in 0.7 mL of DCM, followed by the addition of CDI (13 mg, 0.079 mmol) in one portion. The mixture was stirred in a 50°C oil bath for 2 hours. TLC (10% methanol in dichloromethane) showed the absence of the acid starting material and the appearance of a new spot with a higher _Rf value. N,N-Dimethylsulfonamide (12 mg, 0.098 mmol; purchased from TCI) was then added to the reaction followed by DBU (15 mg, 0.098 mmol). Reheating at 50°C for 2 hours, both TLC and LCMS showed completion of the reaction and formation of product. The reaction was concentrated and loaded directly onto a Biotage 40S silica gel column. It was purified by flash chromatography (eluent = 40% ethyl acetate in hexanes with 1% formic acid) to give the desired product (30 mg, 64%) as a white solid. MS m/z 715.5 (APCI-, M-1).

Examples 2-35 were prepared following a similar procedure as described in Example 1 above, except that in Step F, other suitable sulfonamides were substituted for N,N-dimethylsulfonamide and/or other amines substituted for isoindoline. The following compounds in. The sulfonamides used were either purchased from commercial sources or prepared by Routes A or B as described in Scheme 2 below. Methods similar to route A have been described in the literature (eg, Heteroatom Chemistry, 2001, 12(1), 1-5). The sulfamoylating reagent a in route B was prepared according to the literature procedure (Winum, J-Y et al., Organic Letters, 2001, 3, 2241-2243).

Route A:

Process 2

Synthesis of N-cyclopropylsulfonamide

To a stirred solution of chlorosulfonyl isocyanate (1 mL, 11.5 mmol) in 20 mL DriSolve DCM was added anhydrous tert-butanol (1.1 mL, 1 equiv) at 0 °C. After stirring for 90 minutes, the resulting carbamate sulfamoyl chloride solution and 5 mL TEA in 20 mL DCM were added dropwise to a solution of cyclopropylamine (0.66 g, 1 eq) in 25 mL DCM and 3 mL TEA. The reaction temperature was kept below 5°C during the addition. After the addition the ice bath was removed 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 had formed. The reaction mixture was then diluted with 100 mL of DCM and washed with 0.1 N HCl (2 x 200 mL) and brine (150 mL). The organic layer was dried over _Na2SO4 and concentrated to give Boc protected sulfonamide 1.2 _g as light yellow solid. ¹ H-NMR showed this to be the desired product with minor impurities. The crude product was recrystallized from ethyl acetate/hexane (rt to 0°C) to afford 0.64 g of off-white crystalline pure product. 1H NMR (CDCl ₃ , 400 MHz) δ 0.71-0.77 (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 product from above was dissolved in 10 mL of a 1:1 (by volume) mixture of DCM:TFA and kept at room temperature for 1 hour. Concentration was then performed by rotary evaporation followed by 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 0.66-0.74 (m, 4H), 2.57-2.58 (m, 1H), 5.29 (br s, 2H), 5.42 (br s, 1H).

Synthesis of Pyrrolidinol Sulfonamide

The title compound was prepared according to the same procedure described above for the synthesis of N-cyclopropylsulfonamide, substituting pyrrolidine for cyclopropylamine. For the Boc protected title product: ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.49 (s, 9H), 1.92-1.95 (m, 4H), 3.48-3.52 (m, 4H), 7.02 (br s, 1H). MS m/z 249 (APCI-, M-1).

Synthesis of Morpholinol Sulfonamide

The title compound was prepared following the same procedure described above for the synthesis of N-cyclopropylsulfonamide, substituting morpholine for cyclopropylamine. For the Boc protected title product: 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-ylsulfamate

The title compound was prepared following the same procedure described above for the synthesis of N-cyclopropylsulfonamide, substituting 2-aminothiazole for cyclopropylamine. However, the Boc protected intermediate was never isolated because the protecting group was lost during the reaction workup and after the recrystallization step. The title product was isolated after silica gel column chromatography (Biotage 40M, eluent = 5%-10% MeOH in 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-piperazinylsulfonamide

The title compound was prepared according to Route B in Scheme 2. 4-Methyl-piperazine (0.15 g, 1.50 mmol) was dissolved in 3 mL of DriSolve DCM in 10 mL RBF, followed by the addition of sulfamoylating reagent a (0.45 g, 1.50 mmol). After stirring for about 5 minutes, the latter reagent gradually dissolved to give a clear, almost colorless solution. It was stirred overnight at room temperature. After 17 hours, TLC showed that the reaction was complete (DCM:MeOH 9:1 with 1% TEA). The reaction was concentrated and the resulting pink crude solid was flashed through a Biotage 40S silica gel column (eluent = DCM:MeOH 10:1 with 1% TEA) to afford the Boc protected title product as a white powder in essentially 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 was then removed by the same manner as described for the synthesis of N-cyclopropylsulfonamide, and the resulting title product was used directly in the next coupling step without further purification.

Example 2:

Compound 102

(1S, 4R, 6S, 14S, 18R)-1 was synthesized according to the same procedure as described in Example 1, except that N-cyclopropylsulfonamide was used in place of N,N-dimethylsulfonamide in Step F, 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(N-cyclopropylsulfonyl-aminocarbonyl)-2,15-dioxo-3,16-di Aza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. MS m/z 728 (APCI-, M-1).

Example 3:

Compound 103

(1S,4R,6S,14S,18R)-1,3- Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(pyrrolidinylsulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tri Cyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. MS m/z 742 (APCI-, M-1).

Example 4:

Compound 104

According to the same procedure described in Example 1, except that morpholinolsulfonamide was used in place of N,N-dimethylsulfonamide in Step F, (1S,4R,6S,14S,18R)-1,3- Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(morpholinosulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tri Cyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. MS m/z 758 (APCI-, M-1).

Example 5:

Compound 105

(1S, 4R, 6S, 14S, 18R)-1 was synthesized according to the same procedure described in Example 1, except that thiazol-2-ylsulfamate amide was substituted for N,N-dimethylsulfonamide in Step F. , 3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(thiazol-2-ylaminosulfonylaminocarbonyl)-2,15-dioxo-3,16 di Aza-tricyclo[14.3.0.0 ^4,6 ]nonade-7en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.15(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:

Compound 106

(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 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, CD ₃ OD) δ7.31(q, 1H), 7.13(d, 1H), 7.03-6.97(m, 2H), 6.63(br s, 1H), 5.70(q, 1H), 5.40(br s, 1H), 5.07(t, 1H), 4.78-4.51(m, 7H), 4.10-4.02(m, 1H), 3.83(d, 1H), 2.84(s, 6H), 2.73-2.64 (m, 1H), 2.55-2.47(m, 1H), 2.43-2.29(m, 3H), 1.84-1.67(m, 4H), 1.64-1.57(m, 2H), 1.13(d, 9H), 0.94 -0.82 (m, 4H). MS m/z 733.4 (APCI-, M-1).

Example 7:

Compound 107

(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 ]nonadecan-7-en-18-yl ester . ¹ H NMR (400MHz, CD ³ OD) δ7.32-7.16(m, 4H), 5.75-5.64(m, 2H), 5.47(br s, 1H), 5.05(t, 1H), 4.52-4.45(m , 2H), 4.39-4.17(m, 3H), 4.12-4.02(m, 1H), 3.99-3.88(m, 1H), 3.70-3.38(m, 6H), 3.14-3.00(m, 4H), 2.83 (d, 6H), 2.59-2.24(m, 4H), 2.08-2.01(m, 2H), 1.98-1.65(m, 10H), 1.63-1.51(m, 4H), 1.23(d, 9H), 0.92 -0.84 (m, 1H). MS m/z 826.6 (APCI-, M-1).

Example 8:

Compound 108

Following the same procedure as described in Example 1, except that 1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline was used in step D to replace isoindoline and in step F N-cyclopropylsulfonamide is substituted for N,N-dimethylsulfonamide to synthesize (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-cyclopropyl-sulfonylaminocarbonyl)-3,16-diaza- Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, CD3OD) δ7.31-7.15(m, 4H), 5.75-5.58(m, 2H), 5.47(br s, 1H), 5.11(t, 1H), 4.62-4.57(m, 1H ), 4.52-4.45(m, 1H), 4.41-4.17(m, 3H), 4.15-3.84(m, 3H), 3.73-3.34(m, 5H), 3.16-2.71(m, 5H), 2.70-2.27 (m, 6H), 2.13-2.67 (m, 10H), 1.65-1.24 (m, 15H), 0.73-0.47 (m, 4H); MS m/z 838.4 (APCI-, M-1).

Example 9:

Compound 109

Following the same procedure as described in Example 1, except that 1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline was used in step D to replace isoindoline and in step F Pyrrolidinylsulfonamide is substituted for N, N-dimethylsulfonamide to synthesize (1S, 4R, 6S, 14S, 18R)-1-piperidin-1-ylmethyl-3,4-dihydro-1H- Isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4-(pyrrolidinyl-sulfonylaminocarbonyl)-3,16-diaza-tricyclo[14.3 .0.0 ^4,6 ] nonadecan-7-en-18-yl ester. ¹ H NMR (400MHz, CD ₃ OD) δ8.94(d, 1H), 7.31-7.16(m, 4H), 5.75-5.62(m, 2H), 5.48(br s, 1H), 5.08-4.99(m , 1H), 4.66-3.84(m, 7H), 3.72-3.39(m, 7H), 3.28-3.20(m, 2H), 3.17-2.25(m, 10H), 2.12-1.99(m, 2H), 1.98 -1.66 (m, 11H), 1.64-1.22 (m, 15H); MS m/z 852.5 (APCI-, M-1).

Example 10:

Compound 110

Following the same procedure as described in Example 1, except that 1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline was used in step D to replace isoindoline and in step F Morpholinylsulfonamide is substituted for N, N-dimethylsulfonamide to synthesize (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 ] nonadecan-7-en-18-yl ester. ¹ H NMR (400MHz, CD ₃ OD) δ7.33-7.14(m, 4H), 5.78-5.63(m, 2H), 5.47(br s, 1H), 5.11(t, 1H), 4.63-3.84(m , 7H), 3.74-3.36(m, 9H), 3.29-3.19(m, 3H), 3.16-2.14(m, 11H), 2.13-1.23(m, 24H), 0.94-0.81(m, 1H); MS m/z 868.6 (APCI-, M-1).

Example 11:

Compound 111

Following the same procedure as described in Example 1, except that in Step D substituted 1-morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinoline for isoindoline and in Step F Pyrrolidinylsulfonamide is substituted for N, N-dimethylsulfonamide to synthesize (1S, 4R, 6S, 14S, 18R)-1-morpholin-4-ylmethyl-3,4-dihydro-1H- Isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4-(pyrrolidine-1-sulfonylaminocarbonyl)-3,16-diaza-tricyclo[ 14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. MS m/z 874.3 (APCI-, M+18).

Example 12:

Compound 112

Following the same procedure as described in Example 1, except substituting 2-morpholin-4-yl-1-phenyl-ethylamine for isoindoline in step D and pyrrolidinylsulfonamide for N in step F , N-dimethylsulfonamide, to synthesize (1S, 4R, 6S, 14S, 18R)-(2-morpholin-4-yl-1-phenyl-ethyl)-carbamic acid 14-tert-butoxy Carbonylamino-2,15-dioxo-4-(pyrrolidine-1-sulfonylaminocarbonyl)-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-ene- 18-yl esters. MS m/z 828.3 (APCI-, M-1).

Example 13:

Compound 113

(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 ]nonadec-7-en-18-yl ester. MS m/z 651 (APCI+, M-Boc).

Example 14:

Compound 114

Following the same procedure as described in Example 1 except substituting 5-chloroisoindoline for isoindoline in Step D and N,N-dimethylsulfonamide in Step F Amide, to synthesize (1S, 4R, 6S, 14S, 18R)-5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(N-ring Propyl-sulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. MS m/z 663 (APCI+, M-Boc).

Example 15:

Compound 115

Following the same procedure as described in Example 1, except substituting 5-chloroisoindoline for isoindoline in Step D and pyrrolidinylsulfonamide for N,N-dimethylsulfonamide in Step F, To synthesize (1S, 4R, 6S, 14S, 18R)-5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(pyrrolidinyl-sulfonyl Acyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadeca-7-en-18-yl ester. MS m/z 677 (APCI+, M-Boc).

Example 16:

Compound 116

Following the same procedure as described in Example 1, except substituting 5-chloroisoindoline for isoindoline in step D and morpholinosulfonamide for N,N-dimethylsulfonamide in step F, To synthesize (1S, 4R, 6S, 14S, 18R)-5-chloro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(morpholinyl-sulfo Acyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadeca-7-en-18-yl ester. MS m/z 693 (APCI+, M-Boc).

Example 17:

Compound 117

(1S, 4R, 6S, 14S, 18R)-1 was synthesized according to the same procedure described in Example 1, except that azetidine-1-sulfonamide was used instead of N,N-dimethylsulfonamide in Step F , 3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(azetidinyl-sulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diazepine Hetero-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.21(s, 9H), 1.28-1.54(m, 8H), 1.59-1.63(m, 1H), 1.77-1.89(m, 3H), 2.38-2.42 (m, 1H), 2.46-2.52(m, 2H), 3.77(t, 2H), 3.84-3.94(m, 3H), 4.14-4.22(m, 3H), 4.50(br d, 1H), 4.61- 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 5.6 mL DriSolve DCM in 10 mL 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 to give a clear, almost colorless solution. It was stirred overnight at room temperature. After 17 hours, TLC showed that the reaction was complete (DCM:MeOH 9:1). The reaction was concentrated and the resulting crude white solid was flashed through a Biotage 40S silica gel column (eluent = 5% to 10% MeOH/DCM) to afford the Boc protected title product in essentially quantitative yield. The product was initially a thick oil which gradually solidified overnight under high vacuum. ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.52 (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 TFA/DCM (1:1 volume ratio) mixture and kept at room temperature for 2 hours. Volatiles were then removed. The resulting oily residue was treated with ether and filtered. The filtered white powder product was used in the next coupling step without further purification. ¹ H NMR (d ⁶ -acetone, 400 MHz) δ 2.12-2.19 (m, 2H), 3.77 (t, 4H), 6.05 (br s, 2H).

Example 18:

Compound 118

(1S, 4R, 6S, 14S, 18R )-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(4-methylpiperazine-1-sulfonyl-aminocarbonyl)-2,15-di Oxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.21(s, 9H), 1.19-1.58(m, 9H), 1.70-1.73(m, 1H), 1.85-1.88(m, 2H), 2.24(s , 3H), 2.36-2.48(m, 7H), 2.53(m, 1H), 3.24-3.29(m, 4H), 3.84-3.88(m, 1H), 4.14-4.18(m, 1H), 4.49(br d, 1H), 4.60-4.72(m, 5H), 5.04(t, 1H), 5.44(br s, 1H), 5.71(q, 1H), 6.16(br d, 1H), 7.23-7.36(m, 4H), 8.31 (s, 1H). MS m/z 770.5 (APCI-, M-1).

Example 19:

Compound 119

Synthesized according to the same procedure described in Example 1 except that 4-(2-trimethylsilylethoxycarbonyl)piperazine 1-sulfonamide was used in Step F instead of N,N-dimethylsulfonamide (1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(4-(2-trimethylsilylethyl Oxycarbonyl)piperazine-1-sulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-ene-18 -yl esters. ¹ H NMR (400MHz, d ⁶ -acetone) δ0.06(s, 9H), 0.94-0.98(m, 2H), 1.15(s, 9H), 1.17-1.50(m, 8H), 1.50-1.54(m , 1H), 1.65-1.68(m, 1H), 1.75-1.82(m, 2H), 2.30-2.44(m, 3H), 2.56-2.68(m, 1H), 3.17-3.26(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), 5.56-5.63 (m, 1H), 6.12 (br d, 1H), 7.16-7.30 (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 shown below.

Process 3

Step 1: Piperazine-1-carboxylate tert-butyl ester (1.0 g, 5.4 mmol) was dissolved in 10 mL DriSolve DCM in 50 mL RBF, followed by the addition of sulfamoylated example a (1.6 g, 5.4 mmol). After stirring for about 5 minutes, the latter reagent gradually dissolved to give a clear, almost colorless solution. It was stirred overnight at room temperature. After 17 hours, TLC showed that the reaction was complete (DCM:MeOH 20:1). The reaction was concentrated and the resulting crude white solid was flashed through a Biotage 40S silica gel column (eluent = 2% MeOH/DCM) to afford the Boc protected title 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 approximately 20 mL of a 1:1 (volume ratio) TFA-DCM mixture and kept at room temperature for 2 hours. It is then concentrated. The solid residue was taken up in MeCN and concentrated again to give the deprotected product as a fine white powder.

To this deprotected product was added 20 mL of DriSolve DCM followed by 1 mL of TEA. To the resulting white suspension was added Teoc-succinate (0.70 g, 2.7 mmol) in one portion with stirring. The white suspension disappeared rapidly and the colorless clear solution was stirred overnight at room temperature. The reaction was then concentrated and purified by silica chromatography (Biotage 40S, eluent = hexane:ethyl acetate 2:1) to give the pure product 0.65 g (85%) as a white solid. ¹ H NMR (d ⁶ -acetone, 400MHz) δ0.06(s, 9H), 0.94-0.98(m, 2H), 3.01(t, 4H), 3.48(t, 4H), 4.10-4.14(m, 2H) ), 6.03 (br s, 2H). LCMS m/z 308.2 (APCI-, M-1).

Example 20:

Compound 120

(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 ]nonadec-7-en-18-yl ester. Compound 119 (54.8 mg, 60.7 μmol) was first dissolved in 0.5 mL DriSolve THF, followed by the addition of 1.0 M TBAF THF solution (0.2 mL, 200 μmol). The reaction was heated in a 60 °C oil bath for 2 hours, and TLC showed the reaction was complete. The reaction was purified by chromatography on silica (Biotage 12M; eluent = 0% to 20% MeOH in DCM) to afford compound 120 as a white solid, 42.4 mg (92%). MS m/z 756.4 (APCI-, M-1).

Example 21:

Compound 121

(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 ]nonadecan-7-en-18-yl ester. ¹ H NMR (500MHz, CD ₃ OD) δ8.91(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), 4.80-4.68(m, 4H), 4.61(q, 1H), 4.56-4.49(m, 1H), 4.06(t, 1H), 3.83(br s, 1H ), 3.72(p, 1H), 3.22(p, 1H), 2.72-2.60(m, 1H), 2.57-2.48(m, 1H), 2.46-2.31(m, 4H), 1.83-1.69(m, 4H ), 1.66-1.58 (m, 1H), 1.56-1.19 (m, 5H), 1.13 (d, 9H), 0.71-0.51 (m, 4H). MS m/z 745.3 (APCI-, M-1).

Example 22:

Compound 122

(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 ] nonadecan-7-en-18-yl ester. MS m/z 688.2 (APCI-, M-1).

Example 23:

Compound 123

According to the same procedure described in Example 1, except that 1-cyanocyclopropylsulfonamide was used in place of N,N-dimethylsulfonamide in Step F, (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 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.22(s, 9H), 1.20-1.55(m, 11H), 1.58-1.61(m, 1H), 1.66-1.69(m, 1H), 1.71-1.75 (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:

The title compound 1-cyanocyclopropylsulfonamide was prepared according to the same procedure described above for the synthesis of N-cyclopropylsulfonamide (Scheme 2, Route A), except substituting 1-aminocyclopropylnitrile hydrochloride Cyclopropylamine. 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:

Compound 124

(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 ]nonadecan-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ0.75-0.77(m, 2H), 0.96-1.01(m, 2H), 1.21(s, 9H), 1.20-1.57(m, 7H), 1.60-1.66 (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)sulfonamide was prepared in the same manner as described in Example 17a except substituting N-cyclopropyl-1-methylpiperidin-4-amine azetidine. ¹ H NMR (d ⁶ -DMSO, 400MHz) δ0.67-0.76 (m, 4H), 1.93-1.97 (m, 2H), 2.07-2.18 (m, 2H), 2.22-2.26 (m, 1H), 2.75 (s, 3H), 2.96-3.05 (m, 2H), 3.45-3.48 (m, 2H), 3.77-3.83 (m, 1H), 6.93 (br s, 2H), 9.78 (br s, 1H).

Example 25:

Compound 125

(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 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ0.74-0.78(m, 2H), 0.98-1.01(m, 2H), 1.21(s, 9H), 1.20-1.54(m, 7H), 1.59-1.63 (m, 1H), 1.74-1.77(m, 1H), 1.82-1.87(m, 2H), 2.41-2.65(m, 6H), 2.79-2.83(m, 2H), 3.49-3.56(m, 1H) , 3.84-3.88(m, 1H), 3.97-4.04(m, 1H), 4.14-4.18(m, 1H), 4.50(br d, 1H), 4.60-4.72(m, 5H), 5.05(t, 1H ), 5.45 (br s, 1H), 5.68 (q, 1H), 6.15 (br d, 1H), 7.22-7.36 (m, 4H), 8.33 (s, 1H). MS m/z 781.3 (APCI-,M).

Example 25a:

The title compound 2-cyanoethyl(cyclopropyl)sulfonamide was prepared in the same manner as described in Example 17a except substituting 3-(cyclopropylamino)propionitrile for azetidine. ¹ H NMR (d ⁶ -DMSO, 400MHz) δ0.68-0.76(m, 4H), 2.36-2.37(m, 1H), 2.78(t, 2H), 3.35(t, 2H), 7.05(br s, 2H).

Example 26:

Compound 126

(1S, 4R, 6S, 14S, 18R) was synthesized according to the same procedure described in Example 1, except that N,N-diisopropylsulfonamide was used in Step F instead of N,N-dimethylsulfonamide -1,3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(N,N-diisopropylaminosulfonyl-aminocarbonyl)-2,15-dioxo Substituted-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.21(s, 9H), 1.25-1.53(m, 20H), 1.68-1.71(m, 1H), 1.81-1.87(m, 2H), 2.38-2.45 (m, 3H), 2.56-2.68(m, 1H), 3.84-3.87(m, 1H), 3.94-4.01(m, 2H), 4.14-4.18(m, 1H), 4.47(br d, 1H), 4.58-4.68(m, 5H), 5.03(t, 1H), 5.44(br s, 1H), 5.62(q, 1H), 6.11(br d, 1H), 7.23-7.36(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-diisopropylsulfonamide was prepared in the same manner as described in Example 17a except substituting diisopropylamine for azetidine. 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:

Compound 127

(1S, 4R, 6S, 14S, 18R)-1,3-di Hydrogen-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(phenylaminosulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.20(s, 9H), 1.20-1.50(m, 8H), 1.60-1.70(m, 2H), 1.78-1.86(m, 1H), 2.30-2.44 (m, 4H), 3.81-3.85(m, 1H), 4.12-4.17(m, 1H), 4.45(br d, 1H), 4.54-4.75(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, phenylsulfonamide, was prepared following the same procedure described above for the synthesis of N-cyclopropylsulfonamide (Scheme 2, Route A), substituting aniline for cyclopropylamine. ¹ H NMR (d ⁶ -DMSO, 400MHz) δ6.95-6.98 (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:

Compound 128

(1S, 4R, 6S, 14S, 18R)-1 was synthesized according to the same procedure described in Example 1, except that 4-chlorophenylsulfonamide was used instead of N,N-dimethylsulfonamide in Step F, 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 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.19(s, 9H), 1.18-1.51(m, 8H), 1.61-1.72(m, 2H), 1.76-1.87(m, 1H), 2.32-2.44 (m, 4H), 3.82-3.86(m, 1H), 4.12-4.16(m, 1H), 4.45(brd, 1H), 4.54-4.72(m, 6H), 5.28(q, 1H), 5.43(br s, 1H), 6.10 (br d, 1H), 7.22-7.38 (m, 8H), 8.24 (s, 1H). MS m/z 798.2 (APCI-,M).

Example 28a:

The title compound, 4-chlorophenylsulfonamide, was prepared following the same procedure described above for the synthesis of N-cyclopropylsulfonamide (Scheme 2, Route A), substituting 4-chloroaniline for cyclopropylamine. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 7.09-7.12 (m, 4H), 7.27 (d, 2H), 9.59 (br s, 1H).

Example 29:

Compound 129

(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 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.20(s, 9H), 1.18-1.54(m, 8H), 1.64-1.87(m, 3H), 2.22-2.46(m, 4H), 3.80(s , 3H), 3.77-3.82(m, 1H), 4.14(m, 1H), 4.43(br d, 1H), 4.52-4.70(m, 5H), 4.88(t, 1H), 5.40-5.50(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-methoxyphenylsulfonamide, was prepared following the same procedure described above for the synthesis of N-cyclopropylsulfonamide (Scheme 2, Route A), substituting 4-methoxyaniline for cyclopropylamine. ¹ H NMR (d ⁶ -DMSO, 400 MHz) δ 3.71 (s, 3H), 6.85-6.87 (m, 4H), 7.11 (d, 2H), 9.01 (br s, 1H).

Compound 130

Example 30:

(1S, 4R, 6S, 14S, 18R)-1 was synthesized according to the same procedure described in Example 1, except that 4-methylphenylsulfonamide was used instead of N,N-dimethylsulfonamide in Step F. , 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 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.20(s, 9H), 1.20-1.52(m, 8H), 1.60-1.74(m, 2H), 1.76-1.87(m, 1H), 2.26-2.42 (m, 4H), 2.31(s, 3H), 3.81-3.84(m, 1H), 4.14-4.17(m, 1H), 4.44(br d, 1H), 4.52-4.79(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-methylphenylsulfonamide was prepared following the same procedure described above for the synthesis of N-cyclopropylsulfonamide (Scheme 2, Route A), except that 4-methylaniline was substituted for cyclopropylamine. 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:

Compound 131

(1S, 4R, 6S, 14S, 18R)-1 was synthesized according to the same procedure described in Example 1, except that 4-cyanophenylsulfonamide was used instead of N,N-dimethylsulfonamide in Step F. , 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 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.20(s, 9H), 1.18-1.53(m, 8H), 1.60-1.70(m, 2H), 1.76-1.87(m, 1H), 2.32-2.48 (m, 4H), 3.85-3.88(m, 1H), 4.15-4.17(m, 1H), 4.46(br d, 1H), 4.57-4.71(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-cyanophenylsulfonamide, was prepared according to the same procedure described above for the synthesis of N-cyclopropylsulfonamide (Scheme 2, Route A), substituting 4-aminobenzonitrile for cyclopropylamine. 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:

Compound 132

(1S, 4R, 6S, 14S, 18R) was synthesized according to the same procedure described in Example 1, except that 4-trifluoromethylphenylsulfonamide was used instead of N,N-dimethylsulfonamide in Step F. -1,3-Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(4-trifluoromethylphenylaminosulfonyl-aminocarbonyl)-2,15-dioxo Substituted-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadecan-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.19(s, 9H), 1.18-1.64(m, 10H), 1.82(q, 1H), 2.30-2.46(m, 4H), 3.84-3.87(m , 1H), 4.12-4.16(m, 1H), 4.47(br d, 1H), 4.57-4.71(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:

The title compound 4-trifluoromethylphenylsulfonamide was prepared according to the same procedure described above for the synthesis of N-cyclopropylsulfonamide (Scheme 2, Route A), except substituting 4-(trifluoromethyl)aniline Cyclopropylamine. 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:

Compound 133

(1S, 4R, 6S, 14S, 18R)-1,3- Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(cyclobutylaminosulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diazepine- Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.21(s, 9H), 1.20-1.70(m, 11H), 1.80-1.90(m, 2H), 2.02-2.09(m, 2H), 2.21-2.30 (m, 2H), 2.41-2.47(m, 3H), 2.58-2.68(m, 1H), 3.75-3.87(m, 2H), 4.15-4.18(m, 1H), 4.47(br d, 1H), 4.57-4.72(m, 5H), 5.11(t, 1H), 5.44(s, 1H), 5.63(q, 1H), 6.14(br d, 1H), 6.34(br d, 1H), 7.23-7.36( m, 4H), 8.18 (s, 1H). MS m/z 741.4 (APCI-, M-1).

Example 33a:

The title compound cyclobutylsulfonamide was prepared in the same manner as described in Example 17a except substituting cyclobutylamine for azetidine. ¹ H NMR (d ⁶ -DMSO, 400MHz) δ1.20-1.60 (m, 2H), 1.89-1.94 (m, 2H), 2.14-2.21 (m, 2H), 3.67 (m, 1H), 6.42 (br s, 2H), 6.82 (br s, 1H).

Example 34:

Compound 134

(1S, 4R, 6S, 14S, 18R)-1,3- Dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(cyclopentylaminosulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diazepine- Tricyclo[14.3.0.0 ^4,6 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.21(s, 9H), 1.20-1.73(m, 15H), 1.87-1.96(m, 4H), 2.41-2.49(m, 3H), 2.56-2.68 (m, 1H), 3.55-3.60(m, 1H), 3.84-3.87(m, 1H), 4.15-4.18(m, 1H), 4.48(br d, 1H), 4.57-4.72(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 cyclopentylsulfonamide was prepared in the same manner as described in Example 17a except substituting cyclopentylamine for azetidine. 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:

Compound 135

(1S, 4R, 6S, 14S, 18R)-1,3-di Hydrogen-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-(cyclohexylaminosulfonyl-aminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclic [ ^14.3.0.04,6 ]nonadec-7-en-18-yl ester. ¹ H NMR (400MHz, d ⁶ -acetone) δ1.21(s, 9H), 1.14-2.0(m, 21H), 2.41-2.48(m, 3H), 2.57-2.67(m, 1H), 3.07-3.16 (m, 1H), 3.84-3.87(m, 1H), 4.15-4.19(m, 1H), 4.47(brd, 1H), 4.57-4.72(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 136

(1S, 4R, 6S, 14S, 18R)-1,3-dihydro-isoindole-2-carboxylic acid 14-amino-4-(N,N-dimethylsulfonyl-aminocarbonyl)-2, Synthesis of 15-dioxo-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-18-yl ester hydrochloride (compound 136)

The title compound was synthesized by treating compound 101 (79 mg) in 0.5 mL of 4M HCl/dioxane and stirred at room temperature for 16 hours. The reaction was then concentrated and taken up in acetonitrile to concentrate again. The hydrochloride salt was then dried overnight using a high vacuum pump to give the product (76 mg) as a white solid. +APCI MS m/z 617.1(M+1).

Example 35b:

The title compound cyclohexylsulfonamide was prepared in the same manner as described in Example 17a except substituting cyclohexylamine for azetidine. ¹ H NMR (d ⁶ -DMSO, 400MHz) δ1.08-1.23 (m, 5H), 1.50-1.54 (m, 1H), 1.65-1.68 (m, 2H), 1.86-1.89 (m, 2H), 3.02 (m, 1H), 6.40 (br s, 3H).

Example 36: NS3-NS4 Protease Analysis

Forms the NS3 complex with NS4A-2

Recombinant E. coli or baculovirus full-length NS3 was diluted to 3.33 μM with assay buffer, and this material was transferred into an eppendorf tube and placed in a water bath in a 4°C refrigerator. Add an appropriate amount of NS4A-2 to reach 8.3 mM in assay buffer to equal the volume of NS3 in step 2.1.1 (conversion factor - 3.8 mg/272 µL assay buffer). This material was transferred into an eppendorf tube and placed in a water bath in a 4°C refrigerator.

After equilibrating to 4°C, equal volumes of NS3 and NS4A-2 solutions were combined in eppendorf tubes, mixed carefully using a manual pipette, and the mixture was incubated in a 4°C water bath for 15 minutes. The final concentrations in the mixture were 1.67 μM NS3, 4.15 mM NS4A-2 (2485-fold molar excess of NS4A-2).

After 15 minutes at 4°C, the NS3/NS4A-2 eppendorf tubes were removed and placed in a room temperature water bath for 10 minutes. Aliquot NS3/NS4A-2 into appropriate volumes and store at -80 °C. (When working with 2 nM E. coli NS3 in the assay solution, divide into 25 μL aliquots; when working with 3 nM BV NS3 in the assay solution, divide into 30 μL aliquots).

Example 37: Analysis of NS3 Inhibition

Step 2.2.5. Dissolve sample compounds in DMSO to 10 mM, then dilute to 2.5 mM in DMSO (1:4). Typically, compounds are added to the assay plate at a concentration of 2.5 mM and diluted to give a starting concentration of 50 mM in the assay inhibition curve. Compounds were serially diluted in assay buffer to provide lower concentrations of test solutions.

Step 2.2.6. Dilute E. coli NS3/NS4A-2 to 4nM NS3 (1:417.5 of 1.67 μM stock - 18 μL of 1.67 μM stock + 7497 μL assay buffer). BV NS3/NS4A-2 was diluted to 6nM NS3 (1:278.3 of 1.67 μM stock - 24 μL of 1.67 μM stock + 6655 μL assay buffer).

Step 2.2.7. Using a manual multichannel pipette and being careful not to introduce air bubbles into the plate, add 50 μL of Assay Buffer to wells A01-H01 of a black Costar 96-well polypropylene storage plate.

Step 2.2.8. Using a manual multichannel pipette and being careful not to introduce air bubbles into the plate, add 50 μL of the diluted NS3/NS4A-2 from step 2.2.6 to wells A02-H12 of the plate in step 2.2.7 middle.

Step 2.2.9. Using a manual multichannel pipette and being careful not to introduce air bubbles into the plate, transfer 25 μL from the wells of the drug dilution plate in step 2.2.5 to the corresponding wells of the assay plate in step 2.2.8. Change the nozzles of the multichannel pipette as each row of compounds is transferred.

Step 2.2.10. Using a manual multichannel pipette and being careful not to introduce air bubbles into the plate, mix the wells from the assay plate in step 2.2.9 by pipetting five times and dispensing 35 μL of the 75 μL in each well. Change the nozzle of the multichannel pipette when mixing each row of wells.

Step 2.2.11. Cover the plate with a polystyrene cover and pre-incubate 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 RETS1 substrate to 8 μM (1:80.75 of 646 μM stock - 65 μL of 646 μM stock + 5184 μL of assay buffer).

After preincubating the plate from step 2.2.11, using a manual multichannel pipette, add 25 μL of substrate to all wells on the plate. Mix the contents of the wells of the plate quickly as in step 2.2.10, but mix 65 µL of 100 µL in the wells.

Plates were read in dynamic mode on a Molecular Devices SpectraMax Gemini XS plate reader. Reader settings: Reading time: 30 minutes; Interval: 36 seconds; Number of readings: 51; Excitation wavelength λ: 335nm; Emission wavelength λ: 495nm; Threshold: 475nm; Automix: off; Calibration: once; PMT : high; reads/well: 6; Vmax pts: 21 or 28/51, depending on the linear length of the reaction.

_IC50s were determined using a four parameter curve fitting equation and converted to Ki values using the following Km values:

Full E. coli NS3-2.03μM

Full-length BV NS3 - 1.74 μM

where Ki=IC ₅₀ /(1+[S]/Km)

Quantification by ELISA of the selectable marker protein, neomycin phosphotransferase II (NPTII), in the HCV subgenomic replicon, GS4.3

The HCV subgenomic replicon (I377/NS3-3', accession number AJ242652) is stably maintained in HuH-7 hepatoma cells and was established by Lohmann et al. (Science 285:110-113 (1999)). Cell cultures containing the replicon, designated GS4.3, were obtained from Dr. Christoph Seeger, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

GS4.3 cells were maintained at 37°C, 5% CO ₂ in DMEM (Gibco 11965-092) supplemented with L-glutamine 200 mM (100 times) (Gibco 25030-081), non-essential amino acids (NEAA) (Biowhittaker 13-114E), heat inactivated (HI) fetal bovine serum (FBS) (Hyclone SH3007.03) and 750 μg/ml Geneticin (G418) (Gibco 10131-035). Cells were split again 1:3 or 4 every 2-3 days. 24 hours before analysis, GS4.3 cells were harvested, counted, and plated at 7500 cells/well in 96-well plates (Costar 3585) with 100 μl of standard maintenance medium (as above) and cultured under the conditions described above. To start the analysis, the medium was removed, the cells were washed once with PBS (Gibco 10010-023), and 90 μl of assay medium (DMEM, L-glutamine, NEAA, 10% HI FBS, without G418) was added. Inhibitors were made into 10× stocks in assay media, (3-fold dilution from 10 μM to 56 pM final concentration, 1% final DMSO concentration), added 10 μl to duplicate wells, rocked plate to mix, and incubated as above for 72 Hour.

Obtain NPRII ELISA kit (for the compound direct ELISA test system of neomycin phosphotransferase II, PSP73000/4800) from AGDIA company. The manufacturer's instructions were followed with some modifications. A 10×PEB-1 lysis buffer was prepared to include 500 μM PMSF (Sigma P7626, 50 mM stock solution in isopropanol). After 72 hours of culture, cells were washed once with PBS, and 150 μl of PEB-1 containing PMSF was added to each well. Plates were agitated vigorously for 15 minutes at room temperature and then frozen at -70°C. Thaw the plate, mix the lysate thoroughly, and add 100 μl to the NPTII Elisa plate. to obtain a standard curve. Lysates from DMSO-treated control wells were combined, serially diluted with PEB-1 containing PMSF, and applied to duplicate wells of ELISA plates with initial lysate amounts ranging from 150 μl to 2.5 μl. In addition, 100 µl of buffer was applied in duplicate separately, as a blank group. The plate was sealed and agitated gently for 2 hours at room temperature. After capture incubation, the plates were washed (5 x 300 μl) with PBS-T (0.5% Tween-20, PBS-T is provided in the ELISA kit). For detection, a 1-fold dilution of enzyme conjugate dilution MRS-2 (5×) was prepared in PBS-T, to which 1:100 dilutions of enzyme conjugates A and B were added according to the instructions. Reseal the plate and incubate with agitation: cap, room temperature, 2 hours. The wash step was then repeated and 100 [mu]l of room temperature TMB substrate was added. After approximately 30 minutes of incubation (room temperature, agitation, capping), the reaction was stopped with 50 μl of 3M sulfuric acid. Plates were read on a Molecular Devices Versamax plate reader at 450nm.

Inhibitor effects were expressed as a percentage of the DMSO-treated control signal, and inhibition curves were calculated using the following 4-parameter equation: y=A+((BA)/(1+((C/x)^D))), where C is Maximum Half Activity or _EC50 .

active instance

in:

A represents an IC ₅₀ or EC ₅₀ of less than 1 μM;

and B represents an IC ₅₀ or EC ₅₀ of less than 0.1 μM.

table 3

compound NS3-NS4IC _{50 EC50} 101 B B 102 B B 103 B B 104 B B 105 B N/A 106 B B 107 B B 108 A B 109 B A 110 A N/A 111 B N/A 112 B N/A 113 B B 114 B B 115 B B 116 B A 117 B B 118 B B 119 B B 120 B N/A 121 B B 122 B B 123 B N/A 124 A B 125 B B 126 B B 127 B B 128 B B 129 B B 130 B B 131 B B 132 B B 133 B B 134 B B 135 B B

Example 38: Specificity Analysis

Compounds of formula I were found to be selective when compounds were evaluated in specificity assays, as they did not exhibit significant inhibition in cathepsin B, chymotrypsin, thrombin or leukocyte elastase.

Example 39: Pharmacokinetic Analysis of Compounds

Compounds were first synthesized and tested for potency ( _IC50 ) in the fluorescent NS3/4 protease assay and the cell-based HCV replicon system as described in Example 8 above. Plasma pharmacokinetic analysis in rats (Rattus sp.) after IV administration was then used in combination with in vitro human liver microsome (HLM) and hepatocyte stability studies to design metabolically stable compounds from compounds with potencies less than 20 nM Sexual compounds. The drug-like physical properties of these leads were further optimized and administered orally to rats (Rattus sp.) for assessment of liver, heart and plasma concentrations.

method

Compounds were first synthesized and tested for potency ( _IC50 ) in the fluorescent NS3/4 protease assay and the cell-based HCV replicon system as described in Example 8 above. Plasma pharmacokinetic analysis in rats (Rattus sp.) after IV administration was then used in combination with in vitro human liver microsome (HLM) and hepatocyte stability studies to design metabolically stable compounds from compounds with potencies less than 20 nM Sexual compounds. The drug-like physical properties of these leads were further optimized and administered orally to rats (Rattus sp.) for assessment of liver, heart and plasma concentrations.

Hepatic clearance of compound over time was tested following a single 3 mg/kg oral dose in rats. Doses up to 30 mg/kg orally BID for seven days are used for any compound that exhibits a concentration in the liver that is at least 100-fold greater than the concentration of the compound effective to inhibit 50% of the maximal inhibition in the replicon assay (replicon _EC50 ) 8 hours after dosing Additional toxicology assessments were performed in rats.

result

Compound AR334187 produced a replicon _EC50 value of approximately 2nM and demonstrated in vitro stability in rat, dog, and human hepatocyte culture assays, data that would predict how slowed clearance from the liver would be. In addition, this compound exhibited high selectivity over a panel of other serine proteases and showed no significant inhibitory effect on Cytochrome P450 isoforms or hERG channel activity even at the highest concentration tested (10 μM) .

For compound AR334187, a single oral dose of 30 mg/kg in rats (Rattus sp.) produced concentrations in the liver at 24 hours post-dose that were at least 200-fold higher than the replicon _EC50 value of the compound.

Compound AR334187 produced cardiac and plasma levels up to two orders of magnitude lower than liver concentrations in the same animals and was kinetically linked to liver concentrations. The clinically more reasonable oral dose (3 mg/kg) of the compound AR334187 has a concentration in the liver 8 hours after administration that is more than 100 times greater than the EC ₅₀ value of the compound's replicon. Following exposure to compound AR334187 at a dose of 30 mg/kg po BID, no mortality, body weight changes or clinical chemistry abnormalities were observed in the treated animals.

in conclusion

Potent, metabolically stable, orally available small molecule inhibitors of HCV NS3 protease have been developed. At the most modest oral administration concentration (3 mg/kg), these compounds exhibited high liver levels (100-fold higher than the respective replicon _EC50 values) 8 hours post-dose. Exposure to plasma and heart was up to two orders of magnitude lower than that observed in liver, such low concentrations that any possible systemic toxicological concerns were minimized.

When the compound AR334187 was administered at 30 mg/kg BID for 7 days, it showed no toxicity in rats (Rattus sp.), providing at least a 10-fold safety margin above the presumed effective dose (3 mg/kg), while producing more than this Liver concentrations at 100-fold replicon _EC50 values for compounds.

Preparation of Partial D Virus Inhibitors

The terms and structural names used in this section have the same meanings as in Section D above. Any reference in this section to a specific number or designation should be read in context with the corresponding numbering or numbering scheme used in this section or in Section D above, and not a potentially similar or equivalent numbering or numbering scheme used elsewhere herein The content is to be understood unless otherwise stated.

Compounds of formula XVIII can be synthesized according to the methods described below.

(2S,4R)-4-Amino-1-[benzyloxycarbonyl]pyrrolidine-2-methylcarboxylate hydrochloride available from ArrayBiopharma, 2(S)-tert-butoxycarbonylamino- Non-8-enoic acid and ethyl 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylate can be obtained according to International Application PCT/CA00/00353 (publication No. WO 00/ No. 59929) was prepared by the procedure disclosed. 2(S)-tert-butoxycarbonylamino-non-8-enoic acid is also commercially available from RSP Amino Acids.

Two major aminoproline macrocyclic intermediates, A and B, were used in the preparation of the NS3 inhibitors shown in Examples 1-69.

1. Preparation of oxyprooxyacid macrocyclic acylsulfonamide intermediate A

(1S, 4R, 6S, 14S, 18R)-(18-amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ^{4, 6} ] Synthesis of nonadecan-7-en-14-yl)-tert-butyl carbamate

Process 1

Step A. Add (2S,4R)-4-amino-1-[benzyloxycarbonyl]pyrrolidine-2-methylcarboxylate hydrochloride (2.00g, 2.34mmol) in dichloromethane (25ml ) was added 2-(trimethylsilyl)ethyl p-nitrophenyl carbonate (1.98 g, 6.99 mmol) and triethylamine (1.81 ml, 13.34 mmol). The reaction was stirred for 3 days, placed on silica gel and the product was eluted with 40% EtOAc/hexanes to give a colorless oil. The oil was dissolved in methanol (20ml) and stirred with 10% palladium on carbon under a balloon of hydrogen. After stirring for 4 hours, the reaction was filtered and concentrated. The resulting solid was dissolved in 1N aqueous hydrochloric acid (75 ml), and extracted with dichloromethane (75 ml). The aqueous layer was basified by adding sodium hydroxide and extracted again with dichloromethane (100ml). The two organic extracts were combined, concentrated, and the resulting residue was purified by silica gel chromatography eluting with 10% methanol/dichloromethane to afford a tan solid (1.29 g, 70%). LCMS = 289 (H+).

Step B. Stir overnight 4(R)-(2-Trimethylsilylethylcarbonylamino)-pyrrolidine-2(S)-carboxylic acid methyl ester (1.29 g, 4.50 mmol), 2(S)-tert Butoxycarbonylamino-non-8-enoic acid (1.22g, 4.51mmol), HATU (2.06g, 5.41mmol) and diisopropylethylamine (1.18ml, 6.76mmol) in dimethylformamide (10ml ) in the solution. The reaction was diluted with ethyl acetate (150ml), washed with 1N aqueous hydrochloric acid (2 x 100ml), dried over magnesium sulfate and concentrated. Chromatography on silica gel gave an oil which was stirred with lithium hydroxide (0.28 g, 6.76 mmol) in methanol (5 mL) for 2 hours. The reaction was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid, dried over magnesium sulfate and concentrated to give 1.2 g (49%) of product.

Step C. To ethyl 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylate (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 (1.21g, 2.29mmol), HATU (1.05g, 2.75mmol) and diisopropylethylamine (1.60ml, 9.17mmol) and dichloromethane (10ml) and stirred the mixture at room temperature React for 18 hours. The reaction was placed on silica gel and eluted with 50% ethyl acetate/hexanes solution to give the product (1.27 g, 83%) as a colorless oil. 665 (H+).

Step D. Addition of 1-{[1-(2(S)-tert-butoxycarbonylamino-non-8-enoyl)-4(R)-(2-trimethylsilane) by bubbling _N2 through it Ethylethylcarbonylamino)-pyrrolidine-2(S)-carbonyl]-amino}-2(S)-vinyl-cyclopropane-1-(R)-carboxylic acid ethyl ester (2.57g, 3.87mmol) in The solution in dichloromethane (500ml) was degassed. 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 onto silica gel and eluted with 50% ethyl acetate/hexanes to afford the product (2.01 g, 3.16 mmol, 82%). 637.0 (H+).

Step E. To (1S, 4R, 6S, 14S, 18R)-(14-tert-butoxycarbonylamino-2,15-dioxo-18-(2-trimethylsilyl-ethoxycarbonylamino )-3,16-diaza-tricyclo[ ^14.3.0.04,6 ]nonadecan-7-ene-4-carboxylic acid ethyl ester (1.94g, 3.04mmol) in 10:1 methanol/water (10ml) Lithium hydroxide (1.02g, 24.37mmol) was added to the solution in , and the reaction was stirred overnight at room temperature. The reaction was quenched by adding 1N HCl (50ml) and extracted with dichloromethane (2 x 50ml). The combined organics Washed with brine (50ml), dried over magnesium sulfate and concentrated to a solid (1.78g, 2.92mmol). A solution of the acid and carbonyldiimidazole (0.711g, 4.39mmol) in dichloromethane at 50°C. After 1h , HPLC analysis indicated the presence of starting material, so additional carbonyldiimidazole (0.1 g) was added. After stirring for an additional 1 hour at 50° C., HPLC analysis indicated that the starting material was completely consumed. To this reaction was added cyclopropanesulfonyl chloride (0.46g, 3.80mmol) and DBU (0.57g, 3.80mmol) solution, and the reaction was stirred at 50°C. After 1h, the reaction was judged to be incomplete by HPLC monitoring, so 0.07g cyclopropylsulfonamide and 0.1 g of DBU. After an additional 30 minutes of stirring, the reaction was judged complete. The reaction was allowed to cool, placed on silica gel, and the product was eluted with a gradient of 3% methanol/DCM to 7.5% methanol/DCM to give a white solid. LCMS 710.5 (H-) .

Step F. A solution of 1 (0.80 g, 1.124 mmol) and tetrabutylammonium fluoride (1.0 M solution in THF, 1.4 ml) was stirred together at 50 °C for 1 h. The reaction was allowed to cool, placed on silica gel and the product was eluted with a gradient of 5% methanol/DCM to 25% methanol/DCM to give a white solid (0.51 g). 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[ ^14.3.0.04,6 ]Synthesis of ethyl nonadecan-7-ene-4-carboxylate

Process 2

Compound 1 from Scheme 1 above was treated with TBAF (1.0 M in THF, 1.5 equiv) and heated to 50 °C for 4 hours. The reaction was placed on silica gel and eluted with 20% methanol/dichloromethane to afford B as a tan solid (69% yield). ¹ H NMR (CDCl ₃ , 400MHz): δ1.06-1.66 (m, 17H), 1.85-1.95 (m, 2H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.2- 2.3(m, 1H), 2.65-2.75(M, 1H), 3.40(m, 1H), 3.73-3.83(m, 2H), 4.08-4.19(m, 2H), 4.56(m, 1H), 4.78( d, J=5.5 Hz, 1H), 5.20(t, J=8.1Hz, 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 were then prepared using intermediates A and B above via one of the following two routes. All carboxylic acid NS3 inhibitors in the examples were prepared via Route 2 in Scheme 3.

Route 1:

Route 2:

Process 3

Example 1

(1S, 4R, 6S, 14S, 18R)-(18-[(3-Chloro-benzo[b]thiophene-2-carbonyl)-amino]-4-cyclopropanesulfonylaminocarbonyl-2,15-di Synthesis of tert-butyl oxo-3,16-diaza-tricyclo[14.3.0.0 ^4,6 ]nonadeca-7-en-14-yl}-carbamate

(1S, 4R, 6S, 14S, 18R)-(18-amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza- Tricyclo[ ^14.3.0.04,6 ]nonadecan-7-en-14-yl)-tert-butyl carbamate (0.254g, 0.44mmol), 3-chloro-benzo[b]thiophene-2-carbonyl chloride (0.124g, 0.54mmol) and DIEA (0.087g, 0.67mmol). After 1 hour, the reaction was placed on silica gel and the product was eluted using a gradient of 1% methanol/DCM to 5% methanol/DCM to give a white solid. ¹ H NMR (C ₆ D ₆ , 400MHz) δ7.66-7.70(m, 1H), 7.22-7.24(m, 1H), 7.04-7.07(m, 2H), 6.97(t, 1H), 6.83(bs , 1H), 5.61(d, 1H), 5.18(t, 1H), 5.05(d, 1H), 4.48-4.50(b, 1H), 4.26(t, 1H), 3.8-4.0(m, 1H), 3.65-3.74(m, 1H), 3.20-3.35(M, 1H), 2.78-2.85(M, 1H), 2.55-2.65(m, 1H), 2.3-2.4(m, 1H), 1.95-2.15(m , 2H), 1.75-1.85 (m, 1H), 1.20-1.40 (m, 16H), 0.95-1.15 (m, 5H), 0.4-0.5 (M, 1H), 0.25-0.35 (M, 1H); LCMS = 662 (H ⁺ -Boc).

Example 2-69

Following the general procedure described for the synthesis of Example 1 and substituting the appropriate acid chloride and carboxylic acid/HATU for 3-chloro-benzo[b]thiophene-2-carbonyl chloride, or as described in the synthesis of Example 1 and A The following example was accomplished analogously to the procedure for coupling amides with acylsulfonamides but employing Scheme 3, Route 2.

Table 4

NS3-NS4A Protease Analysis

Forms the NS3 complex with NS4A-2

Recombinant E. coli or baculovirus full-length NS3 was diluted to 3.33 μM with assay buffer, and this material was transferred into an eppendorf tube and placed in a water bath in a 4°C refrigerator. Add an appropriate amount of NS4A-2 to reach 8.3 mM in assay buffer to equal the volume of NS3 in step 2.1.1 (conversion factor - 3.8 mg/272 µL assay buffer). This material was transferred into an eppendorf tube and placed in a water bath in a 4°C refrigerator.

After equilibrating to 4°C, equal volumes of NS3 and NS4A-2 solutions were combined in eppendorf tubes, mixed carefully using a manual pipette, and the mixture was incubated in a 4°C water bath for 15 minutes. The final concentrations in the mixture were 1.67 μM NS3, 4.15 mM NS4A-2 (2485-fold molar excess of NS4A-2).

After 15 min at 4°C, remove the NS3/NS4A-2 eppendorf tube and place in a room temperature water bath for 10 min. Aliquot NS3/NS4A-2 into appropriate volume aliquots and store at -80°C (divide into 25 μL aliquots when working with 2 nM E. coli NS3 in assay solution; when working with 3 nM BV NS3 in assay solution , divided into 30 μL aliquots).

NS3 Inhibition Analysis

Sample compounds were dissolved in DMSO to 10 mM, then diluted to 2.5 mM in DMSO (1:4). Typically, compounds are added to the assay plate at a concentration of 2.5 mM and diluted to give a starting concentration of 50 mM in the assay inhibition curve. Compounds were serially diluted in assay buffer to provide lower concentrations of test solutions.

E. coli NS3/NS4A-2 was diluted to 4 nM NS3 (1:417.5 of 1.67 μM stock - 18 μL of 1.67 μM stock + 7497 μL assay buffer).

Dilute BV NS3/NS4A-2 to 6 nM NS3 (1:278.3 of 1.67 μM stock - 24 μL of 1.67 μM stock + 6655 μL assay buffer).

Using a manual multichannel pipette, and being careful not to introduce air bubbles into the plate, add 50 μL of Assay Buffer to wells A01-H01 of a black Costar 96-well polypropylene storage plate.

Using a manual multichannel pipette, and being careful not to introduce air bubbles into the plate, add 50 µL of the diluted NS3/NS4A-2 from step 2.2.6 to wells A02-H12 of the plate in step 2.2.7.

Using a manual multichannel pipette, and being careful not to introduce air bubbles into the plate, transfer 25 µL from the wells of the drug dilution plate from step 2.2.5 to the corresponding wells of the assay plate from step 2.2.8. Change the nozzles of the multichannel pipette as each row of compounds is transferred.

Using a manual multichannel pipette, and being careful not to introduce air bubbles into the plate, mix the wells from the assay plate in step 2.2.9 by pipetting five times and dispensing 35 µL of the 75 µL in each well. Change the nozzle of the multichannel pipette when mixing each row of wells.

Cover the plate with a polystyrene cover and pre-incubate the plate from step 2.2.10 containing NS3 protease and sample compound for 10 min 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 RETS1 substrate to 8 μM (1:80.75 of 646 μM stock - 65 μL of 646 μM stock + 5184 μL of assay buffer).

After pre-incubating the plate in the step described, 25 μL of substrate was added to all wells on the plate using a manual multichannel pipette. Mix the plate quickly as in step 2.2.10, mixing 65 μL of 100 μL in the wells.

Plates were read in dynamic mode on a Molecular Devices SpectraMax Gemini XS plate reader. Reader settings: Reading time: 30 minutes; Interval: 36 seconds; Number of readings: 51; Excitation wavelength λ: 335nm; Emission wavelength λ: 495nm; Threshold: 475nm; Automix: off; Calibration: once; PMT : high; reads/well: 6; Vmax pts: 21 or 28/51, depending on the linear length of the reaction.

_IC50s were determined using a four parameter curve fitting equation and converted to Ki values using the following Km values:

Full E. coli NS3-2.03μM

Full-length BV NS3 - 1.74 μM

where Ki=IC ₅₀ /(1+[S]/Km)

active instance

in:

A represents an IC ₅₀ of less than 10 μM;

B represents an IC ₅₀ of less than 1 μM;

And C represents an IC ₅₀ of less than 0.1 μM.

table 5

instance number NS3-NS4IC ₅₀ instance number NS3-NS4IC ₅₀ 1 C 36 C 2 C 37 C 3 C 38 C 4 C 39 C 5 C 40 C 6 C 41 C 7 C 42 C 8 C 43 C 9 C 44 C 10 C 45 C 11 C 46 C 12 C 47 C 13 C 48 14 C 49 C 15 C 50 C 16 C 51 C 17 C 52 C

18 C 53 C 19 C 54 C 20 C 55 C twenty one C 56 C twenty two C 57 C twenty three C 58 C twenty four C 59 A 25 C 60 A 26 C 61 A 27 C 62 B 28 C 63 B 29 C 64 B 30 C 65 B 31 C 66 B 32 C 67 A 33 C 68 A 34 C 69 A 35 C

Synthetic intermediate

Certain intermediates derived from the synthetic schemes are included within the scope of the examples. Examples of useful intermediates are shown below.

A compound having the formula:

in:

Q is a core ring selected from the following:

Wherein, the core ring can be unsubstituted or substituted by the following groups: H, halogen, cyano, nitro, hydroxyl, 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 Base, substituted C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide , urea, thiourea, amido, keto, carboxyl, carbamoyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkoxyheterocyclic, alkylamino, alkylcarboxy, carbonyl, Spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl,

Alternatively, Q is R ¹ -R ² , wherein R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridyl Oxazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran , indole or benzimidazole, each of these groups is optionally substituted by up to three of each of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 Cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1- optionally substituted by up to 5 fluorine ₆ alkyl or _C1-6 alkoxy optionally substituted with up to 5 fluorines; and ^R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole , imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of these groups Optionally substituted with up to three of each of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkane C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or optionally substituted with up to 5 fluorines C _1-6 alkoxy;

R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which ^R and ^R are attached together 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 optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate C _1-6 alkyl substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁸ is C _1-6 alkane optionally substituted by up to 5 fluorines or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

Y is COOR ⁹ , wherein 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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines ^, _or phenyl; The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl or 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

A compound having the formula:

in:

R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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, G _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines;

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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which R ^{and R} are attached together 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 these groups are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, as appropriate C _1-6 alkyl substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁸ is C _1-6 alkane optionally substituted by up to 5 fluorines or R ⁸ is a tetrahydrofuran ring connected via the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via the C ₄ position of the tetrapyranyl ring;

Y is COOR ⁹ , wherein R ⁹ is C _1-6 alkyl;

p = 0 or 1;

V is selected from OH, SH or NH ₂ ;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines ^, _or phenyl; The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl or 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ²¹ is pyridyl, pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, Hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

Metabolites

Certain embodiments are metabolites of compounds of Formulas I-XIX. In some instances, the metabolite is the compound of Formulas I-XIX itself. Examples of useful metabolites are shown below.

Metabolites of compounds of formula I-XIX can be identified by the following steps:

1. Suspend hepatocytes in supplemented KHB (Krebs-Henseleit Buffer, pH 7.3) at a concentration of approximately 2×10 ⁶ viable hepatocytes per milliliter.

2. Prepare stock solutions (20 [mu]M) of ITMN-187 and ITMN-191 in KHB.

3. Add 50 μl of ITMN-187 or ITMN-191 to 50 μl of hepatocyte suspension in 96-well polypropylene plate. The final substrate concentration was 10 μM (approximately 7 μg/mL).

4. Incubate the plate for 0 or 2 hours at 37°C, 5% _CO2 in saturated humidity.

5. Stop the reaction with 100 [mu]l acetonitrile and shake the plate at 700 rpm for 30 seconds.

6. Immediately spin the plate (1,500 xg) in a centrifuge for 10 minutes to pellet the denatured hepatocytes.

7. Transfer 180 μl supernatant to another plate.

8. Combine the wells, evaporate the solvent with _N2 at 37°C, reconstitute the residue in water/acetonitrile in a volume ratio of 75/25, and analyze by LC-MS/MS.

While the invention has been described with reference to specific examples thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition, method, method step to the objective, spirit and scope of the invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (as amended under Article 19 of the Treaty)

C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or _C1-6alkoxy optionally substituted by up to 5 fluorines; or ^R6 and ^R7 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 optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 optionally substituted with up to 5 fluoro Alkyl; or R ⁸ is a tetrahydrofuran ring connected via C ₃ or C ₄ of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via C ₄ of the tetrapyranyl ring;

Y is COOR ⁹ , wherein R ⁹ is C _1-6 alkyl; or Y is a sulfonimide of formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, which is optionally substituted by up to two of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl Or C _1-3 alkoxy, or Y is carboxylic acid;

p = 0 or 1;

V and W are each independently selected from O, S or NH;

Dashed lines indicate optional double bonds;

R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; or R ²¹ is C _{6 or 10} aryl, which aryl is optionally substituted by up to 3 The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{or _ _ _} ^R is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

201. The compound of claim 174, wherein L is selected from the group consisting of _-OCH2- and _-NHCH2- .

202. The compound of claim 174, wherein L is selected from the group consisting of -CH=CH- and -C≡C-.

203. The compound of claim 174, wherein L is selected from the group consisting of _-SCH2- , _-SO2- , and _-CH2SO- .

204. The compound according to claim 174, wherein L is selected from the group consisting of -WC(=V)-NH- and -WC(=V)-O-, wherein V and W are each independently selected from O, S or NH.

205. The compound of claim 182, wherein L is selected from the group consisting of _-OCH2- and _-NHCH2- .

206. The compound of claim 182, wherein L is selected from the group consisting of -CH=CH- and -C≡C-.

207. The compound of claim 182, wherein L is selected from the group consisting of _-SCH2- , _-SO2- , and _-CH2SO- .

208. The compound according to claim 182, wherein L is selected from the group consisting of -WC(=V)-NH- and -WC(=V)-O-, wherein V and W are each independently selected from O, S or NH.

209. The compound according to claim 189, wherein L is selected from the group consisting of _-OCH2- and _-NHCH2- .

210. The compound of claim 189, wherein L is selected from the group consisting of -CH=CH- and -C≡C-.

211. The compound according to claim 189, wherein L is selected from the group consisting of _-SCH2- , _-SO2- , and _-CH2SO- .

212. The compound according to claim 189, wherein L is selected from the group consisting of -WC(=V)-NH- and -WC(=V)-O-, wherein V and W are each independently selected from O, S or NH.

Claims (200)

1. A compound of formula I:

in: Q is a core ring selected from the following:

Wherein the core ring can be unsubstituted or substituted by the following groups: H, halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl ring Alkyl, 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, pyridal, pyrimidal, thienyl, furyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy group, sulfonamide group, urea, thiourea, amido group, keto group, carboxyl group, carbamoyl group, sulfide, sulfoxide, sulfone, amino group, alkoxyamino group, alkoxyheterocyclic group, alkylamino group, alkane Carboxyl, carbonyl, spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl, Alternatively, Q is R ¹ -R ² , wherein R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridyl Oxazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran , indole or benzimidazole, each of which is optionally substituted by up to three of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C ₁ optionally substituted by up to 5 fluorine _-6 alkyl, _C1-6 alkoxy optionally substituted with up to 5 fluorines; and ^R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxa azole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, the base Each of the groups is optionally substituted with up to three of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorine or optionally up to 5 Fluorine-substituted C _1-6 alkoxy; R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; 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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which R ^{and R} are attached together 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 optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 optionally substituted with up to 5 fluoro Alkyl; or R ⁸ is a tetrahydrofuran ring connected via C ₃ or C ₄ of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via C ₄ of the tetrapyranyl ring; Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, All of said groups are optionally substituted one to three times by: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁹ is C _{6 or 10} aryl, the aryl Optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2- 6} alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 optionally substituted with up to 5 fluorines Alkoxy; or R ⁹ is C _1-6 alkyl, NR ⁶ R ⁷ , NR ^1a R ^1b or (CO)OH optionally substituted by up to 5 fluoro groups; or R ⁹ is optionally substituted by the following groups Heteroaromatic ring substituted up to twice: halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug; Wherein, 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 optionally substituted by the following groups One to three times: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl, Alternatively, R ^1a and R ^1b are each independently H and C _{6 or 10} aryl optionally substituted with up to three of each of the following groups: halogen, cyano, nitro, hydroxy, C _1-6 alkane 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 Fluorine substituted C _1-6 alkyl or optionally up to 5 fluorine substituted C _1-6 alkoxy, Alternatively, R ^1a and R ^1b are each independently H, a heterocycle, which is a 5-, 6-, or 7-membered saturated or unsaturated heterocyclic molecule, and contains one to four groups selected from the group consisting of nitrogen, oxygen, and sulfur group of heteroatoms, Alternatively, NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally containing one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro Base, C _1-6 alkoxy, amido or phenyl, Alternatively, NR ^1a R ^1b is a heteroaryl selected from the group consisting of: Wherein, R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl, Or R ^1c is NH(CO)OR ^1e , wherein 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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines; Dashed lines indicate optional double bonds; R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; or R ²¹ is C _{6 or 10} aryl, which aryl is optionally substituted by up to 3 The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{or _ _ _} ^R is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and R ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; With the proviso that compounds of formula I do not include compounds of formula II, III or IV:

in: (aa) R ¹ and R ² are each independently H, halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines, C ₁ optionally substituted by up to 5 fluorines _-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, 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 (wherein R ⁹ is imidazolyl or pyrazolyl); said thienyl, pyrimidinyl, furyl, thiazolyl and oxazolyl in the definition of R ^{and R} are optionally substituted by up to two of the following groups: halogen, cyano, nitro radical, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines _or ^C _1-6 alkoxy optionally substituted by up to 5 fluorines; C in the definition of R and R ² _{Or 10} aryl, pyridyl, phenoxy and thiophenoxy are optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 ring Alkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 optionally substituted by up to 5 fluorine Alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines; (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, the phenyl or benzyl is optional Substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkene radical, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines base; (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 optionally at most Three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, Hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁶ and R ⁷ The nitrogens attached together 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 optionally substituted one to three times by the following groups: halogen, cyano , nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl optionally substituted by up to three of the following groups: halogen, 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 alkane radical, C _1-6 alkyl optionally substituted with up to 5 fluoro groups, or C _1-6 alkoxy optionally substituted with up to 5 fluoro groups; or R ⁸ is C optionally substituted with up to 5 fluoro groups _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring connected through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected through the C ₄ position of the tetrapyranyl ring; (gg) Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl ring Alkyl, all of which are optionally substituted one to three times by: halogen, cyano, nitro, _hydroxyl , C alkoxy or phenyl; or ^R is C _or C aryl, The aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C optionally substituted by up to 5 fluorines _1-6 alkoxy; or R ⁹ is C _1-6 alkyl, NR ⁶ R ⁷ or (CO)OH optionally substituted by up to 5 fluoro groups; or R ⁹ is optionally substituted by the following groups at most Two heteroaromatic rings: halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug; (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, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl), all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances up to C _1-6 alkyl substituted by 5 fluorine or C _1-6 alkoxy substituted by up to 5 fluorine as the case may be; said C _{6 or 10} aryl in the definition of R ¹⁰ and R ¹¹ is optionally substituted by Up to three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines ; or R ¹⁰ and R ¹¹ form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbons to which they are attached; or R ¹⁰ and R ¹¹ combine to be 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, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl), all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl: or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances up to C _1-6 alkyl substituted by 5 fluorines or C 1-6 alkoxy substituted by up to 5 fluorines as the case may be; the C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by at most Three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ¹² and R ¹³ together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R ¹² and R ¹³ are each independently optionally substituted with (CH ₂ ) _n OR ⁸ C _1-6 alkyl; (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, optionally C _1-6 alkyl substituted by up to 5 fluorines or (CH ₂ ) _n NR ⁶ R ⁷ , (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 one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{3 -7} cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C optionally substituted by up to 5 fluorine _1-6 alkyl group or C _1-6 alkoxy group optionally substituted by up to 5 fluorines; said C _{6 or 10} aryl group in the definition of R ¹² and R ¹³ is optionally substituted by up to three of the following groups Group substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkane Oxygen, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; (11) n=1-4; (mm) V is selected from O, S or NH; (nn) When V is O or S, W is selected from O, NR ¹⁵ or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ , wherein R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines; (oo) Dashed lines indicate optional double bonds; (pp) R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano , nitro, hydroxyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; or R ²¹ is C _{6 or 10} aryl, which aryl is optionally Substituted by up to 3 of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkene radical, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines or R is ^pyridyl , pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and (qq) R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano , nitro, hydroxyl, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl. 2. The compound according to claim 1, wherein the core ring is

3. The compound according to claim 1, wherein the core ring is

4. The compound of claim 1, wherein the core ring is 5. The compound of claim 1 having formula Ia:

6. The compound of claim 1 having formula Ib:

7. The compound of claim 1 having formula Ic: 8. The compound of claim 1 having the formula Id:

9. The compound of claim 1 having the formula Ie:

10. The compound of claim 1 having the formula If:

11. The compound of claim 1 having the formula Ig:

12. The compound of claim 1 having the formula Ih:

13. The compound of claim 1 having formula Ii: 14. The compound of claim 1 having the formula Ij:

15. The compound of claim 1 having the formula Iz: 16. The compound according to claim 1, wherein Y is a sulfonimide of formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is selected from C _1-6 alkyl, C _3-7 ring A group consisting of alkyl, C _4-10 alkylcycloalkyl and NR ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl or C _3-7 cycloalkyl. 17. The compound according to claim 2, wherein Y is a sulfonimide of formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is selected from C _1-6 alkyl, C _3-7 ring A group consisting of alkyl, C _4-10 alkylcycloalkyl and NR ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl or C _3-7 cycloalkyl. 18. The compound according to claim 3, wherein Y is a sulfonimide of formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is selected from C _1-6 alkyl, C _3-7 ring A group consisting of alkyl, C _4-10 alkylcycloalkyl and NR ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl or C _3-7 cycloalkyl. 19. The compound according to claim 4, wherein Y is a sulfonimide of formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is selected from C _1-6 alkyl, C _3-7 ring A group consisting of alkyl, C _4-10 alkylcycloalkyl and NR ^1a R ^1b , wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl or C _3-7 cycloalkyl. 20. The compound of claim 1, wherein the C13-C14 double bond is cis. 21. The compound of claim 1, wherein the C13-C14 double bond is trans. 22. A pharmaceutical composition comprising: a) a compound according to claim 1; and b) A pharmaceutically acceptable carrier. 23. The pharmaceutical composition according to claim 22, which is a formulation free of any alcohol and any polyol. 24. The pharmaceutical composition according to claim 23, wherein said formulation is free of any sugar alcohol and any polyethylene glycol (PEG). 25. The pharmaceutical composition according to claim 22, which is an aqueous formulation without any excipients that reduce polarity in aqueous formulations. 26. The pharmaceutical composition according to claim 22, which is a tablet formulation. 27. The pharmaceutical composition according to claim 22, which is a caplet formulation. 28. The pharmaceutical composition according to claim 22, which is a capsule formulation. 29. A method of treating a hepatitis C virus infection in an individual, said method comprising administering to said individual an effective amount of a compound of claim 1. 30. The method of claim 29, wherein a sustained viral response is achieved. 31. The method of claim 29, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 32. The method according to claim 31, wherein said nucleoside analog is selected from the group consisting of ribavirin, levovirin, viramidine, L-nucleosides and escha isatoribine. 33. The method of claim 29, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 34. The method of claim 29, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 35. The method of claim 34, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 36. The method of claim 29, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 37. The method of claim 36, wherein the IFN-[gamma] is administered subcutaneously in an amount of about 10 [mu]g to about 300 [mu]g. 38. The method of claim 29, wherein the method further comprises administering to the individual an effective amount of interferon-α (IFN-α). 39. The method of claim 38, wherein the IFN-[alpha] is monopegylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 40. The method of claim 38, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 41. The method of claim 38, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 42. The method of claim 29, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2', 3' -dideoxyinosine (2',3'-dideoxyinosine), 2',3'-dideoxycytidine (2',3'-dideoxycytidine), 2-,3-didehydro-2 ', 3'-dideoxythymidine (2-, 3-didehydro-2', 3'-dideoxythymidine), combivir, abacavir, adefovir dipoxil), cidofovir and inosine monophosphate dehydrogenase inhibitors. 43. A method of treating liver fibrosis in an individual, said method comprising administering to said individual an effective amount of the compound of claim 1. 44. The method of claim 43, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 45. The method of claim 44, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, veramidine, L-nucleosides and exatoribine. 46. The method of claim 43, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 47. The method of claim 43, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 48. The method of claim 47, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 49. The method of claim 43, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 50. The method of claim 49, wherein the IFN-[gamma] is administered subcutaneously in an amount of about 10 [mu]g to about 300 [mu]g. 51. The method of claim 43, wherein the method further comprises administering to the individual an effective amount of interferon-α (IFN-α). 52. The method of claim 51, wherein the IFN-[alpha] is monoPEGylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 53. The method of claim 51, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 54. The method of claim 51, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 55. The method of claim 43, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2',3'-dideoxyhypoxanthine Nucleosides, 2′, 3′-dideoxycytidine, 2-, 3-didehydro-2′, 3′-dideoxythymidine, Shuangtaizhi, abacavir, adefo Inhibitors of vir dipivoxil, cidofovir and inosine monophosphate dehydrogenase. 56. A method of enhancing liver function in an individual having a hepatitis C virus infection, said method comprising administering to said individual an effective amount of a compound of claim 1. 57. The method of claim 56, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 58. The method of claim 57, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, veramidine, L-nucleosides and exatoribine. 59. The method of claim 56, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 60. The method of claim 56, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 61. The method of claim 60, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 62. The method of claim 56, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 63. The method of claim 62, wherein the IFN-[gamma] is administered subcutaneously in an amount of about 10 [mu]g to about 300 [mu]g. 64. The method of claim 56, wherein the method further comprises administering to the individual an effective amount of interferon-α (IFN-α). 65. The method of claim 64, wherein the IFN-[alpha] is monopegylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 66. The method of claim 64, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 67. The method of claim 64, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 68. The method of claim 56, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2',3'-dideoxyhypoxanthine Nucleosides, 2′, 3′-dideoxycytidine, 2-, 3-didehydro-2′, 3′-dideoxythymidine, Shuangtaizhi, abacavir, adefo Inhibitors of vir dipivoxil, cidofovir and inosine monophosphate dehydrogenase. 69. A compound having formula XI:

in: (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 optionally passed through the following groups One to three substitutions: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl, Alternatively, R ^1a and R ^1b are each independently H and C _{6 or 10} aryl optionally substituted with up to three of each of the following groups: halogen, cyano, nitro, hydroxy, C _1-6 alkane 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 Fluorine substituted C _1-6 alkyl or optionally up to 5 fluorine substituted C _1-6 alkoxy; Alternatively, each of R ^1a and R ^1b is independently H or a heterocyclic ring, which is a 5-, 6-, or 7-membered saturated or unsaturated heterocyclic molecule containing one to four groups selected from the group consisting of nitrogen, oxygen, and sulfur group of heteroatoms, Alternatively, NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally containing one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro Base, C _1-6 alkoxy, amido or phenyl, Alternatively, NR ^1a R ^1b is a heteroaryl selected from the group consisting of: Wherein, R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl; Or R ^1c is NH(CO)OR ^1e , wherein 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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines; (e) Q is a bicyclic secondary amine having the following structure:

Wherein R ²¹ and R ²² are each independently H, halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines, C _1-6 optionally substituted by up to 5 fluorines Alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, 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 ; thienyl, pyrimidinyl, furan in the definition of R ²¹ and R ²² Base, thiazolyl and oxazolyl are optionally substituted by up to two of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkane Cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or optionally up to 5 C _1-6 alkoxy substituted by fluorine; said C _{6 or 10} aryl, pyridyl, phenoxy and thiophenoxy in the definition of R ²¹ and R ²² are optionally modified by up to three of the following Group substitution: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; 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, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (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 one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _{1 -6} alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkane 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 substituted by fluorine or C _1-6 alkoxy substituted by up to 5 fluorines as the case may be; the C _{6 or 10} aryl in the definition of R ¹² and R ₁₃ is optionally substituted by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{or _ _ _} R ¹⁰ and R ¹¹ together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon to which they are attached; or R ¹⁰ and R ¹¹ combine to be 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, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (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 one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _{1 -6} alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkane 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 substituted by fluorine or C _1-6 alkoxy substituted by up to 5 fluorines as the case may be; _{the C6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ¹² and R ¹³ together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon to which they are attached; 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, as the case may be C _1-6 alkyl, (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 alkylcycloalkyl), wherein said groups are all optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C ₁ optionally substituted by up to 5 fluorine _-6 alkyl or C _1-6 alkoxy substituted by up to 5 fluorines; the C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally up to three of the following groups Substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy radical, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; where n=0-4; Wherein 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 optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl- C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁶ and R ⁷ are attached to The nitrogens together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; Or R ² is R ² aR ^2b when W=NH and V=O, wherein 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, oxa azole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, the base Each of the groups is optionally substituted with up to three of the following groups: NR ^2c R ^2d , halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorine or optionally up to 5 Fluorine-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 of which is optionally substituted by up to three of each of the following groups: NR ^2c R ^2d , halogen, cyano , nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; The R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl or phenyl, and the phenyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl -C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ^2c and R ^2d are attached to The nitrogens together 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, and said phenyl is optionally modified by up to three of the following groups Substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy radical, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; (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 which are optionally substituted one to three times by the following groups: halogen, cyano , nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, 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 alkane radical, C _1-6 alkyl optionally substituted with up to 5 fluorines, or C _1-6 alkoxy optionally substituted with up to 5 fluorines; and (i) Dashed lines indicate optional double bonds. 70. The compound of claim 69 having formula XII:

in: (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 optionally passed through the following groups One to three substitutions: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl, Or R ^1a and R ^1b are each independently H or a heteroaryl selected from the group consisting of:

Wherein, R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl, Alternatively, NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally containing one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro Base, C _1-6 alkoxy, amido or phenyl, (b) R ²¹ and R ²² are each independently H, halogen, cyano, hydroxyl, 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, halogen, C _1-3 alkyl, or R ¹⁰ and R ¹¹ form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbon to which they are attached ; (g) R ¹² and R ¹³ are each independently H, halogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _{6 or 10} aryl, hydroxyl- C _1-6 alkyl or C _1-6 alkyl optionally substituted by up to 5 halogen atoms; and (h) Dashed lines indicate optional double bonds. 71. The compound of claim 69, having formula XIII:

in: (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 optionally passed through the following groups One to three substitutions: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl, Or R ^1a and R ^1b are each independently H or a heteroaryl selected from the group consisting of:

Wherein, R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl, Alternatively, NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally containing one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro Base, C _1-6 alkoxy, amido or phenyl; (b) R ²¹ and R ²² are each independently H, halogen, cyano, hydroxyl, 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; and (f) Dashed lines indicate optional double bonds. 72. The compound of claim 69 having formula XIV:

in: (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 optionally passed through the following groups One to three substitutions: halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl, Or R ^1a and R ^1b are each independently H or a heteroaryl selected from the group consisting of:

Wherein, R ^1c is H, halogen, 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 , wherein each R ^1d is independently H, C _1-6 alkyl or C _3-6 cycloalkyl, Alternatively, NR ^1a R ^1b is a three to six membered alkyl cyclic secondary amine optionally containing one to three heteroatoms incorporated into the ring and optionally substituted one to three times with: halogen, cyano, nitro Base, C _1-6 alkoxy, amido or phenyl; (b) Q is a C ₆ or C ₁₀ aryl group optionally substituted by up to three of the following groups: NR ^2c R ^2d , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C ₁ optionally substituted by up to 5 fluorine _-6 alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines; The R ^2c and R ^2d are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl or phenyl, and the phenyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl -C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ^2c and R ^2d are attached to The nitrogens together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; Or R ^is an unsaturated five- or six-membered heteroaryl, or a heteroaryl as defined herein is fused with another ring to form a heterocycle or any other ring; (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; and (f) Dashed lines indicate optional double bonds. 73. The compound of claim 69, having formula XV: in: (a) R ^and R are ^each independently H, halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; (b) R ⁵ is H, C(O)OR ⁸ or C(O)NHR ⁸ ; (c) R ⁸ is C _1-6 alkyl, C _5-6 cycloalkyl or 3-tetrahydrofuryl; (d) R ⁹ is C _1-3 alkyl, C _3-5 cycloalkyl or phenyl, said phenyl being optionally substituted by up to two of each of the following groups: halogen, cyano, hydroxyl, C _{1- 3} alkyl or C _1-3 alkoxy; (e) R ¹⁰ and R ¹¹ are each independently H, C _1-3 alkyl or C _4-5 cycloalkyl; (f) W is selected from O or NH; and (g) Dashed lines indicate optional double bonds. 74. The compound of claim 69 having formula XVI:

in: (a) R ^and R are ^each independently H, chlorine, fluorine, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; (b) R ⁵ is H, C(O)OR ⁸ or C(O)NHR ⁸ ; (c) R ⁸ is C _1-6 alkyl or C _5-6 cycloalkyl; (d) R ⁹ is C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, said phenyl being optionally substituted by up to two of each of the following groups: halogen, cyano, hydroxyl, C _{1- 3} alkyl, C _1-3 alkoxy; (e) R ¹⁰ and R ¹¹ are each independently H, C _1-3 alkyl, or R ¹⁰ and R ¹¹ form cyclopropyl or cyclobutyl together with the carbon to which they are attached; and (f) Dashed lines indicate optional double bonds. 75. The compound of claim 69 having formula XVII: in: (a) R ^and R are ^each independently H, chlorine, fluorine, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; (b) R ⁵ is H, C(O)OR ⁸ or C(O)NHR ⁸ ; (c) R ⁸ is C _1-6 alkyl or C _5-6 cycloalkyl; (d) R ⁹ is C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, said phenyl being optionally substituted by up to two of each of the following groups: halogen, cyano, hydroxyl, C _{1- 3} alkyl or C _1-3 alkoxy; and (e) Dashed lines indicate optional double bonds. 76. A pharmaceutical composition comprising: a) a compound according to claim 69, and b) A pharmaceutically acceptable carrier. 77. The pharmaceutical composition according to claim 76, which is a formulation free of any alcohol and any polyol. 78. The pharmaceutical composition according to claim 77, wherein said formulation is free of any sugar alcohol and any polyethylene glycol (PEG). 79. The pharmaceutical composition according to claim 76, which is an aqueous formulation without any excipients that reduce polarity in aqueous formulations. 80. The pharmaceutical composition according to claim 76, which is a tablet formulation. 81. The pharmaceutical composition of claim 76 which is a caplet formulation. 82. The pharmaceutical composition according to claim 76, which is a capsule formulation. 83. A method of treating a hepatitis C virus infection in an individual, said method comprising administering to said individual an effective amount of a compound of claim 69. 84. The method of claim 83, wherein a sustained viral response is achieved. 85. The method of claim 83, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 86. The method of claim 85, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, veramidine, L-nucleosides and exatoribine. 87. The method of claim 83, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 88. The method of claim 83, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 89. The method of claim 88, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 90. The method of claim 83, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 91. The method of claim 90, wherein the IFN-[gamma] is administered subcutaneously in an amount of about 10 [mu]g to about 300 [mu]g. 92. The method of claim 83, wherein the method further comprises administering to the individual an effective amount of interferon-α (IFN-α). 93. The method of claim 92, wherein the IFN-[alpha] is monoPEGylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 94. The method of claim 92, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 95. The method of claim 92, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 96. The method of claim 83, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2',3'-dideoxyhypoxanthine Nucleosides, 2′, 3′-dideoxycytidine, 2-, 3-didehydro-2′, 3′-dideoxythymidine, Shuangtaizhi, abacavir, adefo Inhibitors of vir dipivoxil, cidofovir and inosine monophosphate dehydrogenase. 97. A method of treating liver fibrosis in an individual, said method comprising administering to said individual an effective amount of a compound of claim 69. 98. The method of claim 97, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 99. The method of claim 98, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, veramidine, L-nucleosides and exatoribine. 100. The method of claim 97, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 101. The method of claim 97, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 102. The method of claim 101, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 103. The method of claim 97, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 104. The method of claim 103, wherein the IFN-γ is administered subcutaneously in an amount of about 10 μg to about 300 μg. 105. The method of claim 97, wherein the method further comprises administering to the individual an effective amount of interferon-α (IFN-α). 106. The method of claim 105, wherein the IFN-[alpha] is mono-PEGylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 107. The method of claim 105, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 108. The method of claim 105, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 109. The method of claim 97, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2',3'-dideoxyhypoxanthine Nucleosides, 2′, 3′-dideoxycytidine, 2-, 3-didehydro-2′, 3′-dideoxythymidine, Shuangtaizhi, abacavir, adefo Inhibitors of vir dipivoxil, cidofovir and inosine monophosphate dehydrogenase. 110. A method of enhancing liver function in an individual having a hepatitis C virus infection, said method comprising administering to said individual an effective amount of a compound of claim 69. 111. The method of claim 110, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 112. The method of claim 111, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, veramidine, L-nucleosides and exatoribine. 113. The method of claim 110, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 114. The method of claim 110, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 115. The method of claim 114, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 116. The method of claim 110, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 117. The method of claim 116, wherein the IFN-[gamma] is administered subcutaneously in an amount of about 10 [mu]g to about 300 [mu]g. 118. The method of claim 110, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-alpha). 119. The method of claim 118, wherein the IFN-[alpha] is monopegylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 120. The method of claim 118, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 121. The method of claim 118, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 122. The method of claim 110, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2',3'-dideoxyhypoxanthine Nucleosides, 2′, 3′ dideoxycytidine, 2-, 3-didehydro-2′, 3′-dideoxythymidine, Shuangtaizhi, abacavir, adefovir esters, cidofovir and inosine monophosphate dehydrogenase inhibitors. 123. A compound having formula XVIII: in: (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 of said groups is optionally substituted with up to three of the following groups: NR ⁵ R ⁶ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4- 10} alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorine or optionally Up to 5 C _1-6 alkoxy substituted by fluorine; (b) ^R 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 of said groups optionally substituted by up to three of each of the following groups: NR ⁵ R ⁶ , halogen , cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl -C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; (c) R ³ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl or phenyl, and said phenyl is optionally modified by up to three of the following groups Substitution: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy radical, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; (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 ^R7 ; (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 optionally at most Three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, Hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁵ and R ⁶ The nitrogens attached together 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 substituted one to three times by the following groups as appropriate: halogen, cyano , nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁷ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, 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 alkane radical, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; (g) R ⁸ is C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, said phenyl being optionally substituted by up to two of each of the following groups: halogen, cyano, hydroxyl, C _{1- 3} alkyl or C _1-3 alkoxy; and (h) dashed lines indicate optional double bonds; or a pharmaceutically acceptable salt thereof. 124. The compound according to claim 123, wherein R ¹ is phenyl, benzothiazole, benzothiophene, benzofuran or benzimidazole, each of which is optionally substituted by up to 1-2 of each of the following groups: NR ⁵ R ⁶ , halogen, cyano , nitro, hydroxyl, C _1-2 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, depending on the circumstances _C1-6 alkyl substituted by up to 5 fluorines or _C1-6 alkoxy optionally substituted by up to 5 fluorines; R ^is H, phenyl, pyridine, pyrimidine, thiazole, oxazole, isoxazole or pyrazole, each of which is optionally substituted with up to 1-2 of each of the following groups: NR ⁵ R ⁶ , halogen, Cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl- C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; ^R3 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 ; 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 optionally modified by at most two of the following Substitution of each group: halogen, cyano, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines, or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ^{and R} together with the nitrogen to which they are attached form ind 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 optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkoxy or phenyl; or R ⁷ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; R ⁸ is C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, said phenyl being optionally substituted by up to two of each of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; and the dashed line indicates an optional double bond. 125. The compound according to claim 123, wherein ^R is phenyl, benzothiazole or benzothiophene, each of which is optionally substituted by up to 1-2 of each of the following groups: halogen, hydroxyl, C _1-2 alkyl, optionally by up to 5 Fluorine substituted C _1-6 alkyl or optionally up to 5 fluorine substituted C _1-6 alkoxy; R is ^H or phenyl optionally substituted with up to 1-2 of each of the following groups: halogen, hydroxy, C _1-3 alkyl, alkyl or C optionally substituted with up to 5 fluoro _1-3 alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines; ^R3 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 alkylcycloalkyl or phenyl, the phenyl optionally undergoes at most two of the following Substitution of each group: halogen, cyano, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; R ⁷ is C _1-6 alkyl or C _3-7 cycloalkyl, all of which are optionally substituted one to three times by halogen or phenyl; or R ⁷ is C _{6 or 10} aryl, which aryl is optionally Substituted by at most one of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl , C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines ; R ⁸ is C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, said phenyl being optionally substituted by up to two of each of the following groups: halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 alkoxy; and the dashed line indicates an optional double bond. 126. A pharmaceutical composition comprising: a) a compound according to claim 123, and b) A pharmaceutically acceptable carrier. 127. The pharmaceutical composition according to claim 126, which is a formulation free of any alcohol and any polyol. 128. The pharmaceutical composition according to claim 127, wherein said formulation is free of any sugar alcohol and any polyethylene glycol (PEG). 129. The pharmaceutical composition according to claim 126, which is an aqueous formulation without any excipients that reduce polarity in aqueous formulations. 130. The pharmaceutical composition according to claim 126, which is a tablet formulation. 131. The pharmaceutical composition of claim 126 which is a caplet formulation. 132. The pharmaceutical composition according to claim 126, which is a capsule formulation. 133. A method of treating a hepatitis C virus infection in an individual, said method comprising administering to said individual an effective amount of a compound of claim 123. 134. The method of claim 133, wherein a sustained viral response is achieved. 135. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 136. The method of claim 135, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, veramidine, L-nucleosides and exatoribine. 137. The method of claim 133, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 138. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 139. The method of claim 138, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 140. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 141. The method of claim 140, wherein the IFN-[gamma] is administered subcutaneously in an amount of about 10 [mu]g to about 300 [mu]g. 142. The method of claim 133, wherein the method further comprises administering to the individual an effective amount of interferon-α (IFN-α). 143. The method of claim 142, wherein the IFN-[alpha] is mono-PEGylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 144. The method of claim 142, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 145. The method of claim 142, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 146. The method of claim 133, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2',3'-dideoxyhypoxanthine Nucleosides, 2′, 3′-dideoxycytidine, 2-, 3-didehydro-2′, 3′-dideoxythymidine, Shuangtaizhi, abacavir, adefo Inhibitors of vir dipivoxil, cidofovir and inosine monophosphate dehydrogenase. 147. A method of treating liver fibrosis in an individual, said method comprising administering to said individual an effective amount of the compound of claim 123. 148. The method of claim 147, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 149. The method of claim 148, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, veramidine, L-nucleosides and exatoribine. 150. The method of claim 147, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 151. The method of claim 147, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 152. The method of claim 151, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 153. The method of claim 147, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 154. The method of claim 153, wherein the IFN-[gamma] is administered subcutaneously in an amount from about 10 [mu]g to about 300 [mu]g. 155. The method of claim 147, wherein the method further comprises administering to the individual an effective amount of interferon-α (IFN-α). 156. The method of claim 155, wherein the IFN-[alpha] is mono-PEGylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 157. The method of claim 155, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 158. The method of claim 155, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 159. The method of claim 147, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2',3'-dideoxyhypoxanthine Nucleosides, 2′, 3′-dideoxycytidine, 2-, 3-didehydro-2′, 3′-dideoxythymidine, Shuangtaizhi, abacavir, adefo Inhibitors of vir dipivoxil, cidofovir and inosine monophosphate dehydrogenase. 160. A method of enhancing liver function in an individual having a hepatitis C virus infection, said method comprising administering to said individual an effective amount of a compound of claim 123. 161. The method of claim 160, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 162. The method of claim 161, wherein the nucleoside analog is selected from the group consisting of ribavirin, levovirin, veramidine, L-nucleoside and exatoribine. 163. The method of claim 160, wherein the method further comprises administering an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor to the individual. 164. The method of claim 160, wherein the method further comprises administering to the individual an effective amount of thymosin-alpha. 165. The method of claim 164, wherein the thymosin-alpha is administered subcutaneously twice weekly in an amount of about 1.0 mg to about 1.6 mg. 166. The method of claim 160, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-gamma). 167. The method of claim 166, wherein the IFN-γ is administered subcutaneously in an amount of about 10 μg to about 300 μg. 168. The method of claim 160, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-alpha). 169. The method of claim 168, wherein the IFN-[alpha] is mono-PEGylated (30 kD, linear) complexed IFN-[alpha] administered at a dosing interval of every 8 days to every 14 days. 170. The method of claim 169, wherein the IFN-[alpha] is monopegylated (30 kD, linear) conjugated IFN-[alpha] administered at a dosing interval of once every 7 days. 171. The method of claim 169, wherein the IFN-[alpha] is INFERGEN complex IFN-[alpha]. 172. The method of claim 160, further comprising administering an effective amount of an agent selected from the group consisting of 3'-azidothymidine, 2',3'-dideoxyhypoxanthine Nucleosides, 2′, 3′-dideoxycytidine, 2-, 3-didehydro-2′, 3′-dideoxythymidine, Shuangtaizhi, abacavir, adefo Inhibitors of vir dipivoxil, cidofovir and inosine monophosphate dehydrogenase. 173. A compound having the formula: in: (a) Z is a group configured to hydrogen bond to the NS3 protease His57 imidazole part and hydrogen bond to the NS3 protease Gly137 nitrogen atom; (b) P ₁ ' is a group configured to form a non-polar interaction with at least one NS3 protease S1 ' pocket moiety selected from the group consisting of Lys136, Gly137, Ser139, His57, Gly58, Gln41, A group consisting of Ser42 and Phe43; (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 the following groups: unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl and a substituted heterocyclyl; P2 is positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80, and Asp81; (e) dashed lines indicate optional double bonds; (f) R ^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 optionally at most Three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, Hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁶ and R ⁷ The nitrogens attached together form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and (h) R ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are substituted one to three times by the following groups as appropriate: halogen, cyano , nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, 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 alkane radical, C _1-6 alkyl optionally substituted with up to 5 fluoro groups, or C _1-6 alkoxy optionally substituted with up to 5 fluoro groups; or R ⁸ is C optionally substituted with up to 5 fluoro groups _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring connected through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected through the C ⁴ position of the tetrapyranyl ring; With the proviso that said compounds do not include compounds having formula II, III or IV:

in: (aa) R ¹ and R ² are each independently H, halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines, C ₁ optionally substituted by up to 5 fluorines _-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, 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 (wherein R ⁹ is imidazolyl or pyrazolyl); said thienyl, pyrimidinyl, furyl, thiazolyl and oxazolyl in the definition of R ^{and R} are optionally substituted by up to two of the following groups: halogen, cyano, nitro radical, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxyl-C _1-6 Alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines _or ^C _1-6 alkoxy optionally substituted by up to 5 fluorines; C in the definition of R and R ² _{Or 10} aryl, pyridyl, phenoxy and thiophenoxy are optionally substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 ring Alkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 optionally substituted by up to 5 fluorine Alkyl or C _1-6 alkoxy optionally substituted by up to 5 fluorines; (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, the phenyl or benzyl is optional Substituted by up to three of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkene radical, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines base; (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 optionally at most Three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, Hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or R ⁶ and R ⁷ The nitrogens attached together 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 optionally substituted one to three times by the following groups: halogen, cyano , nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, 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 alkane radical, C _1-6 alkyl optionally substituted with up to 5 fluoro groups, or C _1-6 alkoxy optionally substituted with up to 5 fluoro groups; or R ⁸ is C optionally substituted with up to 5 fluoro groups _1-6 alkyl; or R ⁸ is a tetrahydrofuran ring connected through the C ₃ or C ₄ position of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected through the C ₄ position of the tetrapyranyl ring; (gg) Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl ring Alkyl, all of which are optionally substituted one to three times by: halogen, cyano, nitro, _hydroxyl , C alkoxy or phenyl; or ^R is C _or C aryl, The aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C optionally substituted by up to 5 fluorines _1-6 alkoxy; or R ⁹ is C _1-6 alkyl, NR ⁶ R ⁷ or (CO)OH optionally substituted by up to 5 fluoro groups; or R ⁹ is optionally substituted by the following groups at most Two heteroaromatic rings: halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or Y is carboxylic acid or its pharmaceutically acceptable salt, solvate or prodrug; (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, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl), all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances up to C _1-6 alkyl substituted by 5 fluorine or C _1-6 alkoxy substituted by up to 5 fluorine as the case may be; said C _{6 or 10} aryl in the definition of R ¹⁰ and R ¹¹ is optionally substituted by Up to three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines ; or R ¹⁰ and R ¹¹ form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together with the carbons to which they are attached; or R ¹⁰ and R ¹¹ combine to be 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, hydroxyl-C _{1 -6} alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines, (CH ₂ ) _n NR ⁶ R ⁷ , (CH ₂ ) _n C(O)OR ¹⁴ (wherein R ¹⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl), all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkoxy or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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, depending on the circumstances up to C _1-6 alkyl substituted by 5 fluorines or C _1-6 alkoxy substituted by up to 5 fluorines as the case may be; the C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by Up to three of the following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines or R ¹² and R ¹³ together form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl with the carbon to which they are attached; or R ¹² and R ¹³ are each independently optionally substituted with (CH ₂ ) _n OR ⁸ C _1-6 alkyl; (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, optionally C _1-6 alkyl substituted by up to 5 fluorines or (CH ₂ ) _n NR ⁶ R ⁷ , (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), wherein said groups are all optionally substituted one to three times by the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkane Oxygen or phenyl; or R ¹⁴ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, optionally substituted by up to 5 fluorine C _1-6 alkyl or C _1-6 alkoxy optionally substituted by at most 5 fluorines; said C _{6 or 10} aryl in the definition of R ¹² and R ¹³ is optionally substituted by at most three of the following Group substitution: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; (11) n=1-4; (mm) V is selected from O, S or NH; (nn) When V is O or S, W is selected from O, NR ¹⁵ or CR ¹⁵ ; when V is NH, W is selected from NR ¹⁵ or CR ¹⁵ , wherein R ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines; (oo) Dashed lines indicate optional double bonds; (pp) R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano , nitro, hydroxyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; or R ²¹ is C _{6 or 10} aryl, which aryl is optionally Substituted by up to 3 of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkene radical, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines or R is ^pyridyl , pyrimidyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and (qq) R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano , nitro, hydroxyl, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl. 174. The compound of claim 173, wherein L consists of 2 to 5 atoms. 175. The compound of claim 173, wherein L comprises a -W-C(=V)- group, wherein V and W are each independently selected from O, S, or NH. 176. The compound of claim 173, wherein L is selected from the group consisting of esters, amides, carbamates, thioesters and thioamides. 177. The compound of claim 173, wherein P2 is additionally positioned by L to form 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 . 178. The compound of claim 173, wherein the C13-C14 double bond is cis. 179. The compound of claim 173, wherein the C13-C14 double bond is trans.

180. The compound of claim 173, wherein P2 is 181. The compound of claim 173 having the formula: 182. The compound of claim 181, wherein L consists of 2 to 5 atoms. 183. The compound of claim 181, wherein L comprises a -W-C(=V)- group, wherein V and W are each independently selected from O, S, or NH. 184. The compound of claim 181, wherein L is selected from the group consisting of esters, amides, carbamates, thioesters and thioamides. 185. The compound of claim 181 , wherein P2 is additionally positioned by L to form 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 . 186. The compound of claim 181, wherein the C13-C14 double bond is cis. 187. The compound of claim 181, wherein the C13-C14 double bond is trans.

188. The compound of claim 173 having the formula: 189. The compound of claim 188, wherein L consists of 2 to 5 atoms. 190. The compound of claim 188, wherein L comprises a -W-C(=V)- group, wherein V and W are each independently selected from O, S, or NH. 191. The compound of claim 188, wherein L is selected from the group consisting of esters, amides, carbamates, thioesters and thioamides. 192. The compound of claim 188, wherein P2 is additionally positioned by L to form 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 . 193. The compound of claim 188, wherein the C13-C14 double bond is cis. 194. The compound of claim 188, wherein the C13-C14 double bond is trans. 195. A compound having the formula:

in: Q is a core ring selected from the following: Wherein, the core ring can be unsubstituted or substituted by the following groups: H, halogen, cyano, nitro, hydroxyl, 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 Base, substituted C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide , urea, thiourea, amido, keto, carboxyl, carbamoyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkoxyheterocyclic, alkylamino, alkylcarboxy, carbonyl, Spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl, Alternatively, Q is R ¹ -R ² , wherein R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridyl Oxazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran , indole or benzimidazole, each of which is optionally substituted by up to three of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C ₁ optionally substituted by up to 5 fluorine _-6 alkyl or _C1-6 alkoxy optionally substituted with up to 5 fluorines; and ^R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxa azole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, the base Each of the groups is optionally substituted with up to three of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorine or optionally up to 5 Fluorine-substituted C _1-6 alkoxy; R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; 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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which ^R and ^R are attached together 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 optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 optionally substituted with up to 5 fluoro Alkyl; or R ⁸ is a tetrahydrofuran ring connected via C ₃ or C ₄ of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via C ₄ of the tetrapyranyl ring; Y is COOR ⁹ , wherein 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 , wherein R ¹⁵ is H, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted by up to 5 fluorines; Dashed lines indicate optional double bonds; R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; or R ²¹ is C _{6 or 10} aryl, which aryl is optionally substituted by up to 3 The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{or _ _ _} ^R is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and R ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

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

in: R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines: 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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which ^R and ^R are attached together 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 optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 optionally substituted with up to 5 fluoro Alkyl; or R ⁸ is a tetrahydrofuran ring connected via C ₃ or C ₄ of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via C ₄ of the tetrapyranyl ring; Y is a sulfonimide of the formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, and the phenyl is optionally modified Up to two of the following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl or C _1-3 alkoxy, or Y is carboxylic acid; p = 0 or 1; V is selected from OH, SH or NH ₂ ; Dashed lines indicate optional double bonds; R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which are optionally substituted one to three times by the following groups; halogen, cyano, nitro , hydroxyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; or R ₂₁ is C _{6 or 10} aryl, which aryl is optionally substituted by up to 3 The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines: or ^R is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.

198. The compound of claim 197 having the formula: 199. The compound according to claim 198, wherein Y is a sulfonimide of formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkane or phenyl, optionally substituted by up to two of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl, or C _1-3 alkoxy, and wherein V is selected from OH and _NH2 . 200. A compound having the formula:

in: Q is a core ring selected from the following:

Wherein, the core ring can be unsubstituted or substituted by the following groups: H, halogen, cyano, nitro, hydroxyl, 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 Base, substituted C _1-6 alkoxy, C _{6 or 10} aryl, pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamide , urea, thiourea, amido, keto, carboxyl, carbamoyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkoxyheterocyclic, alkylamino, alkylcarboxy, carbonyl, Spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl, Alternatively, Q is R ¹ -R ² , wherein R ¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridyl Oxazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran , indole or benzimidazole, each of which is optionally substituted by up to three of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C ₁ optionally substituted by up to 5 fluorine _-6 alkyl or _C1-6 alkoxy optionally substituted with up to 5 fluorines; and ^R2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxa azole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, the base Each of the groups is optionally substituted with up to three of the following groups: NR ⁶ R ⁷ , halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorine or optionally up to 5 Fluorine-substituted C _1-6 alkoxy; R ⁴ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, phenyl or benzyl, and the phenyl or benzyl is optionally modified by up to three The following groups are substituted: halogen, cyano, nitro, hydroxyl, 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 by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; 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, and the phenyl is optionally modified by up to three of the following Substitution of each group: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, hydroxyl-C _1-6 alkyl, C _1-6 alkyl optionally substituted by up to 5 fluorines or C _1-6 alkoxy optionally substituted by up to 5 fluorines; or the nitrogen to which R ^{and R} are attached together 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 optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkoxy or phenyl; or R ⁸ is C _{6 or 10} aryl, which aryl is optionally substituted by up to three of the following groups: halogen, cyano, nitro, hydroxyl, 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 C _1-6 alkyl optionally substituted with up to 5 fluorines or C _1-6 alkoxy optionally substituted with up to 5 fluorines; or R ⁸ is C _1-6 optionally substituted with up to 5 fluoro Alkyl; or R ⁸ is a tetrahydrofuran ring connected via C ₃ or C ₄ of the tetrahydrofuran ring; or R ⁸ is a tetrapyranyl ring connected via C ₄ of the tetrapyranyl ring; Y is COOR ⁹ , wherein R ⁹ is C _1-6 alkyl; or Y is a sulfonimide of formula -C(O)NHS(O) ₂ R ⁹ , wherein R ⁹ is C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, which is optionally substituted by up to two of each of the following groups: halogen, cyano, nitro, hydroxyl, C _1-3 alkyl, C _3-7 cycloalkyl Or C _1-3 alkoxy, or Y is carboxylic acid; p = 0 or 1; V and W are each independently selected from O, S or NH; Dashed lines indicate optional double bonds; R ²¹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted by up to 5 fluorines, or phenyl; or R ²¹ is C _{6 or 10} aryl, which aryl is optionally substituted by up to 3 The following groups are substituted: halogen, cyano, nitro, hydroxyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, C _2-6 alkenyl, C _{or _ _ _} ^R is pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and R ²² is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkyl cycloalkyl, all of which are optionally substituted one to three times by the following groups: halogen, cyano, nitro , hydroxy, C _1-6 alkyl optionally substituted with up to 5 fluorines, or phenyl.